tbuckley/cabot-search huggingface dataset:
Analysis of pancreatobiliary adenocarcinoma (PBC) treatment response and resistance utilizing circulating tumor DNA (ctDNA).
Authors: Madhulika Banerjee, Alejandro Recio Boiles, Sumana Veeravelli, Jorge Andres Leiva, Kathylynn Saboda, Denise Roe, Ali McBride, Hani M. Babiker
Journal: Journal of Clinical Oncology (2020)

758 Background: Accurate disease monitoring in PBC is instrumental for optimal therapeutic decision-making. CA 19-9 is the most utilized biomarker, though it has limited sensitivity/specificity and cannot be used in CA 19-9 non-secretors (n-S). ctDNA is a potentially helpful monitoring aid and surrogate for PBC n-S. Serial ctDNA could identify emerging resistant driver mutations. Our study prospectively examined ctDNA in PBC patients receiving treatment and retrospectively correlated it with clinical response. Methods: We performed genomic testing of ctDNA from metastatic PBC patients’ plasma from 11/2016 to 08/2019. This included 77 patients, of those, 18 had &gt;1 ctDNA measurement with 49 correlative data points in total. Demographics, serial CA 19-9 levels and imaging results were collected. ctDNA analysis by parallel sequencing of amplified target genes (74) using Guardant360 was obtained. We correlated imaging and CA 19-9 responses with molecular alterations in patients receiving systemic chemotherapy. Descriptive statistics and logistic regression of the data was performed. Results: Of those included, median age was 66 yo, 50% male, and 92% pancreatic ductal adenocarcinoma. Baseline ctDNA showed 103 mutations including TP53 12.6%, KRAS 9.7%, MET 6.8%, APC, ARID1A and NF1 4.8% each, and others &lt; 3%. 44% of patients were n-S with 75% having both TP53 and KRAS mutations. APC, ARID1A, and NF1 were only present in n-S. 91% vs 90% KRAS and 84% vs 78% TP53 of n-S and secretors (S), respectively, had correlation between ctDNA levels and imaging response. S TP53 and KRAS mutations correlated to CA19-9 levels and scans in 78% and 70% responses. New TP53 subclonal variant mutations were the most common resistance mutations for all progressions (75%). A logistic regression model of imaging progression on change in CA19-9 secretion and TP53 or KRAS expression was not statistically significant. Conclusions: Baseline ctDNA level changes ( TP53 and KRAS) can potentially act as a biomarker of response in PBC, specifically in n-S. TP53 subclonal mutations were the most common resistant alterations at progression and can be explored as future targets. This is being explored in larger prospective trials.
A phase I study of olaparib in combination with capecitabine-based chemoradiation (CRT) in patients (pts) with locally advanced pancreatic cancer (LAPC).
Authors: T.R. Jeffry Evans, Martin McKinlay Eatock, Liz-Anne Lewsley, Caroline Kelly, Elaine McCartney, Aileen Duffton, Peter Houston, Claire Harrison, Colin Purcell, Miranda Ashton, Alanna Morton, Jill Graham, Anthony J. Chalmers, Fiona Thomson, Chantevy Pou, Alan Bilsland, Susie Cooke, David McIntosh, Derek B. Grose
Journal: Journal of Clinical Oncology (2020)

709 Background: Olaparib is a potent inhibitor of PARP-1, which has a critical role in signalling DNA single strand breaks (SSB) as part of the base excision repair pathway, and may have radio-sensitizing effects due to impaired resolution of radiation induced SSB. We hypothesize that O may potentiate the effects of X-CRT in pts with LAPC. Methods: Eligible pts with LAPC, ECOG &lt; 1, tumor diameter &lt; 6cm, with stable disease (SD) or response after 12 weeks’ induction chemotherapy, were treated with 1 of 4 escalating doses of O given bid po starting on day -3, and then in combination with X (830 mg/m2 bid) and radiation (50·4 Gy in 28 fractions) all administered Mon-Fri. Dose limiting toxicities (DLT) were determined on clinical and lab toxicity assessments (NCI-CTC AE v4.03) performed weekly from the start of O until completion of O plus X-CRT (i.e. 6 weeks). Dose escalation