tbuckley/cabot-search huggingface dataset:
Effect of cabozantinib on bone turnover markers (BTM) and bone metastases (BM) in radioiodine refractory (RAIR)-differentiated thyroid cancer (DTC).
Authors: Bhavana Konda, Michael V. Knopp, Peter R. Martin, Susan Geyer, Maria E. Cabanillas, Jonas A. De Souza, Lori J. Wirth, Michael E. Menefee, Stephen V. Liu, Manisha H. Shah
Journal: Journal of Clinical Oncology (2017)

e17580 Background: Cabozantinib is a small molecule multiple-receptor tyrosine kinase inhibitor that primarily targets MET and vascular endothelial growth factor receptor 2 (VEGFR2). We evaluated the effect of cabozantinib on BTM in RAIR DTC. We also assessed the response of BM to cabozantinib using 18F Sodium Fluoride (NaF) PET and radionuclide bone scans. Methods: This prospective analysis was performed as part of a multicenter International Thyroid Oncology Group phase II study of cabozantinibin patients with RAIR DTC who progressed on prior VEGFR-targeted therapy (NCT01811212). BTM [serum C-telopeptide (CTx), osteocalcin, N-telopeptide (NTx), procollagen type 1 (Pc1) and urinary NTx] and NaF PET or Tc-MDP scans were done at baseline and after 8 weeks of therapy. A paired t-test was used between baseline and week 8 BTM. Results: Primary study results were presented elsewhere (Shah, et al. 2015, International Thyroid Congress) showing a response rate of 36% with cabozantinib. Of 25 patients (pts) enrolled, 21 had BM, 10 of whom were on bone-modifying agents (BMA) prior to week 8. Only 2 pts had elevated BTM at baseline. In all pts who had paired BTM, there was a statistically significant decline in all BTM except NTx by week 8 (table). Pts not on BMA also had a significant decline in CTx (p 0.0003), urine NTx (p 0.0300), and Pc1 (p 0.0030) compared to baseline. 19 pts were evaluable for overall response and there was no correlation between BTM and response rate. 6/21 patients underwent paired NaF PET scans and 4/6 had minor reduction in lesion uptake at 8 weeks. Conclusions: Interestingly, most of our patients had normal baseline BTM despite BM. Cabozantinib was associated with a strikingly significant reduction in all BTM (even when BTM were within normal limits at baseline) except NTx by week 8. Minor decreases in bone lesion uptake was noted on NaF PET in 4/6 evaluable patients. Clinical trial information: NCT01811212. [Table: see text]
Phase 2 study of the safety and efficacy of INCB050465 in patients with relapsed or refractory (R/R) diffuse large b-cell lymphoma (DLBCL) (CITADEL-202).
Authors: Morton Coleman, Andres Forero-Torres, Vincent Ribrag, Ian Chau, Douglas James DeMarini, Pier Luigi Zinzani
Journal: Journal of Clinical Oncology (2017)

TPS7579 Background: Aberrant activation of PI3Kδ is implicated in B-cell malignancies. INCB050465, a highly selective PI3Kδ inhibitor, is demonstrating preliminary efficacy in an ongoing phase 1/2 dose-escalation and expansion study as monotherapy for r/r DLBCL as well as for other r/r B-cell malignancies (ASH 2016; Abstract 4195). This phase 2 study will further evaluate the efficacy and safety of single-agent INCB050465 in pts with r/r DLBCL. Methods: In this phase 2, multicenter, open-label study (NCT02998476), eligible adults will have r/r DLBCL diagnosis, defined as receiving 1–5 prior treatments and be ineligible for high-dose chemotherapy or autologous stem-cell transplant (SCT). Pts will also have ≥1 measurable lesion (nodal ≥2 cm or extranodal &gt; 1 cm in longest dimension); Eastern Cooperative Oncology Group performance status ≤2; adequate hematologic, hepatic, and renal function; no mediastinal large B-cell lymphoma or CNS metastases; no allogeneic SCT ≤6 months, or graft-versus-host-disease after allogeneic SCT, or autologous SCT ≤3 months, before first dose; and no prior treatment with PI3K inhibitors. Pts will be enrolled into 2 groups according to prior treatment with a Bruton’s tyrosine kinase (BTK) inhibitor (Group A [n = 100, no BTK inhibitor] or B [n≤20, received BTK inhibitor]). Both groups will receive INCB050465 20 mg orally QD for 8 wks; then 20 mg QW until disease progression, death, unacceptable toxicity, or consent withdrawal. The primary endpoint is the objective response rate in Group A (complete/partial response per independent review committee based on Lugano criteria). Secondary endpoints will include duration of response, progression-free survival, overall survival, and safety in Group A (these endpoints will be exploratory in Group B). Other exploratory assessments will include pharmacokinetics and association between genetic characteristics and treatment response in both groups. In a planned interim futility analysis of Group A, the study will be terminated if ≤13 of the first 40 treated pts respond (no futility analysis of Group B will be conducted). The study is currently recruiting (estimated completion date, March 2020). Clinical trial information: NCT02998476.
