tbuckley/cabot-search huggingface dataset:
Clinical predictors of progression of a hepatic lesion from Li-RADS (LR) 3 to LR5 among patients (pts) at risk of hepatocellular carcinoma (HCC).
Authors: Lindsay Marie Hannan, William Proctor Harris, Patricia I. Ojeda, James O. Park, Rebecca Mieloszyk, Puneet Bhargava, Guy E. Johnson
Journal: Journal of Clinical Oncology (2020)

481 Background: We sought to identify predictors of progression of LR3 lesions (i.e. indeterminate for HCC) to LR5 lesions (i.e. definitely HCC) on follow-up imaging among cirrhotic pts. Methods: Imaging reports with LR assignments were identified among pts seen at the University of Washington, 2013-2017. Cirrhotic pts with a LR3 lesion and follow-up scan within 1 year (yr) of LR3 lesion date were included (n = 313). Clinical features were abstracted from chart review. Survival analyses employing interval censoring were performed. Variables as potentially predictive of LR3 progression were identified in univariate analyses, with backwards elimination done (p &lt; 0.05) to obtain the final multivariate model. Results: 20.4% of LR3 lesions progressed to LR5 within 1 yr; 73% were still LR3, 8% progressed to LR4. The population was predominantly male (61%), Caucasian (71%), older than 55 (63%). The most common cirrhotic etiologies were HCV (46.7%), alcohol (32.6%), and NASH (12.8%), not mutually exclusive. AFP at the time of LR3 scan was low if available (39% with AFP &lt;5, 16% 5-10, 28% unknown). 22.7% had impaired liver function (ALBI grade 3); 19.5% lacked data to calculate ALBI grade. CT scan was the most common exam (56%). Multiple LR3 lesions were seen on 51% of scans. Most LR3 lesions were right sided (75%), &lt; 1 cm (51%); 7% of lesions were &gt; 2cm. Men (HR 2.0, p = 0.02), earlier scan yr (HR 0.47 per yr, p &lt; 0.0001), older age (HR 1.42 per 15 yr, p = 0.047), lesion size (HR 1.21 for 2cm+, global p = 0.02) appeared as independent predictors of LR3 to LR5 progression based on the final model. Of 16 variables examined, men were more likely to have chronic HCV, history of alcohol use and less likely to have autoimmune hepatitis. No other differences were seen. In an a priori analysis, risk of male sex (HR 1.99, p = 0.03) persisted despite control for HCV, alcohol, age, race, scan yr, lesion size, and number of lesions. Conclusions: Identification of clinical factors associated with LR3 progression may allow for risk modeling tools that may assist in determining imaging frequency and timing of intervention. The increased risk among men vs women is not explained by clinical or radiographic features listed above.
Therapeutic vaccination with an autologous TriMix-Dendritic cell vaccine combined with sequential interferon alfa-2b in patients with advanced melanoma
Authors: S. Wilgenhof, A. M. Van Nuffel, D. Benteyn, L. Pierret, C. Heirman, A. De Coninck, I. Van Riet, A. Bonehill, K. Thielemans, B. Neyns
Journal: Journal of Clinical Oncology (2009)

