tbuckley/cabot-search huggingface dataset:
EMBR-23. KIF11 DEPENDENCY ON P53 MUTATIONAL STATUS IN MEDULLOBLASTOMA
Authors: Shiying Huang, Sekar Karthik, Qi Lin, YuChen Du, Ching C Lau, Adesina Adekunle, Jack M F Su, Angela Major, M Tarek Elghetany, Kam-Man Hui, Xiaonan Li, Wan-Yee Teo
Journal: Neuro-Oncology (2021)

Abstract Introduction KIF11, a mitotic kinesin, is a component responsible for assembly and maintenance of mitotic spindle during mitosis. Tumor cells can upregulate KIF11. Inhibition of KIF11 results monopolar spindle formation, resulting in monoastral mitosis in cells. This activates the spindle assembly checkpoint, cells are arrested and prevented from entering cell cycle, resulting in cell death via apoptosis or necrosis, cell division with aneuploidy or mitotic slippage without division into tetraploid G1 phase. Methods We hypothesized that the effect of KIF11 inhibition on medulloblastoma (MB) is dependent of its p53 mutational status. Results Our findings on Hoechst staining demonstrated a small molecule inhibitor of KIF11 which induced apoptosis in p53-wildtype MB cells at 48h (p&amp;lt;0.0001), was able to trigger mitotic catastrophe (p = 0.0010) in p53-mutant MB cells at 24h and subsequent necrosis (p=0.0039) at 48h. KIF11 inhibitor exerted anti-proliferative effects on five MB cell lines at nanomolar concentration range, independent of its p53 mutational status. Cells treated with KIF11 inhibitor were arrested in G2/M phase. Apoptosis was observed on Annexin V flow cytometry 24h after treatment, followed by necrosis after 48h in p53-wildtype cells. In contrast, treated p53-mutant cells underwent necrosis at 24h. Differences in cell death mechanisms upon KIF11 inhibition was confirmed on immunoblotting by upregulated p53 expression and presence of cleaved-PARP and DNA-damage marker in p53-wildtype cells, indicative of apoptosis. While inhibition of KIF11 and increased p53 expression were observed only after 48h, cleaved-PARP expression was detected as early as 24h in p53-wildtype, suggesting KIF11-independent, cleaved-PARP-mediated cell death at 24h. In contrast, treated p53-mutant cells showed decreased p53 expression and absence of cleaved-PARP and DNA-damage marker after 24h. Conclusions Our results suggest that when mitotic arrest is induced, p53-mutant MB cells undergo mitotic catastrophe and necrosis while p53-wildtype MB cells predominantly undergo apoptosis.
Improved risk stratification in an adjuvant radiation therapy (ART) eligible cutaneous squamous cell carcinoma (cSCC) patient population by integration of the 40-gene expression profile prognostic test (40-GEP).
Authors: Shlomo A. Koyfman, Ashley Wysong, Sarah Arron, Ally-Khan B. Somani, Jennifer Siegel, Alison Fitzgerald, Sarah J. Kurley, Matthew S. Goldberg, Chrysalyne Schmults, Jason Newman
Journal: Journal of Clinical Oncology (2021)

