tbuckley/cabot-search huggingface dataset:
Treatment outcomes in renal cell carcinoma patients with metastases to the pancreas and other sites.
Authors: Cassandra Duarte, Benoit Beuselinck, Nicole Weise, Nazli Dizman, Katharine Collier, Haoran Li, Nieves Martinez Chanza, Roy Elias, Tracy L Rose, James Brugarolas, Neeraj Agarwal, Amir Mortazavi, Sumanta K. Pal, Rana R. McKay, Junxiao Hu, Elaine Tat Lam
Journal: Journal of Clinical Oncology (2021)

4557 Background: Metastatic RCC (mRCC) involving the pancreas is distinct from RCC involving other metastatic sites and is characterized by an indolent clinical course, heightened angiogenesis, and an inflamed stroma (PMID: 32271170). We previously reported on outcomes of RCC patients (pts) with pancreatic oligometastasis (ASCO GU 2020). We now report on outcomes in pts with mRCC involving the pancreas in conjunction with other metastases (mets). Methods: We conducted a retrospective, multi-institutional study of mRCC pts with mets to the pancreas and other sites. Data on pt demographics, tumor characteristics, systemic therapy, and outcomes were collected. Pts were classified based on treatment category: immunotherapy (IO) or vascular endothelial growth factor/receptor inhibitors (VEGFI). Outcomes measured included objective response rates (ORR), time-on-treatment (TOT), and overall survival (OS). Results: The analysis included 229 pts from 9 institutions, diagnosed between 1985-2020. Of these, 211 (92%) had clear-cell histology; 131 (57%) had nephrectomy; 41 (18%) had local pancreas-directed therapy; 111 (48%) had synchronous presentation of disease in the pancreas and other sites at time of mets. IMDC risk was favorable in 33%, intermediate in 41%, poor in 11%, and unknown in 15% pts. Median lines of therapy was 2 (range 0-9). Of 219 pts who received first-line (1L) therapy, 151 (69%) had VEGFI therapy, 41 (19%) had IO, and 18 (8%) had VEGFI/IO combination (Table). The IO group included 21 pts on checkpoint inhibitor (CPI), 16 pts on HD-IL2, 4 pts on other IO. 1L ORR was 39.7% for VEGFI (95% CI 31.8-48.0) and 31.7% for IO (95% CI 18.1-48.1) and was not statistically significant (NS, OR 1.4, 95% CI 0.65-3.23, p = 0.371). Median TOT for 1L therapy was 11.6m for VEGFI and 6.5m for IO (p = 0.0106). With a median follow-up of 51.5m, the median OS (mOS) for all pts from time of metastatic disease was 7.7 years (y) (95% CI 6.3-10.3). The mOS for pts who received 1L VEGFI was 7.6y (95% CI 5.5-9.5) and was not reached (NR) for those who got 1L IO (95%CI 6.5-NR); this difference was significant with an unadjusted p-value of 0.029. The pair-wise comparison between mOS of the 1L CPI subgroup compared to that of the 1L VEGFI group was significant (p = 0.0148). Conclusions: Consistent with the literature, mRCC pts with involvement of the pancreas in this study have prolonged OS compared to historical OS for the standard mRCC population. Additionally, our findings suggest that the choice of first-line therapy may impact outcomes. Additional analyses will be presented.[Table: see text]
The cost effectiveness of lenvatinib versus atezolizumab and bevacizumab or sorafenib in patients with unresectable hepatocellular carcinoma (uHCC) in Canada.
Authors: David Trueman, Yifeng Liu, Marc Geadah, Nicholas Hon, Suthakar Sabapathy, Laveena Kamboj, Huimin Li, Melanie Lucero, Genevieve Meier
Journal: Journal of Clinical Oncology (2021)

