tbuckley/cabot-search huggingface dataset:
Association of colon adenocarcinoma in situ in polyp with subsequent colon cancer: A population-based retrospective study.
Authors: Shuai Wang, Apoorva Jayarangaiah, Anahat Kaur, Tarek N. Elrafei, Lewis Steinberg, Abhishek Kumar
Journal: Journal of Clinical Oncology (2021)

e15605 Background: Adenocarcinoma in situ (pTis) of the colon is defined as malignant cells confined within epithelium or mucosa. Since pTis is not invasive, polypectomy alone is usually adequate, especially if resection margins are cancer-free. We performed a population-based study to investigate the association of intrapolyp pTis and subsequent colon cancer. Methods: We queried the SEER database (1975-2017) for patients with pTis in adenoma. We further filtered patients with subsequent colon cancers. Standard incidence ratios (SIRs) were used to evaluate the excess risk of developing subsequent colon cancers comparing to the general population. Difference between patients who did or did not develop colon cancer were analyzed using Chi-square test. Results: A total of 15164 patients with pTis were identified. Among them, 736 (4.85%) patients developed subsequent colon cancer. Age ≥70 years, pTis in villous adenoma, polyp in hepatic flexure, splenic flexure, transverse colon, descending colon, and diagnosis year before 2000 were associated with increased risk of developing subsequent colon malignancy (all p&lt; 0.05). Polypectomy comparing to colectomy (total, subtotal or partial) is associated with a higher rate of developing subsequent colon cancers ( p &lt; 0.05). In patients with intrapolyp pTis, observation/expectation (O/E) of developing colon cancers are elevated to 4.76, 1.84, 1.66, and 1.28 within one year, 1-5 year, 5-10 year, and after ten years, respectively (all p&lt; 0.05). O/E for the male and female is 1.80 and 1.63 (both p&lt; 0.05); for the white and black is 1.64 and 2.21(both p&lt; 0.05). Conclusions: Subsequent colon cancers developed in 4.85% of pTis patients. Excess risk of developing subsequent colon cancers is highest in the first year, and declines with time but persists beyond ten years. Male and black have the highest excess risk. Factors like older age, villous adenoma, location from hepatic flexure to descending colon, and polypectomy are associated with developing subsequent colon cancers.
Open-label, multicenter, phase 1b/2 study of rebastinib in combination with paclitaxel to assess safety and efficacy in patients with advanced or metastatic endometrial cancer.
Authors: Filip Janku, Erika P. Hamilton, Cara Amanda Mathews, Christina Chu, Jennifer Robinson Diamond, John L. Hays, Rebecca Christian Arend, Massimo Cristofanilli, Andrea Jewell, William Reichmann, Keisuke Kuida, Haroun Achour, Rodrigo Ruiz-Soto, Debra L. Richardson
Journal: Journal of Clinical Oncology (2021)

