Cancers

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20 pages, 4993 KiB

Open AccessArticle

A Comparative Analysis of Orthotopic and Subcutaneous Pancreatic Tumour Models: Tumour Microenvironment and Drug Delivery

by Jessica Lage Fernandez, Sara Årbogen, Mohammad Javad Sadeghinia, Margrete Haram, Sofie Snipstad, Sverre Helge Torp, Caroline Einen, Melina Mühlenpfordt, Matilde Maardalen, Krister Vikedal and Catharina de Lange Davies

Cancers 2023, 15(22), 5415; https://doi.org/10.3390/cancers15225415 - 14 Nov 2023

Viewed by 1404

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a challenging malignancy, mainly due to its resistance to chemotherapy and its complex tumour microenvironment characterised by stromal desmoplasia. There is a need for new strategies to improve the delivery of drugs and therapeutic response. Relevant preclinical tumour [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) remains a challenging malignancy, mainly due to its resistance to chemotherapy and its complex tumour microenvironment characterised by stromal desmoplasia. There is a need for new strategies to improve the delivery of drugs and therapeutic response. Relevant preclinical tumour models are needed to test potential treatments. This paper compared orthotopic and subcutaneous PDAC tumour models and their suitability for drug delivery studies. A novel aspect was the broad range of tumour properties that were studied, including tumour growth, histopathology, functional vasculature, perfusion, immune cell infiltration, biomechanical characteristics, and especially the extensive analysis of the structure and the orientation of the collagen fibres in the two tumour models. The study unveiled new insights into how these factors impact the uptake of a fluorescent model drug, the macromolecule called 800CW. While the orthotopic model offered a more clinically relevant microenvironment, the subcutaneous model offered advantages for drug delivery studies, primarily due to its reproducibility, and it was characterised by a more efficient drug uptake facilitated by its collagen organisation and well-perfused vasculature. The tumour uptake seemed to be influenced mainly by the structural organisation and the alignment of the collagen fibres and perfusion. Recognising the diverse characteristics of these models and their multifaceted impacts on drug delivery is crucial for designing clinically relevant experiments and improving our understanding of pancreatic cancer biology. Full article

(This article belongs to the Special Issue Advanced Pancreatic Cancer)

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12 pages, 1032 KiB

Open AccessArticle

Inflammation-Based Prognostic Scores in Pancreatic Cancer Patients—A Single-Center Analysis of 1294 Patients within the Last Decade

by Christopher C. M. Neumann, François Schneider, Georg Hilfenhaus, Loredana Vecchione, Matthäus Felsenstein, Jana Ihlow, Dominik Geisel, Steffen Sander, Johann Pratschke, Sebastian Stintzing, Ulrich Keilholz and Uwe Pelzer

Cancers 2023, 15(8), 2367; https://doi.org/10.3390/cancers15082367 - 19 Apr 2023

Cited by 1 | Viewed by 1348

Abstract

Inflammatory properties are known to promote tumor progression leading to an impaired median overall survival (mOS). Various small studies have focused on a wide range of inflammation-based prognostic indicators. By using sufficient data from 1294 out of 2323 patients diagnosed with pancreatic cancer [...] Read more.

Inflammatory properties are known to promote tumor progression leading to an impaired median overall survival (mOS). Various small studies have focused on a wide range of inflammation-based prognostic indicators. By using sufficient data from 1294 out of 2323 patients diagnosed with pancreatic cancer between 2009 and 2021 at our cancer center, inflammatory markers such as the neutrophil to lymphocyte ratio (NRL), the platelet to lymphocyte ratio (PLR), the lymphocyte to monocyte ratio (LMR) and the CRP to albumin ratio (CAR) were evaluated. We identified a new combined score, termed the inflammatory benchmark index (IBI). We performed univariate and multivariate overall survival analyses and identified optimal prognostic cut-off values for each parameter. In univariate analyses, advanced age (p < 0.001), gender (p < 0.001), tumor stage (p < 0.001), CA19-9 (p = 0.001), NLR (p = 0.001), LMR (p = 0.004), PLR (p = 0.004), CAR (p = 0.001) and IBI (p = 0.001) were identified as prognostic markers. In multivariate analyses advanced age (p < 0.001), gender (p = 0.001), tumor stage (p < 0.001), CA19-9 (p < 0.001), NLR (p = 0.001), LMR (p = 0.038), CAR (p < 0.001) and IBI (p < 0.001) were independent prognostic markers. These findings emphasize the impact of inflammation in pancreatic cancer, provide easily accessible prognostic values for the clinician, and may be useful as stratification parameters for trials aimed at patient inflammation or immune response. Full article

