tbuckley/cabot-search huggingface dataset:
Programmed death-ligand 1 (PD-L1) expression in small cell carcinoma of bladder.
Authors: Angela Sanguino, Arash Samiei, Gurleen Pasricha, Lakshmi Harinath, Ralph Miller, John Lyne, Jan F Silverman, Shifeng Mao
Journal: Journal of Clinical Oncology (2019)

e16019 Background: Small cell carcinoma of bladder (SCCB) is a rare but aggressive variant of bladder neoplasm. There is limited insight for risk prognostication and treatment guidance in this entity. Immune checkpoint inhibitors (ICI), anti-PD-1 or anti-PD-L1 antibodies, have been approved for treating urothelial carcinoma, while the evidence of their efficacy in SCCB is lacking. PD-L1 expression in tumor tissue of urothelial cancer has been postulated to correlate with response to ICI but with controversy. We have studied the expression of PD-L1 in SCCB and its association with patient survival. Methods: Nineteen cases of SCCB diagnosed between 2011 and 2017 in a single center were identified. Formalin-fixed paraffin-embedded tumor samples were stained for PD-L1 (Ventana PD-L1 SP142). Cases showing positive stain in 5% or more of tumor cells and tumor stromal mononuclear cells (TSMC) were considered positive. Results: Among 19 cases of SCCB, 4 (21%) stained positive for PD-L1. All 4 cases had strong PD-L1 staining ( &gt; 30%) seen in the TSMC but barely in tumor cells (focal &lt; 5% cells in 2/4 cases). Except for one patient who died from surgery, all remaining 3 patients with positive PD-L1 staining are still alive. Twelve out of 19 SCCB patients developed metastatic disease; 4 of them were treated with ICI. The only responder of the 4 patients had strong PD-L1 expression in TSMC cells. The overall survival for patients with positive PD-L1 staining was 41 months versus 14 months for those with negative staining (p = 0.09). Age, pathologic stage and treatments were similar between the two groups. Conclusions: In our study, PD-L1 expression was seen in 21% of tumor samples from patients with SCCB, mostly in TSMC, but minimal in tumor cells. The strong expression of PD-L1 in TSMC correlates with a trend of improved survival and potential response to ICI in SCCB. PD-L1 expression in TSMC, rather than tumor cells, could be used as a marker for prognosis in SCCB.
Evaluation of Methylphenidate Safety and Maximum-Dose Titration Rationale in Attention-Deficit/Hyperactivity Disorder
Authors: Cellina Ching, Guy D. Eslick, Alison S. Poulton
Journal: JAMA Pediatrics (2019)

<h3>Importance</h3> Evidence on the titration of stimulant medications for attention-deficit/hyperactivity disorder (ADHD) is lacking. However, this lack of evidence has not prevented medication guidelines from specifying apparently arbitrary dose limitations, which could discourage clinicians from titrating methylphenidate to higher and, perhaps for some patients, more efficacious doses. <h3>Objective</h3> To determine the evidence on dose titration and adverse events associated with dose titration of stimulants for ADHD. <h3>Data Sources</h3> MEDLINE from 1946, Embase from 1974, and PsycINFO from 1806 through April 1, 2019, were searched to identify relevant articles. <h3>Study Selection</h3> The inclusion criteria were that (1) the study was conducted on children up to 18 years of age; (2) children had a diagnosis of ADHD according to the<i>Diagnostic and Statistical Manual of Mental Disorders,</i>or hyperkinetic disorder according to the<i>International Classification of Diseases</i>codes; and (3) the dose of methylphenidate was determined by titration. <h3>Data Extraction and Synthesis</h3> The PRISMA guidelines for abstracting data and assessing data quality and validity were followed. Quality assessment was undertaken using the Jadad scoring system. Statistical analysis was undertaken using a random-effects model. <h3>Main Outcomes and Measures</h3> The outcomes of interest were (1) the doses used in published clinical trials, (2) the clinical justification given by researchers for their selected dose range, and (3) the adverse effects associated with methylphenidate when the dose is established by titration. <h3>Results</h3> A total of 11 randomized clinical trials and 38 cohort studies were analyzed. The randomized clinical trials involved 1304 participants treated with methylphenidate and 887 controls; the 38 cohort studies included 5524 participants. Maximum doses of methylphenidate ranged from 0.8 to 1.8 mg/kg/d. Some studies detailed their method of titration, including starting dose, titration interval, increment dose, and maximum dose. Not all of these studies reported justification for the chosen dose range. Common adverse effects of methylphenidate included insomnia (odds ratio, 4.66; 95% CI, 1.99-10.92;<i>P</i> &lt; .001), anorexia (5.11 higher than for those who took placebo; 95% CI, 1.99-13.14;<i>P</i> &lt; .001), abdominal pain (1.9 times more likely; 95% CI, 0.77-4.77;<i>P</i> = .16), and headache (14% of participants; 95% CI, 10%-20%;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> A range of maximum doses for methylphenidate was recommended in clinical studies; no discernable scientific justification for any particular dose was given. Reports of life-threatening adverse events were absent; further studies of the efficacy, tolerability, and safety of methylphenidate titrated purely on clinical grounds, without reference to any set maximum dose, are needed.
Quality control system of Watson for oncology: Artificial intelligence for supporting clinical decisions in oncology.
Authors: Juemin Fang, Xianling Guo, Zhongzheng Zhu, Hui Wang, Fei Hu, Jianhua Chen, Min Yuan, Yu Zhao, Jianguo Wu, Song Gao, Qing Xu
Journal: Journal of Clinical Oncology (2019)

