Chemotherapy For Pancreatic Cancer Research Articles

Neoadjuvant chemotherapy and stereotactic body radiation therapy for borderline resectable pancreas adenocarcinoma: influence of vascular margin status and type of chemotherapy

BackgroundThe influence of chemotherapy type and vascular margin status after sequential chemotherapy and stereotactic body radiation therapy (SBRT) for borderline resectable pancreatic cancer (BRPC) is unknown. MethodsA retrospective review was performed on BRPC patients treated with chemotherapy and 5-fraction SBRT from 2009 to 2021. Surgical outcomes and SBRT-related toxicity were reported. Clinical outcomes were estimated by Kaplan–Meier with log rank comparisons. ResultsA total of 303 patients received neoadjuvant chemotherapy and SBRT to a median dose of 40 Gy prescribed to the tumor–vessel interface and median dose of 32.4 Gyto 95% of the gross tumor volume. One hundred and sixty-nine patients (56%) were resected and benefited from improved median OS (41.1 vs 15.5 months, P < 0.001). Close/positive vascular margins were not associated with worse OS or FFLRF. Type of neoadjuvant chemotherapy did not influence OS for resected patients, but FOLFIRINOX was associated with improved median OS in unresected patients (18.2 vs 13.1 months, P = 0.001). ConclusionFor BRPC, the effect of a positive or close vascular margin may be mitigated by neoadjuvant therapy. Shorter duration neoadjuvant chemotherapy as well as the optimal biological effective dose of radiotherapy should be prospectively explored.

From bugs to drugs: Bacterial 3-IAA enhances efficacy of chemotherapy in pancreatic cancer

Tintelnot etal.1 identified enrichment of indole-3-acetic acid (3-IAA), a tryptophan metabolite produced by gut microbiota, as a predictor of chemotherapy response in pancreatic adenocarcinoma. Recapitulated in mouse models, 3-IAA represents a novel potential therapeutic approach for chemotherapy sensitization.

Role for Neoadjuvant Systemic Therapy for Potentially Resectable Pancreatic Cancer.

Despite aggressive adjuvant management, a high percentage of patients who undergo appropriate surgical resection for pancreatic cancer will see their cancer recur and thus will not be cured. An important paradigm shift to achieve better outcomes has been therapy sequence, with neoadjuvant chemotherapy preceding surgery. Patients with a borderline resectable cancer, or patients with a resectable cancer but who have other high-risk features, are ideal candidates to consider for neoadjuvant chemotherapy. Among the high-risk features, a baseline elevated CA 19-9 concentration can be particularly useful, as its response trend during neoadjuvant chemotherapy can offer important insights into the prognosis after surgery. When selecting a neoadjuvant chemotherapy regimen, response data available for the use of FOLFIRINOX and gemcitabine and nabpaclitaxel in the metastatic setting support their use in this space. FOLFIRINOX is perhaps the preferred regimen, given its proven adjuvant benefit and possibly its superior tumor response rate; still, patient tolerance and thus ability to complete recommended treatment must be carefully considered. This review presents the evidence supporting neoadjuvant chemotherapy for resectable pancreatic cancer, the factors to consider when making such a recommendation, the selection of specific regimens, and our institutional approach using these tools.

Neoadjuvant chemotherapy for pancreatic cancer: Quality over quantity.

The ideal duration of neoadjuvant chemotherapy (NACT) in patients with localized pancreatic adenocarcinoma (PDAC) treated with curative intent is unclear. We sought to determine the prognostic significance of both duration of NACT and Carbohydrate Antigen 19-9 (CA19-9) normalization to NACT. We examined patients with resectable and borderline resectable PDAC treated with NACT and chemoradiation. Patients were compared by NACT duration (2 vs. 4 months) and by CA19-9 normalization after NACT. Among 171 patients, 83 (49%) received 2 months of NACT, and 88 (51%) received 4 months. After NACT completion, 115 (67%) patients had persistently elevated CA19-9, and 56 (33%) had normalized. Of the 125 patients who had successful surgery, 73 (58%) had normalized CA19-9 postoperatively. Duration of NACT was not associated with overall survival (OS) while CA19-9 normalization after NACT (regardless of duration) was associated with improved OS (hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.35-0.89, p = 0.02). Adjuvant chemotherapy was associated with improved OS among patients without CA19-9 normalization after NACT (HR 0.42, CI 0.20-0.86, p = 0.02) but not among those that normalized, independent of duration. CA19-9 normalization after NACT is a clinically significant endpoint of treatment; patients without CA19-9 normalization may benefit from additional therapy.

