tbuckley/cabot-search huggingface dataset:
The utility of surgery in butterfly glioblastoma: A case-control study.
Authors: Benjamin James Hall, Igor Maleyko, Andrew Brodbelt, Michael D Jenkinson, Emmanuel Chavredakis
Journal: Journal of Clinical Oncology (2019)

e13529 Background: Glioblastoma is the most common primary brain tumour and may rarely infiltrate the corpus callosum. Such ‘butterfly’ glioblastomas (BGBM) are believed to confer a poorer prognosis than their non-callosal counterparts. We aimed to determine the impact of surgery on overall survival (OS) and postoperative morbidity in butterfly glioblastomas. Methods: Retrospective analysis was performed on all case notes of patients histologically diagnosed with GBM from January 2011 to January 2017 at The Walton Centre NHS Foundation Trust, Liverpool. Data was collected under the following headings: demographics, tumour characteristics, surgical data, adjuvant therapy and survival data. A case-matched control group was produced according to age, sex and 1 o resection. Univariate analysis was performed. Results: 632 glioblastoma patients were identified. 37 patients were diagnosed with butterfly BGBM, with a median age of 62.7 years and a gender split of 24 males (64.9%) to 13 females (35.1%). Median tumour volume was 31700mm 3 , with 24 (56%) tumours involving the genu and 13 (22%) the splenium of the callosum. Kaplan-Meier analysis with log-rank testing demonstrated a significant (p = 0.04) decrease in median OS in those with BGBM (100 days (95%CI 57-142)) vs controls (276 days (95%CI 224-327)). Resection of BGBMs resulted in longer median OS than biopsy alone (296 days (95%CI 229-363) vs 81 (66-96)), though this was a non-significant difference (p = 0.36). Multifocal disease occurred significantly more often in BGBM patients (p = 0.01), the exclusion of which from analysis demonstrated a significant survival benefit with resection (427 days (95%CI 207-647)) compared to biopsy (221 days (95%CI 151-291)) (p = 0.04). Postoperative complications did not occur significantly more often in BGBM resections than controls (7/36 (19.4%) vs 5/36 (13.9%) (p = 0.257)). Conclusions: Overall, butterfly glioblastomas confer a worse prognosis than those without callosal involvement. A greater prevalence of multifocal disease is seen in butterfly glioblastoma, warranting further investigation. Resection offers a significant improvement in OS in solitary butterfly glioblastomas without a significant increase in postoperative morbidity, and should therefore be considered an efficacious and safe treatment option.
IMPACT: Immunotherapy in patients with metastatic cancers and CDK12 mutations.
Authors: Melissa Andrea Reimers, Wassim Abida, Jonathan Chou, Daniel J. George, Elisabeth I. Heath, Rana R. McKay, Russell Kent Pachynski, Jingsong Zhang, Jae Eun Choi, Felix Y Feng, Gina Neshewat, Marcin Cieslik, Stephanie Daignault-Newton, Eric Jay Small, Arul Chinnaiyan, Ajjai Shivaram Alva
Journal: Journal of Clinical Oncology (2019)

TPS5091 Background: Tumors with biallelic CDK12 loss have been identified as a distinct subtype in metastatic castration resistant prostate cancer (mCRPC) and other cancer types. The CDK12 biallelic loss mCRPC genomic signature, distinct from homologous recombination deficient (HRD) and ETS fusion signatures, is characterized by excessive tandem duplications, genomic instability, gene fusion-caused putative neoantigens, and increased tumor T cell infiltration. Early clinical experience with anti-PD-1 immunotherapy in CDK12 loss mCRPC patients (pts) is notable for deep and sustained PSA as well as radiographic responses. We hypothesize that CDK12 biallelic loss is a potential biomarker of immune checkpoint immunotherapy (ICI) efficacy in mCRPC and other cancers. Methods: IMPACT (NCT03570619) is a multi-center, open label, phase 2 study of pts with metastatic cancers that harbor CDK12 biallelic loss. mCRPC pts will be enrolled in cohort A (n = 25) in a Mini-Max Simon Two-Stage design, and all other pts in single-stage cohort B (n = 15). All pts will receive induction therapy with nivolumab 3 mg/kg IV and ipilimumab 1 mg/kg IV q3 weeks for up to 4 cycles, followed by maintenance nivolumab at 480 mg IV q4 weeks (up to 52 weeks in