Close relationship between mediators of inflammation and pancreatic cancer: Our experience.

In this editorial, we focus specifically on the mechanisms by which pancreatic inflammation affects pancreatic cancer. Cancer of the pancreas remains one of the deadliest cancer types. The highest incidence and mortality rates of pancreatic cancer are found in developed countries. Trends of pancreatic cancer incidence and mortality vary considerably worldwide. A better understanding of the etiology and identification of the risk factors is essential for the primary prevention of this disease. Pancreatic tumors are characterized by a complex microenvironment that orchestrates metabolic alterations and supports a milieu of interactions among various cell types within this niche. In this editorial, we highlight the foundational studies that have driven our understanding of these processes. In our experimental center, we have carefully studied the mechanisms of that link pancreatic inflammation and pancreatic cancer. We focused on the role of mast cells (MCs). MCs contain pro-angiogenic factors, including tryptase, that are associated with increased angiogenesis in various tumors. In this editorial, we address the role of MCs in angiogenesis in both pancreatic ductal adenocarcinoma tissue and adjacent normal tissue. The assessment includes the density of c-Kit receptor-positive MCs, the density of tryptase-positive MCs, the area of tryptase-positive MCs, and angiogenesis in terms of microvascularization density.

A Case of Pancreatic Ductal Adenocarcinoma in an Elderly Adult With Heterotaxy Syndrome.

Heterotaxy is a syndrome characterized by a spectrum of anatomical anomalies in organ lateralization due to embryological errors. It frequently involves intrathoracic organs, especially the heart, leading to congenital abnormalities. Abdominal organs can also be affected, causing clinical features such as sepsis from asplenia or intestinal volvulus; however, these are less studied. Currently, there is no data on the relationship between heterotaxy and malignancy. We present an interesting case of an elderly adult admitted for a workup of newly diagnosed pancreatic ductal carcinoma, who was found to have heterotaxy of the stomach and spleen, with eventual tumor invasion of these organs. This case suggests that heterotaxy may increase the risk of gastrointestinal malignancy and result in a poorer prognosis due to the complexity of tumor resection involving additional organs.

Scope transition and early arterial inflow control provide safe and comfortable dissection in robotic distal pancreatectomy.

PURPOSE: We describe details and outcomes of a novel technique for optimizing the surgical field during robotic distal pancreatectomy (RDP) for distal pancreatic lesions, which has become common with potential advantages over laparoscopic surgery. METHODS: For suprapancreatic lymph node dissection and splenic artery ligation, we used the basic center position with a scope through the midline port. During manipulation of the perisplenic area, the left position was used by moving the scope to the left medial side. The left lateral position is optionally used by moving the scope to the left lateral port when scope access to the perisplenic area is difficult. In addition, early splenic artery clipping and short gastric artery dissection for inflow block were performed to minimize bleeding around the spleen. We evaluated retrospectively the surgical outcomes of our method using a scoring system that allocated one point for blood inflow control and one point for optimizing the surgical view in the left position. RESULTS: We analyzed 34 patients who underwent RDP or R-radical antegrade modular pancreatosplenectomy (RAMPS). The left position was applied in 14 patients, and the left lateral position was applied in 6. Based on the scoring system, only the 0-point group (n = 8) had four bleeding cases (50%) with splenic injury or blood pooling; the other 1-point or 2-point groups (n = 13, respectively) had no bleeding cases (p = 0.0046). CONCLUSION: Optimization of the surgical field using scope transition and inflow control ensured safe dissection during RDP.

Prospective study on stereotactic body radiotherapy for small pancreatic neuroendocrine tumors: tolerance and effectiveness analysis.