5576 Background: Rebastinib is a first-in-class investigational, orally administered, potent and selective switch-control kinase inhibitor of tunica interna endothelial cell kinase (TIE2). This is a 2-part open-label, multicenter Phase 1b/2 study of rebastinib in combination with paclitaxel. Here we provide updated results (ASCO 2020) from the fully enrolled endometrial cancer (EC) cohort of the study. Methods: Part 2 of the study has five disease-specific cohorts (EC, platinum-resistant ovarian cancer, gynecological carcinosarcoma, TNBC and inflammatory breast cancer). Patients were treated at the RP2D and evaluated for efficacy (RECIST v1.1) and safety (CTCAE v5.0). Results: As of Jan 8, 2021, 38 EC patients were enrolled (median age of 66 years); 42% were of grade 2/3 endometroid histological subtype. All patients received at least 1 prior line of paclitaxel in combination with carboplatin and 79% of patients received ≥3 prior anti-cancer regimens. Sixteen of 38 patients were initially treated with a starting dose of rebastinib 100 mg BID, 11 of which dose reduced to 50 mg BID, and 22 patients were treated with a starting dose of rebastinib 50 mg BID, in combination with paclitaxel 80 mg/m 2 IV weekly (days 1, 8, 15 of 28-day cycle). In 33 evaluable patients with median follow-up of 5.9 months, the ORR was 33% and clinical benefit rate at 8 and 16 weeks was 70% and 55%, respectively, including 11 PRs (8 confirmed) and 12 SDs. Treatment-emergent adverse events ( &gt; 20% of patients; mostly ≤ grade 2) included fatigue (n = 18), constipation, peripheral edema (each at n = 16), peripheral sensory neuropathy, nausea (each at n = 15), dyspnea (n = 13), alopecia, hypokalemia (each at n = 11), diarrhea, hypomagnesemia (each at n = 10), dry mouth, dysgeusia (each at n = 9), arthralgia, hypertension, dehydration, GERD and muscular weakness (each at n = 8). Serious adverse events (SAE) at least possibly related to rebastinib included muscular weakness (n = 2 at 100 mg BID, n = 1 at 50 mg BID), nausea (n = 2), acute myocardial infarction, atrial flutter, dehydration, non-infective encephalitis, peritonsillitis, and stress cardiomyopathy (each at n = 1) and were resolved after dose interruption. Conclusions: The updated results of rebastinib at 50 mg BID in combination with paclitaxel showed encouraging preliminary anti-tumor activity and an acceptable safety profile in heavily pretreated EC patients, and supports further development in patients with EC (NCT03601897). Clinical trial information: NCT03601897.
Is the Consensual Threshold for Defining High Glucose Variability Implementable in Clinical Practice?
Authors: Jean-Baptiste Julla, Pauline Jacquemier, Guy Fagherazzi, Tiphaine Vidal-Trecan, Vanessa Juddoo, Asma Jaziri, Hanane Mersel, Nicolas Venteclef, Ronan Roussel, Pascale Massin, Aude Couturier, Jean-François Gautier, Jean-Pierre Riveline
Journal: Diabetes Care (2021)

Estimating glycemic variability (GV) through within-day coefficient of variation (%CVw) is recommended for patients with type 1 Diabetes (T1D). High GV (hGV) is defined as %CVw > 36%. However, continuous glucose monitoring (CGM) devices provide exclusively total CV (%CVT). We aimed to assess consequences of this disparity.We retrospectively calculated both %CVT and %CVw of consecutive T1D patients from their CGM raw data during 14 days. Patients with hGV with %CVT >36% and %CVw ≤36% were called the "inconsistent GV group".A total of 104 patients were included. Mean ± SD %CVT and %CVw were 42.4 ± 8% and 37.0 ± 7.4% respectively (P < 0.0001). Using %CVT, 81 patients (73.6%) were classified as having hGV, whereas 59 (53.6%) using %CVw (P < 0.0001) corresponding to 22 patients (21%) in the inconsistent GV population.Evaluation of GV through %CV in patients with T1D is highly dependent on the calculation method and then must be standardized.
GS-3583, a novel FLT3 agonist Fc fusion protein, to expand conventional dendritic cells in healthy volunteers.
Authors: Nishanthan Rajakumaraswamy, Anees Dauki, Michelle R. Kuhne, Torsten Trowe, Jing He, Christopher Clarke, Brian Carr, Angela Worth, Anshu Vashishtha, Christian Schwabe, Ahmed A. Othman
Journal: Journal of Clinical Oncology (2021)

