A comparative analysis of robotic versus laparoscopic total pancreatectomy: insights from the National Cancer Database.

Total pancreatectomy is a complex procedure used in the management of pancreatic cancer. While minimally invasive techniques have been increasingly adopted, limited data exist comparing robotic total pancreatectomy (RTP) and laparoscopic total pancreatectomy (LTP). This study evaluates the utilization, short- and long-term outcomes of RTP and LTP using the National Cancer Database. Patients with stages I-III pancreatic adenocarcinoma who underwent RTP or LTP between 2010 and 2019 were identified. Patient demographics, treatment characteristics, pathologic outcomes, postoperative outcomes, and overall survival were compared. Multivariable logistic regression and Cox proportional-hazards models were used to assess the association of surgical approach with outcomes. Of the 995 patients included, 188 (19%) underwent RTP and 807 (81%) underwent LTP. The utilization of minimally invasive techniques increased over time, with RTP accounting for 24% of cases in 2019. RTP had lower conversion rates than LTP (16% vs. 24%, p = 0.031), but this difference was not significant after adjusting for confounders. Postoperative outcomes, including length of stay, 30-day readmission, and 30- and 90-day mortality, were similar between RTP and LTP. The median overall survival was 22.3 months for RTP and 23.6 months for LTP (p = 0.647). RTP and LTP demonstrate comparable perioperative, pathological, and oncological outcomes for the management of pancreatic adenocarcinoma. Despite the increasing adoption of minimally invasive total pancreatectomy, it remains a rare operation and should be performed in experienced centers to optimize outcomes.

Pembrolizumab in Combination with Folfirinox for Treatment of Advanced Pancreatic Adenocarcinoma With MSI-H.

Pancreatic cancer is one of the four most common causes of cancer-related death in the United States. Our patient had metastatic pancreatic cancer with a high tumour burden. He was trialled on an unconventional treatment of combination immunotherapy and chemotherapy. It resulted in decreased cancer burden and decreased FDG activity on a PET scan. Further studies are needed for standard pancreatic cancer treatment. LEARNING POINTS: Very few patients survive pancreatic cancer, especially metastatic disease. Our patient is doing very well after a few years.There is little evidence for concurrent use of chemotherapy and immunotherapy. Our patient received it and has had no new lesions, and there has been an improvement on imaging.

Endoscopic Ultrasound-Guided Radiofrequency Ablation (EUS-RFA) for Pancreatic Adenocarcinoma: A Review.

Pancreatic ductal adenocarcinoma (PDAC) is still one of the deadliest neoplasms in the world. Although various advancements in the treatment and management of this disease have been made, no significant overall survival benefit has been achieved. Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) has been proposed as a treatment for patients who are unfit for surgery or with inoperable PDAC. We conducted a literature review of the PubMed and Embase databases to identify and analyze studies on the use of EUS-RFA in inoperable PDAC. Eleven studies with a total of 122 patients were analyzed to assess the population characteristics, feasibility and safety of the procedure, and overall survival of the population. Technical success was achieved in 95.1% of cases, and no intraoperative complications were reported. The most common early complication reported was abdominal pain (21 out of 122 patients) with a total early complication rate of 29.6%, and none of these complications affected hospital stays or post-procedure recovery. Late complications were reported in four patients (3.2%). Post-procedure cytoreduction was achieved in all patients, although disease progression was reported in 119 of 122 patients. The overall survival rate did not differ from that reported in the literature. We found that EUS-RFA could be a valid palliative option for inoperable patients, a bridge for surgery reducing the size of the tumor and its vascular relationship, or a first-line therapy in a subset of selected patients. Larger cohort and prospective studies should be conducted to establish guidelines for this procedure.

Solitary metastasis to the head of the pancreas from lung adenocarcinoma mimicking pancreatic ductal adenocarcinoma: A case report.

Solitary pancreatic metastasis is a rare cause of pancreatic neoplasm. Pancreatic ductal adenocarcinoma is the primary differential consideration when a solitary pancreatic mass is diagnosed, as it is the most common solitary solid pancreatic neoplasm. A majority of pancreatic ductal adenocarcinomas arise in the region of the head of the pancreas; however, specific neoplastic and non-neoplastic lesions can occur at or adjacent to the pancreatic head, which can mimic a pancreatic ductal adenocarcinoma. Therefore, a histopathological diagnosis is essential for confirming pancreatic ductal adenocarcinoma. Isolated solitary metastasis from primary lung adenocarcinoma is a rare cause of a solitary pancreatic head mass. We report a case in which imaging and pathology were integral to the diagnosis of a solitary lung adenocarcinoma metastasis to the head of the pancreas, which ultimately guided appropriate patient management.

