tbuckley/cabot-search huggingface dataset:
The IRX-2 regimen combined with nivolumab in recurrent/metastatic solid tumors: A phase 1b study to evaluate the safety, determine recommended phase 2 dose (RP2D), and investigate the biologic and clinical activity.
Authors: Rohit K. Jain, Jingsong Zhang, Zeynep Eroglu, Ben C. Creelan, Andrew Scott Brohl, Michael Rahman Shafique, Jhanelle Elaine Gray, Jameel Muzaffar, Julia Ida, Mensura Lacevic, Youngchul Kim, Christine H. Chung, Solmaz Sahebjam
Journal: Journal of Clinical Oncology (2019)

TPS2662 Background: IRX-2 is a biologic immunotherapeutic containing a mixture of cytokines including IL-2, IL-1β IL-6, IL-8, TNFα, GM-CSF, and IFN-γ. It is derived from stimulating human PBMCs with phytohemagglutinin. Preclinical studies have shown that IRX-2 enhances dendritic cell maturation, T cell activation, and NK cell stimulation. In a Phase 2 trial of head and neck squamous cell carcinoma (HNSCC) patients, IRX-2 increased immune activation in the tumor microenvironment and was correlated with greater progression free survival and overall survival. Moreover, it has been shown that the degree of lymphocyte infiltration is an important prognostic factor for treatment with anti- programmed cell death protein 1 (PD-1) monoclonal antibodies. These data provide a compelling rationale for incorporating IRX-2 regimen into anti-PD-1 treatment strategies to increase the level of lymphocyte infiltration in the TME and improve immune response. Methods: This is a phase Ib trial exploring safety and tolerability of IRX-2 regimen in combination with nivolumab. Patients with recurrent or metastatic renal cell carcinoma, urothelial carcinoma, non-small cell lung cancer, HNSCC and melanoma are eligible. Patients who have received prior anti-PD-1/PD-L1 antibodies are eligible. IRX-2 regimen consists of cyclophosphamide 300mg/m2 (Day 1) and subcutaneous IRX-2 injections in 2 or 4 lymph node-bearing regions (based on dose level) for 10 days every 3 months. Two dose levels of IRX-2 regimen will be studied. Nivolumab is administered at 240 mg Q2W. Once the RP2D is determined, an additional 88 pts will be enrolled in an expansion phase, for a planned total enrollment of approximately 100 pts. Dose expansion phase will include cohorts of the 5 different diseases. Each cohort will include two groups: 1) anti-PD-1/PD-L1 antibody naïve tumors, and 2) progressed during or after anti-PD-1/PD-L1 antibodies. The primary study objective is to determine safety and tolerability of combination therapy. Secondary objectives are to evaluate the objective response rate, progression-free survival, and overall survival. Study Progress: Study is actively accruing. Clinical trial information: NCT03758781.
A single-center retrospective analysis of the effect of Radium-223 (Xofigo) on pancytopenia in patients with metastatic castration-resistant prostate cancer.
Authors: William Paul Skelton, Samantha Welniak Dibenedetto, Sarah Pang, Kelsey Pan, Jacob Barish, Adaeze Nwosu-Iheme, Long H. Dang
Journal: Journal of Clinical Oncology (2019)

e16546 Background: Radium-223 (Xofigo) has been shown to increase overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) via the phase 3 ALSYMPCA study. The side effect of persistent pancytopenia was noted in 2% of the patients, however, the incidence seen in our institutional clinical practice is higher than reported in the literature. This analysis serves to identify predictive factors and thereby help impact future therapy directions in this patient population. Methods: A retrospective analysis was performed analyzing patients with mCRPC who received xofigo at UFHealth in a 3 year span (from January 2014 to January 2017). Data collected included CBC, ECOG functional status, kidney and liver function, evidence of bony disease on imaging, prior chemotherapy regimens, total radiation dose, and PSA. This study was IRB approved. Results: 52 patients with mCRPC were identified, 27 of which received xofigo. 23 patients received treatment at UF, and one was lost to follow-up. 16 patients (73%) completed the full course (6 doses) of xofigo, while 6 did not. 10 patients (45%) developed pancytopenia, with 2 recovering counts within eight months while the other 8 had persistent cytopenias (6 of which were transfusion-dependent). Older age (74.0 ± 8.8 vs 68.7 ± 10.2) and higher ECOG score (1.6 ± 0.7 vs 1.2 ± 0.6) correlated with increased risk of pancytopenia. In addition, a higher percentage of patients who received prior radiation therapy were more likely to develop pancytopenia (90% vs 75%). All patients studied had bony disease and received prior chemotherapy. Conclusions: Albeit with a limited sample size, we found a higher rate of xofigo-induced pancytopenia in our patient population than the 2% reported in the literature. This may influence clinical decision making in the treatment of mCRPC, as pancytopenia may preclude patients from other survival-prolonging therapies. Factors such as age, functional status, and prior radiation therapy are important to keep under consideration prior to xofigo treatment. Additional larger studies are necessary to further quantify this effect.