6616 Background: Watson for Oncology (WFO) is an artificial intelligent clinical decision-support system (AI-CDSS) developed by IBM and trained by Memorial Sloan Kattering Cancer Center to assist in cancer care by providing evidence-based treatment options with priority. However, there are disagreements argue that WFO recommends “unsafe and incorrect” cancer treatments. Also, guidelines and drug availability in China are different from USA. Therefore, a quality control system of WFO is urgently needed to help oncologists better use WFO in China. Methods: Experts from medical oncology, surgical oncology, radiology, intervention, radiology and pathology etc. forming a Multiple Disciplinary Team (MDT) to score Watson recommendations in 6 aspects (shown in the table). Results: With this quality control system, the value of WFO was carefully evaluated by MDT. Recommendations with higher score(especially more than 80) were more standardized, reasonable and evidence-based thus more likely to be chosen. Localization and drug availability problem was solved by taking Chinese guidelines and drug approval into evaluation within this scoring system. Treatment options unsuitable or unavailable for patients by the system will be removed and replaced by the advices of MDT. Conclusions: Reliability and security are the top concerns of applying new technology in healthcare. With the MDT quality control system, AI-CDSS can be used safely and efficiently before it is fully mature. Also, the accuracy and advancement are assessed in this system to help oncologists better use WFO in China in the future. Indicators evaluating the WFO recommendations. [Table: see text]
NOTCH3 expression in metastatic TNBC cells.
Authors: Antonino Bonaventura D'Assoro
Journal: Journal of Clinical Oncology (2019)

e12123 Background: Onset of metastases involves a complex multistep biological process termed the invasion-metastasis cascade, which include dissemination of cancer cells from the primary tumor to secondary organs. NOTCH signaling plays a critical role in promoting Triple Negative Breast Cancer (TNBC) metastasis. Although all four NOTCH receptors show oncogenic properties, the unique role of each of these receptors in the sequential stepwise events that typify the invasion-metastasis cascade remains elusive. Methods: We established unique TNBC cells (TNBC-M14, -M25 and –M40), isolated from patient-derived brain metastasis xenografts (PD-BMXs). NOTCH3 genetic targeting was achieved using Lenti-vector shRNAs. Immunoblot analysis was used to assess NOTCH3 expression. ALDH1 activity was measured using the ALDEFLUOR Kit. To assess self-renewal capacity and resistance to docetaxel-based chemotherapy, TNBC cells were cultured under non-adherent conditions to form mammospheres (MPS). A publicly clinical database ( http://kmplot.com ) was employed to analyze NOTCH3 expression in a selected cohort of 107 lymph- node+ TNBC patients. Results: TNBC-M14, -M25 and -M40 MPS showed NOTCH3 overexpression and higher ALDH1 activity compared to MDA-MB 231 MPS used as control. To investigate the causative role of NOTCH3 in inducing ALDH1 activity, self-renewal capacity and chemoresistance, we infected TNBC MPS with Lenti-vector shRNAs targeting NOTCH3. NOTCH3 geneting targeting induced a significant reduction of ALDH1 activity compared to TNBC MPS infected with scrambled Lenti-shRNAs. NOTCH3 geneting targeting significantly impaired MPS formation and restored sensitivity to docetaxel. The correlation between aberrant NOTCH3 expression and poor outcome in patients with advanced TNBC was validated in a publicly clinical database. Conclusions: These findings provide a compelling preclinical rationale for the design of novel clinical trials that will selectively target NOTCH3 to restore chemosensitivity and to improve the progression-free survival of TNBC patients that lack FDA-approved targeted therapies.
Five-Year Follow-up after Face Transplantation
Authors: Sotirios Tasigiorgos, Branislav Kollar, Marvee Turk, Bridget Perry, Muayyad Alhefzi, Harriet Kiwanuka, Marie-Christine Nizzi, Francisco M Marty, Anil Chandraker, Stefan G Tullius, Leonardo V Riella, Bohdan Pomahac
Journal: New England Journal of Medicine (2019)