INTRODUCTION: Surgery is the standard treatment for pancreatic neuroendocrine tumors (pNETs), obtaining favorable results but associating high morbidity and mortality rates. This study assesses stereotactic body radiation therapy (SBRT) as a radical approach for small (< 2 cm) nonfunctioning pNETs. MATERIALS AND METHODS: From January 2017 to June 2023, 20 patients with small pNETs underwent SBRT in an IRB-approved study. Endpoints included local control, tolerance, progression-free survival, and overall survival (OS). Diagnostic assessments comprised endoscopy, CT scans, OctreScan or PET-Dotatoc, abdominal MRI, and histological confirmatory samples. RESULTS: In a 30-month follow-up of 20 patients (median age 55.5 years), SBRT was well-tolerated with no grade > 2 toxicity. 40% showed morphological response, 55% remained stable. Metabolically, 50% achieved significant improvement. With a median OS of 41.5 months, all patients were alive without local or distant progression or need for surgical resection. CONCLUSION: SBRT is a feasible and well-tolerated approach for small neuroendocrine pancreatic tumors, demonstrating effective local control. Further investigations are vital for validation and extension of these findings.

Laparoscopic antegrade spleen-preserving distal pancreatectomy with conservation of the splenic vessels: a prospective multi-centre case series (with video).

Introduction: Laparoscopic spleen-preserving distal pancreatectomy (LSPDP) with conservation of the splenic artery and vein (Kimura' technique) is considered a technically challenging procedure that requires a high level of expertise in laparoscopic and pancreatic surgery. Methods: A prospective descriptive study on 18 patients with laparoscopic "antegrade" spleen-preserving distal pancreatectomy with Kimura' technique from 2018 to 2023. The perioperative indications, clinical data, intraoperative index, pathological postoperative specimens, postoperative complications, and follow-up results were retrospectively evaluated. Results: The mean age was 39.4±13.3. Only 2 male patients accounted for 11.1%. The average operating time is 171±23 min. The average blood loss is 65.7±43 ml. The average tumor size is 4.1 cm. The average hospitalization is 9.4 days. The rate of pancreatic fistula is 66.7%. There is no case of transferring open surgery or blood transfusion during surgery. The results of pathological after surgery there were eight cases of solid pseudopapillary tumors, four cases of mucinous cystadenoma, six cases of neuroendocrine tumors. Conclusion: Kimura's technique for laparoscopic spleen-preserving distal pancreatectomy is safe and feasible, which can be applied to benign tumors in the body and tail of the pancreas. However, this is a difficult technique in laparoscopic surgery that requires surgeons to have a lot of experience and equipment need to be adequate.

CCK Receptor Inhibition Reduces Pancreatic Tumor Fibrosis and Promotes Nanoparticle Delivery.

The poor prognosis for pancreatic ductal adenocarcinoma (PDAC) patients is due in part to the highly fibrotic nature of the tumors that impedes delivery of therapeutics, including nanoparticles (NPs). Our prior studies demonstrated that proglumide, a cholecystokinin receptor (CCKR) antagonist, reduced fibrosis pervading PanIN lesions in mice. Here, we further detail how the reduced fibrosis elicited by proglumide achieves the normalization of the desmoplastic tumor microenvironment (TME) and improves nanoparticle uptake. One week following the orthotopic injection of PDAC cells, mice were randomized to normal or proglumide-treated water for 3-6 weeks. Tumors were analyzed ex vivo for fibrosis, vascularity, stellate cell activation, vascular patency, and nanoparticle distribution. The histological staining and three-dimensional imaging of tumors each indicated a reduction in stromal collagen in proglumide-treated mice. Proglumide treatment increased tumor vascularity and decreased the activation of cancer-associated fibroblasts (CAFs). Additionally, PANC-1 cells with the shRNA-mediated knockdown of the CCK2 receptor showed an even greater reduction in collagen, indicating the CCK2 receptors on tumor cells contribute to the desmoplastic TME. Proglumide-mediated reduction in fibrosis also led to functional changes in the TME as evidenced by the enhanced intra-tumoral distribution of small (<12 nm) Rhodamine-loaded nanoparticles. The documented in vivo, tumor cell-intrinsic anti-fibrotic effects of CCK2R blockade in both an immunocompetent syngeneic murine PDAC model as well as a human PDAC xenograft model demonstrates that CCK2R antagonists, such as proglumide, can improve the delivery of nano-encapsulated therapeutics or imaging agents to pancreatic tumors.

