tbuckley/cabot-search huggingface dataset:
Tumor mutational burden of microsatellite stable metastatic colorectal tumors by patient factors and KRAS, BRAF, and PIK3CA mutation status.
Authors: Jun Gong, Marvin Sy, Marwan Fakih
Journal: Journal of Clinical Oncology (2017)

627 Background: Microsatellite instability (MSI) can predict response to pembrolizumab in metastatic colorectal cancer (mCRC). Benefit to PD-1 blockade is limited in microsatellite stable (MSS) mCRC yet MSS tumors represent &gt;95% of all mCRC cases. Evidence suggests that high mutational load remains an important predictor of benefit to checkpoint inhibition across several tumors. We aimed to explore associations between tumor mutational burden (TMB) and various patient factors and mutations of interest to identify features of patients (pts) with MSS mCRC of potential significance to prognosis and PD-1 targeting. Methods: We conducted a retrospective study based on next-generation sequencing (NGS) of MSS metastatic colorectal tumors at our single institution using FoundationOne. TMB was categorized as high ≥ 20 mutations/megabase (Mb), intermediate 6-19 mutations/Mb, and low ≤ 5 mutations/Mb. TMB frequencies were analyzed according to age (≤50, &gt;50, &gt;65, and &gt;70 years old), gender, race, location of primary tumor, and KRAS, BRAF, and PIK3CA mutations. Results: Among 194 MSS tumors with available TMB data, frequencies of tumors with intermediate TMB were significantly different in pts ≤50 years (24.6%, n=69) than in pts &gt;65 (48.9%, n=47, Fisher’s exact (two-tailed) p=0.0096) and &gt;70 (53.1%, n=32, p=0.0067). Frequencies of tumors with low TMB were significantly different in pts ≤50 years (75.4%, n=69) than in pts &gt;65 (46.8%, n=47, p=0.0029) and &gt;70 (43.8%, n=32, p=0.0032). Frequencies of high TMB tumors by age were 0% (≤50 years), 1.6% (&gt;50), 4.3% (&gt;65), and 3.1% (&gt;70) and did not reach significance. Frequencies of high, intermediate, or low TMB tumors were not significantly different based on gender, race, and location of primary tumor. Frequencies of KRAS, BRAF, and PIK3CA mutations were similar across all TMB categories (p=0.7995, 0.8774, and 0.053, respectively). Conclusions: Older individuals with mCRC are less likely to have a low mutation burden by FoundationOne assay. Further validation of these findings in larger cohorts may indicate a potential higher likelihood for elderly colorectal cancer patients to benefit from immune-based strategies.
Adjuvant treatment in extreme elderly patients with colorectal cancer.
Authors: Marta Llopis Cuquerella, Maria del Carmen Ors Castaño, María Ballester Espinosa, Alejandra Magdaleno Cremades, Vicente Boix Aracil, María del Rocío Ramirez Belloch, Roberto Morales Giménez, Lucía Gómez González, Elena Asensio Martinez, Juan Carlos Navalón Coronado, Jose Manuel Navarro Rodriguez, Edelmira Soliveres Soliveres, Miguel Ángel Morcillo Ródenas, Javier Gallego Plazas
Journal: Journal of Clinical Oncology (2017)

784 Background: Surgical and adjuvant treatment in extreme elderly ( &gt; 80 years) patients with localized colorectal cancer is an unresolved issue. Owing to the lack of available neither clinical practice nor investigational data in this field we present our experience in this scenario. Methods: We retrospectively reviewed data regarding surgical and complementary treatment for colorectal cancer patients aged more than 80 consecutively attended by General Surgery Department in Vega Baja Hospital between 2008 and 2013. Results: A total number of 115 colorectal cancer patients were registered. 95 patients diagnosed of localized disease were selected for analysis. Colon vs rectal cancer ratio was 4:1. Median age was 83.6 years (80-94). Male sex was predominant (60 patients, 63.2%). Emergency surgery was performed in 15 patients (15.8%). Complementary treatment to surgery was advised, according to international guidelines, in 53 patients (55.8%). 10 patients (18.9%) with an advise of adjuvant treatment finally received it. More patients with rectal cancer received recommended treatment (41.7% rectal vs 12.2% colon cancer). Patients with stage III disease were more frequently finally treated according to guidelines (22.2 % stage III vs 11.8% stage II). More patients with stage II rectal cancer were advised and received treatment (recommendation: 66.7% rectal vs 36.1% colon cancer; administration: 25% rectal vs 7.7% colon cancer). Treatment was also more frequently administered to stage III rectal cancer (50% rectal vs 14.3% rectal cancer) (Table). Conclusions: Our experience in localized colorectal cancer in extreme elderly patients ( &gt; 80 years) showed that, although advised according to guidelines, most of them did not receive adjuvant treatment to surgery. Complementary treatment administration was more common in rectal cancer patients and with more advanced disease. [Table: see text]
Association between pioglitazone (PZD) therapy and bladder cancer (BC): A meta-analysis of epidemiologic evidence.
Authors: Alexei Shimanovsky, Juliet Appiah, Basile M. Njei, Jessica Mary Clement
Journal: Journal of Clinical Oncology (2013)