Five-Year Follow-up of Facial Transplantation Facial allograft may restore form and function to patients with severe facial disfigurement for whom other satisfactory therapeutic options are lacking...
Impact of a structured quality management program on survival of patients with advanced (AOC) and relapsed ovarian cancer (ROC) treated in a dedicated tertiary gynecologic-oncology (GO) center.
Authors: Philipp Harter, Florian Heitz, Beyhan Ataseven, Sonia Prader, Stefanie Schneider, Thaïs Baert, Pier Alesina, Harald Groeben, Alexander Traut, Andreas Du Bois
Journal: Journal of Clinical Oncology (2019)

e17048 Background: Treatment of AOC needs interdisciplinary and specialized skills and structures. We report the impact of a dedicated quality management program over 2 decades from learning curve and specialization process started in 1998-2004 when the surgical department was separated from a general clinic of obstetrics and gynecology. The next period from 2005-2010 covers the data after implementation of the first step of our ovarian cancer quality assurance program. In 2011, a dedicated department of GO was founded. Additionally, we investigated the role of subsequent centralized versus decentralized treatment when patients relapsed after they had primary therapy at our institution. Methods: Descriptive analysis of our prospective tumor registry including all consecutive patients with primary diagnosis of AOC FIGO IIB-IV treated from 1998-2004, 2005-2010 and 2011-2017. All patients having started any therapy outside of our center were excluded. Results: The number of patients with untreated AOC increased from 10 to 147 per year from 1998 to 2017. In total, 1,663 pts were analyzed. The annual percentage of FIGO IV increased from 14% in 1998 to 54-61% in recent years (2013-2017). The complete resection rate of upfront surgery was 50%, 67%, and 69% in the periods 1997-2004, 2005-2010, and 2011-2017, respectively. Correspondingly, median PFS increased from 19 to 21 and 26 months (p &lt; 0.001) and median OS increased from 33 to 42 and 56 months, respectively (p &lt; 0.001). Altogether, 893 pts (53.7%) experienced a relapse. 490/893 pts (54.9% of all ROC pts) were treated again in our center, the remaining 45.1% were treated somewhere else. Median OS calculated from first relapse was 43 months for patients re-treated in our institution versus 32 months for others (p &lt; 0.001). Conclusions: We demonstrate a correlation between specialization and improved outcome in AOC. Focusing and implementing a quality assurance program including structural evolution from a department of general obstetrics/gynecology to a department of GO led to an improvement although systemic primary treatment standards did not change during this period.
Ubiquinone Q10 counteracts apoptotic signals unrelated to free radical production in cultured keratocytes
Authors: Rosario Brancato, Laura Papucci, Andrea Lapucci, Martino Donnini, Nicola Schiavone, Ewa Janina Witort, Lucia Formigli, Sz Orlandini, G Carella, Sergio Capaccioli
Journal: Ophthalmology (2001)
Quantification of activated and exhausted immune cell populations and simultaneous characterization of circulating tumor cells (CTCs) in peripheral blood of cancer patients receiving checkpoint inhibitor therapy.
Authors: Gordon Vansant, Rachel Krupa, Robin Richardson, Priscilla Ontiveros, Jiyun Byun, Mark Landers, Ryan Dittamore
Journal: Journal of Clinical Oncology (2019)

