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There are no clear guidelines regarding the optimal treatment sequence for advanced pancreatic cancer, as head‐to‐head phase III randomised trials are missing. We assess real‐world effectiveness of three common sequential treatment strategies by emulating a hypothetical randomised trial. This analysis included 1551 patients with advanced pancreatic cancer from the prospective, clinical cohort study Tumour Registry Pancreatic Cancer receiving FOLFIRINOX (n = 613) or gemcitabine/nab‐paclitaxel (GEMNAB; n = 938) as palliative first‐line treatment. We used marginal structural modelling to compare overall survival (OS) and time to deterioration (TTD) of health‐related quality of life (HRQoL) between three common first‐ to second‐line treatment sequences, adjusting for time‐varying potential confounding. The sequences were: FOLFIRINOX→GEMNAB, GEMNAB→FOLFOX/OFF and GEMNAB→nanoliposomal irinotecan (NALIRI) + 5‐fluorouracil. Outcome was also calculated stratified by patients' prognostic risk according to the Pancreatic Cancer Score. Median OS and TTD of HRQoL independent of risk were 10.7 [8.9, 11.9] and 6.4 [4.8, 7.7] months for FOLFIRINOX→GEMNAB, 8.4 [7.4, 9.7] and 5.8 [4.6, 7.1] months for GEMNAB→FOLFOX/OFF and 8.9 [7.8, 10.4] and 4.6 [4.1, 6.1] months for GEMNAB→NALIRI+5‐fluorouracil. Compared to FOLFIRINOX→GEMNAB, OS and TTD were worse for poor‐risk patients with GEMNAB→FOLFOX/OFF (OS: HR 2.09 [1.47, 2.98]; TTD: HR 1.97 [1.19, 3.27]) and those with GEMNAB→NALIRI+5‐fluorouracil (OS: HR 1.35, [0.76, 2.39]; TTD: HR 2.62 [1.56, 4.42]). Brackets denote 95%‐confidence intervals. The estimated real‐world effectiveness of the three treatment sequences evaluated were largely comparable. Poor‐risk patients might benefit from intensified treatment with FOLFIRINOX→GEMNAB in terms of clinical and patient‐reported outcomes. Future randomised trials on sequential treatments in advanced pancreatic cancer are warranted. [ABSTRACT FROM AUTHOR]

Introduction: Intestinal obstruction is a common complication in patients with advanced malignancies, often attributed to the disease itself or as a side effect of opioid analgesics used for pain management. However, the occurrence of intestinal obstruction following antituberculosis therapy is rare. Case presentation: We report a unique case of a 58-year-old Asian male diagnosed with stage IV pancreatic carcinoma and pulmonary tuberculosis. The patient was initiated on a regimen of ethambutol hydrochloride, pyrazinamide, rifampicin, and isoniazid tablets (II) for tuberculosis, alongside morphine for the management of severe cancer-related pain. Subsequently, he developed symptoms indicative of intestinal obstruction. Despite discontinuation of morphine, the patient's symptoms persisted until he autonomously ceased all medications, leading to a rapid improvement in his condition. This unexpected resolution highlighted the antituberculosis drugs as the probable cause of his intestinal obstruction. Conclusions: This case underscores the importance of considering antituberculosis drugs as a potential cause of intestinal obstruction, especially in patients who do not respond to conventional management strategies for drug-induced gastrointestinal side effects. It also emphasizes the need for heightened vigilance and monitoring when prescribing these medications to patients with advanced malignancies, to promptly identify and address rare but significant side effects. [ABSTRACT FROM AUTHOR]

Background: DNA polymerase theta (POLQ) is a translesion synthesis polymerase essential for the repair of double strand breaks by the error-prone TMEJ (Theta Mediated End Joining) pathway. Although POLQ participates in maintaining genome stability, several studies have shown that its overexpression correlates with cancer progression and poor prognosis. Due to the fact that its role as a biomarker in pancreatic cancer remains unexplored, we aimed to study the usefulness of POLQ H-score as a prognostic factor in a pancreatic cancer patient cohort. Methods: We evaluated POLQ gene expression using a web-based tool to deliver gene expression profiling and interactive analyses based on TCGA and GTEx (GEPIA) and we examined the POLQ immunostaining in 152 biliopancreatic cancer surgical specimens using tissue microarrays. Association with survival was evaluated by Kaplan Meier curves and uni-multivariate Cox regression. Results: GEPIA analysis showed statistical differences according to POLQ mRNA levels in Disease Free Survival (DFS) (log rank 0.023, HR 2.8, p=0.029) and Overall Survival (OS) (log rank 0.011, HR 3.1, p=0.016). For immunohistochemistry (IHC) evaluation, POLQ H-score was calculated, and showed statistical differences for OS in Kaplan Meier curves (log rank 0.001) and uni-multivariate analysis (HR 2.27; 95% CI 1.24-4.15, p=0.008). Conclusions: Our results indicate that POLQ is an independent prognostic factor in pancreatic cancer when analyzed by immunostaining, which is in agreement with the results shown by the POLQ gene expression analysis (GEPIA). [ABSTRACT FROM AUTHOR]

Background: Disease recurrence after surgical resection for pancreatic ductal adenocarcinoma can affect more than 50% of patients in the first 12 months after resection. The goal of this current systematic review and meta‐analysis is to assess the ability of preoperative inflammatory scores to predict early recurrence after resection and to identify the best candidates for surgical resection. Methods: Medline and Web of Science databases were searched for studies reporting inflammatory scores and oncological outcomes in patients with PDAC after curative‐intent resection. The systematic review revealed that the most common scores were modified Glasgow Prognostic Score (mGPS), Prognostic Nutritional Index (PNI), platelet‐to‐lymphocyte ratio (PLR), neutrophil‐to‐lymphocyte ratio (NLR), and Systemic Immune‐Inflammation Index (SII). After, a meta‐analysis was performed to determine the prognostic value of these scores in early recurrence (12 months) after resection. A subgroup analysis was also carried out in patients who had upfront surgery and in those who underwent neoadjuvant chemotherapy. The ROBINS‐I tool was used to assess the risk of bias. Results: The literature search retrieved 1864 articles, 16 of which were eligible for analysis. The included studies comprised 4460 patients. Nine studies reported outcomes for mGPS, four studies for PNI, seven studies for PLR, eight studies for NLR, and two studies for SII. In the meta‐analysis, mGPS, NLR, and PLR showed significantly higher rates of early recurrence in the high‐score groups compared to the low‐score groups. Analyzing the sensitivity and specificity of these scores showed no significant difference in their diagnostic accuracy (mGPS area under the curve [AUC] = 0.534; NLR AUC = 0.628, and PLR AUC = 0.607). High and low PNI and SII scores demonstrated similar rates of early recurrence. Conclusion: mGPS, PNI, PLR, NLR, and SII scores did not show a suitable diagnostic accuracy to predict PDAC recurrence in the first 12 months after resection. Therefore, these inflammatory scores should not be used to select the best candidates or to preclude a possible surgical indication. [ABSTRACT FROM AUTHOR]

AIM: To investigate the impact and regulatory mechanisms of zinc finger protein 36-like protein 1 （ZFP36L1） on pancreatic carcinoma cell growth. METHODS: The ZFP36L1 expression in pancreatic carcinoma and its correlation with patient prognosis were analyzed using online databases UALCAN and GEPIA. Western blot was utilized to detect ZFP36L1 protein expression in pancreatic ductal cells （HPNE） and three different pancreatic carcinoma cell lines. CCK-8 and cell colony formation assays were performed to evaluate the effects of ZFP36L1 on pancreatic cancer cell proliferation. Wound healing and Transwell assays were used to assess the impact of ZFP36L1 expression changes on pancreatic carcinoma cell migration and invasion. Flow cytometry experiments were used to analyze the effect of ZFP36L1 on the pancreatic carcinoma cell cycle process. Bioinformatics analysis was conducted to predict potential ZFP36L1 interacting proteins. Co-immunoprecipitation experiments were carried out to confirm the interaction between ZFP36L1 and mitogen-activated protein kinase 14 （MAPK14）. Rescue experiments were performed to assess the function of MAPK14 in ZFP36L1-regulated pancreatic carcinoma cell growth. RESULTS: （ 1） ZFP36L1 is highly expressed in pancreatic carcinoma and is positively correlated with poor prognosis in pancreatic carcinoma patients. Compared to HPNE, ZFP36L1 is highly expressed in MIA PaCa-2 and ASPC-1 cells, but relatively low in PANC-1 cells. （2） ZFP36L1 overexpression significantly increased the cell viability, colony formation, migration, and invasion abilities of PANC-1 and MIA PaCa-2 cells, while siRNA interference of ZFP36L1 led to opposite results.（ 3） ZFP36L1 promotes the entry of pancreatic carcinoma cells into the S phase of the cell cycle. （4） ZFP36L1 interacts with MAPK14 to regulate pancreatic cancer cell growth. MAPK14 overexpression reversed the cell viability and migration abilities of pancreatic carcinoma cells overexpressing ZFP36L1. Furthermore, it also decreased the cell viability and migration abilities of pancreatic carcinoma cells with ZFP36L1 interference. CONCLUSION: ZFP36L1 is a potential oncogene in pancreatic carcinoma growth and may regulate pancreatic carcinoma cell growth through cell cycle modulation and interaction with MAPK14. [ABSTRACT FROM AUTHOR]

