tbuckley/cabot-search huggingface dataset:
Capmatinib in patients with high-level <i>MET</i>-amplified advanced non–small cell lung cancer (NSCLC): results from the phase 2 GEOMETRY mono-1 study.
Authors: Juergen Wolf, Tobias R. Overbeck, Ji-Youn Han, Maximilian Hochmair, Filippo de Marinis, Kadoaki Ohashi, Egbert F. Smit, Danielle Power, Edward B. Garon, Harry J.M. Groen, Daniel Shao-Weng Tan, Maeve Waldron-Lynch, Sylvie Le Mouhaer, Ngozi Nwana, Monica Giovannini, Rebecca Suk Heist
Journal: Journal of Clinical Oncology (2020)

9509 Background: In the ongoing, multicohort, phase 2 GEOMETRY mono-1 study, capmatinib (INC280) has shown efficacy in METex14–mutated NSCLC patients (pts) who were pretreated (cohort 4) or treatment (tx)-naïve (cohort 5b). Here, we report the efficacy and safety of capmatinib in pts with high-level MET-amplified (gene copy number [GCN] ≥10) advanced NSCLC who were either pretreated with 1 or 2 prior lines of systemic therapy (cohort 1a) or tx-naïve (cohort 5a). Methods: Adult pts (≥18 years), ECOG PS 0–1 who had ALK and EGFR wt, stage IIIB/IV (any histology) MET-amplified NSCLC with GCN≥10 received capmatinib 400 mg twice daily (fasting). Primary and key secondary endpoints were overall response rate (ORR) and duration of response (DOR), respectively, by blinded independent review committee (BIRC) assessment per RECIST v1.1. Other secondary endpoints included investigator-assessed ORR, DOR, disease control rate (DCR), progression-free survival (PFS, BIRC and investigator assessment), overall survival, and safety. Results: As of Jan 06, 2020, 84 pts were evaluable for efficacy (cohort 1a [2 nd /3 rd line], 69 pts; Cohort 5a [1 st line], 15 pts). Tx was ongoing for 3 pts in cohort 1a, none in cohort 5a. Per BIRC assessment in cohorts 1a and 5a, respectively, ORR was 29% and 40%, median DOR was 8.31 months (mo, 20 responders, 95% CI: 4.17–15.44) and 7.54 mo (6 responders, 95% CI: 2.56–14.26), and median PFS was 4.07 (95% CI: 2.86–4.83) and 4.17 (95% CI: 1.45–6.87) mo. Investigator assessment was in line with BIRC assessment (Table). The most common adverse events across all cohorts (≥25%, all grades, N = 364) were peripheral edema (51.1%), nausea (44.8%) and vomiting (28.0%). Data for biomarker analysis and pts with brain metastasis will be presented at the ASCO 2020 meeting. Conclusion: Capmatinib has demonstrated activity in the subset of pts with high-level MET-amplified (GCN≥10) NSCLC, with a higher response rate in tx-naïve pts. Safety profile remains favorable and similar to previous reports of capmatinib. Clinical trial information: NCT02414139 . [Table: see text]
Incidence of hypothyroidism in head and neck squamous cell carcinoma patients receiving radiotherapy with and without immune checkpoint inhibitors.
Authors: Jennifer Leddon, Martina Chirra, Arushi Agrawal, Logan Roof, Danny Trotier, Hira Shaikh, Timothy Stone, Roman Jandarov, Vinita Takiar, Trisha Michel Wise-Draper
Journal: Journal of Clinical Oncology (2020)