e14033 Background: Immune checkpoint inhibitors (ICIs) are becoming standard treatment options in many indications. However, a substantial portion of patients will not respond. Single biomarkers such as PD-L1 are insufficiently accurate to predict patient benefit. We sought to expand the Epic Sciences non-invasive liquid biopsy platform to identify predictive, peripheral blood biomarkers for ICIs using both molecular analyses of CTCs and immune cell changes. Methods: Blood samples from prostate, kidney, and bladder cancer patients treated with ICIs were collected at baseline and on-therapy and sent to Epic Sciences. Nucleated cells were plated on glass slides and stained with CTC (pan-CK, CD45, PD-L1 and DAPI) and immune panels for activation (CD4, CD8, Ki-67, and DAPI) and exhaustion (CD8, Ki-67, PD-1, Lag-3, Tim-3, and DAPI). Changes in populations of immune cells and circulating tumor cells were assessed using high throughput digital pathology. Results: CTCs were detected in 73% (24/33) patients, of which 12% (4/33) had PD-L1 + CTCs detected. No PD-L1 + CTCs were detected in the nine on-therapy samples tested. Of 14 patients with matched samples, 57% (8/14) patients had an increase in activated CD4 + leukocytes and 36% (5/14) patients had an increase in activated CD8 + leukocytes in on-therapy samples compared to baseline. The exhaustion assay was performed on a subset (6 of 14) of matched samples. In baseline and on-therapy samples, one patient had higher levels of exhausted CD8 + leukocytes compared to healthy donor controls, and two patients had lower levels versus controls. No change in exhausted CD8 + leukocytes was observed from baseline to on-therapy. Conclusions: We developed a liquid biopsy-based platform that can simultaneously measure biomarkers in CTCs and leukocytes from a single peripheral blood sample. Changes in activated and exhausted immune cell populations with ICI treatment were detected and PD-L1 expression on CTCs was evaluated. Efforts to further stratify immune and rare cell populations are ongoing.
Novel smartphone app for daily symptom reporting for active chemotherapy patients.
Authors: John Marshall, Lauren Allison Wiebe, Howard Isenstein
Journal: Journal of Clinical Oncology (2019)

e23119 Background: Clinicians, payors and patients are recognizing the value of enhanced symptom monitoring for ambulatory patients between chemotherapy encounters. However, enabling technologies to do so are nascent. Methods: A patient-facing Smartphone app and a clinician-facing dashboard were developed for providers to easily monitor key symptoms in ambulatory patients. Both EHR-integrated and standalone versions were available by provider preference. 250 patients with breast, lung or gastrointestinal cancer in active chemotherapy and their paired clinicians were recruited at three hospital-based practices to test the feasibility and usability of our system. Patients were prompted to report symptoms once per day Monday-Friday. Patients could also track their symptoms and obtain standardized self-care guidance at any time. Clinicians could access their patients’ data via the dashboard at any time. The treating team ould also receive e-mail alerts based on a pre-approved symptom triage protocol. Results: All enrolled clinicians and patients were able to access and use the technology. Clinicians accessed the symptom management dashboard at least once per weekday on average. 75% of clinicians indicated that the technology reduced their workflow somewhat or had no effect on it. The majority (71.5%) of clinicians indicated that the frequency of alerts they received was acceptable. 100% of clinicians who accessed the tool when integrated into the EHR indicated that the it was very convenient to use vs. only 20% of the clinicians who accessed the standalone version. 39.4% of patients reported using our technology on a daily basis. 77.9% of patients said that they would recommend the Smartphone App. Conclusions: The CarePrompter electronic patient-reported outcomes (ePRO) monitoring system demonstrated high technical feasibility and usability, particularly when integrated with the EHR, suggesting that technical barriers to providing robust real-time and historical symptom data are less formidable than they appear.
Larotrectinib efficacy and safety in pediatric TRK fusion cancer patients.
Authors: Cornelis Martinus van Tilburg, Steven G. DuBois, Catherine Michelle Albert, Noah Federman, Ramamoorthy Nagasubramanian, Birgit Geoerger, Daniel Orbach, Stefan S. Bielack, Neerav Narendra Shukla, Brian Turpin, Michela Casanova, Sheri L. Spunt, Hope Qamoos, Shivani Nanda, Barrett H. Childs, Michael Craig Cox, Alberto S. Pappo, Theodore Willis Laetsch, Leo Mascarenhas
Journal: Journal of Clinical Oncology (2019)

