tbuckley/cabot-search huggingface dataset:
Automating incidental findings in radiology reports using natural language processing and machine learning to identify and classify pulmonary nodules.
Authors: Christi French, Maciek Makowski, Samantha Terker, Paul Alexander Clark
Journal: Journal of Clinical Oncology (2019)

e18093 Background: Pulmonary nodule incidental findings challenge providers to balance resource efficiency and high clinical quality. Incidental findings tend to be undertreated with studies reporting appropriate follow-up rates as low as 29%. Ensuring appropriate follow-up on all incidental findings is labor-intensive; requires the clinical reading and classification of radiology reports to identify high-risk lung nodules. We tested the feasibility of automating this process with natural language processing (NLP) and machine learning (ML). Methods: In cooperation with Sarah Cannon Research Institute (SCRI), we conducted a series of data science experiments utilizing NLP and ML computing techniques on 8,879 free-text, narrative CT (computerized tomography) radiology reports. Reports used were dated from Dec 8, 2015 - April 23, 2017, came from SCRI-affiliated Emergency Department, Inpatient, and Outpatient facilities and were a representative, random sample of the patient populations. Reports were divided into a development set for model training and validation, and a test set to evaluate model performance. Two models were developed - a “Nodule Model” was trained to detect the reported presence of a pulmonary nodule and a rules-based “Sizing Model” was developed to extract the size of the nodule in millimeters. Reports were bucketed into three prediction groups: &gt; = 6 mm, &lt; 6 mm, and no size indicated. Nodules were considered positives and placed in a queue for follow-up if the nodule was predicted &gt; = 6 mm, or if the nodule had no size indicated and the radiology report contained the word “mass.” The Fleischner Society Guidelines and clinical review informed these definitions. Results: Precision and recall metrics were calculated for multiple model thresholds. A threshold was selected based on the validation set calculations and a success criterion of 90% queue precision was selected to minimize false positives. On the test dataset, the F1 measure of the entire pipeline (lung nodule classification model and size extraction model) was 72.9%, recall was 60.3%, and queue precision was 90.2%, exceeding success criteria. Conclusions: The experiments demonstrate the feasibility of NLP and ML technology to automate the detection and classification of pulmonary nodule incidental findings in radiology reports. This approach promises to improve healthcare quality by increasing the rate of appropriate lung nodule incidental finding follow-up and treatment without excessive labor or risking overutilization.
Cost disparities with age in the treatment of advanced non-small cell lung cancer (NSCLC) in Ontario, Canada.
Authors: Ying Wang, Peter Michael Ellis, Gregory Russell Pond, Hsien Seow, Amiram Gafni
Journal: Journal of Clinical Oncology (2019)

6629 Background: Previous studies noted an association between age and cost of care in NSCLC. The drivers of these cost disparities have not yet been fully examined. We conducted a cost analysis study examining the differences in, and drivers of, costs of NSCLC care across age groups in Ontario, Canada. Methods: We conducted a retrospective cohort study of patients diagnosed in Ontario from Apr 1, 2007 to Mar 30, 2014, who received palliative chemotherapy for stage IV NSCLC. Variables of interest were extracted from registry data linked by the Institute for Clinical Evaluative Sciences (ICES). The mean total cost of care including systemic therapy and supportive care, was calculated in 2015 CAD dollars by fiscal year of diagnosis. Results: Of all NSCLC cases diagnosed in Ontario (n = 37,786), 17,203 (45.5%) were de novo stage IV, of which 29.7% of patients received any chemotherapy for their disease (n = 5,113), and 281 patients are presumed alive. In this population, median age was 65 to 69 years, 51.9% were male, 43.5% were adenocarcinomas, and 25.1% received second line chemotherapy. After adjusting for comorbidities, income, gender, year of diagnosis, and rural versus urban living, the average lifetime costs per patient remains significantly inversely related to age (p &lt; 0.001). Belonging to the highest income quintile (p = 0.006) and being diagnosed in more recent years (p &lt; 0.001) contributes significantly to increasing overall healthcare costs. Elderly patients (80+) cost less (71%) and have shorter survival time (HR of death 1.28, 95% C.I. 1.10 to 1.50) compared to younger patients (≤45 years old). Accounting for longer survival in younger patients, the youngest group still incur a higher cost per day alive than other age groups ($471/day in ≤45 group, $301/day in &gt; 85 group). Hospitalization accounts for ~30% of total cost in both age groups. Chemotherapy accounts for 1% of total health care costs amongst the elderly (80+) age group and 10% of costs in ≤45 group. Conclusions: Our study shows that, despite everyone receiving systemic therapy in this patient population, younger patients incur significantly higher costs than elderly patients with advanced NSCLC, both before and after adjusting for survival. While hospitalization accounts for the biggest component of total costs, patients with high income and more recent years of diagnosis drive the higher costs of care, and chemotherapy remains a driver of higher costs amongst younger patients.
