bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tremelimumab (day 1 only) and durvalumab in combination with transarterial chemoemobilization (TACE) in patients with hepatocellular carcinoma (HCC).
Authors: Buchalter Jemma , Evans Niamh , Browne Iseult , Mac Eochagain Colm , Flynn Calvin , Carroll Hailey Kathryn , Galligan Marie , Bourke Michele , Lester-Grant Amy , Hoey Katherine , Ryan Ronan , Cantwell Colin P , McCann Jeffrey , McDermott Ray , MacNicholas Ross , Duffy Austin G 
Published: June 2022

e16175 Background: TACE induces a peripheral anti-tumor immune response, which may be amplified by immune checkpoint inhibitors (ICI). Combining TACE with dual ICI therapy has been shown to be safe and feasible. Recent data has suggested that Day-1 only anti-CTLA4 dosing, at a higher level of 300mg, could lead to a stronger immune response, and drive a greater expansion than lower dose regimens, whilst maintaining a tolerable safety profile. This novel schedule has not previously been combined with TACE. Methods: Patients with HCC (Childs Pugh A/B7, Barcelona clinic liver cancer stage B/C; ECOG 0/1; sorafenib-naive or experienced) were enrolled in a pilot study of tremelimumab at 2 dose levels (DL1: 75mg IV q4-weekly x 4 and DL2: 300mg IV D1 only) in combination with durvalumab (1500mg IV q-28d) and TACE (D36 +/- 96 hours) until progression of disease (per irRECIST) or off-study criteria. Peripheral immune monitoring was performed and tumor biopsies were obtained at time of TACE. Results: 13 patients enrolled on study; N = 3 at DL1 and N = 10 at DL2. M:F 10:3. Median age 70 (65-74). BCLC B/C 4/9. Extrahepatic disease 6/7. Aetiology: NASH (N = 3), alcohol-related disease (N = 1), HCV (N = 2), hemochromatosis (N = 1), unknown (N = 6). 1 pt discontinued due to G3 colitis. All patients evaluable for response with 2/10 pts on DL2 experiencing PR (at 8 weeks) and overall 7/13 SD and 1/13 PD as best response. Updated PFS and OS data to be presented. Conclusions: Tremelimumab (Day 1 only) and Durvalumab in combination with TACE is safe and feasible in patients with HCC. Follow-up is ongoing and full safety and efficacy data will be presented. Clinical trial information: 2019-002767-98.
Sintilimab combined sorafenib as first-line therapy in patients with advanced hepatocellular carcinoma: A single-arm, single-center, open-label, phase II study.
Authors: Wang Jiabei , Liu Lianxin 
Published: June 2022

e16182 Background: Combining a PD-1 inhibitor with tyrosine kinase inhibitor has achieved a high response rate for advanced HCC (aHCC) in first-line settings. Sorafenib remains the approved first-line choice for aHCC and demonstrates survival benefit, manageable toxicity and high accessibility in china. This study aimed to explore the efficacy and safety of sintilimab (anti-PD-1 antibody) combined sorafenib in patients (pts) with aHCC. Methods: This is a single-arm phase II study (CTR2000031242). Eligible pts with aHCC, BCLC stage C or B (unresectable or not applicable for TACE), Child-Pugh scores≤7 and ECOG PS ≤ 1 received first-line treatment of sintilimab (200mg, iv, D1) every 3 weeks plus sorafenib (400mg, po, BID) until disease progression or unacceptable toxicity. Primary endpoints was objective response rate (ORR, per RECIST 1.1), and secondary endpoints included safety, disease control rate (DCR), progression free survival (PFS), duration of response (DOR) and overall survival (OS). Results: As of January 30, 2022, 12 pts were enrolled (males 11; median age 54.5 yrs [range 46-68]; BCLC A/B/C: 1/6/5; Child-Pugh A/B7: 5/7; HBV infection 11). All pts received at least 1 cycles of treatments with median cycles 3.5 [range 1-17]. Median follow-up was 3 months [range 0.7-15]. 12 pts were evaluable for response, with an ORR of 17 % (95%CI, 0.1%-41.4%) and a DCR of 33 % (95%CI, 2%- 64%). The median PFS was 3.2 months and median OS was not reached. All pts were evaluable for toxicity, and 6 (50.0 %) pts had at least one treatment-related AE (TRAE). TRAEs occurring in≥20% of pts were pruritus (25%). 1 pt had grade 3 TRAEs. Conclusions: The combination of sintilimab and sorafenib showed promising clinical activities with manageable toxicity for first-line treatment of aHCC. Clinical trial information: CTR2000031242.
