tbuckley/cabot-search huggingface dataset:
Microvascular invasion may guide selection of candidates for combination treatment with sorafenib and TACE for intermediate recurrent hepatocellular carcinoma.
Authors: Zhen-Wei Peng, Shuling Chen, Xiao Han, Yuanqi Wang, Ming Kuang
Journal: Journal of Clinical Oncology (2019)

e15601 Background: To investigate the role of sorafenib combined with transarterial chemoembolization (TACE) for the treatment of intermediate recurrent hepatocellular carcinoma (rHCC) after initial hepatectomy and whether the status of microvascular invasion (MVI) could help screen out the appropriate candidates for the combination treatment. Methods: The study was approved by the ethics committee of two tertiary medical centers in China. From Jan 2010 to Dec 2016, 260 consecutive patients with intermediate rHCC after initial hepatectomy who underwent combination treatment or TACE were enrolled. Overall survival (OS) and progression-free survival (PFS) were compared between these two treatments according to MVI status. Results: The 1-, 3-, 5-year OS (77.1% vs. 62.0%, 49.3% vs. 35.2%, 38.9% vs. 20.5%, P = 0.011) and PFS (74.2% vs. 56.5%, 37.5% vs. 18.7%, 37.5% vs. 18.7%, P = 0.003) rates were significantly higher in the combination group than those in the TACE group for intermediate rHCC. For MVI-positive patients, the median OS (17.2 months vs. 12.1 months, P = 0.024) and PFS (17.0 months vs. 11.0 months, P = 0.022) after combination treatment (n = 55) were significantly longer than those after TACE alone (n = 72). For MVI-negative patients, the median OS (42.7 months vs. 32.6 months, P = 0.247) and PFS (24.6 months vs. 17.2 months, P = 0.113) were comparable between combination therapy (n = 73) and TACE alone (n = 60). Multivariate analysis revealed that tumor number, MVI status and treatment allocation were significant predictors of OS and PFS, while the tumor size was another prognostic factor for PFS. Conclusions: Patients with intermediate rHCC can benefit from sorafenib plus TACE treatment, while MVI-positive patients were good candidates for combination treatment.
Feasibility of a national expert panel to determine resectability in patients with initially unresectable colorectal cancer liver metastases (CRLM).
Authors: Karen Bolhuis, Joost Huiskens, Cornelis H.C. Dejong, Marc R.W. Engelbrecht, Michael F. Gerhards, Dirk J. Grunhagen, Koert P. de Jong, Geert Kazemier, Joost M. Klaase, Mike S.L. Liem, Krijn P van Lienden, I. Quintus Molenaar, Gijs A. Patijn, Arjen M. Rijken, Theo M. Ruers, Rutger-Jan Swijnenburg, Cornelis Verhoef, Johannes H.W. de Wilt, Cornelis J. A. Punt, Thomas M van Gulik
Journal: Journal of Clinical Oncology (2019)

