Hyaluronan heterogeneity in pancreatic ductal adenocarcinoma, primary tumors, and sites of metastasis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16231-e16231
Author(s):  
Veronica Placencio-Hickok ◽  
Marie Lauzon ◽  
Natalie Moshayedi ◽  
Michelle Guan ◽  
Sungjin Kim ◽  
...  

e16231 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with an estimated five-year survival rate of 10%. The dense desmoplastic stroma in PDAC contributes to its aggressive nature and treatment resistance. Among the components comprising the stroma, hyaluronan (HA) has been demonstrated to play a critical role in tumor progression and survival. Previous preliminary studies have suggested differences in HA expression in primary and metastatic foci in PDAC. However, the effects of treatment and location of HA expression as well as the role of CD44, a known receptor for HA, on HA as a biomarker signature remain unknown. Thus, we investigated the potential of HA as a biomarker in primary PDAC and metastases. Methods: PDAC tissue from primary (n = 43) and metastatic (n = 66) sites were obtained from Cedars-Sinai Medical Center along with associated clinical data. Tissue slides were stained with H&E, HA using a histochemical assay, and CD44 by immunohistochemistry. HA staining was scored according to the proportion of stromal staining at an intensity greater than the background stroma. HA status was defined as ≥ 50% staining being HA high and < 50% as being HA low. CD44 staining was recorded as an H-score (percentage of tumor cells staining multiplied by intensity of staining on a scale from 0 to 3). Associations between HA levels and the requested variables were examined with t-test, Wilcoxon rank-sum test, Chi-squared test, Fisher’s exact test, or Cox regression model where appropriate. Kaplan-Meier curves were created to assess progression free survival and overall survival. Analyses were performed using SAS 9.4 with two-sided tests and a significance level of 0.05. Results: HA score was significantly higher in primary PDAC tissue compared to sites of metastases (p = 0.0148). Within the metastases, HA score was significantly higher in liver metastasis compared to other sites of metastasis (p = 0.0478). In the liver metastasis tissue, HA score trended lower in patients with previously treated tissue compared to treatment naïve tissue (p = 0.0622). In the treatment naive liver metastasis cohort, patients with HA high status had decreased progression free survival and overall survival compared to patients with HA low status (p = 0.0032 and p = 0.0478, respectively). Using HA score and CD44 in a Cox regression model demonstrated that for every one unit increase in HA score, the risk for recurrence/progression increased by 4.4% at any fixed point in time, adjusting for CD44 score (p = 0.0049). Conclusions: HA score is variable between primary PDAC, PDAC metastatic to the liver, and PDAC metastatic to other sites. Within liver metastases, patients with HA high status had decreased progression free survival and overall survival compared to patients with HA low status. HA levels can serve as a potential biomarker to guide pancreatic cancer treatments and trial design for agents targeting the stroma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15204-e15204
Author(s):  
Michael Adam Poch ◽  
Diana Mehedint ◽  
Alexandra Curtis ◽  
Kristopher Attwood ◽  
Gregory E. Wilding ◽  
...  

e15204 Background: Epidemiological studies indicate that the use of calcium channel blockers (CCB) is inversely related to prostate cancer (PCa) incidence. The goal of this study was to examine the association between CCB use and PCa aggressiveness at the time of radical prostatectomy (RP) or outcome after RP. Methods: Information on medication use, PCa aggressiveness and outcome after RP was retrieved from a prospective database that contains clinical and follow-up (FU) data for all men that have undergone RP at the Department of Urology at Roswell Park Cancer Institute since 1992. The database was queried for anti-hypertensive medication use at the time of diagnosis for all patients with ≥ 1 year FU. Prostate cancer aggressiveness (risk status) and recurrence were defined using NCCN guideline definitions. Cox regression models were performed to compare the distribution of progression-free survival (PFS) and overall survival (OS) with adjustment for covariates. Chi-Square test was used to assess the relationship between CCB use and PCa aggressiveness. Results: 875 men were included in the study. At diagnosis, mean age was 60 (SD ± 7) years and mean serum PSA value was 7.4 (SD ±7.4) ng/ml. 48%, 37%, and 15% of patients had low risk, intermediate risk, or high risk PCa, respectively. 104 (12%) had a history of CCB use. CCB users and non-users were similar by PSA at diagnosis (p=0.97) and tumor aggressiveness (p=0.88). Patients taking CCB were more likely to be older (p=0.023), have a higher BMI (p=0.006) and use additional anti-hypertensive medications (p<0.01). Margin status after radical prostatectomy was similar (p=0.30) between the two groups. Median FU was 42 months. PFS (p=0.82, HR 95% CI: 0.63-1.44) and OS (p=0.72, HR 95% CI: 0.42-3.52) did not differ between the 2 groups. Adjusting for age and PCa aggressiveness did not alter the results observed for PFS (p=0.44, HR 95% CI: 0.62–1.41) and OS (p=0.50, HR 95% CI: 0.04-3.48). PCa aggressiveness was associated with PFS (p=0.001) in the multivariate model. Conclusions: CCB use does not affect PCa aggressiveness at time of diagnosis or improve PFS or OS.