Splenic rupture secondary to pancreatic malignancy invasion: A rare case.

Malignancy is a rare etiology of splenic rupture, with most documented cases resulting from hematologic cancers. There have been very few reports of splenic rupture resulting from invasion or metastasis of adenocarcinoma and even fewer reports resulting from specifically pancreatic adenocarcinoma. In this case report, we outline the clinical course of a 60-year-old male with splenic rupture and hemoperitoneum following a ground level fall who was transferred to the Shock Trauma Center (STC) from a local emergency department. Outside of the ruptured spleen, no other traumatic injuries were found on examination or imaging. Due to the initial concern for traumatic etiology, exploratory laparotomy was performed with splenectomy and distal pancreatectomy. Postoperative pathology results revealed pancreatic adenocarcinoma with splenic invasion staged pT3N0. This report provides a novel example of splenic rupture in the background of locally advanced pancreatic adenocarcinoma and further solidifies the importance of maintaining a broad differential in cases of seemingly innocuous trauma.

An unusual pAIR: Anti-PKM2 antibody and occult pancreatic adenocarcinoma.

Purpose: To describe the clinical, laboratory and multimodal imaging findings in paraneoplastic autoimmune retinopathy (p-AIR) associated with anti-pyruvate kinase M2 antibody (anti-PKM2) and occult pancreatic adenocarcinoma. Observations: A 70 year old male with blurred vision, nyctalopia and concurrent difficulty with glucose control had retinal vascular attenuation and diffuse punctate pigment clumping in both eyes. Multimodal imaging demonstrated corresponding stippled hypofluorescence on fluorescein angiography, stippled hyperautofluorescence and a hyperautoflourescent macular ring with fundus autofluorescence, and focal hyperreflectivity at the level of the RPE-Bruch's membrane complex with diffuse loss of outer retinal layers on ocular coherence tomography. In addition, diffuse ganglion cell loss and severe visual field constriction were present. Genetic testing for retinitis pigmentosa was normal. Screening for anti-retinal antibodies was positive for only anti-PKM2. Systemic evaluation revealed previously undiagnosed adenocarcinoma of the pancreas. Conclusions and importance: Anti-PKM2 in the setting of autoimmune retinopathy may be associated with occult pancreatic cancer. The diagnosis of pAIR should be considered and systemic investigation for occult malignancy initiated even in the absence of more commonly associated anti-retinal antibodies.

Curative intent treatment for pancreatic duct adenocarcinoma invade superior mesenteric vein.

Pancreatic duct adenocarcinoma (PDAC) accounts for about 85-90% of all solid pancreatic tumors, which is well-known for poor prognosis and high morbidity. Despite the massive advent of chemotherapy and radiotherapy in recent years, surgical removal is still considered the cornerstone management option in this situation. Pancreaticoduodenectomy or Whipple procedure is generally contraindicated in metastasis or tumors that encase more than 50% of vessels. Vascular reconstruction is a state-of-the-art technique which requires the remarkable involvement of vascular experts in the setting of PDAC-invading vessels. In this article, we present an exceptional case of a 38-year-old male patient who underwent radical resection for advanced pancreatic cancer with superior mesenteric vein reconstruction by a great saphenous vein.

HKDC1 promotes autophagy and proliferation in pancreatic adenocarcinoma through interaction with PARP1 and poly(ADP-ribosyl)ation.