A novel 4-gene prognostic signature for hypermutated colorectal cancer (CRC)
Authors: W. Ge, W. Cai, H. Hu
Journal: Annals of Oncology (2018)

Background: As previous studies have reported, hypermutated CRC account for approximately 15%-17% among all CRC. The proportion and number of patients with hypermutated CRC cannot be underrated. Additionally, hypermutated patients' options of therapy are different, as they have a greater potential benefit from immunotherapy. Methods: We sequenced tumor mucosa of CRC patients with more than 24-month follow up data in our center and identified mutation profiles of the hypermutated CRC as the training dataset (ZJU). We obtained patients from The Cancer Genome Atlas (TCGA) as the validation dataset. Recurrently mutated genes were combined to calculate a compound score by summation of a Cox PH weighted sum of mutations. Patients with higher-than-median score were segregated as high-risk group. Outcomes were analyzed with Kaplan-Meier and Cox regression analyses using Python (3.6.0) and R (3.4.0). Results: We constructed a 4-gene signature (ACVR2A, APC, DOCK2 and POLE), training in 45 patients in ZJU and validating in 24 in TCGA. Patients of the high-risk group showed worse survival (HR = 8.62, P = 0.0010) and increased risk of recurrence (HR = 8.40, P = 0.0011, after adjusting age, sex, and TNM stage). We further compared our prognostic signature with other risk factors [including microsatellite instability (MSI) status, POLE driver mutation, BRAF p.V600E, tumor mutational burden and TNM staging], which proved our four-gene signature was better. The subgroup analysis suggested that our 4-gene signature would be more powerful in MSI CRC. Conclusions: Our 4-gene signature is a better predictor of survival and recurrence for hypermutated CRC, especially for MSI CRC. This risk classifier may help us identify patients with poor prognosis but better responding to immunotherapy. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
JAK2 variations and functions in lung adenocarcinoma.
Authors: Xu Yanjun, Fan Yun
Journal: Journal of Clinical Oncology (2017)

e23181 Background: Lung cancer ranks as the first most common cancer and the first leading cause of cancer-related death in China and worldwide. Due to the difficulty in early diagnosis and the onset of cancer metastasis, the 5-year survival rate of lung cancer remains extremely low. JAK2 has emerged as pivotal participant in biological processes, often dysregulated in a range of cancers, including lung cancer. Recently we found that JAK2 might play an important role in lung cancer pathogenesis as an oncogene. While our understanding of JAK2 in the onset and progression of lung cancer is still in its infancy, there is no doubt that understanding the activities of JAK2 will certainly secure strong biomarkers and improve treatment options for lung cancer patients. Methods: The expression level of JAK2 mRNA was assayed using RT-PCR. JAK2 mutations and amplification were detected using next-generation sequencing (NGS). MTT assay, Transwell migration and invasion assay were conducted to study the proliferation, migration and invasion abilities of lung adenocarcinoma cells independently. The shRNA and overexpression plasmids of JAK2 were conducted. Results: JAK2 is up-regulated in lung adenocarcinoma tissues when compared with their adjacent non-tumor tissues, and was associated with lymph node metastasis ( p&lt; 0.05). JAK2 V617F and N30S mutations and JAK2 amplification were detected by NGS in lung adenocarcinoma patient samples. Downregulation of JAK2 inhibits the proliferation, migration and invasion abilities of lung cancer cells. Moreover, overexpression of JAK2 induced the proliferation, migration and invasion abilities of lung cancer cells. Conclusions: These findings demonstrate that JAK2, whose expression is up-regulated in lung adenocarcinoma, whose mutation and amplification were detected in lung adenocarcinoma, may participate in lung cancer progression by regulating cancer cells proliferation, migration and invasion.