9024 Background: Electroporation of dendritic cells (DC) with mRNA encoding fusion-proteins of a HLA-class II targeting signal and a melanoma associated antigen (MAA) together with mRNA encoding CD40 ligand, a constitutively active TLR4 and CD70 (TriMix) improves the immunostimulatory capacity of autologous DC. Methods: Following leukapheresis, immature DCs (derived from adherent PBMC cultured for 6 days in IL-4 / GM-CSF supplemented medium) are electroporated with mRNA encoding MAGE-A3, MAGE-C2, Tyrosinase and gp100 linked to DC-LAMP, and TriMix mRNA. TriMix-DC (12.5 10 6 /antigen) are cryopreserved and administered by 4 ID-injections q2w, and q8w thereafter. After the 4 th vaccination, interferon alfa-2b (IFN- a2b, 5 MIU TIW) is initiated. Immune monitoring is performed by skin biopsy of a vaccine injection site. Biopsies are investigated by IHC and by analyzing the activation (CD137+), cytolytic capacity (CD107a+), and cytokine release (IFN-γ and TNF-α) of DTH infiltrating T-cells in response to autologous EBV-B cells expressing MAA. Results: 29 pts (17M/12F; med age 49, range 28–75) with stage III/IV melanoma, nl LDH, and no CNS metastases were recruited. Vaccine related AE's (first 24 pts): gr2 local injection site reactions (all pts); fever &amp; lethargy (gr2, 1 pt). Pts (20) who initiated IFN-a2b experienced constitutional side effects (gr3, 1 pt). Vaccine-specific DTH infiltrating T cells were documented post-vaccination in 13/17 pts (10/13 pts had a CD137+CD8+ and 2/13 pts a CD4+ response). Out of the 11 pts without evaluable disease, 2 had a local recurrence (salvaged by surgery). After a mFU of 7.8 mths (range 4.3–13.7) all pts remain disease-free. Out of the 13 pts with measurable disease, BOR (RECIST) was 8 SD and 5 PD; 1 pt with initial PD subsequently obtained a PR. Regression of metastases occurred in lung- (2 pts), orbita- (1 pt) and lymph node metastases (3 pts). After a mFU of 7 mths (range 1–14), the mPFS is 3,1 mths (95% CI 2,29–4,08); 4 pts remain progression-free after respectively 5, 8, 10 and 11 mths of follow-up. Conclusions: Therapeutic vaccination with TriMix-DC combined with sequential IFN-a2b is feasible, safe, immunogenic and associated with anti-tumor activity in patients with advanced melanoma. [Table: see text]
Proliferative, degradative smooth muscle cells promote aortic disease
Authors: Maarten Hulsmans, Matthias Nahrendorf
Journal: Journal of Clinical Investigation (2020)

Aneurysms are common in the abdominal and thoracic regions of the aorta and can cause death due to dissection or rupture. Traditionally, thoracic aortic aneurysms have been labeled as a degenerative disease, characterized by alterations in extracellular matrix and loss of smooth muscle cells (SMCs) in the medial layer of the aortic wall. In this issue of the JCI, Li and colleagues introduce an unconventional concept by demonstrating that mTOR-dependent proliferative SMCs render the aortic wall vulnerable to dilatation and dissection rather than prevent disease progression. These vascular SMCs, termed degradative SMCs, compromise the medial properties and function of the aortic wall by enhanced proteolytic and phagocytic activity; however, the cells do not transdifferentiate into macrophages. The degradative SMC phenotype also worsens atherosclerotic disease and could thus be considered as a therapeutic target for diverse aortic diseases.
Immunotherapy with Y90-radioembolization for metastatic colorectal cancer (iRE-C).