BACKGROUND: HKDC1 has been shown to play an important role in promoting malignant progression of pancreatic adenocarcinoma (PAAD), but the exact mechanism is unclear. This study aimed to investigate the function of HKDC1 in autophagy activation and cell proliferation. METHODS: By GSEA analysis of TCGA data of PAAD, we found that HKDC1 was closely associated with autophagy. We evaluated the effects of HKDC1 knockdown and overexpression on the expression of LC3B, an autophagy marker, and Cyclin D1 and PCNA, cell proliferation-associated proteins, by Western blotting (WB) and transmission electron microscopy (TEM) analysis. RESULTS: Knockdown of HKDC1 decreased LC3B expression and led to a decrease in the accumulation of autophagic vesicles and autophagic lysosomes, while overexpression of HKDC1 produced the opposite effect. Meanwhile, HKDC1 overexpression significantly promoted the proliferation of PAAD cells and increased the expression levels of Cyclin D1 and PCNA. Further studies showed that HKDC1 enhanced PARP1's own poly ADP-ribosylation (PARylation) activity by interacting with PARP1, which in turn promoted autophagy. In vivo experiments showed that knockdown of HKDC1 significantly inhibited the growth of pancreatic cancer cells in nude mice in vivo, reduced tumor volume and weight, and down-regulated the expression of PARP1, LC3, Cyclin D1 and PCNA. CONCLUSION: HKDC1 plays a critical role in the malignant progression of PAAD by activating autophagy and promoting cell proliferation. Our findings suggest that targeting HKDC1 and its downstream signaling pathways may provide novel strategies for PAAD treatment.

Early Onset Pancreatic Adenocarcinoma (EOPAC): presentation, clinical course and treatment outcomes in comparison to Average Onset Pancreatic Adenocarcinoma (AOPAC): a retrospective cohort study.

BACKGROUND: Pancreatic adenocarcinoma (PAC) is a disease of decimal prognosis, with around 50% of patients presenting with metastatic disease. Previous trials reported a high incidence of early onset pancreatic cancer (EOPAC) in Egypt, presenting about 25% of patients with PAC. The clinic-pathological features and prognosis of EOPAC needs more study. PATIENTS AND METHODS: A retrospective analysis of patients' records at Shefa Al-Orman comprehensive cancer center database. Patients with histo-pathologically confirmed diagnosis of PAC. We categorized patients according to the age at diagnosis into EOPAC (≤ 50 years) and average onset PAC (AOPAC). Data on risk factors, family history, presenting symptoms, clinic-pathological features, treatment, and prognosis were extracted. Patients with histopathologically confirmed diagnosis of pancreatic cancer diagnosed between December 2016-December 2022 were included. RESULTS: The study cohort consisted of 412 patients. EOPAC represented 20.3% of patients, with no significant differences in risk factors and family history compared to AOPAC. Duration of symptoms before diagnosis is longer in EOPAC, with the majority of EOPAC presenting with localized disease (23.8%) and locally advanced tumors (28.5%) compared to AOPAC. AOPAC presented more with metastatic disease (64% vs. 45.2%, p = 0.003). EOPAC are usually submitted to more aggressive treatment including radical surgery, neoadjuvant therapy, and aggressive chemotherapy regimens in metastatic disease. Disease free survival (DFS) of EOPAC was shorter than AOPAC (11 months vs. 17 months, p = 0.889), but overall survival OS was significantly longer in EOPAC (10 months vs. 6 months, p = 0.013). CONCLUSION: Patients with EOPAC in Egypt represent around 25% of cases. EOPAC tend to have a shorter disease free survival (DFS) in patients presenting with localized disease. The overall survival (OS) is longer in EOPAC compared to AOPAC. Further studies are mandatory to identify the epidemiological and risk factors of EOPAC in Egypt.

Sister Mary Joseph's Nodule as a Cutaneous Expression of Metastatic Pancreatic Adenocarcinoma.

A Sister Mary Joseph's nodule (SMJN) is characterized by a palpable umbilical nodule and is often a clinical indicator of the metastasis of an advanced abdominal or pelvic malignancy. Observing the cutaneous manifestation of an abdomino-pelvic malignancy is a relatively rare phenomenon due to the appearance of visible changes in the later stages of the disease. With the pancreas being a less common primary tumor site for SMJN, this case report describes a 57-year-old male diagnosed with metastatic pancreatic adenocarcinoma with a SMJN. With a history of alcohol use disorder and alcohol pancreatitis, this patient presented to the Emergency Department with worsening abdominal pain and vomiting. A computed tomography (CT) scan with intravenous (IV) contrast revealed a mass in the patient's rectum and a lobulated mass traversing the anterior abdominal wall, which extended into the umbilicus. A physical exam revealed the presence of an umbilical lesion. A biopsy of the umbilical lesion revealed metastatic adenocarcinoma that favored pancreaticobiliary origin. The results of the umbilical biopsy and CT imaging established the diagnosis of SMJN secondary to pancreatic cancer metastasis to the umbilicus.

Chemotherapy-Induced Cutaneous Sclerosis: A Rare Clinical Finding.

