scholarly journals Mitochondrial DNA and MitomiR Variations in Pancreatic Cancer: Potential Diagnostic and Prognostic Biomarkers

2021 ◽  
Vol 22 (18) ◽  
pp. 9692
Author(s):  
Loredana Moro
Keyword(s):  
Pancreatic Cancer ◽  
Current Knowledge ◽  
Locally Advanced ◽  
Prognostic Biomarkers ◽  
Mitochondrial Proteins ◽  
Ductal Adenocarcinoma ◽  
Metastatic Progression ◽  
Response To Chemotherapy ◽  
Personalized Cancer Therapy ◽  
Personalized Cancer

Pancreatic cancer is an aggressive disease with poor prognosis. Only about 15–20% of patients diagnosed with pancreatic cancer can undergo surgical resection, while the remaining 80% are diagnosed with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). In these cases, chemotherapy and radiotherapy only confer marginal survival benefit. Recent progress has been made in understanding the pathobiology of pancreatic cancer, with a particular effort in discovering new diagnostic and prognostic biomarkers, novel therapeutic targets, and biomarkers that can predict response to chemo- and/or radiotherapy. Mitochondria have become a focus in pancreatic cancer research due to their roles as powerhouses of the cell, important subcellular biosynthetic factories, and crucial determinants of cell survival and response to chemotherapy. Changes in the mitochondrial genome (mtDNA) have been implicated in chemoresistance and metastatic progression in some cancer types. There is also growing evidence that changes in microRNAs that regulate the expression of mtDNA-encoded mitochondrial proteins (mitomiRs) or nuclear-encoded mitochondrial proteins (mitochondria-related miRs) could serve as diagnostic and prognostic cancer biomarkers. This review discusses the current knowledge on the clinical significance of changes of mtDNA, mitomiRs, and mitochondria-related miRs in pancreatic cancer and their potential role as predictors of cancer risk, as diagnostic and prognostic biomarkers, and as molecular targets for personalized cancer therapy.

Prognostic impact of chemoradiation-related lymphopenia in patients with locally advanced pancreatic cancer.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 439-439
Author(s):  
Daniel W Kim ◽  
Grace Lee ◽  
Colin D. Weekes ◽  
David P. Ryan ◽  
Aparna Raj Parikh ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cox Model ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Pancreatic Head ◽  
Locally Advanced Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Prognostic Impact ◽  
Entire Cohort ◽  
Grade 3

439 Background: Chemoradiation (CRT) induced lymphopenia is common and associated with poorer survival in multiple solid malignancies. The objective of this study was to evaluate the prognostic impact of lymphopenia in patients with nonmetastatic, unresectable pancreatic ductal adenocarcinoma (PDAC) treated by neoadjuvant FOLFIRINOX (5-fluorouracil [5FU]/leucovorin/irinotecan/oxaliplatin) followed by CRT. We hypothesized that severe lymphopenia would correlate with worse survival. Methods: The inclusion criteria for this single-institution retrospective study were: 1) biopsy-proven diagnosis of unresectable PDAC, 2) absence of distant metastasis, 3) receipt of neoadjuvant FOLFIRINOX followed by CRT, and 4) absolute lymphocyte count (ALC) available prior to and two months after initiating CRT. In general, CRT consisted of 5FU or capecitabine and RT with 58.8 Gy over 28 fractions. Lymphopenia was graded according to CTCAE v5.0. The primary variable of interest was lymphopenia at two months, dichotomized by ALC of < 0.5/μl (Grade 3 lymphopenia). The primary endpoint was overall survival (OS). Cox modeling and Kaplan-Meier methods were used to perform survival analyses. Results: A total of 138 patients were identified. Median follow-up for the entire cohort was 16 months. Median age was 65. Fifty-six percent were female, 86% were Caucasian, and 97% had ECOG ≤1. Median tumor size was 3.8 cm. Tumor location was pancreatic head in 63%, body in 22%, tail in 8%, and neck in 7%. Median baseline ALC for the entire cohort was 1.5 k/ul. Two months after initiating CRT, 106 (77%) had severe (Grade 3 or worse) lymphopenia. While there were no significant differences in baseline patient or disease characteristics, patients with severe lymphopenia received higher doses of RT with longer duration of treatment compared to those without severe lymphopenia. On multivariable Cox model, severe lymphopenia at two months was significantly associated with increased hazards of death (HR = 4.00 [95% CI 2.03-7.89], p < 0.001). Greater number of neoadjuvant FOLFIRINOX cycles received prior to CRT was associated with lower hazards of death (HR = 0.84 [95% CI 0.77-0.92], p < 0.001). The 12-month OS was 73% vs. 90% in the cohort with vs. without severe lymphopenia, respectively (log-rank p < 0.001). Conclusions: Treatment-related lymphopenia is common and severe lymphopenia may be a prognostic marker of poorer survival in locally advanced pancreatic cancer. Closer observation in high-risk patients and minimization of RT dose and duration are potential approaches to mitigating CRT-related lymphopenia. Our findings also suggest an important role of the host immunity in pancreatic cancer outcomes, supporting the ongoing efforts of immunotherapy trials in pancreatic cancer.

