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Cancers
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Multimodal Treatment for Pancreatic Cancer
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Multimodal Treatment for Pancreatic Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: 31 July 2025 | Viewed by 4305

Special Issue Editor

Dr. Cosimo Sperti

E-Mail Website
Guest Editor
Department of Surgery, Oncology and Gastroenterology, Hepatobiliary and Pancreatic Surgery Unit, University of Padua, Padua, Italy
Interests: cystic neoplasms; endocrine tumors; pancreatic cancer; surgical oncology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Pancreatic cancer is the fourth leading cause of cancer-related deaths in western countries, and it will become the second leading cause of gastrointestinal cancer deaths in the coming years. Surgery and adjuvant therapy remain the standard treatment, but the recurrence rate is still high. As novel therapies are regularly introduced, the optimal treatment approaches for this aggressive cancer are becoming more complex. For localized cancers, neoadjuvant and adjuvant approaches are definitively used in clinical practice. For patients with advanced disease, combination regimens and multimodality approaches are being utilized with increasing frequency. Moreover, a new subgroup of patients with advanced disease has been identified, oligometastatic pancreatic cancer patients, who will eventually benefit from aggressive, multidisciplinary management. So, multimodality treatment, i.e., neoadjuvant therapy and combination of chemotherapy, radiotherapy, immunotherapy, loco-regional therapy and surgery, is now increasingly being applied and appears essential in obtaining better results. Moreover, since cancer’s recurrence occurs in most patients, management of recurrent cancer after resection is an important aspect to be considered in order to improve patients’ prognosis. There is a need for a better understanding of the role of genetic alterations in pancreatic cancer to clarify the usefulness of new biomarkers both for precursor and invasive tumors and prognostic factors in order to select individual patients for appropriate, personalized treatment.

The aim of this Special Issue is to focus on the results and problems of multimodality therapy for resectable, locally advanced, or metastatic pancreatic cancer, the search for prognostic factors for early and late outcomes after therapy, and the evaluation of novel strategies for individualized treatment. Up-to-date original research, short communications, and comprehensive review articles on all modalities playing a role in the treatment of pancreatic cancer will be welcomed.

Dr. Cosimo Sperti
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • pancreatic cancer
  • multimodal therapy
  • neoadjuvant therapy
  • surgery of pancreatic cancer
  • surgical complications
  • response to therapy
  • survival
  • recurrence
  • loco-regional therapy
  • novel therapies

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Published Papers (5 papers)

