tbuckley/cabot-search huggingface dataset:
Intra- and inter-observer variability in tumor infiltrating lymphocyte scoring in breast cancer core needle biopsy.
Authors: Klara Geršak, Barbara Gazic, Andreja Klevisar Ivancic, Nina Ruzic Gorenjec, Cvetka Grasic Kuhar
Journal: Journal of Clinical Oncology (2021)

e12626 Background: Morphological evaluation of tumor lymphocyte infiltration (TIL) in breast cancer (BC) is gaining importance in the clinical setting, as it provides good prognostic information. Most institutions adhere to TIL working group guidelines for evaluating TIL, while having to settle on an acceptable error margin due to its subjective nature, which leads to intra and inter-observer scoring discordance. We aimed to analyze both at our institution, using experienced and inexperienced examiners, with a continuous variable scoring system. Methods: 209 BC core needle biopsy (CNB) samples were stained using hematoxylin-eosin. The percentage of stromal TIL was scored using a numerical variable ranging from 1 to 100. The examination group consisted of two experienced pathologists (pathologist A and B) and one inexperienced examiner - a medical oncology resident with a learning process containing study of the TIL working group analysis criteria and about 100 samples analysed together with an experienced pathologist Pathologist A and the resident analyzed the study samples twice, pathologist B once. Intraclass correlation coefficient (ICC) was used to measure overall intra and inter-observer agreement. Statistical analysis was performed using Google Sheets and Python. Results: 203 CNB samples were analysed (6 were excluded due to inadequate quality or an inconclusive diagnosis). Patients were aged 26 to 79 years (median 49). Sample size ranged from 1 to 16 mm (median 8). The proportion of BC subtypes was: luminal A-like 18%, luminal B-like 39%, HER2+ 10%, luminal B-like HER2+ 12%, TNBC 18%, not defined 2%. The highest proportion of high stromal TIL (≥50%) was seen in HER2+ (30%) and TNBC (22%) subtypes, as observed by pathologist A. We found good intra and inter-observer ICC (Table). Conclusions: Acceptable intra and inter-observer variability was observed in experienced pathologists, suggesting that the proposed methodology could reliably be used in clinical practice, research and trials. Interestingly, variability analysis of scores from a trained non-pathologist has also produced good results. However, it is important to note that inexperienced scoring could be prone to errors, for example counting non-lymphocyte cells as such, not recognizing regions of necrosis or sample damage, or not distinguishing between the tumor and peripheral stroma. Intraclass correlation: two-way random, single score (ICC2); pathologist A and resident (R) first and second analysis (A1, A2, R1, R2); pathologist B analysis (B1). Interpretation of ICC: &lt;0.50 poor; 0.50-0.75 moderate; 0.75-0.90 good (0.75 = minimal acceptable value for a reliable clinical measurement); &gt;0.90 excellent. Clinical trial information: 2018-000547-11. [Table: see text]
Real-world data on usage of scalp cooling for chemotherapy associated alopecia in the United States.
Authors: Nicole Olivia Williams, Richard Paxman, Emma Thornhill, Mahmoud Kassem, Michael Grimm, Brittany Dulmage, Elizabeth Cathcart-Rake, Kathryn Jean Ruddy, Ashley Pariser, Margaret Elena Gatti-Mays, Mathew Amprayil Cherian, Jeffrey Bryan VanDeusen, Daniel G. Stover, Sagar D. Sardesai, Robert Wesolowski, Bhuvaneswari Ramaswamy, Charles L. Loprinzi, Maryam B. Lustberg
Journal: Journal of Clinical Oncology (2021)

e18739 Background: Hair loss is a well-known side effect of chemotherapy. The Paxman Hair Loss Prevention System, a scalp cooling device, has been shown to be effective in reducing chemotherapy induced alopecia in patients receiving chemotherapy (Nangia, JAMA, 2017). The National Comprehensive Cancer Network and the European Society for Medical Oncology guidelines have recommended scalp cooling as category 2A and 2B options, respectively. Methods: The real world use of scalp cooling using the Paxman device, as documented by orders through the Paxman Hub during the years of 2017-2020 was summarized. Descriptive statistics were used to summarize demographics and utilization. Results: Data from 6649 patients who used scalp cooling were reviewed. Patients with breast cancer were the most common users of scalp cooling (78%, n=5197) followed by gynecology (12%, n=775), gastrointestinal (3%, n=201), lung (1%, n=81) and genitourinary (1%, n=52). The majority of patients were between the ages of 45-65 (55%), followed by 65-74 (18%), older than 75 (5%), and 25-44 (2%). Average number (#) of cycles of cooling completed was 6.53 (range of average # of cycles 4.50-12). Scalp cooling with this device was commonly used in 39 out of 50 states. Conclusions: This is the largest report of scalp cooling usage in the real world setting in the USA, including scalp cooling usage in older adults. Uptake of scalp cooling across various cancers has not been uniform and this deserves further study.
