The Impact of Molecular Subtyping on Pathological Staging of Pancreatic Cancer

Abstract Background Surgical resection remains the only curative treatment for pancreatic cancer and is associated with significant post-operative morbidity and mortality. Patients eligible for surgery, increasingly receive neo-adjuvant therapy before surgery or adjuvant therapy afterward, inherently exposing them to toxicity. As such, optimizing physical function through exercise during treatment remains imperative to optimize quality of life either before surgery or during rehabilitation. However, current exercise efficacy and prescription in pancreatic cancer is unknown. Therefore, this study aims to summarise the published literature on exercise studies conducted in patients with pancreatic cancer undergoing treatment with a focus on determining the current prescription and progression patterns being used in this population. Methods A systematic review of four databases identified studies evaluating the effects of exercise on aerobic fitness, muscle strength, physical function, body composition, fatigue and quality of life in participants with pancreatic cancer undergoing treatment, published up to 24 July 2020. Two reviewers independently reviewed and appraised the methodological quality of each study. Results Twelve studies with a total of 300 participants were included. Heterogeneity of the literature prevented meta-analysis. Exercise was associated with improvements in outcomes; however, study quality was variable with the majority of studies receiving a weak rating. Conclusions High quality evidence regarding the efficacy and prescription of exercise in pancreatic cancer is lacking. Well-designed trials, which have received feedback and input from key stakeholders prior to implementation, are required to examine the impact of exercise in pancreatic cancer on key cancer related health outcomes.

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Indirect cholinergic activation slows down pancreatic cancer growth and tumor-associated inflammation

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-020-01796-4 ◽

2020 ◽

Vol 39 (1) ◽

Author(s):

Paulo L. Pfitzinger ◽

Laura Fangmann ◽

Kun Wang ◽

Elke Demir ◽

Engin Gürlevik ◽

...

Keyword(s):

Pancreatic Cancer ◽

Mouse Model ◽

Tumor Stage ◽

Ache Inhibitors ◽

Impact On Survival ◽

The Impact ◽

Ache Expression ◽

Cholinergic Activation

Abstract Background Nerve-cancer interactions are increasingly recognized to be of paramount importance for the emergence and progression of pancreatic cancer (PCa). Here, we investigated the role of indirect cholinergic activation on PCa progression through inhibition of acetylcholinesterase (AChE) via clinically available AChE-inhibitors, i.e. physostigmine and pyridostigmine. Methods We applied immunohistochemistry, immunoblotting, MTT-viability, invasion, flow-cytometric-cell-cycle-assays, phospho-kinase arrays, multiplex ELISA and xenografted mice to assess the impact of AChE inhibition on PCa cell growth and invasiveness, and tumor-associated inflammation. Survival analyses were performed in a novel genetically-induced, surgically-resectable mouse model of PCa under adjuvant treatment with gemcitabine+/−physostigmine/pyridostigmine (n = 30 mice). Human PCa specimens (n = 39) were analyzed for the impact of cancer AChE expression on tumor stage and survival. Results We discovered a strong expression of AChE in cancer cells of human PCa specimens. Inhibition of this cancer-cell-intrinsic AChE via pyridostigmine and physostigmine, or administration of acetylcholine (ACh), diminished PCa cell viability and invasion in vitro and in vivo via suppression of pERK signaling, and reduced tumor-associated macrophage (TAM) infiltration and serum pro-inflammatory cytokine levels. In the novel genetically-induced, surgically-resectable PCa mouse model, adjuvant co-therapy with AChE blockers had no impact on survival. Accordingly, survival of resected PCa patients did not differ based on tumor AChE expression levels. Patients with higher-stage PCa also exhibited loss of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT), in their nerves. Conclusion For future clinical trials of PCa, direct cholinergic stimulation of the muscarinic signaling, rather than indirect activation via AChE blockade, may be a more effective strategy.

