tbuckley/cabot-search huggingface dataset:
Impact of timing of lung resection on survival for clinical stage I and II lung cancer.
Authors: Isabel M Emmerick, Maggie M Powers, Melinda C Aldrich, Feiran Lou, Poliana Lin, Mark Maxfield, Karl Uy
Journal: Journal of Clinical Oncology (2019)

6598 Background: Lung cancer has the highest mortality among the leading cancers in the U.S. Surgical resection is considered as the most effective treatment for lung cancer in early stages, providing greater long-term survival. Clinical guidelines on delays in resection of early-stage lung cancer do not exist. This work aims to assess whether increasing time between diagnosis/first doctor visit and surgery for early stage non-small cell lung cancer (NSCLC) is associated with poorer survival. Methods: We identified a retrospective cohort of incident lung cancer cases who had surgical treatment for lung cancer at our institution between January 2009 and December 2017, and no prior radiation or chemotherapy. We assessed overall survival (OS) and predictors included a) time from first contact to surgery; and b) time from diagnosis to surgery. The association between time from diagnosis and time from first contact to surgery, and survival for patients with early stage NSCLC was assessed using multivariable Cox proportional hazard. We investigated four cut-off points: surgery within 15 days, 30 days, 60 days and 90 days. We controlled for sociodemographic characteristics as well as clinical outcomes. Results: Our cohort comprised 491 patients. The age average was 66.9 years, 61% female, 94.7% white, and 9% never smoked. Clinical Stage 1A and 1B corresponded to 86.5% of patients while in pathological stage it was 76%. The 5-year overall survival was 56.0%. Surgery occurred a median 40 days after the diagnosis and 43 days after the first visit and within 35 days if the first appointment was with a thoracic surgeon. The threshold time associated with statistically significant worse survival was 60 days after diagnosis. Surgery was performed more than 60 days of diagnosis in 115 (25.7%) patients, their OS was significantly worse than patients who had surgery earlier (HR=1.7 [95% CI: 1.1-2.6]). Conclusions: Greater intervals between diagnosis of early-stage NSCLC and surgery are associated with worse survival. Efforts to minimize delays, particularly factors that prolong the period from diagnosis to first contact with a lung cancer provider may improve survival. [Table: see text]
Final results of the TALENT trial (GETNE1509): a prospective multicohort phase II study of lenvatinib in patients (pts) with G1/G2 advanced pancreatic (panNETs) and gastrointestinal (giNETs) neuroendocrine tumors (NETs).
Authors: Jaume Capdevila, Nicola Fazio, Carlos Lopez Lopez, Alex Teule, Juan W. Valle, Salvatore Tafuto, Ana B. Custodio, Nicholas Reed, Markus Raderer, Enrique Grande, Rocio Garcia-Carbonero, Paula Jiménez-Fonseca, Vicente Alonso, Lorenzo Antonuzzo, Andrea Spallanzani, Alfredo Berruti, Isabel Sevilla, Adelaida La Casta Munoa, Jorge Hernando-Cubero, Toni Ibrahim
Journal: Journal of Clinical Oncology (2019)

4106 Background: Approved systemic therapies for advanced NETs have showed limited tumor shrinkage and no data of activity after progression to prior targeted agents (TA) is available. Lenvatinib, a potent VEGFR1-3 &amp; FGFR1-4 inhibitor may increase efficacy and revert primary and acquired resistance to TA. We report the final results of the TALENT trial. Methods: Two independent cohorts were included: panNETs and giNETs. All pts had baseline documented progression disease (PD) by RECIST. For panNETs, PD to TA was mandatory, regardless of prior therapy with somatostatin analogs (SSAs) or chemotherapy (CHT); and for giNETs, PD on SSAs. Pts were treated with lenvatinib at 24 mg qd until PD or intolerable toxicity. The primary endpoint was overall response rate (ORR) by central radiology review. Progression-free (PFS) and overall survival (OS) were assessed by investigator. With 55 pts per arm, our study was powered to identify an ORR ≥25% (90% power, 5% α-error). Results: We recruited 111 pts: 55 panNETs and 56 giNETs (78% from small intestine). Prior therapies were CHT 32%, SSAs 87%, everolimus 70% and sunitinib 30% for panNETs. ORR was 29%, 42.3% for panNETs and 16.3% for giNETs. With a median follow-up of 19 m, PFS and OS for panNETs were 15.5 m (95% CI 11.3-not reached (NR)) and 29.2 m (95% CI 23.2-NR); and 15.4 m (95% CI 11.5-19.4) and NR for giNETs, respectively. Pts who obtained a response by RECIST had a significantly better PFS compared with non-responders (NR vs 11.2 m in panNETs (p=0.004); 37.2 m vs 14.9 m in giNETs (p=0.005). In the subgroup analyses, all pts obtained the same benefit in PFS and ORR, including tumor grade, prior therapies, hormone release, primary location and tumor burden. The most frequent G3/4 adverse events were hypertension (22%), fatigue (11%) and diarrhea (11%). Dose reductions/interruptions were needed in 91.8% with a median dose of 20 mg qd. Conclusions: To our knowledge, we report the highest ORR by central radiology assessment with a TA in this setting. Lenvatinib showed a promising PFS and OS in a pretreated population with benefit across subgroups. Further development in advanced NETs is warranted. Clinical trial information: NCT02678780.