2559 Background: Conventional dendritic cells subtype 1 (cDC1) play a vital role in the priming and expansion of tumor specific CD8+ T cells and their recruitment to tumor microenvironment (TME). However, cDC1s are often underrepresented in the TME. Systemic administration of Fms-like tyrosine kinase 3 ligand (FLT3L), a hematopoietic growth factor that binds to FLT3 on myeloid and lymphoid progenitor cells, leads to expansion of cDC1s in the periphery which can then be recruited into the TME. We hypothesize that FLT3 pathway stimulation using GS-3583, a FLT3 agonist Fc fusion protein, has the potential to promote T cell mediated anti-tumor activity. Methods: This was a first-in-human placebo-controlled study of GS-3583 in healthy volunteers to evaluate the safety, PK, and PD of escalating single doses (ranging from 75μg to 2000μg) of GS-3583. The study was blinded to the subjects and the investigator. Each dose cohort enrolled 8-12 healthy subjects who received GS-3583 or placebo as single IV infusion at 3:1 ratio. Subjects were observed in the phase 1 unit for 15 days and then for 12 weeks as outpatients. As part of the PD evaluation, we investigated the changes in the number of cDC1s and cDC subtype 2 (cDC2) cells. Results: As of 8 th Feb 2021, selected safety, PK and PD data from the first 3 cohorts were available. GS-3583 was well tolerated and all subjects had been discharged. To date, there have been no serious or grade 3 or higher adverse events. Preliminary PK analysis suggested dose-dependent increase in GS-3583 exposure (AUC and C max ). Preliminary PD analysis shows that administration of GS-3583 resulted in dose-dependent increases in cDC1/cDC2 cells that peaked at day 5 or day 8 and returned to baseline within three weeks of drug administration. Conclusions: GS-3583 was safe and well tolerated and induced dose dependent expansion of dendritic cells in the periphery. In patients with cancer, this increase in dendritic cells can be utilized to enhance anti-tumor responses to immuno-oncology therapies.[Table: see text]
Efficacy and toxicity of weekly paclitaxel, carboplatin, and cetuximab as induction chemotherapy or in cases of metastases or relapse for head and neck cancer in elderly or frail patients.
Authors: Rebecca Forman, Aarti K. Bhatia, Barbara Burtness
Journal: Journal of Clinical Oncology (2021)

6042 Background: Standard of care treatments for locally advanced and metastatic head and neck squamous cell carcinoma (HNSCC) are not well tolerated, particularly in elderly or frail patients. One combination that has been studied in recent years is paclitaxel, carboplatin and cetuximab (PCC). Studies have shown this regimen yields promising results when used as an induction chemotherapy for locally advanced disease. PCC has also been studied in patients with metastatic or recurrent incurable disease, and has shown good response with tolerable toxicity rates, but there is a relative dearth of evidence surrounding its use. Methods: This retrospective observational study utilized EMR data analysis software to generate the cohort of adult patients that received PCC for HNSCC in 2014-2019 as well as demographic data. Chart review was used to gather details about the patients’ tumors and clinical course. Modified RECIST response rates (MRRR), progression free survival (PFS) and overall survival (OS) were the primary end points calculated for the metastatic/recurrent group, and percentage of successful inductions (e.g., patients went on to definitive treatment, avoided surgery) and MRRR were used for the induction group. Results: There were 80 patients in the cohort. The average age was 65 (range 33-84) and the patients were 81% male. The most common tumor site was the tongue (25 patients), followed by tonsil (15), oropharynx (9), and larynx (7). 13 patients had p16 positive disease. Most patients had Stage IVA (36 patients), followed by IVB (20), and IVC (15); the remainder had stage III or below or unknown stage. The most common reasons patients did not receive cisplatin were performance status (13 patients), hearing loss (11), concern for nephrotoxicity (6) and age (5). 97.5% of patients experienced at least one adverse effect. The most common adverse effect was dermatologic (69%), followed by hematologic (51%), fatigue (41%) and gastrointestinal symptoms (41%). 53 patients (66%) experienced at least one dose interruption due to adverse effects. 11 patients (14%) stopped treatment due to toxicities. 58 patients received PCC for metastatic or recurrent disease. They had received a median of 1 line of systemic treatment prior; 72% had prior radiation, and 26% had prior salvage surgery. The MRRR was 22% (5 patients with complete response, 8 partial response, 15 stable, 27 progression). There was a 7.0 month mean PFS, and 17.3 month mean OS. Of the 22 patients who received PCC as induction, 86% (19) successfully reached their induction endpoint. The MRRR was 64% (8 patients with complete response, 6 partial response). Conclusions: PCC is a relatively well-tolerated combination with a very good induction success rate. More research is needed around alternate options for frail and elderly patients with HNSCC.
Functional recovery by colon organoid transplantation in a mouse model of radiation proctitis
Authors: JooHyun Jee, Jun-Hyeok Park, Jung Ho Im, Mi Sun Kim, Enoch Park, Taegyu Lim, Woo Hee Choi, Jee Hyun Kim, Woo Ram Kim, Ji Su Ko, Sang Yun Jeong, Seung Young Ko, Jung Il Lee, Kyung Jin Lee, Hyemi Jeon, Jae-Hwi Seo, Dong-Youn Hwang, Hyun Soo Shin, Jongman Yoo
Journal: Biomaterials (2021)
LDL receptor related protein 2 to promote colorectal cancer metastasis via enhancing GSK3β/β-catenin signaling.
Authors: Xiaobin Zheng, Huashan Liu, Xiaoli Zhong, Xuanhui Liu, Zerong Cai, Yufeng Chen, Xiaosheng He, Ping Lan, Xiaojian Wu
Journal: Journal of Clinical Oncology (2021)