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Effects of COVID-19 Pandemic on the Treatment of Pancreatic Cancer: A Perspective from Central Europe

Digestive Surgery ◽

10.1159/000513157 ◽

2021 ◽

Vol 38 (2) ◽

pp. 158-165

Author(s):

Ilaria Pergolini ◽

I. Ekin Demir ◽

Christian Stöss ◽

Klaus Emmanuel ◽

Robert Rosenberg ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Patients ◽

Central Europe ◽

Pancreatic Surgery ◽

Online Survey ◽

Viral Infections ◽

High Volume ◽

Tumor Board ◽

Standards Of Care ◽

The Impact

Background: This survey aimed to register changes determined by the COVID-19 pandemic on pancreatic surgery in a specific geographic area (Germany, Austria, and Switzerland) to evaluate the impact of the pandemic and obtain interesting cues for the future. Methods: An online survey was designed using Google Forms focusing on the local impact of the pandemic on pancreatic surgery. The survey was conducted at 2 different time points, during and after the lockdown. Results: Twenty-five respondents (25/56) completed the survey. Many aspects of oncological care have been affected with restrictions and delays: staging, tumor board, treatment selection, postoperative course, adjuvant treatments, outpatient care, and follow-up. Overall, 60% of respondents have prioritized pancreatic cancer patients according to stage, age, and comorbidities, and 40% opted not to operate high-risk patients. However, for 96% of participants, the standards of care were guaranteed. Discussion/Conclusions: The first wave of the COVID-19 pandemic had an important impact on pancreatic cancer surgery in central Europe. Guidelines for prompt interventions and prevention of the spread of viral infections in the surgical environment are needed to avoid a deterioration of care in cancer patients in the event of a second wave or a new pandemic. High-volume centers for pancreatic surgery should be preferred and their activity maintained. Virtual conferences have proven to be efficient during this pandemic and should be implemented in the near future.

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An Efficient Photodynamic Therapy Treatment for Human Pancreatic Adenocarcinoma

Journal of Clinical Medicine ◽

10.3390/jcm9010192 ◽

2020 ◽

Vol 9 (1) ◽

pp. 192 ◽

Cited By ~ 5

Author(s):

Alexandre Quilbe ◽

Olivier Moralès ◽

Martha Baydoun ◽

Abhishek Kumar ◽

Rami Mustapha ◽

...

Keyword(s):

Pancreatic Cancer ◽

Photodynamic Therapy ◽

Immune System ◽

Cancer Cells ◽

Pancreatic Adenocarcinoma ◽

Cell Lines ◽

Folate Receptor ◽

Mice Model ◽

Gene And Protein Expression ◽

The Impact

To date, pancreatic adenocarcinoma (ADKP) is a devastating disease for which the incidence rate is close to the mortality rate. The survival rate has evolved only 2–5% in 45 years, highlighting the failure of current therapies. Otherwise, the use of photodynamic therapy (PDT), based on the use of an adapted photosensitizer (PS) has already proved its worth and has prompted a growing interest in the field of oncology. We have developed a new photosensitizer (PS-FOL/PS2), protected by a recently published patent (WO2019 016397-A1, 24 January 2019). This photosensitizer is associated with an addressing molecule (folic acid) targeting the folate receptor 1 (FOLR1) with a high affinity. Folate binds to FOLR1, in a specific way, expressed in 100% of ADKP or over-expressed in 30% of cases. The first objective of this study is to evaluate the effectiveness of this PS2-PDT in four ADKP cell lines: Capan-1, Capan-2, MiapaCa-2, and Panc-1. For this purpose, we first evaluated the gene and protein expression of FOLR1 on four ADKP cell lines. Subsequently, we evaluated PS2’s efficacy in our cell lines and we assessed the impact of PDT on the secretome of cancer cells and its impact on the immune system. Finally, we evaluate the PDT efficacy on a humanized SCID mouse model of pancreatic cancer. In a very interesting way, we observed a significant increase in the proliferation of activated-human PBMC when cultured with conditioned media of ADKP cancer cells subjected to PDT. Furthermore, to evaluate in vivo the impact of this new PS, we analyzed the tumor growth in a humanized SCID mice model of pancreatic cancer. Four conditions were tested: Untreated, mice (nontreated), mice with PS (PS2), mice subjected to illumination (Light only), and mice subjected to illumination in the presence of PS (PDT). We noticed that the mice subjected to PDT presented a strong decrease in the growth of the tumor over time after illumination. Our investigations have not only suggested that PS2-PDT is an effective therapy in the treatment of PDAC but also that it activates the immune system and could be considered as a real adjuvant for anti-cancer vaccination. Thus, this new study provides new treatment options for patients in a therapeutic impasse and will provide a new arsenal in the fight against PDAC.

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Survival Among Patients With Pancreatic Cancer and Long-Standing or Recent-Onset Diabetes Mellitus

Journal of Clinical Oncology ◽

10.1200/jco.2014.57.5688 ◽

2015 ◽

Vol 33 (1) ◽

pp. 29-35 ◽

Cited By ~ 45

Author(s):

Chen Yuan ◽

Douglas A. Rubinson ◽

Zhi Rong Qian ◽

Chen Wu ◽

Peter Kraft ◽

...