Extrahepatic cholangiocarcinoma versus intrahepatic cholangiocarcinoma: A comparison of survival outcomes and use of palliative care in diagnosed patients.
Authors: Nimish Thakral , Gonzalez Teresita , Nano Olger , Shin Sang Ha , Samuels Shenae , Hussein Atif Mahmoud 
Published: June 2022

e16192 Background: Cholangiocarcinoma (CCA), a malignancy of the biliary tract epithelium, is of increasing importance due to its rising incidence worldwide. However, it also remains one of the most lethal malignances with a survival rate ranging between 6-16 months. Despite poor outcomes, palliative care remains underutilized in CCA. Determining outcomes, and differences in various CCA types remains crucial in helping patients and clinicians make goal of care decisions with regards to aggressive treatment. Objectives:The objective of this study is to compare survival outcomes between intrahepatic (iCCA) and extrahepatic cholangiocarcinoma (eCCA). In addition, it aims to compare the utilization palliative care in either subtype, considering the high morbidity and mortality of the disease. Methods: Pooled cross-sectional observational study of the2004-2017 National Cancer Database (NCDB), which contains almost 400,000 records. The study population included de-identified records of patients with CCA; ages 18-90. Descriptive statistics (frequency, means, and standard deviations) were used. For survival analyses, the Kaplan-Meier method with log-rank test and a multivariate Cox regression model was used. Results: A total of 53,054 patients with CCA were identified. Of which, 63.4% had iCCA and 36.7% of patients had eCCA. There were statistically significant differences between the two cohorts in regard to sex, race/ethnicity, as well as in Charlson Co-Morbidity score. 65.2% of iCCA patients had advanced clinical stages III/IV as compared to 62.5% of eCCA patients. Higher percentage of iCCA patients had bone metastasis (7.8% vs 4.6 %, p < 0.001), pulmonary metastasis (11.5% vs 7.8%; p <0.001) and tumor size greater than 5 cm (62.1% vs 20.7%, p <0.001) compared to eCCA. Regarding treatment, patients with iCCA were more likely to receive multi-agent chemotherapy (35.0% vs 26.2 %, p<0.001). Although statistically significant differences for primary site surgical intervention (25.5% vs 25.0%, p<0.001), as well as for immunotherapy (6% vs 5.4%, p= 0.048), was found, they were not clinically significant. Patients with eCCA had a higher 90-day mortality (11.4% vs 8.2%, p <0.001), with 21% less likelihood of survival compared to iCCA patients (AOR:0.79, CI:0.74-0.84). Palliative care remained underutilized, with a lower utilization in iCCA (15.7% vs 12.5%, p <0.001). Conclusions: Our study demonstrated that iCCA patients have better survival outcomes compared to eCCA patients. This could be due to biological/genomic differences which warrant future investigation. Future clinical trials could also stratify for the location of CCA. Despite CCA’s poor prognosis, palliative care remained underutilized, with lower utilization rates in iCCA compared to eCCA.
Relationship between systemic inflammatory response markers and immune treatment related toxicity (IrAEs) in hepatocellular carcinoma (HCC).