Adjuvant and Neoadjuvant Therapy for Pancreatic Adenocarcinoma

2017 ◽  
Author(s):  
Gregory C Wilson ◽  
Brent T Xia ◽  
Syed A Ahmed
Keyword(s):  
Pancreatic Cancer ◽  
Adjuvant Therapy ◽  
Neoadjuvant Therapy ◽  
Pancreatic Adenocarcinoma ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Advanced Pancreatic Cancer ◽  
Treatment Strategies ◽  
Ductal Adenocarcinoma ◽  
Borderline Resectable

Despite decades of advancement and research into the multimodal care of pancreatic cancer, mortality after the diagnosis of pancreatic ductal adenocarcinoma remains grim. The role of adjuvant therapy following surgical resection has been well established in the literature. However, adjuvant therapy is imperfect, and outside of a clinical trial, there are high rates of omission or delayed initiation of therapy. Neoadjuvant treatment strategies continue to be explored in the management of resectable, borderline-resectable, and locally advanced unresectable pancreatic adenocarcinoma. With improved resection rates and the possibility for tumor downstaging, neoadjuvant therapy has become standard for patients with borderline-resectable and locally advanced unresectable tumors. Additional benefits of neoadjuvant therapy in the treatment of resectable tumors include improved completion rates of systemic therapy and R0 resection rates. Future clinical trials, including the use of novel treatment agents and combination treatment strategies in both neoadjuvant and adjuvant regimens, will add value to the treatment of pancreatic adenocarcinoma. Key words: adjuvant therapy, borderline-resectable pancreatic cancer, locally advanced pancreatic cancer, neoadjuvant therapy, pancreatic adenocarcinoma, resectable disease 

Missing links — epigenetic regulators of the pancreatic cancer–associated inflammation

2021 ◽  
Vol 135 (10) ◽  
pp. 1289-1293
Author(s):  
Gregor Werba ◽  
Tamas A. Gonda
Keyword(s):  
Pancreatic Cancer ◽  
Noncoding Rna ◽  
Current Knowledge ◽  
Treatment Strategies ◽  
Therapeutic Interventions ◽  
Ductal Adenocarcinoma ◽  
Gastrointestinal Cancers ◽  
Novel Treatment ◽  
Epigenetic Regulator ◽  
Novel Treatment Strategies

Abstract Pancreatic ductal adenocarcinoma (PDAC) features a hostile tumor microenvironment (TME) that renders it remarkably resistant to most therapeutic interventions. Consequently, survival remains among the poorest compared with other gastrointestinal cancers. Concerted efforts are underway to decipher the complex PDAC TME, break down barriers to efficacious therapies and identify novel treatment strategies. In the recent Clinical Science, Li and colleagues identify the long noncoding RNA KLHDC7B-DT as a crucial epigenetic regulator of IL-6 transcription in PDAC and illustrate its potent influences on the pancreatic TME. In this commentary, we introduce epigenetics in pancreatic cancer and put the findings by Li et al. in context with current knowledge.