(This article belongs to the Special Issue Advanced Pancreatic Cancer)

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10 pages, 1329 KiB

Open AccessArticle

Prognosis of Pancreatic Cancer Based on Resectability: A Single Center Experience

by Takahiro Einama, Yasuhiro Takihata, Suefumi Aosasa, Fukumi Konno, Kazuki Kobayashi, Naoto Yonamine, Ibuki Fujinuma, Takazumi Tsunenari, Akiko Nakazawa, Eiji Shinto, Hideki Ueno and Yoji Kishi

Cancers 2023, 15(4), 1101; https://doi.org/10.3390/cancers15041101 - 9 Feb 2023

Cited by 4 | Viewed by 1827

Abstract

Although conversion surgery has increasingly been performed for initially unresectable advanced pancreatic ductal adenocarcinoma (PDAC), the rate of conversion, including that for patients who do not undergo resection, remains unclear. Patients with PDAC who were treated between January 2013 and December 2018 were [...] Read more.

Although conversion surgery has increasingly been performed for initially unresectable advanced pancreatic ductal adenocarcinoma (PDAC), the rate of conversion, including that for patients who do not undergo resection, remains unclear. Patients with PDAC who were treated between January 2013 and December 2018 were classified into three groups: resectable (R), borderline resectable (BR), and unresectable (UR). We analyzed patient outcomes, including the rate of surgical resection and survival, in each of these groups. In total, 211 patients (R, 118; BR, 22; UR, 81) were selected. Among them, 117 (99%), 18 (82%), and 15 (19%) patients in the R, BR, and UR groups, respectively, underwent surgical resection. R0 resection rates were 88, 78, and 67%, whereas median overall survival (OS) from treatment initiation were 31, 18, and 11 months (p < 0.0001) in the R, BR, and UR groups, respectively. In patients who underwent surgical resection, relapse-free survival (RFS) and OS were similar among the three groups (R vs. BR vs. UR; median RFS (months), 17 vs. 13 vs. 11, p = 0.249; median OS (months), 31 vs. 26 vs. 32, p = 0.742). Lymph node metastases and incomplete adjuvant chemotherapy were identified as independent prognostic factors for OS. Although the surgical resection rate was low, particularly in the BR and UR groups, the prognosis of patients who underwent surgical resection was similar irrespective of the initial resectability status. Full article

(This article belongs to the Special Issue Advanced Pancreatic Cancer)

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13 pages, 2202 KiB

Open AccessArticle

Real-World Data Validation of NAPOLI-1 Nomogram for the Prediction of Overall Survival in Metastatic Pancreatic Cancer

by Yung-Yeh Su, Nai-Jung Chiang, Yi-Hsin Yang, Chia-Jui Yen, Li-Yuan Bai, Chang-Fang Chiu, Shih-Chang Chuang, Shih-Hung Yang, Wen-Chi Chou, Jen-Shi Chen, Tai-Jan Chiu, Yen-Yang Chen, De-Chuan Chan, Cheng-Ming Peng, Sz-Chi Chiu, Chung-Pin Li, Yan-Shen Shan and Li-Tzong Chen

Cancers 2023, 15(4), 1008; https://doi.org/10.3390/cancers15041008 - 5 Feb 2023

Cited by 3 | Viewed by 1694

Abstract

Background: The nomogram derived from the pivotal phase III NAPOLI-1 study demonstrated a significant ability to predict median overall survival (OS) in gemcitabine-refractory metastatic pancreatic ductal adenocarcinoma (PDAC) treated with liposomal irinotecan plus fluorouracil and leucovorin (nal-IRI+5-FU/LV). However, the NAPOLI-1 nomogram has not [...] Read more.