total). Eligible pts must have identified biallelic CDK12 loss on any CLIA/CAP approved next generation sequencing assay and a histologic diagnosis of metastatic prostate adenocarcinoma or other metastatic carcinoma. No prior ICI is allowed. The primary endpoint is the overall response rate (ORR) in cohort A per PCWG3 criteria. An ORR of 30% is targeted in cohort A. Secondary endpoints include safety, secondary efficacy measures, quality of life, and survival measures. Exploratory objectives include tumor whole exome analysis and changes in immune profiles with therapy. Comprehensive and serial monitoring of peripheral blood immune cell populations will be performed via T cell clonal diversity assessment and multi-parametric flow cytometry. Changes in myeloid and lymphoid populations will be assessed from whole blood. Polarization and effector function of T cells and activation of antigen presenting cells will be further characterized from isolated peripheral blood mononuclear cells. Study accrual is ongoing. Clinical trial information: NCT03570619.
Gender equality and gender norms: framing the opportunities for health
Authors: Geeta Rao Gupta, Nandini Oomman, Caren Grown, Kathryn Conn, Sarah Hawkes, Yusra Ribhi Shawar, Jeremy Shiffman, Kent Buse, Rekha Mehra, Chernor A Bah, Lori Heise, Margaret E Greene, Ann M Weber, Jody Heymann, Katherine Hay, Anita Raj, Sarah Henry, Jeni Klugman, Gary L Darmstadt
Journal: The Lancet (2019)
A phase I study to evaluate safety, tolerability, pharmacokinetics and antineoplastic activity of BPI-7711 in patients with EGFR/T790M mutation advanced or recurrent NSCLC.
Authors: Yuankai Shi, Jian Fang, Yongqian Shu, Donglin Wang, Huiqing Yu, Yanqiu Zhao, Liangming Zhang, Bo Zhu, Xingya Li, Gongyan Chen, Jianhua Shi, Rongsheng Zheng, Jian'An Huang, Sheng Yang, Jieran Long, Wen Gao, Michael Greco, Jing Wang, Xiao Li
Journal: Journal of Clinical Oncology (2019)

9034 Background: BPI-7711 is a 3 rd generation irreversible EGFR-TKI that is selectively against EGFR TKI–sensitizing mutations and the T790M resistance mutations. We are conducting a phase I study to determine the safety and efficacy of BPI-7711 in patients with advanced or recurrent EGFRm+/T790M+ NSCLC. Methods: NSCLC patients who had documented disease progression after 1 st /2 nd generation EGFR-TKI treatment and with EGFRm+/T790M+ confirmed by central lab were enrolled in the multicenter trial (NCT03386955) into “3+3” dose escalation or expansion cohorts. BPI-7711 was orally administered at doses of 30~240 mg in capsules. Patients in dose-escalation cohorts firstly received a single dose of BPI-7711 followed by a 7-day pharmacokinetic (PK) evaluation period then received the same dose daily until disease progression or intolerable toxicity(ies) per CTCAE V4.03. Treatment efficacy per RECIST 1.1 was evaluated every 6 weeks since daily treatment commence. Once efficacy was observed in a dose, its expansion cohort was opened to enroll patients for daily treatment. Results: As of 23 December 2018, 82 patients (median age 55, 27 males, 55 females) were enrolled into 5 dose escalation cohorts (30/60/120/180/240 mg) and 4 dose expansion cohorts (30/60/120/180 mg). No DLT was observed and MTD was not reached. For all safety-evaluable patients, most common treatment emergent adverse events (TEAEs) (≥10%) were white blood cell count decreased (21.3%), neutrophil count decreased (17.3%), upper respiratory tract infection (17.3%), vomiting (12.0%) and diarrhea (10.7%), and all were Grade 1 or 2. Grade 3~4 TEAEs were occurred in 8.0% patients and 4.0% of them were treatment-related per investigators’ judgement. SAEs were reported in 4.0% of patients, and 1.3% were treatment-related. For all efficacy-evaluable patients, the overall ORR of all doses was 54.5% (30/55) including 1.8% CR and 52.7% PR. The disease control rate (DCR) was 96.4%. For patients in 120/180 mg cohorts, the ORR was 64.1% (25/39) and DCR was 97.4%. PK analyses showed BPI-7711 exposure increased in a dose-proportional manner from 30 to 180 mg after single and multiple doses. Conclusions: BPI-7711 was well tolerated and highly effective in acquired T790M+ NSCLC patients. Phase II trials are under preparation. Clinical trial information: NCT03386955.
