scholarly journals Establishment of a pancreatic adenocarcinoma molecular gradient (PAMG) that predicts the clinical outcome of pancreatic cancer

Author(s):  
Rémy Nicolle ◽  
Yuna Blum ◽  
Pauline Duconseil ◽  
Charles Vanbrugghe ◽  
Nicolas Brandone ◽  
...  

AbstractBACKGROUNDA significant gap in pancreatic ductal adenocarcinoma (PDAC) patient’s care is the lack of molecular parameters characterizing tumors and allowing a personalized treatment. The goal of this study was to examine whole PDAC transcriptomic profiles to define a signature that would predict aggressiveness and treatment responsiveness better than done until now.METHODS AND PATIENTSTumors were obtained from 76 consecutive resectable (n=40) or unresectable (n=36) tumors. PDAC were transplanted in mice to produce patient-drived xenografts (PDX). PDX were classified according to their histology into five groups, from highly undifferentiated to well differentiated. This classification resulted strongly associated with tumors aggressiveness. A PDAC molecular gradient (PAMG) was constructed from PDX transcriptomes recapitulating the five histological groups along a continuous gradient. The prognostic and predictive value for PMAG was evaluated in: i/ two independent series (n=598) of resected tumors; ii/ 60 advanced tumors obtained by diagnostic EUS-guided biopsy needle flushing and iii/ on 28 biopsies from mFOLFIRINOX treated metastatic tumors.RESULTSA unique transcriptomic signature (PAGM) was generated with significant and independent prognostic value. PAMG significantly improves the characterization of PDAC heterogeneity compared to non-overlapping classifications as validated in 4 independent series of tumors (e.g. 308 consecutive resected PDAC, HR=0.321 95% CI [0.207;0.5] and 60 locally-advanced or metastatic PDAC, HR=0.308 95% CI [0.113;0.836]). The PAMG signature is also associated with progression under mFOLFIRINOX treatment (Pearson correlation to tumor response: -0.67, p-value < 0.001).CONCLUSIONWe identified a transcriptomic signature (PAMG) that, unlike all other stratification schemas already proposed, classifies PDAC along a continuous gradient. It can be performed on formalin-fixed paraffin-embedded samples and EUS-guided biopsies showing a strong prognostic value and predicting mFOLFIRINOX responsiveness. We think that PAMG could unify all PDAC preexisting classifications inducing a shift in the actual paradigm of binary classifications towards a better characterization in a gradient.Trial RegistrationThe PaCaOmics study is registered at www.clinicaltrials.gov with registration number NCT01692873. The validation BACAP study is registered at www.clinicaltrials.gov with registration number NCT02818829.

2016 ◽  
Vol 31 (2) ◽  
pp. 163-172
Author(s):  
Daniela Vivenza ◽  
Cristiana Lo Nigro ◽  
Nerina Denaro ◽  
Mirella Fortunato ◽  
Martino Monteverde ◽  
...  

Purpose HPV-related locally advanced head and neck cancers (LA-HNCs) show a good prognosis. This study aimed to investigate the HPV prevalence in LA-HNCs and compare the prognostic value of E1, E6 and L1 genomic viral fragments and p16, individually and in combination, in order to find the best prognosticator in terms of overall survival (OS) and progression-free survival (PFS). Patients and Methods HPV16 was searched in 255 LA-HNC formalin-fixed paraffin-embedded tumor tissues, 89 oropharyngeal cancers (OPCs), and 166 non-OPCs by DNA-PCR with 3 primer pairs. p16 was analyzed by immunohistochemistry in 235 patients. Results The prevalence of positive samples decreased constantly from E6 to L1 and E1 in both OPCs and non-OPCs. Each LA-HNC patient highlighted variable positivity for each fragment. OPCs showed a higher prevalence of positive samples compared to non-OPCs. Positive coexistence of all the fragments was more common in OPCs (31.5%) than non-OPCs (4.2%), and E1 detection was always associated with E6 and L1. E1-positive OPCs showed improved OS (p = 0.012) and PFS (p = 0.036), while L1- or E6-positive ones did not. p16-positive patients were more prevalent in the OPC (29.8%) than the non-OPC group (7.3%) (p<0.0001) and its prognostic value was not superior to that of E1. However, the multivariate Cox analysis which included E1, L1, E6 status and p16 expression did not show a significant p value. Conclusions Though HPV16 positivity measured by DNA-PCR was higher for L1 and E6, they performed weakly as prognosticators; E1 might become a strong prognostic marker for OS and PFS in OPCs.