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Research

16 pages, 7408 KiB  
Article
Treatment of Pancreatic Cancer Using Near-Infrared Photoimmunotherapy Targeting Cancer-Associated Fibroblasts in Combination with Anticancer Chemotherapeutic Drug
by Hiroki Yonemura, Masaki Kuwatani, Kohei Nakajima, Atsushi Masamune, Mikako Ogawa and Naoya Sakamoto
Cancers 2025, 17(9), 1584; https://doi.org/10.3390/cancers17091584 - 7 May 2025
Viewed by 78
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC), which has a poor prognosis, involves an overabundance of fibroblasts and extracellular matrix. Cancer-associated fibroblasts (CAFs) are critical for providing structural support by secreting soluble factors and extracellular matrix proteins into the stroma. We assessed the potential [...] Read more.
Background: Pancreatic ductal adenocarcinoma (PDAC), which has a poor prognosis, involves an overabundance of fibroblasts and extracellular matrix. Cancer-associated fibroblasts (CAFs) are critical for providing structural support by secreting soluble factors and extracellular matrix proteins into the stroma. We assessed the potential of near-infrared photoimmunotherapy (NIR-PIT) targeting CAFs in PDAC. Methods: PDAC cells (Capan-1 and SUIT-2) and CAFs (hPSC-5) were used. Anti-human fibroblast activation protein (FAP)/podoplanin (PDPN) antibodies were used to bind to CAFs and conjugates with the specific photosensitizer IRDye®700DX (IR700) to investigate the effects of NIR-PIT. Thereafter, BALB/c Slc-nu/nu mice were transplanted with Capan-1 and/or CAFs and treated with gemcitabine (GEM) with or without NIR-PIT. Results: The binding rate of anti-FAP antibody-AlexaFluor®488 conjugate to hPSC-5 cells was high, whereas that of the anti-PDPN antibody-conjugate was not. The incubation of anti-FAP antibody-IR700 conjugate (αFAP-IR700) with hPSC-5 cells for 3 h led to maximal fluorescence on the surface of hPSC-5 cells. When NIR-PIT with αFAP-IR700 was performed in the co-culture group of Capan-1 and hPSC-5 cells, the proliferative capacity of Capan-1 cells decreased to the same level as that when Capan-1 cells were cultured alone (p < 0.05). In vivo, compared with the GEM group, the NIR-PIT with the GEM group showed a significant reduction in the tumor volume (day 28: 79 vs. 382 mm3, p < 0.05). Tumor volumes in the NIR-PIT group were not reduced compared with those in the control group. Conclusions: Combining NIR-PIT with conventional chemotherapy to target CAFs may enhance the anticancer effects on PDAC. Full article
(This article belongs to the Special Issue Multimodal Treatment for Pancreatic Cancer)
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18 pages, 2940 KiB  
Article
Development of an Intratumoral Holmium Microsphere Injection Method in Ex Vivo Human Pancreatic Ductal Adenocarcinoma: A Preclinical Feasibility Study
by Coen Ysbrand Willink, Sjoerd Franciscus Maria Jenniskens, Nienke Johanna Maria Klaassen, Martijn Willem Jan Stommel, Cornelis Johannes Henricus Martinus van Laarhoven, Jurgen J. Fütterer and Johannes Frank Wilhelmus Nijsen
Cancers 2025, 17(6), 1028; https://doi.org/10.3390/cancers17061028 - 19 Mar 2025
Viewed by 374
Abstract
Background/Objectives: Patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) have a poor prognosis. Local therapy may enhance tumor control and increase resectability. Intratumoral injection of radioactive holmium-166 microspheres presents a promising and minimally invasive treatment with multimodality imaging capabilities (SPECT, CT, MRI). However, holmium-166 [...] Read more.
Background/Objectives: Patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) have a poor prognosis. Local therapy may enhance tumor control and increase resectability. Intratumoral injection of radioactive holmium-166 microspheres presents a promising and minimally invasive treatment with multimodality imaging capabilities (SPECT, CT, MRI). However, holmium-166 microspheres are not commonly used for intratumoral injections, and PDAC is notorious for its high intratumoral pressure. This study developed an intratumoral injection method with nonradioactive holmium-165 microspheres in ex vivo human PDAC specimens using a novel injection system for suspension homogenization. Methods: An injection system was developed and validated in a laboratory setting. Thereafter, intratumoral injections in surgically removed ex vivo PDACs were performed, and parameters were established to optimize feasibility, defined by the ability to inject and control the microsphere distribution. Also, injection limitations and cutoff values were determined. The distribution was assessed by visual confirmation, CT, MRI, ultrasound, and histopathology. Results: With a validated injection system, intratumoral injections were performed in ten ex vivo PDAC samples. Feasible injection guidelines include but are not limited to ultrasound or CT needle guidance, a maximum injection volume of <20.0% from the tumor volume, ≤3 needle positions, and an injection volume of 0.3–1.0 mL per needle position. Conclusions: Intratumoral injection of holmium-165 microspheres in ex vivo pancreatic ductal adenocarcinoma was feasible with adherence to injection parameters necessary for effective intratumoral deposition and minimal leakage. The injection system and parameters developed here provide a foundation for future studies on holmium-166 microsphere injections in pancreatic cancer patients, with the aim to improve local tumor control as a part of a multimodal therapy. Full article
(This article belongs to the Special Issue Multimodal Treatment for Pancreatic Cancer)
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18 pages, 518 KiB  
Article
