tbuckley/cabot-search huggingface dataset:
Pembrolizumab (pembro) for advanced biliary adenocarcinoma: Results from the KEYNOTE-028 (KN028) and KEYNOTE-158 (KN158) basket studies.
Authors: Yung-Jue Bang, Makoto Ueno, David Malka, Hyun Cheol Chung, Adnan Nagrial, Robin Kate Kelley, Sarina Anne Piha-Paul, Willeke Ros, Antoine Italiano, Kazuhiko Nakagawa, Hope S. Rugo, Filippo G. De Braud, Andrea I. Varga, Aaron Richard Hansen, Chao Gao, Suba Krishnan, Kevin Norwood, Toshihiko Doi
Journal: Journal of Clinical Oncology (2019)

4079 Background: Antitumor activity with pembro, an anti–PD-1 antibody, has been observed in patients (pts) with advanced/metastatic biliary tract cancers (BTC), who have limited treatment options. We present follow-up data from pts with advanced BTC treated with pembro in the KN158 (NCT02628067; phase 2) and KN028 (NCT02054806; phase 1) studies. Methods: Eligible pts ≥18 y in the KN158/KN028 BTC cohorts had histologically/cytologically confirmed incurable advanced BTC that progressed after/failed any number of prior standard treatment regimens, measurable disease per RECIST v1.1, ECOG PS of 0/1, and no prior immunotherapy. PD-L1–positivity (membranous PD-L1 expression in ≥1% of tumor and associated inflammatory cells or positive staining in stroma) was required for eligibility in KN028, but not KN158. Pts received pembro 200 mg Q3W (KN158) or 10 mg/kg Q2W (KN028) for up to 2 y. Radiographic imaging occurred Q9W for 12 mo (KN158) or Q8W for 6 mo (KN028) and Q12W thereafter. Primary efficacy endpoint in both studies was ORR by RECIST 1.1. Response assessed by independent central review is reported. Results: Median (range) follow-up was 7.5 (0.6–29.5) mo in the 104 pts from KN158 and 6.5 (0.6–33.1) mo in the 24 pts from KN028 with BTC. All pts in KN028 and 61 in KN158 had PD-L1–positive tumors. No pt had MSI-H tumors (not assessed in KN028). In KN158, ORR was 5.8% (6/104, all PR [including 1 pt with PD-L1–negative tumor]; 95% CI, 2.1%–12.1%) and median duration of response (DOR) was not reached (NR; range, 6.2 to 23.2+ mo). Median OS and PFS were 7.4 mo (95% CI, 5.5–9.6) and 2.0 mo (95% CI, 1.9–2.1). 12-mo OS rate was 32.7%. In KN028, ORR was 13.0% (3/23, all PR; 95% CI, 2.8%‒33.6%) and median DOR was NR (range, 21.5 to 29.4+ mo). Median OS and PFS were 6.2 mo (95% CI, 3.8‒10.3) and 1.8 mo (95% CI, 1.4‒3.7), respectively. 12-mo OS rate was 27.6%. Grade 3–5 treatment-related AEs occurred in 13.5% in KN158 (1 pt had grade 5 renal failure) and 16.7% of pts in KN028 (no grade 5). 18.3% in KN158 and 20.8% of pts in KN028 had an immune-mediated AE or infusion reaction. Conclusions: Pembro provides durable antitumor activity, regardless of PD-L1 expression, and manageable toxicity in a subset of pts with advanced BTC. Clinical trial information: NCT02054806 and NCT02628067.
Efficacy of a novel potent and high water-soluble selective PARP inhibitor CVL218 in glioma.
Authors: Steve Shen, Zehong Miao, Chunhao Yang‘
Journal: Journal of Clinical Oncology (2019)