Scleroderma-like cutaneous sclerosis has been reported as a rare adverse reaction to several drugs, including the chemotherapeutical agent paclitaxel, used in therapeutic regimens for several malignancies. The sclerosis is usually limited to the skin, most commonly presenting in the lower limbs after weeks to months of therapy but is often refractory to treatment and progresses even after discontinuation of the offending agents, with significant resulting morbidity. We report a rare case of severe cutaneous sclerosis secondary to chemotherapy with nab-paclitaxel and gemcitabine, which did not respond to treatment and led to discontinuation of chemotherapy.

Modeling Overall Survival in Patients With Pancreatic Cancer From a Pooled Analysis of Phase II Trials.

BACKGROUND: We evaluated the validity of surrogacy of progression-free survival (PFS) or time-to-progression (TTP) and overall response rate (ORR) in phase II trials of pancreatic ductal adenocarcinoma (PDAC). In addition, we explored the impact of predictive variables on overall survival (OS) and developed an optimal OS model. METHODS: We analyzed 1867 clinical endpoint from 619 phase II PDAC trials with a systematic search from PubMed. Endpoint correlations were determined by Spearman's rank correlation. The assessed predictive factors included PFS/TTP, treatment size, therapy type, stage, and previous treatment. The relationship between predictors and OS was explored by a gamma generalized linear model (GLM) with a log-link function and compared with linear models. RESULTS: The Spearman rank correlation coefficient between PFS/TTP and OS was 0.88 (95% confidence interval [CI] 0.85-0.89; p < 0.0001; n = 610) and between ORR and OS was 0.58 (0.52-0.64; p < 0.0001; n = 514). Model comparison favored the GLM model over the linear model, offering more accurate predictions for higher OS values. Consequently, PFS/TTP was the strongest predictor (pseudo-R2 = 0.75), with 1 added median PFS/TTP month associated with 13% (95% CI 13%-14%) increase in median OS. Subgroup analysis revealed that chemotherapy conferred significantly longer OS compared to targeted therapy in 1-Agent and 2-Agent trials, exhibiting a "very large" and "medium" effect size, respectively (rank biserial, rrb = 0.40 [95% CI 0.22-0.56] and rrb = 0.29 [0.16-0.41], both p < 0.0001), although inconsistent efficacy in 3-Agent trials (rrb = 0.12 [-0.07-0.30], p = 0.21). CONCLUSIONS: PFS/TTP is a more reliable surrogate than ORR and a strong predictor of OS in phase II trials of pancreatic cancer. Moreover, gamma GLM (log-link function) is a robust tool for modeling positively skewed survival data with non-constant variance, thus can be applied to other cancers' OS data of such nature.

MLPH regulates EMT in pancreatic adenocarcinoma through the PI3K-AKT signaling pathway.

Pancreatic adenocarcinoma (PAAD) is an extremely malignant tumor, and most patients develop postoperative metastases. Melanophilin (MLPH) is involved in the progression of various tumors, but its molecular mechanisms and role in pancreatic cancer progression are unknown. In this study, differential MLPH expression in cancer tissues and the adjacent tissues was evaluated using the Gene Expression Profiling Interaction Analysis 2 (GEPIA 2) and Human Protein Atlas (HPA) databases. The role of MLPH in PAAD proliferation, invasion, and migration in vitro was explored via clone formation, Cell Counting Kit-8 assay, Transwell assay, and western blot. The in vivo validation of function was performed using a metastatic nude mouse model. The result showed that the pancreatic cancer tissues had significantly higher MLPH expression levels than the noncancerous pancreatic tissues. MLPH expression changes were related to PAAD cell proliferation, invasion, and migration. The western blotting demonstrated that PAAD cells had reduced Epithelial-mesenchymal transition (EMT)-related marker expression. Furthermore, overexpressing MLPH enhanced cell proliferation, migration, and invasion, and increased EMT-related marker expression. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that the molecular mechanism underlying the effect of MLPH on PAAD was significantly related to the PI3K-AKT pathway. LY294002 blocked the MLPH overexpression-mediated enhanced cell invasion and migration and inhibited EMT-associated marker expression. Conversely, 740Y-P reversed the inhibitory effects of MLPH downregulation and led to cell migration, invasion, and EMT. MLPH regulated EMT to mediate PAAD cell invasive migration through the PI3K-AKT pathway. The results indicated that MLPH is a possible target for blocking PAAD metastasis.