e18551 Background: Treatment for locally advanced head and neck squamous cell carcinoma (HNSCC) involves a combination of surgery, chemotherapy, and radiotherapy (RT). RT for HNSCC is a known risk factor for the development of hypothyroidism. Recently, anti-PD1 therapies have been approved for recurrent and metastatic HNSCC and are moving to the forefront of HNSCC care. Similarly, thyroid dysfunction is a common immune-related adverse event following anti-PD1 therapy. Whether the addition of anti-PD1 to RT increases the likelihood of developing hypothyroidism remains unknown. Methods: The rate of hypothyroidism in HNSCC patients receiving RT (+/- chemotherapy and surgery) was compared to HNSCC patients receiving RT + anti-PD1 therapy either concurrently or after RT. Exclusion criteria were preexisting thyroid dysfunction, RT dose &lt; 45 Gy and patients with incomplete treatment records. We defined clinical hypothyroidism as an elevation of TSH with low T3, T4 or elevation of TSH with symptoms requiring levothyroxine initiation. Hypothyroidism incidence was compared using Fisher’s exact test. Results: 153 patients were evaluated. In the RT group (N = 103), patients received RT +/- surgery or chemotherapy. 82/103 (80%) were male, median age was 57 and primary tumor groups included oropharynx 62/103 (60%), larynx 29/103 (28%), oral cavity 9/103 (9%) and other 3/103 (3%). In the RT + anti-PD1 group (N = 50), 36/50 (72%) were males, median age was 57 and primary tumor groups included oral cavity 19/50 (38%), oropharynx 17/50 (34%), larynx 8/50 (16%), and other 6/50 (12%). In the RT group, median follow up after RT was 801 days. In the RT+ anti-PD1 group, median follow up was 595 days from RT and 388 days from anti-PD1. The rate of hypothyroidism was significantly higher in the RT group 22.3% (23/103) versus 6% (3/50)after anti-PD1 therapy (p = 0.011). Multinomial logistical regression found no significant difference in hypothyroidism based on age, sex, or BMI. Larynx as primary tumor location was an independent risk factor for development of hypothyroidism (OR 4.74, p = 0.002). Conclusions: The addition of anti-PD1 therapy to standard HNSCC treatments does not significantly increase the risk of developing hypothyroidism. In fact, this study finds a lower incidence of hypothyroidism in HNSCC patient receiving RT + PD1 therapy which may be due to shorter duration of follow up and lower proportion of laryngeal cancer patients who are at relatively higher risk for surgical hypothyroidism.
Asymptomatic Intracranial Artery Stenosis—One Less Thing to Worry About
Authors: Seemant Chaturvedi
Journal: JAMA Neurology (2020)

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<i>PALB2</i> mutations in Brazilian patients from North-Northeast regions.
Authors: Thamara Ferreira, Thais Ferreira Bomfim-Palma, Isabelle Joyce de Lima Silva-Fernandes, Gabriela Espirito Santo Felix, Inacelli Queiroz De Souza Caires, Leandro Apolinário Silva, Luciana Garcia Landeiro, Maria Betania Toralles, Renata Gondim Meira Velame Azevedo, Juliana Côrtes, Henrique de Campos Reis Galvão, Marcos Venício Alves Lima, Paulo Goberlanio de Barros Silva, Maria Júlia Barbosa Bezerra, Rosane Oliveira Sant'Ana, Flávio da Silveira Bitencourt, Francisca Fernanda Barbosa Oliveira, Clarissa Gondim Picanço-Albuquerque, Ivana Lucia Oliveira Nascimento, Taisa Manuela Bonfim Machado-Lopes
Journal: Journal of Clinical Oncology (2020)

e13670 Background: Loss-of-function mutations in PALB2 gene are associated with increased risk for breast cancer and possibly pancreatic, ovarian, male breast, prostate, colorectal as others cancers. In Brazil it has been estimated that up to 1,516 new cases of hereditary breast cancer for 2020 in the North and Northeast regions. Analysis of susceptibility gene mutations helps identify precisely the high-risk patient and their families, whom need specific and personalized clinical management as high-risk individuals. Methods: Twenty-six patients with pathogenic mutations in PALB2 gene identify by next-generation sequencing from states of Bahia (11), Ceará (9), Pernambuco (5) and Rondônia (1) in the North and Northeast regions were analyzed. Results: Most of the patients analyzed had only breast cancer (80%), including two cases of male breast cancer (9,5%); the others were isolated cases of endometrial cancer (4%), breast and pancreas cancers (4%), breast and lung cancers (4%), only ovarian cancer (4%) and ovarian and breast cancers (4%). Most cancers were stage II or III (65%). Family history of cancer was observed in 22/26 (84%); the most common tumors were breast, prostate, pancreas and thyroid. The founder mutations were more frequent in exons: 4 (58%) and 12 (15%). Eleven variants were found as follow: c.1240C &gt; T (19%); c.3256delC (15%); c.1671_1674delTATT (11.5%); c.355delC (11.5%); NC_000016.9:g.(?_23632673)_(23652488_?)del (11,5%). The greatest variety of mutations was found in the state of Bahia, probably due to the greater number of patients included (42%). Conclusions: These data suggest that changes in clinical management of PALB2 patients are needed since the phenotype observed exhibited pattern of hereditary tumors, including male breast cancer. Besides that, PALB2 gene should be included in painel gene analysis in patients from the North and Northeast of Brazil because its high frequency of pathogenic variants.
Vismodegib (V) for organ preservation for locally advanced (LA) orbital/periocular basal cell carcinoma (BCC).
Authors: Francis P. Worden, Shelby A Unsworth, Chris A Andrews, May Chan, Scott Bresler, Christopher Keram Bichakjian, Alison Bates Durham, Hakan Demirci, Victor Elner, Christine Nelson, Denise Kim, Shannon Joseph, Paul Swiecicki, Alon Kahana
Journal: Journal of Clinical Oncology (2020)

