bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiplex genomic testing (MGT): Four-year real-world experience of two community oncology practices in central rural Nebraska.
Authors: Copur Mehmet Sitki , Jonglertham Pornchai , Zusag Thomas , Springer Carlene R. , Molnar Sally , Robbins Leslie , Peterson Tonya , Arbogast Jessica , Muske Chandra , Shipman Stacia , Fakkema Emily 
Published: May 2019

e14728 Background: MGT forms the basis of precision oncology. More and more community oncology practices are utilizing MGT to identify somatic Actionable Alterations (AA) in solid tumors. This information is increasingly being used to choose FDA and/or guideline approved treatment options, or clinical trials. Methods: From July 2014 to July 2018, MGT (Foundation Medicine) data of patients (pts) with solid tumors at two community hospital-based oncology practices in central rural Nebraska were retrospectively analyzed. Study population consisted of advanced solid tumor pts (ECOG 0-2) with an available MGT result who had progressed on standard treatment regimens. Treating community oncologists directed treatment choices based on MGT results. Results: 360 pts underwent MGT. Average (avg) turn-around time from order to reporting was 20.19 days. Reimbursements were through commercial insurance (27 %), Medicare (66%), Medicaid (3%), self-pay (2 %) and financial assistance by company (2%). Most common cancer types were non-small cell lung (27%), pancreas (9%), colon (8%), unknown primary (4%), sarcoma (4%), breast (4%), gastro-esophageal (2%) and kidney (1%). 79% of samples had at least one AA. In 69 (19%) pts these alterations were matched to one or more on/off label FDA and/or guideline approved targeted therapies. Only 26/69 pts (37%) in this group were able to have a therapy that was new. 43 (12%) of pts qualified and went on locally available clinical trials (MATCH, LUNG-MAP and TAPUR). Conclusions: Our analysis reflects a 4-year real-world MGT experience in two community oncology practices in central rural Nebraska. In addition to established barriers of cost, long turnaround time, adequate tissue, the low yield of new FDA and/or guideline approved treatments decreases the utility of MGT. Increased variety and availability of precision medicine clinical trials with improved patient access in the rural setting may improve this shortcoming.[Table: see text]
The prognostic role of a novel TP53 mutation classifier in resectable esophageal squamous-cell carcinoma.
Authors: Su Dan , Huang Minran , Jin Jiaoyue , Wu Yingxue , Ying Lisa , Zhang Fanrong , Chen Kaiyan 
Published: May 2019

e14749 Background: TP53 is the most recurrently mutated gene in esophageal squamous-cell carcinoma (ESCC). However, the effect of TP53 mutation status on the prognosis for patients with ESCC remains controversial. Also, there has been no consensus on the minimal genomic region necessary for clinical TP53 genetic testing. Methods: We retrospectively examined somatic mutations in all coding exons of the TP53 gene in 161 resectable ESCC patients by next-generation sequencing. We then stratified patients by multiple TP53 mutation classifiers based on different mutant features and analyzed its association with clinicopathological features and disease outcome by univariable and multivariable analysis. Results: We detected TP53 mutations in 138 of the 161 patients (85.7%), among which 61 patients harbored a non-disruptive mutation in the DNA-binding domain (DBD). The presence of TP53 mutation, hotspot mutant, and the mutation number alone was not predictive of any disease features and prognosis. We identified a prognostic effect of harboring the non-disruptive and DBD mutation of TP53 with an HR 0.362 (95% CI: 0.212–0.620, P < 0.001) and 0.486 (95% CI: 0.277–0.853, P = 0.012) for 5-year progression-free (PFS) and overall survival (OS), respectively. Multivariable analysis revealed it as an independent prognostic predictor for PFS (HR: 0.414, 95% CI: 0.230–0.746, P = 0.003) and OS (HR: 0.414, 95% CI: 0.207–0.825, P = 0.012). In particular, this TP53 mutation classifier defined a patient subset more beneficial from peri-operative radiotherapy with improved 5-year PFS (P = 0.020) and OS (P = 0.036). Conclusions: It is of clinical importance to examine and identify the non-disruptive somatic mutation in DBD of the TP53 gene for resectable ESCC.
