tbuckley/cabot-search huggingface dataset:
Base excision repair (BER) inhibitor TRC 102 (Methoxyamine) combined with pemetrexed (PEM)-based chemo-radiation (CRT) for locally advanced non-squamous non-small cell lung cancer (NS-NSCLC): Results of a phase I trial.
Authors: Tithi Biswas, Afshin Dowlati, Charles Kunos, John Pink, Nancy Oleinick, Shakun M. Malik, Pingfu Fu, Debora S. Bruno, David Lawrence Bajor, Monaliben Patel, Mitchell Machtay
Journal: Journal of Clinical Oncology (2020)

9027 Background: About 35% of all NSCLC presents with locally advanced disease and chemo-radiation results in 5-year OS of only ~31%. PEM-platinum combination is approved in stage IV NSCLC and has similar efficacy to platinum-etoposide in stage 3 NSCLC and a favorable toxicity profile (Proclaim trial). TRC102 is an oral small molecule inhibitor of BER. TRC102 potentiates the cytotoxicity of antimetabolites and alkylators and reverses chemotherapy resistance by rapidly and covalently binding to chemotherapy-induced abasic sites in DNA. TRC102 increased radio-sensitization by PEM of NSCLC cell lines and H1299 and A549 xenografts. Methods: Between 11/2015 and 5/2019, 15 patients were enrolled in a 3+ 3 design: 12 with stage III and 3 with oligometastatic stage IV NS-NSCLC. The primary objective was to determine dose-limiting toxicities (DLT’s) and recommended Phase 2 dose (RP2D) of TRC102 in combination with PEM, cisplatin and radiotherapy. Secondary objectives were to assess toxicity, tumor response and PFS at 6 months. Based on pre-clinical data, PEM-TRC102 was given on day 1, and cisplatin/radiotherapy was initiated on day 3. This schedule was duplicated on day 21 and day 23 of the second cycle. After completion of radiotherapy, two additional cycles of PEM-cisplatin were given. Toxicities were assessed by NCI CTACAE version 4 and 5. Results: Median patient age was 69 years (45-79) and median follow up was 16.6 months (3.1-38.6). There were no DLTs or grade 5 toxicity. Hematologic and GI toxicities were the most common adverse events (Table) and radiation pneumonitis was not seen. The RP2D of TRC102 was 200 mg when given with cisplatin/radiotherapy and PEM. Of 15 evaluable patients, 3 had CR (20%) and 12 had PR (80%). The 2-year PFS rate was 49%. Conclusions: PEM-TRC102 combined with cisplatin/radiotherapy in non-squamous NSCLC was safe and well tolerated, and did not cause safety signals beyond those expected from CRT. Preliminary response data and PFS in this cohort was encouraging. A phase 2 trial, integrating post-CRT immunotherapy with this aggressive DNA-damaging regimen is warranted. Clinical trial information: NCT02535325. [Table: see text]
Long-term follow-up assessment of cardiac safety in SAFE-HEaRt, a clinical trial evaluating the use of HER2-targeted therapies in patients with HER2-positive breast cancer and compromised heart function.
Authors: Katia Khoury, Ana Barac, Filipa Lynce, Xue Geng, Chau T. Dang, Anthony Francis Yu, Karen L. Smith, Christopher Gallagher, Paula Raffin Pohlmann, Raquel Nunes, Pia Maarit Herbolsheimer, Robert D. Warren, M. Barbara Srichai, Mark Hofmeyer, Federico M Asch, Ming Tony Tan, Claudine Isaacs, Sandra M. Swain
Journal: Journal of Clinical Oncology (2020)