e21589 Background: Although cure rates are high for cSCC, an estimated 2-6% of cSCC patients will develop regional/distant metastasis and due to high incidence, mortality levels are similar to melanoma. ART is used for high-risk cSCC (HRcSCC) patients to reduce the risk of recurrence and/or metastasis, but guidelines are confounding and lack clarity regarding which patients may benefit from ART. The 40-GEP test has been validated to predict a patient’s risk for regional/distant metastasis: Class 1-low; Class 2A-moderate; and Class 2B-high risk for metastasis. We hypothesize that a 40-GEP Class result could help further stratify patient risk within an ART-eligible population. Methods: Using criteria within NCCN guidelines and other high-risk features to determine ART-eligibility, 86 cases of the 420 HRcSCC patients having known outcomes from the 40-GEP multicenter validation cohort were identified. Criteria included patients presenting with two or more risk factors: tumor diameter ≥2 cm, poor differentiation, perineural invasion ≥0.1 mm, invasion beyond subcutaneous fat, and immunosuppression. Kaplan-Meier survival analysis and log rank test were used to assess metastasis free survival (MFS). Univariate Cox regression compared metastasis rates between 40-GEP Class results. Results: The 3-year MFS rate for the overall ART-eligible cohort was 65% (n = 86, 32 events, 95% CI: 56 – 76%). The 40-GEP demonstrated statistically significant stratification of risk with MFS rates of 79%, 63% and 33% for Class 1, Class 2A and Class 2B, respectively (p = 0.005). Cox regression was significant between Class 1 and Class 2B 40-GEP results (p = 0.002), with Class 2B having a 4.59-fold increase in metastases. 40% (34/86) of the cohort received a Class 1 result, highlighting HRcSCC patients who may be considered for reduction or avoidance of ART. In 14% (12/86) of cases with a Class 2B result, 2 of 3 patients went on to have metastasis and thus may be appropriate for more aggressive intervention in the setting of a clinical trial. Those cases meeting eligibility for 40-GEP testing but not ART-criteria (n = 334) and with a Class 2B result (n = 11) had a 64% MFS rate, similar to the ART-eligible population. Conclusions: The 40-GEP test stratifies a patient’s risk of regional and/or distant metastasis in patients for whom ART is typically considered. Incorporation of 40-GEP testing may help guide patient management decisions in HRcSCC by potentially decreasing over-treatment of patients with HRcSCC and identifying patients with otherwise lower risk disease who may benefit from ART and/or other adjunctive therapies.
Abstract 13001: Diabetes Prediction and Prevention
Authors: Ernst J Schaefer, Masumi Ai, Joi Gleason, Seiko Otokozawa, Ching-ti Liu, L. Adrienne Cupples, Michael L Dansinger
Journal: Circulation (2019)

Hypothesis: Lifestyle modification decreases diabetes risk. We developed a diabetes prediction model, and our hypothesis was that this model would be effective in targeting high risk subjects in a ...
Clinicogenomic characterization of metastatic thymic epithelial tumors.
Authors: Fatemeh Ardeshir-Larijani, Milan Radovich, Bryan P. Schneider, Patrick J. Loehrer
Journal: Journal of Clinical Oncology (2021)