Patterns of major surgeries among patients diagnosed with cutaneous squamous cell carcinoma (CSCC).
Authors: Chieh-I Chen, Jessica J Jalbert, Michael Andria, Haixin Raymond Zhang, Emily S Ruiz
Journal: Journal of Clinical Oncology (2019)

e21034 Background: CSCC is the second most common skin cancer. Most CSCC cases can be cured with surgical excision alone (5-year cure rate &gt; 95%). We sought to evaluate patterns of major surgeries among patients with CSCC, overall and among those requiring systemic therapy. Methods: From Truven MarketScan claims data, we identified patient’s first CSCC diagnosis between 2013 and 2018 and required that they be continuously enrolled in their healthcare plan and have no CSCC diagnosis in the previous 12 months. Major surgeries included facial excisions over 3.1 cm, parotidectomy, removal of ear/eye/nose, amputations, craniectomy, excision of extracranial nerves, sentinel lymph node biopsy, lymphadenectomy, complex repairs of over 7.5 cm, integra, free flaps, and large grafts over 20 sq cm. Risk of a major surgery was assessed using Kaplan-Meier estimators for patients with CSCC overall and for those who received prior or concurrent systemic therapy, stratified by immune status. Results: A total of 240,122 patients with CSCC (mean age [SD]: 67.7 [12.9] years; male: 56.5%; immunocompromised: 12.4%) were identified with a mean (SD) follow-up of 1.34 (1.15) years. Risk of major surgery (95% confidence interval [CI]) at 1 and 2 years was 15.1% (14.9–15.2) and 18.6% (18.4–18.8), respectively. 782 patients received prior or concurrent systemic therapy, of which 22.4% (n = 175) were immunocompromised. Among those who received systemic therapy, 1- and 2-year risks (95% CI) were 8.4% (5.8–11.0) and 14.2% (10.0–18.2) for immunocompetent and 14.1% (7.7–20.0) and 19.3% (10.7–27.0) for immunocompromised patients, respectively. Conclusions: Over 2 years, approximately one in five patients with CSCC will undergo at least one major surgery. Prior or concurrent treatment with systemic therapy did not appreciably diminish the risk of requiring major surgery. For patients who received systemic therapy, the 1-year and 2-year risk of major surgery was higher for immunocompromised patients compared to immunocompetent patients.
