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Pancreatic ductal adenocarcinoma (PDAC) characterized by an abundant cancer stroma is an aggressive malignancy with a poor prognosis. Periostin (Pn) is a key extracellular matrix (ECM) protein in various tumor progression. Previously, we described the role of Pn alternative splicing variants (ASVs) with specific functional features in breast cancer. Pn is known to associate with a chemoresistance of PDAC, but the functions of the Pn-ASVs remain largely unknown. In this study, we focused on physiological and pathological Pn-ASVs, and examined the characteristics of Pn-expressing cells and the difference in function of each ASV. We found that cancer-associated fibroblasts (CAFs) are a main source of Pn synthesis, which selectively secrete pathological Pn-ASVs with exon 21 both in mouse and human samples. RNA sequencing identified a gene signature of Pn-positive CAFs associated with ECM-related genes and chemokines, factors that shape the chemoresistance tumor microenvironment (TME). Additionally, only pathological Pn-ASVs interacted with heat shock protein 70-1a (HSP70-1a), leading to significant rescue of gemcitabine-induced PDAC apoptosis. In silico analysis revealed that the presence or absence of exon 21 changes the tertiary structure of Pn and the binding sites for HSP70-1a. Altogether, Pn-ASVs with exon 21 secreted from CAFs play a key role in supporting tumor growth by interacting with cancer cell-derived HSP70-1a, indicating that Pn-ASVs with exon 21 might be a potential therapeutic and diagnostic target in PDAC patients with rich stroma. [ABSTRACT FROM AUTHOR]

Simple Summary: This review specifically examines the advancing comprehension and management of intraductal papillary mucinous neoplasms (IPMNs) by integrating various diagnostic approaches, encompassing genomic and molecular biomarkers, alongside clinical and radiographic information. This review highlights the difficulty in differentiating low-risk from high-risk IPMNs and underscores the significance of biomarkers such as KRAS and GNAS mutations, which are directly linked to IPMN progression. Furthermore, it examines the efficacy of advanced imaging modalities, including MRI with MRCP and contrast-enhanced endoscopic ultrasound (EUS), for enhanced malignancy detection. This review also emphasizes novel models that integrate cystic fluid markers, clinical nomograms, and radiomics to enhance risk stratification. This review is unique in that it provides a thorough analysis of new molecular insights and emphasizes customized patient care while providing useful suggestions based on current international guidelines. This review helps clinicians improve IPMN treatment strategies and outcomes. Currently, there is no reliable method of discerning between low-risk and high-risk intraductal papillary mucinous neoplasms (IPMNs). Operative resection is utilized in an effort to resect those lesions with high-grade dysplasia (HGD) prior to the development of invasive disease. The current guidelines recommend resection for IPMN that involve the main pancreatic duct. Resecting lesions with HGD before their progression to invasive disease and the avoidance of resection in those patients with low-grade dysplasia is the optimal clinical scenario. Therefore, the importance of developing preoperative models able to discern HGD in IPMN patients cannot be overstated. Low-risk patients should be managed with nonsurgical treatment options (typically MRI surveillance), while high-risk patients would undergo resection, hopefully prior to the formation of invasive disease. Current research is evolving in multiple directions. First, there is an ongoing effort to identify reliable markers for predicting malignant transformation of IPMN, mainly focusing on genomic and transcriptomic data from blood, tissue, and cystic fluid. Also, multimodal models of combining biomarkers with clinical and radiographic data seem promising for providing robust and accurate answers of risk levels for IPMN patients. [ABSTRACT FROM AUTHOR]