Authors: Pashtoon Murtaza Kasi, Beau M Toskich, Chandrikha Chandrasekharan, Dhivya Prabhakar, Saima Sharif, Daniel James Berg, Ann Miller, Carlos Hou Fai Chan, Sandeep Laroia
Journal: Journal of Clinical Oncology (2020)

TPS276 Background: Immune checkpoint inhibitors have revolutionized the treatment of a number of cancers. In colorectal cancers, their efficacy is limited to mismatch repair deficient or microsatellite stability-high (dMMR/MSI-High) tumors only. These constitute only 4-5% of all metastatic colorectal cancers (mCRC). Novel approaches are needed to make immunotherapy a viable option for mismatch repair proficient or microsatellite stable (pMMR/MSS) tumors. Increasing exposure of neo-antigens to the immune system could be one potential strategy to enhance the response of immunotherapy. Yttrium 90-radioembolization (Y90-RE) in combination with immunotherapy may work synergistically to enhance efficacy of each other. Additionally, radiation can potentially make the tumor microenvironment conducive to effector T-cell recruitment and function. Therefore, we hypothesize and propose the clinical trial of combining immunotherapy with Y90-RE as a feasible and safe strategy that will improve outcomes in patients with mCRC with liver-predominant metastases. Methods: This clinical trial will be conducted as a single-center, open-label, Phase I/II trial to evaluate initially the feasibility and safety of Y90-RE in combination with a fixed dose of immunotherapy (durvalumab) in subjects with liver-predominant, mCRC (Table). It will be offered in the refractory setting. The trial will be performed in 18 subjects with mCRC with liver metastasis and the safety of immunotherapy (durvalumab) with Y90-RE will be investigated in an accelerated titration design. This would allow a maximum tolerated dose with the minimum number of subjects. Correlative studies pertaining to serial circulating tumor DNA (ctDNA - liquid biopsies) testing as well as immune-panel based profiling will be performed alongside pre- and post-biopsies to study changes in the tumor microenvironment. Clinical trial information: NCT04108481. [Table: see text]
The real-world incidence of immunotherapy-related thyroid dysfunction: A retrospective analysis of a single center's experience over five years.
Authors: Heather Mae Brody, Shravanti Macherla, Anushi Bulumulle, Praveen Namireddy, Cynthia R. Cherry
Journal: Journal of Clinical Oncology (2020)

98 Background: Immunotherapy related thyroid abnormalities are well described. Any grade abnormality has been reported in 6-18% of patients. The clinical relevance of thyroid abnormalities in a real-world setting is still unclear. In this retrospective study, we analyzed immunotherapy type with time to thyroid dysfunction, grade of thyroid dysfunction, and number that ultimately required treatment. Methods: We retrospectively collected data for patients who received immunotherapy from April 2015 to August 2019. We recorded the type of immunotherapy, any abnormal TSH and grade of abnormality using the immune checkpoint inhibitor related adverse events Common Terminology Criteria for Adverse Events (IRAE-CTCAE), number of days from start of treatment to first noted abnormal TSH, and number requiring treatment with levothyroxine. At our large academic center, we analyze thyroid function prior to starting immunotherapy and at every treatment. Results: Of our 374 patients, 159 had some grade of thyroid dysfunction after receiving immunotherapy. Of the 159 patients with thyroid dysfunction, 23 had atezolizumab, (A), 81 had nivolumab (N), and 55 had pembrolizumab (P). Within these sub-groups, the majority of the adverse events were grade one, 74% in the A group, 57% in the N group, and 76% in the P group. Of these, zero were treated with levothyroxine. Grade two toxicities were seen in 22% in the A group, 31% in the N group, and 22% in the P group. Of these, a total of eight patient required treatment with levothyroxine. Average days to abnormal TSH was 97 in the A group, 94 in the N group, and 130 in the P group. Conclusions: In our population, 42.5% of patients had some grade of thyroid dysfunction which is higher than the previously reported values, however, the majority of abnormalities were grade one and self-resolved. This may indicate that transient changes in TSH are much more common than previously noted but not necessarily clinically relevant.
Epstein-Barr virus associated gastric carcinoma at the United States-Mexico border: A single institution study.
