tbuckley/cabot-search huggingface dataset:
Phase 2, two-group, two-stage study of avelumab in patients (pts) with microsatellite stable (MSS), microsatellite instable (MSI), and polymerase epsilon (POLE) mutated recurrent/persistent endometrial cancer (EC).
Authors: Panagiotis A. Konstantinopoulos, Joyce F. Liu, Weixiu Luo, Carolyn N. Krasner, Jeffrey Joseph Ishizuka, Allison Ann Gockley, Mary K. Buss, Susana M. Campos, Elizabeth Stover, Alexi A. Wright, Whitfield Board Growdon, Jennifer Curtis, Ariana Peralta, Patrice Basada, Roxanne Quinn, Kathryn P. Gray, Richard T. Penson, Stephen A. Cannistra, Gini F. Fleming, Ursula A. Matulonis
Journal: Journal of Clinical Oncology (2019)

5502 Background: This non-randomized phase 2 study evaluated the PD-L1 inhibitor avelumab in two cohorts of EC: i) MSI/ POLE cohort including ECs with immunohistochemical (IHC) loss of expression of at least one of the mismatch repair (MMR) proteins and/or documented mutation in the exonuclease domain of POLE and ii) MSS cohort including ECs with normal IHC expression of all MMR proteins. Methods: Eligibility criteria included measurable disease, unlimited prior therapies, and any EC histology. Co-primary endpoints were confirmed objective response (OR) and progression-free survival rate at 6 months (PFS6). Avelumab 10 mg/kg IV was given every 2 weeks until progression or unacceptable toxicity. In the 1 st stage, 16 pts were enrolled in each cohort; if there were ≥2 ORs or ≥2 PFS6 responses, accrual would continue to the 2 nd stage with enrollment of 19 additional pts. Overall, if there are ≥4 ORs or ≥8 PFS6 responses, avelumab would be considered worthy of further study in each cohort. Results: As of 12/2018, 33 pts were enrolled. The MSS cohort was closed at the 1 st stage due to futility; of 16 pts in the MSS cohort, only 1 pt exhibited an OR and PFS6 response [ORR and PFS6 rate 6.25% (95% CI 0.16%-30.2%)]. Conversely, the MSI/POLE cohort reached the primary endpoint of 4 ORs after accrual of only 17 pts. Two pts in the MSI/POLE cohort did not initiate protocol therapy and were excluded from all analyses. Of 15 pts in the MSI/POLE cohort, 4 pts exhibited OR [1CR+3PRs, OR rate (ORR) 26.7% (95% CI 7.8%-55.1%)] and 6 pts (including the 4 pts with OR) exhibited PFS6 responses [PFS6 rate 40.0% (95% CI 16.3%-66.7%)], 4 ongoing and 3 approaching 2 yrs. Twenty-two pts (71%) reported treatment related toxicities, 6 patients (19%) G3 toxicities; there were no treatment-related G4 and G5 toxicities. In the MSI/POLE cohort, 5 of 6 PFS6 responses were observed in pts with ≥3 lines of prior therapy (p = 0.011) and in tumors who were PD-L1 negative by IHC. Further correlative work will be reported at the meeting. Conclusions: In EC pts stratified by MSI/POLE status, MSI vs MSS status appears to be correlated with avelumab response even in PD-L1 negative tumors. Responses in the MSI/POLE cohort were more frequent in more heavily pretreated patients, a finding that warrants further investigation. Clinical trial information: NCT02912572.
Comprehensive characterization of pseudomyxoma peritonei.
Authors: Gabriel G. Malouf, Anthony Dohan, Hui Yao, Roger Mouawad, Raphael Carapito, Seiamak Bahram, INSTITUT CANCEROLOGIE Meyer KHAYAT, Jean-Emannuel Kurtz, Xiaoping Su, Marc Pocard
Journal: Journal of Clinical Oncology (2019)