10069 Background: LA BCC of the eye/lacrimal drainage system most often requires disfiguring radical surgery, possibly including exenteration. As an alternative to radical surgery, we evaluated ophthalmologic outcomes following treatment with V using a novel Visual Assessment Weighted Score (VAWS) in patients (pts) with locally advanced periocular BCC. Methods: In this open label, non-randomized trial, pts with globe- and lacrimal-threatening orbital/periocular BCC were scored with VAWS prior to treatment with 150 mg of V daily. Pts were evaluated by ophthalmic exam (OE) every 3 mo &amp; with MRI/CT at 5-9 mo. Pts with progressive disease (PD) were offered salvage surgery. Tumor response was assessed by RECIST v1.1. Responders (CR, PR, SD) continued V if tolerating therapy. Pts with intolerable side effects stopped V &amp; were offered surgery of their residual tumor. Post-surgical specimens were assessed for histologic presence of BCC by a dermatopathologist. The primary endpoint, maintenance of visual function, was evaluated by VAWS at final post treatment assessment (FPTA), 1 yr after the start of V or 2 mo post-surgery. A VAWS of 21/50 was considered successful, representing preservation of a functional eye. Results: 50 pts were planned for enrollment, but the study was stopped early for benefit. From 06/25/2015 to 05/16/2019, 35 pts signed consent; 1 was a screen failure; 34 (97%) received V &amp; 35 were evaluable for analysis by ITT; 1 died from aspiration pneumonia. The median time on study was 261 days. Average treatment with V was 223 days. 32 (91%) underwent OE &amp; 27 (77%) had an MRI/CT. 27 (77%) underwent surgery &amp; 33 (94%) attained organ preservation. Overall response rate (ORR) on OE was 84% (0%-PD,6%-SD,29%-PR,54%-CR, 11% not assessed(NA)). ORR by MRI/CT was 72% (0%-PD,6%-SD, 26%-PR,46%-CR,22% NA). 31 (89%) were scored with VAWS at 3 mo &amp; 30 (86%) at FPTA. The mean VAWS at baseline was 44/50, 46/50 at 3 mo, &amp; 47/50 at FPTA. Of the 35 pts scored at baseline by VAWS, 1 (3%) had a major decline during follow up, 5 (14%) a minor decline, 27 (77%) stable/improved, &amp; 2 (6%) NA. No pts experienced grade 3-5 events. Of the 27 post-surgical pathologic specimens evaluated for histological response, 67% had NED, 22% had clear margins, &amp; 11% had BCC to the margin. Two pts have recurred &amp; underwent Mohs surgery. Conclusions: Treatment with V led to organ preservation for pts with LA periocular BCC, with preservation of visual function. Vismodegib is practice changing as neoadjuvant therapy for LA BCC of the eye/lacrimal drainage system in which surgery would result in unacceptable morbidity. Clinical trial information: NCT02436408.
Potential use of IL-7 and IL-15 for ex vivo generation of LAK.
Authors: Svetlana Yu. Filippova, Oleg I. Kit, Anastasia O. Sitkovskaya, Elena Yu. Zlatnik, Inna A. Novikova, Larisa N. Vashchenko, Emma E. Kechedzhieva, Irina R. Dashkova, Tatiana V. Ausheva, Elena Andreiko, Natalya S. Saforyan, Liubov Yu Vladimirova
Journal: Journal of Clinical Oncology (2020)