R13 preserves motor performance in SOD1<sup>G93A</sup> mice by improving mitochondrial function
Authors: Xiao Li, Chongyang Chen, Xu Zhan, Binyao Li, Zaijun Zhang, Shupeng Li, Yongmei Xie, Xiangrong Song, Yuanyuan Shen, Jianjun Liu, Ping Liu, Gong-Ping Liu, Xifei Yang
Journal: Theranostics (2021)

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by death of motor neurons in the brain and spinal cord. However, so far, there is no effective treatment for ALS. Methods: In this study, R13, a prodrug of 7,8-dihydroxyflavone, selectively activating tyrosine kinase receptor B (TrkB) signaling pathway, was administered prophylactically to 40-day old SOD1G93A mice for 90 days. The motor performance was investigated by rotarod test, climbing-pole test, grip strength test and hanging endurance test. Afterwards, the spinal cord and medulla oblongata of 130-day old mice were harvested, and the proteomics revealed the effect of R13 on mouse protein expression profile. Astrocytes and microglial proliferation were assessed by immunohistochemical analysis. The number of motor neurons in the spinal cord is determined by Nissl staining. The effect of R13 on gastrocnemius morphology was assessed by HE staining. The effect of R13 on the survival rate was accomplished with worms stably expressing G93A SOD1. Results: Behavioral tests showed that R13 significantly attenuated abnormal motor performance of SOD1G93A mice. R13 reduced the advance of spinal motor neuron pathology and gastrocnemius muscle atrophy. The proliferation of microglia and astrocytes was reduced by R13 treatment. Mitochondriomics analysis revealed that R13 modified the mitochondrial protein expression profiles in the medulla oblongata and spinal cord of SOD1G93A mice, particularly promoting the expression of proteins related to oxidative phosphorylation (OXPHOS). Further study found that R13 activated AMPK/PGC-1α/Nrf1/Tfam, promoted mitochondrial biogenesis and ameliorated mitochondrial dysfunction. Lastly, R13 prolonged the survival rate of worms stably expressing G93A SOD1. Conclusions: These findings suggest oral R13 treatment slowed the advance of motor system disease in a reliable animal model of ALS, supporting that R13 might be useful for treating ALS.
NEDD4-1 Modulates the Resistance of Multiple Myeloma to Bortezomib Via PTEN/PI3K/Akt Signaling Pathway
Authors: Xi Huang, Zhang En Fan, Qingxiao Chen, Haimeng Yan, Xu Ruyi, Xinling Liu, Huiyao Gu, Jingsong He, He Huang, Qing Yi, Zhen Cai
Journal: Blood (2017)
Phase I open-label, dose escalation of YH003, an anti-CD40 monoclonal antibody in combination with toripalimab (anti-PD-1 mAb) in patients with advanced solid tumors.
Authors: Jermaine Coward, Afaf Abed, Adnan Nagrial, Ben Markman
Journal: Journal of Clinical Oncology (2021)

2580 Background: YH003, a recombinant, humanized agonistic anti-CD40 IgG2 monoclonal antibody (mAb) specifically recognizes and agonizes CD40 on the antigen-presenting cells to enhance immune responses. Preclinical data have shown potent anti-cancer activity when combined with anti-PD-1 antibodies. Methods: This is an ongoing phase 1 dose-escalation study. Patients with advanced solid tumors receive YH003 by IV administration Q3W as monotherapy at 0.03 to 3.0 mg/kg for the first cycle (21 days) then in combination with Toripalimab at 240 mg Q3W for the 4 subsequent cycles in an accelerated “3+3” design. The safety, tolerability and preliminary efficacy data will be analyzed. Results: As of 31 Dec 2020 data cutoff, 9 patients (pts) were enrolled and treated at 0.03 mg/kg (n = 3), 0.1mg/kg (n = 3), and 0.3mg/kg (n = 3). The median age was 63 years (range 33-68). Baseline ECOG scores were 0 (7 pts) and 1 (2 pts) with a median of 2 prior lines therapy (range 1-7). 5 pts had received prior immunotherapy (PD-1/PD-L1 or PD-1+CTLA-4). As of data cutoff, no dose limiting toxicities (DLT) were observed. No Serious Adverse Event (SAE) or AEs leading to treatment discontinuation were reported. Four drug related AEs were reported including one Grade 1 (G1) choroidal thickening (related to YH003) at 0.03 mg/kg, one G1 fatigue (related to YH003) at 0.1 mg/kg, two G1 febrile episodes (one related to YH003 and the other related to combination treatment) at 0.3 mg/kg. Among 5 patients assessable for response, there were 2 SD (one with anti-PDL1 refractory Merkel cell carcinoma at 0.03 mg/kg and one with anti-PD1 refractory NSCLC at 0.1 mg/kg) and 1 PR with anti-PD1/anti-CTLA4 refractory ocular melanoma at 0.1 mg/kg. Conclusions: YH003 was well tolerated up to 0.3 mg/kg dose levels when combined with Toripalimab and has shown encouraging antitumor activity in patients with advanced solid tumors. Clinical trial information: NCT04481009.