Transcytosis Mediated Deep Tumor Penetration for Enhanced Chemotherapy and Immune Activation of Pancreatic Cancer

AbstractThe hyperproliferative tumor stroma of pancreatic ductal adenocarcinoma (PDAC) severely limits drug permeation and constructs an immunosuppressive microenvironment, causing resistance to chemotherapy and immunotherapy. Traditional nanomedicine mainly focuses on manipulating nanoparticles’ particle size or electrical characteristics to penetrate deep PDAC through the paracellular pathway, but the transcellular pathway is often ignored. Therefore, a versatile drug‐polymer conjugate PODEA‐Gem‐HMI is prepared and assembled into nanoparticles for the codelivery of chemotherapy drug gemcitabine and focal adhesion kinase (FAK) inhibitor defactinib. While sensing the mild acidity in the tumor microenvironment, the nanoparticle will disintegrate and release defactinib to modulate the tumor stroma. The PODEA block of the conjugate can bind with cell membranes reversibly and trigger adsorption‐mediated transcytosis (AMT) for promoted tumor penetration and cellular uptake. The internalized conjugates will release gemcitabine responding to the overexpressed glutathione (GSH) for enhanced chemotherapy, and PHMI can condensate the STING monomers for prolonged spontaneous immune stimulation.

Abstract 3405: Changes in HER3 expression associated with chemotherapy for pancreatic cancer

Abstract Background: Currently, intense efforts towards the development of targeted therapy, including anti-HER3 strategies for cancer treatment, are being made. Recently, HER3 activation was linked to resistance to targeted therapies (EGFR/HER2/MEK/RAF) and hormonal therapy by upregulating HER3 expression after those treatments in several cancer types. However, HER3 expression profile in pancreatic cancer treatment is still unknown. Here, we evaluated the status of HER3 expression after chemotherapy for pancreatic cancer. Methods: Patients with pancreatic cancer who underwent chemotherapy between January 2010 and June 2020 and from whom post-treatment archival tissue specimens were collected were included in this study. All resectable and locally advanced cases were evaluated using resected specimens, and all metastatic cases were evaluated using biopsy specimens. In patients from whom both pre- and post-chemotherapy specimens were collected, changes in HER3 expression status before and after treatment were immunohistochemically evaluated by using HER3/ErbB3 (D22C5) XP Rabbit mAb (Cell Signaling Technology) as a primary antibody. IHC scoring (0, 1+, 2+, 3+) of membranous staining intensity was performed according to HER2 IHC gastric scoring guideline. Results: Post-chemotherapy HER3 expression was evaluable in 41 patients, comprising 12, 14, 14, and 1 case as HER3 3+, 2+, 1+ and 0, respectively. In the HER3 3+/2+ and 1+/0 groups, tumor localization was 69%/67% in the pancreatic head, 23%/13% in the pancreatic body, and 8%/20% in the pancreatic tail; tumor stage was resectable (post-neoadjuvant status) 46%/20%, locally advanced 42%/47%, and metastatic 12%/33%; the median tumor size was 30 mm/35 mm; CEA elevation was 23%/20% and CA19-9 elevation was 69%/73%; treatment regimens were FOLFIRINOX 23%/40%, gemcitabine + nab-paclitaxel 19%/0%, gemcitabine + S-1 (neoadjuvant setting) 42%/27%, and the other chemotherapy 4%/20%, respectively. HER3 expression was able to be evaluated before and after chemotherapy in 5 cases: HER3 IHC score changed from 3+/2+ to 1+/0 for 1 case, from 1+/0 to 3+/2+ for 1 case and maintained at 3+/2+ for 3 cases. The median overall survival was 19.6 and 20.5 months in the HER3 3+/2+ and HER3 1+/0 groups, respectively (P = 0.965). Conclusion: HER3 expression with 3+/2+ is observed in 63% of pancreatic cancer patients, and HER3-expressing pancreatic cancer is of great interest as a therapeutic target. HER3 expression status may change before and after cytotoxic combination therapy in some cases of pancreatic cancer. Citation Format: Tomoyuki Satake, Chigusa Morizane, Mao Okada, Mariko Nishioka, Nobuyoshi Hiraoka, Satoshi Nara, Tomoya Kakegawa, Maki Kobayashi, Kumiko Koyama, Minoru Esaki, Takuji Okusaka. Changes in HER3 expression associated with chemotherapy for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3405.