In Reply
Authors: Philip A. Philip, Michelle R. Mahoney, Cristine Allmer, James Thomas, Henry C. Pitot, George Kim, Ross C. Donehower, Tom Fitch, Joel Picus, Charles Erlichman
Journal: Journal of Clinical Oncology (2007)

of the Journal of Clinical Oncology 1 shows the therapeutic benefit of epidermal growth factor receptor (EGFR) blockade with erlotinib in patients with biliary tract carcinoma.The results are interesting because in a cohort composed of 24 chemotherapy-refractory patients and 18 chemotherapy-naive patients, erlotinib as a single agent can achieve disease control in 50% of patients with a median duration of disease control of 5.1 months.However, the authors conclude that the activity of erlotinib is modest because only 17% of the patients achieved the primary end point of the study, which was progression-free survival at 24 weeks.Although gefitinib and erlotinib are active in unselected patients with non-small-cell lung cancer (NSCLC), clinical characteristics and tumor molecular markers associated with enhanced benefit have been identified.3][4] Emerging data also suggest that increased EGFR copy number is a predictor of response to gefitinib therapy, regardless of EGFR kinase domain mutational status. 5 Furthermore, in contrast to wild-type EGFR, the EGFR mutations are mutually exclusive of K-Ras mutations, 6-8 which are found in biliary tract carcinomas with a particularly high incidence in some geographical areas. 9-11Mutations of the EGFR kinase domain have recently been described by our group in 15% of biliary tract carcinoma specimens. 12One of these mutations was a T790M substitution, which is known to correlate with an acquired resistance to small molecule inhibitor treatment in NSCLC.Whereas 28% of the EGFR-positive patients were progression free at 24 weeks, the study by Philip et al, based on the lack of correlation between EGFR expression level and treatment outcome in other tumor types, includes six undetermined and seven EGFRnegative patients.This patient number is too small to provide evidence of any correlation.Thus, it would be of interest to know if other molecular analyses, such as sequencing of EGFR tyrosine kinase or of downstream members of the signaling pathway, like K-Ras, B-Raf or PTEN, or EGFR gene amplification, have been planned in this group of biliary tract cancer patients treated with erlotinib.This finding will have extraordinary implications and will serve as a critical step toward individualized patient-specific treatment plans based on the molecular constitution of the tumor of each individual.
Hafnium oxide nanoparticles NBTXR3 activated by radiotherapy as a new therapeutic option for elderly/frail HNSCC patients.