Postoperative pancreatic fistula, a significant complication following pancreaticoduodenectomy, can lead to the development of pseudoaneurysms, which in turn can result in hemorrhagic and septic complications. Here, we present the case of a 67-year-old male patient diagnosed with pancreatic head carcinoma who underwent partial pancreatectomy. Ten days postsurgery, the patient experienced hemorrhagic shock due to intraperitoneal bleeding. Emergency exploratory laparotomy and implantation of a stent in the common hepatic artery successfully stopped the bleeding. However, the patient later developed gastrointestinal bleeding, and no apparent source was detected during endoscopic examination. Two complex transcatheter arterial embolization procedures were performed, successfully stopping the bleeding. It is crucial to consider pseudoaneurysm in cases of suspected biliary and pancreatic leakage. This case also underscores the importance of a thorough vascular assessment prior to placing a coated stent, to prevent postoperative obstruction of catheter access to the responsible vessel. Additionally, embolization via the external path of the stent proved feasible.

Abstract Introduction Intestinal obstruction is a common complication in patients with advanced malignancies, often attributed to the disease itself or as a side effect of opioid analgesics used for pain management. However, the occurrence of intestinal obstruction following antituberculosis therapy is rare. Case presentation We report a unique case of a 58-year-old Asian male diagnosed with stage IV pancreatic carcinoma and pulmonary tuberculosis. The patient was initiated on a regimen of ethambutol hydrochloride, pyrazinamide, rifampicin, and isoniazid tablets (II) for tuberculosis, alongside morphine for the management of severe cancer-related pain. Subsequently, he developed symptoms indicative of intestinal obstruction. Despite discontinuation of morphine, the patient’s symptoms persisted until he autonomously ceased all medications, leading to a rapid improvement in his condition. This unexpected resolution highlighted the antituberculosis drugs as the probable cause of his intestinal obstruction. Conclusions This case underscores the importance of considering antituberculosis drugs as a potential cause of intestinal obstruction, especially in patients who do not respond to conventional management strategies for drug-induced gastrointestinal side effects. It also emphasizes the need for heightened vigilance and monitoring when prescribing these medications to patients with advanced malignancies, to promptly identify and address rare but significant side effects.

AIM: To investigate the effect of a disintegrin and metalloproteinase (ADAM) domain-like decy-sin 1(ADAMDEC1) knockdown on the proliferation, migration and invasion of pancreatic carcinoma cells. METHODS: Expression levels of ADAMDEC1 in pancreatic carcinoma tissues were analyzed using the GEPIA and UALCAN online databases. Western blot analysis was employed to detect the protein expression levels of ADAMDEC1 in pancreatic carcinoma cell lines (MIA PaCa-2 and PANC-1) and pancreatic ductal cell line (hTERT-HPNE). The effects of ADAMDEC1 knockdown on cell proliferation, migration and invasion were evaluated using CCK-8, colony formation, wound-healing and Transwell assays. Additionally, Western blot analysis was used to detect the effects of ADAMDEC1 knockdown on the expression levels of migration and invasion markers, as well as Wnt/β-catenin signaling pathway-related proteins in pancreatic carcinoma cells. Furthermore, a recovery experiment was conducted to assess the role of Wnt/β-catenin signaling pathway agonist CHIR-99021 in ADAMDEC1 knockdown-induced inhibition of pancreatic carcinoma cell growth and migration. RESULTS:(1) ADAMDEC1 was highly expressed in pancreatic carcinoma cells. (2) Knockdown of ADAMDEC1 led to a significant reduction in the proliferation, migration and invasion of pancreatic carcinoma cells. (3) Knockdown of ADAMDEC1 resulted in increased E-cadherin protein expression and decreased levels of matrix metalloproteinase 9, N-cadherin and vimentin proteins, alongside a reduction in the expression of Wnt/β-catenin signaling pathway-related proteins. (4) Co-treatment of pancreatic carcinoma cells with CHIR-99021 and ADAMDEC1 small interfering RNA reversed the inhibitory effects of ADAMDEC1 knockdown on cell proliferation, migration, and invasion. CONCLUSION: ADAMDEC1 is highly expressed in pancreatic carcinoma. Targeted silencing of ADAMDEC1 has the potential to inhibit the proliferation, migration and invasion of pancreatic carcinoma cells by regulating the Wnt/β-catenin signaling pathway. [ABSTRACT FROM AUTHOR]

Laminin is an extracellular matrix molecule that is the major component of the basement membrane and plays a key role in regulating various processes. However, the association between the laminin gene family and the prognosis of pancreatic carcinoma has not been systematically investigated. The role of the laminin gene family in pancreatic cancer was evaluated using data from the TCGA database. The effects of different expressions of members of the laminin gene family on pancreatic cancer survival were compared, and their primary cellular roles were examined. The effects of different expressions of positive family genes on proliferation, metastasis, and invasion, as well as EMT and ferroptosis in pancreatic cancer, were also examined. Based on univariate and multifactorial analysis of pancreatic cancer patients, LAMA3 was identified as an independent prognostic factor for overall survival in pancreatic cancer. LAMA3 was found to be enriched in the actin cytoskeleton, P53 signaling pathway, adhesion molecule junctions, pentose phosphate pathway, and regulatory differences in the cell cycle and focal adhesion. Additionally, high expression of LAMA3 was found to promote cancer proliferation, invasion, and metastasis, facilitate the EMT process, and inhibit ferroptosis. Our results identified LAMA3 was associated with the prognosis of patients with pancreatic cancer and may serve as a prognostic biomarker for pancreatic cancer. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Disease recurrence after surgical resection for pancreatic ductal adenocarcinoma can affect more than 50% of patients in the first 12 months after resection. The goal of this current systematic review and meta‐analysis is to assess the ability of preoperative inflammatory scores to predict early recurrence after resection and to identify the best candidates for surgical resection. Methods Medline and Web of Science databases were searched for studies reporting inflammatory scores and oncological outcomes in patients with PDAC after curative‐intent resection. The systematic review revealed that the most common scores were modified Glasgow Prognostic Score (mGPS), Prognostic Nutritional Index (PNI), platelet‐to‐lymphocyte ratio (PLR), neutrophil‐to‐lymphocyte ratio (NLR), and Systemic Immune‐Inflammation Index (SII). After, a meta‐analysis was performed to determine the prognostic value of these scores in early recurrence (12 months) after resection. A subgroup analysis was also carried out in patients who had upfront surgery and in those who underwent neoadjuvant chemotherapy. The ROBINS‐I tool was used to assess the risk of bias. Results The literature search retrieved 1864 articles, 16 of which were eligible for analysis. The included studies comprised 4460 patients. Nine studies reported outcomes for mGPS, four studies for PNI, seven studies for PLR, eight studies for NLR, and two studies for SII. In the meta‐analysis, mGPS, NLR, and PLR showed significantly higher rates of early recurrence in the high‐score groups compared to the low‐score groups. Analyzing the sensitivity and specificity of these scores showed no significant difference in their diagnostic accuracy (mGPS area under the curve [AUC] = 0.534; NLR AUC = 0.628, and PLR AUC = 0.607). High and low PNI and SII scores demonstrated similar rates of early recurrence. Conclusion mGPS, PNI, PLR, NLR, and SII scores did not show a suitable diagnostic accuracy to predict PDAC recurrence in the first 12 months after resection. Therefore, these inflammatory scores should not be used to select the best candidates or to preclude a possible surgical indication.