3562 Background: Decision on optimal treatment strategy for CRLM remains complex because uniform (un)resectability criteria are lacking. We hypothesize that the use of an expert panel can improve the identification of patients with potentially resectable CRLM. The Dutch Colorectal Cancer Group (DCCG) Expert Panel was established in conjunction with the CAIRO5 study (Huiskens J et al. BMC Cancer 2015), a multicenter, randomized, phase-3 trial, investigating optimal systemic induction treatment in patients with initially unresectable CRLM. Here, we present the feasibility of this panel. Methods: The DCCG Expert Panel consists of 13 liver surgeons and 4 radiologists. Consensus was reached on predefined (un)resectability criteria at baseline. An online platform allowed resectability-assessment by 3 surgeons in case of inter-surgeon agreement, and 5 surgeons if they disagreed. CRLM were assessed as 1) resectable 2) potentially resectable, or 3) permanently unresectable. Patients with initially unresectable CRLM were evaluated at baseline and subsequently every 2 months as long as CRLM were considered potentially resectable. Results: Overall, 397 panel evaluations in 183 patients were analyzed. Median time to panel conclusion was 7 days (IQR 5-11 days) and 204 (51%) evaluations showed inter-surgeon disagreement, with major disagreement (resectable versus permanently unresectable) in 24 (14%) and 12 (29%) evaluations after 2 and 4 months of systemic treatment. Ultimately, 84 (79%) patients with resectable CRLM underwent resection and 23 (27%) resections included portal vein embolization or 2-stage procedures. In resectable CRLM with inter-surgeon agreement versus disagreement, R0 resection was achieved in 39 (75%) versus 28 (52%) patients, p = 0.013. Median time to recurrence was similar between resections with panel agreement versus disagreement, 8 versus 6 months, p = 0.447. Conclusions: This study shows the feasibility of a national Liver Expert Panel for prospective resectability assessment of patients with initially unresectable CRLM. High inter-surgeon disagreement supports the use of a panel. We aim to further validate the panel with outcome parameters. Clinical trial information: NCT02162563.
CD4<sup>+</sup> T-cell immunity predicts long-lasting antitumor immunity after PD-1 blockade therapy.
Authors: Kyoichi Kaira, Ou Yamaguchi, Kenichi Yoshimura, Atsuto Mouri, Ayako Shiono, Fuyumi Nishihara, Yu Miura, Shun Shinomiya, Kosuke Hashimoto, Yoshitake Murayama, Shigehisa Kitano, Kunihiko Kobayashi, Hiroshi Kagamu
Journal: Journal of Clinical Oncology (2019)

2545 Background: Patients treated with programmed cell death 1 (PD-1)-blockade therapy fall into 3 distinct subgroups: non-responders presenting early disease progression, long survivors who achieve durable disease control, and the remaining short-term responders. We reported that the prediction formula comprised of the percentages of CD62L-downregulated (CD62L low ) and CD25 + FOXP3 + CD4 + T cells in the peripheral blood predicted non-responders of non-small cell lung cancer patients (n = 50) scheduled to receive anti-PD-1-antibody (nivolumab) therapy in the 2017 ASCO meeting. In this study, we included 171 patients with NSCLC who were scheduled for nivolumab treatment after obtaining written informed consent. Peripheral blood mononuclear cells (PBMC) were examined before and after Nivolumab therapy up to 2 years to investigate the differences between long survivors and short-term responders. Methods: The patients received Nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks. Tumor response was assessed with the use of the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, at week 8 and every 8 weeks thereafter. PBMCs were analyzed with a 18-color microfluorometer, LSR Fortessa and a masscytometer, CyTOF. Results: The responder-type patient group whose prediction formula values were greater than 192 showed significantly longer PFS ( P&lt; 0.0001) and OS ( P&lt; 0.0001). The long survivors who consisted of tail plateau of PFS exhibited significantly more CD62L low CD4 + T cells than the short-term responders as pre-existing immunity. The remaining responders kept significantly higher percentages of CD62L low CD4 + T cells ( P= 0.0088) and prediction formula values ( P= 0.017) than the patients with acquired resistance. Conclusions: The pre-existing CD4 + T cell balance between primed effector and regulatory T cells correlated with anti-PD-1 therapy response. Further, CD62L low cell-dominant CD4 + T cell immunity was required to maintain durable antitumor reactivity induced by anti-PD-1 antibody therapy. These results have important clinical implication, as they support anti-PD-1 therapy provision to all potentially responding patients and pave the way for new treatment strategies for patients with distinct CD4 + T cell immune statuses. Clinical trial information: UMIN000020719.
Comparison of the seventh and eighth editions of the American Joint Committee on Cancer (AJCC) staging for oropharyngeal squamous cell carcinomas (OPSCC): A Surveillance, Epidemiology and End Results Program (SEER) database analysis.
Authors: Sumita Trivedi, Haocan Song, Yuan Liu, Conor Ernst Steuer, William Stokes, Azeem Kaka, Mihir Patel, Zhuo Georgia Chen, Dong Moon Shin, Ashley Aiken, Jonathan Jay Beitler, Nabil F. Saba
Journal: Journal of Clinical Oncology (2019)