Abstract 272: The Orphan Receptor GPRC5B Increases Pro-Inflammatory Signaling in Neonatal Rat Cardiac Fibroblasts and Cardiac MMP-9-expression <i>in vivo</i>
Authors: Friedrich A von Samson-Himmelstjerna, Greta Freundt, Norbert Frey, Hans-Joerg Hippe
Journal: Circulation Research (2017)

Background: Inflammatory processes driven by cardiac fibroblasts (CF) play a major role in cardiac fibrosis and eventually diastolic dysfunction leading to heart failure. GPRC5B, a novel G protein-coupled orphan receptor, is involved in inflammatory pathways in adipocytes and endogenously expressed in CF. Hypothesis: We assessed the impact of GPRC5B on inflammatory and fibrotic pathways in isolated neonatal rat CF and mouse heart. Methods &amp; Results: We show that 48h-stimulation of CF with Tumor Necrosis Factor α (TNFα, 50ng/ml) or Lipopolysaccharides (LPS, 100ng/ml) leads to a significant up-regulation of GPRC5B protein levels compared to unstimulated cells (TNFα +74%, p&lt;0.01; LPS +111%, p&lt;0.001, n=8) . This is confirmed by evaluation of mRNA levels after 12h-stimulation ( TNFα +69%, p&lt;0.01; LPS +61%, p&lt;0.01, n=9) . Similarly, a mechanical stretch of 18% of CF length for 24h increases GPRC5B-mRNA by 83% (p&lt;0.01, n=6). Adenoviral overexpression of GPRC5B results in an increased TNFα- ( +84%, p&lt;0.01) , Interleukin 1ß- (IL1ß, +56%, p&lt;0.05 ), Interleukin 6- (IL6, +32%, p&lt;0.05 ) and Matrix-Metalloproteinase 9- (MMP9, +133%, p&lt;0.01 ) mRNA production in CF ( AdLacZ vs. AdGPRC5B, n=9) . After an additional 24h-stimulation with LPS (10ng/ml), IL1ß-, IL6- and MMP9-mRNA increases as compared to AdLacZ-infected control cells ( AdLacZ+LPS vs. AdGPRC5B+LPS : IL1ß +114%, p&lt;0.01; IL6 +113%, p&lt;0.05; MMP9 +195%, p&lt;0.01; n=8). Conversely, siRNA mediated knockdown to 25% of endogenous protein levels followed by 24h-stimulation with LPS (10ng/ml) lowers significantly the expression of TNFα-, IL1ß- and IL6-mRNA when compared to control-transfected cells (siNeg+LPS vs. siGPRC5B+LPS: TNFα -28%, p&lt;0.05; IL1ß -30%, p&lt;0.05; MMP9 -34%, p&lt;0.05; n=8). These findings are supported by Western Blot analysis of heart tissue from GPRC5B-transgenic mice revealing an increased protein expression of MMP9 in contrast to wild type mice (WT vs. GPRC5B-TG: MMP9 +60%, p&lt;0.001; n=10). Conclusion: GPRC5B is up-regulated in cardiac models of inflammation and mechanical stress. GPRC5B modulates cellular inflammatory response by increasing the levels of key cytokines in CF and of MMP9 expression in mouse heart pointing to a role in myocardial inflammation and cardiac remodeling.
Assessing quality of life (QoL) of patients and their caregivers on phase I clinical trials.
Authors: Gloria HJ Chan, Diana Fransiska, Cheng Ean Chee
Journal: Journal of Clinical Oncology (2019)

e23130 Background: Patients on Phase I trials help advance science through their participation but there is a paucity of data regarding QoL of patients and their caregivers. Methods: Phase I trial patients from a single Asian centre were assessed at baseline and at 3 time intervals after treatment initiation with EORTC-core (QLQ-C30) and Comprehensive Score for Financial Toxicity (COST) questionnaires. Caregivers’ QoL were assessed with Zarit-Burden Interview (ZBI). Paired-sample t-tests were used to test for QoL differences at different time intervals. Results: 35 patients have been recruited with 70 individual visits so far. 60% of patients were female, 74% were Chinese. The most common cancer types were gastrointestinal (51.5%) and gynaecological (25.7%). Patients had a median of 3 lines of prior treatment (range: 0-9). QLQ-C30 scores range from 0 to 100, higher scores represent a high level of QoL/functioning. At baseline, the mean global QoL score was 51.9 (range: 16.7-100). The mean physical, role, cognitive, emotional and social functioning scores (FS) were 74.1 64.7, 86.6, 78.8 and 69.5 respectively. Patients were most bothered by fatigue and pain. 65.7% experienced grade 1 or 2 financial toxicities based on COST. There were significant improvements in physical (14.5 +/- 16.7, p &lt; 0.001), cognitive (18.1 +/- 25.0, p = 0.002) and emotional (10.5 +/- 18.4, p = 0.012) FS at baseline and 1-month post treatment. Patients experienced a reduction in fatigue, but no change in pain or financial concerns. Only 28.6% of patients were referred to palliative care medicine. Of 19 caregivers surveyed with ZBI, 10 experienced little/no burden, 8 had mild-moderate levels of burden and 1 reported severe burden. Conclusions: This is the first Asian study reporting QoL of cancer patients and their caregivers in Phase I clinical trials. In this group of heavily pre-treated patients, Phase I options can result in QoL improvement. Two-thirds of caregivers had minimal burden. Identifying QoL issues of patients and their caregivers will improve supportive care rendered to them.
