tbuckley/cabot-search huggingface dataset:
Pharmacodynamics of PI3K, MEK, and AKT inhibitors through isoform-specific measurements of MEK, ERK, AKT, and ribosomal protein S6 in needle biopsies.
Authors: William Herrick, Casey Kilpatrick, Dominic Esposito, Howard Stotler, Melinda G. Hollingshead, James H. Doroshow, Ralph E. Parchment, Apurva K. Srivastava
Journal: Journal of Clinical Oncology (2019)

3134 Background: The success of drugs targeting the MAPK or PI3K pathways in cancer has been slowed by insufficient pathway suppression or onset of resistance through rebound or cross-pathway activation. Isoform-specific measurement of key signaling molecules and a pathway convergence marker ribosomal protein S6 (RPS6), may provide valuable pharmacodynamic (PD) evidence to assess drug effectiveness. Methods: We developed Luminex multiplex assays to measure total and phosphorylated forms of RPS6, ERK1, ERK2, MEK1, MEK2, AKT1, AKT2, and AKT3 from a single tumor biopsy. Fit-for-purpose validation was performed with three drugs currently in clinical trials. A SW620 (KRAS G12V) model was tested with selumetinib (NSC741078, 20 mg/kg), MK2206 (NSC756656, 24 mg/kg), and two PTEN-null models (PC3 &amp; HCC70) with AZD8186 (NSC777572, 25 &amp; 50 mg/kg). Tumors were collected at multiple timepoints after single and repeated dosing, processed by a validated method (PMID 27001313) and data analyzed relative to vehicle control (n = 4-5/grp). Results: The multiplexed assays demonstrated satisfactory analytical performance. Treatment of the SW620 model with a single dose of selumetinib suppressed pERK1/2 ( &gt; 90%), MEK1/2 (50%) and pRPS6 (40-60%) up to 4 h (last time point tested) which was reversed by 24 h. AKT inhibitor, MK2206, suppressed pAKT1/2 (75%) and pAKT3 (50%) 2 h post-dose with reversal at 24 h but did not significantly suppress pRPS6, implying limited downstream modulation. Dosing selumetinib for 21 days had no added effect on pERK isoforms. In both PTEN-null models, AZD8186 suppressed all pAKT isoforms by 40-75% up to 4 h post-dose. The pAKT remained suppressed at 7 h in HCC70 but both pAKT and pRPS6 rebounded by 7 h in PC3. The basal pERK1/2 levels were low and unaffected by AZD8186 in PC3 and HCC70. Conclusions: We established the fitness of PD assays to provide critical evidence regarding the duration of on-target effects, timeline of biomarker reversal and effectiveness of pathway suppression for three distinct classes of drugs. The PD assays are ready for an ongoing clinical trial of AZD8186 and to support clinical development of FGFR inhibitors. Funded by NCI Contract HHSN261200800001E.
Cryoglobulins Today: Detection and Immunologic Characteristics of 1,675 Positive Samples From 13,439 Patients Obtained Over Six Years
Authors: Marie N. Kolopp‐Sarda, Anaïs Nombel, Pierre Miossec
Journal: Arthritis & Rheumatology (2019)

Objective Cryoglobulins are cold‐precipitating immunoglobulins. Through progress in techniques, we undertook this study to update information on the biologic characteristics of cryoglobulins in a very large population. Methods A cohort of 13,439 patients was tested for cryoglobulins from January 2010 to December 2016. The analysis included cryoglobulin isotype, clonality, concentration, and IgM rheumatoid factor (IgM‐ RF ) in cryoprecipitate, as well as serum complement and RF . Markers of gammopathy, viral infection, and autoimmunity were also investigated. Results Of the 13,439 patients, 1,675 (12.5%) tested positive for cryoglobulins: 155 patients (9.3%) with type I, 788 (47%) with type II , and 732 (43.7%) with type III cryoglobulins. Nine percent of patients who were retested after initially testing negative for cryoglobulins showed a positive result on a follow‐up test (196 of the 2,213 retested patients). In type I cryoglobulins, IgM was more frequent but occurred at lower concentrations than IgG. Mixed cryoglobulins were found in 34.8% of the tested patients who were positive for hepatitis C virus and &lt;5% of those who were positive for hepatitis B virus or HIV . Of the patients with anti–double‐stranded DNA , anti‐ SSA , or anti–cyclic citrullinated peptide autoantibodies, 25.4% tested positive for mixed cryoglobulins, with type III occurring more frequently than type II . Both cryoprecipitate and serum were RF ‐positive in 21.6% of type II and 10.1% of type III cryoglobulins. A decrease of C4, with or without accompanying decreases of C3 and CH 50, was found in 23.6% of cryoglobulin samples. Conclusion Obtained with the use of modern assays, our findings from this very large collection of cryoglobulins provide an update on cryoglobulin distribution and characteristics, with minimal selection bias. Despite strict preanalytical conditions, a negative finding for the presence of cryoglobulin must be confirmed in a second sample. RF activity and complement decreases were rarely detected.
Feasibility and clinical impact of next-generation sequencing (NGS) in patients with stage IV or recurrent malignancies.
Authors: Fahrettin Covut, Tariq Zuheir Kewan, Bicky Thapa, Abdo S. Haddad, Timothy Peter Spiro, Hamed Daw
Journal: Journal of Clinical Oncology (2019)