8579 Background: Thymic epithelial tumors (TET) are one of the rarest adult malignancies. Overall, patients have favorable survival outcomes, however a small subset develop metastatic disease. Genomic characterization of this very rare, clinically aggressive TET subset is lacking. Herein, we evaluated the clinical and genomic characteristics of metastatic TET (mTET) compared to a large cohort (n = 117) of primary TET (pTET) from The Cancer Genome Atlas (TCGA). Methods: From 2015 to 2020, 52 pts with mTET underwent clinical CLIA-based sequencing using either whole-exome (n = 35), panel-based testing (n = 13) and/or liquid biopsy (n = 22). The specimen was taken from a metastatic organ (n = 34) or relapsed primary mediastinal mass (n = 14); 4 pts had liquid bx only. Data on pTET was derived from the TCGA. Kaplan-Meier and log-rank test was used for assessment of PFS, OS. Results: The median age was 56 yrs in mTET (range 32-74) vs. 60 yrs (range 17-84) in TCGA data. The M/F (%) was 40/60 in mTET and 48/52 in TCGA, respectively. Of note, 13 mTET pts had other types of cancer prior or concurrent with TET diagnosis (4-breast, 2-bladder, 5-other) in which radiotherapy (n = 4) and/or chemotherapy (n = 3) was administered prior to TET diagnosis. In our cohort, 19 pts had stage IVA and 33 pts had stage IVB (most common metastatic site was liver in 17 pts). WHO histologic classification was: A = 1, A/B = 3, B1 = 4, B2 = 10, B3 = 12, TC = 18, TC with neuroendocrine feature = 3, and lymphoepithelial carcinoma = 1. WHO B3 and TC histologies were more common in our cohort of mTET than in the TCGA cohort (63% (33/52) vs. 17% (20/117), respectively). Pts with TC had worse mOS compare to thymoma (109m vs. 163m, HR = 2.78, P = 0.04). The most common genomic alteration in mTET was TP53 (n = 17, 33%) compared to 3% in TCGA. This was followed by CDKN2A (n = 5, 10%), PIK3CA (n = 4, 8%), CDKN2B (n = 3, 6%) and NF1 (n = 3, 6%). All TP53 missense mut functionality was analyzed with polyphen-2 software and 91.6% (22/24) had 98-100% damaging probability. 70% of pts that harbored TP53 muts were TC (41%) or B3 (29%) histology. Clinically actionable genomic alterations targetable with available or investigational agents (e.g. high TMB; gain-of-function mutations in PIK3CA, CDK4, and mTOR; loss-of-function mutations in NF1) were seen in 23% (12/52) of pts. Conclusions: Patients with mTET are associated with more aggressive WHO histology (B3 and TC). Greater frequency of TP53 mutations are observed in mTET compared to pTET. Clinically actionable genomic alterations are frequently seen in mTET suggesting value in the routine sequencing of these patients.
Associations between preexisting nociplastic pain and early discontinuation of aromatase inhibitor therapy in breast cancer.
Authors: Elizabeth Joyce, Sidi Wang, Mehrdad Motamed, Kelley M. Kidwell, Norah Lynn Henry
Journal: Journal of Clinical Oncology (2021)

12068 Background: Aromatase inhibitors (AI) are recommended for at least five years to reduce risk of breast cancer recurrence in postmenopausal women with hormone receptor-positive disease. Despite the potential benefit, up to 50% of patients discontinue AI early, primarily because of musculoskeletal side effects. Some patients, including those with fibromyalgia and other chronic pain conditions, have preexisting pain that arises from altered nociception without clear evidence of tissue or peripheral nerve damage, called nociplastic or centralized pain. We hypothesized that preexisting nociplastic pain is associated with early discontinuation of AI therapy due to toxicity. Methods: Patients diagnosed with breast cancer between 2012-19 and who enrolled in the Michigan Genomics Initiative (MGI) were identified. Patients who were female, had hormone receptor-positive breast cancer, had not received neoadjuvant therapy, and who initiated adjuvant AI therapy were included in the analysis. Prior to breast cancer surgery patients completed surveys about pain in the affected breast and overall worst pain (Brief Pain Inventory [BPI]), nociplastic pain (2011 Fibromyalgia Survey [FS], which assesses widespread pain plus somatic symptom severity), and anxiety (PROMIS Anxiety 4a v.1). Demographics, cancer characteristics, and treatment history, including date and reason for discontinuation of AI therapy, were abstracted from the medical record. Patients were censored at date of last oncology follow-up. Univariate and multivariable analyses were conducted to assess relationship between age, BMI, surgical site pain, overall worst pain, FS score, anxiety, and time to discontinuation of initial AI medication. Results: Of 207 analyzed patients, the average age was 61 years, average BMI was 30.3 kg/m 2 , 181 (87%) were postmenopausal at the time of breast cancer diagnosis, and 31% received chemotherapy. The majority were prescribed anastrozole (n=196); 6 took letrozole and 5 took exemestane. Average scores prior to surgery were 1.5/10 for worst pain, 0.2/10 for surgical site pain, 4.2/31 for FS score, and 54.1/100 for anxiety. On univariate analysis, only use of exemestane (HR 5.55, p&lt;.001) and use of letrozole (HR 3.11, p&lt;.001) were associated with shorter time to ET discontinuation; age, BMI, surgical site pain, worst pain, FS score, and anxiety were not statistically significantly associated with time to AI discontinuation. On multivariable analysis, only higher FS score was statistically significantly associated with time to AI discontinuation (HR 1.11, p=.021). Conclusions: Greater pre-existing nociplastic pain was associated with early discontinuation of AI therapy. For these patients, early interventions that target centralized pain, or treatment with tamoxifen instead of AI therapy, may be appropriate in order to reduce risk of nonpersistence with AI therapy.
Cancer treatment among the elderly in the United States: Examining the interplay of race/ethnicity and comorbidities.
Authors: Tung Pham, Avonne Connor, Gita Suneja, Anne Rositch
Journal: Journal of Clinical Oncology (2021)