Muscle wasting, visceral and subcutaneous adiposity, inflammation, nutritional deficiencies, and metastatic esophageal cancer (MEC) prognosis.
Authors: Jaspreet K Bajwa, Aline Fusco Fares, George Dong, Daniel Vilarim Araujo, Katrina Hueniken, Devalben Patel, Kirsty Taylor, Gail Elizabeth Darling, Rebecca Wong, Eric Xueyu Chen, Jennifer J. Knox, Raymond Woo-Jun Jang, Elena Elimova, Wei Xu, Geoffrey Liu, Dmitry Rozenberg, Micheal McInnis
Journal: Journal of Clinical Oncology (2019)

e14595 Background: MEC, associated with fatigue and dysphagia, leads to loss of skeletal muscle mass, malnutrition, subcutaneous and visceral adiposity. Cancer inflammation mobilizes muscle and adipose tissue, potentially leading to cachexia and sarcopenia. Supportive management depends on understanding the cancer frailty determinants that lead to poor outcomes. Methods: We retrospectively identified de novo MEC patients pts treated in Toronto, Canada (2007-2014). Body composition including visceral (VA) and subcutaneous adiposity (SA) at L3 level were assessed with baseline CT scans using SliceOMatic software by two outcome-blinded radiologists (Intraclass correlation, 0.92-1.00). Sarcopenia was assessed using Skeletal Muscle Index (SMI) with cut-offs defined either by optimized-stratification (OpS) or gender-dependent consensus cutoffs (GdC). Cox proportional hazard models generated adjusted hazard ratios (aHR). Results: Of 101 patients, 82% were male; 96% Caucasian; median age at diagnosis 61y (29-88); mean body mass index (BMI) 25.4; 69%/31% adeno/squamous cell carcinoma; median overall and progression free survival were: 6.4 (OS) and 3.9 mos (PFS). Median follow-up time was 5.6 mos. SMI-OpS and SMI-GdC were correlated (Rho = 0.67). Nutritional risk index, BMI, neutrophil-to-lymphocyte and neutrophil-to-platelet ratios were not associated with outcome (p &gt; 0.20, each comparison). However, univariable analyses identified serum albumin, LDH, and either SMI-OpS or SMI-GdC as being associated with OS. In multivariable models, sarcopenia was associated with worse OS (SMI-OpS aHR = 1.93 (1.0-3.7) p = 0.046; SMI-GdC aHR = 2.30 (1.3-4.1) p = 0.004), and worse PFS (SMI-OpS aHR = 2.16 (1.2-4.0) p = 0.01; SMI-GdC aHR = 1.66 (1.0-2.9) p = 0.07)). In 55 pts receiving chemotherapy at diagnosis, less VA (p = 0.01) and SA (p = 0.02), as continuous variables, were associated with worse OS. Conclusions: Though no associations were found between nutritional deficiencies or inflammatory markers and prognosis, there was approximately a two-fold worse prognosis in the presence of sarcopenia, and associations with loss of adiposity. (JB/AFF/DR/MM contributed equally).