BackgroundDNA polymerase theta (POLQ) is a translesion synthesis polymerase essential for the repair of double strand breaks by the error-prone TMEJ (Theta Mediated End Joining) pathway. Although POLQ participates in maintaining genome stability, several studies have shown that its overexpression correlates with cancer progression and poor prognosis. Due to the fact that its role as a biomarker in pancreatic cancer remains unexplored, we aimed to study the usefulness of POLQ H-score as a prognostic factor in a pancreatic cancer patient cohort.MethodsWe evaluated POLQ gene expression using a web-based tool to deliver gene expression profiling and interactive analyses based on TCGA and GTEx (GEPIA) and we examined the POLQ immunostaining in 152 biliopancreatic cancer surgical specimens using tissue microarrays. Association with survival was evaluated by Kaplan Meier curves and uni-multivariate Cox regression.ResultsGEPIA analysis showed statistical differences according to POLQ mRNA levels in Disease Free Survival (DFS) (log rank 0.023, HR 2.8, p=0.029) and Overall Survival (OS) (log rank 0.011, HR 3.1, p=0.016). For immunohistochemistry (IHC) evaluation, POLQ H-score was calculated, and showed statistical differences for OS in Kaplan Meier curves (log rank 0.001) and uni-multivariate analysis (HR 2.27; 95% CI 1.24-4.15, p=0.008).ConclusionsOur results indicate that POLQ is an independent prognostic factor in pancreatic cancer when analyzed by immunostaining, which is in agreement with the results shown by the POLQ gene expression analysis (GEPIA).

Abstract Background Interleukin-6 (IL-6) is a multifunctional cytokine that controls the immune response, and its role has been described in the development of autoimmune diseases. Signaling via its cognate IL-6 receptor (IL-6R) complex is critical in tumor progression and, therefore, IL-6R represents an important therapeutic target. Methods An albumin-binding domain-derived highly complex combinatorial library was used to select IL-6R alpha (IL-6Rα)-targeted small protein binders using ribosome display. Large-scale screening of bacterial lysates of individual clones was performed using ELISA, and their IL-6Rα blocking potential was verified by competition ELISA. The binding of proteins to cells was monitored by flow cytometry and confocal microscopy on HEK293T-transfected cells, and inhibition of signaling function was examined using HEK-Blue IL-6 reporter cells. Protein binding kinetics to living cells was measured by LigandTracer, cell proliferation and toxicity by iCELLigence and Incucyte, cell migration by the scratch wound healing assay, and prediction of binding poses using molecular modeling by docking. Results We demonstrated a collection of protein variants called NEF ligands, selected from an albumin-binding domain scaffold-derived combinatorial library, and showed their binding specificity to human IL-6Rα and antagonistic effect in HEK-Blue IL-6 reporter cells. The three most promising NEF108, NEF163, and NEF172 variants inhibited cell proliferation of malignant melanoma (G361 and A2058) and pancreatic (PaTu and MiaPaCa) cancer cells, and suppressed migration of malignant melanoma (A2058), pancreatic carcinoma (PaTu), and glioblastoma (GAMG) cells in vitro. The NEF binders also recognized maturation-induced IL-6Rα expression and interfered with IL-6-induced differentiation in primary human B cells. Conclusion We report on the generation of small protein blockers of human IL-6Rα using directed evolution. NEF proteins represent a promising class of non-toxic anti-tumor agents with migrastatic potential.

BackgroundActivating mutations of the KRAS occurs in >90% of pancreatic ductal adenocarcinoma (PDAC) cases. However, direct pharmacological targeting of the activated KRAS protein has been challenging. We previously reported that KR12, a DNA-alkylating pyrrole-imidazole polyamide designed to recognize the KRAS G12D/V mutation, showed an anti-tumor effect in colorectal cancer. In this study, we evaluated the anti-tumor effect of KR12 in PDAC.MethodsKR12 was synthesized by an automated peptide synthesizer PSSM-8 and tested for anti-tumor effect in PDAC mouse models.ResultKR12 inhibited tumor growth in a spontaneous PDAC mouse model, although the anti-tumor activity appeared to be limited in a human PDAC xenograft model. We developed a pyrrole-imidazole polyamide screening process based on the hypothesis that genetic elements otherwise unaffected by KR12 could exert attenuating effects on KRAS-suppression-resistant PDAC. We identified RAD51 as a potential therapeutic target in human PDAC cells. A RAD51 inhibitor showed an inhibitory effect on cell growth and affected the cytotoxic activity of KR12 in PDAC cells.ConclusionThese data suggested that the simultaneous inhibition of RAD51 and mutant KRAS blockage would be an important therapeutic strategy for PDAC.

Although CA 19-9 is a commonly used tumor marker in the management of PBMs, the literature describing outcomes in patients with PBMs who have undetectable or low (hereinafter "low") CA 19-9 levels remains scarce. In this study, we sought to compare clinical features and outcomes in patients with PBMs and low CA 19-9 levels to those with normal and elevated CA 19-9 levels.MethodsWe retrospectively collected data on patients with biopsy-confirmed PBMs and stratified patients into categories based on their CA 19-9 level at diagnosis. Survival curves were estimated for patients in each of the three aforementioned CA 19-9 groups using the Kaplan-Meier method and compared using a Cox proportional hazards regression model.ResultsOf the 283 patients identified, 23 (8.1%) had low, 70 (24.7%) had normal, and 190 (67.1%) had elevated CA 19-9 levels. After controlling for sex, age, BMI, the presence of metastases at the time of diagnosis, and treatment with curative intent, the hazard ratio for death in the elevated CA 19-9 group compared to the low CA 19-9 group was 1.993 (95% CI 1.089-3.648; p = 0.025).ConclusionThe elevated CA 19-9 level compared to the low CA 19-9 level and the presence of metastases were associated with an increased hazard of death, while treatment with curative intent was associated with a decreased hazard of death.

Objective To observe change of proliferation, migration and invasion abilities of pancreatic cancer cells with over-/down-expression of circSTON2, and to preliminarily investigate the biological function of circSTON2 in pancreatic cancer. Methods Human pancreatic cancer cell line PANC-1 was in vitro cultured. CircSTON2 over-expression group, circSTON2 down-expression group, and control group were established. Plasmid transfection and siRNA interference were used to transfect the circSTON2 overexpression plasmid and circSTON2-siRNA interference plasmid and blank control plasmid into the above groups. At 24, 36 and 48 hours of culture, CCK-8 assay was used to detect cell proliferation and Transwell assay was used to detect cell migration and invasion. Results At 24, 36 and 48 hours of culture, cell proliferation ability was as follows: circSTON2 over-expression group > control group > circSTON2 down-expression group (all P<0. 05); the number of migration cells and the number of invasion cells were as follows: circSTON2 over-expression group > control group > circSTON2 down-expression group (all P<0. 05）. Conclusions The over-expression of circSTON2 promotes proliferation, migration, and invasion of pancreatic cancer cells. However, the effect of down-expression of circSTON2 is the opposite. [ABSTRACT FROM AUTHOR]