e18547 Background: As the life expectancy of Americans continues to increase, so does the number of individuals who are diagnosed with cancer and other comorbidities. Management of these patients can become increasingly complicated as physicians administer multiple combinations of interventions and drug therapies. To further complicate this issue, the average number of comorbidities among racial/ethnic minority patients is higher than non-Hispanic (NH) white patients, and this disparity could adversely affect receipt of curative cancer treatment among these minority groups. Therefore, we explored the association between race/ethnicity, comorbidities, and curative cancer treatment among elderly Americans diagnosed with the four most common cancer types. Methods: SEER-Medicare linked data was used to identify 727,136 individuals over 65 years old diagnosed with breast, colorectal, lung, or prostate cancer from 1992-2011. Comorbidity burden was measured using the Charlson Comorbidity Index (CCI) and analyzed as tertiles (T1: lowest CCI score to T3: highest CCI score). Treatment with curative intent was defined as receipt of any cancer-type-specific surgery, chemotherapy, radiation, hormone, or immune therapy within 6 months of cancer diagnosis. Modified Poisson regression models were used to assess the joint association between comorbidities and race/ethnicity on cancer treatment. Results: For all cancers, the percentage of patients receiving treatment declined rapidly with increasing age, CCI scores, number of comorbidities, and advanced cancer stage. In addition, variability in receipt of treatment by race/ethnicity was observed: 76% for NH-White patients, 75% for Hispanic patients, and 68% for NH-Black patients. Taking into account age, genders (for colorectal, lung cancer), year of diagnosis, stage at diagnosis, and socioeconomic status, we found that treatment proportions among NH-Black and Hispanic patients with low CCI score (T1) were 2%-15% lower than NH-White patients with the same CCI score (all p &lt; 0.001). Although treatment proportions decreased with increasing CCI among NH White patients (ranging from 2.5-11.3%; p &lt; 0.01), there was little difference in treatment by CCI among NH Black and Hispanic patients (ranging from 0.5%-2%; p &gt; 0.05). Conclusions: Our findings suggested that racial disparities may exist in cancer treatment among patients with low comorbidities. This finding was unexpected as these patients are less likely than highly comorbid patients to experience drug interactions and other complications due to concurrent disease management therapies.
Phase II study of brigatinib in ROS1 positive non-small cell lung cancer (NSCLC) patients previously treated with crizotinib: Barossa cohort 2.
Authors: Haruko Daga, Seiji Niho, Jun Sakakibara-Konishi, Hiroshi Tanaka, Yasushi Goto, Kadoaki Ohashi, Ryo Toyozawa, Masahiro Kodani, Toshiaki Takahashi, Yoshihiro Hattori, Masahiro Morise, Takaya Ikeda, Shingo Matsumoto, Kiyotaka Yoh, Shogo Nomura, Koichi Goto
Journal: Journal of Clinical Oncology (2021)