e14697 Background: Feasibility and outcomes of routine NGS in patients with stage IV or recurrent malignancies remain debatable. Methods: We reviewed patients who underwent Foundation One NGS between 9/2012 and 10/2018 after diagnosis of stage IV or recurrent solid cancer at Cleveland Clinic. Overall survival (OS) was estimated by the Kaplan-Meier method. Logistic and Cox regression analysis were performed to identify predictors of receiving targeted gene therapy (TGT) and OS, respectively. Results: We identified 1699 patients, 825 (49%) were female, 1634 (96%) had stage IV and 65 (4%) had recurrent cancer. At diagnosis of stage IV/recurrent cancer, median age was 61 (range: 18 – 94) and ECOG performance score was 0, 1, and ≥ 2 for 578 (34%), 859 (51%), and 258 (15%) patients, respectively. Most common primary cancers were lung (20%), colorectal (17%), urothelial/prostate (12%), and breast (10%). NGS revealed median of 4 mutated genes (range: 0 – 34), ≥ 1 FDA approved TGT was available in 505 (30%) and 1114 (66%) patients for the same and different primary cancer, respectively. Overall, 219 (13%) patients received 247 lines of TGT for median of 3 months (range: 0.1 – 62) based on NGS results. TGT use was via clinical trials for 49 (22%) and off-label for 83 (38%) patients. Best response was complete/partial response for 63 (29%) and stable disease for 40 (18%) patients. Commonly targeted genes were EGFR (12%), ERBB2/3 (11%), BRAF (10%), BRCA1/2 (8%), and PIK3CA (7%). Median follow-up after diagnosis of stage IV/recurrent cancer was 19 months. Two-year OS for TGT and no TGT cohorts were 70% (95% CI: 64 – 77) and 55% (95% CI: 53 – 58), respectively (p &lt; 0.0001). On multivariable analysis, ECOG ( &lt; 2vs ≥2), systemic therapy between diagnosis of stage IV/recurrent cancer and NGS (≥2 vs &lt; 2 lines), and each 1 increase in number of mutated genes were predictors of receiving TGT (p &lt; 0.05 for all). On multivariable analysis, age (≤65 vs &gt; 65), ECOG ( &lt; 2vs ≥2), stage (recurrent vs IV), and systemic therapy before NGS (≥2 vs &lt; 2 lines) predicted longer OS (p &lt; 0.01 for all). Conclusions: In this large cohort, NGS provided further therapeutic options including clinical trials for approximately 1 out of 10 patients with stage IV or recurrent cancer.
Applying machine learning strategy for microsatellite status detection in plasma sample type.
Authors: Lili Zhao, Wenbo Han, Wei Zhou, Lu Fang, Yuanyuan Hong, Chen Tian, Weizhi Chen, Ji He
Journal: Journal of Clinical Oncology (2019)