AB1166 SUBCLINICAL ENTHESEAL INVOLVEMENT IN LOWER LIMBS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS: AN ULTRASOUND STUDY
Authors: Mohamed Omar, Mohamed Abdelkareem, Mohammed Moneer, Mohamed Elwan
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Diabetes mellitus (DM) is a group of metabolic diseases characterized by hyperglycemia, which results from defects in insulin secretion, insulin action, or both (1). DM impacts the connective tissue and causes various changes in peri-articular and articular structures.An increase in enthesopathic complications in diabetic patients such as patellar tendinitis bursitis, achilles tendinopathy and plantar fasciitis, was observed In many studies. <h3>Objectives</h3> This study aims to detect subclinical lower limb enthesitis in type 2 DM by musculoskeletal ultrasonography &amp; its relation to poor glycemic control &amp; disease duration <h3>Methods</h3> This study was carried out on 80 persons. Diabatic group forty patients diagnosed as diabetes according to ADA diagnostic criteria. Control group Forty apparent healthy volunteers both groups was matched at age and sex.Sonographic evaluations and scoring were performed according to Glasgow Ultrasound Enthesitis Scoring System(GUESS) on the enthses of both lower limbs. <h3>Results</h3> At the diabetic group the Musculoskeletal Ultrasound findings was as following. The Quariceps tendon enthesitis in 30 patients (75%), proximal patellar enthesitis was in 28 patients (70%), Distal patellar enthesitis in 22 patients (55%), Achilles enthesitis in 27 patients (67.5) &amp; planter aponeurosis enthesitis in 25 patients (55%).There is a statistically significant difference between age and Ultrasound findings p. value &lt;0.05.There is a statistically significant correlation between disease duration and (proximal patellar ligament,Achilles tendon, quadriceps tendon and plantar fascia) thickness p. value&lt;0.05. <h3>Conclusion</h3> Entheseal abnormalities can be documented by ultrasonography in clinically asymptomatic patients with Diabetes. These findings could be related to a subclinical entheseal inflammation. <h3>References</h3> [1] Okur SC, YaseminPekinDogan, Murat Mert, OzgeAksu, OzerBurnaz, Nil SayinerCaglar(2017): Ultrasonographic Evaluation of Lower Extremity Entheseal Sites in Diabetic Patients Using Glasgow Ultrasound Enthesitis Scoring System Score, Journal of Medical Ultrasound (2017), http://dx.doi.org/10.1016/j.jmu..03.011 [2] SMITH, L., BURNET, S. &amp; MCNEIL, J. (2003): Musculoskeletal manifestations of diabetes mellitus. British journal of sports medicine, 37, 30-35. <h3>Disclosure of Interests</h3> None declared
Integrating Stimuli-Responsive Properties in Host-Guest Supramolecular Drug Delivery Systems
Authors: Adam S. Braegelman, Matthew J. Webber
Journal: Theranostics (2019)

Host-guest motifs are likely the most recognizable manifestation of supramolecular chemistry.These complexes are characterized by the organization of small molecules on the basis of preferential association of a guest within the portal of a host.In the context of their therapeutic use, the primary application of these complexes has been as excipients which enhance the solubility or improve the stability of drug formulations, primarily in a vial.However, there may be opportunities to go significantly beyond such a role and leverage key features of the affinity, specificity, and dynamics of the interaction itself toward "smarter" therapeutic designs.One approach in this regard would seek stimuli-responsive host-guest recognition, wherein a complex forms in a manner that is sensitive to, or can be governed by, externally applied triggers, disease-specific proteins and analytes, or the presence of a competing guest.This review will highlight the general and phenomenological design considerations governing host-guest recognition and the specific types of chemistry which have been used and are available for different applications.Finally, a discussion of the molecular engineering and design approaches which enable sensitivity to a variety of different stimuli are highlighted.Ultimately, these molecular-scale approaches offer an assortment of new chemistry and material design tools toward improving precision in drug delivery.