continued with a rolling-six design until the Maximum Tolerated Dose (MTD) was reached. Blood samples for PK analyses of O and PD measurement (inhibition of PARP activity) were collected on day -3 (O monotherapy) and during week 1 of O + X-CRT. Results: 18 pts, (9 m, 9 f, ECOG 0/1 [n=6/12]), age range 49-81 (median=70) years, with histologic (14) or cytologic (4) proven LAPC, had received induction chemotherapy with gemcitabine [GEM] (n=2), GEM + X (12), or FOLFIRINOX (3) with partial response (n=4) or stable disease (14). Pts received 50 (3), 100 (4), 150 (6), or 200 (5) mgs bid of O with X+CRT. DLTs were observed in 2 pts (both at 200mgs bid): 1 pt with grade 3 nausea (on optimal anti-emetics) and grade 3 fatigue, 1 pt with grade 3 anorexia. 6 pts were subsequently recruited at 150mgs bid with no DLTs. No pts had complete response, 2 pts had partial response (1 pt each at 100 and 150 mgs bid) and 1 pt (at 100 mgs bid) had progressive disease; the remaining 14 pts had SD. Conclusions: The recommended dose (RP2) of O is 150mgs bid when given in combination with X + CRT in LAPC. Recruitment of up to 12 pts with borderline operable LAPC at the RP2 is ongoing. PK analyses of O, PD studies (PARP inhibition – PBMCs; cytokeratin 18 – serum; γH2AX foci – hair follicles), and exploratory predictive marker studies (tumor – NGS; RNA exome sequencing) are ongoing. Clinical trial information: ISRCTN10361292.
Pilot study to test safety and efficacy of avelumab in small bowel adenocarcinoma (SBA).
Authors: Dana Backlund Cardin, Jennifer Whisenant, G. Dan Ayers, Jill Gilbert, Kimberly Brown Dahlman, Chanjuan Shi, Jordan Berlin
Journal: Journal of Clinical Oncology (2020)

797 Background: SBA is rare and often grouped with, and treated like, large intestinal adenocarcinomas. However, SBA has a very different microenvironment and could respond differently to the same therapies, potentially lowering efficacy. Also no standard treatments exist due to the lack of prospective randomized trials. We presented data at GI ASCO 2016 that suggested SBAs might benefit from targeting the PD-1/PD-L1 axis based on strong PD-L1 staining in ~50% of SBAs tested. Thus, we designed a pilot phase 2 trial to study safety and efficacy of avelumab in SBA. Methods: Patients (pts) with advanced (not amenable to surgery) or metastatic disease were eligible; ampullary tumors were considered part of the duodenum and allowed. Pts with prior PD-1/PD-L1 were excluded. Avelumab (10 mg/kg) was given every 2 weeks in 14-day cycles, and imaging was performed every 8 weeks. Primary endpoint was response rate (RR). Enrollment of 25 pts were planned, and avelumab would be considered active if ≥4 responses (RR≥16%) were observed (80% power, a = 5%). Secondary endpoints included disease-control rate (DCR) and progression-free survival (PFS). Results: Eight SBA pts (5 small intestine; 3 ampullary) were enrolled, with a majority (88%) being male and a median age of 61 years. Median time on treatment was 3.4 months; 1 patient is still on study with an ongoing partial response (PR). Of 7 efficacy-evaluable patients, 2 had a PR for a RR of 29%; DCR was 71% (5/7). Median PFS was 8.0 months. Most frequent, related adverse events were fatigue (38%), elevated alkaline phosphatase (25%), and infusion related reaction (25%), all ≤G2; a G3 (not serious) hypokalemia and a G4 (serious) diabetic ketoacidosis occurred in 1 pt each. Conclusions: Avelumab was considered safe, and antitumor activity was observed as evidenced by a 29% RR and 71% DCR. Despite this benefit, accrual was slower than expected and the study was closed early due to feasibility. A general clinical observation is that more pts are receiving immunotherapy off-label as the availability of these agents increases. This was a likely contributor to slow accrual, in addition to disease rarity. Analysis of PD-L1 expression, MSI status, and other immune cell markers is planned and will be compared to response. Clinical trial information: NCT03000179 .