2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A283-A283
Author(s):  
Gulam Manji ◽  
Nathan Bahary ◽  
Vincent Chung ◽  
Florence Dalenc ◽  
Michel Ducreux ◽  
...  

BackgroundThe MORPHEUS platform comprises multiple randomized Phase Ib/II trials to identify early safety and efficacy signals for treatment combinations across cancers. Seli interacts with CD40 on antigen presenting cells, resulting in activation and priming of CD8 T-cells. Atezo (anti-PD-L1)+seli (CD40 agonist) was evaluated with gem+nabP for pancreatic ductal adenocarcinoma (PDAC), or with bev for triple-negative breast cancer (TNBC) and colorectal cancer (CRC).MethodsMORPHEUS-PDAC, MORPHEUS-TNBC and MORPHEUS-CRC enrolled 1L metastatic (m) PDAC, 2L locally advanced or mTNBC or 3L mCRC patients, respectively. Experimental arm patients received atezo (840 mg IV q2w) and seli (16 mg SC on D1 every 28-day cycle for C1-4 and every third cycle thereafter). Patients also received gem (1000 mg/m2) and nabP (1000 mg/m2, 125 mg/m2 respectively, IV on D1, 8, 15 every 28-day cycle) in PDAC or bev (10 mg/kg IV q2w) in TNBC and CRC. Control treatments were gem+nabP in PDAC, capecitabine in TNBC, and regorafenib in CRC. Primary endpoints were safety and objective response rate (ORR; investigator-assessed RECIST 1.1). PD-L1 and CD8/panCK IHC were tested in all biopsies.ResultsAll treated patients were safety evaluable. MORPHEUS-PDAC (20-week interim analysis): 9 patients received atezo+seli+gem+nabP and 4 received control. Treatment-related adverse events (TRAEs) were seen in all. Treatment-related serious AEs (SAEs) occurred in 6 patients (67%) receiving atezo+seli+gem+nabP and 1 (25%) receiving control. Confirmed ORRs: 44% (95%CI:14–79) and 25% (95%CI:6–81), respectively. MORPHEUS-TNBC (27-week interim analysis): 6 patients received atezo+seli+bev and 24 received control. TRAEs were seen in 5 patients (83%) receiving atezo+seli+bev and 18 (75%) receiving control. Treatment-related SAEs occurred in 1 patient in each arm (17% and 4%, respectively). Confirmed ORRs: 17% (95%CI:0.4–64) and 21% (95%CI:7–42), respectively. All 6 patients receiving atezo+seli+bev were PD-L1 negative (SP142 IHC assay) at baseline; the only patient with partial response (PR) showed upregulation of PD-L1 expression at week 3. MORPHEUS-CRC (18-week interim analysis): 6 patients received atezo+seli+bev and 13 received control. TRAEs were seen in all patients receiving atezo+seli+bev and 12 (92%) receiving control. Treatment-related SAEs occurred in 3 patients (50%) receiving atezo+seli+bev and 1 (8%) receiving control. No responses occurred in either study arm. Paired biopsies for 3 patients (60%) receiving atezo+seli+bev suggest on-treatment increases in CD8 T-cell infiltration into tumors.ConclusionsToxicities related to the atezo+seli combinations were consistent with individual study treatments. Preliminary efficacy was observed for atezo+seli+gem+nabP in PDAC. Together with preliminary evidence of on-treatment pharmacodynamic effects in CRC and TNBC tumor samples, CD40 agonist strategies warrant further investigation.Trial RegistrationMORPHEUS-PDAC: NCT03193190; MORPHEUS-TNBC: NCT03424005; MORPHEUS-CRC: NCT03555149.Ethics ApprovalThe trial was conducted according to the principles of the Declaration of Helsinki. All patients provided written informed consent. Protocol approval was obtained from independent review boards or ethics committees at each site.


2019 ◽  
Vol 9 (02) ◽  
Author(s):  
Haider S Al-Hadad ◽  
Aqeel Abbas Matrood ◽  
Maha Abdalrasool Almukhtar ◽  
Haider Jabur Kehiosh ◽  
Riyadh Muhi Al-Saegh