e15701 Background: Pseudomyxoma peritonei (PMP) is a rare malignant tumor characterized by the infiltration of the peritoneum by mucus-secreting tumor cells. The genetic landscape of these tumors and correlation with clinico-pathological tumor features is unclear to date. Methods: We performed whole-exome sequencing (WES) on 8 PMPs and matched normal. We then validated our finding using ultra-deep sequencing of hotspot mutations (~82.270 x) in 45 clinically annotated samples. In addition, bulk RNAseq was performed on 10 samples and MCP-counter was used to infer absolute abundance of eight immune and two stromal cell populations. Results: Overall, 323 somatic mutations were identified through WES with most frequent mutations involving GNAS (R186H) (50%), KRAS (G12D) (50%), AHNAK2 (25%) and ATXN1 (25%). Furthermore, ultra-deep sequencing uncovered KRAS, GNAS and IDH1/2 hotspots mutations in 16 (35.5%), 11 (24.4%) and 2 (4.4%) PMPs, respectively. Strikingly, KRAS mutations were enriched in females (79% vs 39%, p = 0.03) while GNAS in males (67% vs 28%, p = 0.04). No other significant associations were identified between mutations and other clinico-pathological features. Using MCP-counter, fibroblasts, endothelial cells and moncoytic cells were the most frequent inferred cells. Unsupervised clustering using expression of most variable cells identified two PMP clusters, namely C1 (n = 4) and C2 (n = 6). C2 cluster displayed higher T cells as compared to C1 (p &lt; 0.0001), consistent with increased cytotoxic lymphocytes (p = 0.04). Notably, C2 was enriched for tumors with higher grade as compared to C1 (80% vs 0%; p = 0.04). Conclusions: Our study represents the largest study to data exploring genetic and immune alterations in PMPs. We uncovered puzzling associations between genetic landscape of PMPs and patients gender, which deserve further validation in an independent cohort. The association of high-grade tumors with increased tumor infiltrating lymphocytes suggests the existence of an immunogenic microenvironment; PD-1/PD-L1 blockade might represent a therapeutic option for these patients.
FGFR-altered, advanced urothelial carcinoma (UC) and response to chemotherapy prior to receiving erdafitinib.
Authors: Andrea Necchi, Arlene O. Siefker-Radtke, Bob Zhong, Parthiv Jasvant Mahadevia, Ademi E. Santiago-Walker, Peter De Porre, Yohann Loriot
Journal: Journal of Clinical Oncology (2019)

4542 Background: FGFR-altered, advanced UC has predominantly a luminal 1 subtype, which is associated with lower response rates to immunotherapy and possibly also to chemotherapy. Objective response rates (ORR) for first-line cisplatin-based regimens, such as gemcitabine-cisplatin (gem/cis) and methotrexate-vinblastine-doxorubicin-cisplatin (MVAC), historically range between 45-60% and for gemcitabine-carboplatin (gem/carbo) 35-45%. However, the ORR on chemotherapy for the ~20% of patients with FGFR-altered tumors is unknown. Methods: BLC2001 (NCT02365597) is an ongoing global open-label phase 2 study of the pan-FGFR inhibitor erdafitinib in patients with locally advanced or metastatic UC with specific FGFR2/3 gene alterations. Patients who had received first-line (1L) or second-line (2L) chemotherapy for advanced UC were identified. Investigator-reported ORR (complete + partial responses) and median time to progression (TTP) on these pretreatments were analyzed. Results: Of 210 patients treated with erdafitinib in BLC2001, 191 had received prior systemic therapy including 184 and 83 patients who had received 1L and 2L chemotherapy, respectively. ORR were 29.3% (54/184; 95% CI 22.8%, 35.9%) to 1L chemotherapy and 24.1% (20/83; 95% CI 14.9%, 33.3%) to 2L chemotherapy. 1L therapy consisted of gem/cis in 94 patients, gem/carbo in 59 patients, and MVAC in 22 patients, with ORR (95% CI) of 35.1% (25.5%, 44.8%), 25.4% (14.3%, 36.5%), and 22.7% (5.2%, 40.2%), respectively. In the 2L setting, of 46 patients who had received a regimen containing a taxane (paclitaxel or docetaxel) or vinflunine, 8 patients (17.4%; 95% CI 6.4%, 28.3%) achieved an objective response. Median TTP was 7.16 mo (95% CI 6.18, 7.49) after 1L chemotherapy (7.6 mo for gem/cis, 6.3 mo for gem/carbo, and 5.3 mo for MVAC) and 4.35 mo (95% CI 3.3, 5.5) after 2L chemotherapy (3.6 mo for taxane or vinflunine). Conclusions: In this post-hoc analysis, the overall ORR to prior 1L chemotherapy was lower, but within the range expected based on historical data. Further investigation into the response to chemotherapy in FGFR alteration positive patients is warranted and may be useful for the development of 1L trials of combination therapy. Clinical trial information: NCT02365597.
End the postcode lottery for cataract surgery
Authors: Michael Burdon
Journal: BMJ (2019)