9040 Background: Brigatinib is a next-generation tyrosine kinase inhibitor targeting ALK and ROS1. Crizotinib is the first drug approved for the treatment of ROS1 fusion-positive NSCLC. Standard treatment for crizotinib-resistant ROS1 positive NSCLC is not established. Barossa is a multicenter, phase II basket, study of brigatinib in patients with ROS1 positive solid tumors. This study is composed of three cohorts. ROS1 inhibitor-naïve ROS1 positive NSCLC patients were enrolled in the cohort 1, and ROS1 positive NSCLC patients previously treated with crizotinib were enrolled in the cohort 2. Patients with ROS 1 positive solid tumors other than NSCLC were enrolled in the cohort 3. This time we report the cohort 2 results. Methods: Patients with advanced, previously treated with crizotinib, ROS1 positive NSCLC received brigatinib at a dose of 180 mg once daily with a 7-day lead-in period at 90 mg. The primary end point was objective response rate (ORR; RECIST 1.1) by independent review. Key secondary endpoint was PFS, OS, and safety. The sample size was set at 19 patients, with a one-sided alpha of 0.05, beta of 0.2, and threshold and expected values for primary endpoint of 20% and 50%, respectively. Results: From July 2019 and Jan 2020, 19 patients were enrolled from 9 institutions. Baseline characteristics as follows: median age (range): 60 (31-75) years; women, n = 10 (53%); ECOG PS of 0 to 1, n = 18 (95%); never smoker, n = 11 (58%); tumor histopathological type: adenocarcinoma, n = 18 (95%). Five and 6 patients achieved PR and SD, respectively at data cutoff date of 30 Oct 2020. The ORR was 26.3% (90%CI, 11.0-47.6), and the disease control rate was 57.9% (95%CI, 33.5-79.7). The median duration of follow-up for PFS was 12.0 months. The median PFS was 7.3 months (95% CI, 1.3-9.3), and the 1-year PFS rate was 26.9% (95%CI, 9.2-48.6). Grade ≥3 TRAEs were CPK increased (21.1%), infection (5.3%), AST and/or ALT increased (5.3%), hypercalcemia (5.3%), anorexia (5.3%), hypoxia (5.3%), erythema (5.3%), hypertension (5.3%). Pneumonitis was observed in one patient (5.3%, Grade 2). No treatment-related death was observed. Conclusions: Brigatinib has modest activity for ROS1 positive NSCLC patients previously treated with crizotinib. The safety profile of brigatinib was consistent with previous studies. Enrollment of the cohort 1 for ROS1 inhibitor-naïve NSCLC patients is ongoing, and the data will be presented at a future congress. Clinical trial information: JapicCTI-194851.
General practice on the brink: three key solutions the government must implement
Authors: Michael Craig Watson, Patricia Owen
Journal: BMJ (2021)

Salisbury provides an accurate description of the importance of general practice to the NHS and its current state of crisis.1 The UK urgently needs efficient and proactive general practice services, and we think there are three key solutions that the government should implement immediately.

A growing body of research indicates that many GPs are experiencing high stress levels, and this is contributing to low morale, …
Use of deep learning frameworks to detect super-responder and super-survivor stage IV squamous non-small-cell lung cancer (NSCLC) patients treated with a gemcitabine and cisplatin combination.
Authors: Carlos Maria Galmarini, Maximiliano Lucius
Journal: Journal of Clinical Oncology (2021)