Authors: Dharmapuri Sirish , Ozbek Umut , Saeed Anwaar , Muzaffar Mahvish , Amara Suneetha , Personeni Nicola , Pressiani Tiziana , Nishida Naoshi , Paul Sonal , Bettinger Dominik , Khan Uqba , Fessas Petros , Huang Yi-Hsiang , Kaseb Ahmed Omar , Pillai Anjana , Rimassa Lorenza , Pinato David J. James , Ang Celina 
Published: June 2022

e16204 Background: A well-recognized class effect of immune check point inhibitors (ICI) is IrAEs ranging from low grade toxicities to life-threatening end organ damage requiring permanent discontinuation of ICI. Treatment related deaths are reported in ̃5% of patients (pts) treated with ICI. There are, however, no reliable markers to predict the onset & severity of IrAEs. We tested the association between neutrophil-lymphocyte ratio (NLR) & platelet-lymphocyte ratio (PLR) at baseline with development of clinically significant IrAE (graded ≥2) in HCC pts treated with ICI. Methods: Data was extracted from a large international database from a consortium of 11 tertiary-care referral centers located in the USA, Europe & Asia. NLR=Absolute neutrophil count/ Absolute lymphocyte count (ALC) & PLR=Platelet count/ALC. A cutoff of 5 for was used NLR & 300 for PLR based on literature. We also tested the association between antibiotic & steroid exposure to IrAEs. Results: Clinical data was collected from 361 pts treated between 2016–2020 across the USA (66%), Asia (12%) & Europe (22%) in this multinational database. Most pts received Nivolumab monotherapy (n=318, 74%). 167 (46%) pts developed at least one IrAE, highest grade 1 in 80 (48%), grade ≥2 in 87(52%) pts. Baseline characteristics did not differ significantly between the groups (Table). In a univariable regression model to predict grade ≥2 IrAEs, a PLR >300 was associated with a lower incidence of clinically significant IrAEs (OR = 0.40; p=0.044). NLR >5 was associated with a trend toward lower incidence of clinically significant IrAEs (OR = 0.58; p=0.097). Multivariate analyses confirmed PLR as independent predictive marker of grade ≥2 IrAEs (OR = 0.24; p=0.007). Antibiotics use was not associated with IrAE incidence (OR = 1.02; p=0.954). Steroid use was associated with a >2-fold higher incidence of grade ≥2 IrAEs (OR = 2.74; p<0.001), though it may be noted that 37% of pts received steroids for treatment of IrAEs. Conclusions: Lower NLR & PLR may predict the appearance of IrAEs in HCC treated with ICI, although this conclusion warrants prospective validation. This finding is in keeping with several studies that showed improved survival in pts who develop of IrAEs & have a lower NLR & PLR.[Table: see text]
Immune cell molecular pharmacodynamics of lanreotide in relation to treatment response.
Authors: Alaklabi Sabah , Maguire Orla , Minderman Hans , Iyer Renuka V. 
Published: June 2022

e16213 Background: Lanreotide is clinically effective in advanced neuroendocrine tumors (NETs). The inhibitory effect of lanreotide on tumor cells proliferation is due to binding to somatostatin receptors (SSTR1-5). It has been demonstrated that immune cells express SSTR1-5 differentially. The exact effect of somatostatin analogs (SSAs) on T cells function is not understood. Methods: In vitro and in vivo effects of lanreotide on immune cells were investigated, with regards to clinical response correlates. In vitro, SSTR1-5 expression was measured on CD4+ T helper cells, CD8+ cytotoxic T cells, and CD4+CD25+ T regulatory cells from healthy donors (HD), and lanreotide effect on key functional immune response parameters (NFkB, NFAT, ERK1/2 signaling, IFN, and IL-2 production) were studied. To assess in vivo effects of lanreotide on immune cells of NET pts, peripheral blood mononuclear cells (n = 16) obtained pre and 3 months post treatment were studied for gene and protein expression profiles in sorted T cell subsets using a NanoString immune cell panel. Results: HD T cells had high expression of SSTR2 and low/no expression of the other SSTRs. In vitro, lanreotide had no effect on the functional immune response parameters investigated. For the in vivo study, the patient cohort consisted of 8 responders (no progression by 19 months) and 8 non-responders. Clinicopathological features, see table. Pretreatment immunological competence of responders was greater than non-responders, as indicated by upregulation of TCR signaling (in CD4+) and interferon signaling (in CD8+ and T reg). Irrespective of clinical response, lanreotide had most significant effect on CD8+ T cells, down regulating WNT, TCR, and NF-kB signaling. Compared to non-responders, responders had down regulation of cytokine and chemokine signaling but upregulation of ubiquitination and proteasome degradation associated genes. Several myeloid specific genes were found to be significantly changed in the CD4 T helper population, possibly due to co isolated myeloid cells interacting with T cells during sorting. Conclusions: The in vivo immune effects of lanreotide seen reflect the relevance of parameters in tumor microenvironment such as interactions with myeloid components of the immune system not accounted for under the experimental in vitro conditions.[Table: see text]
Efficacy and safety profile of antivascular endothelial growth factor receptor tyrosine kinase inhibitors (avRTKIs) in patients (Pts) with neuroendocrine tumors(NETs): A systematic review and meta-analysis (SRMA).