Phase I extension clinical study of BB503, a first-in-class cancer stemness kinase inhibitor, in adult patients with advanced head and neck cancer.
Authors: Gregory Michael Cote, Nicole Grace Chau, Alexander I. Spira, William Jeffery Edenfield, Donald A. Richards, Stephen Lane Richey, Scott Andrew Laurie, Sharon Wilks, Fadi S. Braiteh, Kemeng Wang, Youzhi Li, Harry Rogoff, Matthew Hitron, Chiang Li
Journal: Journal of Clinical Oncology (2016)

6018 Background: BB503 (BBI-503) is an oral first-in-class cancer stemness kinase inhibitor. By targeting multiple serine-threonine stemness kinases, BB503 inhibits Nanog and other cancer stemness pathways. A Phase I clinical trial of BB503 demonstrated safety and signs of anti-cancer activity in patients (pts) with advanced solid tumors. Dose escalation and RP2D expansion accrual included a cohort for pts with refractory head and neck cancer (HNCA). Methods: Pts with metastatic, unresectable HNCA who had exhausted standard therapies were enrolled. BB503 was administered orally, daily, in continuous 28-day cycles. Pts were assessed for safety and preliminary activity including Disease Control Rate (DCR), defined as stable disease of at least 8 weeks or objective partial (PR) or complete response (CR) per RECIST 1.1. Results: 33 pts were enrolled: 13 with adenoid cystic carcinoma (ACC), 15 with head and neck squamous cell carcinoma (HNSCC), and 5 with parotid/salivary tumors. All ACC pts received prior radiation (XRT), 92% prior surgery, and 54% prior systemic therapy. For HNSCC and parotid/salivary pts, 90% received prior XRT, 80% prior surgery, and 90% prior systemic therapy. Pts were treated with BB503 10 mg to 300 mg daily, which was well tolerated. Grade 3 AE included rapidly reversible diarrhea (n = 5) and nausea/vomiting (n = 1). For evaluable pts with HNSCC and parotid/salivary tumors (n = 16), 19% achieved PR and 25% achieved disease control for ≥ 24 weeks. The 4 non-evaluable pts had clinical deterioration prior to receiving ≥80% of 1 cycle of study drug per protocol. For ITT HNSCC or parotid/salivary pts (n = 20), median overall survival (mOS) is 35 weeks. For all ACC pts (ITT, n = 13), 38% had disease control for ≥ 24 weeks, 69% have survived more than 1 year, and mOS is not reached. Conclusions: BB503 demonstrated tolerability and encouraging signs of anti-cancer activity in pts with refractory HNCA, including partial response and prolonged disease control. Further clinical investigation of BBI503 for HNCA is warranted. Clinical trial information: NCT01781455.