Simple Summary: MRI can provide better visualization of tumors and nearby organs at risk (OAR) than CT for fast and accurate contouring during online adaptive MRI-guided stereotactic body radiation treatment (MRI-guided SBRT) for pancreatic and other intra-abdominal cancers. Pre-set MRI sequences provided in a 1.5T MRI scanner hybrid with a linear accelerator can be used during MRI-guided SBRT, but they often limit tumor and OAR visualization and require a long image acquisition time. This study retrospectively analyzed 26 patients with pancreatic and intra-abdominal cancers that underwent CT and MR simulations and 3–5 fractionated MRI-guided SBRT. The visualization of tumors and OAR was improved with T1W imaging, which is essential for online adaptive planning and resulted in fast and accurate contouring in a shorter imaging time. A 1.5T MRI combined with a linear accelerator (Unity®, Elekta; Stockholm, Sweden) is a device that shows promise in MRI-guided stereotactic body radiation treatment (SBRT). Previous studies utilized the manufacturer's pre-set MRI sequences (i.e., T2 Weighted (T2W)), which limited the visualization of pancreatic and intra-abdominal tumors and organs at risk (OAR). Here, a T1 Weighted (T1W) sequence was utilized to improve the visualization of tumors and OAR for online adapted-to-position (ATP) and adapted-to-shape (ATS) during MRI-guided SBRT. Twenty-six patients, 19 with pancreatic and 7 with intra-abdominal cancers, underwent CT and MRI simulations for SBRT planning before being treated with multi-fractionated MRI-guided SBRT. The boundary of tumors and OAR was more clearly seen on T1W image sets, resulting in fast and accurate contouring during online ATP/ATS planning. Plan quality in 26 patients was dependent on OAR proximity to the target tumor and achieved 96 ± 5% and 92 ± 9% in gross tumor volume D90% and planning target volume D90%. We utilized T1W imaging (about 120 s) to shorten imaging time by 67% compared to T2W imaging (about 360 s) and improve tumor visualization, minimizing target/OAR delineation uncertainty and the treatment margin for sparing OAR. The average time-consumption of MRI-guided SBRT for the first 21 patients was 55 ± 15 min for ATP and 79 ± 20 min for ATS. [ABSTRACT FROM AUTHOR]

Simple Summary: The MET receptor and its ligand Hepatocyte Growth Factor (HGF) sustain cell proliferation, survival, motility, and invasion. Several pieces of evidence suggest that these biological activities support the metastatic potential of transformed cells. Cancer cell dissemination is sustained by cell-autonomous (executed by cancer cells) and non-cell-autonomous (executed by cells composing the tumor microenvironment) functions. To define the role of the HGF/MET axis in this complex process, we genetically knocked out the MET gene in cancer cells that were not dependent on MET signaling for their growth. In this way, we exclusively evaluated the relevance of the HGF/MET axis in prompting cell-autonomous activities (MET signaling in tumor microenvironment cells is maintained intact) independently of their intrinsic ability to proliferate (that is sustained by different oncogenic drivers). Our results proved that HGF/MET axis plays a crucial role in directing cell-autonomous functions regulating cancer cell dissemination, supporting a possible use of MET inhibitors in metastatic cancers. Cancer cell dissemination is sustained by cell-autonomous and non-cell-autonomous functions. To disentangle the role of HGF (Hepatocyte Growth Factor) and MET ligand/receptor axis in this complex process, we genetically knocked out the MET gene in cancer cells in which MET is not the oncogenic driver. In this way, we evaluated the contribution of the HGF/MET axis to cancer cell dissemination independently of its direct activities in cells of the tumor microenvironment. The lack of MET expression in MET−/− cells has been proved by molecular characterization. From a functional point of view, HGF stimulation of MET−/− cancer cells was ineffective in eliciting intracellular signaling and in sustaining biological functions predictive of malignancy in vitro (i.e., anchorage-independent growth, invasion, and survival in the absence of matrix adhesion). Cancer cell dissemination was assessed in vivo, evaluating: (i) the ability of MET−/− lung carcinoma cells to colonize the lungs following intravenous injection and (ii) the spontaneous dissemination to distant organs of MET−/− pancreatic carcinoma cells upon orthotopic injection. In both experimental models, MET ablation affects the time of onset, the number, and the size of metastatic lesions. These results define a crucial contribution of the HGF/MET axis to cell-autonomous functions driving the metastatic process. [ABSTRACT FROM AUTHOR]