Impact of single/dual HER2 inhibition and chemotherapy (CT) backbone upon pathologic complete response (pCR) in patients receiving neoadjuvant CT for operable/locally advanced breast cancer (O/LABC): A treatment-interaction analysis of randomized trials.
Authors: Jenny Furlanetto, Vanja Vaccaro, Chiara Caliolo, Michele De Laurentiis, Maria Bonomi, Sara Pilotto, Francesco Massari, Rolando Nortilli, Daniela Cianniello, Francesco Cognetti, Diana Giannarelli, Giampaolo Tortora, Emilio Bria
Journal: Journal of Clinical Oncology (2012)

630 Background: Although the addition of trastuzumab to neoadjuvant CT for O/LABC have dramatically increased pCR, clinical research is moving forward to further improve the overall outcome. In this regard, the DUAL inhibition of the HER-2 pathway and the choice of the best CT backbone may represent an issue to be addressed. Methods: Phase II randomized/Phase III trials were considered. pCR events/rates were extracted from papers/presentation and cumulated (R[pCR]) according to a random-effect model; 95% confidence intervals (CI) were derived. A sensitivity analysis according to SINGLE/DUAL HER-2 inhibition and to administered CT (anthracyclines-taxanes: anthra-TAX; TAX alone) was accomplished, in order to test for interaction. Results: 7 trials (2155 pts) were gathered; 1855 pts were enrolled in arms where anti-HER-2 targeted therapy was administered. HER-2 inhibition was obtained with trastuzumab, lapatinib and pertuzumab (alone or combined). Results according to HER-2 inhibition follow in the table below. With regard to CT, a significant interaction (p=0.0001) in favour of the addition of Anthra to TAX was found in the context of SINGLE HER-2 inhibition subgroup (R[pCR] 46.5%, 95% CI 37-51, vs 26.9%, 95% CI 23-31), while no significant interaction was determined in the context of the DUAL subgroup (R[pCR] 49.0%, 95% CI 26-72, vs 49.0%, 95% CI 43-55). A significant interaction (p=0.0001) in favour of the addition of Anthra to TAX was found for pts receiving trastuzumab (R[pCR] 45.5%, 95% CI 37-53, vs 26.5%, 95% CI 21-32) as well. Conclusions: Although biases in the pCR definition, the DUAL inhibition of HER-2 pathway may significantly increase pCR, regardless of the CT backbone; if confirmed, this strategy allows to reduce toxicities by sparing Anthra. For pts receiving SINGLE HER-2 inhibition, Anthra-TAX-based CT should be still considered the best treatment option. [Table: see text]
The impact of a digital solution on case discussion time at tumor boards.