Small molecules for fat combustion: targeting obesity
Authors: Jingxin Liu, Yitao Wang, Ligen Lin
Journal: Acta Pharmaceutica Sinica B (2018)

Obesity is increasing in an alarming rate worldwide, which causes higher risks of some diseases, such as type 2 diabetes, cardiovascular diseases, and cancer. Current therapeutic approaches, either pancreatic lipase inhibitors or appetite suppressors, are generally of limited effectiveness. Brown adipose tissue (BAT) and beige cells dissipate fatty acids as heat to maintain body temperature, termed non-shivering thermogenesis; the activity and mass of BAT and beige cells are negatively correlated with overweight and obesity. The existence of BAT and beige cells in human adults provides an effective weight reduction therapy, a process likely to be amenable to pharmacological intervention. Herein, we combed through the physiology of thermogenesis and the role of BAT and beige cells in combating with obesity. We summarized the thermogenic regulators identified in the past decades, targeting G protein-coupled receptors, transient receptor potential channels, nuclear receptors and miscellaneous pathways. Advances in clinical trials were also presented. The main purpose of this review is to provide a comprehensive and up-to-date knowledge from the biological importance of thermogenesis in energy homeostasis to the representative thermogenic regulators for treating obesity. Thermogenic regulators might have a large potential for further investigations to be developed as lead compounds in fighting obesity.
Hair-mass-index (HMI) as indicator for the efficacy of scalp cooling (SC) and the associated quality of life (EORTC QLQ C30).
Authors: Doerthe Schaffrin-Nabe, Rudolf Voigtmann, Anke Josten-Nabe, Andrea Tannapfel, Inge Schmitz, Ulrike von Hehn
Journal: Journal of Clinical Oncology (2016)

e21692 Background: SC is considered as valuable supportive therapy combined with CTX. The aim of the study was to judge and increase the efficacy basing on standardized and objective parameters (trichogram,HMI analysis via trichometry). Methods: 40 patients with breast cancer received (neo)adjuvant EC-Taxol regimes, optionally combined with SC. 8 patients out of this group opted against SC (control group). Pre- (T0) and post-therapeutically (T1) crownhair density was documented via trichometer, a trichogram was created, the diameter of hairbulbus and shaft was determined, and the association of HMI with general medical factors was investigated too. Results: HMI declined for all SC patients in median from 80 to 55 , for the control group from 76 to 5; divergence and T1 data showed significant differences (U-Test p < 0,001). In 20 SC patients (63%) no visible hairloss was found and only6 out of 12 SC patients with visible effluvium decided for a head cover. Complete hairloss was seen in the control group. A strong correlation of HMI with diameter of hair shaft (Spearman-correlation, R = 0,580; p < 0,001), bulbus (R 0 0,317; p = 0,077) as well as anagen rate (R = 0,436; p = 0,013) was seen. Patients in premenopausal status had a significant greater shaft diameter in T0 and T1 as patients in postmenopausal status (U-Test, p = 0,038 and p = 0,022). Patients with systemic comorbidities, regular medication and postmenopausal status showed a significant lower anagen rate in T0 compared to patients without these conditions (U-Test, p = 0,012; p = 0,003, p = 0,010). We found a strong correlation between HMI and psychological strain (Kendal-Correlation T = -0,386, p = 0,005; t = -0,502, p < 0,001) as well as contentment (t = 0,556, p < 0,001; t = 0,399, p = 0,003). The EORTC QLQ C30 survey indicated a significant higher quality of life and impressive positive emotional status for all SC patients compared to the control group (U-Test, p < 0,001, p = 0,012). Conclusions: All SC patients showed significant better trichological hair results, an impressive higher quality of life and less psychological strain compared to the control group. In future, selected factors might allow a predictive statement on the success of SC in advance.
Cumulative dose of oxaliplatin in adjuvant therapy for stage III colon cancer patients: Impact on survival.