e14219 Background: Microsatellite(MS) status is an important biomarker in cancer diagnosis . Most of available detection algorithms were based on figuring out number of validated allele types from control and cases, then determine the MS status by identify the difference. That would be suitable for tissue like samples due to their clear and sufficient tumor nucleic acid content. But for liquid biopsy such as plasma, lower ctDNA concentration and higher background ratio induced from laboratory and sequencing procedure make it necessary to develop novo method for plasma MS status detection. Methods: We developed an machine learning based approach to detect the MS status by using NGS sequencing data from plasma sample. 98 blood cell , 12 tumor tissue samples with PCR confirmed MSS status and 87 plasma samples from 134 patients were used to build normal baseline, and check the sequencing stability and population polymorphism of 207 candidate SSR locus in our panel. 97 locus then passed and were chosen as original biomarkers for model construction. For each coming sample, the allele probability distribution were obtained for each locus. Followed by calculating the Kullback–Leibler Divergence (KLD) value between target and baseline samples for each locus, the KLD value was used as input for feature selection and machine learning model fitting. Finally a leave one out strategy was used for model performance evaluation. Results: We obtained 17 most relevant SSR locus with suitable for MS status analysis of plasma sample. By using a SVM model fitted with 49 real patients sample data (21 MSI and 28 MSS) , The MS status prediction of plasma sample was of high sensitivity and specificity which were 90.47% and 96.42% respectively. Conclusions: Our results suggest that our MSI calculation model by using KLD value and SVM method is appropriate for the plasma sample. Further large-scale prospective studies are needed to validate our model.
Final results of JASPAC05: Phase II trial of neoadjuvant S-1 and concurrent radiotherapy followed by surgery in borderline resectable pancreatic cancer.
Authors: Shinichiro Takahashi, Izumi Ohno, Masafumi Ikeda, Masaru Konishi, Tatsushi Kobayashi, Tetsuo Akimoto, Motohiro Kojima, Soichiro Morinaga, Hirochika Toyama, Yasuhiro Shimizu, Atsushi Miyamoto, Shoichi Hishinuma, Norihisa Takakura, Wataru Takayama, Satoshi Hirano, Takehito Otsubo, Masato Nagino, Wataru Kimura, Keishi Sugimachi, Katsuhiko Uesaka
Journal: Journal of Clinical Oncology (2019)

4127 Background: Borderline resectable pancreatic cancer (BRPC) is frequently associated with positive surgical margins and a poor prognosis when treated with upfront surgery. This study was designed to assess whether neoadjuvant chemoradiotherapy (CRT) with S-1 increases the R0 resection rate. Methods: This was a multicenter, single-arm, phase II study. Patients with BRPC received S-1 (40 mg/m 2 bid) and concurrent radiotherapy (50.4 Gy in 28 fractions) before surgery if they fulfilled any of the following: (1) bilateral impingement of the superior mesenteric vein or portal vein; and (2) tumor contact ≤180° with the superior mesenteric artery, common hepatic artery, or celiac axis. The primary endpoint was the R0 resection rate in BRPC confirmed by central review. Secondary endpoints were overall survival (OS), progression-free survival (PFS), response rate (RECISTv1.1), pathological response rate, surgical morbidity (Clavien–Dindo classification), and toxicity (CTCAEv4.0). At least 40 patients were required, with one-sided α = 0.05 and β = 0.05, with an expected and threshold value for the primary endpoint of 30% and 10%. Results: Fifty-two patients were eligible, of whom 41 had BRPC by central review. CRT was completed in 50 (96%) patients and was well tolerated. The rate of grade 3/4 toxicity with CRT was 43%. The R0 resection rate was 52% (95% CI, 37.6%–66.0%) in 52 eligible patients and 63% (95% CI, 46.9%–77.9%) in 41 patients with BRPC. The radiological response rate was 5.8%, while destruction of &gt; 50% of tumor cells was shown microscopically in 32% of patients. Postoperative grade III/IV adverse events were observed in 7.5% of operated patients. Among the 52 eligible patients, the 2-year OS rate, median OS, and median PFS were 51%, 25.8 mo, and 6.7 mo. Of the 41 patients with BRPC, the 2-year OS rate, median OS, and median PFS were 58%, 30.8 mo, and 10.4 mo. Conclusions: S-1 and concurrent radiotherapy appear to be feasible and effective at increasing the R0 resection rate with encouraging survival rates in BRPC. A phase II/III trial evaluating this treatment is ongoing. Clinical trial information: NCT02459652.
Tumor microenvironment (TME), longitudinal biomarker changes, and clinical outcome in patients (pts) with advanced <i>BRAF</i> V600–mutant melanoma treated with first-line spartalizumab (S) + dabrafenib (D) + trametinib (T).
Authors: Reinhard Dummer, Daniel Gusenleitner, Catarina D. Campbell, Celeste Lebbe, Victoria Atkinson, Mario Mandalà, Paul D. Nathan, Ana Arance, Erika Richtig, Naoya Yamazaki, Caroline Robert, Dirk Schadendorf, Hussein Abdul-Hassan Tawbi, Paolo Antonio Ascierto, Antoni Ribas, Keith Flaherty, Eduard Gasal, Jan C. Brase, Georgina V. Long
Journal: Journal of Clinical Oncology (2019)