Abstract 3963: Mass spectrometry reveals a downregulation of calreticulin after neoadjuvant chemotherapy in pancreatic cancer

Abstract Introduction: Pancreatic ductal adenocarcinomas are one of the deadliest cancer types with limited response to current therapies. Thus, this study examined changes in the proteome of epithelial cells in pancreatic cancer after neoadjuvant chemotherapy with gemcitabine, to identify new therapeutic targets. Methods: Upon receiving patient consent, fresh pancreatic cancer tissue was received from surgical tumor resections at the University Hospital of Bonn. We mechanically and enzymatically digested and purified the tissue to create single-cell suspensions. After staining the cells against CD45 und CD326, we purified epithelial cells, blood cells, and stroma through FACS. To analyze their proteome, the sorted cells were lysed in TEAB buffer and the protein lysates were measured by the mass spectrometry core facility at the University of Bonn. We then analyzed the data using DAVID and Shiny GO. Results: Gene enrichment analyses showed a significantly reduced expression of calreticulin after neoadjuvant chemotherapy in epithelial cells. A direct comparison between untreated and treated epithelium cancer cells using a heat map showed a decreased expression of actin and enzymes of glycolysis in treated cancer cells. Moreover, untreated epithelial cells showed an increase of proteins related to MHC class Ib protein complex assembly and antigen processing and presentation of endogenous peptide antigen via MHC class. In contrast, treated cells showed a higher presence of proteins for nutrient supply from the blood. Furthermore, untreated stroma cells exhibited an increased number of proteins responsible for mesenchymal migration and for actin filament fragmentation. Conclusion: This study shows that neoadjuvant chemotherapy with gemcitabine leads to distinct changes in the proteome of tumor cells in pancreatic cancers. In particular, a decreased expression of the “eat-me-signal” calreticulin impairs macrophage-mediated cancer cell phagocytosis, thereby indicating a mechanism by which cancer cells protect themselves after chemotherapy. Citation Format: Michael C. Stoffel, Elisabeth BH Dingendorf, Dahlia L. Kittel, Glen Kristiansen, Tristan Lerbs. Mass spectrometry reveals a downregulation of calreticulin after neoadjuvant chemotherapy in pancreatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3963.

Abstract 5907: The tumor microbiome associates with features of the tumor microenvironment, treatment outcomes, and histologies: A national collaboration of the exORIEN Consortium