e13539 Background: Glioma is the most common, deadly, and difficult-to-treat intracranial tumor. Up to 70% of gliomas are found to carry isocitrate dehydrogenase (IDH) mutations, which induce a homologous recombination defect (HRD) that renders glioma cells sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi). However, 4 launched PARPi have limitation for IDH-mutant glioma because of low concentration level in brain. CVL218 is a novel potent and high water-soluble selective PARP-1/2 inhibitor. Pharmacokinetic studies in rats showed that CVL218 can easily across the BBB, has 10 times higher concentration in brain than in the plasma, indicating its therapeutic potential in glioma. Here, we examined its effect on glioma in vitro and in vivo. Methods: BT142 mut/- glioma cells with a homozygous IDH1 R132H mutation were exploited. Chemotherapeutic agent temozolomide (TMZ), PARPi Olaparib and Niraparib, were used as controls. The inhibition of BT142 cell growth by compounds in vitro was measured by MTT assay. Female NOD/SCID mice with orthotopic xenografts of BT142 glioma cells were used to evaluate the antitumor efficacy of compounds in vivo. Medium survival time (MST) was compared using the Kaplan-Meier method and logrank test. Results: CVL218 inhibited the BT142 cell growth in vitro with an IC50 of 2.07 ± 0.62 μM, better than Olaparib and Niraparib. Orthotopic xenograft glioma mice model study showed that CVL218 group significantly extended the MST to 98.0 days ( p= 0.0206), while MST of TMZ treated group is 85.0 days. Conclusions: CVL218 inhibits IDH1-mutant BT142 glioma cell growth in vitro and in vivo. The present findings suggest that CVL218 is a potential agent which could be useful as a treatment for IDH-mutant glioma. We will start its phase I clinical study for glioma soon.
ATM loss in primary prostate cancer: Analysis of &gt;1000 cases using a validated clinical-grade immunohistochemistry (IHC) assay.
Authors: Emmanuel S. Antonarakis, Harsimar B Kaur, Jessica Hicks, Colin C. Pritchard, Angelo M De Marzo, William B. Isaacs, Tamara L. Lotan
Journal: Journal of Clinical Oncology (2019)

5069 Background: ATM is a protein kinase acting as the main signal transducer of double-strand DNA break repair, in addition to mediating other cellular functions. Germline and somatic pathogenic mutations in ATM occur in a significant fraction of prostate cancers, and targeted therapies for ATM-deficient tumors ( e.g. ATR inhibitors) appear promising. Because DNA sequencing assays frequently cannot distinguish mono-allelic from bi-allelic ATM alterations, a clinical-grade protein IHC assay for ATM loss is needed to select men for these trials and better characterize ATM-deficient tumors. Methods: We validated an automated dichotomously-scored IHC assay to detect ATM protein loss in primary prostate cancer using prostate cancer cell lines with and without bi-allelic ATM inactivation and 49 high-grade (primary Gleason pattern 5) prostate tumors with known ATM genomic status. We then examined the frequency of ATM loss among 23 tumors with pathogenic germline ATM mutations, as well as &gt; 1000 additional primary prostate carcinomas using tissue microarrays (TMA). Results: ATM loss by IHC was found in 14% (7/49) of primary Gleason pattern 5 (5+4 = 9 and 5+5 = 10) tumors. Of these, all cases with adequate tumor content and DNA yield had underlying pathogenic ATM mutations. Of the remaining 42 cases without ATM protein loss, none had ATM alterations. Among men with pathogenic germline ATM mutations, 74% (17/23) had ATM loss by IHC. Of these, 76% (13/17) had homogeneous loss of ATM protein in all tumor cells within a dominant tumor nodule, suggesting that ATM loss was an early clonal event. On TMA analysis, 90% (944/1044) of tumors were evaluable for ATM status by IHC. Among these, ATM loss was seen in 3.3% (31/944), and was significantly more common in tumors with Gleason scores 9-10 (20/198; 10.1%) than in those of all other Gleason grades (11/746; 1.5%) ( P&lt; 0.0001). Conclusions: Validated ATM IHC is a sensitive assay for detecting underlying genomic ATM alterations. ATM protein loss appears to be an early event occurring in the majority of tumors with underlying germline pathogenic ATM mutations, and is significantly enriched in high-grade prostate cancers (especially Gleason grades 9-10).
2018 Cholesterol Clinical Practice Guidelines: Synopsis of the 2018 American Heart Association/American College of Cardiology/Multisociety Cholesterol Guideline*
Authors: Scott M. Grundy, Neil J. Stone
Journal: Annals of Internal Medicine (2019)