Authors: Jolanta Zok, Barbara Radecka, Krzysztof Adamowicz, JAN Korniluk, Renata Duchnowska, Ewa Maria Wysokinska
Journal: Journal of Clinical Oncology (2018)

e15671 Background: The oxaliplatin-based therapy administerated over 6 months remains the standard of adjuvant treatment for stage III colon cancer patients.The IDEA study demonstrated that in certain substages (T1-3N1) 3-month therapy was nearly as effective as 6 months, and less toxic. In MOSAIC, NASBP-C07 and NO16968 studies, round 30% of patients didn‘t complete oxaliplatin-based therapy due to side effects.The cumulative-doses of oxaliplatin in MOSAIC and NASBP-C07 were lower than planned. We evaluated retrospectively the correlation between the cumulative-dose of adjuvant oxaliplatin and the clinical outcomes in stage III colon cancer patients. Methods: Retrospective analysis included III colon cancer patients managed between 2000 and 2014, with surgery and adjuvant chemotherapy using single-agent fluoropyrimidines (continuous 5-FU infusion with leucovorin or oral capecitabine) or oxaliplatin-based regimens (FOLFOX-4 or XELOX). Results: Study group included 620 patients (age 25-85 years), 67% pT3, 62% pN1a-b. Oxaliplatin-based and single-agent fluoropyrimidine chemotherapy was administered to 365 (59%) and 255 (41%) patients, respectively. The median follow-up in both groups was 53 months (4.8-192) and 52 months (8.2-115), respectively. In 71 patients (19%) the oxaliplatin treatment was prematurely terminated due to adverse events. The median oxaliplatin dose was 1666 mg/m2 (SD 1309-1897 mg/m2). In the multivariate analysis variables correlated with lower probability of relapse included oxaliplatin-based chemotherapy (HR = 0.57, p = 0.023), higher number of removed lymph nodes (HR = 0.95, p = 0.019 and patient age (HR = 0.97, p = 0.05, respectively). Oxaliplatin-based chemotherapy correlated with increased overall survival (OS) in the univariate analysis (HR = 0.63, p = 0.000) but not in multivariate analysis. The cumulative-dose of oxaliplatin did not correlate with disease free survival and OS (HR = 1.00, p = 0.57 and HR = 1.00, p = 0.17). Conclusions: The adjuvant oxaliplatin-based therapy in stage III colon cancer is associated with lower risk of relapse compared to non-oxaliplatin regimens. The cumulative dose of oxaliplatin doesn’t seem to significantly impact treatment outcomes.
Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study
Authors: Ronald F van Vollenhoven, Bevra H Hahn, George C Tsokos, Carrie L Wagner, Peter Lipsky, Zahi Touma, Victoria P Werth, Robert M Gordon, Bei Zhou, Benjamin Hsu, Marc Chevrier, Manon Triebel, Jarrat L Jordan, Shawn Rose
Journal: The Lancet (2018)
Prospective validation of a novel geriatric screening tool, the Korean cancer study group geriatric score (KG)-7, in older patients with advanced cancer undergoing 1<sup>st</sup> line palliative chemotherapy.
Authors: Jin Won Kim, Se Hyun Kim, Yun-Gyoo Lee, In Gyu Hwang, Hong-Suk Song, Su-Jin Koh, Yoon Ho Ko, SeongHoon Shin, In Sook Woo, Soojung Hong, Tae Yong Kim, Ji Yeon Baek, Hyun Jung Kim, Hyo Jung Kim, Myung Ah Lee, Jung Hye Kwon, Yong Sang Hong, Hun-Mo Ryoo, Kyung Hee Lee, Jee Hyun Kim
Journal: Journal of Clinical Oncology (2017)

e21540 Background: Full geriatric assessment is time-consuming and labor intensive, and most screening tools were developed in Western countries, which cannot reflect differences in some domains such as nutrition deficit, in Asians. Methods: This prospective study to validate a novel geriatric screening tool, the Korean Cancer Study Group Geriatric Score (KG)-7, was conducted as a substudy of a multicenter study for the prediction tool of toxicity in older cancer patients receiving 1st line chemotherapy (KCSG PC13-09). Abnormal GA was defined as deficits in at least 2 out of 6 domains [activities of daily living (ADL), Korean-instrument ADL (K-IADL), Mini-Mental Status Examination in the Korean version