Reanalysis of the efficacy of molecular targeted agents (MTAs) given in the randomized trial SHIVA01 according to the ESMO ESCAT scale of actionability.
Authors: Moreira Aurelie , Vacher Sophie , Morel Claire , Lecerf Charlotte , Frelaut Maxime , Sablin Marie Paule , Loirat Delphine , Ricci Francesco , Hescot Segolene , Borcoman Edith , Torossian Nouritza , Masliah-Planchon Julien , Callens Celine , Servant Nicolas , Salomon Anne Vincent- , Bieche Ivan , Le Tourneau Christophe , Kamal Maud 
Published: May 2019

e14750 Background: SIVHA01 was the first randomized precision medicine trial in patients (pts) with metastatic solid tumors comparing the efficacy of matched MTA outside their indications and conventional chemotherapy in pts with any kind of cancer who had failed standard of care therapy (Le Tourneau et al., Lancet Oncol 2015). No statistical difference was reported between the 2 groups in terms of progression-free survival (PFS), challenging the treatment algorithm used. Several scales of actionability have been developed to address this point, the latest one being the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) that defines clinical evidence-based criteria to prioritize genomic alterations to select MTAs for pts (Mateo et al., Ann Oncol 2018). We aimed to retrospectively evaluate the efficacy of MTAs given in SHIVA01 according to ESCAT. Methods: All SHIVA01 molecular alterations targeted were ranked according to ESCAT by assessing the level of evidence reported in the literature, taking into account the tumor type and the administered MTA among 11. PFS and overall survival (OS) according to the ESCAT rank were compared using a log-rank test. Results: The 153 pts treated with a MTA in SHIVA01 were included. Molecular alterations were ranked as II, IIIA, IIIB, and IVA according to ESCAT in 38 (25%), 98 (64%), 7 (5%), and 10 pts (7%), respectively. Median PFS was 2.0 months (mo) in tier II, 3.1 mo in IIIA; 1.7 mo in IIIB, and 3.2 mo in IVA (p = 0.13). Median OS was 11.7 mo in tier II, 11.2 mo in IIIA, 6.3 mo in IIIB, and 12.1 mo in IVA (p = 0.002). Conclusions: The majority of molecular alterations taken into account in SHIVA01 were tier IIIA hypothetical targets according to ESCAT. Pts with a tier IIIB molecular alteration had the worst survival, highlighting the crucial impact of the types of molecular alterations beyond the gene and the signaling pathway.
Type 2 diabetes as a potential risk marker for early onset colorectal cancer.