e15507 Background: LDL receptor related protein 2 (LRP2), a multi-ligand endocytic receptor, has been implicated in the tumourigenesis of various human cancers. However, the biological roles and underlying regulatory mechanism of LRP2 in CRC remain unclear. Methods: Real-time PCR (RT-PCR), western blot, and immunohistochemistry were used to examine LRP2 expression. Gene silencing and overexpressing efficiencies of LRP2 were confirmed by RT-PCR and western blot. Then wound-healing, migration assay and invasion assay were used to investigate the function of LRP2 in CRC cells. The protein expression and cellular localization of LRP2 and β-catenin were characterized by immunofluorescence staining. The nude mice tail vein metastasis model was established to observe the effect of LRP2 on the lung metastasis of CRC cells in vivo. In addition, gene set enrichment analysis was carried out to explore the potential mechanism of LRP2 in CRC. Results: LRP2 expression was highly upregulated in CRC compared with matched adjacent normal tissue. LRP2 overexpression was positively correlated with shorter overall survival in CRC patients. The biological function observation indicated that LRP2 promoted CRC metastasis in vitro and in vivo. Further molecular mechanism investigation demonstrated that LRP2 protein interacted with glycogen synthase kinase-3β (GSK-3β) and led to decreased expression of GSK3β at ser9, followed by enhanced β-catenin signaling pathway in CRC cells. Conclusions: Our study demonstrated that LRP2 could enhance the metastatic abilities of CRC cells in vitro and in vivo by inhibiting the expression of GSK3β and enhancing the activity of β-catenin signaling pathway, providing that LRP2 might be a novel therapeutic target for metastasis in CRC.
ARTISTRY-1: Nemvaleukin alfa monotherapy and in combination with pembrolizumab in patients (pts) with advanced solid tumors.
Authors: Valentina Boni, Ira Seth Winer, Lucy Gilbert, Ulka N. Vaishampayan, Seth David Rosen, Jameel Muzaffar, Anna Spreafico, David F. McDermott, Quincy S. Chu, Olivier Dumas, Aman Chauhan, Arvind Chaudhry, Piotr Tomczak, MD, Debora S. Bruno, Yangchun Du, Ilda Bidollari, Jessicca Martin Rege, Marc S. Ernstoff, James F. Strauss, Vamsidhar Velcheti
Journal: Journal of Clinical Oncology (2021)

2513 Background: Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel, engineered cytokine that selectively binds the intermediate-affinity interleukin-2 (IL-2) receptor complex to preferentially activate CD8 + T cells and natural killer cells with minimal expansion of regulatory T cells, designed to leverage antitumor effects of the IL-2 pathway while mitigating potential toxicity that would limit use. Methods: ARTISTRY-1 (NCT02799095) is a phase 1/2 study. Parts A (dose escalation 0.1-10 µg/kg) and B (6 µg/kg [recommended phase 2 dose]) are monotherapy; pts receive intravenous nemvaleukin for 5 days every 14 or 21 days. In Part C, pts receive nemvaleukin (3 or 6 µg/kg) every 21 days in combination with pembrolizumab (200 mg on day 1). We present safety and antitumor activity (RECIST v1.1, iRECIST) data as of 12/02/2020. Results: In Part A, 39 pts received nemvaleukin. No dose-limiting toxicities were observed; maximum tolerated dose was not reached. Part B enrolled immune checkpoint inhibitor–pretreated pts into melanoma or renal cell carcinoma (RCC) cohorts. 18 pts with melanoma enrolled; 10 were evaluable, 2 (both with metastatic mucosal melanoma) achieved a partial response (PR; 1 unconfirmed). 24 pts with RCC enrolled; 1 of 16 evaluable pts achieved a PR (awaiting confirmation). 12 pts in each cohort continue on study. In Parts A and B, treatment-related adverse events in ≥40% included chills (74.4% and 52.4%, respectively) and pyrexia (74.4% and 47.6%, respectively). In Part C (83 evaluable pts), 12 objective responses (OR) were observed; an additional 5 pts had stable disease (SD) &gt;6 months (1 pt with breast cancer, 2 with ovarian cancer, and 2 with non-small-cell lung cancer). Nemvaleukin did not demonstrate any additive toxicity to that already established with pembrolizumab alone. OR data are summarized in the table. Conclusions: Nemvaleukin was generally well tolerated and demonstrated antitumor activity as monotherapy and in combination with pembrolizumab. Pharmacodynamic studies to identify biomarkers are ongoing. Future research of monotherapy and combination therapy with nemvaleukin is warranted. Clinical trial information: NCT02799095. [Table: see text]
Light-controllable charge-reversal nanoparticles with polyinosinic-polycytidylic acid for enhancing immunotherapy of triple negative breast cancer
Authors: Lei Fang, Zitong Zhao, Jue Wang, Ping Xiao, Xiangshi Sun, Yaping Ding, Pengcheng Zhang, Dangge Wang, Yaping Li
Journal: Acta Pharmaceutica Sinica B (2021)