The decision of 76 of the 195 clinical commissioning groups (CCGs) in England to impose a visual acuity threshold for access to cataract surgery is a clear demonstration of the willingness of those responsible for healthcare spending decisions to ignore best advice in a flawed attempt to save money.1 In October 2017, the National Institute for Health and Care …
Research tools for extrapolating the disposition and pharmacokinetics of nanomaterials from preclinical animals to humans
Authors: Michael S. Valic, Gang Zheng
Journal: Theranostics (2019)

A critical step in the translational science of nanomaterials from preclinical animal studies to humans is the comprehensive investigation of their disposition (or ADME) and pharmacokinetic behaviours.Disposition and pharmacokinetic data are ideally collected in different animal species (rodent and nonrodent), at different dose levels, and following multiple administrations.These data are used to assess the systemic exposure and effect to nanomaterials, primary determinants of their potential toxicity and therapeutic efficacy.At toxic doses in animal models, pharmacokinetic (termed toxicokinetic) data are related to toxicologic findings that inform the design of nonclinical toxicity studies and contribute to the determination of the maximum recommended starting dose in clinical phase 1 trials.Nanomaterials present a unique challenge for disposition and pharmacokinetic investigations owing to their prolonged circulation times, nonlinear pharmacokinetic profiles, and their extensive distribution into tissues.Predictive relationships between nanomaterial physicochemical properties and behaviours in vivo are lacking and are confounded by anatomical, physiological, and immunological differences amongst preclinical animal models and humans.These challenges are poorly understood and frequently overlooked by investigators, leading to inaccurate assumptions of disposition, pharmacokinetic, and toxicokinetics profiles across species that can have profoundly detrimental impacts for nonclinical toxicity studies and clinical phase 1 trials.Herein are highlighted two research tools for analysing and interpreting disposition and pharmacokinetic data from multiple species and for extrapolating this data accurately in humans.Empirical methodologies and mechanistic mathematical modelling approaches are discussed with emphasis placed on important considerations and caveats for representing nanomaterials, such as the importance of integrating physiological variables associated with the mononuclear phagocyte system (MPS) into extrapolation methods for nanomaterials.The application of these tools will be examined in recent examples of investigational and clinically approved nanomaterials.Finally, strategies for applying these extrapolation tools in a complementary manner to perform dose predictions and in silico toxicity assessments in humans will be explained.A greater familiarity with the available tools and prior experiences of extrapolating nanomaterial disposition and pharmacokinetics from preclinical animal models to humans will hopefully result in a more straightforward roadmap for the clinical translation of promising nanomaterials.
Real-world efficacy of bone modifying agents (BMAs) in patients with breast cancer (BC) treated in an academic health system: Use of the “green button.
Authors: Yasmin Karimi, Saurabh Gombar, Latanya Dean, Jennifer Hansen, Alison Callahan, Ken Jung, Vasu Divi, Douglas W. Blayney
Journal: Journal of Clinical Oncology (2019)

e18054 Background: BC patients (pts) have a high incidence of bone metastases (mets) and associated morbidity. BMAs – zoledronic acid (ZA) and denosumab (Den) – reduce bone met related skeletal related events (SREs). ASCO guidelines do not recommend one over another, and survival and real-world outcome data to guide point-of-care decision-making is lacking. We used the previously developed “Green Button” informatics consult service, designed to rapidly test hypotheses when no applicable published data is available to guide treatment choices (Longhurst et al Health Affairs 2014), to compare BMA efficacy in BC patients. Methods: Patients treated for BC at Stanford HealthCare between 2009 - 2018, receiving standard of care cancer and BMA therapy, as determined by their oncologists, were identified who had &gt; 2 electronic health records (EHRs) documenting BMA administration, and had either ICD9 174 or ICD10 C50 diagnostic codes. Pts were grouped into Den only, ZA only, or both. Two outcomes were analyzed: 1) SREs as a composite outcome of pathologic fracture (1st ICD10 M84.5); spinal cord compression (1st ICD10 M47.1 or G95.2), radiation therapy (1st CPT 77300) or hypercalcemia (calcium ≥10.5); and 2) death. Effects were compared relative to baseline treatment with ZA; we show results of log rank tests for differences in survival outcomes. Three analyses were performed: 1) Unadjusted analysis; 2) Basic matching analysis accounting for length of medical record, age, sex and year of treatment; 3) Propensity score matching using all available data; all prior to index treatment with either Den or ZA. Results: 802 patients had ≥ 2 records of BMA administration. Comparison of Den only and ZA only pts is shown in the table below. Median ages and length of medical record were balanced in all groups. Conclusions: This preliminary retrospective analysis of unsupervised BMA use suggests that Den is superior to ZA for the outcomes of interest; confirmatory analyses are underway.[Table: see text]
Seek and You Shall Find — Unknown Pathogens?
Authors: Nikos Vasilakis, David H Walker
Journal: New England Journal of Medicine (2019)