4546 Background: There is evidence suggesting that PZD use may be a risk factor for BC, yet these reports are controversial. The aim of this meta-analysis is to review available data and evaluate the association between PZD and BC. Methods: Two independent reviewers conducted a systematic search of the Cochrane Library, OvidSP and PubMed for articles published January 1970 to April 2012. MeSH search terms included PZD, Actos, thiazolidinediones, diabetes mellitus (DM), and BC. Only studies reporting an effect measure for the association between PZD and BC were included. Subgroup analyses by study design and country were performed. Analysis was done using a random effect model after a preliminary review showed evidence of study heterogeneity. This was then assessed using the Cochrane’s Q and I2 statistics. Publication bias was evaluated using the Begg’s and Egger’s tests, and funnel plots. All analyses were performed using REVMAN 5.1. Results: A total of 6 studies (3 cohort and 3 case control) met the inclusion criteria. The overall pooled risk ratio (RR) for the association between PZD and BC was 1.12 (95% CI 1.09, 1.15; P &lt;0.001). The summary RR for cohort and case control studies were 1.13(95% CI 1.07, 1.19; P &lt;0.001) and 1.11(95% CI 1.07, 1.15; P &lt;0.001), respectively. The subgroup analysis showed a significant association with BC in the USA and Europe, but not in Asia (RR 0.98, 95% CI 0.71, 1.34; P = 0.88). The association of PZD and BC was more sensitive for treatment duration (&gt;12 month). Conclusions: Our study analyzed 1,214,071 patients, demonstrating a weak association between PZD and BC. The results were significant with increase in treatment duration, which corresponds to previous studies. This meta-analysis has limitations. Not all studies reported known variables associated with BC, such as smoking or occupational exposure. They did not address patient BMI, time from DM diagnosis or previous drug therapy. These parameters reflect severity of disease and level of insulin-resistance. Future studies should evaluate markers of insulin-resistance with PZD use and correlate with BC. Understanding the link between PZD and BC in the context of DM may allow physicians to determine a more accurate risk of PZD use.
Analysis of survival with modified docetaxel, cisplatin, fluorouracil (mDCF), and bevacizumab (BEV) in patients with metastatic gastroesophageal (GE) adenocarcinoma: Results of a phase II clinical trial
Authors: D. Kelsen, M. Jhawer, D. Ilson, A. Tse, J. Randazzo, E. Robinson, M. Capanu, M. A. Shah
Journal: Journal of Clinical Oncology (2009)