Authors: Sumit Gaur, Ramadevi Subramani, Meghan Mcalice, Osvaldo Padilla, Brenda Sofia Castillo, Ahmed Alshaban, Rajkumar Laxmanswamy
Journal: Journal of Clinical Oncology (2020)

440 Background: Globally, gastric cancer (GC) is the fourth most prevalent cancer, and the second leading cause of cancer related deaths. Epstein-Barr virus is implicated in the pathogenesis of 5-10% of gastric cancers. Based upon the results obtained from of the cancer genome atlas, EBV related GC is characterized by promoter hypermethylation, PIK3CA mutations (80%) and increased expression of PD-1 and PD-L1, making it an attractive target for molecularly targeted therapy and immunotherapeutic options. As such, a case can be made for routine testing for EBV in all GC patients. University medical center, El Paso is a tax payer funded safety net health system in El Paso country, TX. We conducted a pilot study to characterize the prevalence of EBV associated gastric cancer seen at this facility. Methods: After obtaining institutional review board (IRB) approval, we identified cases of GC that were diagnosed between January 1, 2008- and December 31-2017. A total of 104 cases were identified of which 17 samples were randomly selected. Pathology specimens were reviewed to identify grade, subtype (intestinal vs diffuse), degree of lymphocytic infiltration and presence/absence of H. pylori. Representative sections from archived tumors were used to perform in-situ hybridization to look for the presence of Epstein-Barr virus. Samples were analyzed using the Rembrandt In situ Hybridization and Detection Universal RISH&amp; HRP Detection Kit for Epstein-Barr early RNA. Results: The median age of the 17 patients is 63 years with 59% being males. 95% self identified as Hispanic. 41% were smokers, 18% used alcohol. The mean BMI was 27.3. Forty one percent of gastric cancer cases were found in the body, 29% in the antrum, 12% in the cardia, and 6% in the fundus. Forty one percent of cases were Stage IV, 24% stage II, 17% Stage III and 17% Stage I. 95% of cases were high grade, 53% of them had signet ring features. 18% of samples were H. pylori positive. None of the seventeen samples tested positive for EBV. Conclusions: EBV does not seem to contribute significantly to the pathogenesis of gastric cancer in our local population. As such routine testing for EBV in all gastric cancer patients may not be a cost effective utilization of resources at our hospital.
Hepatic and hematological toxicity associated with selective internal radiation therapy (SIRT): A meta-analysis of randomized clinical trials.
Authors: Ashish Manne, Michael Behring, Upender Manne, Rojymon Jacob, Ravi Kumar Paluri
Journal: Journal of Clinical Oncology (2020)

546 Background: For advanced hepatocellular cancers (HCCs) and colorectal cancers (CRCs) with liver metastasis, the impact of selective internal radiation therapy(SIRT) with yttrium-90 on survival outcomes is not established. A meta-analysis of randomized clinical trials (RCT) was performed to determine the relative risk (RR) of hepatic and hematological toxicities with the use of SIRT, compared to therapies not including SIRT. For patients with advanced HCC or CRC, we assessed the RR of high grade (grades 3 and 4) hyperbilirubinemia, fatigue, leucopenia, thrombocytopenia and elevated liver enzymes (AST and ALT) with use of SIRT. Methods: Citations from PubMed/Medline, clinical trials.gov, package inserts, and abstracts from major conferences were reviewed to include RCTs comparing arms with or without SIRT. Potential publication bias was assessed using the Egger test for funnel plot asymmetry. There was no publication bias and the trials were of high quality per Jadad scoring. Patients in control arms received trans-arterial chemo-embolization (TACE) or sorafenib for HCC or FOLFOX for CRC. The proportion and 95% confidence intervals (CIs) for patients with adverse events were derived for each arm of each study and used to calculate the RR. For the meta-analysis, both the fixed-effects model and the random-effects model were considered; the method proposed by DerSimonian and Laird was used to estimate the random-effects model. Results: The RR of grade 3/4 leucopenia was consistently high across high with the use of SIRT across all the studies (RR 2.05, 95% CI (1.22-3.42), p-value 0.027). The risk of hepatic dysfunction and fatigue was higher with SIRT but not statistically significant. Conclusions: Since SIRT is associated with increased risk of high-grade leukopenia, caution is advised in selecting patients with HCC’s with underlying decompensated cirrhosis or with CRCs and on cytotoxic therapy. Proper selection of patients would reduce toxicities from SIRT alone or SIRT in combination with systemic chemotherapy.
Phase II study of nanoliposomal irinotecan (nal-IRI) with 5-fluorouracil (5-FU)/folinic acid (FA) in refractory advanced high-grade neuroendocrine cancer (HG-NEC) of gastroenteropancreatic (GEP) or unknown origin.