Authors: Young Joanne , Price Timothy Jay , Hardingham Jenny , Symonds Erin , Smith Eric , Ruszkiewicz Andrew , Townsend Amanda Rose , Palethorpe Helen , Tomita Yoko , Wittert Gary , Young Graeme P. , Hewett Peter , Roder David , Drew Paul , Jesudason David , Poplawski Nicola 
Published: May 2019

e15005 Background: Colorectal cancer (CRC) is rising in incidence in young adults. Because they are not included in population screening, and are more likely to present at an advanced stage, there is a need to identify young adults at increased risk for CRC. An association has been reported between type 2 diabetes (T2D) and CRC in the general population. Though lifestyle risk factors may be involved, the early occurrence of CRC in young adults suggests that there may also be a role for inherited predispositions. We therefore investigated whether having a personal and/or first-degree family history of T2D was a potential risk marker for early onset CRC. Methods: The South Australian Young Onset (SAYO) CRC study is an unselected series of young adults with CRC up to age 55. Fifty unrelated young adults (31/50 or 62% female) diagnosed with CRC were recruited to the study. Personal history of T2D was confirmed. Detailed family history of T2D was recorded. 253 patients with clear colonoscopies and no known CRC predisposition served as controls for personal history studies of T2D. Diabetes status was recorded on admission for colonoscopy controls. Associations were explored using a chi-squared statistic. Results: CRC patients ranged in age from 23-54 years (median age 42) and controls from 18-54 (median age 45). Six patients (12%) met the WHO clinical criteria for serrated polyposis, and two (4%) carried a Lynch syndrome mutation. CRC was present in the distal colon in 15/19 males (79%) and 17/31 females (55%) (p = 0.12). A personal history of T2D was confirmed in 12/50 (24%) CRC patients compared with clear colonoscopy controls under 55 years (13/258 or 5% P < 0.001; OR = 5.9; 95%CI 2.5-13.8). T2D was seen in 7/31 or 23% females and 5/19 or 26% males. Young adults with CRC frequently reported at least one first-degree relative with T2D (24/47 or 51%). All patients with personal history of T2D also had first-degree relatives with T2D. A first-degree family history of T2D was observed in 12/27 (44%) CRC patients aged under 45 yrs and 12/20 (60%) of CRC patients aged between 45 and 54 yrs having this characteristic (p = 0.29), and was present in both males and females (10/17 or 58% and 13/30 or 43% respectively; p = 0.37). Conclusions: Though the mechanism remains unclear, given the prevalence of T2D in those aged < 55yrs is 5% in Australia, our observations suggest that there is a striking enrichment for personal and first-degree family history of T2D in young adults with CRC. These features could potentially identify a subset of young adults at increased risk for CRC and in whom early screening might be appropriate.
Aflibercept (Afl) for patients (pts) with metastatic colorectal cancer (mCRC): Clinical predictors of nonhematologic (nonhem) toxicity.
Authors: Vladimirova Liubov Yu , Fedyanin Mikhail , Chubenko Viacheslav , Fakhrudinova Olga , Bolotina Larisa , Moiseenko Fedor Vladimirovich , Khasanova Alfiya , Belonogov Alexandr , Musaeva Hedi , Novikova Olga , Stradaeva Irina , Mukhametshina Guzel , Orlova Rashida , Feoktistova Polina , Kuzmina Evgeniya , Karabina Elena , Nekrasova Oksana , Sherstnev Viktor , Micshenko Andrey , Tjulandin Sergei 
Published: May 2019

e15007 Background: Afl is one of the antiagiogenic agents used for the treatment for mCRC. Cardiovascular toxicity of Afl is shown to be a main reason of the drug discontinuation but there are no studies on factors associated with nonhem adverse events(AEs). The aim of the study was to define clinical factors associated with the development of Gd.3-4 nonhem AEs. Methods: Pts with mCRC treated with FOLFIRI+Afl were included in a multicenter prospective base from 2016-18. Multivariative regression analysis was performed with Chicago, IL v.22.0. Factors studied included demographic, disease characteristics, data about concomitant diseases(CD) and concomitant medications. Results: 278 pts with mCRC from 18 centers were included. Mean age – 58.7, 48.6% were male, mean number of metastases– 2. ECOG 0-1–97.5%pts. RASm had 133 (47.8%) pts. Afl+FOLFIRI was used as the 2nd line therapy–in 67.6%. CD were in 194 (69.8%), cardiovascular–in 175 (62.9%). ORR(CR+PR)17.3%, SD-43.9%. MedPFS was 6.0 mos. Afl discontinuation due to AEs 11.9%. AE were reported in 201 (72.3%), Gd3-4 – in 69 (24.8%); nonhem AEs – in 178 (64%), Gd3-4–52 (18.8%)pts. Among Gd3-4 nonhem AEs were arterial hypertension Gd1-2–77 (27.7%), Gd3-4-in 36 (12.9%), vomiting Gd1-2–45 (16.2%), diarrhea Gd1-2–in 32 (11.5%), asthenia Gd1-2 –in 29 (10.4%), hepatotoxicity Gd1-2–in 2(5%), thrombosis–in 2 (5%) pts. Multivariate regression analysis showed that among the factors studied number of lines of treatment (OR1.4,95%CI1.1-2.1,p=0.03) and CD requiring medical support (OR 2.0,95%CI1.1-3.7,p=0.03) were found as independent factors of nonhem AE Gd3-4 development. ACE-inhibitors (OR2.2,95%CI1.2-4.3,p=0.02), calcium-channel blockers (CCB)(OR4.1,95%CI1.6-10.4,p=0.003 ) were the medical drugs considered to be significant. Conclusions: Number of lines and CD requiring medical support, especially with ACE-inhibitors or CCB, identifies a significant risk of developing cardiovascular non-hem AEs Gd3-4 with FOLFIRI + Afl.