Abstract A tumor microbiome has recently been established as present in many cancer types. Further study is needed to define the scope of its role in cancer tumorigenesis, progression, and treatment outcomes. The Oncology Research Information Exchange Network (ORIEN) established a collaboration among eight member institutions to study the tumor microbiome and clinical features across several cancers. We evaluated RNAseq data from n = 2,892 tumors, including colorectal adenocarcinomas, lung adeno- and squamous cell carcinomas, pancreatic adenocarcinomas, sarcomas, melanomas, and thyroid carcinomas, using the tool {exotic}. Matched cancers from the Cancer Genome Atlas were processed by the same method (n = 2,720 samples). Clinical data, including treatment information, lab values, detailed histology, and long-term follow-up, were collected and harmonized across sites. Microbe abundances (bacteria, fungi, and viruses) were associated with clinical features and human gene expression, which was deconvolved into immune cell composition using {CIBERSORT} and {TIMEx}, and aggregated into expression signatures using {tmesig} and {IOSig}. Microbes were found in all tumors and associated with treatment outcomes for all modalities tested, including radiation in colorectal cancer, chemotherapy in pancreatic cancer, and immunotherapy in melanoma. In the case of radiation treatment in colorectal cancer, the microbes also affected outcomes in preclinical model systems and were modified by altering hypoxia levels with the drug atovaquone. Virus prevalence associated with histological subtypes in lung cancer. Similar microbes in ORIEN and TCGA tumors associated with overall survival in subtypes of sarcoma (dedifferentiated liposarcoma, leiomyosarcoma, and others). Finally, microbes associated with expression-based indicators of the tumor microenvironment across cancer types. These results suggest that the tumor microbiome may have broad clinical utility as a biomarker of treatment outcomes and as a target for rational manipulation. Citation Format: Rebecca Hoyd, Caroline E. Wheeler, Samuel Coleman, Louis Denko, Carlos Chan, Yousef Zakharia, Rebecca Dodd, Cornelia M. Ulrich, Sheetal Hardikar, Jennifer Ose, Michelle Churchman, Ahmad Tarhini, Lary A. Robinson, Eric Singer, Alexandra P. Ikeguchi, Martin McCarter, Kyra Anderson, John Carpten, Gabriel Tinoco, Marium Hussain, Nicolas Denko, YunZhou Liu, Ning Jin, Youngchul Kim, Asgeir Masson, Naomi Fei, Martin Benej, McKenzie Kreamer, Dennis Dennis Grencewicz, Ahmed Hussein, Aik Choon Tan, Daniel Spakowicz. The tumor microbiome associates with features of the tumor microenvironment, treatment outcomes, and histologies: A national collaboration of the exORIEN Consortium. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5907.

Abstract 2929: Modular peptide cargo delivery by targeting CD40 enables ligandome driven, precision immunotherapy via the Adaptable Drug Affinity Conjugate (ADAC™) technology

Abstract Agonistic anti-CD40 therapy has shown impressive efficacy in preclinical murine models, models inert to toxicity of high systemic drug exposure. Clinical data consist of pharmacodynamic responses reported as non-specific cytokine release, transient drop of CD40-expressing cells in blood and induction of co-stimulatory ligands/receptors on antigen-presenting cells, but so far clinically meaningful efficacy data on monotherapy use is lacking. Clinical data also indicate a bell-shaped dose-response curve, with excessive immune activation leading to immune exhaustion when combined with check-point inhibitors[1]. Intratumoral route of administration, bispecific antibodies for tumor drug localization or Antibody-Drug Conjugates (ADCs) carrying antigenic cargo are or have been assessed, but have associated clinical utility enigmas. Herein we present a novel solution ensuring modular peptide delivery along with an efficient T cell priming strategy; a bivalent anti-CD40 agonistic antibody equipped with a peptide-binding single chain variable fragment (scFv) that binds a short peptide tag (pTag) in the low nM range. The resulting drug strategy makes use of synthetic long peptide production of any tumor-associated antigen (TAA) of choice where the pTag itself ensures simple conjugate production to the protein, through affinity linkage, leading to a final rapid in-hospital mixing step. Data suggest that the novel candidate drug (STRIKE2001), now developed based on the ADAC concept[2], retains similar agonistic activity in its bispecific, IgG2 format and does not inhibit CD40L binding to the CD40 protein. Data further show impressive expansion of endogenous tumor-specific T cells (as measured by tetramer staining), along with effective anti-tumor responses in the TC1 model. In addition, by using the subcutaneous delivery strategy CD40 agonist exposure to liver and spleen is vastly reduced, limiting systemic immune toxicity/exhaustion risks[3]. [1] Padrón, L.J., et al. Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial. Nat Med 28, 1167-1177 (2022). https://doi.org/10.1038/s41591-022-01829-9 [2] Eltahir, M., et al. (2022), An Adaptable Antibody-Based Platform for Flexible Synthetic Peptide Delivery Built on Agonistic CD40 Antibodies. Adv. Therap., 5: 2200008. https://doi.org/10.1002/adtp.202200008 [3] Sandin, L., et al. Locally Delivered CD40 Agonist Antibody Accumulates in Secondary Lymphoid Organs and Eradicates Experimental Disseminated Bladder Cancer. Cancer Immunol Res 1 January 2014; 2 (1): 80-90. https://doi.org/10.1158/2326-6066.CIR-13-0067 Citation Format: Aman Mebrahtu, Ida Lauren, Rosanne Veerman, Alexandros Kostakis, Gözde Gucluler Akpinar, Oskar Andersson, Lindvi Gudmundsdotter, Tina Furebring, Helena Persson, Pierre Donnes, Johan Rockberg, Sara Mangsbo. Modular peptide cargo delivery by targeting CD40 enables ligandome driven, precision immunotherapy via the Adaptable Drug Affinity Conjugate (ADAC™) technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2929.