Authors: Christophe Le Tourneau, Victor Moreno, Sebastien Salas, Xavier Mirabel, Emiliano Calvo, Bernard Doger, Carmen Florescu, Juliette Thariat, Jacek Fijuth, Tomasz Rutkowski, Nicolas Magné, Xavier Liem, Nicolas Fakhry, Stéphanie Wong-Hee-Kam, Valentin Calugaru, Caroline Hoffmann
Journal: Journal of Clinical Oncology (2019)

6069 Background: New therapeutic approaches are needed for elderly or frail head and neck squamous cell carcinoma (HNSCC) patients (pts) ineligible for standard of care treatment. NBTXR3, a crystalline solution of hafnium oxide nanoparticles may represent such an option. Injected intratumorally, NBTXR3 enters tumor cells and yields an increased cell-localized energy deposit upon exposure to radiotherapy (RT), leading to increased tumor cell death compared to the same dose of RT alone. Methods: Phase I study of NBTXR3 activated by RT in pts ≥70 years old or ≥65 years old and unable to receive cisplatin, eligible for exclusive RT with stage III or IV HNSCC of the oral cavity or oropharynx [NCT01946867]. A 3+3 dose escalation design was implemented with dose levels corresponding to 5%, 10%, 15% and 22% of baseline tumor volume, followed by an expansion phase. Pts received an intratumoral (IT) injection of NBTXR3 and intensity modulated RT (IMRT; 70 Gy/35 fractions/7 weeks). Determination of Recommended Phase 2 Dose (RP2D) and Dose Limiting Toxicities (DLT) were primary endpoints of phase I. Absence of NBTXR3 leakage and preliminary efficacy using RECIST 1.1 principles were also evaluated. Results: The dose-escalation is complete. Nineteen pts were enrolled: 3 at 5%, 3 at 10%; 5 at 15% and 8 at 22% with no observed DLT or SAE related to NBTXR3 or IT injection. One grade 1 NBTXR3-related AE (asthenia at 22%) and four IT injection-related AE (grade 2 oral pain; grade 1 tumor hemorrhage; grade 1 asthenia, and grade 1 injection site hemorrhage) were reported. RT-related toxicity was as expected with IMRT. RP2D has been determined to be 22%. CT-scan assessment between 24h and 7 weeks post-IT injection demonstrated absence of NBTXR3 leakage in the surrounding tissues. Among 13 evaluable pts treated at doses ≥10%, 9 achieved a complete response of the injected lesion. Conclusions: These results show that NBTXR3 activated by RT is safe and well tolerated at all doses with preliminary encouraging efficacy results. It thus represents a promising future treatment for frail and elderly pts with locally advanced HNSCC with limited therapeutic options. Expansion phase has started at the RP2D. Clinical trial information: NCT01946867.
Prediction of response to pelareorep plus pembrolizumab in pancreatic ductal adenocarcinoma (PDAC).
Authors: Christos Fountzilas, Grey A Wilkinson, Kevin H. Eng, Paul Fields, Sukeshi Patel Arora, Pawel Kalinski, Patrick Raber, Gerard Nuovo, Matthew C. Coffey, Devalingam Mahalingam
Journal: Journal of Clinical Oncology (2019)

e15726 Background: Pelareorep is an oncolytic reovirus that can induce an inflamed T-cell-infiltrated (hot) phenotype in PDAC. In a phase Ib trial, pelareorep was administered in combination with pembrolizumab and chemotherapy in patients (pts) with advanced, pre-treated PDAC. The safety profile was acceptable and efficacy results were encouraging (Mahalingam ASCO GI 2018). Here we present the results of immune analysis in peripheral blood. Methods: Peripheral blood mononuclear cells (PBMCs) were collected on cycle 1 day 1 (C1D1, pre-pelareorep), C1D8 (pre-pembrolizumab) and C2D1 (pre-pelareorep). RNA from PBMCs was analyzed using a customized Nanostring panel. The research-use only immunoSEQ Assay (Adaptive Biotechnologies, Seattle, WA) was used to characterize T-cell receptors from PBMCs. Results: Eleven pts were enrolled. Disease control was achieved in 50% of the 6 efficacy-evaluable pts. One pt achieved PR that lasted 17.4m. Two additional pts achieved SD, lasting 277 and 126 days. Downregulation (relative change &lt; -1.5) of CD1b (C1D1), HLA-C, MAPK14 (C1D8), CD63, LY96, LTF, TXK, TNFSF13, IL25, C1QB (C2D1) and upregulation ( &gt; 1.5) of IL17F (C1D1), MAGEA4, CCL7 (C1D8), CSF1, ICOS, LILRA4, TICAM2 (C2D1) was observed in pts with clinical benefit vs. no clinical benefit (raw p &lt; 0.05). Increase in clonal diversity was noted during therapy overall (Table). C2D1 had significantly more clonal expansion than C1D8; ~30% of expanded clones from C1D8 were also expanded at C2D1 (durable). High numbers of early expanded (C1D8 only) and durable clones were associated with longer survival. Conclusions: Pts with disease control had higher baseline IL17F compared to non-responders. On-treatment relative decrease in IL25 (Th2), increase in LILRA4, TICAM2 (antiviral response) and ICOS were noted in these pts. There was new clone expansion after treatment overall; ~30% of expanded clones at C1D8 were durable. Early and durable clonal expansion correlated with survival. A phase II trial with pelareorep plus pembrolizumab in advanced PDAC is ongoing. Clinical trial information: NCT02620423. [Table: see text]
Initiation of targeted therapy based on ctDNA only in metastatic NSCLC.