Stereotactic body radiotherapy (SBRT) for colorectal liver metastasis: Clinical outcomes from the international multi-institutional RSSearch Patient Registry.
Authors: D'Avila Leite Pollyanna , Gaya Andrew M. , Lanciano Rachelle Marie , Yang Jun J. , Blanck Oliver , Urwin Robert , Davis Joanne N. , Mahadevan Anand 
Published: May 2019

e15040 Background: We investigated factors associated with clinical outcome for liver metastases from colorectal primary tumors treated with Stereotactic Body Radiotherapy (SBRT) from a multi-center, international, prospective patient registry. Methods: A subgroup of patients with colorectal liver metastases treated with SBRT was identified from the RSSearch Patient Registry. Patient, tumor and treatment characteristics associated with outcome were evaluated. Dose fractionations were normalized to BED10. Overall survival (OS) and local control (LC) were evaluated using Kaplan Meier analysis and log-rank test. Results: 217 patients with 233 liver metastases from primary colorectal cancer treated with SBRT between 2005-2017 and enrolled in the RSSearch Patient Registry were included. The median follow-up was 15 months (1–75 months). 77% of patients received prior or concurrent chemotherapy. Median tumor volume was 21.95 cm3 (0.5 – 638 cc), median SBRT dose was 45 Gy (16 – 60 Gy) delivered in a median of 3 fractions (1-5). Median number of liver metastases was 1 (1-8). Median overall survival (OS) was 27 months; median local control (LC) was 41 months. One and two-year OS was 75% and 55%, respectively. One and two-year LC was 75% and 66%, respectively. Higher BED10 was associated with improved LC with median LC of 44 months for BED10 ≥ 100 Gy vs 39 months for BED10 < 100 Gy (p = 0.0007). Higher BED10 was also associated with improved OS: median of 33 months for BED10 ≥ 100 Gy vs to 18 months for BED10 < 100 Gy (p = 0.0009). Smaller tumor volume was associated with improved OS: median OS of tumor volume was 34 months for tumors < 20 cc vs 20 months for tumors ≥ 22cc (p = 0.0037). Local control was not significantly associated with tumor volume: median LC for tumor < 22 cc vs ≥ 22cc was 44 months vs 39 months, respectively (p = 0.193). Age, prior or current chemotherapy and BMI were not associated with OS or LC. Conclusions: In this multi-institutional prospective cohort, OS and LC were favorably correlated with small tumor volume and higher BED10.
Evaluation of complete pathological remission rates in surgically resected MSI-high metastatic colorectal cancers (mCRC).
Authors: Ludford Kaysia , Cohen Romain , Foo Wai Chin , Thomas Jane V , Parc Yann , Svrcek Magali , Kopetz Scott , Andre Thierry , Overman Michael J. 