Abstract 2186: An exploratory analysis of the intestinal microbiome in neoadjuvant chemotherapy for pancreatic cancer

Abstract Background: Pancreatic cancer portends a very poor prognosis. It is the third leading cause of cancer deaths in the United States. African Americans have a 50- 90% increased incidence of pancreatic cancer in comparison to other racial groups. 20% of patients with pancreatic cancer present with early-stage disease and will have a median overall survival of 2.5 years if able to undergo surgical resection. There is a desperate need to discover novel ways of treating pancreatic cancer. Understanding of the microbiome may be informative to overcoming chemotherapy resistance, toxicity and improving outcomes and disparities. The aim of this study is to (1) identify changes in the intestinal microbiota during neoadjuvant treatment of pancreatic ductal adenocarcinoma that correlate with treatment response and (2) identify changes in the intestinal microbiota during neoadjuvant treatment of pancreatic ductal adenocarcinoma that correlate with treatment toxicity in a diverse patient population. Methods: Patients with resectable or borderline resectable pancreatic cancer who are enrolled in a multi-site clinical trial (NCT03483038) receiving neoadjuvant NEO-Nali-IRI (oxaliplatin, liposomal irinotecan and 5- FU) followed by surgical resection were asked to provide stool samples and a dietary log during the following four (or five) time points: baseline, mid-therapy (after C4), at completion of chemotherapy (after C8), after radiation if applicable, and at 4-6 weeks post-operative. Participants will be given stool collection kits at clinic visits for home sample acquisition. All samples will be mailed to the University of Florida Health Cancer Center Microbiome Biorepository. Data will be collected regarding demographics, stage, medical history and concurrent medications including antimicrobics and probiotics, chemotherapy dose-reductions, delays, discontinuations, adverse events, safety adverse events, attribution of causality, and hospitalizations. Outcomes will include imaging response using RECIST criteria, CA 19-9 trend, development of metastatic disease, and the ability to proceed to definitive surgical resection. DNA will be extracted from stool and analyzed using 16S rRNA sequencing methods to determine signatures and biodiversity. Descriptive statistics and correlative analysis will be reported. Continuous and categorical variables will be compared with Student’s t-test and Chi-squared test. Multiple groups will be compared by ANOVA. Kaplan-Meier logistic regression will be performed to compare outcomes between the different microbiota groupings. Conclusion: Stool collection from a multi-site clinical trial is feasible during neoadjuvant chemotherapy for pancreatic cancer and can increase diversity of the sample population. Citation Format: Sherise Rogers, Ryan Thomas, Brain Ramnaraign, Ilyas Sahin, Jesus Fabregas, Karen Russell, Steven Hughes, Ibrahim Nassour, Kathyrn Hitchcock, Omar Kayaleh, Anita Turk, Ji-Hyun Lee, David DeRemer, Carmen Allegra, Thomas George. An exploratory analysis of the intestinal microbiome in neoadjuvant chemotherapy for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2186.