In pancreatic cancer, the activation of quiescent pancreatic stellate cells (PSCs) is a critical event that leads to a characteristic dense desmoplastic stroma. The fibrotic network resulting from the bidirectional cross talk between pancreatic cancer cells (PCCs) and PSCs creates a complex tumor microenvironment that considerably hinders drug delivery and penetration. To improve pancreatic cancer treatment, a promising parallelization strategy with cross‐action property is urgently required that can simultaneously act on PCCs and PSCs to normalize activated PSCs (aPSCs), that is reverse them back to quiescent phenotype. Herein, a novel parallelization delivery system (CoA‐A&B‐γPGA) with dual‐pathway PSC quiescence restoration functions is designed. Metformin downregulates the secretion of transforming growth factor‐beta in PCCs, and all‐trans‐retinoic acid re‐educates aPSCs. CoA‐A&B‐γPGA thus induces aPSC quiescence and homeostatic restoration of desmoplastic stroma in vitro and in vivo. Importantly, CoA‐A&B‐γPGA exhibits deep penetration, improved accumulation and long‐term retention, and enhanced combination chemotherapy effects in multicellular spheroid and xenograft models. Furthermore, this dual‐targeting and co‐delivery system shows high specificity and sensitivity for detecting pancreatic cancer in patient samples. The innovative but simple peptide amphiphile co‐assembly strategy provides a new paradigm to design desired nanomedicines for stroma‐enriched pancreatic cancer therapy. [ABSTRACT FROM AUTHOR]

Introduction: Celiac plexus neurolysis (CPN) has been developed as adjunctive therapy to medical management (MM) of abdominal pain associated with unresectable pancreatic cancer. We aimed to conduct a systematic review and meta‐analysis to obtain updated and more accurate evidence on the efficacy of additional types of CPN, including endoscopic ultrasound‐guided CPN (EUS‐CPN). Methods: On March 16, 2021, we performed searches of PubMed, Web of Science, and CENTRAL for original randomized controlled trials (RCTs). We defined the primary outcome as a standardized pain intensity score with a range of 0–10, and evaluated the mean difference between the CPN + MM and MM groups at 4, 8, and 12 weeks after the initiation of treatment. We used a random‐effects model to synthesize the mean differences across RCTs. Results: We selected 10 RCTs involving 646 individuals. The synthesized mean difference in the pain intensity score between the CPN + MM and MM groups was −0.58 (95% confidence interval [CI]: −1.09 to −0.07) (p = 0.034) in favor of CPN + MM at 4 weeks, −0.46 (95%CI: −1.00 to 0.08) (p = 0.081) at 8 weeks, and − 1.35 (95%CI: −3.61 to 0.92) (p = 0.17) at 12 weeks. Conclusions: This updated meta‐analysis of CPN demonstrates its efficacy for managing abdominal pain at 4 weeks. Although there are various limitations, when abdominal pain in patients with unresectable pancreatic cancer is poorly controlled with MM alone, CPN should be an option even if the duration of effect is short‐lived, taking into account the absence of serious adverse events. [ABSTRACT FROM AUTHOR]

Abstract Background Tumor-infiltrating lymphocytes (TILs) are major participants in the tumor microenvironment. The prognostic value of TILs in patients with pancreatic cancer is still controversial. Methods The aim of our meta-analysis was to determine the impact of FoxP3+Treg cells on the survival of pancreatic cancer patients. We searched for related studies in PubMed, EMBASE, Ovid, and Cochrane Library from the time the databases were established to Mar 30, 2017. We identified studies reporting the prognostic value of FoxP3+Treg cells in patients with pancreatic cancer. Overall survival (OS) and disease-free survival (DFS)/progression-free survival (PFS)/relapse-free survival (RFS) were investigated by pooling the data. The pooled hazard ratios (HRs) with 95% confidence intervals (95% CI) were used to evaluate the association between FoxP3+Treg cells and survival outcomes of pancreatic cancer patients. A total of 972 pancreatic cancer patients from 8 studies were included in our meta-analysis. Results High levels of infiltration with FoxP3+Treg cells were significantly associated with poor OS (HR=2.13; 95% CI 1.64–2.77; P