1548 Background: Synthetic fingerprints integrate clinical data within computational models allowing the identification of particular clinical subpopulations at a given moment. We here describe a deep learning strategy to detect super-responder and super-survivor patients with squamous NSCLC by setting up synthetic fingerprints and using unsupervised deep learning frameworks (UDLF). Methods: Through www.projectdatasphere.org, we accessed the control arm clinical data (N = 548) of the randomised phase III SQUIRE trial (NCT00981058). This trial included patients with stage IV squamous NSCLC who had not received previous chemotherapy. These patients were treated with gemcitabine 1,250 mg/m 2 (IV, 30-min infusion, d1/d8) and cisplatin 75 mg/m 2 (IV, 120 min infusion, d1) on a 3-week cycle for a maximum of six cycles. Synthetic fingerprints resulted of the integration of 180 features collected during the first 3 cycles including demographics, medical history, physical exam, concomitant medication, histopathology, PK parameters, adverse events and common labs. These fingerprints were used as input for the UDLF. The resultant clusters were correlated with overall-response rate (ORR) and overall survival (OS). Results: After missing data removal and feature standardization, 192 patients were eligible for the study. The UDLF was able to generate two different clusters: P0 (n = 107) and P1 (n = 84). ORR was higher in the P1 than in the P0 cluster (mean 41.6% [95% CI 31.7-52.3] vs. 28.0% [95% CI 20.4-37.2]; p = 0.04). OS was significantly longer in the P1 than in the P0 cluster (median 13.2 months vs. 9.7 months; hazard ratio 1.56 [95% CI 1.12-2.17; p = 0.008]). Feature contribution analysis showed that P1 had more patients and more events of grade III/IV neutropenia. In contrast, P0 had more patients and more events of grade III/IV nausea and vomiting. Other major differences were observed on vital signs (SBP, DBP, HR, RR, Temp), concomitant medication (osmotically-active laxatives, dexamethasone, furosemide, granisetron and ondansetron) and in hematological (RBC, HGB, HCT, MCV, WBC, neutrophils, monocytes, lymphocytes) and biochemistry (albumin, globulins, ALP, LDH, creatinine, BUN, urea, sodium, magnesium and phosphate) tests. Conclusions: Our findings show that synthetic fingerprints and subsequent deep learning analysis can be of use to identify patients with clinical characteristics associated with high-response rate and long-term survival.
Leptin receptor-expressing pericytes mediate access of hypothalamic feeding centers to circulating leptin
Authors: Liliia I. Butiaeva, Tal Slutzki, Hannah E. Swick, Clément Bourguignon, Sarah C. Robins, Xiaohong Liu, Kai-Florian Storch, Maia V. Kokoeva
Journal: Cell Metabolism (2021)
The PROVIEW+ tool: Developing and validating a tool to predict risk of poor performance status and severe symptoms in cancer patients over time.
Authors: Hsien Seow, Rinku Sutradhar, Lisa Catherine Barbera, Peter Tanuseputro, Dawn Guthrie, Sarina Isenberg, Rosalyn A. Juergens, Jeffrey A. Myers, Melissa C. Brouwers, Semra Tibebu, Craig Earle
Journal: Journal of Clinical Oncology (2021)

12095 Background: There are numerous predictive cancer tools that focus on survival. However, no tools predict risk of low performance status or severe symptoms, which are important for patient decision-making and early integration of palliative care. The aim of this study was to develop and validate a model for all cancer types that predicts the risk for having low performance status and severe symptoms. Methods: A retrospective, population-based, predictive study using linked administrative data from cancer patients from 2008-2015 in Ontario, Canada. Patients were randomly selected for model derivation (60%) and validation (40%). The derivation cohort was used to develop a multivariable logistic regression model to predict the risk of having the reported outcomes in the subsequent 6 months. Model performance was assessed using discrimination and calibration plots. The main outcome was low performance status using the Palliative Performance Scale. Secondary outcomes included severe pain, dyspnea, well-being, and depression using the Edmonton Symptom Assessment System. Outcomes were recalculated after each of 4 annual survivor marks. Results: We identified 255,494 cancer patients (57% female; median age of 64; common cancers were breast (24%) and lung (13%)). At diagnosis, the risk of having low performance status, severe pain, well-being, dyspnea, and depression in 6-months is 1%, 3%, 6%, 13% and 4%, respectively for the reference case (i.e. male, lung cancer, stage I, no symptoms). Generally these covariates increased the outcome risk by &gt; 10% across all models: obstructive lung disease, dementia, diabetes; radiation treatment; hospital admission; high pain; depression; Palliative Performance Scale score of 60-10; issues with appetite; or homecare. Model discrimination was high across all models. Conclusions: The model accurately predicted changing cancer risk for low performance status and severe symptoms over time. Providing accurate predictions of future performance status and symptom severity can support decision-making and earlier initiation of palliative care, even alongside disease modifying therapies.