Authors: Medhavi Gupta, Minsig Choi, Robert A. Ramirez, Kristopher Attwood, Sarbajit Mukherjee, Renuka V. Iyer
Journal: Journal of Clinical Oncology (2020)

TPS636 Background: The incidence of GEP HG-NEC is increasing and the prognosis is poor. Etoposide–platinum (EP) combination is considered the standard (std) therapy (Rx), but survival is less than 1 year. There is an unmet need for an optimal 2 nd line Rx in these patients (pts). Nal-IRI has shown efficacy in small cell lung cancer (pathologically similar to HG-NEC) and in 2 nd line pancreatic adenocarcinoma. In a retrospective study, HG-NEC pts with progression on 1 st line EP when treated with 2 nd line FOLFIRI (FA+5-FU+ IRI) had a good response and a tolerable safety profile (Hentic et al, 2012). Based on this data and the fact that no std 2 nd line Rx option exists in HG-NEC, we are evaluating the efficacy of nal-IRI+ 5-FU/FA in a prospective single-arm multicenter study. Methods: Advanced GEP or unknown origin HG-NEC pts with progressive disease/intolerance to 1 st line Rx with EP or temozolomide/capecitabine; ECOG PS 0-2 would receive nal-IRI 70 mg/m2, FA 400 mg/m2 followed by 5-FU 2400 mg/m2 on D1 &amp; 15 of 28-days cycle. Rx to continue till disease progression or unacceptable toxicity. Tumor assessment by CT/MRI per RECIST 1.1 q6 wks. Primary end point is to measure ORR (CR+PR). Secondary endpoints include PFS, TTP, OS, safety and QOL changes. Assuming a historic ORR of 15% with std Rx, 37 pts (upto 41 pts considering non-evaluable pts) are required to show an ORR of 30% at a power of 80% at 1-sided significance of α = 0.1. In stage 1, n 1 = 18 pts will be enrolled. If 3 or more responses are seen, an additional n 2 = 19 pts to be enrolled. If 8 or more responses are observed of the n = 37 evaluable pts, the Rx would be considered promising for further study. Genomic mutational profiling to be conducted on pre-study tumor samples and correlated with circulating tumor DNA (CT DNA). CT DNA level, assessed serially, will be correlated with Rx response and disease recurrence. We plan to accrue over 3 years at 3 sites. As of August 2019, 1-patient has been enrolled. The trial is funded by Ipsen Pharmaceuticals and the North American Neuroendocrine Tumor Society through the Clinical Investigator Scholarship. Clinical trial information: NCT03736720.
A study of preoperative FOLFIRINOX in potentially curable pancreatic cancer.
Authors: Hamed Javan, Tamim Niazi, Tsafrir Vanounou, Jean-Sebastien Pelletier, Richard Dalfen, Magali Lecavalier-Barsoum, Gerald Batist, Petr Kavan
Journal: Journal of Clinical Oncology (2020)

719 Background: Although Folfirinox (FFX) prolonged survival in metastatic and adjuvant setting, the role of preoperative FFX is still controversial. Our aim is to evaluate how surgery after neoadjuvant FFX with or without radiotherapy (RT) affects the clinical outcome in these patients. Methods: This is a single arm, open-label, phase 2 prospective study. Based on resectability criteria (NCCN-V.1.2017), patients prospectively were divided into 3 groups of resectable, borderline resectable (BR), locally advanced (LA). Patients received 6 cycles of preoperative FFX. Patients with adequate response, underwent resection. Continuation of chemotherapy or radiation was given to the patients who were deemed unresectable after 6 cycles. Primary objective is time to progression (TTP), and secondary objectives are safety, R0/R1 resection rate, response rate (RR) and overall survival (OS). Results: 20 consecutive patients with pancreatic adenocarcinoma enrolled. The frequency of each group was 4, 8, 8 patients, respectively. Median age was 64 years old (range, 49-78). 