Purpose: To evaluate customizing a knowledge-based planning (KBP) model using dosimetric analysis for volumetric modulated arc therapy for pancreatic cancer. Materials and Methods: The first model (M1) using 56 plans and the second model (M2) using 31 plans were created in the first 7 months of the study. The ratios of volume of both kidneys overlapping the expanded planning target volume to the total volume of both kidneys (Voverlap/Vwhole) were calculated in all cases to customize M1. Regression lines were derived from Voverlap/Vwhole and mean dose to both kidneys. The third model (M3) was created using 30 plans which data put them below the regression line. For validation, KBP was performed with the three models on 21 patients. Results: V18 of the left kidney for M1 plans was 7.3% greater than for clinical plans. Dmean of the left kidney for M2 plans was 2.2% greater than for clinical plans. There was no significant difference between all kidney doses in M3 and clinical plans. Dmean of the left kidney for M2 plans was 2.2% greater than for clinical plans. Dmean to both kidneys did not differ significantly between the three models in validation plans with Voverlap/Vwhole lower than average. In plans with larger than average volumes, the Dmean of validation plans created by M3 was significantly lower for both kidneys by 1.7 and 0.9 Gy than with M1 and M2, respectively. Conclusions: Selecting plans to register in a model by analyzing dosimetry and geometry is an effective means of improving the KBP model.

Background: Tumor-infiltrating lymphocytes (TILs) are major participants in the tumor microenvironment. The prognostic value of TILs in patients with pancreatic cancer is still controversial. Methods: The aim of our meta-analysis was to determine the impact of FoxP3+Treg cells on the survival of pancreatic cancer patients. We searched for related studies in PubMed, EMBASE, Ovid, and Cochrane Library from the time the databases were established to Mar 30, 2017. We identified studies reporting the prognostic value of FoxP3+Treg cells in patients with pancreatic cancer. Overall survival (OS) and disease-free survival (DFS)/progression-free survival (PFS)/relapse-free survival (RFS) were investigated by pooling the data. The pooled hazard ratios (HRs) with 95% confidence intervals (95% CI) were used to evaluate the association between FoxP3+Treg cells and survival outcomes of pancreatic cancer patients. A total of 972 pancreatic cancer patients from 8 studies were included in our meta-analysis. Results: High levels of infiltration with FoxP3+Treg cells were significantly associated with poor OS (HR=2.13; 95% CI 1.64–2.77; P<0.05) and poor DFS/PFS/RFS (HR=1.70; 95% CI 1.04 ~ 2.78; P< 0.05). Similar results were also observed in the peritumoral tissue; high levels of FoxP3+Treg cells were associated with poor OS (HR =2.1795% CI, CI 1.50–3.13). Conclusion: This meta-analysis indicated that high levels of intratumoral or peritumoral FoxP3+Treg cell infiltration could be recognized as a negative factor in the prognosis of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Despite the use of many types of chemotherapies for pancreatic cancer, optimal efficacy has not been obtained so far. Pancreatic cancer shows a high incidence of TP53 mutations, inactivating its tumor suppressor activity. In this study, we identified sodium cantharidinate as a novel, potential anti-pancreatic cancer agent that activates p53 function. Sodium cantharidinate reduced the viability of pancreatic cancer cells, including the human primary pancreatic cancer cells, PANC-1, AsPC-1, SW1990 and BXPC-3, in a dose-dependent manner. Sodium cantharidinate induced apoptosis and DNA damage of pancreatic cancer cells. Furthermore, proteome-wide sequencing analysis detected a marked perturbation in p53 signaling pathway on PANC-1 cells upon sodium cantharidinate. Consistent with the previous results, sodium cantharidinate treatment decreased Bcl-2 and mitochondrial cytochrome-c protein expression, as well as phosphorylation of MDM2; meanwhile, it increased the levels of cleaved-caspase-3, cleaved-caspase-9, cleaved-PARP, Bax, and phosphorylated p53, thus inducing the apoptosis of pancreatic cancer cells. The p53-activating effect of sodium cantharidinate was strongly abrogated by treatment with TP53-targeting shRNA. Moreover, sodium cantharidinate inhibited neoplasm growth via the JAK2-STAT3 pathway, which was inhibited by shRNA-TP53 and triggered by combination with gemcitabine. Combination therapy indicated that sodium cantharidinate and gemcitabine synergistically reduced ex vivo and in vivo growth of pancreatic neoplasm. Further docking studies revealed the different binding fates of sodium cantharidinate to activate wild-type p53 function. Thus, sodium cantharidinate could be a potential agent with promising anti-pancreatic cancer efficacy. [ABSTRACT FROM AUTHOR]