scholarly journals Homologous Recombination Deficiency in Patients With Pancreatic Ductal Adenocarcinoma and Response to Chemotherapy

2018 ◽  
pp. 1-11 ◽  
Author(s):  
Safi Shahda ◽  
Kirsten M. Timms ◽  
Ashley A. Ibrahim ◽  
Julia E. Reid ◽  
Harvey M. Cramer ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Needle Aspiration ◽  
Response To Therapy ◽  
Ductal Adenocarcinoma ◽  
Response To Chemotherapy ◽  
Formalin Fixed Paraffin Embedded ◽  
Mutation Data

Purpose Mutations or copy number abnormalities of genes involved in homologous recombination (HR) occur in pancreatic ductal adenocarcinoma (PDAC). DNA-based measures of HR deficiency (HRD) have been developed and may help identify tumors with better response to DNA-damaging agents. This study aimed to describe the HR pathway mutations and HRD status and determine their association with treatment response and outcome in patients with PDAC. Patients and Methods We performed a retrospective analysis of tumor samples from patients treated at Indiana University for locally advanced or metastatic PDAC. Patients were included if they received gemcitabine plus nanoparticle albumin-bound paclitaxel (control) or fluorouracil, oxaliplatin, leucovorin, and irinotecan (FOLFIRINOX) and had adequate follow-up to assess survival and response to therapy. Tumor analysis generated a three-biomarker HRD score and mutation data for 44 genes. Results Ninety-one samples met inclusion criteria, and 78 samples (formalin-fixed paraffin-embedded, n = 15; fine-needle aspiration, n = 63) generated mutation data. HRD analysis was successful for 57 samples (HRD score: median, 18; range, 5 to 61); the primary cause of failure was low tumor cellularity. Six BRCA1/ 2 mutations were detected, four with HRD scores in the top decile ( P = .011). There was no statistically significant correlation between HRD score and radiographic response (odds ratio per interquartile range, 1.40; P = .32 adjusted for treatment) in either treatment group. In patients treated with FOLFIRINOX, HRD score dichotomized at the median was not associated with progression-free survival (median, 5.3 v 9.4 months for low v high HRD score, respectively; P = .083) or overall survival (median, 11.9 v 10.7 months for low v high HRD score, respectively; P = .76). Conclusion Mutations in DNA repair genes occur in PDAC, and HRD scores can be generated in the majority of patients. The HRD score was not significantly associated with higher response rate or prolonged survival in patients treated with FOLFIRINOX.

scholarly journals Locally Advanced Pancreatic Cancer: Work-Up, Staging, and Local Intervention Strategies

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 976 ◽  
Author(s):  
Eran van Veldhuisen ◽  
Claudia van den Oord ◽  
Lilly J. Brada ◽  
Marieke S. Walma ◽  
Jantien A. Vogel ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stable Disease ◽  
Tumor Regression ◽  
Locally Advanced ◽  
Irreversible Electroporation ◽  
Advanced Pancreatic Cancer ◽  
Locally Advanced Pancreatic Cancer ◽  
Vascular Involvement ◽  
Response To Chemotherapy ◽  
Ablative Techniques

Locally advanced pancreatic cancer (LAPC) has several definitions but essentially is a nonmetastasized pancreatic cancer, in which upfront resection is considered not beneficial due to extensive vascular involvement and consequent high chance of a nonradical resection. The introduction of FOLFIRINOX chemotherapy and gemcitabine-nab-paclitaxel (gem-nab) has had major implications for the management and outcome of patients with LAPC. After 4–6 months induction chemotherapy, the majority of patients have stable disease or even tumor-regression. Of these, 12 to 35% are successfully downstaged to resectable disease. Several studies have reported a 30–35 months overall survival after resection; although it currently remains unclear if this is a result of the resection or the good response to chemotherapy. Following chemotherapy, selection of patients for resection is difficult, as contrast-enhanced computed-tomography (CT) scan is unreliable in differentiating between viable tumor and fibrosis. In case a resection is not considered possible but stable disease is observed, local ablative techniques are being studied, such as irreversible electroporation, radiofrequency ablation, and stereotactic body radiation therapy. Pragmatic, multicenter, randomized studies will ultimately have to confirm the exact role of both surgical exploration and ablation in these patients. Since evidence-based guidelines for the management of LAPC are lacking, this review proposes a standardized approach for the treatment of LAPC based on the best available evidence.