Authors: Jean Gabriel Bustamante Alvarez, Kristin Dittmar, Sarah A Janse, Stephanie Kiourtsis, Dwight Hall Owen, Erin Marie Bertino, Kai He, David Paul Carbone, Gregory Alan Otterson
Journal: Journal of Clinical Oncology (2019)

e20687 Background: Next generation sequencing (NGS) of circulating tumor DNA (ctDNA) can identify sensitizing and resistance mutations in Non-Small Cell Lung Cancer (NSCLC). ctDNA is helpful when tissue is insufficient for genomic testing, or repeat biopsy is undesirable. Here we report a single institution experience of ctDNA testing on diagnosis (DX) and progression (PD), and how this intervention can help avoid further invasive interventions and warrant change in management. Methods: This is a single institution retrospective study of advanced NSCLC patients (pts) who had ctDNA from plasma tested using Guardant360, which identifies somatic genomic alterations by massively parallel sequencing of target genes. An institutional CLIA tissue panel using FISH (for MET, RET, ROS1 and ALK) and NGS for selected genes was used for tissue analysis. Actionable mutations are those with FDA approved (EGFR, ALK, ROS, BRAF) or NCCN recommended targeted therapies (RET fusions and MET amplifications or MET Exon 14 skipping mutation). All the included patients had cancer confirmed by pathology analysis. IRB approval was obtained prior to data collection. Results: A total of 163 ctDNA samples from 143 pts were evaluated (82 at DX and 81 on PD) . 17 out of 82 (20.7%) ctDNA samples sent at DX had actionable mutations identified (4 EGFR exon 19 deletion, 2 EGFR Exon 21 L858R, 1 EGFR L861R, 4 EML4-ALK Fusion, 2 CD74-ROS1 Fusion, 2 MET exon 14 skipping mutation, 2 KIF5B-RET fusion). 7 out of 82 (8.5%) pts initiated targeted therapy based on ctDNA results only (5 with no or insufficient tissue available, 2 with negative tissue analysis). Among them, 1 CR, 5 PR, and 1 SD were achieved. For the 2 pts with negative tissue analysis , one had initial PR for 4 months with crizotinib and on progression tissue rebiopsy was positive for ALK rearrangement on FISH, for L1152R on NGS and on ctDNA for EML4-ALK Fusion, ALK G1202R and L1152P. On second line this patient achieved a near CR with Carboplatin/Pemetrexed/Pembrolizumab. The second patient with negative tissue had CD74-ROS1 fusion on ctDNA and achieved a CR with crizotinib for 8 months. The Response Rate for patients started on targeted therapies based on ctDNA only was 85%. Conclusions: A substantial number of NSCLC pts benefited from targeted ctDNA NGS by identifying actionable mutations that led to appropriate targeted treatments. Initiation of targeted therapy for advanced NSCLC was possible based on ctDNA testing only .