To improve the efficacy of gemcitabine (GEM) for the treatment of advanced pancreatic cancer via local hyperthermia potentiated via a multi-functional nanoplatform permitting both in vivo heating and drug delivery is the goal of this study. Here, a chemohyperthermia approach to synergistically achieve high intra-tumoral drug concentrations, while permitting concurrent hyperthermia for more effective tumor cell kill and growth inhibition, is proposed. Drug delivery and hyperthermia are achieved using a hydroxypropyl cellulose (HPC)-grafted porous magnetic drug carrier that is MRI visible to permit in vivo visualization of the biodistribution. These synthesized magnetic drug carriers produce strong T2 -weighted image contrast and permit efficient heating using low-magnetic-field intensities. The thermomechanical response of HPC permits triggered GEM release confirmed during in vitro drug release studies. During in vitro studies, pancreatic cancer cell growth is significantly inhibited (≈82% reduction) with chemohyperthermia compared to chemotherapy or hyperthermia alone. Using PANC-1 xenografts in nude mice, the delivery of injected GEM-loaded magnetic carriers (GEM-magnetic carriers) is visualized with both MRI and fluorescent imaging techniques. Chemohyperthermia with intra-tumoral injections of GEM-magnetic carriers (followed by heating) results in significant increases in apoptotic cell death compared to tumors treated with GEM-magnetic carriers injections alone. Chemohyperthermia with GEM-magnetic carriers offers the potential to significantly improve the therapeutic efficacy of GEM for the treatment of pancreatic cancer. In vivo delivery confirmation with non-invasive imaging techniques could permit patient-specific adjustments therapeutic regimens for improve longitudinal outcomes.

The objective of this review article is to discuss clinical data from studies on Pakistani pancreatic cancer population and its comparison with international data. This review article will allow researchers to identify gaps in the data and hence to design further research in order to address these gaps accordingly. Search was carried out via Google Scholar, PubMed and PakMediNet search engines using keywords "Pancreatic cancers", "Pancreatic adenocarcinoma" and "Pakistan". Pancreatic cancers are one of the most lethal cancers globally. Statistics show that 97.8% of cases of pancreatic cancers in Pakistan have led to mortality. For various cancers around the world, epidemiological data has been used for development of diagnostic tools and therapies. Despite the alarming situation of pancreatic cancers in Pakistan, only limited work has been done in this area. Majority of the studies are based exclusively on reporting of clinical data. Pakistan has not been able to even gather sufficient data to proceed research based on association of molecular aspects of tumor with clinical characteristics. On the contrary, researchers, scientists and clinicians from other parts of the world are already working on association studies, prediction of prognosis, treatment selection and improving the survival of their population. It is an immense need of the situation that molecular based studies are carried out on Pakistani pancreatic cancer population so that diagnosis, prognosis, treatment and survival of these patients can be made better. [ABSTRACT FROM AUTHOR]