scholarly journals Conversion Surgery for Advanced Pancreatic Cancer

2019 ◽  
Vol 8 (11) ◽  
pp. 1945
Author(s):  
Thomas Hank ◽  
Oliver Strobel
Keyword(s):  
Pancreatic Cancer ◽  
Locally Advanced ◽  
Palliative Therapy ◽  
Advanced Pancreatic Cancer ◽  
Treatment Strategies ◽  
Ductal Adenocarcinoma ◽  
Conversion Surgery ◽  
Radiological Criteria ◽  
Intention To Treat ◽  
Conversion Rates

While primarily unresectable locally advanced pancreatic cancer (LAPC) used to be an indication for palliative therapy, a strategy of neoadjuvant therapy (NAT) and conversion surgery is being increasingly used after more effective chemotherapy regimens have become available for pancreatic ductal adenocarcinoma. While high-level evidence from prospective studies is still sparse, several large retrospective studies have recently reported their experience with NAT and conversion surgery for LAPC. This review aims to provide a current overview about different NAT regimens, conversion rates, survival outcomes and determinants of post-resection outcomes, as well as surgical strategies in the context of conversion surgery after NAT. FOLFIRINOX is the predominant regimen used and associated with the highest reported conversion rates. Conversion rates considerably vary between less than 5% and more than half of the study population with heterogeneous long-term outcomes, owing to a lack of intention-to-treat analyses in most studies and a high heterogeneity in resectability criteria, treatment strategies, and reporting among studies. Since radiological criteria of local resectability are no longer applicable after NAT, patients without progressive disease should undergo surgical exploration. Surgery after NAT has to be aimed at local radicality around the peripancreatic vessels and should be performed in expert centers. Future studies in this rapidly evolving field need to be prospective, analyze intention-to-treat populations, report stringent and objective inclusion criteria and criteria for resection. Innovative regimens for NAT in combination with a radical surgical approach hold high promise for patients with LAPC in the future.

Correlation of SMAD4 mutational status and local or metastatic progression in patients with pancreatic cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14730-e14730
Author(s):  
Olfa Derbel ◽  
Arnaud de la Fouchardière ◽  
Julien Peron ◽  
Michel Rivoire ◽  
Françoise Desseigne ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Metastatic Disease ◽  
Expression Profiles ◽  
Locally Advanced ◽  
Chemotherapeutic Agents ◽  
Clinicopathological Parameters ◽  
Molecular Heterogeneity ◽  
Metastatic Progression ◽  
Molecular Features ◽  
Mutational Status

e14730 Background: Pancreatic cancer remains resistant to many key cytotoxic chemotherapeutic agents and novel targeted therapies. The molecular heterogeneity of this cancer may account for therapy failures to date, although the growing arsenal of novel targeted agents could translate into patient survival. A better understanding of the cellular and molecular features of advanced disease will afford new opportunities for investigation, therapeutic intervention and clinical management of patients afflicted with pancreatic cancer. Methods: This study examined the expression profiles of Smad4 in 45 samples of surgically resected pancreatic cancer. Of these 45 patients, 32 underwent pancreaticoduodenectomy. The clinicopathological parameters, the histologic features were determined and correlated to the stage at initial diagnosis, patterns of failure (locally advanced v metastatic disease) and the status SMAD4 genes. Results: Among the 45 patients, 40% of patients died with metastatic disease and 15 % died with locally advanced evolution. SMAD4 genetic status was determined in 25 patients and seems to be correlated with a high grade histologic features and progression to metastasis. Complementary data about correlation between the mutational status of SMAD4 and survival will be presented during congress. Conclusions: SMAD4 gene inactivation seems to be associated with poorer prognosis and disease progression. Prospective validation of SMAD4 as a predictive biomarker may personalize treatment strategies for patients with pancreatic cancer.