Prognostic and diagnostic value of circulating IGFBP2 in pancreatic cancer.

Insulin-like growth factor binding protein 2 (IGFBP2) is overexpressed in tumor tissues of several malignancies, including pancreatic cancer. Because of its role in tumor progression, IGFBP2 has been investigated as a tumor biomarker. However, little is known about its utility in pancreatic cancer. Plasma IGFBP2 levels were determined using enzyme-linked immunosorbent assay in 75 patients with pancreatic ductal adenocarcinoma (PDAC), 73 matched healthy controls, and 17 chronic pancreatitis patients. Our results showed that the plasma IGFPB2 level was significantly higher in PDAC patients than in patients with chronic pancreatitis and healthy controls. At a cut-off value of 333.9 ng/mL, the specificity and sensitivity were 78.08 and 65.33%, respectively. IGFBP2 level alone did not outperform carbohydrate antigen 19-9 (CA19-9) in diagnostic accuracy, but it successfully identified 9 out of 24 PDAC patients who were misidentified by CA19-9. The combination of IGFBP2 and CA19-9 was more accurate in the detection of PDAC than CA19-9 alone. IGFBP2 was more accurate than the other in discriminating between chronic pancreatitis and PDAC. Plasma IGFBP2, rather than CA19-9, was higher in the new-onset diabetes, lymph node involvement, and distant metastasis subgroups. IGFBP2 level was notably higher in stage IV cases than in stage I/II or stage III disease. However, CA19-9 did not show a difference between stages. After adjusting for lymph node involvement and distant metastasis, plasma IGFBP2 was identified as an independent prognostic marker for PDAC. The median survival time for patients with an IGFBP2 level ≥333.9 ng/mL was significantly shorter than that for patients with an IGFBP2 level <333.9 ng/mL. Marked elevation of plasma IGFBP2 in PDAC is associated with poorer survival. IGFBP2 may be considered as a supplementary biomarker for the diagnosis and prognostic prediction in Chinese pancreatic cancer patients.

Insulin receptor substrate 1 is a novel member of EGFR signaling in pancreatic cells.

Pancreatic ductal adenocarcinoma is an extremely incurable cancer type characterized by cells with highly proliferative capacity and resistance against the current therapeutic options. Our study reveals that IRS1 acts as a bridging molecule between EGFR and IGFR/InsR signalization providing a potential mechanism for the interplay between signaling pathways and bypassing EGFR-targeted or IGFR/InsR-targeted therapies. The analysis of IRS1 phosphorylation status in four pancreatic cell lines identified the impact of EGFR signaling on IRS1 activation in comparison with InsR/IGFR signaling. Significantly reduced viability was observed in IRS1-silenced cells even upon EGF stimulation showing the critical role of IRS1 in the EGFR signaling network in both malignant and normal pancreatic cells. This study also demonstrated that EGFR binds directly to IRS1 and at least on two tyrosine sites, Y612 and Y896, IRS1 becomes phosphorylated in response to EGF stimulation. Mechanistically, the EGFR-mediated phosphorylation of IRS1 can further activate the MAPK signaling pathway with the recruitment of GRB2 protein. Collectively, in this study, IRS1 was identified as a crucial regulator in the EGFR signaling suggesting IRS1 as a potential target for more durable responses to targeted PDAC therapy.

LDHA as a predictive biomarker and its association with the infiltration of immune cells in pancreatic adenocarcinoma.

Background: Lactate dehydrogenase A (LDHA) plays a crucial role in the final step of anaerobic glycolysis, converting L-lactate and NAD+ to pyruvate and nicotinamide adenine dinucleotide (NADH). Its high expression has been linked to tumorigenesis and patient survival in various human cancers. However, the full implications of LDHA's role and its correlation with clinicopathological features in pancreatic adenocarcinoma (PAAD) remain to be fully understood. This study was thus conducted to elucidate the specific functions of LDHA in PAAD, with the aim of providing more robust evidence for clinical diagnosis and treatment. Methods: In an extensive systems analysis, we searched through numerous databases, including The Cancer Genome Atlas (TCGA) and Oncomine. Our objective was to clarify the clinical implications and functional role of LDHA in PAAD. Bioinformatics was used to identify the biological function of LDHA expression and its correlation with tumor immune status. Results: Our analysis revealed that the LDHA gene is overexpressed in PAAD and that this upregulation was associated with a worse patient prognosis. Through gene set enrichment analysis, we found that LDHA's influence on PAAD is linked to signaling pathways involving Kirsten rat sarcoma viral oncogene homolog (K-Ras), transforming growth factor-ß (TGF-ß), and hypoxia inducible factor-1 (HIF-1). Mutation of K-Ras could upregulate its own expression and was positively correlated with LDHA expression. Moreover, our data demonstrated that LDHA expression was linked to immune infiltration and poor prognosis in PAAD, indicating its role in disease pathogenesis. Overexpression of LDHA may suppress tumor immunity, suggesting it as a potential target for the diagnosis and treatment of PAAD, thus providing new insights into managing this aggressive cancer. Conclusions: Overall, our results showed that LDHA as a prognostic biomarker could serve as a novel target for future PAAD immunotherapy.