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease. Few biomarkers for SLE have been validated and widely accepted for the laboratory follow-up of inflammatory activity. In SLE patients, with lupus nephritis (LN), complement activation leads to fluctuation of serum C3 and C4 that are frequently used as clinicalm biomarker of disease activity in SLE. Patients and Methods: In this study the number of patients were 37, seven patients were excluded for incomplete data collection, 28 were females ,2 were males. The duration of the study is two years from 2015 to 2017. Patients were considered to have SLE and LN according to American College of Rheumatology (ACR) criteria, and International Society of Nephrology/ Renal Pathology Society (ISN/RPS). All patients were evaluated withm clinical presentation, laboratory investigations. Our patients underwent kidney biopsy according to standard procedure by Kerstin Amann, and their tissue specimens were studied in the laboratory with light microscope (LM) and immunofluorescence microscope reagents. The relationship between the serological markers and immunofluorescence deposits in kidney biopsy of all patients were studied using the statistical analysis of Pearson correlation and single table student's T test. A P value 0.05 was considered statistically significant. Results: The granular pattern of IF deposits was present in all LN patients, and in more than two third of patients these IF deposits presented in glomerular, tubular, and mesangium sites. While less than one third of patients had IF deposits in the mesangium only. There was no statistically significant correlation between serum ANA, anti-dsDNA, and IF deposits of different types. There was significant correlation between serum C3 and C4 hypocomplementemia and IgG immune deposits in kidney biopsy, and there was significant relationship between serum C3 hypocomplementemia and full house immunofluorescence (FHIF) deposits inm kidney biopsy.Conclusions:Immunofluorescence deposits is mainly granular pattern in LN patients. There was no significant association between serum ANA, anti-dsDNA, and immune deposits in kidney tissue. Immunofluorescence deposits of IgG type correlates significantly with serum C3 and C4 hypocomplemetemia, and these immune deposits in association with low complement levels correlates with LN flare. There was significant correlation between C3 hypocomplementemia and FHIF.


2016 ◽  
Vol 4 (1) ◽  
pp. 3-7
Author(s):  
Tanka Prasad Bohara ◽  
Dimindra Karki ◽  
Anuj Parajuli ◽  
Shail Rupakheti ◽  
Mukund Raj Joshi

Background: Acute pancreatitis is usually a mild and self-limiting disease. About 25 % of patients have severe episode with mortality up to 30%. Early identification of these patients has potential advantages of aggressive treatment at intensive care unit or transfer to higher centre. Several scoring systems are available to predict severity of acute pancreatitis but are cumbersome, take 24 to 48 hours and are dependent on tests that are not universally available. Haematocrit has been used as a predictor of severity of acute pancreatitis but some have doubted its role.Objectives: To study the significance of haematocrit in prediction of severity of acute pancreatitis.Methods: Patients admitted with first episode of acute pancreatitis from February 2014 to July 2014 were included. Haematocrit at admission and 24 hours of admission were compared with severity of acute pancreatitis. Mean, analysis of variance, chi square, pearson correlation and receiver operator characteristic curve were used for statistical analysis.Results: Thirty one patients were included in the study with 16 (51.61%) male and 15 (48.4%) female. Haematocrit at 24 hours of admission was higher in severe acute pancreatitis (P value 0.003). Both haematocrit at admission and at 24 hours had positive correlation with severity of acute pancreatitis (r: 0.387; P value 0.031 and r: 0.584; P value 0.001) respectively.Area under receiver operator characteristic curve for haematocrit at admission and 24 hours were 0.713 (P value 0.175, 95% CI 0.536 - 0.889) and 0.917 (P value 0.008, 95% CI 0.813 – 1.00) respectively.Conclusion: Haematocrit is a simple, cost effective and widely available test and can predict severity of acute pancreatitis.Journal of Kathmandu Medical College, Vol. 4(1) 2015, 3-7


2019 ◽  
Vol 20 (9) ◽  
pp. 2082
Author(s):  
Chiara Zanusso ◽  
Eva Dreussi ◽  
Roberto Bortolus ◽  
Chiara Romualdi ◽  
Sara Gagno ◽  
...  