Background: Despite a strong association between nutritional indices and disease prognosis, evidence regarding the evaluation of nutritional indices after preoperative treatment for pancreatic ductal adenocarcinoma (PDAC) is insufficient. We evaluated the clinical significance of the prognostic nutritional index (PNI) in patients with resectable (R‐) and borderline resectable (BR‐) PDAC who received neoadjuvant chemoradiotherapy (NACRT) followed by pancreatic resection. Methods: We assessed 153 patients with R‐ and BR‐PDAC who underwent NACRT followed by curative resection between 2009 and 2022. We evaluated the association between preoperative PNI after NACRT and short‐ and long‐term outcomes. Results: The median preoperative PNI value after NACRT was 42.1, and the optimal cutoff value from the time‐dependent receiver operating characteristic curve was 38.6. The low PNI group (PNI < 38.6, n = 44) exhibited significantly worse inflammatory parameters, surgical outcomes, and prognoses than the high PNI group (PNI ≥ 38.6, n = 109). Multivariate analysis identified preoperative PNI ≤ 38.6 (hazard ratio [HR]: 2.32, 95% confidence interval [CI]: 1.00–5.38, p =.049), blood loss ≥1642 mL (HR: 3.05, 95% CI: 1.65–5.64, p <.001), node positive pathology (HR: 2.10, 95% CI: 1.32–3.34, p =.002), and lack of postoperative adjuvant chemotherapy (HR: 3.55, 95% CI: 2.05–6.15, p <.001) as significant predictors of overall survival. Conclusions: For patients with R‐ and BR‐PDAC receiving preoperative treatment, it is imperative to closely monitor their nutritional status when determining the optimal surgical procedure timing. [ABSTRACT FROM AUTHOR]

We aimed to assess the diagnostic utility of an immunohistochemical panel including calcium-binding protein P, p53, Ki-67, and SMAD family member 4 and K-ras mutation for diagnosing pancreatic solid lesion specimens obtained by endoscopic ultrasound-guided fine-needle biopsy and to confirm their usefulness in histologically inconclusive cases. Immunohistochemistry and peptide nucleic acid-clamping polymerase chain reaction for K-ras mutation were performed on 96 endoscopic ultrasound-guided fine-needle biopsy specimens. The diagnostic efficacy of each marker and the combination of markers was calculated. The diagnostic performances of these markers were evaluated in 27 endoscopic ultrasound-guided fine-needle biopsy specimens with histologically inconclusive diagnoses. A classification tree was constructed. K-ras mutation showed the highest accuracy and consistency. Positivity in more than two or three of the five markers showed high diagnostic accuracy (94.6 % and 93.6 %, respectively), and positivity for more than three markers showed the highest accuracy for inconclusive cases (92.0 %). A classification tree using K-ras mutation, Ki-67, S100P, and SMAD4 showed high diagnostic performance, with only two misclassifications in inconclusive cases. K-ras mutation detection via peptide nucleic acid-clamping polymerase chain reaction is a stable and accurate method for distinguishing between pancreatic ductal adenocarcinoma and non-pancreatic ductal adenocarcinoma lesions. A classification tree using K-ras mutation, Ki-67, S100P, and SMAD4 helps increase the diagnostic accuracy of cases that are histologically difficult to diagnose. [ABSTRACT FROM AUTHOR]

Inadequate specimen quality or quantity hinders comprehensive genomic profiling in identifying actionable mutations and guiding treatment strategies. We investigated the optimal conditions for pancreatic cancer specimen selection for comprehensive genomic profiling. We retrospectively analyzed 213 pancreatic cancer cases ordered for comprehensive genomic profiling and compared results from pancreatic biopsy, liver biopsy of pancreatic cancer metastases, pancreatectomy, liquid, and nonliver metastatic organ specimens. We examined preanalytical conditions, including cellularity (tumor cell count/size). The successfully tested cases were those that underwent comprehensive genomic profiling tests without any issues. The successfully tested case ratio was 72.8%. Pancreatic biopsy had the highest successfully tested case ratio (87%), with a high tumor cell percentage, despite the small number of cells (median, 3425). Pancreatic biopsy, liver biopsy of pancreatic cancer metastases, and non‐liver metastatic organ had higher successfully tested case ratios than that for pancreatectomy. Liver biopsy of pancreatic cancer metastases and pancreatectomy cases with tumor size (mm2) × tumor ratio (%) > 150 and >3000, respectively, had high successfully tested case ratios. The success of comprehensive genomic profiling is significantly influenced by the tumor cell ratio, and pancreatic biopsy is a potentially suitable specimen for comprehensive genomic profiling. [ABSTRACT FROM AUTHOR]

Objectives: To determine the role of diffusion-weighted imaging (DWI) for predicting response to neoadjuvant therapy (NAT) in pancreatic cancer. Materials and methods: MEDLINE, EMBASE, and Cochrane Library databases were searched for studies evaluating the performance of apparent diffusion coefficient (ADC) to assess response to NAT. Data extracted included ADC pre- and post-NAT, for predicting response as defined by imaging, histopathology, or clinical reference standards. ADC values were compared with standardized mean differences. Risk of bias was assessed using the Quality Assessment of Diagnostic Studies (QUADAS-2). Results: Of 337 studies, 7 were included in the analysis (161 patients). ADC values reported for the pre- and post-NAT assessments overlapped between responders and non-responders. One study reported inability of ADC increase after NAT for distinguishing responders and non-responders. A correlation with histopathological response was reported for pre- and post-NAT ADC in 4 studies. DWI's diagnostic performance was reported to be high in three studies, with a 91.6–100% sensitivity and 62.5–94.7% specificity. Finally, heterogeneity and high risk of bias were identified across studies, affecting the domains of patient selection, index test, reference standard, and flow and timing. Conclusion: DWI might be useful for determining response to NAT in pancreatic cancer. However, there are still too few studies on this matter, which are also heterogeneous and at high risk for bias. Further studies with standardized procedures for data acquisition and accurate reference standards are needed. Clinical relevance statement: Diffusion-weighted MRI might be useful for assessing response to neoadjuvant therapy in pancreatic cancer. However, further studies with robust data are needed to provide specific recommendations for clinical practice. Key Points: •The role of DWI with ADC measurements for assessing response to neoadjuvant therapy in pancreatic cancer is still unclear. •Pre- and post-neoadjuvant therapy ADC values overlap between responders and non-responders. •DWI has a reported high diagnostic performance for determining response when using histopathological or clinical reference standards; however, studies are still few and at high risk for bias. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is one of the most aggressive forms of malignant disease, often with a long asymptomatic course, early metastases to distant organs and with an extremely poor prognosis. Here we present the case of a 70-year-old female patient, who was hospitalized in a pulmonology institution with a severe general condition. Due to bilateral lung changes seen on the chest radiograph, she was under suspicion for pneumonia, respiratory insufficiency and had elevated markers of inflammation. On physical examination, paraumbilically on the right, a subcutaneous swelling had been palpated with a harder consistency measuring 7 cm in diameter. She presented an ulcerated umbilicus with a purulent discharge. Nineteen hours after admission, a fatal outcome occurred and the autopsy proved an extended malignant disease (pancreatic ductal adenocarcinoma (aT3N2M1, Stage IV)) with multiple metastases. It is necessary to adhere to the differential diagnostic algorithm of bilateral lung lesions. Each umbilical nodule should arouse suspicion of the existence of malignant diseases in the abdominal-pelvic region. Therefore, it is of great importance to raise people's awareness about taking control of their health.

Objective: Pancreatic carcinoma is characterised by high aggressiveness and a bleak prognosis; optimising related treatment decisions depends on the availability of reliable prognostic markers. This study was designed to compare various blood biomarkers, such as neutrophil/lymphocyte ratio (NLR), lymphocyte/monocyte ratio (LMR), platelet/lymphocyte ratio (PLR), C-reactive protein (CRP), albumin (Alb), plasma fibrinogen (PF), and CRP/Alb in patients with pancreatic carcinoma. Methods: Our study retrospectively reviewed 250 patients with pancreatic carcinoma diagnosed between July 2007 and December 2018. The Cutoff Finder application was used to calculate the optimal values of CRP/Alb and PF. The Chi-square test or Fisher’s exact test was used to analyse the correlation of CRP/Alb and PF with other clinicopathological factors. Conducting univariate and multivariate analyses allowed further survival analysis of these prognostic factors. Results: Multivariate analysis revealed that, in a cohort of 232 patients with pancreatic ductal adenocarcinoma (PDAC), the PF level exhibited statistical significance for overall survival (hazard ratio (HR) = 0.464; p = 0.023); however, this correlation was not found in the entire group of 250 patients with pancreatic carcinoma. Contrastingly, the CRP/Alb ratio was demonstrated statistical significance in both the entire pancreatic carcinoma cohort (HR = 0.471; p = 0.026) and the PDAC subgroup (HR = 0.484; p = 0.034). CRP/Alb and PF demonstrated a positive association (r=0.489, p<0.001) as indicated by Spearman’s rank correlation analysis. Additionally, in 232 PDAC patients, the combination of the CRP/Alb ratio and PF had synergistic effects on prognosis when compared with either the CRP/Alb ratio or the PF concentration alone. Conclusion: PF concentration is a convenient, rapid, and noninvasive biomarker, and its combination with the CRP/Alb ratio could significantly enhance the accuracy of prognosis prediction in pancreatic carcinoma patients, especially those with the most common histological subtype of PDAC. [ABSTRACT FROM AUTHOR]