10010 Background: TRK fusions involving NTRK1, NTRK2, and NTRK3 genes have been identified in a broad range of pediatric and adult malignancies. Larotrectinib, a highly-selective oral TRK inhibitor, was well tolerated and showed encouraging antitumor activity in 17 pediatric patients (pts) with TRK fusion cancer (Laetsch et al, Lancet Oncol 2018). Here, we present data on the clinical efficacy and safety of larotrectinib in 38 pediatric pts with TRK fusion cancer from an expanded dataset. Methods: Pediatric pts enrolled in two larotrectinib clinical trials (NCT02637687, NCT02576431) with TRK fusion cancer detected by local testing were included; pts with primary CNS tumors were excluded from this report. Larotrectinib was administered until complete surgical resection, disease progression, withdrawal, or unacceptable toxicity. Disease status was investigator-assessed using RECIST v1.1. Data cutoff: July 30, 2018. Results: As of July 30, 2018, 38 children and adolescents &lt; 18 y with TRK fusion cancer were enrolled. Median age was 2.3 y (range 0.1–14.0); 14 (37%) were &lt; 1 y. 18 (47%) had infantile fibrosarcoma, 15 (39%) other soft tissue sarcoma, 2 (5%) thyroid cancer and 1 (3%) each had gastrointestinal stromal tumor, melanoma, or mesoblastic nephroma. TRK fusions involved NTRK1, 2, and 3 in 18 (47%), 2 (5%), and 18 (47%) pts, respectively. Half of the pts had metastatic disease and half locally advanced disease at entry. 26 pts (68%) had received prior systemic therapy (median lines: 1 [range 0–4]) and 6 were treatment-naïve. In 34 evaluable pts, the overall response rate was 94%: 12 CRs, 18 confirmed PRs, and 2 PRs pending confirmation; 2 had stable disease. Median duration of response had not been reached (range 1.6+ to 26.7+ months); 84% &gt; 1 y. At data cutoff, 28 pts (74%) remained on treatment; 4 pts discontinued due to complete surgical resection and 4 due to disease progression while on therapy, 2 of whom initially responded (PR). Adverse events were mostly grade 1–2. Conclusions: Larotrectinib treatment resulted in a high and durable response rate in pediatric pts with TRK fusion cancer together with a favorable safety profile. Routine testing for NTRK gene fusions in pediatric cancer pts is recommended in the appropriate clinical context. Clinical trial information: NCT02637687 and NCT02576431.
The Case of <i>Juliana v. U.S.</i> — Children and the Health Burdens of Climate Change
Authors: Renee N. Salas, Wendy Jacobs, Frederica Perera
Journal: New England Journal of Medicine (2019)

The Case of Juliana v. U.S. In June, the Ninth Circuit Court of Appeals will hear oral arguments in a suit filed by 21 children and adolescents charging that the federal government’s inaction on ad...
Clinical observation of low-dose apatinib in the treatment of small cell lung cancer with antidiuretic hormone secretion.
Authors: Yuming Jia, Wenjing Ye
Journal: Journal of Clinical Oncology (2019)

e20087 Background: The treatment of extensive small cell lung cancer (ED-SCLC) is still based on radiotherapy and chemotherapy, but the overall survival is short and the prognosis is poor. The prognosis of ED-SCLC with hyponatremia is worse. At present, the anti-angiogenic small molecule targeted drug apatinib has achieved satisfactory clinical efficacy in advanced non-squamous non-small cell lung cancer. Although there are reports of a small number of apatinib in the treatment of small cell lung cancer, there is still a lack of low integration. In the study of sodiumemia, in this study, we evaluated the efficacy and safety of low-dose abatatinib in the treatment of ED-SCLC with hyponatremia. Methods: Retrospective analysis of 8 patients with hyponatremia at least twice during hospitalization between January 2016 and September 1818, after low-dose apafitini (125 mg or 250 mg, QD, orally; 28 days for one observation period) Case data for patients with SCLC who progressed after first-line or second-line treatment. Efficacy was assessed using the RECIST criteria and adverse reactions (AEs) were graded using the NCI CTC criteria. Results: The efficacy was evaluated as 4 PR, 2 SD, and 2 PD. ORR and DCR are 50% (4/8) and 100% (75%), respectively. The median progression-free survival (PFS) was 91 days (95% CI, 30-167) and the median overall survival (OS) was 150 days (95% CI, 110-197). Up to the follow-up date, 3 patients survived and 5 died; 1 grade 3/4 hypertension, 1 case of neutropenia, and grade 3/4 toxicity were relieved by symptomatic treatment. Did not affect the use of apatinib. Conclusions: The efficacy and tolerability of patients with LD-SCLC with hyponatremia after low-dose atentinil treatment for first- and second-line treatment were good. However, the conclusion still requires a large sample of prospective studies to further evaluate. [Table: see text]