of the Consortium (MMSE-KC), Short-Form Geriatric Depression Scale (SGDS), the Mini Nutritional Assessment (MNA), Timed Get Up and Go test (TGUG)]. KG-7 questionnaire was answered before full GA. We compared the performance of KG-7 with G-8 score, obtained from MNA, by calculating AUC of accuracy, and also sensitivity (SE), specificity (SP), positive and negative predictive value (PPV and NPV). Results: Baseline GA and KG-7 results of 301 patients were collected. Median age was 75 years old (range 70-93). Eighty six (28.6%) and 124 patients (41.2%) showed dependent ADL and IADL, respectively. Impairment for domains of MMSE, SGDS, MNA, and TGUG was identified in 166 (55.1%), 132 (43.9%), 230 (76.4%), and 52 patients (17.3%), respectively. Abnormal GA was documented in 221 patients (73.4%). Based on the ≤ 5 cut-off value of KG-7 for abnormal GA, the AUC was 0.741 (95% CI, 0.683-0.800), and the SE, SP, PPV, and NPV were 75.6%, 58.7%, 84.3%, and 44.9%, respectively. Abnormal KG-7 score was shown in 198 patients (66.9%). With the ≤ 14 cut-off value of G-8 for abnormal GA, the G-8 showed a SE, SP, PPV, and NPV of 93.6%, 28.0%, 79.2%, and 60.0% with AUC of 0.766 (95% CI, 0.703-0.829). Abnormal G-8 score was shown in 260 patients (88.1%). Conclusions: KG-7 could identify patients with abnormal GA with comparable performance with G-8 and can be a useful screening tool for Asian countries with limited resources and high patient volume.
Examination of factors that influence use of extended adjuvant endocrine therapy (ET).
Authors: Kunal C. Kadakia, Kelley M. Kidwell, Debra L. Barton, Jennifer J. Griggs, Norah Lynn Henry
Journal: Journal of Clinical Oncology (2017)

e21618 Background: Extending adjuvant ET from 5 to 10 years has been shown to improve outcomes; however, limited data are known about if and why women pursue extended ET. The primary objective was to estimate the proportion of women who were willing to receive extended ET and secondarily, to determine what factors were associated with this decision. Methods: 133 women on ET for 3-5 years who had not made a decision on extended ET completed a survey about willingness to continue ET, quality-of-life (Functional Assessment of Cancer Therapy-Endocrine Subscale [FACT-ES]), and beliefs about medicines (Beliefs about Medicines Questionnaire Specific [BMQ-S]). BMQ-S assesses patients need for a treatment (necessity beliefs) and concerns about its adverse effects (AEs). The primary outcome, responses to "If in meeting with your doctor, he or she recommends continuing hormonal therapy for longer than 5 years (up to 10 years), how willing ("Not at all" to "Extremely") would you be to continue taking your current hormonal therapy?" was analyzed descriptively. Logistic regression tested for associations between clinical factors (age, stage, chemotherapy), FACT-ES, BMQ-S, and the primary outcome. Results: Most women (112, 85%, 95% confidence interval, CI, 78-91%) were "Moderately" to "Extremely" likely to pursue extended ET. On univariate analysis, younger age (&lt;49 vs ≥50), lower total and social well-being on FACT-ES, and lower necessity and higher concerns on BMQ-S were associated with less willingness to pursue extended ET. Neither stage nor prior chemotherapy was associated with this decision. On multivariable analysis, age and FACT-ES were not associated with this decision (odds ratio, OR 1.03, 95% CI 0.96-1.09, p=0.41; OR 1.01, 95% CI 0.98-1.05, p=0.49). Greater patient perception of necessity of ET compared to concern for AEs was the only independent factor associated with willingness to pursue extended ET (BMQ-S OR 1.34, 95% CI 1.15-1.57, p=0.0005). Conclusions: Most women are likely to purse extended ET if recommended by their physician. Patient decision-making appears to be largely influenced by beliefs of medicines rather than breast cancer-specific clinical factors and should be considered when counseling patients on extended ET.