Neoadjuvant chemotherapy for resectable pancreatic cancer: a new standard of care?

Aim. To evaluate the potential of neoadjuvant chemotherapy in resectable pancreatic cancer based on the results of randomized clinical trials and meta-analyses. Materials and methods. PubMed, Сochrane, EMBASE, GoogleScholar databases were used for bibliographic search with keywords MESH “neoadjuvanttherapy” in combination with “pancreaticcancer”, “resectable”, “pancreaticoduodenectomy”. Results. At the beginning of the 21st century the understanding of pancreatic cancer biology changed. A tumor should be considered a systemic disease even in its early stages, with small size and without lymph node involvement. The necessity for application of neoadjuvant polychemotherapy in patients with resectable tumors is an important issue. The efficacy and safety of the method has been proved. However, a number of questions are still to be answered. Whether neoadjuvant polychemotherapy in patients with resectable pancreatic cancer will be a new achievement of chemotherapy and the standard of care is a matter for future clinical research. Conclusion. Neoadjuvant polychemotherapy in patients with resectable pancreatic cancer is a promising therapy that can improve oncological outcomes of treatment. However, the evidence for this argument is currently insufficient.

Clinical Practice Guidelines for Pancreatic Cancer 2022 from the Japan Pancreas Society: a synopsis

ObjectivesClinical Practice Guidelines for Pancreatic Cancer was first published in 2006 by the Japan Pancreas Society, and revised in 2009, 2013, 2016, and 2019. In July 2022, Clinical Practice Guidelines for Pancreatic Cancer was newly revised in Japanese.MethodsFor this revision, we developed an entirely new guideline according to the Minds Manual for Guideline Development 2020, which includes the concepts of GRADE—Grading Recommendations Assessment, Development, and Evaluation, to enable a better understanding of the current guidelines. Patients and the public were actively involved in both the development and implementation of the guideline.ResultsThe guideline includes algorithms for diagnosis, treatment, chemotherapy, and precision medicine of pancreatic cancer, and addresses 7 subjects: diagnosis, surgical therapy, adjuvant therapy, radiation therapy, chemotherapy, stent therapy, and supportive & palliative medical care. It includes 73 clinical questions and 112 statements. The statements correspond to the clinical questions, evidence levels, recommendation strengths, and agreement rates.ConclusionsThis guideline represents the most standard clinical and practical management guideline available until date in Japan. This is the English synopsis of the Clinical Practice Guidelines for Pancreatic Cancer 2022 in Japanese, and is an attempt to disseminate the Japanese guideline worldwide to introduce the Japanese approach to the clinical management of pancreatic cancer.

Impact of skeletal muscle mass on the prognosis of patients undergoing neoadjuvant chemotherapy for resectable or borderline resectable pancreatic cancer

Neoadjuvant chemotherapy is a common therapeutic procedure for patients with pancreatic cancer. This study aimed to investigate the association between the total psoas area (TPA) and prognosis in patients undergoing neoadjuvant chemotherapy for resectable or borderline resectable pancreatic cancer. This retrospective study included patients who underwent neoadjuvant chemotherapy for pancreatic cancer. TPA was measured at the level of the L3 vertebra using computed tomography. The patients were divided into low-TPA and normal-TPA groups. These dichotomizations were separately performed in patients with resectable and those with borderline resectable pancreatic cancer. In total, 44 patients had resectable pancreatic cancer and 71 patients had borderline resectable pancreatic cancer. Overall survival among patients with resectable pancreatic cancer did not differ between the normal- and low-TPA groups (median, 19.8 vs. 21.8months, p = 0.447), whereas among patients with borderline resectable pancreatic cancer, the low-TPA group had shorter overall survival than the normal-TPA group (median, 21.8 vs. 32.9months, p = 0.006). Among patients with borderline resectable pancreatic cancer, the low-TPA group was predictive of poor overall survival (adjusted hazard ratio, 2.57, p = 0.037). Low TPA is a risk factor of poor survival in patients undergoing neoadjuvant chemotherapy for borderline resectable pancreatic cancer. TPA evaluation could potentially suggest the treatment strategy in this disease.