4098 Background: Hepatocellular carcinoma (HCC) represents 72% of liver cancers in Canada. In the phase III REFLECT trial, lenvatinib met the primary endpoint of non-inferiority in overall survival (OS) versus sorafenib and demonstrated superiority in secondary endpoints of progression free-survival (PFS), time to progression and objective response rate. Based on the REFLECT trial, lenvatinib has become the standard of care in the treatment of Canadian patients with unresectable HCC (uHCC). In the Phase III IMbrave150 trial, the use of the combination of atezolizumab and bevacizumab (atezo+bev) resulted in statistically significant improvement in OS and PFS versus sorafenib for patients with uHCC. The aim of this analysis was to estimate the cost-effectiveness of lenvatinib versus atezo+bev or sorafenib as first-line treatment for patients with uHCC from the perspective of Ministry of Health in Canada. Methods: A cost-utility analysis was conducted using a partitioned survival analysis. Health state membership for lenvatinib and sorafenib were estimated based on patient level data and clinical inputs from REFLECT and extrapolated using parametric survival models. Relative efficacy for atezo+bev was estimated from a de novo network meta-analysis. In the base-case analysis, estimates from REFLECT used in the NMA were adjusted for imbalances in baseline characteristics. Sensitivity analyses included the use of alternative approaches to determine relative efficacy. Health state utility values were determined with EQ-5D data collected in REFLECT. Drug acquisition costs were obtained from publicly available sources and medical resource utilization was based on a survey of Canadian clinicians. The time horizon was 10 years. Results of the incremental analysis were calculated sequentially. Results: In the base case lenvatinib was associated with cost savings of CAD$4,640 and CAD$120,095 and a QALY difference of 0.15 and -0.28 vs sorafenib and atezo+bev, respectively. The base case deterministic analysis resulted in lenvatinib being dominant over sorafenib and cost-effective vs. atezo+bev (sequential ICER for atezo+bev was CAD$425,754 per QALY). Results of the probabilistic sensitivity analysis (PSA) were consistent with the base case findings with lenvatinib being the optimal treatment strategy in &gt;99% of iterations. Conclusions: Results of this analysis demonstrate that lenvatinib represents the optimal use of healthcare resources as a first-line treatment for uHCC in Canada.
What It Takes to Transform a T Cell
Authors: Ivana Spasevska, June H. Myklebust
Journal: Cancer Research (2021)

Abstract The role of fusion genes and cancer driver genes in malignant transformation has traditionally been explored using transgenic or chimeric mouse models. It has been challenging to develop models that fully resemble the characteristics and morphology of human cancers. This applies to anaplastic large-cell lymphoma (ALCL), a malignancy classified as a peripheral T-cell lymphoma. It is still unclear at which stage of T-cell development ALCL can occur, as well as the early molecular events required for malignant transformation. In this issue of Cancer Research, Pawlicki and colleagues introduced the NPM–ALK fusion gene and mutant variants into primary T cells from healthy donors. By monitoring transduced T-cell clones over time, they demonstrated that transformed T cells undergo a progressive loss of T-cell identity accompanied with upregulation of epithelial-to-mesenchymal transition program and reemergence of an immature, thymic profile. Introduction of NPM–ALK was, however, not sufficient to convert healthy T cells to malignant clones, as this process required activation of T-cell receptor signaling. The study sets the stage for modeling early genetic changes in human tumors. See related article by Pawlicki et al., p. 3241
Association of Neuropathic Itch With Patients’ Quality of Life
Authors: Zoe M. Lipman, Qai Ven Yap, Leigh Nattkemper, Gil Yosipovitch
Journal: JAMA Dermatology (2021)

Association of Neuropathic Itch With Patients' Quality of LifeThe negative association of chronic itch with patients' quality of life (QOL) has been well established in literature, with similar burden of disease and influences on self-esteem as chronic pain. [1]2][3] However, most studies to date have focused on chronic inflammatory pruritic conditions.Neuropathic pruritus, including brachioradial pruritus (BRP) and notalgia paresthetica (NP), is unique from other chronically itchy conditions because it is less frequently associated with visible primary dermatologic findings but can be just as bothersome and debilitating. 4 In the current study, we aimed to assess the association of neuropathic pruritus with patients' quality of life.
Olaparib in recurrent IDH-mutant high-grade glioma (OLAGLI).
Authors: Francois Ducray, Marc Sanson, Olivier L. Chinot, Maxime Fontanilles, Romain Rivoirard, Laure Thomas-Maisonneuve, Stephanie Cartalat, Emeline Tabouret, Alice Bonneville-Levard, Amelie Darlix, Roxana Ameli, David Meyronet, Francois Gueyffier, Laurent Remontet, Delphine Maucort-Boulch, Caroline Dehais, Jerôme Honnorat
Journal: Journal of Clinical Oncology (2021)