9515 Background: Although pts with both low tumor mutation burden (TMB) and T-cell–inflamed gene expression profiles (TI-GEPs) usually have poor outcomes with anti–PD-1 therapy, an analysis in the adjuvant melanoma setting suggested that these pts benefited from adjuvant D+T therapy. Here we analyze TMB/TI-GEPs and other biomarkers in pts receiving a combination of anti–PD-1 and D+T therapy. Methods: The phase 3 COMBI-i study (NCT02967692) is evaluating S in combination with D+T in previously untreated pts with BRAF V600–mutant unresectable/metastatic melanoma. In the safety run-in (part [p] 1) and biomarker (p2) cohorts, blood/tissue samples were collected at baseline (BL), after 2-3 and 8-12 wk of treatment, and at disease progression. TMB/circulating tumor DNA (ctDNA) and TI-GEPs were examined by targeted DNA-seq and RNA-seq, respectively. Results: At data cutoff, 6 of 22 pts with DNA- and RNA-seq data available had a PFS event. At BL, these pts had low TMB, low TI-GEPs (4 of 6), or high levels of immunosuppressive TME signatures (eg, fibroblast, M2 macrophages) vs pts without a PFS event. Elevated BL ctDNA was significantly associated with PFS events ( P&lt; .001). Pts with a complete response (CR) on S+D+T had significantly lower levels of BL immunosuppressive TME signatures (eg, M2 macrophages; P&lt; .01) than pts without a CR. We observed a consistent increase in TI-GEPs and decrease in MAPK pathway activity score (MPAS) from BL to biopsy at 2-3 wk in all pts regardless of subsequent progression. Pts with a PFS event and available longitudinal biomarker data were characterized by a subsequent decrease in TI-GEPs and an increase in MPAS per the 8- to 12- wk biopsy sample. Conclusions: These results suggest that S+D+T had an early impact on tumor cells and the TME, potentially promoting antitumor activity. The majority of PFS events occurred in the TMB-low/TI-GEP-low subgroup. An immunosuppressive TME might preclude early CRs. The predictive implications of coupling TMB/GEP subgroups with other TME marker subgroups need further validation. The randomized placebo-controlled p3 of COMBI-i is ongoing. Clinical trial information: NCT02967692.
Alectinib exposure-response (ER) in ALK-inhibitor naïve ALK-positive NSCLC patients: Pooled analysis across phase III studies.
Authors: Kevin Smart, Joy C Hsu, Felix Jaminion, Elena Guerini, Alice Tsang Shaw, Caicun Zhou, Tony S. K. Mok, Walter Bordogna, Nicolas Frey, Peter N. Morcos
Journal: Journal of Clinical Oncology (2019)

e20575 Background: Alectinib superiority to crizotinib has been demonstrated in ALK-inhibitor naïve ALK-positive NSCLC patients (pts) in Phase III studies conducted in Japanese (J-ALEX; JapicCTI-132316) pts receiving alectinib 300 mg BID and global (ALEX; NCT02075840) and Asian (ALESIA; NCT02838420) pts receiving alectinib 600mg BID. ER analyses are undertaken to confirm the appropriate alectinib dosing regimen for the global population. Methods: A previous population PK analysis (Hsu et al, ASCO 2016) assessed PK of alectinib and major metabolite, M4, to identify factors influencing PK variability. ER analyses across the 3 Phase III studies investigated the relationship between alectinib and progression-free survival (PFS) by a Cox proportional hazards (CPH) analysis. PK simulations for alectinib 300 mg and 600 mg BID doses were conducted to determine the proportion of pts falling above and below an identified optimal PK threshold for PFS. ER for key safety events were investigated for alectinib 600 mg BID using logistic regression. Results: Alectinib PK is influenced only by body weight and not by race/ethnicity. CPH analysis demonstrated a statistically significant relationship between alectinib exposure and PFS across the 3 Phase III studies, with an improved PFS above an identified optimal PK threshold (Table). PK simulations indicate 49% and 7% of global alectinib treated patients would fall below the optimal PK threshold for 300 and 600mg BID, respectively. Alectinib 600mg BID ensures a distribution of exposures that maximize the PFS benefit while lower alectinib doses/exposures could result in reduced efficacy. Baseline tumor size (BSIZ) was shown to negatively impact PFS with larger BSIZ seen in global pts. No significant exposure-safety relationships were identified for alectinib 600mg BID. Conclusions: Alectinib 600mg BID is the most appropriate dose in the global ALK-inhibitor naïve population. Clinical trial information: NCT02075840; JapicCTI-132316; NCT02838420. [Table: see text]
SP0060 TOWARDS OPTIMAL INTENSITY
Authors: George Metsios
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> There is ample evidence now to suggest that exercise can help ameliorate RMD symptoms and comorbidities. Similar to the prescription of medication, the dosage of exercise should be optimized to achieve the best health benefits. However, a consensus on the dosage of exercise prescription for RMD patients is currently missing. <h3>Objectives:</h3> This talk will explore the data required from RMD patients to develop the best exercise prescription, exercise principles and current state-of-the-art, as well as how we can use the current evidence to identify the optimum dosage for the exercise prescription in people with RMDs. <h3>Methods:</h3> Suggestions have been synthesized using existing evidence-based resources, including recent systematic reviews and meta-analyses (EULAR, Cochrane Library and peer-reviewed journals publications) as well as randomized controlled trials. Data for the effectiveness of exercise dosage on various different outcomes has been extracted and will be explored. <h3>Results:</h3> Different dosages of exercise have differing effects on symptoms of RMDs. The optimal dosage depends on various factors and on the outcome that the exercise prescription aims to improve. <h3>Conclusion:</h3> Despite the increasing research on exercise in RMDs, a currently a consensus for the optimal exercise dosage is currently missing. More interdisciplinary research, with a heavy patient involvement, is required in the area. <h3>Disclosure of Interests:</h3> None declared
Chemotherapy (CT) or chemoradiation (CTRT) in postoperative (simple cholecystectomy) carcinoma gall bladder (GBC) with residual disease, unsuitable for revision surgery.
Authors: Sushma Agrawal, Nawed Alam, Neeraj Rastogi, KJ Maria Das, Punita Lal
Journal: Journal of Clinical Oncology (2019)