45% of patients had primary tumor in head or uncinate process. 25% of cases presented with normal CA 19-9 value. 85% (17/20) of patients completed the preoperative treatment. Folfirinox was given within median of 11.5 weeks (range, 8-17) and median of 6 cycles (range, 1-7). Median relative dose intensity (RDI) was 85.89%. Grade III-IV (G3+4) adverse event (CTCAE-4.03) observed in 47.4% (9/19). RR (RECIST) was 89% (16/18). Best response was partial response (PR) and stable disease (SD) with 22.2% (4/18) and 66.7% (12/18). Resection rate was 64.3% (9/14, 1 case scheduled for resection). R0 and negative lymph node (LN) achieved in 87.50% (7/8) and 62.50% (5/8) of patients. Complete pathological response (cPR) was seen in one patient 12.5% (1/8) who preoperatively reported as SD. Patients TTP and OS will be reported during the meeting. Conclusions: Preoperative FFX was associated with high clinical and pathological response rate translating in high resection rate in majority of BRPC and LAPC, and appears to be a safe treatment strategy. Patients received higher FFX dose intensity than it was reported in adjuvant setting. However, these results need to be assessed in a randomized trial. Clinical trial information: NCT03167112.
Biological characteristics and prognostic value of Tfh-like cells in the tumor tissue of breast cancer.
Authors: Linxiaoxi Ma, Liang Guo, Shyamal Goswami, Xiaoming Zhang, Jiong Wu
Journal: Journal of Clinical Oncology (2020)

5 Background: T follicular helper (Tfh) cells formed in germinal center are CXCR5 + ICOS + PD-1 hi Bcl-6 + CXCL13 + IL-21 + CD4 + T cells. They have been identified in different types of tumors. However, it still remains unclear in breast cancer, with one indicating the positive prognostic value of 8-gene Tfh signature. Methods: Freshly resected invasive breast cancer tissues from Fudan University Shanghai Cancer Center of all 386 patients were collected during 03/2015 to 05/2017. Data was analyzed based on the result from Multiparameter Flow Cytometry and IHC. The correlation between Tfh-like cells and clinicopathological characteristics in breast cancer was examined with t test or one way ANOVA with Tukey’s multiple comparisons test. Results: A subpopulation of PD1 hi CD4 + T cells in the tumor tissues of breast cancer was identified as Tfh-like cells, with the specific expression of Bcl-6 and CXCL13. Tfh-like cells were of a high level of ICOS but negative for CXCR5. They had high levels of activated molecules such as CD38, CD71, CD95 and HLADR, high levels of suppressive markers as Tim3, TIGIT, and LAG3 and high level of proliferation marker Ki-67, specifically secreting cytokine IL-21 with stimulation. Data showed that high grade (N = 166; mean±SEM, 17.62±0.87) compared with low grade (N = 220; mean±SEM, 12.41±0.46) or high Ki-67 level (N = 300; mean±SEM, 15.38±0.58) with low Ki-67 level (N = 86; mean±SEM, 12.10±0.67), and negative ER expression (N = 115; mean±SEM, 17.47±1.05) compared with positive ER expression (N = 271; mean±SEM, 13.46±0.50) or negative PR expression (N = 177; mean±SEM, 16.87±0.83) compared with positive PR expression (N = 209; mean±SEM, 12.77±0.50) was associated with higher frequency of Tfh-like cells (P &lt; 0.01 to all). Patients with triple negative had higher frequency of Tfh-like cells than those with Luminal A (difference, 6.83; P = 0.0006) and Luminal B (HER2-) (difference, 4.61; P = 0.0124). These results indicate that higher frequency of Tfh-like cells could have negative prognostic influence. Conclusions: Our study defined a PD1 hi Bcl6 + CXCL13 + CD4 + IL-21 + T cell subpopulation. Higher frequency of Tfh-like cells is more likely to be seen in patients with poor prognosis.