2007 Background: There is a need to develop new treatments in IDH-mutant high-grade gliomas recurring after radiotherapy and chemotherapy. Based on preclinical studies showing that IDH-mutant tumors could be vulnerable to PARP inhibition we launched a phase II study to test the efficacy of olaparib (Lynparza) monotherapy in this population. Methods: Adults with recurrent high-grade IDH-mutant gliomas after radiotherapy and at least one line of alkylating chemotherapy (PCV or TMZ), KPS &gt; 60, normal organ function were enrolled. The primary endpoint was 6 months PFS according to RANO criteria. Patients were treated with olaparib 300 mg twice daily. We used a single-stage Fleming design with p0 = 30%, p1 = 50%, a type I unilateral error rate of 5% and a power of 80%. Results: 35 patients with recurrent IDH-mutant gliomas (IDH1R132H-mutant n = 32, other IDH mutation n = 3, 1p/19 codeleted n = 16, 1p/19q non-codeleted n = 14) were enrolled (malignantly transformed low-grade gliomas n = 21, anaplastic gliomas n = 8, glioblastomas n = 6). Median time since diagnosis was 7.4 years (1-22 years), median time since radiotherapy was 2.8 years (0.6-18 years), median number of previous chemotherapy lines was 2 (1-5). With a median follow-up of 11 months, 30 patients had stopped treatment due to tumor progression and 2 patients were still on treatment 16 to 18 months after treatment start. At 6 months, 11/35 patients were progression-free (31 %). According to RANO criteria, based on local investigator analysis, 2 patients (5%) had a partial response and 14 patients a stable disease (37%) with a median duration of response of 9 months (4-18 months+). Median PFS and OS were 2.3 and 15.9 months and were similar in 1p/19q codeleted and non-codeleted patients. A grade 3 olaparib-related adverse event was observed in 5 patients (14%, lymphopenia n = 3, fatigue n = 2, diarrhea n = 1) and a grade 2 in 15 patients (43%), most frequently consisting in fatigue (23%), gastrointestinal disorders (20%) and lymphopenia (20%). No patient definitively stopped olaparib due to side effects. Conclusions: In this heavily pre-treated population of recurrent IDH-mutant gliomas, olaparib monotherapy was well tolerated and resulted in some activity supporting its evaluation in association with alkylating chemotherapy in recurrent IDH-mutant gliomas in future studies. Clinical trial information: NCT03561870.
Prognostic impact of inflammatory profiling during and after multimodal treatment for stage III NSCLC.
Authors: Lukas Käsmann, Natalia Christina Cabeza-Boeddinghaus, Julian Taugner, Chukwuka Eze, Thomas Philipp Hofer, Carolyn Pelikan, Claus Belka, Elfriede Noessner, Claudia Staab-Weijnitz, Farkhad Manapov
Journal: Journal of Clinical Oncology (2021)

e20559 Background: Immune cells have a broad impact on tumor initiation, growth, and progression, and many of these effects are mediated by proinflammatory cytokines. The prognostic impact of dynamic changes of inflammatory cytokines in non-operable stage III NSCLC patients treated with (chemo)-radiotherapy ± immune checkpoint inhibition is unknown. In a prospective analysis, pro-inflammatory cytokines including interleukin 2, 6, and 8 from peripheral blood samples were evaluated 5-10 days before treatment start (T1), on the last day of thoracic radiotherapy (T2), and 3 weeks after radiation (T3) for their impact on overall survival (OS) and progression-free survival (PFS). Methods: Twenty patients, 85% male, at a median age of 65.5 (range 33-77) years were prospectively enrolled in this study. Eighteen (90%) patients received platinum-based concurrent chemoradiotherapy (CRT); seven (35%) patients additional concurrent and/or sequential immune checkpoint inhibition (four patients nivolumab and three durvalumab); patients treated with nivolumab received induction chemotherapy. Thoracic irradiation (TRT) was applied in all patients with a median cumulative dose in equivalent 2Gy fractions (EQD2) of 64Gy (range: 52-65Gy). Results: Median follow-up achieved 25 (range 14-30) months, median OS was not reached and median PFS was 11.8 (95%CI 5.2-18.4) months. To analyze pre-treatment data, median values were used as cut-off for dichotomization. Higher IL6 levels (≥9.75pg/ml) before irradiation (T1) were associated with impaired OS (median 11 months vs. not reached; p &lt; 0.001) and PFS (median 7.0 months vs. not reached; p = 0.041). Higher IL8 levels (≥4.62pg/ml) were also associated with shorter OS (median 16 months vs. not reached; p = 0.009) and PFS (median 7 months vs. not reached p = 0.040). Patients with a decline of ≥10% of IL8 level between T1 and T2 had a significantly shorter PFS (11.8 months vs. not reached; p = 0.028). Conclusions: High proinflammatory cytokine levels were significantly associated with deterioration of outcome regarding OS and PFS in patients enrolled in multimodal treatment for stage III NSCLC. A decline of ≥10% of IL8 level during TRT was associated with impaired PFS.
Impact of Obesity and Heavy Alcohol Consumption on Hepatocellular Carcinoma Development after HCV Eradication with Antivirals
Authors: Tatsuya Minami, Ryosuke Tateishi, Naoto Fujiwara, Ryo Nakagomi, Takuma Nakatsuka, Masaya Sato, Koji Uchino, Kenichiro Enooku, Hayato Nakagawa, Hidetaka Fujinaga, Masashi Izumiya, Kazuyuki Hanajiri, Yoshinari Asaoka, Yuji Kondo, Yasuo Tanaka, Motoyuki Otsuka, Takamasa Ohki, Masahiro Arai, Atsushi Tanaka, Kiyomi Yasuda, Hideaki Miura, Itsuro Ogata, Toshiro Kamoshida, Kazuaki Inoue, Yukihiro Koike, Masatoshi Akamatsu, Hiroshi Mitsui, Hajime Fujie, Keiji Ogura, Hideo Yoshida, Tomonori Wada, Kiyohiko Kurai, Hisato Maekawa, Shuntaro Obi, Takuma Teratani, Naohiko Masaki, Kayo Nagashima, Takashi Ishikawa, Naoya Kato, Kyoji Moriya, Hiroshi Yotsuyanagi, Kazuhiko Koike
Journal: Liver Cancer (2021)