High Serum 3-IAA Improves Chemotherapy Response in Pancreatic Cancer.

The microbiota-derived metabolite 3-IAA amplifies the response to chemotherapy in pancreatic cancer.

Intra-arterial regional chemotherapy for pancreatic cancer (review)

Pancreatic cancer, despite its low prevalence, is the fourth most common cause of cancer death, with a 5-year survival rate of no more than 10 %. Experts predict that by 2030, pancreatic cancer will become the second most common cause of death from malignant neoplasms, surpassing colorectal and breast cancers. Thus, pancreatic cancer is characterized by very unfavorable prognosis, primarily due to the chemoresistant nature of the tumor.Only a few treatment options for pancreatic cancer are currently available, with low response rates, short progression-free survival and short overall survival, and severe toxicity. In order to improve clinical outcomes, a number of studies on the use of regional chemotherapy as a treatment option for pancreatic cancer have demonstrated dose-dependent tumor sensitivity. Chemotherapy by intra-arterial perfusion of the pancreas made it possible to increase local concentrations of chemotherapeutic agents with minimal effect on healthy tissues and a lower incidence of side effects compared to systemic chemotherapy. This therapeutic approach has demonstrated a good therapeutic effect in the treatment of malignant neoplasms of other localizations. This review summarizes clinical approaches to chemotherapeutic administration by intra-pancreatic intra-arterial perfusion in terms of methods, pharmacokinetics, and clinical outcomes.

Effect of exosomes as drug carriers in chemotherapy of pancreatic cancer.

Pancreatic cancer (PC) is a malignant tumor of the digestive tract with poor patient prognosis. The PC incidence is still increasing with a 5-year survival rate of only 10%. At present, surgical resection is the most effective method to treat PC, however, 80% of the patients missed the best time for surgery after they have been diagnosed as PC. Chemotherapy is one of the main treating methods but PC is insensitive to chemotherapy, prone to drug resistance, and is accompanied by many side effects which are related to a lack of specific target. Exosomes are nanoscale vesicles secreted by almost all cell types and can carry various bioactive substances which mediate cell communication and material transport. They are characterized by a low immunogenicity, low cytotoxicity, high penetration potential and homing capacity, and possess the potential of being used as advanced drug carriers. Therefore, it is a hot research topic to use drug-loaded exosomes for tumor therapy. They may alleviate chemotherapy resistance, reduce side effects, and enhance the curative effect. In recent years, exosome drug carriers have achieved considerable results in PC chemotherapy studies.

Research Highlights Role of Adjuvant Chemotherapy in Pancreatic Cancer

Research Highlights Role of Adjuvant Chemotherapy in Pancreatic Cancer

A small Rho GTPase RAB25 with a potential role in chemotherapy resistance in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) is one of the major human health challenges with minimal therapeutic benefits due to its late detection, and de novo - and acquired chemotherapy resistance. In this work we unravel the potential pro-survival role of RAB25 in pancreatic cancer chemotherapy resistance and aim to identify if RAB25is a prognostic marker of patients' survival in PDA. We used RNA sequencing, shRNA mediated gene knockdown, BioGRID open repository of CRISPR screens (ORCS), GEPIA, kmplot.com, and cBioPortal.org databases to identify the role of RAB25 in PDA cell proliferation, chemotherapy response, expression in tumour versus normal tissues, and overall patients' survival. RNA sequencing show Rab25 to be one of the top upregulated genes in gemcitabine resistant mouse PDA cells. Knockdown of Rab25 in these cells enhanced gemcitabine toxicity. In addition, re-analysis of previously published CRISPR/Cas9 data confirm RAB25 to be responsible for chemotherapy resistance in KRASG12D mutant human pancreatic cancer cell line. Finally, we used publicly available TCGA datasets and identify the upregulation of RAB25 in tumour tissues compared to the adjacent normal tissue, co-occurrence of KRASG12 mutations with RAB25 amplifications, and poor patients' survival in cohorts with higher mRNA expression of RAB25. RAB25 expression is a prognostic marker for patient's survival and gemcitabine resistance in PDA.