12069 Background: HER2-targeted therapies are associated with cardiotoxicity, mostly asymptomatic and reversible. The impact of withholding these therapies on breast cancer outcomes is unknown. SAFE-HEaRt trial was the first study to evaluate the safety of HER2-targeted agents in patients with reduced left ventricular ejection fraction (LVEF) receiving concomitant cardioprotective medications and close cardiac monitoring. We report the 3-year follow-up (f/u) results. Methods: Thirty patients with stage I-IV HER2-positive breast cancer receiving trastuzumab, pertuzumab or ado-trastuzumab emtansine (TDM-1), with asymptomatic LVEF 40-49%, were started on beta blockers (ß-blockers) and/or ACE inhibitors/ARBs, with the primary endpoint being completion of HER2-targeted therapy without cardiac events (CE) or protocol-defined asymptomatic worsening of LVEF. Results: Patients were accrued from 10/2013 to 12/2017 and median f/u as of 2/7/20 is 37 months. The study met its primary endpoint with 27 patients (90%) completing their HER2-targeted therapies without cardiac issues. 24 patients were reconsented for long-term f/u. There were 23 evaluable patients (1 lost for f/u). Off study, 2 patients continued treatment with trastuzumab, 3 with trastuzumab and pertuzumab, and 3 with TDM-1 for metastatic disease. 1 of the 2 patients who had developed a CE with symptomatic heart failure (HF) died of progressive oncological disease, and the second had LVEF recovery on cardiac medications after completion of adjuvant HER2-targeted therapy. Almost 5 years later, she had an asymptomatic decline in her LVEF to 35% after deciding to stop her ß-blocker and ARB. Of the remaining 21 patients, 15 had recovery of their LVEF to ≥50%, 9 of whom remain on cardiac medications. 5 patients had stable LVEF 40-49% and remain asymptomatic on cardiac medications. Only 1 patient had symptoms suggestive of HF, with last documented LVEF stable at 45-50%, but she has not sought medical care for the last 15 months since relocating to another country. There were no new CE and no cardiac deaths. Mean LVEF was 45% at baseline, 46% at end of treatment, and 51.5% at long term f/u. Conclusions: Long-term f/u of the SAFE-HEaRt study continues to provide safety data of HER2-targeted therapy use in patients with compromised heart function. The late development of cardiac dysfunction is uncommon and continued multi-disciplinary oncologic and cardiac care of patients is essential for improved patient outcomes. Clinical trial information: NCT04143594 .
The impact of socioeconomic factors and survivorship on radiation induced hypothyroidism in a single institution cohort study.
Authors: Zvonimir Milas, Daniel R. Carrizosa, Daniel Brickman, Catherine Frenkel, Ashley Stewart, Ashley Love Sumrall, Brittany Neelands, Sally Jeanne Trufan, Shwetha Sudhakar, Matthew Christopher Ward
Journal: Journal of Clinical Oncology (2020)

e24065 Background: To determine factors associated with the development of post-treatment hypothyroidism (HY) in the head and neck (HN) population as well as evaluate the impact of socio-economic factors and survivorship program. Methods: We collected demographics, insurance coverage, disease staging, treatment characteristics, and details of thyroid function measurement as well as supplementation for all HN oncology patients (n = 608) who presented between January 2011 and January 2019 at Levine Cancer Institute, Charlotte, North Carolina. Insurance was categorized as Government (Medicaid or Medicare), Private, or Uninsured. Patient malignancies were grouped as oropharynx, oral cavity, larynx/hypopharynx, nasopharynx, nasal cavity/sinus, or primary salivary gland. Thyroid function was evaluated by use of laboratory thyroid stimulating hormone (TSH) values. Timing of thyroid supplementation was standardized to start of treatment. Details of thyroid hormone supplementation was collected. Data was analyzed with Chi-square and ANOVA methods, using SAS 9.4 (Cary, NC). Results: 483 patients (79%) had post treatment surveillance with TSH. The patients (n = 125, 21%) with no identifiable thyroid surveillance did not have any racial or socioeconomic disparities identified. Caucasian and African American thyroid surveillance rates were similar at 79% and 81%, respectively. There was no difference based on insurance: Government 81%, Uninsured 81%, and Private 76%. Of patients with thyroid surveillance, 203 (42%) developed post-treatment HY. The mean and median time frame until HY identification was 544 days and 450 days, respectively. A mean and median dose of thyroid hormone supplementation of 75 mcg of levothyroxine. Most patients had lower rates of thyroid dysfunction with TSH levels between 5-10. Fewer African Americans (24%) developed HY than Caucasians (47%). Patients with laryngeal cancer were at greatest risk to develop HY (57%), followed by oropharynx (40%) and oral cavity (40%). Staging did not demonstrate a significant difference between development of HY. Conclusions: This study is the largest cohort of HN patients to be evaluated for post HN treatment induced HY. Oncology team providers and primary care physicians should be aware of the significant rates of HY. In our institution we identified a consistency of care provided regardless of socioeconomic and racial factors.
A prospective study of <sup>68</sup>Ga-RM2 PET/MRI in patients with biochemically recurrent prostate cancer and negative conventional imaging.
Authors: Lucia Baratto, Hong Song, Heying Duan, Carina Mari Aparici, Guido Davidzon, Farshad Moradi, Sandy Srinivas, Andrei Iagaru
Journal: Journal of Clinical Oncology (2020)