Authors: Das Satya , Phillips Sharon E. , Lee Cody L , Laferriere Heather E. , Agarwal Rajiv , Ramirez Robert A. , Berlin Jordan , Dasari Arvind 
Published: June 2022

e16216 Background: Vascular endothelial growth factor mediated signaling is central to NETs. As such, multiple avRTKIs have been tested in NETs over the last 2 decades, mostly in small phase II studies. In fact, there have been no randomized phase III trials conducted in United States apart from the one leading to approval of sunitinib in pancreatic (p) NETs. Several other avRTKIs have demonstrated clinical promise including surufatinib in phase III trials conducted in China; this drug is currently under FDA review for potential approval. In the current SRMA, we aim to address this deficiency by benchmarking efficacy and safety profiles of avRTKIs. Methods: A literature search was done to identify all phase II and phase III studies of avRTKIs in pts with NETs published between 1/1/2000–7/31/2021. Data abstraction was performed by one author and validated by another. Efficacy was assessed by aggregating progression-free survival (PFS) and overall response rate (ORR) data. PFS and ORR were assessed using a random effects model separately for pts with pNETs and extra-pancreatic (ep) NETs. Toxicity was assessed by calculating the relative risk (RR) compared to control arm and incidence of adverse events (AEs) of interest. Results: Of 92 identified studies, 17 (with 8 individual avRTKIs) were included in the meta-analysis after excluding redundant studies; baseline study characteristics are listed in the Table.A total of 1611 pts (853 men, 758 women) were available for the analysis; 1194 received avRTKIs. The ORR in pNETs was 18% (95% confidence interval (CI) 13-25%) while the ORR in pts with epNETs was 8% (95% CI 5-12%); test for differences between pNETs and epNETs (x12 = 8.47, p < .01). The median PFS in pNETs was 13.9 months (95% CI 11.43-16.38 months) while median PFS in epNETs was 12.71 months (95% CI 9.37-16.05 months); test for differences between pNETs and epNETs (x12 = .32, p = .57). The incidence (and RR compared to control) of most common ≥ grade 3/4 AEs were hypertension 22.4% (4.48, p < .001), diarrhea 6.4% (RR 3.03, p = .005), neutropenia 5.2% (20.4, p = .036) and proteinuria 4.6% (27.25, p = .001). Incidence (and RR compared to control) of rare but serious complications included non-central nervous system bleeding 8.7% (2.17, p < .001) and cardiac dysfunction 6.4% (2.52, p = .01). Conclusions: Among pts tx with avRTKIs, pts with pNETs demonstrated improved ORR but not PFS compared to these outcomes in pts with epNETs. In addition, this study also benchmarks the incidence and RR of AEs in pts with NETs treated with avRTKIs who are often on therapy longer than other pts.[Table: see text]
Efficacy and safety of neoadjuvant therapy with stereotactic body radiation therapy followed by nab-paclitaxel/gemcitabine plus camrelizumab for resectable, borderline resectable and locally advanced pancreatic cancer: Preliminary results.
Authors: Xue Jun , Hu Yue , Gou ShanMiao , Yin Tao , Li Xin , Wang Jing , Liu Hongli , Yang Ming , Ma Hong , Hu Jianli , Lin Zhenyu , Li Pindong , Wu Heshui , Zhang Tao 
Published: June 2022

e16227 Background: Neoadjuvant therapy has been attempted to improve local control and prolong survival for pancreatic cancer patients. However, the standard treatment has not been defined. This trial was to evaluate the efficacy and safety of nab-paclitaxel/gemcitabine plus camrelizumab with or without stereotactic body radiation therapy (SBRT) in patients with resectable, borderline-resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC). Methods: This prospective clinical trial was designed to include patients pathologically confirmed and previously untreated resectable pancreatic cancer, BRPC and LAPC. Patients were randomized to receive either SBRT (5 Gy × 5), four courses of nab-paclitaxel 125 mg/m2, gemcitabine 1000 mg/m2 (administered intravenously on days 1, 8 of each 21-day cycle) plus Camrelizumab 200mg (every three weeks) followed by surgery (Arm A) or only four courses of nab-paclitaxel, gemcitabine and Camrelizumab followed by surgery (Arm B). The primary endpoint was objective response rate (ORR), and the second endpoints were disease control rate (DCR), margin-negative (R0) resection rate, progression-free survival (PFS), overall survival (OS) and toxicity. Results: From March 2021 to Jan 2022, 14 eligible patients were enrolled. Eight patients were randomly assigned to Arm A while 6 to Arm B. The median follow-up duration was 33 weeks. Overall, 9 patients completed preoperative therapy and were eligible for response assessment. Among the 9 patients, 4 (44.4%) had partial response (PR), 4 (44.4%) had stable disease (SD), while one had progressive disease (PD). The ORR was 44.4% (4/9), and DCR was 88.9% (8/9). Five of these 9 patients received pancreatectomy with a resection rate of 71.4% (5/7) and the R0 resection rate was 100% (5/5). The reasons why the other 4 patients did not undergo surgery were progression of disease (n = 1), refusal of surgery (n = 1), and still in the interval of neoadjuvant therapy to surgery (n = 2). The most common adverse events of grade 3 or higher were neutropenia (22.2%), neuropathy (11.1%) and thrombocytopenia (11.1%). Median CA 19-9 level was 116U/ml (2 to 12000) in baseline while decreased to 69U/ml (2 to 4832) before surgery. The median OS or PFS has not been reached yet. Conclusions: The neoadjuvant therapy of nab-paclitaxel/gemcitabine plus camrelizumab with or without SBRT had a good safety and efficacy in patients with resectable pancreatic cancer, BRPC and LAPC. Clinical trial information: ChiCTR2100042415. [Table: see text]
Pathologic and clinical outcomes after neoadjuvant modified FOLFIRINOX and gemcitabine and NAB-paclitaxel for pancreatic cancer.