e17538 Background: The recently released eighth edition of the American Joint Committee on Cancer (AJCC) Staging Manual, Head and Neck Section, incorporates significant changes to the prior seventh edition. The changes reflect the improved understanding of tumor biology, prognostic factors and molecular markers that effect outcomes in Head and Neck cancers. A key update restages OPSCC by human papilloma virus (HPV) positive and negative cancers as data demonstrated that these tumors have significantly different biology and outcomes. Methods: Using SEER data from 2004 – 2014, we identified male patients with squamous cell carcinomas of the tonsil, base of tongue and soft palate aged between 21 and 64 years old (those clinical characterizes were considered as surrogate markers for HPV positive status). We classified them by the AJCC 8 th edition staging for HPV positive OPSCC and by AJCC 7 th edition staging. The prediction performance by two staging editions were compared regarding overall survival (OS) and Disease free survival (DFS). Kaplan-Meier method and Cox proportional hazard model were applied, and the discrimination performance was measured by the concordance statistics (C-statistics). Results: A total of 8202 eligible patients were included in the analysis with a median follow up period of 51 months. 7415 (90.4%) patients had previously received radiation and 7038 (85.8%) patients had previously received chemotherapy. The median age of patients was 56 years. Distribution of stage I disease increased from 2% to 19.6% in AJCC 8 th edition. 10-year overall survival (OS) for AJCC 8 th stages I (74%), II (78%), III (55%) and IV (32%). Using Stage I as reference, the hazard ratio for stage II, III, and IV is 0.98 (95%CI: 0.87-1.09), 2.29 (95%CI: 2.04-2.57), and 5.88 (95%CI: 4.96-6.98). Similar results were noted for ten year disease free survival. The C-statistics measured overall discrimination for 8 th edition is 0.68 and 0.63 for the 7 th edition (P &lt; 0.001). Conclusions: Based on this SEER analysis, the overall performance of discrimination improved from AJCC 7th to 8th edition; but in this study population, AJCC 8 th edition does not distinguish stage I and II sufficiently as expected as it does for stages III and IV disease. Limitations of the SEER database include the surrogate for P16 status and under reported and incomplete data.
Case 42-1986
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, David M. Dawson, E. Tessa Hedley-Whyte, Nancy L. Harris
Journal: New England Journal of Medicine (1986)

Presentation of CaseA 28-year-old man with a renal transplant was admitted to the hospital because of recent disorientation.There was a history of the nephrotic syndrome that began at the age of three years. He was seen at this hospital, and a percutaneous renal biopsy was performed; the findings were interpreted as consistent with lipoid nephrosis. Cortisone was administered daily in a dose that ranged as high as 400 mg per square meter of body-surface area, without response. A brief course of nitrogen mustard was followed by improvement, and the patient was discharged on maintenance cortisone. Edema and proteinuria . . .
Embracing digital technology in chronic respiratory care: Surveying patients access and confidence
Authors: C. Jácome, F. Marques, C. Paixão, P. Rebelo, A. Oliveira, J. Cruz, C. Freitas, M. Rua, H. Loureiro, C. Peguinho, A. Simões, M. Santos, C. Valente, P. Simão, A. Marques
Journal: Pulmonology (2019)