In November 2018, the American Heart Association and American College of Cardiology (AHA/ACC) released a new clinical practice guideline on cholesterol management. It was accompanied by a risk assessment report on primary prevention of atherosclerotic cardiovascular disease (ASCVD).A panel of experts free of recent and relevant industry-related conflicts was chosen to carry out systematic reviews and meta-analyses of randomized controlled trials (RCTs) that examined cardiovascular outcomes. High-quality observational studies were used for estimation of ASCVD risk. An independent panel systematically reviewed RCT evidence about the benefits and risks of adding nonstatin medications to statin therapy compared with receiving statin therapy alone in persons who have or are at high risk for ASCVD.The guideline endorses a heart-healthy lifestyle beginning in childhood to reduce lifetime risk for ASCVD. It contains several new features compared with the 2013 guideline. For secondary prevention, patients at very high risk may be candidates for adding nonstatin medications (ezetimibe or proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors) to statin therapy. In primary prevention, a clinician-patient risk discussion is still strongly recommended before a decision is made about statin treatment. The AHA/ACC risk calculator first triages patients into 4 risk categories. Those at intermediate risk deserve a focused clinician-patient discussion before initiation of statin therapy. Among intermediate-risk patients, identification of risk-enhancing factors and coronary artery calcium testing can assist in the decision to use a statin. Compared with the 2013 guideline, the new guideline gives more attention to percentage reduction in low-density lipoprotein cholesterol as a treatment goal and to long-term monitoring of therapeutic efficacy. To simplify monitoring, nonfasting lipid measurements are allowed.
Case 19-1980
Authors: Richard C. Cabot, Robert E. Scully, James J. Galdabini, Betty U. McNeely, Blake Cady
Journal: New England Journal of Medicine (1980)

CASE 19-1980Presentation of Case First admission. A 52-year-old mentally retarded man was admitted to the hospital because of chest pain.Six years before admission a diagnosis of thrombophlebitis was made, and warfarin was begun. Two years before entry an electrocardiogram demonstrated a pattern of old anteroseptal myocardial infarction. Seven months before entry he came to the hospital because of anterior chest pain. Progressive exertional dyspnea developed and improved after the administration of digoxin. For several days before entry the abdominal girth increased, and he passed bloody stools. On the day of admission anterior chest pain recurred.He had . . .
Biomarker driven phase II umbrella trial study of AZD1775, AZD2014, AZD2811 monotherapy in relapsed small cell lung cancer.
Authors: Sehhoon Park, Joonho Shim, Hyun Ae Jung, Jong-Mu Sun, Se-Hoon Lee, Woong-Yang Park, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park
Journal: Journal of Clinical Oncology (2019)

8514 Background: Recent progress in genomic profiling of small cell lung cancer (SCLC) has demonstrated that a high proportion of SCLC harbor mutations in cell cycle-related genes and RICTOR amplification. With the recent introduction of cell-cycle altering small molecules, AZD1775 (WEE1 inhibitor), AZD2811 (aurora kinase B inhibitor) and mTOR1/2 inhibitor (AZD2014), biomarker-driven umbrella study is being conducted in relapsed SCLC. Methods: This is a phase II umbrella trial study with multiple monotherapy arms in resistant SCLC who has failed prior platinum-based chemotherapy and known genomic profile from pre-designed screening study of SUKSES-S (Small cell lung cancer Umbrella Korea StudiES, NCT02688894). Patients with MYC family amplification or co-alteration in CDKN2A and TP53 were allocated to SUKSES-C (AZD1775 arm, NCT02593019); RICTOR amplification to SUKSES-D (AZD2014 arm, NCT03106155). Otherwise, patients were randomly assigned to non-biomarker specific arms, SUKSES-N1 (AZD1775 arm, NCT02593019) or SUKSES-N3 (AZD2811 arm, NCT03366675). Each cohort was designed as Simon 2-stage scheme. Results: Patients allocated to SUKSES-C (n = 7) &amp; N1 (n = 24) showed no objective response rate and stable disease was observed in 3 patients (42.9%) and 6 patients (25.0%), respectively. The median progression-free survival (PFS) was 1.28 months (95% confidential interval [CI] 1.18–not available [NA]) and 1.21 months (95%CI 1.15-2.33), respectively. SUKSES-D (n = 4) showed no objective response as well as no stable disease with PFS of 1.25 months (95%CI 0.98-NA). SUKSES-N3 (n = 15) showed no objective response with 5 stable disease (33.3%) and PFS of 1.61 months (95%CI 1.18-NA). For the safety record, adverse events (AEs) grade≥3 were observed as follows: SUKSES-C &amp; -N1 (n = 1, 3.2%), -D (n = 3, 75.0%), -N3 (n = 9, 60%). Notably, neutropenia (grade≥3) was frequently observed (n = 8, 53.3%) in AZD2811 arm including a case of septic shock. Conclusions: SUKSES is the first biomarker-driven umbrella study with the largest cohort of genomic profile pre-screened in resistant SCLC patients (n = 275). However, it does not support further development of the current regimens of AZD1775, AZD2811, AZD2014. Altered administration schedule or combination regimen is under development. Clinical trial information: NCT02593019, NCT03106155, NCT03366675.
Adherence to the guidelines: A comparison of biomarker testing implementation in metastatic non-squamous, non-small cell lung cancer in university versus community institutions.
Authors: Sufana Shikdar, Zachary Michael Trisel, Erika Correa, Mariola A. Vazquez Martinez, Kevin Ye Hou, Shaun Bryan Hanson, Vinay Edlukudige Keshava, Peter Lambert, Rajesh Thirumaran, Michael Joseph McCormack, Kristine Marie Ward, Michael Styler
Journal: Journal of Clinical Oncology (2019)