e15201 Background: A review of scientific literature has shown that IL-2 is most often used for the LAK generation, while the potential of other NK-stimulating interleukin cells remains poorly understood. In this study, we investigated the effect of IL-7 and IL-15 on ex vivo LAC generation. Methods: A fraction enriched in NK cells was isolated by magnetic cell sorting with the NK Cell Isolation Kit (#130-092-657, Miltenyi Biotec, Germany) from PBMC in 11 patients with stage II-III breast cancer without treatment. Cells were introduced into a 6-well 3x10 5 plate in RPMI medium (Gibco, USA) supplemented with 10% FBS (Gibco, USA). Cytokines 40 ng/ml were added to the wells in 6 variants: 1) IL-15; 2) IL-2; 3) IL-7; 4) IL-15+IL-7; 5) IL-15+IL-7+IL-2; 6) control without cytokines. Cells were cultured at 5.0% CO 2 and 37°C. Cells were counted with a hemocytometer daily for 5 days and on days 8, 9 and 10 of cultivation. Results: The number of NK cells in control samples gradually decreased: by 2 times on day 5 and by 3 times on day 10. On day 5, the number of NK cells was 1.5 times higher than in the control when cultured with IL-2, and 1.4 times higher when cultured with IL-7+IL-15. After 9 days, a statistically significant increase in the number of cells, compared to the control sample, was observed with the addition of IL-2 (1.6 times); IL-15 and IL-7+IL-15 (1.5 times). On day 10, significant differences from the control were found in most samples: the number of cells was higher in samples cultured with IL-2 and IL-7+IL-15 (1.9 times) and with IL-15 and IL-2+IL-7+IL-15 (1.7 times). IL-7 alone led to a gradual decrease in the number of cells, and on days 8, 9 and 10 it was lower than in the control samples. Conclusions: In general, the introduction of cytokines into the samples enriched with NK cells contributed to the preservation of this subpopulation on days 5-10 of cultivation. However, the use of IL-7 and IL-15, both alone and in combination, did not lead to a significant increase in LAK compared to the use of IL-2.
Predicting nodal positivity in women with hormone receptor-positive (HR+), early stage breast cancer (ESBC).
Authors: Emily Miller Ray, Paula D. Strassle, Charles E. Gaber, Hyman B. Muss, Stephanie M. Downs-Canner
Journal: Journal of Clinical Oncology (2020)

574 Background: Omission of axillary surgery is appropriate in some patients with clinically node-negative (cN0), HR+ ESBC; however, there are no pre-operative tools to predict pathologic node positivity (pN+) in these women. We propose a clinically validated predictive model to inform treatment decisions regarding axillary evaluation. Methods: We constructed a cohort of adult women with ESBC (clinical T1/T2, N0, M0) diagnosed 2012-2016, who underwent lumpectomy or mastectomy and lymph node surgery without neoadjuvant therapy using the National Cancer Database breast cancer dataset. The dataset was non-randomly split into training (2012-2015) and testing (2016) for development and validation. Stepwise logistic regression was used to identify predictors of pathologic node positivity (pN0 vs pN+) in the training dataset. Potential predictors included: age, race, ethnicity, comorbidity score, histologic type, clinical T, ER positivity, PR positivity, HER2 positivity, and grade. Predictor variables required a bivariate p-value &lt;0.30 to be entered into model, and an adjusted p-value &lt;0.35 to stay in model. A partial score method was used to develop a lymph node prediction score (LNPS) by assigning a weighted value to each strong predictor variable (OR &gt;1.5) and adding together the values for each included variable. LNPS was treated as a linear variable for prediction in validation dataset. Results: 423,068 women were included (2012-2015: 334,778; 2016: 88,290). Pathologic node positivity was 17% in 2012-2015 and 2016. All variables were included in the final stepwise model. Strong predictors were age, histologic type, clinical T, and grade. Scores ranged from 0-11. In the validation dataset, predicted pN+ by LNPS was very similar to actual pN+ (Table). A 1-point increase in LNPS was associated with a 3.3% increase in absolute risk of pN+. Conclusions: A novel lymph node prediction score can be used in HR+ cT1-T2 cN0 breast cancers to estimate the probability of pN+ and guide decisions regarding axillary surgical evaluation. [Table: see text]
Salt generates antiinflammatory Th17 cells but amplifies pathogenicity in proinflammatory cytokine microenvironments
Authors: Julia Matthias, Sylvia Heink, Felix Picard, Julia Zeiträg, Anna Kolz, Ying-Yin Chao, Dominik Soll, Gustavo P. de Almeida, Elke Glasmacher, Ilse D. Jacobsen, Thomas Riedel, Anneli Peters, Stefan Floess, Jochen Huehn, Dirk Baumjohann, Magdalena Huber, Thomas Korn, Christina E. Zielinski
Journal: Journal of Clinical Investigation (2020)