CCR2-engineered mesenchymal stromal cells accelerate diabetic wound healing by restoring immunological homeostasis
Authors: Shuhong Kuang, Feng He, Guihua Liu, Xiangzhou Sun, Jian Dai, Ani Chi, Yali Tang, Zhuoran Li, Yong Gao, Chunhua Deng, Zhengmei Lin, Haipeng Xiao, Min Zhang
Journal: Biomaterials (2021)
MASS-FIX versus standard methods to predict for PFS and OS among multiple myeloma patients participating on the STAMINA trial.
Authors: Angela Dispenzieri, Amrita Y. Krishnan, Bonnie Arendt, Surendra Dasari, Yvonne Adeduni Efebera, Nancy Geller, Sergio Giralt, Theresa Hahn, Mindy C. Kohlhagen, Heather Jolie Landau, Parameswaran Hari, Marcelo C. Pasquini, Muzaffar H. Qazilbash, Philip L. McCarthy, Nina Shah, David H. Vesole, Dan T. Vogl, Paul K. Wallace, Edward A. Stadtmauer, David L. Murray
Journal: Journal of Clinical Oncology (2021)

8009 Background: Measuring response among patients with multiple myeloma is essential for the care of patients. Deeper responses have been associated with better progression free survival (PFS) and overall survival (OS). Serum (SIFE) and urine immunofixation are the currently used markers for biochemical documentation of CR after which marrow is tested for plasma cell clearance. Next generation flow cytometry and sequencing are used to document the presence of minimal residual disease (MRD). Mass spectrometry of blood by MALDI (Mass-Fix) is a new simple, inexpensive, sensitive, and specific means of detecting monoclonal immunoglobulins. To better test the hypothesis that Mass-Fix is superior to existing methodologies to predict for survival outcomes—especially SIFE-- samples from the STAMINA trial (NCT01109004), a trial comparing 3 transplant approaches among patients who have already received induction, were employed. Methods: Five-hundred and seventy-five patients were included. Samples from enrollment post-induction (post-I) and 1-year post enrollment (1YR) were tested when available. Four response parameters were assessed univariately: Mass-Fix, SIFE, complete response, and MRD by next generation flow cytometry. Mass spectrometry spectra were evaluated in a blinded fashion. Complete response was according to the 2006 International Myeloma Working Group criteria. Multivariate Cox proportional hazard models using stepwise regression were developed to explore the independent effect of the different response parameters on PFS and OS and interactions with other risk factors. Results: Of the 4 response measures, only MRD and Mass-Fix predicted for PFS and OS at multiple testing points on multivariate analyses (Table). Of the 4 post-I measurements, only MRD predicted for PFS; however, Mass-Fix was the only post-I measurement to predict for OS. Of all the 1-year measures, both 1YR Mass-Fix and 1YR MRD positivity predicted for inferior PFS and OS. In models including MRD and Mass-Fix, SIFE and CR were not prognostic for PFS or OS. Conclusions: Mass-Fix is a powerful means to track monoclonal proteins. The full utility of Mass-Fix was not exploited given the absence of a diagnostic sample and the fact that only serum (and not urine) was tested. Despite these limitations, it performed well at pre-induction and at 1 year. Mass-Fix provides a convenient and non-invasive means of predicting for myeloma outcomes. Clinical trial information: NCT01109004. [Table: see text]
Mortgage Lending Bias and Breast Cancer Survival Among Older Women in the United States
Authors: Kirsten M. M. Beyer, Yuhong Zhou, Purushottam W. Laud, Emily L. McGinley, Tina W. F. Yen, Courtney Jankowski, Nicole Rademacher, Sima Namin, Jamila Kwarteng, Sara Beltrán Ponce, Ann B. Nattinger
Journal: Journal of Clinical Oncology (2021)

The objective was to examine the relationship between contemporary redlining (mortgage lending bias on the basis of property location) and survival among older women with breast cancer in the United States.