Background: We previously conducted a retrospective study investigating pancreatic morphological abnormalities that lead to early diagnosis of pancreatic cancer (PC) using computed tomography (CT). We reviewed 41 of 308 PC patients between 2011 and 2017 who had previously undergone CT to look for morphological changes leading to cancer development. In 24 patients (58.5%), a K‐shaped constriction of the pancreas ("K‐sign") was observed before the appearance of cancer. This study aimed to investigate whether an early PC diagnosis is possible by prospective CT follow‐up of patients with the K‐sign. Methods: We investigated PC development through prospective surveillance of patients exhibiting K‐signs identified on CT. Results: Of approximately 87 000 CT scans performed between April 2019 and August 2022, the K‐sign was observed in 54 patients. A total of 30 patients provided informed consent and were subsequently monitored using CT. Five patients (16.7%) were diagnosed with PC and underwent surgery after 3–24 months follow‐up. Pathologically, four of five patients (80%) were diagnosed with early‐stage pancreatic cancer (stage 0–IA). All patients exhibited defects in acinar structure, fibrous tissue, fat replacement, and inflammatory cells, suggesting their potential involvement in PC development. Conclusion: The detection and surveillance of the K‐sign may be helpful for early PC diagnosis. [ABSTRACT FROM AUTHOR]

Background: We compared the results of preoperative pancreatic juice cytology (PJC) and final pathological diagnosis after resection in patients who underwent resection of intraductal papillary mucinous neoplasm (IPMN) of the pancreas to determine whether preoperative PJC can help determine therapeutic strategies. Methods: Of 1130 patients who underwent surgical resection IPMN at 11 Japanese tertiary institutions, the study included 852 patients who underwent preoperative PJC guided by endoscopic retrograde cholangiopancreatography (ERCP). Results: The accuracy of preoperative PJC for differentiation between cancerous and noncancerous lesions were 55% for IPMN overall; 59% for the branch duct type; 49% for the main pancreatic duct type; 53% for the mixed type, respectively. On classifying IPMN according to the diameters of the mural nodule (MN) and main pancreatic duct (MPD), the corresponding values for diagnostic performance were 40% for type 1 (MN ≥5 mm and MPD ≥ 10 mm); 46% for type 2 (MN ≥5 mm and MPD < 10 mm); 61% for type 3 (MN < 5 mm and MPD ≥ 10 mm); 72% for type 4 (MN < 5 mm and MPD < 10 mm), respectively. Conclusions: PJC in IPMN is not a recommended examination because of its low overall sensitivity and no significant difference in diagnostic performance by type, location, or subclassification. Although the sensitivity is low, the positive predictive value is high, so we suggest that pancreatic juice cytology be performed only in cases where the patient is not sure about surgery. [ABSTRACT FROM AUTHOR]

Pancreatitis, encompassing acute and chronic forms, and pancreatic cancer pose significant challenges to the exocrine tissue of the pancreas. Recurrence rates and complications following acute pancreatitis episodes can lead to long-term risks, including diabetes mellitus. Chronic pancreatitis can develop in approximately 15% of cases, regardless of the initial episode's severity. Alcohol-induced pancreatitis, idiopathic causes, cigarette smoking, and hereditary pancreatitis contribute to the progression to chronic pancreatitis. Chronic pancreatitis is associated with an increased risk of pancreatic cancer, with older age at onset and smoking identified as risk factors. This scoping review aims to synthesise recent publications (2017–2022) on the diagnostic differentiation between pancreatitis and pancreatic cancer while identifying knowledge gaps in the field. The review focuses on biomarkers and imaging techniques in individuals with pancreatitis and pancreatic cancer. Promising biomarkers such as faecal elastase-1 and specific chemokines offer non-invasive ways to assess pancreatic insufficiency and detect early biomarkers for chronic pancreatitis. Imaging techniques, including computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasound (EUS), and positron emission tomography (PET), aid in differentiating between chronic pancreatitis and pancreatic cancer. However, accurately distinguishing between the two conditions remains a challenge, particularly when a mass is present in the head of the pancreas. Several knowledge gaps persist despite advancements in understanding the association between pancreatitis and pancreatic cancer, including the correlation between histopathological grading systems, non-invasive imaging techniques, and biomarkers in chronic pancreatitis to determine the risk of progression to pancreatic cancer, as well as differentiating between the two conditions. Further research is necessary to enhance our understanding of these aspects, which can ultimately improve the diagnosis and management of pancreatitis and pancreatic cancer. [ABSTRACT FROM AUTHOR]

Heparanase (Hpa1) is expressed by tumor cells and cells of the tumor microenvironment and functions to remodel the extracellular matrix (ECM) and regulate the bioavailability of ECM-bound factors that support tumor growth. Heparanase expression is upregulated in human carcinomas, sarcomas, and hematological malignancies, correlating with increased tumor metastasis, vascular density, and shorter postoperative survival of cancer patients, and encouraging the development of heparanase inhibitors as anti-cancer drugs. Among these are heparin/HS mimetics, the only heparanase-inhibiting compounds that are being evaluated in clinical trials. We have synthesized dicarboxylated oxy-heparins (DCoxHs) containing three carboxylate groups per split residue (DC-Hep). The resulting lead compound (termed XII) was upscaled, characterized, and examined for its effectiveness in tumor models. Potent anti-tumorigenic effects were obtained in models of pancreatic carcinoma, breast cancer, mesothelioma, and myeloma, yielding tumor growth inhibition (TGI) values ranging from 21 to 70% and extending the survival time of the mice. Of particular significance was the inhibition of spontaneous metastasis in an orthotopic model of breast carcinoma following resection of the primary tumor. It appears that apart from inhibition of heparanase enzymatic activity, compound XII reduces the levels of heparanase protein and inhibits its cellular uptake and activation. Heparanase-dependent and -independent effects of XII are being investigated. Collectively, our pre-clinical studies with compound XII strongly justify its examination in cancer patients. [ABSTRACT FROM AUTHOR]