Cystic Fluid Total Proteins, Low-Density Lipoprotein Cholesterol, Lipid Metabolites, and Lymphocytes: Worrisome Biomarkers for Intraductal Papillary Mucinous Neoplasms
by Fahimeh Jafarnezhad-Ansariha, Nicole Contran, Chiara Cristofori, Manuela Simonato, Veronica Davanzo, Stefania Moz, Paola Galozzi, Paola Fogar, Evelyn Nordi, Andrea Padoan, Ada Aita, Matteo Fassan, Alberto Fantin, Anna Sartori, Cosimo Sperti, Alessio Correani, Virgilio Carnielli, Paola Cogo and Daniela Basso
Cancers 2025, 17(4), 643; https://doi.org/10.3390/cancers17040643 - 14 Feb 2025
Viewed by 555
Abstract
Objectives: Pancreatic cystic neoplasms (PCNs), particularly intraductal papillary mucinous neoplasms (IPMNs), present a challenge for their potential malignancy. Despite promising biomarkers like CEA, amylase, and glucose, our study investigates whether metabolic indices in blood and cystic fluids (CFs), in addition to lymphocyte subsets [...] Read more.
Objectives: Pancreatic cystic neoplasms (PCNs), particularly intraductal papillary mucinous neoplasms (IPMNs), present a challenge for their potential malignancy. Despite promising biomarkers like CEA, amylase, and glucose, our study investigates whether metabolic indices in blood and cystic fluids (CFs), in addition to lymphocyte subsets and hematopoietic stem/progenitor cells (HSPCs), can effectively differentiate between high- and low-risk PCNs. Materials and Methods: A total of 26 patients (11 males, mean age 69.5 ± 9 years) undergoing Endoscopic Ultrasound-guided Fine Needle Aspiration were consecutively enrolled. Analyses included blood, serum, and CF, assessing glucose, CEA, cholesterol (total, HDL, and LDL), and total proteins. Flow cytometry examined immunophenotyping in peripheral blood and cystic fluids. Mass spectrometry was used for the metabolomic analysis of CF. Sensitivity, specificity, and ROC analyses evaluated discriminatory power. Results: A total of 25 out of 26 patients had IPMN. Patients were categorized as low or high risk based on multidisciplinary evaluation of clinical, radiological, and endoscopic data. High-risk patients showed lower CF total proteins and LDL cholesterol (p = 0.005 and p = 0.031), with a marked reduction in CF lymphocytes (p = 0.005). HSCPs were absent in CF. In blood, high-risk patients showed increased non-MHC-restricted cytotoxic T cells (p = 0.019). The metabolomic analysis revealed significantly reduced middle and long-chain acyl carnitines (AcCa) and tryptophan metabolites in high-risk patients. ROC curves indicated comparable discriminant abilities for CF lymphocytes (AUC 0.868), CF total proteins (AUC 0.859), and CF LDL cholesterol (AUC 0.795). The highest performance was achieved by the AcCa 14:2 and 16:0 (AUC: 0.9221 and 0.8857, respectively). Conclusions: CF levels of glucose, CEA, LDL cholesterol, and total proteins together with lymphocyte counts are easy translational biomarkers that may support risk stratification of PCNs in IPMN patients and might be endorsed by metabolomic analysis. Further studies are required for potential clinical integration. Full article
(This article belongs to the Special Issue Multimodal Treatment for Pancreatic Cancer)
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19 pages, 1410 KiB  
Article
Comparative Efficacy of 21 Treatment Strategies for Resectable Pancreatic Cancer: A Network Meta-Analysis
by Fausto Petrelli, Roberto Rosenfeld, Antonio Ghidini, Andrea Celotti, Lorenzo Dottorini, Matteo Viti, Gianluca Baiocchi, Ornella Garrone, Gianluca Tomasello and Michele Ghidini
Cancers 2024, 16(18), 3203; https://doi.org/10.3390/cancers16183203 - 20 Sep 2024
Viewed by 1245
Abstract
The primary treatment for operable pancreatic cancer (PC) involves surgery followed by adjuvant therapy. Nevertheless, perioperative or neoadjuvant chemotherapy (CT) may be used to mitigate the likelihood of recurrence and mortality. This network meta-analysis (NMA) assesses the comparative efficacy of various treatment approaches [...] Read more.
The primary treatment for operable pancreatic cancer (PC) involves surgery followed by adjuvant therapy. Nevertheless, perioperative or neoadjuvant chemotherapy (CT) may be used to mitigate the likelihood of recurrence and mortality. This network meta-analysis (NMA) assesses the comparative efficacy of various treatment approaches for resectable PC. A thorough search was carried out on January 31, 2023, encompassing PubMed/MEDLINE, Cochrane Library, and Embase databases. We incorporated randomized clinical trials (RCTs) that compared surgical interventions with or without (neo)adjuvant or perioperative therapies for operable PC. We conducted a fixed-effects Bayesian NMA. We presented the effect sizes in terms of hazard ratios (HRs) for overall survival (OS) along with 95% credible intervals (95% CrIs). The treatment was deemed statistically superior when the 95% credible interval (CrI) did not encompass a null value (hazard ratio < 1). Treatment rankings were established based on the surface under the cumulative ranking curve (SUCRA). A total of 24 studies were incorporated, comparing 21 treatments with surgery in isolation. Eleven treatments showed superior efficacy compared to surgery alone, with HRs ranging from 0.38 for perioperative treatments to 0.73 for adjuvant 5-fluorouracil. After the exclusion of studies conducted in Asia, it was found that the perioperative regimen of gemcitabine combined with nab-paclitaxel was the most effective regimen (SUCRA, p = 0.99). The findings endorse the utilization of perioperative CT, especially multi-agent CT, as the favored intervention for operable PC in Western nations. Full article
(This article belongs to the Special Issue Multimodal Treatment for Pancreatic Cancer)
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Figure 1