Different maintenance strategies versus observation in patients with hormone receptor-positive metastatic breast cancer after first-line chemotherapy: A real-world study and meta-analysis.
Authors: Huangming Hong, Ying Wang, Yunfang Yu, Chenchen Li, Wei Ren, Jun Tang, Guolin Ye, Herui Yao
Journal: Journal of Clinical Oncology (2019)

e12529 Background: Current guidelines lack definitive evidence regarding the clinical outcomes associated with different maintenance strategies for hormone-receptor (HR) positive metastatic breast cancer (MBC). We aimed to evaluate different maintenance modalities after first-line chemotherapy in this setting. Methods: We conducted a multicenter real world study to compare maintenance chemotherapy, endocrine therapy and observation in patients with HR positive MBC who achieved disease control after first-line chemotherapy. The primary endpoint was overall survival (OS), secondary endpoint was progression-free survival (PFS). We further examined the results from fourteen multicenter prospective studies in a meta-analysis. Results: A total of 928 patients were enrolled in the real world study. The median age was 48 years (range, 18 to 76 years). Of these patients, 269 received chemotherapy, 330 received endocrine therapy and 329 received observation as their maintenance treatment. OS was significantly longer in the chemotherapy group and endocrine therapy group than in the observation group (median 33.0 vs 36.0 vs 19.0 months, respectively, P &lt; 0.001), as was PFS (median 12.0 vs 14.0 vs 8.0 months, respectively, P &lt; 0.001). However, there was no significant difference of OS between chemotherapy group and endocrine therapy group (HR, 0.947, 95% CI: 0.743-1.207, P = 0.656), so did PFS (HR, 0.969, 95% CI: 0.787-1.194, P = 0.765). In the meta-analysis of all cohorts (2706 participants), maintenance endocrine therapy provide similar PFS and OS compare with chemotherapy, but with lower odds of G1-G2 adverse events. Conclusions: Our study provided strong evidence for OS and PFS benefits of maintenance therapy over observation after first-line chemotherapy in HR positive MBC patients. Maintenance endocrine therapy was noninferior to chemotherapy with less treatment-related toxicity, which was worthy of a clinical recommendation.
Central venous catheter-related complications in the treatment of cancer patients: A prospective study of over 124,000 catheter days.
Authors: Binliang Liu, Junying Xie, Yanfeng Wang, Zongbi Yi, Fei Ma
Journal: Journal of Clinical Oncology (2019)

e18264 Background: Central venous catheters (CVCs) play an essential role in the management of cancer patients, however, but it causes some adverse events like catheter-related thrombi, catheter correlation infection, exudate, catheter blockage and catheter exfoliation. This research aims to evaluate incidence and risk factors of CVC-related complications in cancer patents. Methods: A prospective study of cancer patients with CVC insertion was performed from January 1, 2015 to December 31, 2018. Chest X-ray examination was performed to determine the position of the catheter tip after insertion. All patients received catheter care twice a week in our hospital until CVC were removed. Doppler ultrasound was used in all patients during the use of the CVC device or before extubation. Patients without thrombus recorded the value of the D-Dimer at the time of catheterization, while those diagnosed with thrombi recorded the value of D-Dimer the nearest time before the discovery of thrombi. Results: From 5356 patients with 6519 cases, 1398 patients with 1626 cases were enrolled, for a total of 124,242 catheter-days. 207 (12.7%) cases of various complications were recorded, with an incidence of 1.67 per 1000 catheter days. The most common complications were catheter-related thrombi (n = 139, 8.6%), followed by exudate (n = 42, 2.6%), catheter related blood stream infection (CRBSI) (n = 8, 0.5%), catheter blockage (n = 5, 0.3%) and catheter exfoliation (n = 5, 0.3%), local infection at insertion site (n = 3, 0.2%), severe skin allergy (n = 2, 0.1%). The most common site of thrombi was subclavian vein which account for 87.1% (121/139). 22 cases (22/139, 15.8%) found thrombi in two or more vessels at the same time. Multivariate analysis showed that underlying disease, position of the catheter tip, secondary adjustment of CVC position, the value of D-Dimer all closely related to catheter-related thrombi. Conclusions: Catheter-related thrombi was one of the most common complications in CVC patients. Reducing the chance of secondary adjustment, using X-ray to locate the tip of the CVCs, and regular monitoring of vascular ultrasound and D-dimer during catheterization are essential for timely detection and prevention of thrombi, especially for cancer patients with higher risk of thrombi.
ctDNA analysis for personalization of consolidation immunotherapy in localized non-small cell lung cancer.