Nucleic acid drugs are highly applicable for cancer immunotherapy with promising therapeutic effects, while targeting delivery of these drugs to disease lesions remains challenging. Cationic polymeric nanoparticles have paved the way for efficient delivery of nucleic acid drugs, and achieved stimuli-responsive disassembly in tumor microenvironment (TME). However, TME is highly heterogeneous between individuals, and most nanocarriers lack active-control over the release of loaded nucleic acid drugs, which will definitely reduce the therapeutic efficacy. Herein, we have developed a light-controllable charge-reversal nanoparticle (LCCN) with controlled release of polyinosinic-polycytidylic acid [Poly(I:C)] to treat triple negative breast cancer (TNBC) by enhanced photodynamic immunotherapy. The nanoparticles keep suitably positive charge for stable loading of Poly(I:C), while rapidly reverse to negative charge after near-infrared light irradiation to release Poly(I:C). LCCN-Poly(I:C) nanoparticles trigger effective phototoxicity and immunogenic cell death on 4T1 tumor cells, elevate antitumor immune responses and inhibit the growth of primary and abscopal 4T1 tumors in mice. The approach provides a promising strategy for controlled release of various nucleic acid-based immune modulators, which may enhance the efficacy of photodynamic immunotherapy against TNBC.
Rabphillin-3A-Like gene is a candidate tumor suppressor in colorectal adenocarcinoma
Authors: Venkat Katkoori, Xu Jia, Tom Callens, Sanjay Kumar, Selvarangan Ponnazhagan, Ludwine Messiaen, William Grizzle, Upender Manne
Journal: Cancer Research (2007)

3650  Background: The recently identified human ortholog of the Rabphillin-3A-Likegene (RPH3AL), located at the 17p13.3 locus, has been assessedfor molecular status and for its clinical significance in colorectal adenocarcinoma (CRC).  Methods: To determine the role of RPH3AL in CRC we screened 95 prospectively collected frozen CRCs andtheir matching control (benign epithelial) tissues for the mutational status of RPH3AL using the polymerase chain reaction (PCR) and direct sequencing methods. We assessed the loss of heterozygosity (LOH) at D17S643, DS17S849, D17S926 and D17S1866 loci in genomic DNA samples isolated from 53 CRCs and their matching controls. Also, the mRNA levels of this gene were measured by quantitative real-time-polymerase chain reaction (qRT-PCR) in 95 paired tissues. The LOH status of the RPH3AL gene was correlated with different clinicopathologic features and patient survival.  Results: The mutational analysis of RPH3AL has detected five novel missense mutations: at codons 67 (GTG > ATG; Val > Met) in 2 CRCs, at codon 175 (CCC > TCC; Pro > Ser) in 1 CRC, at codon 268 (GCC > GGC; Ala > Gly) in 1 CRC and at codon 290 (AGG > AAG; Arg > Lys) in 1 CRC, and a novel silent mutation at codon 98 (TGC> TGT; Cys > Cys) in 1 CRC. Additionally, 14 single nucleotide polymorphisms were identified: three at codon 49, nine at codon 62, and two at codon 303, in the coding region of the RPH3AL gene. Loss of heterozygosity was found in 26 of 44 (59%) informative cases demonstrating allelic loss in at least one of the four loci analyzed. The levels of mRNA expression were significantly reduced in CRCs (average copy number = 0.42, range 0.038-1.70) compared to their matching controls (average copy number=2.36, range 0.15-10.32) (χ2, P  Conclusions These preliminary findings suggest that the RPH3AL gene is a candidate tumor suppressor whose inactivation is involved in aggressiveness of colorectal adenocarcinoma.This work is supported partially by funds from the Departmentof Pathology, University of Alabama at Birmingham and by a grantfrom the National Institute of Health/National Cancer Institute(RO1-CA98932-01).
Fat Cell Size: Measurement Methods, Pathophysiological Origins, and Relationships With Metabolic Dysregulations
Authors: Run Zhou Ye, Gabriel Richard, Nicolas Gévry, André Tchernof, André C Carpentier
Journal: Endocrine Reviews (2021)