Analyzing the role of TM4SF1 expression in pancreatic adenocarcinoma: understanding prognostic implications and therapeutic opportunities.

Background: Pancreatic adenocarcinoma (PAAD) is a highly lethal malignancy characterized by aggressive growth and poor prognosis. Understanding the molecular mechanisms underlying PAAD is crucial for developing effective therapies. This study aimed to explore the role of TM4SF1 and other key genes in PAAD progression, their prognostic implications, and therapeutic opportunities. Methods: Differential gene expression analysis was performed using PAAD and normal tissue samples to identify upregulated genes, with TM4SF1 emerging as significantly elevated in PAAD. Functional enrichment analysis elucidated associated signaling pathways. A prognostic model comprising BPIFB4, PLEKHN1, CPTP, DVL1, and DDR1 was developed using least absolute shrinkage and selection operator (LASSO) regression and validated in an independent cohort. Genetic mutation analysis provided insights into the functional significance of identified genes. Pharmacogenomic analysis examined associations between gene expression and drug sensitivity. Experimental validation included quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot analyses to confirm gene expression patterns and protein levels. Results: Lower TM4SF1 expression correlated with enhanced anti-tumor immune activity in PAAD, suggesting a complex interplay between genetic expression and immune response. The prognostic model showed robust associations with patient survival outcomes, validated across diverse patient cohorts. Genetic mutation analysis highlighted potential therapeutic targets. Pharmacogenomic analysis revealed correlations between gene expression profiles and drug responsiveness, suggesting personalized treatment strategies. Experimental validation confirmed elevated TM4SF1 levels in tumor tissues and demonstrated its role in promoting cancer cell proliferation and colony formation. Conclusions: This study advances understanding of the molecular landscape of PAAD, emphasizing TM4SF1 as a key regulator and potential therapeutic target. The integration of genetic expression, immune response dynamics, and pharmacogenomics offers a multifaceted approach to personalized treatment strategies for PAAD, paving the way for improved patient outcomes and novel therapeutic interventions. Further research is warranted to elucidate the clinical utility of targeting TM4SF1 and other identified genes in PAAD management.

Impact of Neoadjuvant Therapy on Oncological Outcomes of Patients With Distal Pancreatic Adenocarcinoma.

BACKGROUND: Distal pancreatic ductal adenocarcinoma (D-PDAC) often presents at an advanced stage. The efficacy of neoadjuvant therapy (NAT) in improving outcomes for D-PDAC is not well-established. This study evaluates the impact of NAT on the oncological outcomes of patients with D-PDAC. METHODS: A retrospective cohort study of consecutive patients with resectable and borderline-resectable D-PDAC treated at a single center from 2012 to 2020 was performed. Stratification was based on initial treatment-NAT or surgery first (SF). Survival analysis, following intention-to-treat framework, used Kaplan-Meier and Cox regression to assess NAT's impact on progression-free survival (PFS) and overall survival (OS) of D-PDAC. RESULTS: Among 141 patients (median age 69.8 years, 51.8% females) included in the study, 71 (50.4%) received NAT and 70 (49.6%) were planned for SF. Patients receiving NAT were younger (65.9 vs. 72.6 years) and had higher incidence of borderline-resectable disease (31% vs. 4.3%) (both p < 0.05) than those undergoing SF. Thirteen patients (18.3%) undergoing NAT and five (7.1%) in SF group, failed to undergo resection. Univariate comparison showed no difference in the PFS (SF:13.97 vs. NAT:17.00 months, p = 0.6), and OS (SF:23.73 vs. NAT:32.53 months, p = 0.35). Multivariate Cox regression analysis noted significantly improved PFS (HR = 0.64, 95%CI = 0.42-0.96, p = 0.031) and OS (HR = 0.60, 95%CI = 0.39-0.93, p = 0.021) with NAT. CONCLUSION: NAT is associated with improved PFS and OS in patients with -D-PDAC. Further randomized controlled trials are warranted to confirm these findings.