This work is integrated in the project Revitalizing Pulmonary Rehabilitation (3R), SAICT-POL/23926/2016, was funded by Fundo Europeu de Desenvolvimento Regional (FEDER) – Comissao Diretiva do Programa Operacional Regional do Centro and by Fundacao para a Ciencia e Tecnologia (FCT) and partially funded by Programa Operacional Competitividade e Internacionalizacao (COMPETE), through COMPETE 2020 (POCI-01-0145-FEDER-016701) and FCT (UID/BIM/04501/2013, UID/BIM/04501/2019, and POCI-01-0145-FEDER-007628-iBiMED). CJ is a pos-doc fellow (SFRH/BPD/115169/2016) funded by Fundacao para a Ciencia e Tecnologia (FCT), reimbursed by Fundo Social Europeu and by national funds of MCTES.
Prognostic value of serum apolipoprotein B (ApoB) to apolipoprotein A-I (ApoA-I) ratio in hepatocellular carcinoma patients with transcatheter arterial chemoembolization treatment: propensity score-matched analysis.
Authors: Meng meng Liu, Zhan-Hong Chen, Yu-tong Chen, Zi-xian Wang, Xiangyuan Wu, Min Dong
Journal: Journal of Clinical Oncology (2019)

e14589 Background: The aim of our research was to assess the prognostic value of ApoB to ApoA-I ratio (ApoB/ApoA-I) in hepatocellular carcinoma (HCC) patients with transcatheter arterial chemoembolization (TACE) treatment. Methods: We collected clinicopathological data of 455 HCC patients with TACE treatments. The cutoff value of ApoB/ApoAI identified by receiver-operating curve (ROC) was 0.56. Correlation analysis was carried out to explore the relationship among ApoB/ApoA-I and other clinicopathological variables. Propensity score-matched (PSM) analysis was carried out to eliminate the unbalance of baseline characteristics of high and low ApoB/ApoA-I group. Finally, 278 patients were included in the PSM cohort, 139 patients in the high APOB/APOA-I group and 139 patients in the low APOB/APOA-I group. Univariate and multivariate analysis were conducted to explore the independent prognostic value of ApoB/ApoA-I in 455 patients and in the PSM cohort. Results: ApoB/ApoA-I was significantly correlated with AFP, NCCN T stage, distant metastasis status and TNM system(P &lt; 0.05). Patients with AFP≥400ng, T3-4, distant metastasis and TNM III-IV had significantly higher serum ApoB/ApoA-I level than that of patients with AFP ≥ 400 ng/ml, T1-2, without metastasis and TNM I-II(P &lt;0.05). Patients in high ApoB/ApoA-I group had significantly shorter overall survival compared to those in low ApoB/ApoA-I group in 455 HCC patients and in the PSM cohort (P &lt; 0.01). Multivariate analysis indicated that ApoB/ApoA-I was an independent prognostic index for OS in 455 HCC patients and the PSM cohort (HR = 1.443, P = 0.006; HR = 1.564, P = 0.006, respectively.) Conclusions: Serum ApoB/ApoA-I is a novel independent prognostic factor for the HCC patients treated with TACE.
CTC enumeration and characterization as a pharmacodynamic marker in the phase I clinical study of APX3330, an APE1/Ref-1 inhibitor, in patients with advanced solid tumors.
Authors: Lincy Chu, Amanda K. L. Anderson, Mark Andrew Landers, Yipeng Wang, Mark R. Kelley, Richard Adam Messmann
Journal: Journal of Clinical Oncology (2019)