2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 146-146
Author(s):  
Avivit Peer ◽  
Maya Ish-Shalom ◽  
Natalie Maimon ◽  
Maya Gottfried ◽  
Ben Boursi ◽  
...  

146 Background: Abi is a standard treatment (tx) in pts with mCRPC refractory to deocetaxel. It is a potent and selective CYP 17 inhibitor that blocks the synthesis of androgens in the testis, adrenal glands, and prostate. However, in many countries where abi has not been approved yet, keto is used as an alternative CYP 17 inhibitor. Although preclinical data suggests that keto is a less specific and potent inhibitor of CYP 17, there are limited clinical data comparing both agents. We aimed to compare the clinical effectiveness of abi vs keto in pts with mCRPC refractory to D. Methods: Records from 156 mCRPC pts treated with keto 200 - 400 mg 3x day, in 4 centers across the US and Israel, were reviewed retrospectively. 26 pts treated post D were individually matched by clinicopathologic factors to pts treated with abi (selected from a multicenter Israeli database, n=120). We compared the PSA response (decrease ≥50% from baseline), biochemical and radiological progression free survival, and overall survival between the groups. Progression free survival and overall survival were determined by Cox regression. Results: The groups were matched by Gleason score, pre-tx disease extent (limited-axial skeleton and/or nodal vs extensive- appendicular skeleton and/or visceral), ECOG PS, pre-tx risk category (favorable, intermediate, poor; Keizman, Oncologist 2012). Furthermore, they were balanced regarding median age (71 abi vs 69 keto), time from primary tx to disease relapse, time to progression on prior GnRH-a and antiandrogen, PSA response and time to progression on prior D, pre-tx pain score/alkaline phosphatase/hemoglobin/ neutrophil to lymphocyte ratio/PSADT/PSA. In the groups of abi vs keto, PSA response was 46% vs 19% (OR 4.4, p=0.043), median biochemical PFS 7 vs 2 months (HR 0.65, p=0.02), median radiological PFS 6 vs 2.5 months (HR 0.63, p=0.016), median overall survival 17 vs 12 months (HR 0.53, p=0.79), and tx interruption d/t adverse events 12% vs 23% (0R 0.6, p=0.023). Conclusions: In mCRPC refractory to D, the outcome of pts treated with abiraterone was superior to ketoconazole.


Blood ◽  
2014 ◽  
Vol 123 (4) ◽  
pp. 494-500 ◽  
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Giuseppe Saglio ◽  
Juan Luis Steegmann ◽  
Neil P. Shah ◽  
...  

Key Points In a 3-year follow-up of the DASatinib versus Imatinib Study In treatment-Naive CML patients trial, first-line dasatinib resulted in faster and deeper responses compared with imatinib. Deeper responses at 3, 6, and 12 months were associated with better 3-year progression-free survival and overall survival.


2017 ◽  
pp. 1-12 ◽  
Author(s):  
Dawn L. Hershman ◽  
Cathee Till ◽  
Jason D. Wright ◽  
Scott Ramsey ◽  
William E. Barlow ◽  
...  