Retrospective analysis of the safety and efficacy of immune checkpoint inhibitors (CPI) among patients (pts) with pre-existing autoimmune disorders (AD) and renal cell carcinoma (RCC) or urothelial carcinoma (UC).
Authors: Nieves Martinez Chanza, Wanling Xie, Majd Issa, Hannah Elizabeth Dzimitrowicz, Abhishek Tripathi, Benoit Beuselinck, Elaine Tat Lam, Yousef Zakharia, Rana R. McKay, Sumit Shah, Amir Mortazavi, Michael Roger Harrison, Toni K. Choueiri, Lauren Christine Harshman
Journal: Journal of Clinical Oncology (2019)

4571 Background: RCC and UC pts with clinically significant AD were generally excluded from CPI trials due to potential AD exacerbation. Thus, the safety and clinical activity of CPI in AD pts are not well characterized. Methods: We retrospectively collected data from RCC and UC pts with AD treated with CPI at 9 centers. Adverse events (AEs) were assessed using CTCAEv5 criteria. Objective response rate (ORR) was assessed by RECIST principles. Overall survival (OS) was estimated by Kaplan Meier. Results: Of 103 pts (57 RCC &amp; 46 UC) with a broad spectrum of AD such as psoriasis (22%), thyroiditis (20%), rheumatoid arthritis (13%), polymyalgia rheumatica (8%), inflammatory bowel disease (6%), multiple sclerosis (3%) and lupus (3%), most received CPI as 1 st or 2 nd line (77% RCC, 93% UC) and anti-PD-1/L1 monotherapy (65% RCC, 98% UC). At CPI start, 36 had clinically active AD (all grade 1-2) and 4(11%) requiring systemic immunosuppression. AD exacerbations occurred in 37% (n = 38); most frequent: arthritis (12% RCC, 24% UC), rash (11% RCC, 9% UC). New onset immune related (ir) AEs occurred in 36% (n = 37); most frequent: colitis (12% RCC, 4% UC), rash (11% RCC, 9% UC), hypothyroid (each 7%), nephritis (7% UC). Table details timing and management. Median followup was 12.5 (1-52) mos for RCC and 14.5 (1-53) mos for UC. Median time on CPI was 6 mos (1-36) RCC and 4 mos (0.5-40) UC. At data cutoff, 39 RCC &amp; 36 UC had discontinued CPI; 16% for toxicity. ORR was 31% for RCC and 35% for UC. 1 yr-OS rate was 74% (95%CI 58-84) for RCC and 60% (95%CI 43-74) for UC. Conclusions: AD exacerbations or new irAEs occurred in 37% and 36% respectively and were generally manageable. Only a minority required CPI cessation due to toxicity. [Table: see text]
Timeliness of treatment for patients referred urgently with a high suspicion of cancer in New Zealand.