Authors: Everett J Moding, Yufei Liu, Barzin Nabet, Jacob J. Chabon, Aadel Chaudhuri, Angela B. Hui, Jianzhong He, Yawei Qiao, John Heymach, Anne S. Tsao, Zhongxing X. Liao, Daniel Richard Gomez, Kavitha Ramchandran, Joel W. Neal, Heather A. Wakelee, Billy W. Loo, Steven H. Lin, Ash A. Alizadeh, Maximilian Diehn
Journal: Journal of Clinical Oncology (2019)

2547 Background: Detection of molecular residual disease via circulating tumor DNA (ctDNA) analysis after chemoradiation (CRT) in localized non-small cell lung cancer (NSCLC) predicts risk of relapse. We explored the hypotheses that (1) patients with undetectable ctDNA after CRT may not require consolidation immunotherapy (CI) and (2) ctDNA analysis could monitor the effectiveness of CI in patients with residual ctDNA after CRT. Methods: We applied CAPP-Seq ctDNA analysis to 88 plasma and matched leukocyte samples collected pre-CRT, post-CRT but pre-CI, and mid-CI in 22 patients with Stage IIB-IIIB NSCLC treated with CRT followed by CI. Identification of patient-specific tumor variants was performed using tumor tissue or pretreatment plasma, and ctDNA was quantified using a tumor mutation-informed bioinformatic strategy. Freedom from progression (FFP) defined radiographically by RECIST 1.1 criteria was compared in patients with ctDNA detected or not detected at pre-CI and mid-CI landmarks. Results: Median follow up from the start of CRT was 11 months. ctDNA detection was associated with inferior rates of FFP when compared to patients with ctDNA not detected both pre-CI (12-month 33% vs. 76%, P = 0.015, HR 7.51, 95% CI 1.47-38.24) and mid-CI (12-month 0% vs. 86%, P &lt; 0.0001, HR 123.3, 95% CI 16.21-937.8). In patients with undetectable ctDNA after CRT, FFP was similar to a historical cohort of patients with undetectable ctDNA after CRT alone (12-month 88% vs. 87%, P = 0.56, HR 0.55, 95% CI 0.07-4.18), suggesting that such patients may not benefit from CI. All patients with detectable ctDNA pre-CI in whom ctDNA increased mid-CI developed progressive disease. Finally, in 2 patients with ctDNA detected after CRT, CI led to elimination of ctDNA at the mid-CI timepoint. One of these patients developed an isolated local recurrence 22 months after CRT and the other patient is currently disease free at 11 months, suggesting clinical benefit from CI. Conclusions: Our results suggest that ctDNA analysis may allow personalization and response monitoring of CI following CRT for NSCLC. Validation in more patients followed by prospective testing in clinical trials will be required to establish clinical utility of such an approach.
c-AMP/MAPK dysregulation and its impact on survival and response to immunotherapy in advanced melanomas.