Purpose Diabetes is common, increases with age, and may affect outcomes among people with cancer. Understanding the association between diabetes and cancer outcome is challenging, because patients with diabetes have increased all-cause mortality compared with patients without diabetes. Methods We systematically examined the phase III trial database of SWOG to identify patients enrolled in trials during the period from 1999 to 2011. We linked the SWOG clinical records to Medicare claims data according to Social Security number, sex, and date of birth. Medicare claims were used to identify diabetes with at least 6 months of continuous Medicare coverage immediately before registration. Multivariable Cox regression was used to compare survival outcomes between patients with and without diabetes for each of 10 tumor cohorts. The primary outcome was overall survival. We also examined progression-free survival and cancer-free survival. Results In total, 6,422 patients from 15 trials were ≥ 65.5 years of age, of whom 3,173 patients (49%) met the criteria for linkage to Medicare claims. Thirty percent (n = 952) had claims for diabetes before registration. Patients with diabetes were more likely to be black ( P < .001), but no other differences in demographic characteristics were observed. In multivariable Cox regression, no association was found between baseline diabetes and overall or progression-free survival; in one case, patients with diabetes had marginally worse cancer-free survival (advanced non–small-cell lung cancer; P = .05). A global test found that baseline diabetes was associated with worse overall survival ( P = .03) across the entire panel of analyses. Conclusion Diabetes is common among elderly patients enrolled in clinical trials. Unlike prior observational studies, among patients treated with uniform treatment regimens, and controlling for known prognostic factors, we did not observe an association between diabetes and progression-free or cancer-free survival.


2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 352-352 ◽  
Author(s):  
Thomas Jens Ettrich ◽  
Lukas Perkhofer ◽  
Volker Kaechele ◽  
Andreas W. Berger ◽  
Melanie Guethle ◽  
...  

352 Background: Pancreatic ductal adenocarcinoma still remains a major cause of cancer related deaths in the western world. The current study was conducted to confirm the activity and feasibility of docetaxel/ oxaliplatin combination in second line treatment of advanced pancreatic ductal adenocarcinoma. Methods: Prospective single arm, non-randomized, multi-center, Simon’s two stage phase II trial using docetaxel (75 mg/m2, 60 min, d 1) and oxaliplatin (80 mg/m2, 120 min, d 2) in 21-day cycles. Duration of the trial was scheduled up two 8 cycles. Primary endpoint was tumor response according to RECIST 1.0. Secondary endpoints were progression free survival, overall survival, safety/toxicity, quality of life and clinical benefit. Results: Data represents the intention to treat analysis of 44 patients included between 2008 and 2012. The majority of patients received a gemcitabine based first-line chemotherapy (95.5%). The primary endpoint of tumor response was achieved in 15.9% (7 partial remissions, no complete remission), with a disease control rate of 48% after the first two treatment cycles. Median progression free survival was 7 weeks (CI 6-15.9 weeks) and overall survival 40 weeks (CI 20.4-56.4 weeks). No unexpected adverse events occured. The recorded AEs were mainly hematologic (neutropenia grade 3/4 63.6%, febrile neutropenia 4.6%), gastrointestinal (29.6% grade 3/4 AEs) and infectious (18.2% grade 3/4 AEs). Conclusions: In this single-arm second line trial for the treatment of advanced PDAC, the combination of docetaxel and oxaliplatin shows promising results comparable with other second line protocols such as OFF (oxaliplatin, 5-FU, leucovorin) or liposomal irinotecan (MM-398) plus 5-FU/leucovorin (NAPOLI 1-trial). Some patients seem to benefit particularly as indicated by long periods of treatment in this setting. Even after 8 cycles of treatment with DocOx, partial response was observed in 2 patients and stable disease in another 6 patients corresponding to a disease control rate of 18%. The toxicity profile was quite tolerable and comparable to other second line studies. Clinical trial information: NCT00690300.