Background: The nomogram derived from the pivotal phase III NAPOLI-1 study demonstrated a significant ability to predict median overall survival (OS) in gemcitabine-refractory metastatic pancreatic ductal adenocarcinoma (PDAC) treated with liposomal irinotecan plus fluorouracil and leucovorin (nal-IRI+5-FU/LV). However, the NAPOLI-1 nomogram has not been validated in a real-world setting and therefore the applicability of the NAPOLI-1 nomogram in daily practice remains unknown. This study aims to evaluate the NAPOLI-1 nomogram in a multicenter real-world cohort. Methods: The NAPOLI-1 nomogram was applied to a previously established cohort of metastatic PDAC patients treated with nal-IRI+5-FU/LV in nine participating centers in Taiwan. Patients were divided into three risk groups according to the NAPOLI-1 nomogram. The survival impact of relative dose intensity at 6 weeks (RDI at 6 weeks) in different risk groups was also investigated. Results: Of the 473 included patients, the median OSs of patients classified as low (n = 156), medium (n = 186), and high (n = 131) risk were 10.9, 6.3, and 4.3 months, respectively (p < 0.0001). The survival impact of RDI at 6 weeks remained significant after stratification by risk groups, adjustment with Cox regression, inverse probability weighting, or propensity score matching. Conclusions: Our results support the usefulness of the NAPOLI-1 nomogram for risk stratification in gemcitabine-refractory metastatic PDAC treated with nal-IRI+5-FU/LV in daily practice. We further showed that the RDI at 6 weeks is an independent prognostic factor beyond the NAPOLI-1 nomogram. Full article

(This article belongs to the Special Issue Advanced Pancreatic Cancer)

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12 pages, 687 KiB

Open AccessArticle

Treatment Outcomes and Prognostic Factors of Gemcitabine Plus Nab-Paclitaxel as Second-Line Chemotherapy after Modified FOLFIRINOX in Unresectable Pancreatic Cancer

by Takafumi Mie, Takashi Sasaki, Tsuyoshi Takeda, Takeshi Okamoto, Tsuyoshi Hamada, Takahiro Ishitsuka, Manabu Yamada, Hiroki Nakagawa, Takaaki Furukawa, Akiyoshi Kasuga, Masato Matsuyama, Masato Ozaka and Naoki Sasahira

Cancers 2023, 15(2), 358; https://doi.org/10.3390/cancers15020358 - 5 Jan 2023

Cited by 2 | Viewed by 1435

Abstract

Outcomes and prognostic factors of second-line gemcitabine plus nab-paclitaxel (GnP) after modified FOLFIRINOX (mFFX) for unresectable pancreatic cancer were unclear. We retrospectively analyzed consecutive patients with unresectable pancreatic cancer treated with GnP after first-line mFFX treatment between March 2015 and March 2022 at [...] Read more.

Outcomes and prognostic factors of second-line gemcitabine plus nab-paclitaxel (GnP) after modified FOLFIRINOX (mFFX) for unresectable pancreatic cancer were unclear. We retrospectively analyzed consecutive patients with unresectable pancreatic cancer treated with GnP after first-line mFFX treatment between March 2015 and March 2022 at our hospital. A total of 103 patients were included. Median overall survival (OS) from the start of first-line and second-line treatments was 14.9 months and 7.2 months, respectively. Median progression-free survival (PFS) was 3.6 months. Performance status, modified Glasgow prognostic score, and neutrophil-to-lymphocyte ratio were independently associated with OS. Our prognostic model using these parameters classifies patients into good (n = 70) and poor (n = 33) prognosis groups. Median OS and PFS were longer in the good prognosis group than in the poor prognosis group (OS: 9.3 vs. 3.8 months, p < 0.01; PFS: 4.1 vs. 2.3 months, p < 0.01). Grade 3/4 adverse events were observed in 70.9% of patients, with neutropenia being the most frequent. While GnP as second-line treatment was well-tolerated, efficacy of second-line gemcitabine plus nab-paclitaxel was notably limited, particularly in the poor prognosis group. Full article