Published: May 2019

e15046 Background: Immune checkpoint inhibition (ICKi) for mCRC with deficient mismatch repair (dMMR) or microsatellite instability high (MSI-H) demonstrates a high clinical activity rate that appears durable. The impact of immunotherapy on pathological tumor response in dMMR/MSI-H CRC is unknown. Our aim was to assess the pathological response and clinical outcomes following surgical resection in dMMR/MSI-H CRC patients who undergo surgical resection following immunotherapy. Methods: All dMMR/MSI-H mCRC patients treated with anti-PD1/L1 based ICKi between November 2016 and December 2018 at MD Anderson Cancer Center, Houston, Texas and Saint-Antoine Hospital, Paris, France who then underwent surgical resection were included in this retrospective analysis. MSI-H status was determined by ICH in 4 patients and by PCR and ICH in 8 patients. The primary outcome was pathological response in resected surgical specimens following at least 1 cycle of ICKi. Complete pathological response was defined as the absence of residual cancer cells in the surgical specimen. Results: 12 patients (median age at diagnosis 45 years (range 30-70); 10 germline mutations,2 sporadic) of 111 who received ICKi (11%) underwent surgical resection of primary tumor only (n = 5), metastases only (n = 6) or both primary tumor and metastases (n = 1). 42% of patients received PD1 combined with CTLA4 iCKi while 58% received PD1 monotherapy. The median time from ICKi introduction to surgery was 12 months (range 2-28). Prior to surgery 1 patient had complete radiographic response while 11 patients had residual tumor on imaging. 9 surgeries were done with curative intent and 3 with palliative intent. 11 patients achieved pCR while 1 achieved near pCR with rare viable tumor remaining (prior ICKi duration was 2 months). Median follow-up from surgery is 7 months. No patients have progressed following surgical resection. Conclusions: Complete pathological response is achievable with ICKi for dMMR/MSI-H mCRC. For these patients this data supports the curative potential of anti-PD1 based therapy and suggests that residual radiographic tumor may not require surgical resection following response to anti-PD1 based therapy.
Efficacy of PD-1/PD-L1 inhibitor-based therapies in refractory microsatellite instability (MSI)-unselected metastatic colorectal cancer (mCRC): A network meta-analysis (NMA) of randomized controlled trials (RCTs).
Authors: Wang Zi-xian , Chen Yu-tong , Zhou Yi-xin , Wu Hao-xiang , Chen Zhan-Hong , Wang Tian-tian , Wu Xiangyuan , Wang Feng , Xu Rui-hua 
Published: May 2019

e15048 Background: PD-1/PD-L1 inhibitor-based monotherapies and combination therapies are being investigated to challenge microsatellite stable (MSS) mCRC. This NMA aimed to assess the efficacy of anti-PD-1/PD-L1-based therapies against active comparators (regorafenib, trifiuridine+tipiracil, and fruquintinib [R/T/F]) and negative controls (placebo and best supportive care [P/BSC]) in patients with refractory MSI-unselected mCRC, which are predominantly MSS. Methods: We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and major oncology websites for relevant RCTs comparing the above therapies with each other up to Feb 15, 2019. We used the frequentist NMA to evaluate hazard ratios (HRs) for pairwise treatment comparisons in terms of overall survival (OS). Results: Seven RCTs were included, totaling nine comparisons between five therapies (durvalumab+tremelimumab [anti-PD-L1+Tre] vs. P/BSC [n = 1], atezolizumab+cobimetinib [anti-PD-L1+Cobi] vs. R/T/F [n = 1], atezolizumab [anti-PD-L1-only] vs. R/T/F [n = 1], anti-PD-L1+Cobi vs. anti-PD-L1-only [n = 1], and R/T/F vs. P/BSC [n = 5]). No significant heterogeneity was detected in the NMA (P = 0.340 in Q test; I2= 11.6%). Compared to P/BSC, OS was significantly improved with anti-PD-L1+Tre (fixed-effects model HR, 0.72 [95% confidence interval, 0.54-0.96]; P = 0.014) and anti-PD-L1+Cobi (HR, 0.70 [0.50-0.98]; P = 0.018), but not with anti-PD-L1-only (HR, 0.83 [0.57-1.21]; P = 0.172). OS with anti-PD-L1+Tre and anti-PD-L1+Cobi did not significantly differ from that with R/T/F (P = 0.565 and P = 0.500, respectively). Conclusions: In refractory MSI-unselected mCRC, anti-PD-L1 monotherapy was ineffective but anti-PD-L1+Tre and anti-PD-L1+Cobi therapies exhibited efficacies comparable to that of R/T/F.