12 pages, 4286 KiB  
Article
Thermosensitive Liposomes for Gemcitabine Delivery to Pancreatic Ductal Adenocarcinoma
by Cesar B. Aparicio-Lopez, Sarah Timmerman, Gabriella Lorino, Tatiana Rogers, Marla Pyle, Tej B. Shrestha and Matthew T. Basel
Cancers 2024, 16(17), 3048; https://doi.org/10.3390/cancers16173048 - 1 Sep 2024
Cited by 2 | Viewed by 1484
Abstract
Treatment of pancreatic ductal adenocarcinoma with gemcitabine is limited by an increased desmoplasia, poor vascularization, and short plasma half-life. Heat-sensitive liposomes modified by polyethylene glycol (PEG; PEGylated liposomes) can increase plasma stability, reduce clearance, and decrease side effects. Nevertheless, translation of heat-sensitive liposomes [...] Read more.
Treatment of pancreatic ductal adenocarcinoma with gemcitabine is limited by an increased desmoplasia, poor vascularization, and short plasma half-life. Heat-sensitive liposomes modified by polyethylene glycol (PEG; PEGylated liposomes) can increase plasma stability, reduce clearance, and decrease side effects. Nevertheless, translation of heat-sensitive liposomes to the clinic has been hindered by the low loading efficiency of gemcitabine and by the difficulty of inducing hyperthermia in vivo. This study was designed to investigate the effect of phospholipid content on the stability of liposomes at 37 °C and their release under hyperthermia conditions; this was accomplished by employing a two-stage heating approach. First the liposomes were heated at a fast rate, then they were transferred to a holding bath. Thermosensitive liposomes formulated with DPPC: DSPC: PEG2k (80:15:5, mole%) exhibited minimal release of carboxyfluorescein at 37 °C over 30 min, indicating stability under physiological conditions. However, upon exposure to hyperthermic conditions (43 °C and 45 °C), these liposomes demonstrated a rapid and significant release of their encapsulated content. The encapsulation efficiency for gemcitabine was calculated at 16.9%. Additionally, fluorescent analysis during the removal of unencapsulated gemcitabine revealed an increase in pH. In vitro tests with BxPC3 and KPC cell models showed that these thermosensitive liposomes induced a heat-dependent cytotoxic effect comparable to free gemcitabine at temperatures above 41 °C. This study highlights the effectiveness of the heating mechanism and cell models in understanding the current challenges in developing gemcitabine-loaded heat-sensitive liposomes. Full article
(This article belongs to the Special Issue Multimodal Treatment for Pancreatic Cancer)
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