Authors: Rob McNeill
Journal: Journal of Clinical Oncology (2019)

e18147 Background: Delays in diagnosis and treatment have the potential to impact negatively on clinical outcomes for cancer patients. Guidelines for timeliness have been established for many cancer types and national targets have been established in some countries. At the end of 2014 New Zealand introduced a target for patients referred urgently with a high suspicion of cancer, aiming to have 90% of patients from referral to first treatment within 62 days. Methods: Timeliness data from 13,865 patients who were referred for their first specialist appointment in the years 2015-7 were obtained from the Ministry of Health. Z-tests for proportions were used to compare target performance across the time period. Cox regression was used to establish whether age, gender, and ethnicity were associated with timeliness. Results: The proportion of patients meeting the 62 day target increased significantly from 2015 (72.7%, 95%CI: 71.3-74.0; Median: 46 days) to 2016 (80.2%, 95%CI: 79.0-81.3; Median 43 days), but was not significantly higher in 2017 (80.7%, 95%CI: 79.6-81.8; Median 41 days). The Cox regression found that males (HR 0.965; 95% CI, 0.9330.999) and older people (HR 0.996; 95% CI, 0.9950.998) at a small but significantly higher risk of longer times to treatment. Much larger differences in risk of delay were found for Maori (HR 0.789; 95% CI, 0.7480.832), Pacific (HR 0.754; 95% CI, 0.6920.822) and Asian (HR 0.885; 95% CI, 0.8160.960), compared to European/Other ethnic group patients. Conclusions: This research has produced evidence that the introduction of the 62 day target was associated with a significant improvement in timeliness of treatment for this subgroup of patients. The results also highlight the large ethnic disparities in timeliness that exist both in New Zealand and in other countries. These are also reflected in ethnic disparities in outcomes across many cancer types. Further policy, system and practice changes are necessary to try to reduce these.
NRG Oncology CC003: A randomized phase II/III trial of prophylactic cranial irradiation with or without hippocampal avoidance for small cell lung cancer.
Authors: Vinai Gondi, Stephanie L Pugh, Minesh P. Mehta, Wolfgang Tome, Tammie Benzinger, Joseph A Bovi, Benjamin W. Corn, Shannon E. Fogh, Cliff Grant Robinson, Jeffrey Scott Wefel, Lisa A. Kachnic
Journal: Journal of Clinical Oncology (2019)

TPS8578 Background: Multiple clinical trials have shown that prophylactic cranial irradiation (PCI) prevents brain metastases and may prolong survival in small cell lung cancer (SCLC). However,prophylactic cranial irradiation can lead to decline in cognitive function. Preclinical evidence suggests that the pathogenesis of this toxicity includes inflammatory injury to proliferating neuronal progenitor cells in the peri-hippocampal stem cell niches. We hypothesized that conformal avoidance of the hippocampal neural stem cell compartment during brain irradiation using intensity-modulated radiotherapy (IMRT) would decrease the likelihood and/or severity of this toxicity. This hypothesis was recently validated by positive results from NRG Oncology CC001, a phase III trial of hippocampal avoidance during whole-brain radiotherapy for patients with brain metastases. NRG Oncology CC003 is an ongoing randomized phase II/III trial of hippocampal avoidance during prophylactic cranial irradiation (HA-PCI) for small cell lung cancer, conducted in parallel with NRG Oncology CC001. Methods: The primary endpoints of the phase IIR and III components are 12-month intracranial relapse rate and 6-month deterioration in Hopkins Verbal Learning Test-Revised (HVLT-R) Delayed Recall, respectively. This is a seamless phase IIR/III trial, with the phase IIR designed to demonstrate non-inferiority. If the non-inferiority margin of the phase IIR component is not exceeded, then the trial would transition to the phase III component. Following accrual of 182 of planned 172 patients on the phase IIR component, the trial closed to accrual on 10/13/17 to assess the phase IIR primary endpoint. The DSMB evaluated the IIR outcomes, and on 1/9/19, the trial was reactivated to accrue an additional 122 patients to the phase III component. Eligibility criteria include: 1) small cell lung cancer with at least partial response to chemotherapy; 2) contrast-enhanced thin-slice volumetric MRI scan; and, 3) Zubrod performance status 0-2. Supported by grant UG1CA189867 (NCORP) from the National Cancer Institute. Clinical trial information: NCT02635009.