Add-on anti-vascularendothelial growth factor agents with the second-line chemotherapy in metastatic colorectal cancer: A meta-analysis of randomized trials.
Authors: Kuan Feng-Che , Kuo Liang-Tseng , Hsieh Meng-Chiao , Chen Min-Chi , Lee Kuan-Der 
Published: May 2019

e15059 Background: Whether the survival benefits of anti-VEGF agents in second-line treatment for metastatic colorectal cancer (mCRC) are confounded by clinical factors is unclear. Methods: We searched literatures from PubMed, Embase, Cochrane Library, and conference abstracts through February 2017. Results: Seven randomised controlled trials with total 4931 patients comparing add-on anti-VEGF agents and second-line chemotherapy with chemotherapy alone were included with extracted outcomes from published reports. The primary outcomes were progression-free survival (PFS) and overall survival (OS). Anti-VEGF agents improved PFS and OS (PFS: hazard ratio [HR], 0·78; 95% CI, 0·69–0·88; OS: HR, 0·86; 95% CI, 0·78–0·95) without significant subgroup differences in age(< 65 or ≥65 years, p = 0·815), gender (p = 0·322), ECOG performance status (0 or ≥1, p = 0·514), number of metastases (1 or > 1, p = 0·903), metastasis to the liver only (yes or no, p = 0·713), second-line chemotherapy regimen (oxaliplatin- or irinotecan-based, p = 0·509), and the previous use of bevacizumab (yes or no, p = 0·185). The funnel plots showed symmetrical patterns and the result of Egger’s test was insignificant (PFS, p = 0·220; OS, p = 0·361), indicating no apparent publication bias. Conclusions: For second-line treatment in mCRC, anti-VEGF agents play an important role in PFS and OS in all subgroups of patients.
Mutational profiles and amplifications on circulating tumor DNA testing in patients with young-onset colorectal cancer.
Authors: Kamatham Saivaishnavi , Colibaseanu Dorin , Merchea Amit , Shahjehan Faisal , Kasi Pashtoon Murtaza 
Published: May 2019

e15067 Background: There has been a concerning rise of colorectal cancer (CRC) in young individuals (<50 years). There appears to be a preponderance of left-sided tumors and rectal cancers, however, the etiology and biology is not entirely known. Our aim was to describe the results of circulating tumor DNA based (ctDNA) testing in young-onset CRC. Methods: We studied the results of 186 patients with CRC who had ctDNA testing, of whom 41 (22%) had young-onset CRC from January 2017 to January 2019 at Mayo Clinic, Florida. They were categorized based on their age at diagnosis. Results: The age distribution and the aberrations seen are summarized in the table. 25 (61%) were left sided, 9 (22%) were right sided, 7 (17%) were rectal tumors. ctDNA testing was able to identify mutations in 4 (9.8%) patients with BRAFV600E, 8 (19.5%) with RAS and categorized 29 (70.7%) as RAS/RAF wild-type. Furthermore, amplifications were detected in MYC 6 (14.6%) , MET 3 (7.3%) and ERBB2 1 (2.4%). 3(7.3%) were MSI-High and there were 4 individuals with BRCA1/2 noted on ctDNA testing. Conclusions: ctDNA testing for young onset CRC is feasible and identifies a spectrum of clinically meaningful and actionable aberrations. These can further be of use to evaluate treatment response, progression or help in selection of clinical trials. [Table: see text]