4512 Background: Metastatic GE cancer is an aggressive disease with poor patient (pt) outcomes. Despite response rates of 30–60% to combination chemotherapy, response duration is usually 4–6 mo and 24-mo survival is 5–10%. The addition of BEV to chemotherapy has improved survival in several solid tumors, and has demonstrated encouraging activity in GE cancer (Shah et al, JCO 2006). We report mature tolerability and efficacy results of mDCF+BEV in GE cancer, with an emphasis on prolonged pt survival. Methods: Previously untreated metastatic GE pts with adequate end organ function received BEV 10mg/kg, Docetaxel 40mg/m2, FU 400mg/m2, Leucovorin 400mg/m2 on day 1, FU 1000 mg/m2/day x 2 days IVCI, and Cisplatin 40mg/m2 on day 3. Treatment is repeated every 14 days without prophylactic growth factor support. The primary objective is to improve 6-month progression free survival (PFS) from 43% (historical DCF control) to 63% with the addition of BEV. Target accrual is 44 evaluable pts, with 10% type I &amp; II error. Secondary objectives include tolerability, response rates (RECIST), median PFS, 12-mo survival, and overall survival (OS). Results: Pt enrollment has completed: median age 57(range 29–74), median KPS 80% (70–100), M:F 32:12, gastric/GEJ/esophagus 22:17:5. In 39 patients with measurable disease we observed 26 confirmed partial responses (67%, 95% CI 50%- 81%), and 12 (31%) stable disease. Six-month PFS is 79% (95% CI 68%-93%), the median PFS is 12 mo (95% CI: 8.8–16). At median follow up of 12.3 mo, median OS is 16.2 mo (95%CI 11.4-infinitiy). 12- and 18-mo OS is 63% (95%CI 44–77%) and 46% (95%CI 27–63%), respectively. Minimal chemotherapy related grade 3–4 adverse events were observed: fatigue (20%), dehydration (13%), mucositis (9%), nausea/vomiting (7%), febrile neutropenia (4%). BEV related adverse event was perforation (n=1) and bleeding (n=1). 31% developed grade 3–4 venous thromboembolism, of which 93% were asymptomatic. No grade 3–4 hypertension, proteinuria or arterial thrombosis was observed. Conclusions: mDCF+BEV appears tolerable and has notable long term pt outcomes: 6-mo PFS is 79% (surpassing our efficacy endpoint), median OS 16.2 mo, and 18-mo OS 46%. No significant financial relationships to disclose.
Abstract P027: Preconditioning Cardiosphere-Derived Cells by Hypoxia and Prolyl Hydroxylase Inhibitors to Induce HIF-Related Metabolic Changes and C-Kit Expression
Authors: Suat Cheng Tan, Carolyn A Carr, Kar Kheng Yeoh, Lisa C Heather, Lucy Ambrose, Chris Schofield, Kieran Clarke
Journal: Circulation Research (2011)

Cardiosphere-derived cells (CDCs) decrease loss of cardiac function following infarction, but the potential of CDC therapy is limited due to the low retention rate and the time required to obtain sufficient cells for transplantation. AIM: Here, we aimed to precondition CDCs by culturing under hypoxia, or with prolyl hydroxylase inhibitors (PHIs), to prepare the cells for the hypoxic environment within the infarcted heart. METHODS: Rat heart explants were cultured under hypoxia (2% O2) or normoxia (21% O2) to generate explant-derived cells (EDC). EDCs were isolated, cultured to form cardiosphere and expanded into monolayer CDCs. At 80% confluency, normoxic CDCs were treated with dimethyloxalyl glycine (DMOG), Ethyl 2-(2,3-dihyroxybenzamido) (KKC226) and FG-2216 for 24 h. RESULTS: Hypoxia, 1 mM DMOG, 0.5 mM KKC226 and 30 μM FG-2216 treated CDCs showed significantly increased HIF-1α protein expression (3.9-fold, 2.6-fold, 2.1-fold and 1.5-fold, respectively) and reduced oxygen consumption (81%, 32%, 47% and 35%, respectively), compared with normoxic CDCs. Hypoxia and PHI treatment increased protein levels of GLUT-1 (6.7-fold, 3.2-fold, 4.0-fold and 2.1-fold, respectively), resulting in significant increases in glucose uptake and lactate accumulation in the culture medium, compared with controls, commensurate with increased glycolytic metabolism after hypoxia or PHI treatment. Further, hypoxia and KKC226 increased c-Kit mRNA expression 5.1-fold and 1.5-fold, respectively. qRT-PCR confirmed increased CXCR-4 mRNA in all hypoxia and PHI-treated CDCs. EDC and CDC proliferation were 1.7-fold faster under hypoxia, compared with normoxia, but did not increase with PHI treatment. CONCLUSION: Hypoxia and PHIs stabilized and activated HIF, which induced metabolic changes in CDCs, including GLUT-1 upregulation and a switch to anaerobic glycolytic metabolism. All preconditioned cells had reduced oxygen consumption and were better adapted to survive within an hypoxic infarct scar. HIF-induced upregulation of CXCR-4 may increase the homing of these cells to the infarcted myocardium. Finally, increased proliferation and expression of the cardiac stem cell marker, c-Kit, could decrease the time required for cell expansion prior to therapy by a week.
포스터전시 : 만성 B형간염에서 알코올과 비만이 엔테카비어나 클레부딘의 치료 효과에 미치는 영향
Authors: 김태선, 박정호, 박동일, 김홍주, 조용균, 손정일, 전우규, 김병익
Journal: Clinical and Molecular Hepatology (2009)
An evaluation of the knowledge, attitudes and beliefs of oncologists’ regarding fertility preservation: A survey of Midwest area oncologists.
Authors: Frances W Grimstad, Anup Kasi, Sarah A. Taylor, Catherine L Satterwhite, Samuel S Kim
Journal: Journal of Clinical Oncology (2015)