e17536 Background: 68 Ga-RM2 is a synthetic bombesin receptor antagonist targeting gastrin-releasing peptide receptors (GRPr) that are overexpressed in several human tumors, including prostate cancer (PC). Methods: We enrolled 114 men with BCR PC, 45-83-year-old (mean±SD: 68.2±7.0). Imaging started at 40-89 minutes (mean±SD: 51.3±9.2 after injection of 113.8-152.6 MBq (mean±SD: 140.7±6.4) of 68 Ga-RM2 using a time-of-flight (TOF)-enabled simultaneous positron emission tomography (PET) / magnetic resonance imaging (MRI) scanner. Twenty-four and 23 patients also underwent 68 Ga-PSMA11 and 18 F-DCFPyL PET/CT, respectively. Results: All patients had rising PSA and negative conventional imaging prior to enrollment. 68 Ga-RM2 PET identified recurrent PC in 78 of the 114 participants, while the simultaneous MRI was positive for PC in 45 of the 103 patients. Positivity rate of 68 Ga-RM2 PET was: 31.8% for PSA &lt; 0.5 ng/dl ( n= 22), 60% for PSA 0.5 – 1.0 ng/dl ( n= 15), 64.7% for PSA 1.0 – 2.0 ng/dl ( n= 17), 81.8% for PSA 2.0 – 5.0 ng/dl ( n= 22) and 87.2% for PSA &gt; 5.0 ng/dl ( n= 38). PSA velocity values were 1.9±2.7 ng/ml/year (range: 0-9.1) in patients with negative PET scans and 5.8±9 ng/ml/year (range: 0.2-45.4) in patients with positive PET scans ( P: 0.01). Twenty-eight and 34 lesions were detected by 68 Ga-RM2 PET and 68 Ga-PSMA11 PET, respectively, while 25 lesions in 13 patients were identified by both radio-pharmaceuticals. The mean SUV max ranged 1.6-51.2 (mean±SD:14.7±12.5) for PSMA and ranged 2.5-52.5 (mean±SD: 10.7±11.6) for RM2 ( P= 0.096). Three lesions in 2 patients were RM2-avid only (all lymph nodes) and 9 lesions in 7 patients were PSMA avid only (7 lymph nodes, 1 skeletal and 1 lung nodule). 32 and 48 lesions were detected by 68 Ga-RM2 PET and 18 F-DCFPyL PET, respectively. 28 lesions in 12 patients were identified by both radio-pharmaceuticals. The mean SUV max ranged 1.7-79.3 (mean±SD: 22.2±23) for DCFPyL and ranged 1.7-46.8 (mean±SD: 7±9.2) for RM2 (P &lt; 0.01). Four lesions in 2 patients were RM2 avid only (1 adrenal and 3 skeletal); 17 lesions in 6 patients were DCFPyL avid only (7 lymph nodes, 9 skeletal and 1 prostate). Conclusions: 68 Ga-RM2 may identify higher risk patients given the highly statistically significant difference PSA velocity values between patients with negative and positive scans and may be a complementary radiopharmaceutical to the PSMA-targeting tracers to ultimately allow for personalized medicine. Clinical trial information: NCT02624518 .
A comprehensive characterization of anatomical and molecular risk factors in gastric gastrointestinal stromal tumor.
Authors: Kjetil Boye, Anne Marit Wiedswang, Leonardo A. Meza-Zepeda, Ivar Hompland, Ingvild Lobmaier, Jeanne-Marie Berner, Stephan Stoldt, Toto Hølmebakk
Journal: Journal of Clinical Oncology (2020)