6618 Background: Molecular biomarkers have become essential in determining optimal treatment for patients with advanced non-small-cell-lung cancer (NSCLC). Few studies have evaluated the implementation of biomarker assessment (e.g. EGFR, ALK and ROS1) in routine clinical practice. We endeavored to assess adherence to biomarker testing guidelines in different clinical settings, specifically in a university hospital versus a community hospital in the same region. Methods: A retrospective analysis was conducted in newly diagnosed metastatic non-squamous-NSCLC patients comparing the compliance of biomarker testing based on nationally established guidelines available at the time of diagnosis. De-identified electronic health record (EHR) data were collected from Mercy Catholic Medical Center (MCMC) and Hahnemann University Hospital (HUH) between 1/1/15- 1/30/19. Results were compared in each setting to determine utilization of biomarker testing. Results: 27 patients were identified at MCMC and 41 at HUH. 22 (81%) patients at MCMC and 36 (88%) patients at HUH underwent appropriate molecular testing based on guidelines available at the time of diagnosis. Conclusions: Our data suggests that both university and community institutions have appropriately adapted the evolving guidelines for molecular testing for patients with non-squamous NSCLC. In the rare instances that molecular testing was not performed, the most common reason was inadequate amounts of tissue available. Newer technologies, such as next-gen sequencing and serum based testing, will make compliance with guidelines easier in the future, particularly as increasing numbers of molecular markers will need to be assessed.
Trends in the US and Canadian Pathologist Workforces From 2007 to 2017
Authors: David M. Metter, Terence J. Colgan, Stanley T. Leung, Charles F. Timmons, Jason Y. Park
Journal: JAMA Network Open (2019)

The current state of the US pathologist workforce is uncertain, with deficits forecast over the next 2 decades.To examine the trends in the US pathology workforce from 2007 to 2017.A cross-sectional study was conducted comparing the number of US and Canadian physicians from 2007 to 2017 with a focus on pathologists, radiologists, and anesthesiologists. For the United States, the number of physicians was examined at the state population level with a focus on pathologists. New cancer diagnoses per pathologist were compared between the United States and Canada. These data from the American Association of Medical Colleges Center for Workforce Studies' Physician Specialty Data Books and the Canadian Medical Association Masterfile were analyzed from January 4, 2019, through March 26, 2019.Numbers of pathologists were compared with overall physician numbers as well as numbers of radiologists and anesthesiologists in the United States and Canada.Between 2007 and 2017, the number of active pathologists in the United States decreased from 15 568 to 12 839 (-17.53%). In contrast, Canadian data showed an increase from 1467 to 1767 pathologists during the same period (+20.45%). When adjusted for each country's population, the number of pathologists per 100 000 population showed a decline from 5.16 to 3.94 in the United States and an increase from 4.46 to 4.81 in Canada. As a percentage of total US physicians, pathologists have decreased from 2.03% in 2007 to 1.43% in 2017. The distribution of US pathologists varied widely by state; per 100 000 population, Idaho had the fewest (1.37) and the District of Columbia had the most (15.71). When adjusted by new cancer cases per year, the diagnostic workload per US pathologist has risen by 41.73%; during the same period, the Canadian diagnostic workload increased by 7.06%.The US pathologist workforce decreased in both absolute and population-adjusted numbers from 2007 to 2017. The current trends suggest a shortage of US pathologists.
IMpower150: Analysis of efficacy in patients (pts) with liver metastases (mets).
Authors: Mark A. Socinski, Robert M. Jotte, Federico Cappuzzo, Tony S. K. Mok, Howard West, Makoto Nishio, Vassiliki Papadimitrakopoulou, Francisco J Orlandi, Daniil Stroyakovskiy, Christian A. Thomas, Naoyuki Nogami, Fabrice Barlesi, Anthony Lee, Geetha Shankar, Wei Yu, Marcus Ballinger, Ilze Bara, Alan Sandler, Martin Reck
Journal: Journal of Clinical Oncology (2019)