&lt;b&gt;&lt;i&gt;Background and Aims:&lt;/i&gt;&lt;/b&gt; It remains unclear whether obesity increases the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C who achieved a sustained virological response (SVR) with antiviral therapy. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; In this multicenter cohort study, we enrolled patients with chronic hepatitis C who achieved SVR with interferon (IFN)-based therapy (IFN group) or direct-acting antiviral (DAA) therapy (DAA group) between January 1, 1990, and December 31, 2018. The patients underwent regular surveillance for HCC. Cumulative incidence of and the risk factors for HCC development after SVR were assessed using the Kaplan-Meier method and Cox proportional hazard regression analysis, respectively. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Among 2,055 patients (840 in the IFN group and 1,215 in the DAA group), 75 developed HCC (41 in the IFN group and 34 in the DAA group) during the mean observation period of 4.1 years. The incidence rates of HCC at 1, 2, and 3 years were 1.2, 1.9, and 3.0%, respectively. Multivariate analysis revealed that in addition to older age, lower albumin level, lower platelet count, higher alpha-fetoprotein level, and absence of dyslipidemia, obesity (body mass index ≥25 kg/m&lt;sup&gt;2&lt;/sup&gt;) and heavy alcohol consumption (≥60 g/day) were independent risk factors for HCC development, with adjusted hazard ratio (HR) of 2.53 (95% confidence interval [CI]: 1.51–4.25) and 2.56 (95% CI: 1.14–5.75), respectively. The adjusted HR was not significant between the 2 groups (DAA vs. IFN; HR 1.19, 95% CI: 0.61–2.33). &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; Obesity and heavy alcohol consumption increased the risk of HCC development after SVR.
IMMU-06. DELTA-24-RGD EXPRESSING POSITIVE IMMUNE MODULATORS SHOW ANTI-DIPG EFFECT AND INCREASE TUMOR IMMUNE INFILTRATION
Authors: Virginia Laspidea, Sumit Gupta, Montserrat Puigdelloses, Sara Labiano, Iker Ausejo-Mauleon, Daniel de la Nava, Oren J Becher, Joy Gumin, Juan Fueyo, Candelaria Gomez-Manzano, Marta M Alonso
Journal: Neuro-Oncology (2021)