Author(s):  
Dorota Lubgan ◽  
Sabine Semrau ◽  
Ulrike Lambrecht ◽  
Udo S. Gaipl ◽  
Rainer Fietkau

Abstract Purpose The aim of this study was to evaluate the safety and long-term tumor control after stereotactic radiotherapy (SRT) with 12 × 6 Gy of patients with primary bronchial carcinoma (BC) or with pulmonary metastases (MET) of various solid tumors. Local progression-free survival (LPFS), progression-free survival (PFS), overall survival (OS), and prognostic factors were compared. Methods Between May 2012 and January 2020, 168 patients with 206 pulmonary lesions (170 MET and 36 primary BC) were treated with 12 × 6 Gy (BED10 116 Gy). The irradiated pulmonary MET were from the following cancers: 47 (27.6%) head and neck, 37 (21.8%) rectum or colon, 30 (17.6%) bronchial, 13 (7.6%) malignant melanoma, 9 (5.3%) esophageal, 9 (5.3%) sarcoma, and 25 (14.8%) other. Results The median follow-up was 16.26 months (range: 0.46–89.34) for BC and 19.18 months (0.89–91.11) for MET. Survival rates at 3 years were: OS 43% for BC and 35% for MET; LPFS BC 96% and MET 85%; PFS BC 35% and MET 29%. The most frequently observed grade 3 adverse events (AEs) were pneumonitis (5.9% BC, 4.8% MET), pulmonary fibrosis (2.9% BC, 4% MET), and pulmonary embolism (2.9% BC, 0.8% MET). The favorable prognostic effects on overall survival of patients with MET were female gender (log-rank: p < 0.001), no systemic progression (log-rank; p = 0.048, multivariate COX regression p = 0.039), and malignant melanoma histology (log-rank; p = 0.015, multivariate COX regression p = 0.020). For patients with BC, it was tumor location within the lower lobe (vs. upper lobe, log-rank p = 0.027). LPFS of patients with metastatic disease was beneficially influenced by female gender (log-rank: p = 0.049). Conclusion The treatment concept of 12 × 6 Gy is associated with 96% local progression-free survival for BC and 85% for pulmonary metastases after 3 years. There was no difference in response after SRT of primary lung carcinoma or pulmonary metastases.


2021 ◽  
Author(s):  
Aitao Nai ◽  
SHOAIB BASHIR ◽  
Ling Jin ◽  
Zirui He ◽  
Shuwen Zeng ◽  
...  

Abstract Background: Interleukin-11 receptor subunit alpha (IL-11RA) contributes to multiple biological processes in various tumors. However, the role of IL-11RA in Lung adenocarcinoma (LUAD) is still undetermined. The study aims to explore the role of IL-11RA in LUAD via an integrated bioinformatics analysis. Methods: TIMER, GEPIA, TCGA and HPA databases analysis were used to detect IL-11RA expression. UALCAN database was used to analysis the correlation between IL-11RA expression and clinicopathological parameters of LUAD. Kaplan-Meier Plotter, TCGA and GEO databases were used to analysis overall survival (OS) and progression-free survival (PFS) of the LUAD patients. Univariate Cox regression analysis was used to assess the prognostic value of IL-11RA in different clinical characteristics. GSEA, and TIMER were used to investigate the relationship between IL-11RA and immune infiltration.Results: The expression of IL-11RA was down-regulated in LUAD tissues. Furthermore, IL-11RA expression was closely associated with clinical stage, lymph node stage and smoking habits. The patients with lower IL-11RA expression had poorer overall survival (OS) and progression-free survival (PFS). Lower IL-11RA expression was significantly associated with its hypermethylation, and the hypermethylation of CpG site at cg14609668 and cg21504624 was obviously correlated with poorer OS. Then, we found that IL-11RA may play an important role in LUAD progression and immune regulations. Notably, High expression of IL-11RA may suppress the progression of LUAD through inhibiting cell proliferation and immune cell infiltration, especially in B cells, CD4+ T cells, and Dendritic Cell. Conclusions: Decreased IL-11RA expression correlates with poor prognosis and immune infiltration in LUAD. Our work highlights IL-11RA might be a potential biomarker for prognosis and provide a new therapeutic target for LUAD patients.


BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Se Jun Park ◽  
Hyunho Kim ◽  
Kabsoo Shin ◽  
Tae Ho Hong ◽  
Ja Hee Suh ◽  
...  