Phase II randomized study of neoadjuvant metformin plus letrozole versus placebo plus letrozole for ER-positive postmenopausal breast cancer [METEOR Study].
Authors: Jisun Kim, Wonshik Han, Eun-Kyu Kim, Yongsik Jung, Hyun-Ah Kim, Soo Min Chae, Eun Sook Lee, Sei-Hyun Ahn, Tae Hyun Kim, Joon Jeong, Su Yun Choi, Seok Jin Nam, Nam-Sun Paik, Lee Su Kim, Gyungyub Gong, Jong Han Yu, So-Youn Jung, Hee Jeong Kim, Sung Gwe Ahn, Min Kyoon Kim
Journal: Journal of Clinical Oncology (2019)

576 Background: Neoadjuvant endocrine therapy with an aromatase inhibitor has shown efficacy comparable to that of neoadjuvant chemotherapy in postmenopausal breast cancer. Pre-/Clinical data have shown that metformin, a widely used anti-diabetic drug also one of mTOR inhibitor have shown anti-tumor activity. We report the result of prospective, multicenter, phase II randomized, placebo controlled trial aiming to evaluate the direct anti-tumor effect of metformin in non-diabetic postmenopausal women with hormone-receptor (HR) positive breast cancer. Methods: 203 postmenopausal women diagnosed with hormone receptor positive, T1-3/N0-2 invasive breast cancer were randomized to 24 weeks of neoadjuvant letrozole (2.5 mg/day) and either metformin (2000 mg/day) or placebo. Women with history of diabetes were excluded. Primary endpoint was clinical response rate (complete, partial response by caliper). Secondary endpoint was pathologic complete response rate, breast conservation rate, percent mammographic density change. PEPI score and toxicity profile were compared between two groups. Results: 153 intention-to treat population were analyzed (72 metformin, 75 placebo group). Overall clinical response rate was 61.4% (94/153) by caliper and did not reach statistical significance between metformin versus placebo groups (66.7% versus 56.4%, p = 0.193). Breast conservation rate was 68.0% (100/147) (66.7% versus 69.3%). Overall, 87.3% (103/118) displayed Ki67 &lt; 10% at surgical specimen and 16.7% (21/126) had zero PEPI score. Neither Ki67% nor PEPI score was different between two groups. However, among the 20 patients with core-needle biopsy after 4 weeks of medication, greater number of patients displayed Ki67 &lt; 10% in metformin group than in placebo group (87.5% versus 33.3%, p = 0.017). Patients with 4week Ki67 &lt; 10% had higher clinical response rate (100% versus 57.1%, p = 0.038). Grade 3 side effects were reported in three patients (vomiting, high blood pressure, weight loss) and no hypoglycemia event was observed. Conclusions: 61.7% overall clinical response was achieved with 24-weeks of neoadjuvant letrozole, with numerically &gt; 10% higher response rate in letrozole+metformin group (66.7% versus 56.4%). 4-weeks Ki67 &lt; 10% level was predictive of clinical response. With &lt; 2% grade 3 side effects, preoperative letrozole (with/without metformin) followed by 4-week Ki67 evaluation may indeed serve as primary choice to postmenopausal hormone receptor positive breast cancers. Clinical trial information: NCT01589367.
Development of a digital immunohistochemistry records’ management system at the Moi Teaching and Referral Hospital (MTRH), Eldoret, Kenya.