Up to 30–50% of patients with locally advanced prostate cancer (PCa) undergoing radiotherapy (RT) experience biochemical recurrence (BCR). The immune system affects the RT response. Immunogenetics could define new biomarkers for personalization of PCa patients’ treatment. The aim of this study is to define the immunogenetic biomarkers of 10 year BCR (primary aim), 10 year overall survival (OS) and 5 year BCR (secondary aims). In this mono-institutional retrospective study, 549 Caucasian patients (a discovery set n = 418; a replication set n = 131) were affected by locally advanced PCa and homogeneously treated with RT. In the training set, associations were made between 447 SNPs in 77 genes of the immune system; and 10 year BCR and 10 year OS were tested through a multivariate Cox proportional hazard model. Significant SNPs (p-value < 0.05, q-value < 0.15) were analyzed in the replication set. Replicated SNPs were tested for 5 year BCR in both sets of patients. A polymorphism in the PDL1 gene (rs4143815) was the unique potential genetic variant of 10 year BCR (training set: p = 0.003, HR (95% CI) = 0.58 (0.41–0.83); replication set: p = 0.063, HR (95% CI) = 0.52 (0.26–1.04)) that was significantly associated with 5 year BCR (training set: p = 0.009, HR (95% CI) = 0.59 (0.40–0.88); replication set: p = 0.036, HR (95% CI) = 0.39 (0.16–0.94)). No biomarkers of OS were replicated. rs4143815-PDL1 arose as a new immunogenetic biomarker of BCR in PCa, giving new insights into the RT/immune system interaction, which could be potentially useful in new approaches using anti-PDL1 therapies for PCa.


2013 ◽  
Vol 01 (01) ◽  
pp. 001-003
Author(s):  
Aruna Singh ◽  
Nymphea Pandit ◽  
Monica Sharma

Abstract Aim- 1. The aim of this study was to investigate the average maximum range of inter-incisal mouth opening in a representative sample of the adult subjects of Haryana. 2. To see any correlation between maximal inter-incisal opening with age. Methods- Maximum mouth opening was studied in 756 adult subjects with age range of 20-50 years in Yamunanagar, Haryana. Age limit was further divided into three groups (20-30, 31-40, 41-50). Those with clinical history of TMJ involvement, OSMF, any trauma, odontogenic and non-odontogenic infections, dental prosthesis on the anterior teeth, congenital anomalies in the maxillofacial region were excluded from this study. The measurements were recorded twice and mean of the two values were taken. Statistical Analysis- Independent sample t-test was calculated to compare age and mouth opening in both male and females respectively. Bivariate pearson correlation was used to see any relationship between age and mouth opening. P-value ≤ 0.05 and CI (confidence interval) at 95% were considered statistically significant. The Results- The average mouth opening of males (45.36±6.70 mm) subjects was higher as compared to female (41.27 ± 6.75 mm) with significant, p-value 0.000. The mean mouth opening ± SD for both sexes combined was 43.39 ± 7.02 mm. The corresponding values for mean inter-incisal opening in male population aged 20-30, 31-40, 41-50 were 45.52 ± 7.15, 46.16 ± 5.47, 42.96 ± 6.82 mm and in female population aged 20-30, 31-40, 41-50 were 41.40 ± 7.08, 41.60 ± 6.29 and 40.03 ± 6.38 mm respectively. Conclusion- Maximal mouth opening differ significantly with gender. There is a decrease in MMO with older age group.


2021 ◽  
pp. 026921552110068
Author(s):  
Elien Van der Gucht ◽  
Lore Dams ◽  
Vincent Haenen ◽  
Lode Godderis ◽  
Bart Morlion ◽  
...  

Objective: To synthesize the evidence on the effectiveness of pain science education on pain, psychological factors and physical functioning in adults who underwent surgery. Data sources: A systematic literature search of English articles using PubMed/Medline, Embase, Web of Science Core Collection, and Cochrane Library. Review methods: The search strategy was constructed as follows: (((pain) AND (education)) OR (pain education)) AND (surgery). Only controlled quantitative studies in adults reporting outcome(s) on pain, psychological factors and/or physical functioning were included. Risk of bias was assessed using the Cochrane risk of bias tools. P-values and corresponding effect sizes for interaction-effect (time × group) portrayed the difference in change over time between groups were of interest. The last search was conducted on February 28, 2021. Results: Nine papers ( n = 1078) were deemed eligible for this review. Two randomized controlled trials showed significant interaction effects. Breast cancer patients who had received one preoperative pain science education session showed a significant increase in postoperative pain compared to controls ( P-value = 0.0394). Furthermore, p sychological factors (pain catastrophizing and kinesiophobia) decreased in participants who had received pain science education before total knee arthroplasty, while this was not the case in the control group ( P-value < 0.001, ƞ2p:0.11). Conclusions: Overall, pain science education did not result in any significant postoperative effects on pain, psychological factors and/or physical functioning compared to controls. There is currently no strong evidence for the implementation of pain science education in the perioperative period. Registration number: PROSPERO: ID 161267, registration number CRD42020161267


Endoscopy ◽  
2021 ◽  
Author(s):  
Jeevinesh Naidu ◽  
Dylan Bartholomeusz ◽  
Joshua Zobel ◽  
Romina Safaeian ◽  
William Hsieh ◽  
...  