First-line durvalumab + monalizumab, mFOLFOX6, and bevacizumab or cetuximab for metastatic microsatellite-stable colorectal cancer (MSS-CRC).
Authors: Zev A. Wainberg, Jennifer Robinson Diamond, Giuseppe Curigliano, Sanjeev Deva, Johanna C. Bendell, Sae-Won Han, Aparna Kalyan, Jarushka Naidoo, Richard D. Kim, Sandip Pravin Patel, Panagiotis Kourtesis, Xia Li, Maria Ascierto, Xuyang Song, Mayukh Das, Neil Howard Segal
Journal: Journal of Clinical Oncology (2020)

128 Background: Targeting multiple immune checkpoint pathways and combining checkpoint inhibition with chemotherapy may enhance response in MSS-CRC. In a Phase 1/2, multicenter, open-label study, the anti-PD-L1 antibody durvalumab (D) was added to monalizumab (M; an anti-NKG2A antibody). In dose-exploration cohorts, D+M was added to chemotherapy and a biologic agent (bevacizumab [DMCB] or cetuximab [DMCC]) for first-line treatment of advanced/metastatic MSS-CRC. Initial data showed DMCB was well tolerated and clinically active. Here we report updated efficacy and safety of DMCB and initial safety of DMCC. Methods: Eligible patients (pts) had MSS-CRC ( RAS/BRAF wt with a left-sided colon primary tumor in the DMCC cohort) and ECOG PS 0–1. They received D 1500 mg Q4W, M 750 mg Q2W, mFOLFOX6 Q2W and bevacizumab 5 mg/kg Q2W or cetuximab 250/400 mg/m 2 QW (up to 500 mg/m 2 Q2W) for up to 3 yr. The primary endpoint was safety and tolerability; secondary endpoints included antitumor activity. Results: As of Aug 26, 2019, 18 pts received DMCB and 17 pts received DMCC. Treatment-emergent adverse events (AEs) occurred in 100.0% of the DMCB cohort (most commonly fatigue, nausea and peripheral neuropathy) and 94.1% of the DMCC cohort (most commonly peripheral neuropathy, rash and dermatitis acneiform). The AEs were grade 3/4 in 77.8% of pts receiving DMCB and 70.6% of pts receiving DMCC, and were serious in 38.9% and 47.1%, respectively. Response was evaluable in 17 pts receiving DMCB; objective response rate was 41.2% (all PRs; Table). Responses occurred early and the median duration of response has not yet been reached. Conclusions: In advanced/metastatic MSS-CRC, first-line DMCB and DMCC had a manageable safety profile and DMCB showed promising preliminary activity. Clinical trial information: NCT02671435. [Table: see text]
Deep brain stimulation for Tourette’s syndrome
Authors: Wenying Xu, Chencheng Zhang, Wissam Deeb, Bhavana Patel, Yiwen Wu, Valerie Voon, Michael S. Okun, Bomin Sun
Journal: Translational Neurodegeneration (2020)

Abstract Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by the presence of multiple motor and vocal tics. TS usually co-occurs with one or multiple psychiatric disorders. Although behavioral and pharmacological treatments for TS are available, some patients do not respond to the available treatments. For these patients, TS is a severe, chronic, and disabling disorder. In recent years, deep brain stimulation (DBS) of basal ganglia-thalamocortical networks has emerged as a promising intervention for refractory TS with or without psychiatric comorbidities. Three major challenges need to be addressed to move the field of DBS treatment for TS forward: (1) patient and DBS target selection, (2) ethical concerns with treating pediatric patients, and (3) DBS treatment optimization and improvement of individual patient outcomes (motor and phonic tics, as well as functioning and quality of life). The Tourette Association of America and the American Academy of Neurology have recently released their recommendations regarding surgical treatment for refractory TS. Here, we describe the challenges, advancements, and promises of the use of DBS in the treatment of TS. We summarize the results of clinical studies and discuss the ethical issues involved in treating pediatric patients. Our aim is to provide a better understanding of the feasibility, safety, selection process, and clinical effectiveness of DBS treatment for select cases of severe and medically intractable TS.