e23522 Background: Gastric gastrointestinal stromal tumors (GISTs) demonstrate a remarkable diversity in clinical behavior. Established risk criteria identify patients prone to recurrence with high sensitivity, but factors that could add specificity are needed. The aim of this study was to give a comprehensive picture of localized, gastric GIST and to investigate prognostic factors in a large population-based series. Methods: Patients with primary gastric GISTs completely resected between 2000 and 2018 were identified in the sarcoma database at Oslo University Hospital. Gastric subsite was divided into the upper, middle and lower thirds. Macroscopic growth pattern was coded as luminal, exophytic or transmural based on imaging and surgical reports. Mutation analysis was performed by Sanger sequencing of selected exons in KIT and PDGFRA and by targeted next-generation sequencing. Results: The cohort comprised 295 patients, representing 98% of patients in the region reported to the Cancer Registry of Norway. Of 292 tumors suitable for anatomical classification, 122 were located in the upper third of the stomach (41.8%), 120 in the middle (41.1%), and 50 in the lower third (17.1%). The number of luminal, exophytic and transmural tumors were 100 (34.1%), 94 (32.1%) and 99 (33.8%), and 2 tumors were not possible to classify. KIT mutations were detected in 183 of 256 tumors (71.5%), PDGFRA mutations in 62 (24.2%), whereas only 11 patients (4.3%) had KIT and PDGFRA wild-type tumors. Transmural tumors were larger, more often located in the upper third, had higher mitotic activity, and more frequently had KIT del557/558 mutations. KIT mutated tumors had a predilection for the upper two thirds and PDGFRA mutated tumors for the lower two thirds. Recurrences were rare among patients with luminal or exophytic tumors, with a 5-year RFS of 96% versus 71% with transmural tumors (HR 8.45; 95% CI 3.69-19.36; P&lt; 0.001). RFS was inferior with transmural tumor growth also among high-risk patients, 46% versus 83% at 5 years ( P= 0.001). Excluding patients with tumor rupture, there was only one recurrence among 24 high-risk patients with luminal or exophytic primaries, of whom 11 did not receive adjuvant therapy. Conclusions: This study provides a comprehensive, population-based description of the anatomical and molecular landscape of gastric GIST, with findings of potential clinical relevance. Transmural tumor growth was a predictor of poor outcome and could supplement established risk factors in selecting patients for adjuvant imatinib treatment.
Using digital engagement to proactively manage symptoms in patients on capecitabine.
Authors: Mandeep Sohal, Sarah McLarty, Kayla E Friend, Kathryn D Johnson, Melissa Johlie, Christine Sawicki, Kjel Andrew Johnson
Journal: Journal of Clinical Oncology (2020)

12079 Background: Adherence to oral chemotherapy is a challenge due to the toxic adverse events (AEs) patients’ experience. Capecitabine (CAP) may cause patients to experience AEs such as diarrhea and hand and foot syndrome (HFS), leading to therapy non-adherence. Digital patient engagement has successfully improved patient adherence and has been used to monitor AEs in a variety of cancer types. We used proprietary secure messaging to engage specialty patients receiving CAP and to message them at the expected onset of diarrhea and HFS; nurse care management was deployed for patients reporting an AE. The objective of this study was to determine whether nurse engagement using digital tools to manage oncology AEs resulted in improved medication adherence. Methods: CAP patients were sent outgoing SMS branching logic messages during November 2019, and respondents reporting AEs were engaged by nurses using a proprietary secure messaging platform. Nurses made clinical interventions in these patients by either making a pharmacologic or non-pharmacologic recommendation or referring the patient to an oncologist. The number of patients responding to outgoing SMS and secure messaging, nurse interventions, and medication fill history were measured. We compared 30-day post-intervention proportion of days covered (PDC) in the intervention group (those that engaged with nurses and received digital adherence and clinical messages) to standard of care (those who received digital adherence and clinical messages but did not engage) using the Student’s t-test. Results: 1,421 outgoing messages were sent to utilizers of CAP; 95 patients replied indicating the occurrence of either diarrhea or HFS. Nurse care managers reached 49 (52%) unique patients resulting in 54 interventions where care coordination was provided. The majority of engaged patients reached (74%) had symptom resolution as a result of nurse intervention. PDC was 79.3% in the intervention group and 68.8% (p = 0.038) in the standard of care group. Conclusions: SMS and secure messaging patients with AEs on CAP resulted in clinical interventions by nurse care managers. Nurse intervention resulted in the majority of patients having symptomatic resolution and therapy continuation. PDC indicated greater medication adherence in the engaged group. These results for one drug suggest that nurse digital engagement can be effective in increasing adherence for patients treated with oral oncolytics suffering from AEs. Proactive symptom tracking supports the early identification of potential AEs and effective nurse care coordination.
Overcoming Genetically Based Resistance Mechanisms to PD-1 Blockade
Authors: Davis Y. Torrejon, Gabriel Abril-Rodriguez, Ameya S. Champhekar, Jennifer Tsoi, Katie M. Campbell, Anusha Kalbasi, Giulia Parisi, Jesse M. Zaretsky, Angel Garcia-Diaz, Cristina Puig-Saus, Gardenia Cheung-Lau, Thomas Wohlwender, Paige Krystofinski, Agustin Vega-Crespo, Christopher M. Lee, Pau Mascaro, Catherine S. Grasso, Beata Berent-Maoz, Begoña Comin-Anduix, Siwen Hu-Lieskovan, Antoni Ribas
Journal: Cancer Discovery (2020)