Aim: This study evaluated clinical outcomes of combined chemotherapy and Endoscopic Ultrasound (EUS) guided intra-tumoral radioactive phosphorus-32 (32P OncoSil) implantation in locally advanced pancreatic adenocarcinoma (LAPC). Methods: Consecutive patients with a new histological diagnosis of LAPC were recruited over 20 months. Baseline CT and 18FDG PET-CT were performed and repeated after 12 weeks to assess response to treatment. Following 2 cycles of conventional chemotherapy, patients underwent EUS-guided 32P OncoSil implantation followed by a further six cycles of chemotherapy. Results: Twelve patients with LAPC (8M:4F; median age 69 years, IQR 61.5-73.3) completed the treatment. Technical success was 100% and no procedural complications were reported. At 12 weeks, there was a median reduction of 8.2cm3 (95% CI 4.95-10.85; p=0.003) in tumour volume, with minimal or no 18FDG uptake in 9 (75%) patients. Tumour downstaging was achieved in 6 (50%) patients, leading to successful resection in 5 (42%) patients, of which 4 patients (80%) had clear (R0) resection margins. Conclusions: EUS guided 32P OncoSil implantation is feasible and well tolerated and was associated with a 42% rate of surgical resection in our cohort. However, further evaluation in a larger randomized multicenter trial is warranted. (32P funded by OncoSil Medical Ltd, equipment and staff funded by the Royal Adelaide Hospital, ClinicalTrials.gov number, NCT03003078).


2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1848.2-1849
Author(s):  
M. A. Mortada ◽  
H. Eitta ◽  
R. Elmallah ◽  
A. Radwan ◽  
A. Elsaman

Background:Musculoskeletal Ultrasonography (MSUS) is now a widely used tool for monitoring of rheumatoid arthritis (RA). Although there are many proposed sets of composite scores, a fixed set of joints may not be an ideal tool to assess a disease like RA, which affects many joints and tendons in different presentations. In previous study (1) U9 score was proven to be correlated with disease activity parameters.Objectives:To determine whether US assessment using U9 score is useful for monitoring response to treatment for RA or not?Methods:A prospective, multicenter study were conducted in period from July 2019 to December 2019. All recruited RA patients were subjected to: Disease activity assessment by clinical disease activity indices (CDAI and DAS28 ESR). Functional status assessment by (HAQ) and ultrasonographic assessment using U9 score which include 8 joints (bilateral wrists,2ndMCP,3RDMCP and knees) plus most clinically affected joint or tendon (one joint or one tendon). Most clinically affected joints from 48 joints. Any affected tendons could be choosing. All targeted joints were evaluated according to EULAR guidlines and by EULAR/ OMERACT combined score (0-3). Targeted tendons were scored (0-3).All patients received their treatment (biologic and non biologic DMARDs) according to the decision of the treating physicians. No specific therapy is needed. CDAI and DAS28 ESR, HAQ and U9 score were repeated after 3 months to detect the response to change after receiving the therapy.Results:One hundred and forty patients (23.6% were male) with mean age 39.26±11.30 were recruited from 4 tertiary referral university hospitals.There was a significant difference (<0.001) between the first and second visits as regards clinical, laboratory and ultrasonographic parameters. DAS 28 decreased form (5.29±1.21) to (3.95±0.99), ESR decreased from (42.12±15.24) to (26.84±12.32), HAQ2 improved from (0.652±0.350) to (0.510±0.237) and U9 total US score decreased from (13.56±5.18) to (8.02±4.28).There was significant correlation between U9 ultrasonographic score and clinical parameters at both visits (table 1).Table 1.correlation between U9 ultrasonographic score and clinical parameters.U9 at 1stvisitU9 at 2ndvisitDAS-28Pearson Correlation(P value)0.806<0.0010.790<0.001CDAIPearson Correlation(P value)0.787<0.0010.773<0.001HAQPearson Correlation(P value)0.431<0.0010.317<0.001We found that the most suitable cut-off value of U9 score to predict high disease activity was 11.5 (sensitivity 85.7% and specificity 80.6%), cut off value for moderate disease activity was 5.5(sensitivity 83.2% and specificity 88%) and cut off value for low disease activity was 3.5 (sensitivity of 83.3% and specificity 57.1%). These results are summarized in the following table:Conclusion:U9 ultrasonographic score is very useful method for evaluating the monitoring the response of treatment.References:[1]Mortada, et al. Annals of the Rheumatic Diseases 2019;78:1009.Disclosure of Interests:None declared


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