(This article belongs to the Special Issue Advanced Pancreatic Cancer)

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11 pages, 749 KiB

Open AccessArticle

Appropriate Lymph Node Dissection Sites for Cancer in the Body and Tail of the Pancreas: A Multicenter Retrospective Study

by Kimitaka Tanaka, Yasutoshi Kimura, Tsuyoshi Hayashi, Yoshiyasu Ambo, Makoto Yoshida, Kazufumi Umemoto, Takeshi Murakami, Toshimichi Asano, Toru Nakamura and Satoshi Hirano

Cancers 2022, 14(18), 4409; https://doi.org/10.3390/cancers14184409 - 11 Sep 2022

Cited by 6 | Viewed by 1593

Abstract

Distal pancreatectomy (DP) with lymphadenectomy is the standard surgery for pancreatic body–tail cancer. However, the optimal lymph node (LN) dissection area for DP remains controversial. Thus, we evaluated the frequency and patterns of LN metastasis based on the tumor site. In this multicenter [...] Read more.

Distal pancreatectomy (DP) with lymphadenectomy is the standard surgery for pancreatic body–tail cancer. However, the optimal lymph node (LN) dissection area for DP remains controversial. Thus, we evaluated the frequency and patterns of LN metastasis based on the tumor site. In this multicenter retrospective study, we examined 235 patients who underwent DP for pancreatic cancer. Tumor sites were classified as confined to the pancreatic body (Pb) or pancreatic tail (Pt). The efficacy index (EI) was calculated by multiplying the frequency of metastasis to each LN station by the five-year survival rate of patients with metastasis to that station. LN metastasis occurred in 132/235 (56.2%) of the patients. Patients with Pb tumors showed no metastasis to the splenic hilum LN. Distal splenic artery LNs and anterosuperior/posterior common hepatic artery LNs did not benefit from dissection for Pb and Pt tumors, respectively. In multivariate analysis, splenic artery LN metastasis was identified as an independent predictor of poor overall survival in patients with pancreatic body–tail cancer. In conclusion, differences in metastatic LN sites were evident in pancreatic body–tail cancers confined to the Pb or Pt. Spleen-preserving pancreatectomy might be feasible for Pb cancer. Full article

(This article belongs to the Special Issue Advanced Pancreatic Cancer)

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Review

Jump to: Research, Other

33 pages, 2586 KiB

Open AccessReview

Earlier Diagnosis of Pancreatic Cancer: Is It Possible?

by Tomas Koltai

Cancers 2023, 15(18), 4430; https://doi.org/10.3390/cancers15184430 - 5 Sep 2023

Cited by 1 | Viewed by 1734

Abstract

Pancreatic ductal adenocarcinoma has a very high mortality rate which has been only minimally improved in the last 30 years. This high mortality is closely related to late diagnosis, which is usually made when the tumor is large and has extensively infiltrated neighboring [...] Read more.

Pancreatic ductal adenocarcinoma has a very high mortality rate which has been only minimally improved in the last 30 years. This high mortality is closely related to late diagnosis, which is usually made when the tumor is large and has extensively infiltrated neighboring tissues or distant metastases are already present. This is a paradoxical situation for a tumor that requires nearly 15 years to develop since the first founding mutation. Response to chemotherapy under such late circumstances is poor, resistance is frequent, and prolongation of survival is almost negligible. Early surgery has been, and still is, the only approach with a slightly better outcome. Unfortunately, the relapse percentage after surgery is still very high. In fact, early surgery clearly requires early diagnosis. Despite all the advances in diagnostic methods, the available tools for improving these results are scarce. Serum tumor markers permit a late diagnosis, but their contribution to an improved therapeutic result is very limited. On the other hand, effective screening methods for high-risk populations have not been fully developed as yet. This paper discusses the difficulties of early diagnosis, evaluates whether the available diagnostic tools are adequate, and proposes some simple and not-so-simple measures to improve it. Full article