Abstract Diffuse Intrinsic Pontine Gliomas (DIPG) are aggressive pediatric brain tumors that arise in the pons of children, being the leading cause of pediatric death caused by cancer. We have previously demonstrated that Delta-24-RGD administration is safe and efficacious in DIPG preclinical models, indicating that it could be a good candidate as therapeutic approach for DIPG. However, our data underscore that there is still room to improve the anti-DIPG effect obtained with Delta-24-RGD. For that purpose, we have constructed three new virus by engineering Delta-24-RGD with different T cell activators: 4-1BBL (Delta-24-ACT), OX40-L (Delta-24-RGDOX) and GITRL (Delta-24-GREAT), to further increase the immune response generated by the viral effect. In vitro, the three virus were able to infect murine and human DIPG cell lines, produce oncolytic effect in a dose-dependent manner and express the corresponding functional ligand (4-1BBL, OX40L or GITRL) in the membrane of infected cells (almost 100% of cells expressing them at 10 MOIs). As expected, viral replication was optimal in human cell lines but semipermissive in murine cells. In vivo, the intratumoral administration of armed oncolytic viruses was safe and significantly increased survival of mice bearing orthotopic DIPG murine tumors, leading to long-term survivors. In addition, we analyzed the effect of the virus in the tumor microenvironment by flow cytometry and immunohistochemistry, which indicated that there was a significant increase of immune infiltration in brains of treated mice. Moreover, the immune infiltrated showed a functional active phenotype. Although deeper characterization is needed, these data show that the incorporation of a positive immune modulator into Delta-24-RGD could improve the oncolytic effect of the virus by boosting the immune response, while maintaining a safe profile in immunocompetent models offering a feasible option treatment for DIPG.
Trial in progress: A phase 1b/2 study of the PARP inhibitor niraparib in combination with trastuzumab in patients with metastatic HER2+ breast cancer (TBCRC 050).
Authors: Erica Michelle Stringer-Reasor, Yufeng Li, Felicia Witherspoon, Jennifer M. Specht, Jesus Del Santo Anampa Mesias, Rita Nanda, Elizabeth Claire Dees, Antonio C. Wolff, Ian E. Krop, Nancy U Lin, Mothaffar F. Rimawi, Eddy Shih-Hsin Yang
Journal: Journal of Clinical Oncology (2021)

TPS1098 Background: Approximately 20% of breast cancers (BC) express the human epidermal growth factor receptor 2 (HER2). Although HER2-directed therapies result in improved patient outcome, resistance ultimately occurs. Poly (ADP-Ribose) polymerase (PARP) inhibitors are currently indicated in cancers that express germline mutations in the DNA repair proteins BRCA1/2 due to their synthetic lethality against the homologous recombination repair (HR) pathway. In addition to its role in DNA damage repair, PARP1 has also been implicated in other cellular functions, including co-activation of genes such as NF-κB, which regulate tumor proliferation and HER2 drug resistance. Our group identified that HER2+ BC overexpress the PARP1 and phospho-p65 protein. In HER2+ BC cells and animal models, PARP inhibitors initiated apoptosis independent of a DNA repair deficiency, via inhibition of NF-kB signaling. Key proteins (p65, IKK-α) of the NF-κB-mediated growth pathways were reduced and IκBα was increased in the presence of PARPi, implicating another oncologic pathway in which HER2+ BC cells may be dependent. Methods: The study is a phase 1b/2, multicenter, single arm clinical trial evaluating the safety and efficacy of niraparib 200 mg orally days 1-21 with trastuzumab 6 mg/kg (cycle 1 loading dose of 8 mg/kg) intravenously on day 1 of a 21-day cycle for patients with unresectable or metastatic HER2+ BC. Eligible patients include metastatic HER2+ BC, progression on at least 1 prior HER2-targeted therapy, measurable disease, ECOG PS 0-1, and LVEF ≥ 50%. Stable/treated CNS disease allowed. Prior PARPi and known germline BRCA 1/2 excluded. Forty patients will be enrolled at 7 US sites within the Translational Breast Cancer Research Consortium. The primary objectives are determining the dose-limiting toxicity (DLT) of the combination and assessing the objective response rate. The phase 1b cohort has been completed (N=6). Enrollment in phase 2 began February 2021 with a total accrual goal of 40. Gehan’s two-stage design will be used assuming the response rate is at least 24% and the response rate will be estimated with Clopper-Pearson exact method. Correlative aims include assessing blood and tissue biomarkers (e.g. PARP1, p65, phosphor-p65, let-7a miRNA, NF-kB, ctDNA, etc.) for association with clinical benefit and to predict response to therapy. Clinical trial information: NCT03368729 .
Doxycycline host-directed therapy in human pulmonary tuberculosis
Authors: Qing Hao Miow, Andres F. Vallejo, Yu Wang, Jia Mei Hong, Chen Bai, Felicia S.W. Teo, Alvin D.Y. Wang, Hong Rong Loh, Tuan Zea Tan, Ying Ding, Hoi Wah She, Suay Hong Gan, Nicholas I. Paton, Josephine Lum, Alicia Tay, Cynthia B.E. Chee, Paul A. Tambyah, Marta E. Polak, Yee Tang Wang, Amit Singhal, Paul T. Elkington, Jon S. Friedland, Catherine W.M. Ong
Journal: Journal of Clinical Investigation (2021)

BACKGROUND. Matrix metalloproteinases (MMPs) are key regulators of tissue destruction in tuberculosis (TB) and may be targets for host-directed therapy. We conducted a phase II double-blind, randomized, controlled trial investigating doxycycline, a licensed broad-spectrum MMP inhibitor, in patients with pulmonary TB.