Knowledge about risks, benefits, and curative potential of immunotherapy among patients with advanced lung cancer or melanoma.
Authors: Laura A Petrillo, Ashley Zhou, Ryan J. Sullivan, Angelo E. Volandes, Joseph A. Greer, Jennifer S. Temel, Areej El-Jawahri
Journal: Journal of Clinical Oncology (2021)

6579 Background: Immunotherapy is a novel treatment paradigm that has improved survival for patients with advanced melanoma and lung cancer and poses new risks of immune-related adverse events, which are important for patients to recognize promptly. We aimed to describe patients’ knowledge about the risks and benefits of immunotherapy, and their understanding of the goal of treatment with immunotherapy. Methods: We conducted a cross-sectional study of patients at a single institution who had initiated therapy with an immune checkpoint inhibitor for advanced melanoma, small cell lung cancer, or non-small cell lung cancer in the past 12 weeks. We assessed patients’ knowledge about immunotherapy with a 9-item knowledge questionnaire (score range 0-100; higher score represents greater knowledge). We used the Perception of Treatment and Prognosis Questionnaire to assess patients’ understanding of the goal of their treatment. We used the two-sample t-test to compare knowledge scores and chi-square test to compare goals of therapy between patients with melanoma and lung cancer. Results: A total of 105 patients (57 with melanoma, 48 with lung cancer) completed the study questionnaire. Participants had a median age of 69 years (range 36-89), and 33% (35/105) were female. Participants’ mean knowledge score was 69.0 (SD = 23.3). Overall, 91% (96/105) of patients endorsed that immunotherapy works by turning on the body’s immune system to recognize and attack cancer cells and 33% (35/105) correctly identified that immunotherapy does not kill all rapidly dividing cells. With respect to immunotherapy side effects, 68% (71/105) of patients reported that immunotherapy side effects can affect any organ in the body and 65% (68/105) endorsed that side effects from immunotherapy can occur at any time, even after the treatment ends. Overall, 34% (36/105) of participants reported that the primary goal of their treatment is to cure their cancer. Participants with melanoma had higher mean knowledge scores compared to those with lung cancer (74.7 vs. 62.3, P = 0.003). Participants with melanoma were also more likely to report that the goal of their immunotherapy was to cure compared to those with lung cancer (58% [33/57] vs. 6% [3/48], P &lt; 0.001) and that their oncologist had said that immunotherapy would cure their cancer (19% [11/57] vs. 0% [0/48], p = 0.005). Conclusions: We observed substantial knowledge deficits about immunotherapy and perceptions that immunotherapy is a cure for advanced cancer, particularly among patients with melanoma. These findings underscore the need for interventions to enhance patients’ knowledge about immunotherapy and to help them understand the goal of immunotherapy for patients with advanced cancer.
BIOL-06. MIR-1253 POTENTIATES CISPLATIN RESPONSE IN PEDIATRIC GROUP 3 MEDULLOBLASTOMA BY REGULATING FERROPTOSIS
Authors: Ranjana Kanchan, Parvez Khan, Naveenkumar Perumal, Pranita Atri, Ramakanth Chirravuri Venkata, Ishwor Thapa, David Doss, Mohd Wasim Nasser, Surinder Batra, Sidhartha Mahapatra
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma (MB), the most common malignant pediatric brain tumor and a leading cause of childhood mortality, is stratified into four primary subgroups, i.e. SHH (sonic hedgehog), WNT (wingless), and non-SHH/WNT groups 3 and 4, the latter representing high-risk MB. Haploinsufficiency of 17p13.3, which houses the tumor suppressor gene miR-1253, characterizes high-risk tumors. Despite improvements in targeted therapies, a limited proportion of these patients survive the disease. Capitalizing on the tumor suppressive properties of miRNAs as adjuncts to chemotherapy provides a promising alternative to current therapeutic strategies. In this study, we explored the potentiating effects of miR-1253 on cisplatin cytotoxicity in group 3 MB. First, in silico and in vitro analyses revealed an upregulation of ABCB7, a mitochondrial iron transporter and putative target of miR-1253, in MB cell lines and group 3 MB tumors. Overexpression of miR-1253 resulted in downregulation of ABCB7 and GPX4, a critical ferroptosis regulator, which consequently increased labile mitochondrial iron pool and, in turn, mitochondrial ROS (mtROS). Complementarily, we demonstrated, using CRISPR knockdown of ABCB7, ferroptosis induction with downregulation of GPx4 expression, liberation of free iron, mtROS generation and lipid peroxidation. Cisplatin is reported as an inducer of both apoptosis and ferroptosis-mediated cancer cell death. Therapeutically, the combination of miR-1253 and cisplatin led to an additive effect on cell viability, colony formation, apoptosis, and ROS generation. In turn, treatment with mtROS inhibitor (MnTBAP) and ferroptosis inhibitor (Ferrostatin) lead to partial recovery from the cytotoxic effects of this combination therapy. These studies identify an miR-1253-induced ferroptosis pathway targeting the ABCB7/GPX4/mtROS axis in group 3 MB. They further provide proof-of-concept in using miR-based therapeutics to augment treatment efficacy of current chemotherapeutics in the treatment of high-risk tumors.