Authors: Rami Al-Rohil, Etan Marks, Varshini Vasudevaraja, Stephen Kelly, Matija Snuderl, Douglas Buckner Johnson, George Jour
Journal: Journal of Clinical Oncology (2019)

3086 Background: Immunotherapies blocking the interaction of CTLA-4 or Programmed Death 1 (PD-1) with their ligands are the standard of care for advanced MEL although many pts fail to benefit from immunotherapy. Herein, we seek to identify epigenetic and genetic signatures associated with lack of response in patients treated with immunotherapy . Methods: We performed whole exome sequencing of 580 cancer-related genes and whole-genome DNA methylation arrays targeting &gt; 850k CpG sites covering promoters, enhancers, and transcription factor sites in 28 MEL samples from patients treated with PD-1 +/- CTLA-4 inhibitors. Findings were correlated with collected clinical history. Results: Findings are summarized in the table . Unsupervised clustering and multi-parametric analysis showed a distinct methylation signature independent of age, sex, stage, site of metastasis, or type of treatment (adj. p&lt;0.01). Pathway analysis identified c-AMP/MAPK and PI3K-Akt signaling pathways (adj. p=2.10E-05 and 8.19E-06, respectively) enrichment in non-responders . This coincided with significant increase of mutational events in c -AMP/MAPK and PI3K-Akt pathways (p= 0.0001) including deleterious events affecting PDE4DIP (p=0.0002), a negative regulator of mTORC1, in non-responders. C-AMP/MAPK/PI3K genomic alterations were associated with a worse OS and PFS but not worse response rate (p=0.04, p=0.01, and p=0.20). PDE4DIP deleterious events were associated with decreased response rate, worse OS and PFS (p=0.002; p=0.002;p=0.00003). Conclusions: Convergent epigenetic dysregulation of cAMP/MAPK signaling and inactivation of PDE4DIP is associated with worse outcome and lack of response to immunotherapy, respectively. [Table: see text]
Copy number variant and runs of homozygosity detection by microarrays enabled more precise molecular diagnoses in 11,020 clinical exome cases
Authors: Avinash V. Dharmadhikari, Rajarshi Ghosh, Bo Yuan, Pengfei Liu, Hongzheng Dai, Sami Al Masri, Jennifer Scull, Jennifer E. Posey, Allen H. Jiang, Weimin He, Francesco Vetrini, Alicia A. Braxton, Patricia Ward, Theodore Chiang, Chunjing Qu, Shen Gu, Chad A. Shaw, Janice L. Smith, Seema Lalani, Pawel Stankiewicz, Sau-Wai Cheung, Carlos A. Bacino, Ankita Patel, Amy M. Breman, Xia Wang, Linyan Meng, Rui Xiao, Fan Xia, Donna Muzny, Richard A. Gibbs, Arthur L. Beaudet, Christine M. Eng, James R. Lupski, Yaping Yang, Weimin Bi
Journal: Genome Medicine (2019)

Exome sequencing (ES) has been successfully applied in clinical detection of single nucleotide variants (SNVs) and small indels. However, identification of copy number variants (CNVs) using ES data remains challenging. The purpose of this study is to understand the contribution of CNVs and copy neutral runs of homozygosity (ROH) in molecular diagnosis of patients referred for ES.In a cohort of 11,020 consecutive ES patients, an Illumina SNP array analysis interrogating mostly coding SNPs was performed as a quality control (QC) measurement and for CNV/ROH detection. Among these patients, clinical chromosomal microarray analysis (CMA) was performed at Baylor Genetics (BG) on 3229 patients, either before, concurrently, or after ES. We retrospectively analyzed the findings from CMA and the QC array.The QC array can detect ~ 70% of pathogenic/likely pathogenic CNVs (PCNVs) detectable by CMA. Out of the 11,020 ES cases, the QC array identified PCNVs in 327 patients and uniparental disomy (UPD) disorder-related ROH in 10 patients. The overall PCNV/UPD detection rate was 5.9% in the 3229 ES patients who also had CMA at BG; PCNV/UPD detection rate was higher in concurrent ES and CMA than in ES with prior CMA (7.2% vs 4.6%). The PCNVs/UPD contributed to the molecular diagnoses in 17.4% (189/1089) of molecularly diagnosed ES cases with CMA and were estimated to contribute in 10.6% of all molecularly diagnosed ES cases. Dual diagnoses with both PCNVs and SNVs were detected in 38 patients. PCNVs affecting single recessive disorder genes in a compound heterozygous state with SNVs were detected in 4 patients, and homozygous deletions (mostly exonic deletions) were detected in 17 patients. A higher PCNV detection rate was observed for patients with syndromic phenotypes and/or cardiovascular abnormalities.Our clinical genomics study demonstrates that detection of PCNV/UPD through the QC array or CMA increases ES diagnostic rate, provides more precise molecular diagnosis for dominant as well as recessive traits, and enables more complete genetic diagnoses in patients with dual or multiple molecular diagnoses. Concurrent ES and CMA using an array with exonic coverage for disease genes enables most effective detection of both CNVs and SNVs and therefore is recommended especially in time-sensitive clinical situations.