A case of pancreatic PEComa with prominent inflammatory cell infiltration: the inflammatory subtype is a distinct histologic group of PEComa.

BACKGROUND: PEComa is a mesenchymal tumor that can occur in various organs including the uterus and soft tissues. PEComas are composed of perivascular epithelioid cells, and angiomyolipoma (AML), clear cell sugar tumor (CCST), and lymphangiomyomatosis (LAM) are considered lesions of the same lineage as tumors of the PEComa family. Histologically, a common PEComa shows solid or sheet-like proliferation of epithelioid cells. This is accompanied by an increase in the number of dilated blood vessels. Here, we report a case of pancreatic PEComa with marked inflammatory cell infiltration. CASE PRESENTATION: A 74-year-old male patient underwent an appendectomy for acute appendicitis. Postoperative computed tomography and magnetic resonance imaging revealed a 30 × 25 mm non-contrast-enhanced circular lesion in the tail of the pancreas. The imaging findings were consistent with a malignant tumor, and distal pancreatectomy was performed. Histologically, most area of the lesion was infiltrated with inflammatory cells. A few epithelioid cells with large, round nuclei, distinct nucleoli, and eosinophilic granular cytoplasm were observed. Spindle-shaped tumor cells were observed. Delicate and dilated blood vessels were observed around the tumor cells. Immunohistochemically, the atypical cells were positive for αSMA, Melan A, HMB-45, and TFE3. The cytological characteristics of the tumor cells and the results of immunohistochemical staining led to a diagnosis of pancreatic PEComa. CONCLUSIONS: A histological variant known as the inflammatory subtype has been defined for hepatic AML. A small number of tumor cells present with marked inflammatory cell infiltration, accounting for more than half of the lesions, and an inflammatory myofibroblastic tumor-like appearance. To our knowledge, this is the first report of pancreatic PEComa with severe inflammation. PEComa is also a generic term for tumors derived from perivascular epithelioid cells, such as AML, CCST, and LAM. Thus, this case is considered an inflammatory subtype of PEComa. It has a distinctive morphology that is not typical of PEComa. This histological phenotype should be widely recognized.

Solid pseudopapillary neoplasm of the pancreas: a retrospective study of 195 cases.

Objective: Solid pseudopapillary neoplasm of the pancreas (SPN) is a rare exocrine tumor of the pancreas. The aim of our study is to summarize the clinical features of SPN and to analyze the risk factors for malignant SPN. Methods: From May 2013 to September 2022, patients who were pathologically confirmed to have SPN were retrospectively reviewed. Demographic data, clinical and pathological features, follow-up data were collected and analyzed. To investigate the factors influencing the benign or malignant nature of SPN, we employed logistic regression. Additionally, we utilized Kaplan-Meier curves to depict and analyze the overall prognosis. Results: A total of 195 patients were included, 163 of whom were female and the average age of all patients was 31.7 years old. Among 195 patients, 101 patients (51.8%) had no obvious clinical symptoms and their pancreatic lesions were detected during routine examination. The primary symptom was abdominal pain and distension in 64 cases (32.8%). The maximum diameter of SPN tumors ranged from 1-17 cm (mean 6.19 cm). Forty-eight postoperative complications developed in 43 (22.1%) patients. After a median follow-up duration of 44.5 months, the overall 5-year survival rate was 98.8% and the recurrence rate was 1.5%. Furthermore, we observed a statistically significant difference in the completeness of the tumor capsule between benign and malignant SPN. Conclusion: SPN is associated with a favorable long-term survival after surgery in our large sample size cohort. For malignant SPN, tumor capsule incompleteness is an independent risk factor.

Twenty-one years of experience with resected solid pseudopapillary neoplasm: a retrospective single-institutional cohort study.