Pandemic potential of 2019-nCoV
Authors: Robin Thompson
Journal: The Lancet Infectious Diseases (2020)

An important determinant of whether or not 2019 novel coronavirus (2019-nCoV) will ultimately cause a global pandemic is its ability to become established upon its importation to a new country. Cases of 2019-nCoV infection have so far been reported in 24 countries, yet little human-to-human transmission outside of China has occurred. The key quantity governing whether or not 2019-nCoV can establish and generate a sustained outbreak on arrival in a new country is the reproduction number, R, which represents the average number of individuals that each infector will transmit the virus to. If R is greater than 1, sustained transmission can occur; if R is less than 1, then chains of transmission will simply stutter out. In the ongoing outbreak, assuming an R of 2·2, as reported by Li and colleagues,1Li Q Guan X Wu P et al.Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia.N Engl J Med. 2020; (published online Jan 29.)DOI:10.1056/NEJMoa2001316Crossref Scopus (10982) Google Scholar then just over half of infections must be prevented to bring R below 1. This might be expected to be challenging if 2019-nCoV can be transmitted when infectors are not symptomatic. However, there is little evidence to suggest presymptomatic transmission of 2019-nCoV.2Kupferschmidt K Study claiming new coronavirus can be transmitted by people without symptoms was flawed.Science. 2020; (published online Feb 3.)DOI:10.1126/science.abb1524Crossref Google Scholar Even if 20% of infections are occurring because of presymptomatic infectors (a level roughly halfway between the respective values for severe acute respiratory syndrome and influenza viruses,3Fraser C Riley S Anderson RM Ferguson NM Factors that make an infectious disease outbreak controllable.Proc Natl Acad Sci USA. 2004; 101: 6146-6151Crossref PubMed Scopus (808) Google Scholar which is likely to be an overestimate), then 80% of infections would be due to symptomatic infectors. Because only slightly more than half of infections need to be prevented to bring R below 1, effective isolation of symptomatic hosts alone should be sufficient to prevent sustained outbreaks of 2019-nCoV outside China. Of course, detection and isolation of symptomatic hosts is not always carried out effectively, and detection is challenging when symptoms are mild. Therefore, efforts to counter presymptomatic transmission might sometimes be merited. However, when implementing such measures (eg, the UK's isolation of passengers returning from Hubei, infected or not), the substantial cost to individuals who might not be carrying the virus should be considered carefully. With fast isolation of symptomatic individuals alone, including self-isolation of those with mild symptoms, sustained outbreaks outside of China can be prevented. I declare no competing interests. Challenges of coronavirus disease 2019
An economic evaluation of palliation of dysphagia in esophageal cancer: Analysis of the TROG 03.01/NCIC ES.2 phase III study in advanced esophageal cancer in patients treated with radiotherapy versus chemoradiotherapy.