No survival benefit with suboptimal CA19-9 response: defining effective neoadjuvant chemotherapy in resectable or borderline resectable pancreatic cancer

Background/purposeNeoadjuvant chemotherapy (NAC) is gaining popularity over a surgery-first (SF) approach in treating resectable and borderline resectable pancreatic ductal adenocarcinoma (PDAC). However, what constitutes effective neoadjuvant chemotherapy is unknown. MethodsWe retrospectively analyzed resectable and borderline resectable PDAC patients who underwent pancreaticoduodenectomy (2010–2019) at a single institution. Optimal CA19-9 response was defined as normalization AND >50% reduction. We utilized Kaplan-Meier and multivariable-adjusted Cox models and competing risk subdistribution methods for statistical analysis. Results586 patients were included in this study. The multivariable-adjusted analysis demonstrated OS benefit in the NAC group only when OS was calculated from diagnosis (HR = 0.72, p = 0.02), but not from surgery (HR = 0.81, p = 0.1). However, in 59 patients who achieved optimal CA19-9 response, OS is significantly longer than the 134 patients with suboptimal CA19-9 response (39.3 m vs. 21.5 m, p = 0.005) or the 117 SF patients (39.3 m vs. 19.5 m, p < 0.001). Notably, a suboptimal CA19-9 response conferred no OS advantage compared to SF patients. The accumulative incidence of liver metastases (but not other metastases) was significantly reduced only in patients with optimal CA19-9 response to NAC (multivariable-adjusted subdistribution HR = 0.26, p = 0.03). ConclusionCA19-9 response to NAC may serve as the marker for effective NAC. These findings warrant validation in a multi-institutional study.

Clinical therapeutic effects of neoadjuvant chemotherapy in resectable pancreatic cancer.

677 Background: Results from the phase III Prep-02/JSAP-05 trial demonstrated the efficacy and safety of gemcitabine plus S-1 as neoadjuvant chemotherapy for resectable pancreatic cancer. However, consensus on neoadjuvant chemotherapy for pancreatic cancer has not yet been established, and the effects of neoadjuvant therapy on clinical features of the tumor and improvement in prognosis have not been fully investigated. We aimed to investigate the effect of neoadjuvant chemotherapy on resectable pancreatic cancer. Methods: Between 2013 and 2021, 291 patients who underwent curative resection for resectable pancreatic cancer at our hospital were enrolled. The patients were categorized into groups of those who received neoadjuvant chemotherapy (NAC group: n = 91) and those who received up-front surgery (US group: n = 200). Prognostic predictors were examined in (i) all patients, (ii) US group, and (iii) NAC group. Statistical significance was considered at p &lt; 0.05. Results: The median follow-up periods were 20.7 and 33.2 months in the NAC and US groups, respectively. In the NAC group, 84 of the 91 patients (94.5%) received gemcitabine-based chemotherapy, and three (3.3%) received chemoradiotherapy. There was no difference in overall survival (OS) and recurrence free survival (RFS) between the two groups. In the background, the NAC group had lower preoperative CA19-9 levels, lower lymph node ratio (LNR), and smaller tumor size than in the US group. During multivariable analysis of OS, preoperative CA19-9 levels, LNR, modified Glasgow prognostic score (mGPS), resection margin, and tumor size were identified as possible prognostic predictors in all patients and in the US group, whereas LNR and mGPS were identified in the NAC group. Conclusions: The prognostic significance of preoperative CA19-9 level, tumor size, and LNR were counteracted in the NAC group. These findings may indicate the effect of neoadjuvant chemotherapy for resectable pancreatic cancer.