e15594 Background: Approximately 25% patients of GBC present after SC. Revision surgery is the standard of care, which is possible only in few patients because of delayed presentation ( &gt; 3 months after SC), major vessels encasement by residual lymph-nodes or medical reasons. It is unclear whether these patients should be offered CT /CTRT/ CT followed by consolidation CTRT. The purpose of this analysis is to evaluate whether single modality or dual modality is required in these patients. Methods: Records of GBC patients with SC (non-metastatic based on a staging CECT abdomen) registered between January 2008 - December 2016 were retrieved. Based on the presence and extent of residual disease, they were risk stratified into 3 groups: (1) No residual disease [NRD], (2) LR1: residual disease in GB bed, peri-portal and peri-choledochal lymph-nodes, (3) LR2: residual disease in GB bed, peri-portal and peri-choledochal, coeliac, superior mesenteric or paraaortic lymph-nodes. Patients were either offered CT or CTRT due to lack of any guidelines and according to physician discretion. Those receiving CT were offered 6 cycles of Cisplatin and Gemcitabine. Patients in Consolidation CTRT arm received 3-4 cycles of Cisplatin and Gemcitabine followed by consolidation CTRT (Concurrent Capecitabine daily with RT upto 50.4Gy/28#/5.5 weeks). Response assessment was according to RECIST criteria (CR, PR, SD, PD). Overall survival (OS) was computed by Kaplan Meier method. Results: Out of 300 patients with SC, 87 had the inclusion criteria mentioned above and rest were metastatic. At a median follow-up of 21 months (range 2-129 months), the median OS was not reached (NR) for NRD (n = 17) ( both CT and CTRT), 19 months for LR1 (n = 33) (27 mo with CTRT and 19 mo with CT, p = 0.003) and 14 months for LR2 (14 mo with CTRT and 18 mo with CT, p = 0.29). The median OS was NR, 17 mo, 16 mo and 9 mo for CR (n = 30), PR(n = 31), SD (n = 5), PD (n = 5), p = 0.001. Conclusions: While NRD should be offered single modality, Consolidation CTRT benefits LR1 but not LR2. Risk stratification according to residual disease burden after SC is a prognostic marker for OS.
Genetic Variation in <i>LPA</i>, Calcific Aortic Valve Stenosis in Patients Undergoing Cardiac Surgery, and Familial Risk of Aortic Valve Microcalcification
Authors: Nicolas Perrot, Sébastien Thériault, Christian Dina, Hao Yu Chen, S. Matthijs Boekholdt, Sidwell Rigade, Audrey-Anne Després, Anthony Poulin, Romain Capoulade, Thierry Le Tourneau, David Messika-Zeitoun, Mikaël Trottier, Michel Tessier, Jean Guimond, Maxime Nadeau, James C. Engert, Kay-Tee Khaw, Nicholas J. Wareham, Marc R. Dweck, Patrick Mathieu, Philippe Pibarot, Jean-Jacques Schott, George Thanassoulis, Marie-Annick Clavel, Yohan Bossé, Benoit J. Arsenault
Journal: JAMA Cardiology (2019)

Genetic variants at the LPA locus are associated with both calcific aortic valve stenosis (CAVS) and coronary artery disease (CAD). Whether these variants are associated with CAVS in patients with CAD vs those without CAD is unknown.