Sequential neoadjuvant chemotherpy with nab-paclitaxel plus gemcitabine and FOLFIRINOX in locally advanced pancreatic cancer (LAPC): A PILOT study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15193-e15193 ◽  
Author(s):  
Volker Kunzmann ◽  
Ingo Hartlapp ◽  
Michael Scheurlen ◽  
Hermann Einsele ◽  
Justus Mueller ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pilot Study ◽  
Neoadjuvant Chemotherapy ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Sensory Neuropathy ◽  
Disease Stage ◽  
Ductal Adenocarcinoma ◽  
Hematological Toxicity ◽  
Highly Active

e15193 Background: Nab-Paclitaxel (nab-P) + Gemcitabin (G) and FOLFIRINOX have both shown promising activity in metastatic pancreatic cancer (mPC). Our group has developed sequential usage of both regimens in order to exploit the stromal depletion effects of nab-P and increase global efficacy of chemotherapy in the neoadjuvant setting of LAPC. Methods: This pilot study evaluated patients with cytological/histological confirmed diagnosis of locally advanced pancreatic ductal adenocarcinoma without evidence of metastatic disease (stage III). nab-P+G was administered for 2 cycles (nab-P 125 mg/m2, G 1000 mg/ 2; on days 1, 8, 15; every 28 days) followed by 2 cycles of FOLFIRINOX (as reported by Conroy et al., NEJM 2011). Results: We report the preliminary analysis of 8 pts treated in our institution. Patients characteristics were M/F: 5/3; median age 63 (46-79); PS 0/1: 6/2. 3 pts (37%) had a biliary stent before starting treatment. All pts received the planned 4 cycles of neoadjuvant chemotherapy without dose reductions. There were no treatment-related deaths and none of pts stopped treatment due to toxicity. Grade 3-4 toxicities were neutropenia (50 %), nausea (12%), diarrhea (12%) and thrombopenia (25%). Grade 2-3 sensory neuropathy occured in 25% of pts. Prior nab-P+G did not result in increased hematological or non-hematological toxicity of FOLFIRINOX. Among the 8 patients evaluable so far, 5 partial responses (63%) and 3 stable disease (37%) have been observed, resulting in a disease control rate of 100%. After sequential chemotherapy 3 pts (37%) underwent radical surgical resection. Of note, all resected patients pts showed regression of the tumor (Evans Regression Score 2-4) with 1 patient fullfilling the criteria of a complete pathological remission (pCR). 4 pts received concomitant chemo-radiotherapy and 1 pt underwent an explorative laparotomy with evidence of occult (micronodular) peritoneal metastasis. Conclusions: Sequential neoadjuvant chemotherapy with nab-P+G and FOLFIRINOX seems to be highly active with manageable toxicity profile and may allow to achieve pCR in LAPC. These results are encouraging to test this approach in a prospective phase II trial.

Clinicopathological features of pancreatic cancer-related diabetes.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 675-675
Author(s):  
Michael Lee ◽  
Hui-Li Wong ◽  
Erica S. Tsang ◽  
Sean McKay Fenlon Addison ◽  
James T. Topham ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Locally Advanced ◽  
Retrospective Chart Review ◽  
Clinicopathological Features ◽  
Initial Diagnosis ◽  
Ductal Adenocarcinoma ◽  
Diabetic Patients ◽  
Diabetes Diagnosis ◽  
Pancreatic Cancer Screening ◽  
Diabetes Status