e17662 Background: Fertility preservation (FP) is a growing quality of life issue in the world of oncology as the number of young long-term cancer survivors increase. In 2008, the Centers for Disease Control and Prevention put out a call to action to strengthen national efforts to address infertility, specifically in cancer survivors, and recognized the need for FP in this group. The ASCO also recommends that oncologists address infertility with their patients before cancer therapy and be prepared to discuss FP and referral options. Methods: In December 2014, a 42-item anonymous survey was administered to determine the knowledge, attitudes, and practices of oncologists in a Midwest community regarding FP with the goal of identifying gaps in education within our region. Results: The survey had 41 respondents. Fifteen percent practiced in Missouri, 68% in Kansas and 17% in both. Eighty-eight percent practiced in an urban setting. Their practices were roughly 50/50 male/female patients, and 51% saw greater than 40 patients per week. There was overwhelming understanding (90%) that the majority of young women, without children at the time of cancer diagnosis, desired future fertility, and 98% of physicians agreed that banking sperm can have a positive impact on male patients coping with cancer, even if the samples are never used. Seventeen percent were aware this can be done after initiation of chemotherapy. Forty-nine percent of respondents felt they lacked adequate knowledge about FP. Fifty-four percent felt it difficult to find the proper facilities and specialists for FP. Twenty-nine percent had a navigator program for their cancer patients that included discussing FP. Conclusions: Most oncologists in this survey acknowledge the importance of FP, but many lack knowledge, access or a combination of both to help their patients. (We will provide further details of the knowledge deficits present in this group in our presentation.) Hence, future endeavors should include development of educational tools for our oncology providers, (and patients), with the aim to improve FP counseling and referrals in our cancer population.
Long-term complications after staging laparotomy for Hodgkin lymphoma.
Authors: Beth A Rymeski, Karen Cristly Burns, Rajaram Nagarajan, Judy Correll, Debra A. Kent, Maureen Megan O'Brien, John Peter Perentesis, Roshni Dasgupta
Journal: Journal of Clinical Oncology (2012)

e20007 Background: There are over 164,000 long-term survivors of Hodgkin lymphoma in the US. Awareness of the potential for preventable high risk late complications is critical for avoiding early mortality and insuring quality of life. We sought to identify key late complications in patients who had undergone staging laparotomy Methods: Retrospective review of hospital records and database of cancer survivors at our institution. Results: 95 patients with HL were identified; of these 24 patients with HL underwent staging laparotomy from 1971-1994. 18 patients had complete data available with median age at diagnosis of 13.7 years and median follow-up of 27.9 years. 16 patients underwent splenectomy, 12 patients received chemotherapy and 17 received XRT. Six patients (33%) had findings of intra-abdominal disease on laparotomy. Three patients (17%) required four repeat laparotomies for bowel obstruction more than 10 years after staging laparotomy. Of the 3 patients requiring repeat laparotomy for bowel obstruction, one had radiation to the inguinal region, one had mantle radiation (patient with 2 bowel obstructions requiring laparotomy and lysis of adhesions), and one had unknown radiation therapy history. In contrast, there were no cases of bowel obstruction in the other 71 patients who did not receive initial staging laparotomy. There were no documented cases of post-splenectomy sepsis and all post splenectomy patients received some prophylactic antibiotics. Conclusions: This is the first study to examine long term complications after staging laparotomy in a longitudinal cohort of survivors of HL. In long term follow-up, patients who underwent staging laparotomy for HL appear to have an increased incidence of repeat laparotomy, 3-4 fold higher than the expected rate of post laparotomy bowel obstruction incidence in the literature. Otherwise, the long term outcome of splenectomy in these patients appears to be very good with no episodes of post splenectomy sepsis, These findings underscore the importance of a high index of suspicion for bowel obstruction and related complications in HL survivors who had previous abdominal operative procedures. This work also underscores the importance of long term follow-up and screening in this population.
A retrospective analysis of upfront tandem autologous stem cell transplantation (ASCT) for high-risk (HR) myeloma (MM) patients (Pts).
Authors: Sara Farshchi Zarabi, Gurdeep Parmar, Esther Masih-Khan, Sophia Farooki, Christine Chen, Vishal Kukreti, Anca Prica, Rodger Tiedemann, Suzanne Trudel, Donna Ellen Reece
Journal: Journal of Clinical Oncology (2015)