Authors: Michael Gordon Penniment, Paolo De Ieso, Rebecca Wong, Hossein Afzali
Journal: Journal of Clinical Oncology (2020)

340 Background: In advanced oesophageal cancer (OC), 90% of patients have dysphagia as a principal symptom. The randomised TROG 03.01 trial reported no significant overall survival or dysphagia relief difference between 15 fractions (#) radiotherapy alone (RT) or RT plus chemotherapy (CRT) Future studies may consider RT hypofractionation, different chemotherapy, esophageal stenting, and best supportive care. Comparing costs and outcomes, economic evaluation often informs public funding decisions in countries such as Australia and the UK. The objective of this analysis was to derive baseline cost and outcome for further studies. Methods: Given equal outcomes (non-inferiority) between treatment arms, cost-minimisation analysis (CMA) was used to evaluate cost-effectiveness, cost a deciding factor if no other benefit was predicted. We explored 15 and 10 # courses used in TROG 03.01 and alternatives, 1 or 5 # Study design and uncertainty analyses were provided. Sub-analysis assessed salvage therapy for local and systemic progression. The EQ-5D (and SF-12) was used to determine utility values to estimate Quality-Adjusted Life years (QALYs) for evaluation. Results: From a health system perspective, costs and outcomes of RT were estimated at $4,700 AUD (15 # course). If, compared with RT alone, an alternative option is more costly but more effective, then a cost-utility analysis (CUA) is preferred economic evaluation. Intervention and in/outpatient costs, initial phase and post treatment were considered for stent insertion and alternative chemotherapy regimens. Alternatively, autocontoured CT planning and machine learning were modelled to reduce RT planning cost (est. $650/p). Total cost for 5 # is $3200 could be further reduced through process efficiency savings using CMA approach. Conclusions: The value of palliative approaches in common malignancies is difficult to assess. This study uses economic analysis to guide paying authority decisions. RT can be simplified from the TROG 03.01 approach to lessen cost and simplify treatment. The clinical efficiency of 1 or 5 # should be evaluated.
Real-world data validation for differential expression of immunoregulatory molecules and targetable cancer genes may provide therapeutic insights into agnostic-driven trial designs.
Authors: Jacob J. Adashek, Christopher W. Szeto, Sandeep K. Reddy, Philippe E. Spiess
Journal: Journal of Clinical Oncology (2020)

10 Background: Targeting actionable genes and using immunotherapy have increased treatment options. We previously reported that some immunoregulatory molecules are found differentially regulated in the presence of certain gene mutations regardless of cancer subtype. Here we validated a subset of these associations in an independent, real-world dataset with distinct clinicopathological characteristics. Methods: Previously, 2740 TCGA patients were identified to have at least one potentially oncogenic mutation (mt) within an established 50-gene hotspot panel. Differential expression of 10 immunoregulatory molecules (IRM) was analyzed between mutant (mt) vs. wild-type (wt). To ensure observed significant associations were not confounded by tumor-type, differential IRM expression within mt-enriched tumor-types was compared to that of mt vs. wt. Now, using the NantHealth external database of 2739 unselected clinical cases these associations were validated. Results: Within the TCGA cohort 19/50 gene mutations were found to be significantly associated with ≥1 IRM expression. In many, the mt effect-size was larger than that of tumor-type; e.g. head &amp; neck carcinomas (HNSCC) are highly enriched for CDKN2A mt (OR = 4.9, p = 4.3e-9), yet CDKN2A mt are more associated with CTLA4 expression than HNSCC histology (t = 7.0 vs. 5.4). Of these 15 associations, 6 were validated within the independent later-stage NantHealth cohort. Most notably, CDKN2A mt was validated as associated with increased PD1 and CTLA4 expression while KRAS and APC mt were validated as associated with decreased PDL1/2 expression. Conclusions: The presented differential checkpoint expression patterns are strongly associated with mutation status and are not primarily driven by tissue-type, which have been further validated by an external database. Strategies combining genomic targets have been shown to yield success as well as using immunotherapies. Our data suggests there may be a role for combining NGS targets along with IRM expression patterns to better guide future design of clinical trials in combatting various cancers in a tissue-agnostic fashion.
Association between postoperative pneumonia and prognosis of patients with esophageal cancer.