Abstract Background According to the NAPOLI-1 trial, nanoliposomal irinotecan (nal-IRI) plus fluorouracil/folinic acid (5-FU/LV) showed improved overall survival compared to fluorouracil alone for patients with metastatic pancreatic cancer who were previously treated with gemcitabine-based therapy. In that trial, Asian patients had frequent dose modification due to haematological toxicity. There has been limited information on the clinical benefits and toxicity of this regimen in real-world settings. In this study, we assessed real-world experience of nal-IRI plus 5-FU/LV in patients with advanced pancreatic cancer after gemcitabine failure. Methods We conducted a single institution, retrospective analysis of response, survival and safety in patients who had been treated with nal-IRI with 5-FU/LV. Patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy received nal-IRI (80 mg/m2) with 5-FU/LV every 2 weeks. Kaplan-Meier analysis was performed to obtain median progression free survival and median overall survival. The hazard ratio and 95% confidence interval (CI) were estimated using a stratified Cox regression model. A multivariate Cox proportional hazards regression model was used to identify the effects of clinical factors. Results Fifty-one patients received nal-IRI plus 5-FU/LV between January 2015 and December 2020. The median age was 67 years, and males were 58.8%. A total of 40 (78.4%) and 11 (21.6%) patients had received one and two lines of prior chemotherapy before enrollment, respectively. Median progression-free survival was 2.8 months (95% CI 1.8–3.7) and median overall survival was 7.0 months (95% CI 6.0–7.9). Chemotherapy doses were reduced or delayed in 33 (64.7%) patients during the first 6 weeks and median relative dose intensity was 0.87. Thirty-six (70.6%) patients experienced grade 3 or 4 adverse events, most commonly neutropenia (58.8%). Most non-haematologic adverse events were under grade 2. Since the start of first-line chemotherapy, median overall survival was 16.3 months (95% CI 14.1–18.4). Conclusions Nal-IRI plus 5-FU/LV seems to be effective, with manageable toxicities, following gemcitabine-based treatment in patients with metastatic pancreatic ductal adenocarcinoma. Nal-IRI plus 5-FU/LV following gemcitabine with nab-paclitaxel is a feasible sequential treatment option in patients with metastatic pancreatic cancer. Trial registration Retrospectively registered.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4549-4549
Author(s):  
Matthew D. Tucker ◽  
Martin H Voss ◽  
Toni K. Choueiri ◽  
Mehmet Asim Bilen ◽  
Marc-Oliver Grimm ◽  
...  

4549 Background: Baseline NER has been reported to be associated with outcomes of immuno-oncology based combination treatment in advanced renal cell carcinoma (aRCC). We report outcomes by baseline NER of patients with aRCC in the JAVELIN Renal 101 trial who received avelumab + axitinib (A + Ax) or sunitinib (S). Methods: We calculated the median NER (mNER) for patients in the A + Ax and the S arms at the data cutoff (April 20, 2020) for the 3rd interim analysis (IA3). Progression-free survival (PFS), overall survival (OS), and objective response (OR) by NER are reported. Multivariate Cox regression analyses of PFS and OS were also conducted. Results: At the IA3 cutoff date, the mNERs for the A + Ax arm (n = 383) and S arm (n = 396) were 29.2 and 27.0, respectively. OR, PFS and OS for both arms are summarized in the table below. Better observed treatment outcomes in OR (63.9% vs 55.2%) and median PFS (15.5 vs, 11.1 months) were observed for patients with a NER < median vs. NER ≥ median in the A + Ax arm, while there were not major differences in outcome based on NER in the S arm. The stratified hazard ratio (HR) for PFS in patients with a NER < median compared with those with a NER ≥ median in the A + Ax arm was 0.81 (95% CI, 0.630-1.035) and 0.93 (95% CI, 0.728-1.181) in the S arm. Patients with a NER < median had improved OS compared with those with a NER ≥ median in the A + Ax arm (stratified HR, 0.67; 95% CI, 0.481-0.940) and the S arm (stratified HR, 0.57; 95% CI, 0.424-0.779). Multivariate analysis showed that a low NER was associated with longer PFS and OS by treating baseline NER as either a continuous variable or a binary variable (dichotomized by median). Conclusions: Baseline NER may be predictive of OR and PFS in aRCC patients treated with A + Ax, and prognostic for overall survival regardless of therapy. Clinical trial information: NCT02684006. [Table: see text]


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