Authors: Markabawi Danny , Ianiro Cora , Burton Jeffrey , Bolton Nathan , Mizrahi Jonathan 
Published: June 2022

e16236 Background: Surgical resection is the only potentially curative option for pancreatic cancer (PC). Unfortunately, just 15-20% of patients (pts) have resectable disease at the time of diagnosis. Recently, for a variety of reasons, neoadjuvant chemotherapy (NAC) has been widely adopted in both borderline resectable and resectable tumors. Most guidelines recommend either modified FOLFIRINOX (mFOLFIRINOX) or gemcitabine and NAB-paclitaxel (GnP) in this setting. This is largely based on phase II trials and extrapolations from trials in the metastatic setting. Here we investigate the difference in tumor regression score (TRS) and clinical outcomes between these regimens. Methods: We retrospectively collected data from pts who underwent resection of PC after NAC at Ochsner Health between July 2012 and July 2021. Primary objective was TRS on operative pathology as assessed by the reading pathologist. Secondary objectives were progression free survival (PFS) from the date of surgery and overall survival (OS) from the date of diagnosis. TRSs were dichotomized as complete (0)/moderate (1) responses versus (vs) minimal (2)/poor (3) responses. The dichotomized score was assessed using log-binomial regression. Kaplan-Meier survival analysis was utilized to estimate PFS and OS. Survival curves were compared by the log-rank test. Results: We identified 96 pts with PC who had NAC followed by surgical resection. Mean age at diagnosis was 65.7. 55% had borderline resectable and 45% had clearly resectable disease at diagnosis. 74 pts received mFOLFIRINOX and 22 pts received GnP. Pts receiving GnP were more likely to be older (71 vs 64, P = 0.001) and have a worse Eastern Cooperative Oncology Group performance status (PS) (P = 0.019). TRSs were similar between the 2 groups with 58.1% and 59.1% in each group achieving a TRS of 2. 7 pts in the mFOLFIRINOX group had TRS of 0 (CR) while 0 pts in the GnP group had a TRS of 0. When controlling for age and PS, risk ratio for a lower TRS (0/1 vs 2/3) with mFOLFIRINOX vs GnP was 1.22 (0.27 - 5.47). 40% and 36.4% had disease recurrence after mFOLFIRINOX and GnP, respectively. Median PFS and OS were 15.6 and 23.4 months (m) in the mFOLFIRINOX group and 18.9 and 27.6 m in the GnP group (P = 0.996, P = 0.933, respectively). On multivariate analysis, controlling for age and PS, hazard ratios for OS and PFS with mFOLFIRINOX vs GnP were 0.86 (95% CI 0.38–2.18) and 1.17 (95% CI 0.53–2.84), respectively. Conclusions: Our study showed no difference in TRS between mFOLFIRINOX or GnP as NAC, although the small number of pts who received GnP precluded statistical inference. Differences in survival outcomes between the two NAC regimens were not significantly different, and outcomes were comparable to those reported in the phase II SWOG S1505 trial. Large prospective trials comparing these two regimens in terms of efficacy and toxicity will be required to better answer these questions.