Introduction: Among all malignant tumors of the digestive system, pancreatic carcinoma exhibits the highest mortality rate. Currently, prevention and effective treatment are urgent issues that need to be addressed. Methods: The study focused on meiotic nuclear divisions 1 (MND1), integrating data from the Gene Expression Profiling Interactive Analysis (GEPIA) database with prognostic survival analysis. Simultaneously, experiments at cellular level were employed to demonstrate the effect of MND1 on the proliferation and migration of PC. The small-molecule inhibitor of MND1 was used to suppress the migration of PC cells by knocking down MND1 using small interfering RNA (siRNA) in Patu-8988 and Panc1 cell lines. Results: The results of Cell Counting Kit-8 indicated that the suppression of MND1 resulted in a decrease in cell proliferation. Wound healing and Transwell assays revealed that MND1 knockdown reduced cell migration and invasion. Flow cytometry revealed that inhibiting MND1 hindered the cell cycle. Furthermore, MND1 could stimulate the proliferation, migration, and invasion of Patu-8988 and Panc1 cells by increasing the expression of MND1. Notably, MND1 had a positive effect on H2AFX expression in PC cells. Elevated MND1 expression suggests the low overall survival rate of individuals diagnosed with PC. Conclusion: These findings suggest that MND1 has the potential to be a gene with the ability to accurately diagnose and treat PC. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is the most common (90%) type of solid pancreatic neoplasm. Due to its late presentation and poor survival rate, early diagnosis and timely treatment is of utmost importance for better clinical outcomes. Endoscopic ultrasound provides high-resolution images of the pancreas and has excellent sensitivity in the diagnosis of even small (<2 cm) pancreatic lesions. Apart from imaging, it also has an advantage of tissue acquisition (EUS fine-needle aspiration, FNA; or fine-needle biopsy, FNB) for definitive diagnoses. EUS-guided tissue acquisition plays a crucial role in genomic and molecular studies, which in today's era of personalized medicine, are likely to become important components of PDAC management. With the use of better needle designs and technical advancements, EUS has now become an indispensable tool in the management of PDAC. Lastly, artificial intelligence for the detection of pancreatic lesions and newer automated needles for tissue acquisition will obviate observer dependency in the near future, resulting in the wider dissemination and adoption of this technology for improved outcomes in patients with PDAC. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the prognostic value of CT-based markers of sarcopenia and myosteatosis in comparison to the Eastern Cooperative Oncology Group (ECOG) score for survival of patients with advanced pancreatic cancer treated with high-intensity focused ultrasound (HIFU). Materials and methods: For 142 retrospective patients, the skeletal muscle index (SMI), skeletal muscle radiodensity (SMRD), fatty muscle fraction (FMF), and intermuscular fat fraction (IMFF) were determined on superior mesenteric artery level in pre-interventional CT. Each marker was tested for associations with sex, age, body mass index (BMI), and ECOG. The prognostic value of the markers was examined in Kaplan-Meier analyses with the log-rank test and in uni- and multivariable Cox proportional hazards (CPH) models. Results: The following significant associations were observed: Male patients had higher BMI and SMI. Patients with lower ECOG had lower BMI and SMI. Patients with BMI lower than 21.8 kg/m2 (median) also showed lower SMI and IMFF. Patients younger than 63.3 years (median) were found to have higher SMRD, lower FMF, and lower IMFF. In the Kaplan-Meier analysis, significantly lower survival times were observed in patients with higher ECOG or lower SMI. Increased patient risk was observed for higher ECOG, lower BMI, and lower SMI in univariable CPH analyses for 1-, 2-, and 3-year survival. Multivariable CPH analysis for 1-year survival revealed increased patient risk for higher ECOG, lower SMI, lower IMFF, and higher FMF. In multivariable analysis for 2- and 3-year survival, only ECOG and FMF remained significant. Conclusion: CT-based markers of sarcopenia and myosteatosis show a prognostic value for assessment of survival in advanced pancreatic cancer patients undergoing HIFU therapy. Clinical relevance statement: The results indicate a greater role of myosteatosis for additional risk assessment beyond clinical scores, as only FMF was associated with long-term survival in multivariable CPH analyses along ECOG and also showed independence to ECOG in group analysis. Key Points: • This study investigates the prognostic value of CT-based markers of sarcopenia and myosteatosis for patients with pancreatic cancer treated with high-intensity focused ultrasound. • Markers for sarcopenia and myosteatosis showed a prognostic value besides clinical assessment of the physical status by the Eastern Cooperative Oncology Group score. In contrast to muscle size measurements, the myosteatosis marker fatty muscle fraction demonstrated independence to the clinical score. • The results indicate that myosteatosis might play a greater role for additional patient risk assessments beyond clinical assessments of physical status. [ABSTRACT FROM AUTHOR]

Case summary This report describes the case of a 7-year-old male neutered domestic mixed-breed cat that was initially referred to the Veterinary Hospital of the State University of Londrina for evaluation of a 2-week history of abdominal distension and a 2-day history of anorexia, infected with feline immunodeficiency virus (FIV). Abdominal ultrasound revealed an expansive mass located around the pancreas and right hepatic lobe. In the transoperative macroscopic observation, multiple white nodules were visualized in the liver, pancreas, mesentery, intestine, stomach and peritoneal wall. Immunohistochemical examination revealed that neoplastic cells demonstrated a strong positivity for AE1/AE3 and CK20. A sparse immunoreactivity to chromogranin A was observed, which demonstrates neuroendocrine cell labeling. The histopathologic changes associated with the immunohistochemical profile confirmed the diagnosis of metastatic carcinoma with neuroendocrine differentiation, originating from the pancreas. Relevance and novel information Neuroendocrine tumors of the pancreas are rare and are associated with a poor prognosis in humans. In humans, approximately 7% of neuroendocrine tumors develop in the pancreas, and the 5-year survival rate for a pancreatic neuroendocrine tumor is 53%, according to the American Cancer Society. To our knowledge, only one case has been described in the feline species so far. Due to the rarity of this type of tumor in cats, there is little information about predisposition related to age, sex or breed, as well as the main clinical signs presented, survival time and treatment options. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) is a common and lethal cancer. From diagnosis to disease staging, response to neoadjuvant therapy assessment and patient surveillance after resection, imaging plays a central role, guiding the multidisciplinary team in decision-planning. Review aims and findings: This review discusses the most up-to-date imaging recommendations, typical and atypical findings, and issues related to each step of patient management. Example cases for each relevant condition are presented, and a structured report for disease staging is suggested. Conclusion: Despite current issues in PDAC imaging at different stages of patient management, the radiologist is essential in the multidisciplinary team, as the conveyor of relevant imaging findings crucial for patient care.

The aim of the study was to evaluate the potential diagnostic and prognostic value of gene, Poly A-Binding Protein Interacting Protein 2B (PAIP2B) in pancreatic cancer. We used the gene expression data and clinical information of pancreatic adenocarcinoma patients from The Cancer Genome Atlas database and Gene Expression Omnibus database to analyze the expression of PAIP2B in pancreatic cancer samples, and validated the expression of PAIP2B in tumor tissue, using bioinformatics technology to explore the prognostic value of PAIP2B and its possible biological function. A significantly lower level of PAIP2B was observed in pancreatic cancer patients than in controls, and validated by immunohistochemistry. PAIP2B reduced the proliferation and invasion of cancer cells and had a significantly high expression in early stage. Patients with lower levels of PAIP2B had a significantly shorter median survival time than those with higher levels. DNA demethylation played an important role in PAIP2B expression. In addition, PAIP2B expression was significantly associated with the tumor-infiltrating immune cells, especially T cells CD8, T cells CD4 memory resting, macrophages M0, and dendritic cells resting. Our study also found that PAIP2B regulated miRNA function leading to disease progression in pancreatic cancer patients. Our study explored the potential value of PAIP2B as a biological link between prognosis and pancreatic cancer, and provided reference for the follow-up study on the role of PAIP2B in pancreatic cancer.

Background: The dense stroma of pancreatic ductal adenocarcinoma (PDAC) is thought to impede tumour drug delivery. LSTA1, a novel cyclic tumour-penetrating peptide internalising arginylglycylaspartic acid, promotes tumour-specific drug delivery. In the phase Ib setting, LSTA1 3.2 mg/kg with gemcitabine and nab-paclitaxel showed a 92% disease control rate at 16 weeks and was well tolerated. Methods/design: This is a multicentre, phase II, double-blinded, placebo-controlled, randomised trial evaluating the activity and safety of LSTA1 in combination with gemcitabine and nab-paclitaxel in untreated advanced PDAC. Initially, participants were randomised 2 : 1 to receive gemcitabine 1000 mg/m2, nab-paclitaxel 125 mg/m2 and LSTA1 3.2 mg/kg or placebo. The trial design was updated in a protocol amendment (v4.0) to include a second placebo-controlled cohort which receives a second dose of LSTA1/placebo 4 h following chemotherapy. Treatment is administered on days 1, 8, and 15 of each 28-day cycle until progression (progressive disease). The sample size is 155 based on a clinically worthwhile increase in 6-month progression-free survival (PFS) of 16%-63% with 80% power and 95% confidence to exclude the null hypothesis. The recruitment period is 22 months and follow-up 18 months. Study endpoints are: (1) PFS; (2) objective response rate (RECIST 1.1), safety (Common Terminology Criteria for Adverse Events v5.0), overall survival, participant-reported outcomes; (3) predictive/prognostic biomarkers via archival tissue, and to assess whether a second dose of LSTA1 warrants further evaluation.