Efficacy and Safety of Once Weekly Bortezomib In Multiple Myeloma Patients
Authors: Sara Bringhen, Alessandra Larocca, Davide Rossi, Alessandra Romano, Mariella Genuardi, Roberto Ria, Pietro Leoni, Francesca Patriarca, Chiara Nozzoli, Tommasina Guglielmelli, Giulia Benevolo, Vincenzo Callea, Fabiana Gentilini, Francesca Elice, Barbara Olivero, Mariella Grasso, Antonietta Pia Falcone, Daniela Gottardi, Vittorio Montefusco, Alessandro Allegra, Manuela Rizzo, Giovanna Leonardi, Daniela Oddolo, Fortunato Morabito, Mario Boccadoro, Antonio Palumbo
Journal: Blood (2010)
Systematic review and meta-analysis of post-progression outcomes in ER+/HER2- metastatic breast cancer after treatment with endocrine therapy and CDK 4/6 inhibitors within randomized clinical trials.
Authors: Elisabetta Munzone, Eleonora Pagan, Vincenzo Bagnardi, Emilia Montagna, Giuseppe Cancello, Silvia Dellapasqua, Monica Iorfida, Manuelita Mazza, Marco Colleoni
Journal: Journal of Clinical Oncology (2021)

1059 Background: CDK4/6 inhibitors combined with endocrine therapy (ET) deeply transformed the treatment landscape of HR+/HER2− advanced breast cancer. After progression with the combination, there are no established guidelines for an optimal sequencing of the various therapeutic options. Data from randomized clinical trials (RCT) suggest that subsequent progression free survival (PFS2) was not compromised by the use of these drugs and time to subsequent chemotherapy (TTC) may be delayed. Therefore, we performed a meta-analysis to evaluate the benefit of such treatments on PFS2 and on delaying the TTC. Methods: We conducted a systematic literature search using PubMed to select all available randomized clinical trials of CDK4/6-inhibitors and ET reporting PFS2 or TTC data in first- or second-line therapy of HR+/HER2- pre- or postmenopausal metastatic breast cancer. We also reviewed abstracts and presentations from all major conference proceedings. We calculated the pooled hazard ratios (HR) for PFS2 and TTC with 95% confidence intervals (CI) using fixed-effects models. The pooled HRs for PFS and OS were also calculated. I 2 was used to quantify heterogeneity between studies’ results. Results: Seven studies (PALOMA 1-2-3, MONALEESA 3-7, MONARCH 2-3) were included in our analyses (n = 3912 patients). A clear PFS2 benefit was observed in patients who received CDK 4/6 inhibitors + ET (pooled HR = 0.67, 95% CI = 0.61 to 0.74, I 2 = 0.0%) and also a delay in subsequent TTC (pooled HR = 0.63, 95% CI = 0.58 to 0.70, I 2 = 0.0%). As previously reported, the benefit in terms of PFS (pooled HR = 0.54, 95% CI = 0.50 to 0.59, I 2 = 0%) and OS (pooled HR = 0.77, 95% CI = 0.68 to 0.86, I 2 = 0%) was also confirmed. Conclusions: CDK4/6-inhibitors plus ET compared with ET alone improve PFS2, and TTC. The delay of chemotherapy can spare the patients toxicities, potentially improving the quality of life. Thus, the observed benefit in PFS2 may postpone the onset of endocrine resistance and may offer an additional therapeutic advantage in this setting.