Real-world outcomes of advanced melanoma patients treated with pembrolizumab who have failed prior lines of therapy.
Authors: Wanmei Ou, Emilie Taymor, Scott J. Diede, Eric D. Whitman
Journal: Journal of Clinical Oncology (2019)

e21031 Background: Pembrolizumab (PEM), a humanized antibody targeting programmed death-1 receptor, has been approved by FDA for the treatment of patients (pts) with advanced melanoma (AM) in the US since 2014. Real-world (RW) data supports the clinical effectiveness of 1L use of PEM, but there is limited information of PEM later line use. The study examined the RW outcomes of pts treated with PEM who have failed prior lines of therapy in US oncology clinical practices. Methods: Flatiron Health longitudinal database was used to identify adult pts with AM who received ≥1 dose of PEM in second line (2L) or later (3L+) between September 4, 2014 and May 31, 2017. Pts were followed up to May 31, 2018. Pts in clinical trials were excluded. Pt demographic, treatment, and clinical characteristics were described. Time on treatment (ToT) and overall survival (OS) were analyzed using the Kaplan Meier (KM) method, with the first dose of PEM as the starting point. Results: Two hundred thirty-six pts were included in the analysis, of which there were 171 2L and 65 3L+. Overall, median age at PEM initiation was 66 years; most were male (66.1%) and Caucasian (95.4%). 41.1% of pts’ tumors were confirmed BRAF mutant; 49.6% of pts’ tumors were confirmed BRAF wildtype; the rest was not tested or indeterminate. When data were available, 26.2% had an elevated lactate dehydrogenase (&gt; ULN), 24.6% had brain metastases, and 25.5% had an ECOG performance status of &gt; 1. At the time of analysis, pts were followed for a median of 12.5 months (mo, range, 0.1-44.6). Overall median ToT was 4.4 mo (95% CI, 3.5-5.3), with 4.7 and 4.4 mo in 2L and 3L+, respectively. Overall median OS was 16.8 mo (95% CI, 12.2-25.9), with 16.8 and 18.9 mo for 2L and 3L+ respectively. 1-year and 2-year survival, using the KM method, was 58.0% (95% CI, 51.2-64.1; 2L, 57.4%; 3L+, 59.6%) and 44.7% (95% CI, 37.9-51.3; 2L, 44.3%; 3L+, 46.1%) respectively. Conclusions: The study reports RW use of PEM in a large cohort of pts with AM who have failed initial therapy in US oncology clinical practices, with a heterogeneous study population compared to clinical trials. The findings of OS based on RW use suggest PEM is an effective treatment option for patients in later lines of therapy.
Impact of next-generation sequencing (NGS) in patients with high grade glioma.