Background The effects of dipeptidyl peptidase 4 (DPP-4) inhibitors over the course of long-term treatment remain unclear, and concerns have been raised regarding the role of DPP-4 inhibitors in carcinogenesis in the pancreas. Earlier studies of pancreatic adverse events have reported conflicting results. Methods This study analyzed Korean National Health Insurance Service data from January 2009 to December 2012. Patients who had type 2 diabetes mellitus and took two or more oral glucose-lowering drugs (GLDs) were included. Patients prescribed DPP-4 inhibitors (n=51,482) or other GLDs (n=51,482) were matched at a 1:1 ratio using propensity score matching. The risk of pancreatic cancer was calculated using Kaplan-Meier curves and Cox proportional-hazards regression analysis. Results During a median follow-up period of 7.95 years, 1,051 new cases of pancreatic cancer were identified. The adjusted hazard ratio (HR) for DPP-4 inhibitor use was 0.99 (95% confidence interval [CI], 0.88 to 1.12) compared with the other GLD group. In an analysis limited to cases diagnosed with pancreatic cancer during hospitalization, the adjusted HR for the use of DPP-4 inhibitors was 1.00 (95% CI, 0.86 to 1.17) compared with patients who took other GLDs. Using the other GLD group as the reference group, no trend was observed for elevated pancreatic cancer risk with increased DPP-4 inhibitor exposure. Conclusion In this population-based cohort study, DPP-4 inhibitor use over the course of relatively long-term follow-up showed no significant association with an elevated risk of pancreatic cancer.

Abstract Background Gemcitabine resistance has brought great challenges to the treatment of pancreatic cancer. The N6-methyladenosine (m6A) mutation has been shown to have a significant regulatory role in chemosensitivity; however, it is not apparent whether gemcitabine resistance can be regulated by fat mass and obesity-associated protein (FTO). Methods Cells with established gemcitabine resistance and tissues from pancreatic cancer patients were used to evaluate FTO expression. The biological mechanisms of the effects of FTO on gemcitabine resistant cells were investigated using CCK-8, colony formation assay, flow cytometry, and inhibitory concentration 50. Immunoprecipitation/mass spectrometry, MeRIP-seq, RNA sequencing and RIP assays, RNA stability, luciferase reporter, and RNA pull down assays were employed to examine the mechanism of FTO affecting gemcitabine resistant pancreatic cancer cells. Results The results revealed that FTO was substantially expressed in cells and tissues that were resistant to gemcitabine. Functionally, the gemcitabine resistance of pancreatic cancer could be enhanced by FTO, while its depletion inhibited the growth of gemcitabine resistant tumor cells in vivo. Immunoprecipitation/mass spectrometry showed that the FTO protein can be bound to USP7 and deubiquitinated by USP7, leading to the upregulation of FTO. At the same time, FTO knockdown significantly decreased the expression level of NEDD4 in an m6A-dependent manner. RNA pull down and RNA immunoprecipitation verified YTHDF2 as the reader of NEDD4, which promoted the chemoresistance of gemcitabine resistant cells. FTO knockdown markedly increased the PTEN expression level in an NEDD4-dependent manner and influenced the chemosensitivity to gemcitabine through the PI3K/AKT pathway in pancreatic cancer cells. Conclusion In conclusion, we found that gemcitabine resistance in pancreatic cancer can be influenced by FTO that demethylates NEDD4 RNA in a m6A-dependent manner, which then influences the PTEN expression level and thereby affects the PI3K/AKT pathway. We also identified that the FTO level can be upregulated by USP7.

Primary pancreatic lymphoma (PPL) is a rare malignancy, which is defined as a mass centered in pancreas with involvement of contiguous lymph nodes and distant spread may exist. Accurate diagnosis of PPL prior to pathological confirmation remains challenging, underscoring the critical significance of preoperative imaging assessments. This case report collected two instances of PPL that underwent initial evaluation via 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) between August 2021 and July 2022. Correspondingly, pertinent literature encompassing 18F-FDG PET/CT data related to PPL was meticulously reviewed. Including our aforementioned pair of cases, a cumulative total of 25 instances of PPL were assembled. The distinctive profile of 18F-FDG PET/CT images of PPL predominantly manifests as hypermetabolic lesions with diminished density. Primarily characterized by singular lesions and comparatively substantial volumetric dimensions, a total of eleven cases revealed contiguous lymph node engagement, with five instances displaying distant dissemination encompassing lymph nodes in multiple locations. Amongst these, ten patients underwent sequential 18F-FDG PET/CT follow-up post-intervention. In comparison to pancreatic carcinoma, PPL lesions exhibited heightened hypermetabolism, augmented volumetric proportions, and distinct patterns of distant metastasis. This study indicates that the pivotal role of 18F-FDG PET/CT in the diagnosis and assessment of therapeutic efficacy in PPL is unequivocal. Combined with the clinical attributes of patients, the integration of 18F-FDG PET/CT augments the differential diagnostic capacity differentiating PPL from pancreatic carcinoma.

Metastasis is the key cause of treatment failure in most oncological patients. The spreading of cancer cells to distal tissues and organs can be associated with the epithelial-to-mesenchymal transition (EMT) that reduces or nullifies the effectiveness of the actual treatments. In this context, the establishment of effective antimetastatic agents is the final frontier in cancer research. Noble metal nanomaterials may allow advancements in this regard, but the issue of their persistence precludes their translation to clinics despite their antimetastatic properties. Here, we demonstrate that non-persistent gold and copper ultrasmall-in-nano architectures (NAs) conceived by a safe-by-design approach reduce tumor growth and modulate the progression of the metastasis by altering gene and protein expression of the EMT-related factors in alternative in vivo models of pancreatic ductal adenocarcinoma. Together with these findings, we also introduce an alternative biomodel for the evaluation of metastasis to mimic the heterogeneity of the metastatic phenomenon. On a broader basis, our results represent a promising step forward in the development of novel families of ultrasmall-in-nano antimetastatic agents for the establishment of the next clinical approaches for pancreatic cancer metastasis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Plastin 1 (PLS1) expression has been implicated in the malignant progression of some cancers. however, its involvement in pancreatic carcinoma (PC) is unknown. This study aimed to determine whether and how PLS1 might contribute to PC progression. METHODS: TCGA database and GEPIA website were to analyze PLS1 expression and percent survival in PC patients. BxPC-3 and PANC-1 cells were transfected with si-PLs1, PCDNA3.1-PLS1, or empty vectors using Lipofectamine 2000. The expression of PLS1 was assessed with real-time quantitative polymerase chain reaction (RT-qPCR), western blotting and immunohistochemistry. The Cell Counting Kit-8 (CCK-8), 5-ethynyl-2-deoxyuridine (EdU), flow cytometry, wound healing, and transwell assays were executed to examine proliferation, apoptosis, migration, and invasion of PC cells, respectively. The glucose metabolism of PC cells was analyzed by testing the glucose uptake, pyruvate production, and lactate production. Western blot was applied to assess glycolysis-related protein expression. RESULTS: PLS1 was upregulated in PC tissues and cells and high PLs1 expression predicted poor prognosis. overexpression of PLS1 in PC cells markedly increased proliferation, migration, and invasion and inhibited apoptosis, whereas PLS1 silencing had the opposite effects. GSEA analysis revealed that PLS1 activated the glycolytic signaling pathway. PLS1 overexpression increased glucose uptake, pyruvate production, lactate production, and the expression of glycolysis-related proteins (glucose transporter 1, hexokinase 2, lactate dehydrogenase A, 6-phospho- fructokinase, and pyruvate kinase isozyme type M2 in BxPC-3 and PANC-1 cells, whereas PLS1 silencing inhibited these events in BXPC-3 and PANC-1 cells. In in-vivo experiments, PLS1 overexpression promoted tumor growth, whereas this effect was reversed by glycolysis inhibitor 2-deoxy-D-glucose. CONCLUSIONS: These findings indicate that PLS1 contributes to PC progression by activating the glycolytic signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Gemcitabine resistance has brought great challenges to the treatment of pancreatic cancer. The N6-methyladenosine (m6A) mutation has been shown to have a significant regulatory role in chemosensitivity; however, it is not apparent whether gemcitabine resistance can be regulated by fat mass and obesity-associated protein (FTO). Methods: Cells with established gemcitabine resistance and tissues from pancreatic cancer patients were used to evaluate FTO expression. The biological mechanisms of the effects of FTO on gemcitabine resistant cells were investigated using CCK-8, colony formation assay, flow cytometry, and inhibitory concentration 50. Immunoprecipitation/mass spectrometry, MeRIP-seq, RNA sequencing and RIP assays, RNA stability, luciferase reporter, and RNA pull down assays were employed to examine the mechanism of FTO affecting gemcitabine resistant pancreatic cancer cells. Results: The results revealed that FTO was substantially expressed in cells and tissues that were resistant to gemcitabine. Functionally, the gemcitabine resistance of pancreatic cancer could be enhanced by FTO, while its depletion inhibited the growth of gemcitabine resistant tumor cells in vivo. Immunoprecipitation/mass spectrometry showed that the FTO protein can be bound to USP7 and deubiquitinated by USP7, leading to the upregulation of FTO. At the same time, FTO knockdown significantly decreased the expression level of NEDD4 in an m6A-dependent manner. RNA pull down and RNA immunoprecipitation verified YTHDF2 as the reader of NEDD4, which promoted the chemoresistance of gemcitabine resistant cells. FTO knockdown markedly increased the PTEN expression level in an NEDD4-dependent manner and influenced the chemosensitivity to gemcitabine through the PI3K/AKT pathway in pancreatic cancer cells. Conclusion: In conclusion, we found that gemcitabine resistance in pancreatic cancer can be influenced by FTO that demethylates NEDD4 RNA in a m6A-dependent manner, which then influences the PTEN expression level and thereby affects the PI3K/AKT pathway. We also identified that the FTO level can be upregulated by USP7. [ABSTRACT FROM AUTHOR]