Authors: Yosuke Atsumi, Toru Aoyama, Ayako Tamagawa, Hiroshi Tamagawa, Mihwa Ju, Keisuke Koumori, Yukio Maezawa, Kazuki Kano, Keisuke Kazama, Masaaki Murakawa, Masakatsu Numata, Tsutomu Sato, Norio Yukawa, Munetaka Masuda, Yasushi Rino
Journal: Journal of Clinical Oncology (2020)

370 Background: We examined the association between postoperative pneumonia and prognosis of patients with esophageal cancer after curative surgery. Methods: We enrolled 122 patients who underwent curative resection for esophageal cancer between 2008 and 2018. The patients who had postoperative pneumonia were categorized into the pneumonia group, while those without postoperative pneumonia were classified into the non-pneumonia group. We identified the risk factors for the recurrence-free survival (RFS) and the overall survival (OS). Postoperative pneumonia was defined using the revised Uniform Pneumonia Score. Results: Thirty-four of the 122 patients (27.9%) had postoperative pneumonia. The 5-year OS rate after surgery in the pneumonia group was significantly lower than that in the non-pneumonia group (28.2% versus 55.1%, p = 0.006). Although not significant, the 5-year RFS rate after surgery in the pneumonia group tended to be lower than that in the non-pneumonia group (18.9% versus 49.2%, p = 0.061). A multivariate analysis identified postoperative pneumonia as a significant independent risk factor for the OS (hazard ratio = 2.15; 95% confidence interval, 1.25 to 3.68; P = 0.006). Conclusions: Our analysis showed postoperative pneumonia was an independent risk factor for worse overall survival in patients who underwent curative resection for esophageal cancer. This finding suggests that we should plan the surgical procedure, perioperative care and surgical strategy to prevent postoperative pneumonia.
Treatment patterns and long-term clinical outcomes in Chinese patients with nonmetastatic gastric cancer: Results from the non-interventional EVIDENCE registry study.
Authors: Jiafu Ji, Shukui Qin, Xin Wang, Weiping Zhou, Lin Chen, Zhichao Zheng, Wuyun Su, Helong Zhang, Jianhua Wang, Qi Luo, Yong Tang, Lin Shen
Journal: Journal of Clinical Oncology (2020)

307 Background: Although gastric cancer (GC) is a leading cause of cancer-related death in China, important questions about optimal management remain unanswered. The EVIDENCE registry study evaluated data from patients with GC in China to assess the pattern of treatments and long-term clinical outcomes. Methods: Five cohorts of patients with different HER2 and metastatic (m) status were evaluated from April 2013 to June 2018 in this prospective, multicenter, non-interventional, real-world study. Data from patients with operable non-mGC are reported: Cohort III (HER2+) and Cohort V (HER2−). Outcome measures included overall survival (OS), event-free survival (EFS), and disease-free survival (DFS). Results: Cohorts III/V included 758 patients (Cohort III, 271; Cohort V, 487); 75.5% were male and the mean age was 58.8 years. The majority of Cohort III/V patients (538/758; 71.0%) received only adjuvant treatment, with 215/758 (28.4%) receiving S1+oxaliplatin. Neoadjuvant or adjuvant trastuzumab was administered to 43/758 patients (Cohort III, 42; Cohort V, 1). Radiation during neoadjuvant or adjuvant treatment was administered to 23/758 (3.0%) patients. The median duration of follow-up was 515 days, during which 72 (9.5%) patients died due to progressive disease. OS rates (95% CI) for Cohorts III and V were 94% (89–96) and 95% (92–97) at 1 year, and 76% (67–83) and 70% (64–75) at 3 years, respectively. Respective EFS rates were 82% (76–87) and 86% (83–89) at 1 year, and 62% (53–70) and 57% (51–63) at 3 years; and respective DFS rates were 88% (82–93) and 86% (81–89) at 1 year and 69% (58–78) and 62% (55–68) at 3 years. Multivariate analysis indicated that the primary tumor site (p = 0.004) and overall cancer stage (p &lt; 0.001) were associated with DFS. Regarding the primary tumor site, there was a trend towards better DFS for antrum tumors (hazard ratio 0.59; 95% CI 0.32–1.07) when evaluated against gastroesophageal junction tumors. Conclusions: This longitudinal analysis of clinicopathologic characteristics and outcomes of Chinese patients with non-mGC will provide critical information that will help to inform disease management. Clinical trial information: NCT01839500.