Keyword(s):

Pancreatic Cancer ◽

Median Survival ◽

Case Series ◽

Health Study ◽

Survival Times ◽

Recent Onset ◽

Onset Diabetes ◽

Diabetes Status ◽

The Impact

Purpose Long-standing diabetes is a risk factor for pancreatic cancer, and recent-onset diabetes in the several years before diagnosis is a consequence of subclinical pancreatic malignancy. However, the impact of diabetes on survival is largely unknown. Patients and Methods We analyzed survival by diabetes status among 1,006 patients diagnosed from 1986 to 2010 from two prospective cohort studies: the Nurses' Health Study (NHS) and Health Professionals Follow-Up Study (HPFS). We validated our results among 386 patients diagnosed from 2004 to 2013 from a clinic-based case series at Dana-Farber Cancer Institute (DFCI). We estimated hazard ratios (HRs) for death using Cox proportional hazards models, with adjustment for age, sex, race/ethnicity, smoking, diagnosis year, and cancer stage. Results In NHS and HPFS, HR for death was 1.40 (95% CI, 1.15 to 1.69) for patients with long-term diabetes (> 4 years) compared with those without diabetes (P < .001), with median survival times of 3 months for long-term diabetics and 5 months for nondiabetics. Adjustment for a propensity score to reduce confounding by comorbidities did not change the results. Among DFCI patient cases, HR for death was 1.53 (95% CI, 1.07 to 2.20) for those with long-term diabetes compared with those without diabetes (P = .02), with median survival times of 9 months for long-term diabetics and 13 months for nondiabetics. Compared with nondiabetics, survival times were shorter for long-term diabetics who used oral hypoglycemics or insulin. We observed no statistically significant association of recent-onset diabetes (< 4 years) with survival. Conclusion Long-standing diabetes was associated with statistically significantly decreased survival among patients with pancreatic cancer enrolled onto three longitudinal studies.

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Stromal protein βig-h3 reprogrammes tumour microenvironment in pancreatic cancer

Gut ◽

10.1136/gutjnl-2018-317570 ◽

2018 ◽

Vol 68 (4) ◽

pp. 693-707 ◽

Cited By ~ 18

Author(s):

Delphine Goehrig ◽

Jérémy Nigri ◽

Rémi Samain ◽

Zhichong Wu ◽

Paola Cappello ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumour Growth ◽

Matrix Protein ◽

Immune Escape ◽

Interaction Mechanism ◽

Tumour Microenvironment ◽

Extracellular Matrix Protein ◽

Ductal Adenocarcinoma ◽

The Impact

ObjectivePancreatic cancer is associated with an abundant stromal reaction leading to immune escape and tumour growth. This massive stroma drives the immune escape in the tumour. We aimed to study the impact of βig-h3 stromal protein in the modulation of the antitumoural immune response in pancreatic cancer.DesignWe performed studies with p48-Cre;KrasG12D, pdx1-Cre;KrasG12D;Ink4a/Arffl/fl, pdx1-Cre;KrasG12D; p53R172H mice and tumour tissues from patients with pancreatic ductal adenocarcinoma (PDA). Some transgenic mice were given injections of anti-βig-h3, anti-CD8, anti-PD1 depleting antibodies. Tumour growth as well as modifications in the activation of local immune cells were analysed by flow cytometry, immunohistochemistry and immunofluorescence. Tissue stiffness was measured by atomic force microscopy.ResultsWe identified βig-h3 stromal-derived protein as a key actor of the immune paracrine interaction mechanism that drives pancreatic cancer. We found that βig-h3 is highly produced by cancer-associated fibroblasts in the stroma of human and mouse. This protein acts directly on tumour-specific CD8+ T cells and F4/80 macrophages. Depleting βig-h3 in vivo reduced tumour growth by enhancing the number of activated CD8+ T cell within the tumour and subsequent apoptotic tumour cells. Furthermore, we found that targeting βig-h3 in established lesions released the tissue tension and functionally reprogrammed F4/80 macrophages in the tumour microenvironment.ConclusionsOur data indicate that targeting stromal extracellular matrix protein βig-h3 improves the antitumoural response and consequently reduces tumour weight. Our findings present βig-h3 as a novel immunological target in pancreatic cancer.

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