BACKGROUND: Although the incidence of solid pseudopapillary neoplasm (SPN) is <2% of the incidence of pancreatic tumor, the prevalence seems to be increasing. SPNs are mostly benign. However, they also show malignant features. This study aimed to identify the clinical outcomes of patients who underwent surgery for SPN at a single center. METHODS: Data on 217 patients with SPN who underwent surgery in Samsung Medical Center between 2000 and 2020 were retrospectively analyzed. RESULTS: Herein, the mean age of the 217 patients was 40.0 ± 12.6 years, with a female predominance (80.6%). Most patients had no comorbidity. The mean tumor size was 4.4 ± 3.1 cm. The tumor was located at the pancreatic head in 36 patients (16.6%), the body of the pancreas in 69 patients (31.8%), and the pancreatic tail in 96 patients (44.2%). Of note, 35 patients (16.1%) underwent pancreaticoduodenectomies, 148 patients (68.2%) had distal pancreatectomies, and the other patients had subtotal /total pancreatectomy (9.7%) or enucleation/mass excision (6.0%). No patient had lymph node (LN) metastasis. Moreover, 6 patients (2.8%) had a recurrence in the liver or regional LNs. The 5-year recurrence-free survival rate was 96.8%. The only factor affecting recurrence was tumor size (P = .007). CONCLUSION: Because SPN predominates in relatively young women, patients often hesitate to undergo surgery. Nevertheless, as size is the prognostic factor, early resection is recommended for a better prognosis in the case of surgically feasible, young age, and healthy patients.

A case of progressive xanthogranulomatous pancreatitis with splenic abscess.

Xanthogranulomatous inflammation is a chronic inflammatory reaction microscopically characterized by aggregation of foamy histiocytes, fibrous tissue, and infiltration of various inflammatory cells. In contrast to xanthogranulomatous inflammation in the gallbladder or kidney, xanthogranulomatous pancreatitis is rare. We herein present a case of xanthogranulomatous pancreatitis in a patient who underwent distal pancreatectomy with splenectomy under preoperative suspicion of a pancreatic pseudocyst or pancreatic tumor. A 77-year-old woman with a 1 month history of epigastric pain, anorexia, and general fatigue was admitted to our hospital. Contrast-enhanced computed tomography revealed a cystic mass with ill-defined margins at the pancreatic tail together with a splenic abscess. Contrast-enhanced endoscopic ultrasound detected a hyperechoic cystic lesion at the tail of the pancreas with heterogeneous internal echogenicity, and part of the intra-cystic content was enhanced by the contrast agent. Endoscopic retrograde cholangiopancreatography showed a cystic lesion at the tail of the pancreas that continued into the main pancreatic duct, and the main pancreatic duct was slightly narrowed downstream of the cystic lesion. Pancreatic juice cytology revealed suspicious cells, leading to the possibility of intraductal papillary mucinous carcinoma. Distal pancreatectomy with splenectomy was performed, and the histopathological diagnosis was xanthogranulomatous pancreatitis with no malignant findings.

IgG4-related inflammatory pancreatic head pseudotumor mirrors pancreatic head tumor: A novel case series with a review of the literature.

Key Clinical Message: In this noteworthy case series regarding pancreatic pseudo tumors, we intend to spread knowledge among physicians for the diagnostic and therapeutic approach and eventual disease prognosis. Abstract: Inflammatory pseudotumor of pancreatic head greatly mimics pancreatic head tumor. One of them is IgG4-related pancreatic disease, which is commonly mistaken as neoplastic disease on imaging. In our novel case series, we report three cases of IgG4-related pancreatic head pseudotumor with patients ranging from 35 to 72 years of age. Patients presented with jaundice and abdominal pain. Alongside initial laboratory workup, abdominal CTs and serum IgG4 levels were also obtained. Imaging features in conjunction with IgG4 levels confirmed the diagnosis of IgG4-related autoimmune pancreatitis. Pancreatic pseudotumors are notorious for being often reported as real tumors. Through our noteworthy case series, we intend to highlight the imaging features and laboratory markers that are crucial in such cases to avoid invasive procedures.