e14531 Background: APE1/Ref-1 is a dual-function protein with a pleiotropic role in regulating transcription factors involved in cancer cell signaling via redox control, as well as responding to oxidative and base DNA damage. APX3330 is a highly selective inhibitor of the Ref-1 mediated redox function in tumors, while enhancing the neuronal protective function of APE1. APX3330 is undergoing clinical development as an anti-tumor agent that also protects and reverses oxidative damage to neurons. We now report on the CTC analysis conducted as part of the study (NCT0337508). Results of the clinical study are reported in a separate abstract. Methods: A total of 19 patients with 10 various solid tumors, including rectal, pancreatic, colon, endometrial, gall bladder, hepatocellular, prostate, melanoma, bladder, and ovarian cancers received APX3330 in escalating divided daily doses of 240, 360, 480, 600, and 720mg. Blood samples were collected from all patients prior to receiving APX3330 and after achieving steady-state serum concentrations of the drug. Samples were sent to Epic Sciences to analyze circulating tumor cells (CTCs) in peripheral blood via their CTC Platform. Results: Cumulatively, 37 samples from 19 patients were received. 35/37 (95%) samples passed technical quality control and were feasible for downstream analysis. 9/17 (53%) baseline samples (BL) had CTCs detected, while 9/18 (50%) on-treatment (OTx) draws had CTCs detected. 16 patients had BL and OTx samples that were further evaluated with the longitudinal analysis. Of these, 7/16 (44%), 6/16 (38%), and 3/16 (19%) patients showed a reduction trend, an increase trend, and no change in all CTC populations (delta greater than or equal to 0 CTC/ml), respectively. Patient follow-up is ongoing and the correlation of CTC biomarkers with clinical outcomes is pending. Conclusions: APX3330 is undergoing clinical evaluation as an anti-tumor agent that protects against and reverses CIPN. In this phase I study, 44% of evaluable blood samples showed a reduction in CTCs after initiation of treatment with APX3330. Additional studies are now being planned. Clinical trial information: NCT0337508.
Precise cell behaviors manipulation through light-responsive nano-regulators: recent advance and perspective
Authors: Do Cong Thang, Zhimin Wang, Xiaoling Lu, Bengang Xing
Journal: Theranostics (2019)

Nanotechnology-assisted spatiotemporal manipulation of biological events holds great promise in advancing the practice of precision medicine in healthcare systems. The progress in internal and/or external stimuli-responsive nanoplatforms for highly specific cellular regulations and theranostic controls offer potential clinical translations of the revolutionized nanomedicine. To successfully implement this new paradigm, the emerging light-responsive nanoregulators with unparalleled precise cell functions manipulation have gained intensive attention, providing UV-Vis light-triggered photocleavage or photoisomerization studies, as well as near-infrared (NIR) light-mediated deep-tissue applications for stimulating cellular signal cascades and treatment of mortal diseases. This review discusses current developments of light-activatable nanoplatforms for modulations of various cellular events including neuromodulations, stem cell monitoring, immunomanipulation, cancer therapy, and other biological target intervention. In summary, the propagation of light-controlled nanomedicine would place a bright prospect for future medicine.
CD49d (high) T cells in the ovarian cancer microenvironment are a potential target for the optimization of immune checkpoint therapy in ovarian cancer.
Authors: Henning De May, Sharina Palencia Desai, Ichiko Kinjyo, Jaryse Harris, Sarah Foster Adams
Journal: Journal of Clinical Oncology (2019)