Authors: Tariq Zuheir Kewan, Fahrettin Covut, Bicky Thapa, Timothy Peter Spiro, Abdo S. Haddad, Hamed Daw
Journal: Journal of Clinical Oncology (2019)

e13541 Background: Clinical utility of NGS in high grade glioma patients remain debatable. Methods: We reviewed patients who underwent Foundation One NGS between 7/2013 and 10/2018 after high-grade glioma diagnosis at Cleveland Clinic. Overall survival (OS) and progression free survival (PFS) were estimated by the Kaplan-Meier method and compared by log-rank test. Cox regression analysis was performed to identify predictors of OS. Results: We identified 153 patients, 130 (85%) had glioblastoma multiforme (GBM) and 23 (15%) had grade III glioma, 51 (33%) were female, and median age at diagnosis was 58 (range: 18 – 92). Sixteen (10%) patients had secondary glioma and 34 (22%) had multilobar involvement. ECOG performance score at diagnosis was 0 or 1, 2, and ≥ 3 for 79 (52%), 54 (35%), and 13 (9%) patients, respectively. Glioma was surgically resected for 112 (73%) patients, 85 (56%) had total and 27 (18%) had subtotal resection, whereas other 41 (27%) patients underwent biopsy only. Radiotherapy, temozolomide, and bevacizumab were given to 132 (86%), 129 (84%), and 67 (44%) patients, respectively. NGS revealed median of 5 mutated genes (range: 0 – 19), commonly mutated genes were TERT (63%), CDKN2AB (60%), EGFR (42%), TP53 (42%), PTEN (38%), and IDH1/2 (20%). Two patients received bevacizumab for KDR amplification, 1 received off-label lapatinib for EGFR amplification, and 3 received off-label everolimus for multiple mutations. Median follow-up was 18 months. Three-year OS and PFS for patients with GBM vs grade III glioma were 29% (95% CI: 22 – 39) vs 78% (95% CI: 63 – 97) and 17% (95% CI: 11 – 25) vs 74% (95% CI: 58 – 94), respectively (p &lt; 0.0001 for both). On univariable analysis, each 10 increase in age, ECOG ≥3 vs &lt; 3, grade IV vs III glioma, surgical resection vs biopsy, radiotherapy, temozolomide, bevacizumab, and IDH / TP53 / EGFR / TERT / PTEN / CDKN2AB / ATRX mutations predicted OS (p &lt; 0.01 for all). On multivariable analysis, ECOG ≥3 vs &lt; 3, grade IV vs III glioma, surgical resection vs biopsy, temozolomide, bevacizumab, PTEN and CDKN2AB mutations have remained to predict OS (p &lt; 0.01 for all). Conclusions: In our cohort, NGS results provided additional prognostic value, however led to change in the management for only 4% of patients with high-grade glioma.
Association of co-occuring mutations in exosomal DNA and clinical outcomes of patients with metastatic colorectal cancer.
Authors: Chuanhua Zhao, Lianpeng Chang, Cong Cui, Zhaoli Tan, Ru Jia, Yan Wang, Rongrui Liu, Yun Zhang, Jianzhi Liu, Jian-Ming Xu
Journal: Journal of Clinical Oncology (2019)

e15001 Background: Blood-based liquid biopsies offer easy access to genomic material for molecular diagnostics in cancer. Compared with cell-free DNA (cfDNA) derived from apoptotic cells, exosomal nucleic acids (exoNAs) released from living cells, which include more complete DNA, RNA and protein component, can better reflect underlying cancer biology. However, little evidence supports the clinical relevance of such a biomarker in metastatic colorectal cancer (mCRC). Methods: From May 2013 to July 2016, patients with mCRC received chemotherapy with or without molecular targeted drugs were enrolled in the Fifth Medical Center, General Hospital of PLA. Clinical response was evaluated using RECIST 1.1. Serial blood samples were collected and used to extract exosomal DNA. Targeted amplicon ultradeep sequencing was employed to analyze mutations in exosomal DNA with a customized-designed 10-genes panel including prognostic-related and cetuximab-resistant genes of CRC. Results: 91 patients were enrolled in this study, and median follow-up time was 11.7 months. In total of 82 pretreatment samples, 58% were detected to harboring mutations in designed targeted regions. The most frequent mutant genes were TP53 (56%), KRAS (54%), and PIK3CA (33%). Co-occuring genes were detected in 25 (31%) patients, including 16 patients with mutation in both KRAS and TP53 gene. Patients with co-occurring TP53/KRAS mutations showed significantly poor outcome (median OS=9.23m ), than those without co-occuring in these two genes (median OS=18.75m; P=.0141). Further analysis showed progress disease with new metastasis was enriched in patients with co-occurring KRAS/TP53-mutant patients (p=.0016). Of 23 samples from progressed patients received cetuximab, 39% were detected with acquired cetuximab-resistance related mutations in KRAS (26%), PIK3CA (17%), NRAS (4%) and BRAF (4%). In addition, exosomal DNA abundance increased was observed at or before disease progression (mean leading time = 8.90 weeks). Conclusions: This study provided clinical evidence for exosomal DNA as a potential biomarker of prognosis and cetuximab-resistant mechanism of mCRC.