Over the past decade, there has been a renaissance of virus discovery fueled by the advent of new technologies such as next-generation sequencing; these technologies have greatly accelerated the pace of discovery of new viruses in a wide range of hosts.1-4 This bonanza of discovery has presented both opportunities and challenges for virologists, epidemiologists, taxonomists, and evolutionary biologists. The ever-decreasing cost of obtaining complete genome sequences has allowed the refinement of viruses’ taxonomic assignments, analysis of their phylogenetic and evolutionary relationships, and (importantly) evaluation of the potential risks they may pose to human and animal populations.5,6 Viruses belonging to the . . .
A 18F-FDG PET/CT-based radiomics model predicts prognosis of synchronous oligometastatic non-small cell lung cancer.
Authors: Xiaoxia Zhu, Yu Zhang, Zhihao Zheng, Jiaxiu Luo
Journal: Journal of Clinical Oncology (2019)

e20610 Background: Oligometastatic non-small cell lung cancer (NSCLC) exists high heterogeneity with distinct outcome, and there is a lack of available biomarkers for patient stratification. In this study, we identified a positron emission tomography (PET)/computed tomography(CT)-based radiomics signature capable of predicting overall survival (OS) in patients with synchronous oligometastatic NSCLC. Methods: This study consisted of 46 patients with synchronous oligometastatic NSCLC (≤5 metastases) between 2012-2018. Clinicopathologic data was acquired from medical records and database. A total of 20648 radiomic features were extracted from pretreatment CT and PET images, which were generated from the same PET/CT scanner. A radiomics signature was built by using the least absolute shrinkage and selection operator (LASSO) regression model. Multivariate Cox regression analysis was performed to establish the predictive model. The performance was evaluated with Harrell' concordance index (C-index). Results: 7 radiomics features were selected to build the radiomics signature. Multivariate analysis indicated that the radiomics signature (P = 0.007) was an independent prognostic factor, with a C-index of 0.810. Smoking status (P = 0.01) was the only independent clinicopathologic risk factor for overall survival prediction. Incorporating the radiomics signature with clinicopathologic risk factors resulted in higher performance with a C-index of 0.899. Conclusions: This study developed a radiomics model for predicting OS in synchronous oligometastatic NSCLC, which may serve as a predictive tool to identify individualized treatment strategy. Further internal and external validation of the model are required. Support: 81572279, 2016J004, LC2016PY016, 2018CR033. [Table: see text]
Low-dose metronomic chemotherapy (LDMC) as an efficient treatment option in metastatic breast cancer: Results of an exploratory case-control study.
Authors: Marco Johannes Battista, Carola Schnatz, Katrin Almstedt, Walburgis Brenner, Anne-Sophie Heimes, Sandra Nezi-Cahn, Roxana Schwab, Annette Hasenburg, Marcus Schmidt, Slavomir Krajnak
Journal: Journal of Clinical Oncology (2019)

e12578 Background: There is a growing importance of low-dose metronomic chemotherapy (LDMC) in metastatic breast cancer (MBC). In this retrospective case-control-analysis we compared the efficacy of LDMC and conventional chemotherapy in MBC. Methods: Each LDMC patient receiving oral cyclophosphamide (CTX) (50 mg daily) and methotrexate (MTX) (2.5 mg every other day) was matched with two patients who received conventional chemotherapy. Age, number of chemotherapy lines and metastatic lesions as well as hormone receptor (HR) status were considered as matching criteria. Primary endpoint was disease control rate greater than 24 weeks (DCR). Secondary endpoints were DCR in subgroups (number of chemotherapy lines, number of different metastatic lesions and HR status), progression-free survival (PFS) and duration of response (DoR). Results: A total of 35 cases and 70 controls entered the study. 31% patients with LDMC and 26% patients with conventional chemotherapy showed DCR (p = 0.644). Among younger patients DCR was 41% in LDMC vs. 30% in the control group (p = 0.534). In addition, DCR was achieved in 35% vs. 27% patients with ≤ 2 chemotherapy lines (p = 0.560) and in 36% vs. 20% patients with ≤ 2 different metastatic lesions (p = 0.168), respectively. In the triple negative group 30% LDMC vs. 5% control patients showed DCR (p = 0.095). PFS was 12.0 vs. 13.5 weeks (p = 0.415), DoR was 26.5 vs. 20.5 weeks (p = 0.628), respectively. Conclusions: In this retrospective case-control study we demonstrated a similar efficacy of LDMC compared to conventional chemotherapy in the treatment of MBC. Moreover, no significant differences were found in the subgroups studied. Therefore, the concept of LDMC may also be a treatment option in both younger and non-heavily pre-treated MBC patients who do not need rapid remission.
Mutational analysis of key genes in patients from the Kazakh population with early onset of breast cancer.
Authors: Dilyara Kaidarova, Nazgul Omarbayeva, Gulnur Zhunussova, Aliya Abdrakhmanova, Saltanat Abdikerim, Leila Djansugurova
Journal: Journal of Clinical Oncology (2019)