Authors: Donna Fowler, Lincoln R Sheets, Matthew S Prime, Athanasios Siadimas, Yariv Z Levy, Richard D Hammer
Journal: Journal of Clinical Oncology (2019)

e18028 Background: A multidisciplinary tumor board (MTB) provides an interdisciplinary approach for decision-making in cancer care. Information factors such as, multiple data sources, incomplete or missing information and teleconferencing failures, have been identified as issues contributing to variability in MTB conduction and impact. Little is known about how digital tumor board solutions can optimize MTB meeting conduction. Methods: A prospective IRB approved cohort study was undertaken to evaluate the time for patient case discussions,before and after the implementation of the NAVIFY Tumor Board (NTB) solution, at University of Missouri Health Care. Data was collected using a digital time-tracking application. The NTB manual version was implemented via a phased roll-out (Breast May 18, 2018; Gastrointestinal (GI) Jul 11, 2018; ENT Oct 30, 2018 – no manual version phase). Subsequently, the integrated version was introduced (Oct 4, 2018) whereby automated electronic medical record (EMR) data extraction was enabled. Results: Patient case discussion time was recorded at 138 MTBs (1109 patient cases) during 2018 (Breast 40 MTB; 236cases / GI 49 MTB; 389 cases / ENT 49 MTBs; 484 cases). Case discussion time significantly reduced at the Breast MTB (6.6mins to 5.3 mins; p-value = 0.01). Case discussion time at ENT MTB and GI MTB showed no significant change (Table 1). Time variance in case discussions significantly decreased post-NTB implementation at the Breast MTB (p-value = 0.008). For the GI &amp; ENT MTBs, there was no significant difference post-NTB implementation (GI p-value =0.199; ENT p-value = 0.511), however, variance was already sma Conclusions: Introduction of the NTB reduced the time spent discussing cases for the Breast MTB, but showed no change forGI MTB and ENT MTB. Interestingly, case discussion times converged to between 5.5 - 6.5 minutesirrespective of the MTB type. Furthermore, variance decreased or was already small, for all MTB types. Both observations suggest that NTB standardized the case discussion process, perhaps because it created a common format for case presentation. A common workflow tool for MTB meeting conduction could ensure availability of all required data, increase efficiency of therapy decision-making, and lead to higher throughput of cases resulting in shorter time-to-treatment.
Effect of postoperative adjuvant treatment in the therapeutic management of stage I, morcellated uterine leiomyosarcoma: A Korean multicenter study.
Authors: Se Ik Kim, Chel Hun Choi, Kidong Kim, Deok Ho Hong, Jeong-Yeol Park, Byung Su Kwon, Keun Ho Lee, Dae Gy Hong, So-Jin Shin, Sang-Il Park, Yun Hwan Kim, Seung-Ho Lee, Sanghoon Lee, Jin Hwa Hong, Jung-Yun Lee, Yong Beom Kim, Jae Hong No, Dong-Hoon Suh
Journal: Journal of Clinical Oncology (2019)

e17106 Background: To evaluate the effectiveness of postoperative adjuvant treatment for morcellated, uterus-limited leiomyosarcoma in a multicenter setting. Methods: We included primary FIGO stage I uterine leiomyosarcoma patients treated between 2003 and 2016. All received one of the following morcellation methods: (1) intracorporeal morcellation using motorized device; (2) intracorporeal morcellation using surgical knife or electrocautery; and (3) vaginal morcellation. Patients’ survival outcomes were compared according to the implementation of postoperative adjuvant treatment. Results: In total, 55 patients were enrolled from 13 institutions, and 24 and 31 patients were assigned to surgery alone group and adjuvant treatment group, respectively. Characteristics including age, mass size, morcellation methods, and extent of surgery were similar between the two groups. On pathologic examination, there were no differences in degree of nuclear pleomorphism, necrosis, and lymphovascular space invasion. In adjuvant treatment group, 67.7%, 19.4%, and 12.9% received chemotherapy, concurrent chemoradiation therapy, and radiation, respectively. While the two groups showed similar overall survival ( P= 0.959) after a median follow up of 50.5 months, adjuvant treatment group showed a trend towards worse progression-free survival (PFS; 3-year survival rate, 78.2% vs. 46.1%; P= 0.060). However, in multivariate analyses, adjuvant treatment did not influence PFS (adjusted HR, 3.478; 95% CI, 0.659–18.367; P= 0.142). Confined to 17 cases where motorized morcellation device was used, surgery only and adjuvant treatment groups also showed similar PFS (3-year survival rate, 57.1% vs. 44.4%; P= 0.874). Conclusions: In FIGO stage I, morcellated uterine leiomyosarcoma, post-operative adjuvant treatment did not improve patients’ survival outcomes. Further prospective cohort studies are warranted.