Generation of allogenic chimera carrying mutations in PDX1 and TP53 genes via phytohemagglutinin-mediated blastomere aggregation in pigs.

The generation of genetically engineered pig models that develop pancreas-specific tumors has the potential to advance studies and our understanding of pancreatic cancer in humans. TP53 mutation causes organ-nonspecific cancers, and PDX1-knockout results in the loss of pancreas development. The aim of the present study was to generate a PDX1-knockout pig chimera carrying pancreas complemented by TP53 mutant cells via phytohemagglutinin (PHA)-mediated blastomere aggregation using PDX1 and TP53 mutant blastomeres, as a pig model for developing tumors in the pancreas with high frequency. First, the concentration and exposure time to PHA to achieve efficient blastomere aggregation were optimized. The results showed that using 300 µg/mL PHA for 10 min yielded the highest rates of chimeric blastocyst formation. Genotyping analysis of chimeric blastocysts derived from aggregated embryos using PDX1- and TP53-edited blastomere indicated that approximately 28.6% carried mutations in both target regions, while 14.3-21.4% carried mutations in one target. After the transfer of the chimeric blastocysts into one recipient, the recipient became pregnant with three fetuses. Deep sequencing analysis of the PDX1 and TP53 regions using ear and pancreas samples showed that one fetus carried mutations in both target genes, suggesting that the fetus was a chimera derived from embryo-aggregated PDX1 and TP53 mutant blastomeres. Two out of three fetuses carried only the PDX1 mutation, indicating that the fetuses developed from embryos not carrying TP53-edited blastomeres. The results of the present study could facilitate the further improvement and design of high-frequency developing pancreatic tumor models in pigs.

Hemostasis with Metallic Stent for Multiple Metastatic Pancreatic Tumors Complicated with Hemobilia.

Introduction: Hemobilia, which refers to bleeding from the bile duct, is rare and difficult to treat. We report a case of successful hemostasis of a pancreatic tumor complicated by hemobilia. Case Presentation: A 76-year-old man was referred to our hospital with a pancreatic head tumor. Endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasonography-FNA were performed, and the patient was diagnosed with pancreatic metastasis of renal cell carcinoma. After discharge, the patient noted worsening jaundice and progressive anemia and was readmitted. ERCP reveals active bleeding from the duodenal papillae. The patient was placed on a fully covered metallic stent and discharged after confirming hemostasis. Conclusion: Renal cell carcinoma is a tumor with abundant blood flow. If hemobilia occurs, bleeding from pancreatic metastatic tumors should be considered. Additionally, hemostasis using a fully covered metallic stent is useful for treating hemobilia in tumors.

Identification of activity-based biomarkers for early-stage pancreatic tumors in blood using single-molecule enzyme activity screening.

Single-molecule enzyme activity-based enzyme profiling (SEAP) is a methodology to globally analyze protein functions in living samples at the single-molecule level. It has been previously applied to detect functional alterations in phosphatases and glycosidases. Here, we expand the potential for activity-based biomarker discovery by developing a semi-automated synthesis platform for fluorogenic probes that can detect various peptidases and protease activities at the single-molecule level. The peptidase/protease probes were prepared on the basis of a 7-amino-4-methylcoumarin fluorophore. The introduction of a phosphonic acid to the core scaffold made the probe suitable for use in a microdevice-based assay, while phosphonic acid served as the handle for the affinity separation of the probe using Phos-tag. Using this semi-automated scheme, 48 fluorogenic probes for the single-molecule peptidase/protease activity analysis were prepared. Activity-based screening using blood samples revealed altered single-molecule activity profiles of CD13 and DPP4 in blood samples of patients with early-stage pancreatic tumors. The study shows the power of single-molecule enzyme activity screening to discover biomarkers on the basis of the functional alterations of proteins.