e13038 Background: Breast cancer (BC) represents the most common malignancy and has the highest mortality among women, both in the world and in Kazakhstan. Approximately 20-30% of cases of hereditary BC are caused by presence of BRCA1/2 genes defects. Also, there are additional genes which can increase the risk of BC and they are still under study.The aim of this study was to identify new, detectable and objective markers of key cancer genes by next-generation sequencing (NGS) of young BC patients. Methods: Blood was collected from 129 BC patients (average age 34.87±5.587). DNAs were extracted using GeneJET Genomic DNA Purification Kit. NGS was done on the MiSeq platform using TruSightCancer Kit. NGS data were analyzed by the MiSeq Reporter v. 2.4 software. Variant annotation and interpretation was done by Variant Studio 3.0 software. Results: We perform the NGS and did the detailed bioinformatics analysis of sequences of 16 key genes of BC (BRCA1/BRCA2, BRIP1, ATM, CDH1, CHEK2, NBN, NF1, PALB2, STK11, TP53, RAD51C, RAD51D, BARD1, MUTYH and FANCC). At all 3016 variants were detected, 1080 (35.8%) out of which were missense; 1494 (49.5%) synonymous; 17 (0.6%) frameshifts; 2 (0.06%) inframe deletions, 8 (0.3%) stop gained; 4 (0.1%) splice variant, 411 (13.6%) intron or non-coding variants. We identified 24 pathogenic and likely pathogenic mutations in 31 patients (24% of all patient cohort), 3 mutations are novel. All mutations were in heterozygous state and were rare or had frequency data not available (NA) in 1000G, ESP6500and ExAC databases. Analysis of mutation type revealed 17 frameshift mutations, 2 missense mutations, 8 stop gained mutations, 4 mutations involving uncorrected splicing. Out of the 31 pathogenic and likely pathogenic variants, were detected 14 in BRCA1, 9 in BRCA2, 4 in TP53 genes, 3 in PALB2 and 1 in NBN. (BRCA2: c.6468_6469delTC, c.7567_7568delCT, c.9976A &gt; T, c.8174G &gt; A, c.2442delC, c.2808_2811delACAA, c.9253delA, c.9409dupA and c.6058G &gt; T; BRCA1: c.2498delT, c.5224C &gt; T, c.3020C &gt; G, c.3352C &gt; T, c.5530+1G &gt; A, c.5341-2delA and BRCA1-c.5329dupC in 6 cases; NBN: c.657_661delACAAA; PALB2: c.172_175delTTGT, c.1034T &gt; G and c.18_22delGAAGC; TP53- c.156dupA, c.1024C &gt; T, c.844C &gt; T and c.584T &gt; C). The most frequent genes were BRCA1 (45%) and BRCA2 (29%). Conclusions: The study focused on identifying mutation profile of early onset BC using NGS. Clinically significant variants was detected which are promising biomarkers for the successful diagnosis and therapy of BC at women in reproductive age.
Case 50-1985
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, David Center, Max L. Goodman
Journal: New England Journal of Medicine (1985)

Presentation of CaseA 41-year-old man was admitted to the hospital because of hypertension and dyspnea.He was well until 13 years earlier, while he was spending a year in France, when cough, sore throat, hoarseness, and fever developed. An injection of penicillin was followed by urticaria, and no further antibiotic treatment was prescribed. His other symptoms subsided, but the cough continued and was productive of purulent sputum. X-ray examination of the chest and a tuberculin skin test were reported to be negative. After six weeks his symptoms disappeared, but bilateral episcleritis developed and resolved after the topical administration of . . .