Mechanism-based strategies to overcome resistance to PD-1 blockade therapy are urgently needed. We developed genetic acquired resistant models of JAK1, JAK2, and B2M loss-of-function mutations by gene knockout in human and murine cell lines. Human melanoma cell lines with JAK1/2 knockout became insensitive to IFN-induced antitumor effects, while B2M knockout was no longer recognized by antigen-specific T cells and hence was resistant to cytotoxicity. All of these mutations led to resistance to anti-PD-1 therapy in vivo. JAK1/2-knockout resistance could be overcome with the activation of innate and adaptive immunity by intratumoral Toll-like receptor 9 agonist administration together with anti-PD-1, mediated by natural killer (NK) and CD8 T cells. B2M-knockout resistance could be overcome by NK-cell and CD4 T-cell activation using the CD122 preferential IL2 agonist bempegaldesleukin. Therefore, mechanistically designed combination therapies can overcome genetic resistance to PD-1 blockade therapy. SIGNIFICANCE: The activation of IFN signaling through pattern recognition receptors and the stimulation of NK cells overcome genetic mechanisms of resistance to PD-1 blockade therapy mediated through deficient IFN receptor and antigen presentation pathways. These approaches are being tested in the clinic to improve the antitumor activity of PD-1 blockade therapy.This article is highlighted in the In This Issue feature, p. 1079.
Online questionnaire survey on knowledge of systemic lupus erythematosus among general practitioners in Beijing Dongcheng district
Authors: Junxia Wang, Yue Sha
Journal: BMJ (2019)

Objective
To survey knowledge of systemic lupus erythematosus (SLE) among general practitioners in Beijing Dongcheng district.


Methods
In November 2017, an online questionnaire survey on knowledge of SLE was conducted among 226 general practitioners from 7 community health service centers and 44 community health service stations in Beijing Dongcheng district. The questionnaire included three parts: the basic information of participants, SLE-related knowledge and the demand of continuing education for SLE.


Results
Total 225 valid questionnaires were received with a retrieval rate of 99.6%. The overall accuracy rate was 47.0%(1 269/2 700). And the rates of correct answer for SLE diagnosis, treatment and management were 28.3% (191/675), 58.4%(526/900) and 49.0%(551/1 125), respectively. Educational background, professional titles and working years had a certain impact on the level of SLE disease-related knowledge. Higher educational level and longer working years were associated with the higher knowledge level of SLE treatment goals (χ2=6.054, 4.296; P<0.05). Knowledge scores regarding side effects of glucocorticoid were slightly higher in GPs who were working for a longer time and in senior positions (χ2=6.048,5.499;P<0.05). In addition, the study also identified SLE patients in 5 community health centers and 15 community health service stations, who were given medications of glucocorticoids and immunosuppressants. Fewer SLE patients presented to the community health service and lack of learning resources mainly affected the GPs′ perception of SLE, as well as patient management. Besides, 79.6%(179/225) of GPs perceived that community management of SLE patients is necessary and they would be interested in receiving further training on SLE. The most preferred method of training delivery was short courses and lectures.


Conclusion
The knowledge and practice of SLE need improvement among GPS, especially early identification and long-term management. Fewer patients and lack of learning resources are the primary barriers. The results of the study are of practical significance for the training of general practitioners in the future.


Key words: 
Systemic lupus erythematosus; General practitioner; Questionnaire
Contextualizing Potential Risks of Medications in Pregnancy for the Newborn—the Case of Ondansetron
Authors: Krista F. Huybrechts, Sonia Hernández-Díaz, Brian T. Bateman
Journal: JAMA Pediatrics (2020)

This Viewpoint argues that the magnitude of the absolute risk increase, the potential benefits of the medication, and the safety of therapeutic alternatives should be considered when assessing the safety of medications taken during pregnancy.