Th cells integrate signals from their microenvironment to acquire distinct specialization programs for efficient clearance of diverse pathogens or for immunotolerance. Ionic signals have recently been demonstrated to affect T cell polarization and function. Sodium chloride (NaCl) was proposed to accumulate in peripheral tissues upon dietary intake and to promote autoimmunity via the Th17 cell axis. Here, we demonstrate that high-NaCl conditions induced a stable, pathogen-specific, antiinflammatory Th17 cell fate in human T cells in vitro. The p38/MAPK pathway, involving NFAT5 and SGK1, regulated FoxP3 and IL-17A expression in high-NaCl conditions. The NaCl-induced acquisition of an antiinflammatory Th17 cell fate was confirmed in vivo in an experimental autoimmune encephalomyelitis (EAE) mouse model, which demonstrated strongly reduced disease symptoms upon transfer of T cells polarized in high-NaCl conditions. However, NaCl was coopted to promote murine and human Th17 cell pathogenicity, if T cell stimulation occurred in a proinflammatory and TGF-β–low cytokine microenvironment. Taken together, our findings reveal a context-dependent, dichotomous role for NaCl in shaping Th17 cell pathogenicity. NaCl might therefore prove beneficial for the treatment of chronic inflammatory diseases in combination with cytokine-blocking drugs.
Assessing real-world clinical response in patients with multiple myeloma (MM): A survey of the literature.
Authors: Daniel Lane, Andrew D. Norden, Andrew J. Belli, Ching-Kun Wang
Journal: Journal of Clinical Oncology (2020)

e19260 Background: A recent study (Foster, Tromanhauser et al. 2019) utilizing Electronic Health Record (EHR) data found that patients with MM rarely have both serum protein electrophoresis (SPEP) and 24-hour urine protein electrophoresis (UPEP) documented in routine clinical practice settings. These elements are necessary to classify response using the International Myeloma Working Group (IMWG) consensus criteria. It could be hypothesized that adding the additional requirements for bone marrow biopsy necessary to confirm a complete response would further reduce the rate of strict adherence to the IMWG criteria in the real world (RW). Clinicians are however assessing response and progression in RW settings and often report these assessments in published literature. In this study, we survey the literature to determine how RW response is being captured and reported outside of the clinical trial setting. Methods: A systematic search was performed using Medline 2010-2019. Using a standardized grading system, English language articles were evaluated that utilized EHR data from routine clinical practice to report RW response in patients with active MM. Registry based and/or pragmatic observational studies were excluded as many had mandatory reporting procedures in place. Studies were then categorized based on methods of assessing response, progression and use of IMWG criteria. Results: The majority of studies grade 1 studies identified (21/25) utilized best response achieved based on treating physician-documented assessment and either did not specify the use of IMWG(10/21) criteria or explicitly stated they did not use conventional criteria (11/21). Progression event capture and reporting varied greatly with many using physician-documented progression, change in regimen, addition of additional agents to existing regimen, stem cell transplant, or an individually created algorithm. Conclusions: Our findings suggest that there is a need for further research on objective techniques for the assessment of RW progression and response in patients with MM. Additionally, validation of an approach that utilizes partial adherence to IMWG criteria would help in the ability to compare findings across clinical trial and RW settings. This validation work is under way, and preliminary results will be reported at the meeting.