9012 Background: Atezolizumab (atezo) + bevacizumab (bev) + chemo (carboplatin + paclitaxel [CP]; ABCP) showed improved PFS and OS vs bev + CP (BCP) in pts with chemo-naive NSCLC (IMpower150). Benefit with ABCP vs BCP extended to key subgroups, including pts with baseline (BL) liver mets, which is a poor prognostic factor in metastatic NSCLC. Similar outcomes were not seen with atezo + chemo (IMpower150 [atezo + CP; ACP]; IMpower130; IMpower132), suggesting that the addition of bev to atezo + chemo is important for conferring clinical benefit in these pts. Here we further explore characteristics and responses of pts with BL liver mets in IMpower150. Methods: 1202 ITT pts were randomized 1:1:1 to receive ABCP, ACP or BCP. Doses were: A, 1200 mg; B, 15 mg/kg; C, AUC 6 mg/mL/min; P, 200 mg/m 2 . Coprimary endpoints were OS and investigator-assessed PFS in ITT–wild-type pts. Exploratory analyses included efficacy and safety in pts with liver mets. Results: The data capture ≥ 20-mo follow-up in ITT pts (data cutoff: Jan 22, 2018). 162 pts had BL liver mets (ABCP, n = 52; ACP; n = 53; BCP, n = 57), with a median of 3 metastatic sites and median BL tumor SLD of 109 mm (range, 10-249). BL characteristics in these pts were generally balanced across study arms. PFS and OS were improved with ABCP vs BCP (Table). Gr 3-4 treatment-related AEs occurred in 52.1%, 36.5% and 54.5% of pts with liver mets in the ABCP, ACP and BCP arms, respectively. Conclusions: ABCP reduced the risk of death in pts with liver mets by 48% vs BCP and may represent an important new treatment option for this population. Clinical trial information: NCT02366143. [Table: see text]
Impact of resectable lung adenocarcinoma pathological subtypes on patients prognosis and surgical strategies determination: A SEER population-based data analysis.
Authors: Di Lu, Jianjun Yang, Siyang Feng, Xiguang Liu, Xiaoying Dong, Zhizhi Wang, He Wang, Xiaoshun Shi, Hua Wu, Kaican Cai
Journal: Journal of Clinical Oncology (2019)

e20035 Background: The prognosis difference among lung adenocarcinoma patients with different pathological subtypes remains controversial. Furthermore, the appropriate surgical plan according to each subtype for early-staged adenocarcinoma patients is undetermined. Methods: We retrospectively analyzed patients with solid, papillary and acinar lung carcinoma from 2004 to 2015 using SEER*Stat 8.3.4. The primary readout of this study were overall survival (OS). The Kaplan–Meier method was used to determine OS. Results: 2282 patients with lung adenocarcinoma were finally included (solid, N = 117, papillary, N = 739, acinar, N = 1426). For patients received radical resection (lobectomy/bilobectomy, radical and extended pneumonectomy), those with acinar adenocarcinoma had the best survival (median OS: solid, 59 months, papillary, 91 months, acinar,102 months, solid VS papillary, P = 0.258, solid VS acinar, P = 0.014, papillary VS acinar, P = 0.008). For early diagnosed patients in stage I, those with acinar adenocarcinoma who received radical resection had a better OS compared to those received partial resection (wedge resection and segmentectomy) (median OS: wed&amp;seg, 88 months, radical 106 months, P = 0.024). Particularly, patients underwent radical resection or segmentectomy had a better OS compared to those received wedge resection (mean OS of seg: 99.175±5.336 months; median OS: wed, 67 months, radical, 106 months, wed VS radical, P = 0.001, wed VS seg P = 0.026, seg VS radical, P = 0.353), while those treated with radical resection had comparable prognosis compared with patients with segmentectomy. As for patients with stage I papillary adenocarcinoma, those who received partial resection tended to have a worse prognosis compared to those who received lobectomy, although no significant difference was detected (median OS: wed&amp;seg, 74 months, radical 111 months, P = 0.151. N of patients: wed, N = 72, seg, N = 20, radical, N = 415). Conclusions: Patients with acinar lung adenocarcinoma have a better prognosis than solid and papillary adenocarcinoma patients after radical resection. For patients with stage I acinar adenocarcinoma, segmentectomy and radical resection have similar therapeutic effects. For patients with stage I papillary adenocarcinoma, radical resection is the first option.