(This article belongs to the Special Issue Advanced Pancreatic Cancer)

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32 pages, 4145 KiB

Open AccessReview

Current Pathology Model of Pancreatic Cancer

by Krzysztof Szymoński, Katarzyna Milian-Ciesielska, Ewelina Lipiec and Dariusz Adamek

Cancers 2022, 14(9), 2321; https://doi.org/10.3390/cancers14092321 - 7 May 2022

Cited by 8 | Viewed by 4963

Abstract

Pancreatic cancer (PC) is one of the most aggressive and lethal malignant neoplasms, ranking in seventh place in the world in terms of the incidence of death, with overall 5-year survival rates still below 10%. The knowledge about PC pathomechanisms is rapidly expanding. [...] Read more.

Pancreatic cancer (PC) is one of the most aggressive and lethal malignant neoplasms, ranking in seventh place in the world in terms of the incidence of death, with overall 5-year survival rates still below 10%. The knowledge about PC pathomechanisms is rapidly expanding. Daily reports reveal new aspects of tumor biology, including its molecular and morphological heterogeneity, explain complicated “cross-talk” that happens between the cancer cells and tumor stroma, or the nature of the PC-associated neural remodeling (PANR). Staying up-to-date is hard and crucial at the same time. In this review, we are focusing on a comprehensive summary of PC aspects that are important in pathologic reporting, impact patients’ outcomes, and bring meaningful information for clinicians. Finally, we show promising new trends in diagnostic technologies that might bring a difference in PC early diagnosis. Full article

(This article belongs to the Special Issue Advanced Pancreatic Cancer)

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Other

Jump to: Research, Review

11 pages, 282 KiB

Open AccessSystematic Review

Optimizing First-Line Chemotherapy in Metastatic Pancreatic Cancer: Efficacy of FOLFIRINOX versus Nab-Paclitaxel Plus Gemcitabine

by Francesco Di Costanzo, Federica Di Costanzo, Lorenzo Antonuzzo, Ernesto Mazza and Elisa Giommoni

Cancers 2023, 15(2), 416; https://doi.org/10.3390/cancers15020416 - 8 Jan 2023

Cited by 6 | Viewed by 2811

Abstract

Pancreatic cancer (PC) is one of the most lethal tumors in Europe with an overall 5-year survival rate of 5%. Since 1992, gemcitabine (Gem) has been the treatment of choice for metastatic disease with significant improvement in median overall survival (OS) compared to [...] Read more.

Pancreatic cancer (PC) is one of the most lethal tumors in Europe with an overall 5-year survival rate of 5%. Since 1992, gemcitabine (Gem) has been the treatment of choice for metastatic disease with significant improvement in median overall survival (OS) compared to fluorouracil. A good performance status (PS) at diagnosis appears to be a strong predictive factor for better survival. Overall, 50% of PC are metastatic or locally advanced at diagnosis, and more than 70% of the resected patients will experience a recurrence, with a median OS ranging from 4 to 10 months (mos). FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) and Nab-paclitaxel (Nab-p) plus Gem have recently increased survival of patients with metastatic PC, over Gem. Treatment with FOLFIRINOX is generally considered more effective with respect to the doublet, with toxicity concerns, FOLFIRINOX achieves an overall response rate (ORR) of 31.6%, while for Nab-p plus Gem ORR is 23%; however, FOLFIRINOX was associated with higher rates of grade 3 and higher adverse events. Although the international guidelines indicate that both regimens can be used as first-line therapy for patients with metastatic PC, FOLFIRINOX is the most widely used; Nab-p plus Gem is more frequently used in patients with lower PS. In this review, we critically analyze these two regimens to give a pragmatic guide to treatment options. Full article

(This article belongs to the Special Issue Advanced Pancreatic Cancer)

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