e17075 Background: Despite the correlation between tumor infiltrating lymphocytes and long-term survival, immune-based therapies have underperformed for the treatment of ovarian cancer. This is attributed to an immune suppressive intraperitoneal microenvironment. With evidence that T cell dysfunction in the ovarian tumor environment is not reflected peripherally, we hypothesized that anatomically restricted T cell subsets play a role in local disease regulation. High expression of integrin α4 (CD49d) is selectively seen on peritoneal T cells in patients and healthy mice. Here we tested whether CD49d(high) CD8 T cells also contribute to anti-tumor immunity in ovarian cancer models. Methods: Using a syngeneic immune competent model of high grade serous ovarian cancer (ID8ova), we evaluated the phenotype of CD49d(high) T cells at varying stages of intraperitoneal disease by flow cytometry. Antigen specificity was tested using a SIINFEKL/H-2Kb NIH tetramer assay. Results: CD49d is highly expressed by peritoneal CD8 T cells but not by splenocytes in tumor-bearing mice (29.8% vs. 3.3% of CD8 cells respectively). Supporting a role in anti-tumor immunity, 92% of tumor antigen-specific CD8 T cells in the peritoneal cavity expressed high CD49d. While the proportion of peritoneal CD8 cells that express high CD49d is similar in healthy and tumor-bearing mice, CD49d(high)CD8 cells upregulate the expression of co-inhibitory receptors with tumor progression. At late stages of the disease, PD-1, TIM3, and LAG3 are exclusively expressed by peritoneal CD49d(high) cells (range 94.7 +/- 3.05%). Consistent with our prior data, PD1+TIM3+LAG3+ CD8 T cells were not present in the spleen, confirming the anatomic specificity of this lymphocyte subset. Conclusions: These findings add to the accumulating evidence that tumor immunity is locally regulated and identify an IP specific subset of CD8 T cells that could be selectively targeted with immune checkpoint blockade. We predict that strategies directing immune therapy to the peritoneal tumor microenvironment will enhance treatment efficacy and limit off-target toxicities in women with ovarian cancer.
A retrospective cohort study of anti-PD-1 therapy combined with chemotherapy in patients with advanced biliary tract cancer.
Authors: Danyang Sun, Junxun Ma, Jinliang Wang, Chun Han, Yuanyu Qian, Guangying Chen, Xiaoyan Li, Juan Zhang, Pengfei Cui, Wushuang Du, Zhaozhen Wu, Shixue Chen, Xuan Zheng, Zhichao Yue, Jia Song, Xiaochen Zhao, Shangli Cai, YI HU
Journal: Journal of Clinical Oncology (2019)

e14100 Background: Biliary tract cancer (BTC) is highly aggressive with poor prognosis and few treatment options following progression on gemcitabine-based chemotherapy. Disappointing results from clinical trials for refractory BTC highlight the need for more effective therapies. Immune checkpoint inhibitor (ICI) has been hailed as a major breakthrough for cancer treatment. However, evidence for the efficacy of immunotherapy in biliary tract cancer (BTC) is limited and unsatisfactory. KEYNOTE-158 trial has merely shown a 5.8% of overall response rate with pembrolizumab monotherapy in advanced BTCs. Thus, combining other therapies with ICIs is becoming the researching focus. Herein, we constructed a cohort to evaluate the efficacy and safety of ICIs combined with chemotherapy in advanced BTCs. Methods: Chinese BTC patients receiving PD-1 inhibitors with chemotherapy, PD-1 inhibitors monotherapy or chemotherapy alone were retrospectively analyzed. The primary outcome was overall survival (OS). The key secondary outcome were progression-free survival (PFS) and safety. Patients previously treated with any agent targeting T-cell co-stimulation or immune checkpoints were excluded. Results: The study included 77 patients (PD-1 inhibitors plus chemotherapy, n = 38; PD-1 inhibitors monotherapy, n = 20; chemotherapy, n = 19). Median OS was 14.9 months with PD-1 inhibitors plus chemotherapy, 4.1 months with PD-1 inhibitors and 6.0 months with chemotherapy, with significantly longer for anti-PD-1 combination therapy than monotherapy (HR 0.37, 95% CI 0.17-0.80, P= 0.001) or chemotherapy (HR 0.63, 95% CI 0.42-0.94, P= 0.011). Median PFS was 5.1 months with PD-1 inhibitors plus chemotherapy, 2.2 months with PD-1 inhibitors and 2.4 months with chemotherapy, with significant difference for anti-PD-1 combination therapy versus anti-PD-1 monotherapy (HR 0.59, 95% CI 0.31-1.10, P= 0.014) or chemotherapy (HR 0.61, 95% CI 0.45-0.83, P= 0.003). Grade 3 or 4 treatment-related adverse events were similar between anti-PD-1 combination group and chemotherapy group (34.2% and 36.8%). Conclusions: PD-1 inhibitors plus chemotherapy is effective and tolerable for advanced BTC.