Optimizing Pancreatic Cancer Therapy: The Promise of Immune Stimulatory Oncolytic Viruses.

Pancreatic cancer presents formidable challenges due to rapid progression and resistance to conventional treatments. Oncolytic viruses (OVs) selectively infect cancer cells and cause cancer cells to lyse, releasing molecules that can be identified by the host's immune system. Moreover, OV can carry immune-stimulatory payloads such as interleukin-12, which when delivered locally can enhance immune system-mediated tumor killing. OVs are very well tolerated by cancer patients due to their ability to selectively target tumors without affecting surrounding normal tissues. OVs have recently been combined with other therapies, including chemotherapy and immunotherapy, to improve clinical outcomes. Several OVs including adenovirus, herpes simplex viruses (HSVs), vaccinia virus, parvovirus, reovirus, and measles virus have been evaluated in preclinical and clinical settings for the treatment of pancreatic cancer. We evaluated the safety and tolerability of a replication-competent oncolytic adenoviral vector carrying two suicide genes (thymidine kinase, TK; and cytosine deaminase, CD) and human interleukin-12 (hIL12) in metastatic pancreatic cancer patients in a phase 1 trial. This vector was found to be safe and well-tolerated at the highest doses tested without causing any significant adverse events (SAEs). Moreover, long-term follow-up studies indicated an increase in the overall survival (OS) in subjects receiving the highest dose of the OV. Our encouraging long-term survival data provide hope for patients with advanced pancreatic cancer, a disease that has not seen a meaningful increase in OS in the last five decades. In this review article, we highlight several preclinical and clinical studies and discuss future directions for optimizing OV therapy in pancreatic cancer. We envision OV-based gene therapy to be a game changer in the near future with the advent of newer generation OVs that have higher specificity and selectivity combined with personalized treatment plans developed under AI guidance.

Revealing a cancer-associated fibroblast-based risk signature for pancreatic adenocarcinoma through single-cell and bulk RNA-seq analysis.

PURPOSE: Proliferation of stromal connective tissue is a hallmark of pancreatic adenocarcinoma (PAAD). The engagement of activated cancer-associated fibroblasts (CAFs) contributes to the progression of PAAD through their involvement in tumor fibrogenesis. However, the prognostic significance of CAF-based risk signature in PAAD has not been explored. METHODS: The single-cell RNA sequencing (scRNA-seq) data sourced from GSE155698 within the Gene Expression Omnibus (GEO) database was supplemented by bulk RNA sequencing data from The Cancer Genome Atlas (TCGA) and microarray data retrieved from the GEO database. The scRNA-seq data underwent processing via the Seurat package to identify distinct CAF clusters utilizing specific CAF markers. Differential gene expression analysis between normal and tumor samples was conducted within the TCGA-PAAD cohort. Univariate Cox regression analysis pinpointed genes associated with CAF clusters, identifying prognostic CAF-related genes. These genes were utilized in LASSO regression to craft a predictive risk signature. Subsequently, integrating clinicopathological traits and the risk signature, a nomogram model was constructed. RESULTS: Our scRNA-seq analysis unveiled four distinct CAF clusters in PAAD, with two linked to PAAD prognosis. Among 207 identified DEGs, 148 exhibited significant correlation with these CAF clusters, forming the basis of a seven-gene risk signature. This signature emerged as an independent predictor in multivariate analysis for PAAD and demonstrated predictive efficacy in immunotherapeutic outcomes. Additionally, a novel nomogram, integrating age and the CAF-based risk signature, exhibited robust predictability and reliability in prognosticating PAAD. Moreover, the risk signature displayed substantial correlations with stromal and immune scores, as well as specific immune cell types. CONCLUSIONS: The prognosis of PAAD can be accurately predicted using the CAF-based risk signature, and a thorough analysis of the PAAD CAF signature may aid in deciphering the patient's immunotherapy response and presenting fresh cancer treatment options.