ORION: A Phase 2, randomized, multicenter, double-blind study to assess efficacy and safety of durvalumab+olaparib vs durvalumab alone as maintenance therapy in Stage IV non-small cell lung cancer (NSCLC).
Authors: Myung-Ju Ahn, Yufan Liu, Teresa Improta, Michelle Marcovitz, Kate DiPiazza, Mark C. Lanasa
Journal: Journal of Clinical Oncology (2019)

TPS9126 Background: Systemic chemotherapy for first-line (1L) metastatic NSCLC shows mixed outcomes. Results from studies using immunotherapy alone or combined with chemotherapy as 1L treatment in patients (pts) with metastatic NSCLC represent a substantial advance, but further improvement is needed. Increased DNA damage triggered by polyadenosine 5’diphosphoribose polymerase inhibition may confer antitumor activity, modify tumor immunogenicity, and further sensitize tumors to immune checkpoint inhibition, thus promoting a more durable antitumor response. This Phase 2, randomized, multicenter, double-blind study (NCT03775486) is designed to assess the efficacy and safety of durvalumab + olaparib vs durvalumab alone as maintenance therapy in pts whose Stage IV NSCLC has not progressed following 1L platinum-based chemotherapy + durvalumab. Methods: Adult pts with Stage IV NSCLC with tumors lacking activating EGFR mutations and ALK fusions are eligible. In the initial therapy phase, all pts will receive durvalumab (1500 mg IV) concurrent with platinum-based doublet therapy. Durvalumab + chemotherapy will be administered for 4 cycles for both squamous NSCLC (nanoparticle albumin-bound [nab]-paclitaxel + carboplatin or gemcitabine + carboplatin/cisplatin) and nonsquamous NSCLC (nab-paclitaxel + carboplatin or pemetrexed + carboplatin/cisplatin). Pts whose disease does not progress (complete or partial response [CR/PR] or stable disease [SD]; investigator-assessed RECIST 1.1) will be randomized (1:1) to durvalumab (1500 mg IV, every 4 weeks) + either olaparib (300 mg, oral, BID) or its matching placebo until disease progression. Randomization will be stratified based on objective response to durvalumab + chemotherapy (CR/PR or SD) during the initial therapy phase and histology (squamous or nonsquamous). The primary endpoint is PFS (investigator-assessed, RECIST 1.1). Secondary endpoints are OS, PFS in pts with homologous recombination repair related gene mutation, ORR, duration of response, HRQoL, pharmacokinetics and immunogenicity of durvalumab, and safety. Pt enrollment is ongoing. Clinical trial information: NCT03775486.
Gene delivery based on macrocyclic amphiphiles
Authors: Wen-Chao Geng, Qiaoxian Huang, Zhe Xu, Ruibing Wang, Dong-Sheng Guo
Journal: Theranostics (2019)

Gene therapy, with an important role in biomedicine, often requires vectors for gene condensation in order to avoid degradation, improve membrane permeation, and achieve targeted delivery.Macrocyclic molecules are a family of artificial receptors that can selectively bind a variety of guest species.Amphiphilic macrocycles, particularly those bearing cationic charges and their various assemblies represent a new class of promising non-viral vectors with intrinsic advantages in gene condensation and delivery.The most prominent examples include amphiphilic cyclodextrins, calixarenes and pillararenes.Herein, we systemically reviewed reported assemblies of amphiphilic macrocycles for gene delivery and therapy.The advantages and disadvantages of each type of macrocyclic amphiphiles for gene delivery, as well as the perspectives on the future development of this area are discussed.