The obesity pandemic increasingly causes morbidity and mortality from type 2 diabetes, cardiovascular diseases and many other chronic diseases. Fat cell size (FCS) predicts numerous obesity-related complications such as lipid dysmetabolism, ectopic fat accumulation, insulin resistance, and cardiovascular disorders. Nevertheless, the scarcity of systematic literature reviews on this subject is compounded by the use of different methods by which FCS measurements are determined and reported. In this paper, we provide a systematic review of the current literature on the relationship between adipocyte hypertrophy and obesity-related glucose and lipid dysmetabolism, ectopic fat accumulation, and cardiovascular disorders. We also review the numerous mechanistic origins of adipocyte hypertrophy and its relationship with metabolic dysregulation, including changes in adipogenesis, cell senescence, collagen deposition, systemic inflammation, adipokine secretion, and energy balance. To quantify the effect of different FCS measurement methods, we performed statistical analyses across published data while controlling for body mass index, age, and sex.
원저 : 위정맥류 출혈에서 역행성 경정맥 위정맥류 폐색술의 임상적 유용성
Authors: 김은수, 박수영, 권기태, Dong-Seok Lee, 박민재, 정인권, 박진형, 조창민, Won Young Tak, 권영오, Sung Kook Kim, Yong-Hwan Choi, 성창규
Journal: Clinical and Molecular Hepatology (2003)

목적: 위정맥류 출혈에 대한 내시경적 치료는 식도 정맥류 출혈에 비해 효과적이지 못하며, TIPS 또한 간기능악화나 간성 뇌증의 유발로 치료 후 결과가 만족스럽지 못하다. 최근 BRTO가 위정맥류 출혈에서의 새로운 치료로 소개되고 있어 이의 임상적 유용성 및 합병증에 대하여 알아보고자 하였다. 대상과 방법: 2001년 9월에서 2003년 4월까지 위정맥류 출혈로 내원하여 BRTO를 시술한 13명의 환자를 대상으로 하였다. 위신정맥 단락을 통하여 경화제인 5% ethanolamine oleate을 위정맥류내로 주입하였고 측부 순환이 있는 경우는 색전술을 이용하여 폐쇄하였다. 위내시경 및 복부 전산화 단층 촬영으로 추적하였다. 결과: 12예에서 기술적 성공을 보였고 3개월 후 위내시경을 시행하였던 7명 모두에서 위정맥류의 소실 혹은 크기 감소 소견을 보였다. 평균 17.7개월 동안의 추적한 11명의 환자에서 위정맥류의 재출혈은 없었다. 시술을 실패한 경우는 TIPS를 시행하여 출혈을 조절할 수 있었다. 시술 전 간성 뇌증이 있었던 1예에서 시술 후 증세가 호전되었고 6예에서 추적 내시경상 식도 정맥류가 악화 혹은 새로이 발생하였다. 결론: BRTO는 위정맥류 출혈의 치료에 성공률이 높고 합병증은 적어, TIPS 및 내시경적 치료와 함께 위정맥류 출혈의 효과적인 치료 방법 중 하나로 기대되며 시술 후 기존 식도 정맥류의 악화나 새로운 식도 정맥류의 발생 가능성이 있으므로 시술 후 주기적인 내시경적 관찰이 필요할 것으로 사료된다.