Little research has been conducted on the experience of pancreatic cancer from a patient's perspective. Several factors suggest that trajectory models of chronic illness or other cancers cannot be applied to pancreatic cancer. Within this grounded theory study, 26 problem-centred interviews were conducted with people with pancreatic cancer from Germany. A cancer-specific trajectory model was developed, depicting both curative and palliative courses. Two successive phases form the core: Immediately after diagnosis, there is an acute phase in which patients focus on mere survival, attempt to overcome the short-term consequences of pancreatic cancer and search for information. This initial phase is followed by a circular phase of living on with pancreatic cancer, characterized by adaptation to the long-term consequences of the disease and a repeated experience of fear of recurrence or progression and threat in the context of follow-up examinations. Understanding disease trajectories from a patient's perspective enables health professionals better to understand patients' needs, concerns, and fears and better support them in coping. Trial registration: German Clinical Trials Register, DRKS00020251, 13.01.2020. [ABSTRACT FROM AUTHOR]

Objectives: To critically appraise methodology and reproducibility of published studies on CT radiomics of pancreatic ductal adenocarcinoma (PDAC). Methods: PRISMA literature search of MEDLINE, PubMed, and Scopus databases was conducted from June to August 2022 relating to CT radiomics human research articles pertaining to PDAC diagnosis, treatment, and/ or prognosis, utilising Image Biomarker Standardisation Initiative-compliant (IBSI) radiomic software. Keyword search included [pancreas OR pancreatic] AND [radiomic OR [quantitative AND imaging] OR [texture AND analysis]]. Analysis included cohort size, CT protocol used, radiomic feature (RF) extraction, segmentation, and selection, software used, outcome correlation, and statistical methodology, with focus on reproducibility. Results: Initial search yielded 1112 articles; however, only 12 articles met all inclusion/exclusion criteria. Cohort sizes ranged from 37 to 352 (median = 106, mean = 155.8). CT slice thickness varied among studies (4 using ≤ 1 mm, 5 using > 1 to 3 mm, 2 using > 3 to 5 mm, 1 not specifying). CT protocol varied (5 using a single portal-venous (pv)-phase, 5 using a pancreas protocol, 1 study using a non-contrast protocol). RF extraction and segmentation were heterogeneous (RF extraction: 5 using pv-phase, 2 using late arterial, 4 using multi-phase, 1 using non-contrast phase; RF selection: 3 pre-selected, 9 software-selected). 2D/3D RF segmentation was diverse (2D in 6, 3D in 4, 2D and 3D in 2 studies). Six different radiomics software were used. Research questions and cohort characteristics varied, ultimately leading to non-comparable outcome results. Conclusion: The current twelve published IBSI-compliant PDAC radiomic studies show high variability and often incomplete methodology resulting in low robustness and reproducibility. Clinical relevance statement: Radiomics research requires IBSI compliance, data harmonisation, and reproducible feature extraction methods for non-invasive imaging biomarker discoveries to be valid. This will ensure a successful clinical implementation and ultimately an improvement of patient outcomes as part of precision and personalised medicine. Key Points: • Current state of radiomics research in pancreatic cancer shows low software compliance to the Image Biomarker Standardisation Initiative (IBSI). • IBSI-compliant radiomics studies in pancreatic cancer are heterogeneous and not comparable, and the majority of study designs showed low reproducibility. • Improved methodology and standardisation of practice in the emerging field of radiomics has the potential of this non-invasive imaging biomarker in the management of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Pancreatic cancer has a poor prognosis due to its aggressive nature and ability to metastasize at an early stage. Currently, its management is still a challenge because this neoplasm is resistant to conventional treatment approaches, among which is chemo‐radiotherapy (CRT), due to the abundant stromal compartment involved in the mechanism of hypoxia. Hyperthermia, among other effects, counteracts hypoxia by promoting blood perfusion and thereby can enhance the therapeutic effect of radiotherapy (RT). Therefore, the establishment of integrated treatments would be a promising strategy for the management of pancreatic carcinoma. Here, the effects of joint radiotherapy/hyperthermia (RT/HT) on optimized chick embryo chorioallantoic membrane (CAM) pancreatic tumor models are investigated. This model enables a thorough assessment of the tumor‐arresting effect of the combined approach as well as the quantitative evaluation of hypoxia and cell cycle‐associated mechanisms by both gene expression analysis and histology. The analysis of the lower CAM allows to investigate the variation of the metastatic behaviors of the cancer cells associated with the treatments. Overall, this study provides a potentially effective combined strategy for the non‐invasive management of pancreatic carcinoma. [ABSTRACT FROM AUTHOR]

Objective To study the expression of Xklp2 target protein (targeting protein for Xenopus kinesin-like protein2, TPX2) in pancreatic carcinoma and its potential value in predicting prognosis. Methods Based on 200 genes related to glycolysis, the information of pancreatic patients was obtained from TCGA and GEO databases, and the characteristics of glycolysis metabolism of the latter were evaluated. At the same time, the metabolic characteristics and differential genes of the patients were evaluated, the risk model was established by Cox regression and Lasso regression analysis, and the key glycolysis related gene TPX2 was obtained. The prognostic validity of the model was verified by GEO database based on the expression of prognostic genes, the overall survival (OS) of patients with pancreatic cancer, the difference in the expression of prognostic genes between normal pancreatic tissue and pancreatic cancer was analyzed and finally the function of prognostic genes was verified at the cellular level. Results The case cohort was divided into three characteristic groups: high, medium and low glycolysis metabolism. Patients with low-rate glycolysis metabolism had certain survival advantages. TPX2 was the key gene of this model. Pancreatic cancer patients showed high expression of TPX2 and had poor prognosis. Knocking down TPX2 at cellular level can inhibit the proliferation and colony formation of pancreatic cancer cells. Conclusions The model based on glycolysis metabolism can effectively predict the prognosis of patients with pancreatic cancer. TPX2 is expected to become a potential marker gene for predicting the prognosis of pancreatic cancer.

Introduction:Solid and/or cystic lesions of the pancreas can range from benign to malignant, and the differential diagnosis of pancreatic carcinoma (PC) is of uttermost importance. Endoscopic ultrasonography (EUS) is frequently used and is helpful in detecting small (37 U/mL, and partial atrophy in the pancreas were independently associated with PC. For solid lesions, age and size >24 mm; and for cystic lesions, male gender and mucinous pathology were independently associated with PC. Thirty-six of the cystic lesions had mucinous pathology. Cyst and serum CEA, string sign, wesung connection, and tail location was associated with mucinous pathology. Cyst CEA cut-off for mucinous pathology was 80 ng/mL (AUC: 0.89). CEA >80 ng/mL was found to be associated with mucinous pathology in multivariate analysis.Conclusion:High CA19-9, solid lesion, and lesion-related partial atrophy of the pancreas are associated with PC, and these should be alarming for clinicians in practice. The mucinous character, which is a significant risk of PC for cystic lesions, can be optimally defined with the CEA cut-off value of 80 ng/mL.