An oncolytic system produces oxygen selectively in pancreatic tumor cells to alleviate hypoxia and improve immune activation.

INTRODUCTION: Hypoxia is one of the important reasons for the poor therapeutic efficacy of current pancreatic cancer treatment, and the dense stroma of pancreatic cancer restricts the diffusion of oxygen within the tumor. METHODS: A responsive oxygen-self-supplying adv-miRT-CAT-KR (adv-MCK) cascade reaction system to improve hypoxia in pancreatic cancer is constructed. We utilized various experiments at multiple levels (cells, organoids, in vivo) to investigate its effect on pancreatic cancer and analyzed the role of immune microenvironment changes in it through high-throughput sequencing. RESULTS: The adv-MCK system is an oncolytic adenovirus system expressing three special components of genes. The microRNA (miRNA) targets (miRTs) enable adv-MCK to selectively replicate in pancreatic cancer cells. Catalase catalyzes the overexpressed hydrogen peroxide in pancreatic cancer cells to generate endogenous oxygen, which is catalyzed by killerRed to generate singlet oxygen (1O2) and further to enhance the oncolytic effect. Meanwhile, the adv-MCK system can specifically improve hypoxia in pancreatic cancer, exert antitumor effects in combination with photodynamic therapy, and activate antitumor immunity, especially by increasing the level of γδ T cells in the tumor microenvironment. CONCLUSION: The responsive oxygen-self-supplying adv-MCK cascade reaction system combined with photodynamic therapy can improve the hypoxic microenvironment of pancreatic cancer and enhance antitumor immunity, which provides a promising alternative treatment strategy for pancreatic cancer.

A novel likely pathogenetic variant p.(Cys235Arg) of the MEN1 gene in multiple endocrine neoplasia type 1 with multifocal glucagonomas.

PURPOSE: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary endocrine syndrome caused by pathogenic variants in MEN1 tumor suppressor gene. Diagnosis is commonly based on clinical criteria and confirmed by genetic testing. The objective of the present study was to report on a MEN1 case characterized by multiple pancreatic glucagonomas, with particular concern on the possible predisposing genetic defects. METHODS: While conducting an extensive review of the most recent scientific evidence on the unusual glucagonoma familial forms, we analyzed the MEN1 gene in a 35-year-old female with MEN1, as well as her son and daughter, using Sanger and next-generation sequencing (NGS) approaches. We additionally explored the functional and structural consequences of the identified variant using in silico analyses. RESULTS: NGS did not show any known pathogenic variant in the tested regions. However, a new non-conservative variant in exon 4 of MEN1 gene was found in heterozygosity in the patient and in her daughter, resulting in an amino acid substitution from hydrophobic cysteine to hydrophilic arginine at c.703T > C, p.(Cys235Arg). This variant is absent from populations databases and was never reported in full papers: its characteristics, together with the high specificity of the patient's clinical phenotype, pointed toward a possible causative role. CONCLUSION: Our findings confirm the need for careful genetic analysis of patients with MEN1 and establish a likely pathogenic role for the new p.(Cys235Arg) variant, at least in the rare subset of MEN1 associated with glucagonomas.

Robotic pancreatic tumor enucleation by the double bipolar technique using the da Vinci SP system: An initial case report with a technical detail.

Pancreatic tumor enucleation is a procedure that can preserve pancreatic function and is sometimes performed using a minimally invasive approach. Recently, a single-port robotic platform called da Vinci SP has been developed. However, the technical details of pancreatic tumor enucleation using da Vinci SP have not been reported to date. We report a male patient in his 70s who underwent robotic SP pancreatic tumor enucleation for a pancreatic neuroendocrine tumor. The dissection between the tumor and pancreatic parenchyma was performed using the double bipolar technique. The operative time was 139 min, and the estimated blood loss was 4 mL. The patient had an uneventful recovery and was discharged on the sixth day after the surgery. Robotic SP pancreatic tumor enucleation appears to be a feasible procedure with lower invasiveness and better cosmesis.