675 Background: Epidemiological studies suggest pancreatic ductal adenocarcinoma (PDAC) may be strongly interrelated with diabetes. However, little is known about the clinicopathological features of pancreatic cancer related diabetes. Methods: A retrospective chart review was undertaken of all patients with advanced PDAC treated with at least one cycle of palliative chemotherapy at BC Cancer, Vancouver between Jan 2012- Dec 2015. Diagnosis of diabetes was determined by consultation documentation and/or fasting glucose > 7mmol/L or HbA1c > 48mmol/L. Peripancreatic diabetes is defined as diabetes diagnosis < 3 years prior to PDAC diagnosis. Results: 578 patients were identified with median age 66 (49-81), 54.6% male, 39.5% non-smoker and 63.5% ECOG 0/1. 27.3% confirmed diabetics, of which 75.8% (119/157) have peripancreatic diabetes. At initial diagnosis, 11.2% were deemed upfront resectable, 44.0% borderline/locally advanced, and 55.1% metastatic. Median overall survival (OS) for the cohort based on stage of disease at initial diagnosis for borderline, locally advanced and metastatic was 22 months (16.1-27.9), 12 months (10.1-13.9) and 6 months (5.0-7.0) respectively. There was no association with diabetes status and OS noted (p = 0.58). Statistical differences were noted in BMI (24.1 v 26.1, p = 0.003), and proportion of Charlson comorbidity index (CCI) of 2 (2.2 v 88.3%, p < 0.01) between non-diabetic and diabetic patients respectively. Statistical difference between peripancreatic diabetes compared to long-term diabetes were noted in resectable status (18.6 v 7.6%, p = 0.048), weight loss > 2kg (78.6 v 60.5%, p = 0.035), hypertension (25.9 v 59.8%, p = 0.002) and dyslipidemia (18.5 v 42.7%, p = 0.024). Conclusions: The majority of patients diagnosed with advanced PDAC with diabetes appeared to develop diabetes within 3 years prior to diagnosis. Further studies to assess the potential role of pancreatic cancer screening investigations in newly diagnosed diabetics are warranted.

scholarly journals Primary Thromboprophylaxis in Pancreatic Cancer Patients: Why Clinical Practice Guidelines Should Be Implemented

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 618 ◽  
Author(s):  
Dominique Farge ◽  
Barbara Bournet ◽  
Thierry Conroy ◽  
Eric Vicaut ◽  
Janusz Rak ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Practice ◽  
Cancer Patients ◽  
Clinical Practice Guidelines ◽  
Practice Guidelines ◽  
Randomized Trials ◽  
Treatment Options ◽  
Locally Advanced ◽  
Ductal Adenocarcinoma ◽  
Recent Advances

Exocrine pancreatic ductal adenocarcinoma, simply referred to as pancreatic cancer (PC) has the worst prognosis of any malignancy. Despite recent advances in the use of adjuvant chemotherapy in PC, the prognosis remains poor, with fewer than 8% of patients being alive at 5 years after diagnosis. The prevalence of PC has steadily increased over the past decades, and it is projected to become the second-leading cause of cancer-related death by 2030. In this context, optimizing and integrating supportive care is important to improve quality of life and survival. Venous thromboembolism (VTE) is a common but preventable complication in PC patients. VTE occurs in one out of five PC patients and is associated with significantly reduced progression-free survival and overall survival. The appropriate use of primary thromboprophylaxis can drastically and safely reduce the rates of VTE in PC patients as shown from subgroup analysis of non-PC targeted placebo-controlled randomized trials of cancer patients and from two dedicated controlled randomized trials in locally advanced PC patients receiving chemotherapy. Therefore, primary thromboprophylaxis with a Grade 1B evidence level is recommended in locally advanced PC patients receiving chemotherapy by the International Initiative on Cancer and Thrombosis clinical practice guidelines since 2013. However, its use and potential significant clinical benefit continues to be underrecognized worldwide. This narrative review aims to summarize the main recent advances in the field including on the use of individualized risk assessment models to stratify the risk of VTE in each patient with individual available treatment options.

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