e19532 Background: Previously, the median progression-free survival (PFS) and overall survival (OS) of MM pts with HR cytogenetics by FISH was ~9 mos and ~18 mos, respectively, after single ASCT (Chang H, Bone Marrow Transplant 2005; 36: 793). Since then, novel agents have been integrated before (often bortezomib [BTZ]) and after (often lenalidomide [len]) ASCT. We also offered upfront tandem ASCT for HR pts, and now retrospectively review the results of this approach. Methods: After IRB approval, HR pts who underwent upfront planned tandem ASCT were identified using the Princess Margaret Myeloma Database. Retrospective chart review was used to update pt outcomes. Results: Between 06/05 and 02/14, 38 HR pts underwent tandem ASCT at Princess Margaret Cancer Centre. 23 had del 17p, 17 had t(4;14), 4 had t(14;16), 3 had both t(4;14) + del 17p and 3 had both t(14;16) + del 17p. Median age was 56.5 yrs (range 31-71); 26 were male. ISS stage was I in 8, II in 14, III in 10 and N/A in 6 pts. Induction therapy was BTZ-based in 31 (CyBorD in 28); 9 pts required a 2nd regimen before ASCT. The median time from diagnosis to 1st ASCT was 6.3 mos (range 4.7 -27.9). The median time between transplants was 3.5 mos (range 1.0- 6.3); 16 pts received len between ASCTs to prevent early relapse. After the 2ndASCT, maintenance included thalidomide in 7, len +/- steroids in 25 and BTZ +/- len in 4 pts. No transplant-related deaths occurred. The PFS of the 4 pts with t(14;16) alone was 3.4+, 5, 14.6 and 19.2+ mos. Following progression after ASCT, the median survival of all 38 pts was 7.4 mos. Conclusions: 1) Although some pts experienced prolonged benefit, the median PFS and OS of pts with HR cytogenetics, particularly t(4;14), remains suboptimal even in the era of novel agents and tandem ASCT; 2) further analysis to identify pts who may benefit from tandem ASCT is underway. HR Group # Calculated from diagnosis Calculated from 2nd ASCT Median PFS, mos (range) Median OS, mos (range) Median PFS, mos (range) Median OS, mos (range) All 38 22.3 (9.0-77.4) 32.6 (11.9-105.2) 11.25 (1.26-63.6) 20.9 (3.8-94) t(4;14) 17 19.9 (13.2-47.2) 27.2 (17.9-84.3) 9.4 (3.2-23.4) 17.2 (6.9-73.6) Del 17p 23 24.3 (9.1-77.4) 34.7 (11.9-105.2) 12.5 (1.26-63.6) 25.3 (3.8-94)
VEGFR3 Modulates Vascular Permeability by Controlling VEGF/VEGFR2 Signaling
Authors: Krista Heinolainen, Sinem Karaman, Gabriela D’Amico, Tuomas Tammela, Raija Sormunen, Lauri Eklund, Kari Alitalo, Georgia Zarkada
Journal: Circulation Research (2017)

Vascular endothelial growth factor (VEGF) is the main driver of angiogenesis and vascular permeability via VEGF receptor 2 (VEGFR2), whereas lymphangiogenesis signals are transduced by VEGFC/D via VEGFR3. VEGFR3 also regulates sprouting angiogenesis and blood vessel growth, but to what extent VEGFR3 signaling controls blood vessel permeability remains unknown.To investigate the role of VEGFR3 in the regulation of VEGF-induced vascular permeability.Long-term global Vegfr3 gene deletion in adult mice resulted in increased fibrinogen deposition in lungs and kidneys, indicating enhanced vascular leakage at the steady state. Short-term deletion of Vegfr3 in blood vascular endothelial cells increased baseline leakage in various tissues, as well as in tumors, and exacerbated vascular permeability in response to VEGF, administered via intradermal adenoviral delivery or through systemic injection of recombinant protein. VEGFR3 gene silencing upregulated VEGFR2 protein levels and phosphorylation in cultured endothelial cells. Consistent with elevated VEGFR2 activity, vascular endothelial cadherin showed reduced localization at endothelial cell-cell junctions in postnatal retinas after Vegfr3 deletion, or after VEGFR3 silencing in cultured endothelial cells. Furthermore, concurrent deletion of Vegfr2 prevented VEGF-induced excessive vascular leakage in mice lacking Vegfr3.VEGFR3 limits VEGFR2 expression and VEGF/VEGFR2 pathway activity in quiescent and angiogenic blood vascular endothelial cells, thereby preventing excessive vascular permeability.