Authors: Kirtika Tushar Patel, Ashwinder Singh Bhamra, Kibor Keitany Kibet, Naftali Wisindi Busakhala, Fredrick Chite Asirwa
Journal: Journal of Clinical Oncology (2019)

e18075 Background: Cancer diagnosis using immunohistochemistry (IHC) is important for quality care of patients. The utility of IHC services in management of cancer patients in low- middle income countries (LMIC) has gained popularity. Paper-based IHC records storage systems have made it cumbersome to retrieve records and thus impair the management of quality care for patients. We describe here the setup of a digitised records’ management system (RMS) in a LMIC which is user friendly, easy to access, prone to minimal errors and aid in research. Methods: A spreadsheet with blank templates containing key fields was designed and populated along the process until all records to the date of completion of data collection were recorded from January 2012 to November 2017. The complete reported tests were clustered into categories based on the diagnoses reached and frequencies for each cluster were derived. Information collected included patient identifiers, gross, histology, and immunohistochemical markers tested and the diagnosis. A provision is also made to store pictures of stained slides on the RMS. Results: Using RMS, a total of 948 immunohistochemistry staining was performed between January 2012 and November 2017; 677 of these have been reported, 200 were controls and 71 were repeats. Testing for breast cancer was the most common investigation performed (39.9% [n = 270]). Anti-LANA tests for Kaposi Sarcoma closely followed at 15.1% (102), followed by Non-Hodgkin’s lymphoma at 13.4% (n = 91). The RMS brings up the IHC test to be performed after HE diagnosis is entered, helping the technician to prepare and plan for IHC staining. Conclusions: The RMS has made it easier for clinicians taking care of patients to get results and provide quality care. This system is helpful in answering research questions and data analysis. Models such as these are especially useful in LMIC as they can assist technicians to perform IHC as they await the consultant pathologist. RMS will also help incorporation of IHC in telemedicine, aiding transmission of photographs taken by mobile phones in remote setups to pathologists in distant places.
Effective cancer immunotherapy by natural mouse conventional type-1 dendritic cells bearing dead tumor antigen
Authors: Stefanie K. Wculek, Joaquín Amores-Iniesta, Ruth Conde-Garrosa, Sofía C. Khouili, Ignacio Melero, David Sancho
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> The manipulation of dendritic cells (DCs) for cancer vaccination has not reached its full potential, despite the revolution in cancer immunotherapy. DCs are fundamental for CD8+ T cell activation, which relies on cross-presentation of exogenous antigen on MHC-I and can be fostered by immunogenic cancer cell death. Translational and clinical research has focused on in vitro-generated monocyte-derived DCs, while the vaccination efficacy of natural conventional type 1 DCs (cDC1s), which are associated with improved anti-tumor immunity and specialize on antigen cross-presentation, remains unknown. <h3>Methods</h3> We isolated primary spleen mouse cDC1s and established a protocol for fast ex vivo activation and antigen-loading with lysates of tumor cells that underwent immunogenic cell death by UV irradiation. Natural tumor antigen-loaded cDC1s were transferred and their potential for induction of endogenous CD8+ and CD4+ T cell responses in vivo, cancer prevention and therapy were assessed in three grafted cancer models. Further, we tested the efficacy of natural cDC1 vaccination in combination and comparison with anti-PD-1 treatment in two "wildtype" tumor models not expressing exogenous antigens. <h3>Results</h3> Herein, we reveal that primary mouse cDC1s ex vivo loaded with dead tumor cell-derived antigen are activated and induce strong CD8+ T cell responses from the endogenous repertoire upon adoptive transfer in vivo through tumor antigen cross-presentation. Notably, cDC1-based vaccines enhance tumor infiltration by cancer-reactive CD8+ and CD4+ T cells and halt progression of engrafted cancer models, including tumors that are refractory to anti-PD-1 treatment. Moreover, combined tumor antigen-loaded primary cDC1 and anti-PD-1 therapy had strong synergistic effects in a PD-1 checkpoint inhibition susceptible cancer model. <h3>Conclusions</h3> This preclinical proof-of-principle study is first to support the therapeutic efficacy of cancer immunotherapy with syngeneic dead tumor cell antigen-loaded mouse cDC1s, the equivalents of the human dendritic cell subset that correlates with beneficial prognosis of cancer patients. Our data pave the way for translation of cDC1-based cancer treatments into the clinic when isolation of natural human cDC1s becomes feasible.