Glutathione (GSH) depletion-induced ferroptosis has emerged as a promising treatment for malignant cancer. It works by inactivating glutathione peroxidase 4 (GPX4) and facilitating lipid peroxidation. However, effectively delivering inducers and depleting intracellular GSH remains challenging due to the short half-lives and high hydrophobicity of small-molecule ferroptosis inducers. These inducers often require additional carriers. Herein, diselenide-containing polymers can consume GSH to induce ferroptosis for pancreatic cancer therapy. The diselenide bonds are controllably built into the backbone of the polycarbonate with a targeting peptide CRGD (Cys-Arg-Gly-Asp), which allows for self-assembly into stable nanoparticles (denoted CRNSe) for self-delivery. Significantly, at a concentration of 12 µg mL -1 , CRNSe binds to the active site cysteine of GSH resulting in a thorough depletion of GSH. In contrast, the disulfide-containing analog only causes a slight decrease in GSH level. Moreover, the depletion of GSH inactivates GPX4, ultimately inducing ferroptosis due to the accumulation of lipid peroxide in BxPC-3 cells. Both in vitro and in vivo studies have demonstrated that CRNSe exhibits potent tumor suppressive ability with few side effects on normal tissue. This study validates the anti-tumor mechanism of diselenide-containing polymers in addition to apoptosis and also provides a new strategy for inherently inducing ferroptosis in cancer therapy., (© 2024 Wiley‐VCH GmbH.)

Introduction: Early and accurate diagnosis is paramount for improving the therapeutic efficacy of pancreatic cancers. Endoscopic ultrasonography–fine needle aspiration (EUS-FNA) cytology has come up with the advantage of an early and accurate diagnosis of pancreatic cancers. This study was conducted to analyze the spectrum of pancreatic lesions cytology, and appraise the diagnostic accuracy of EUS-FNA cytology for pancreatic solid and cystic lesions. Materials and Methods: This retrospective study includes 288 EUS-guided pancreatic FNA cases. Clinical data, laboratory tests, cytopathology, histopathology, and imaging reports were retrieved. The final diagnosis was based on EUS-FNA cell block and/or pathology in surgical specimens, with immunohistochemistry support. The results of EUS-guided FNA were compared with the final diagnoses to calculate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results: Among 288 EUS-guided pancreatic FNA cases, 175 (62.0%) were malignant. The mean age was 57.8 ± 13.5 years and 50.1 ± 13.7 years, and the mean size of the lesion was 4.1 ± 1.8 cm and 2.2 ± 1.1 cm in malignant and benign groups, respectively. Sensitivity, specificity, PPV, and NPV of EUS-FNA cytology for solid malignant lesions were 98.3%, 95.1%, 98.3%, and 95.1%, and those for cystic lesions were 88%, 92.3%, 100%, and 100%. Diagnostic accuracy of EUS-FNA cytology for solid and cystic pancreatic lesions is 97.4% and 95.0%, respectively. In conclusion of the above; diagnosis of pancreatic solid and cystic malignancy can be assigned from a composite of the EUS-FNA cytology, cell block preparation and immunohistochemistry Diagnosis of pancreatic solid and cystic malignancy can be assigned from a composite of the EUS-FNA cytology, cell block preparation, and immunohistochemistry.

Qinglin Shen,1,2,* Haitao Yang,3,* Caixia Peng,4,5,* Han Zhu,6 Jia Mei,1 Shan Huang,1 Bin Chen,7 Jue Liu,8 Wenbo Wu,3 Shaokui Cao3 1Department of Oncology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 2Cancer Center, Renmin Hospital, Wuhan University, Wuhan, China; 3School of Materials Science and Engineering, Zhengzhou University, Zhengzhou, China; 4Key Laboratory for Molecular Diagnosis of Hubei Province, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 5Central Laboratory, The Central Hospital of Wuhanper, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 6Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering, Jiangnan University, Wuxi, China; 7Central Laboratory, Renmin Hospital, Wuhan University, Wuhan, China; 8Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China *These authors contributed equally to this work Background: Efficient and precise circulating tumor cells’ (CTCs) capture and release with minimal effect on cell viability for CTCs’ analysis are general requirements of CTCs’ detection device in clinical application. However, these two essential factors are difficult to be achieved simultaneously. Methods: In order to reach the aforementioned goal, we integrated multiple strategies and technologies of staggered herringbone structure, nanowires’ substrate, peptides, enzymatic release, specific cell staining, and gene sequencing into microfluidic device and the sandwich structure peptide-silicon nanowires’ substrate was termed as Pe-SiNWS. Results: The Pe-SiNWS demonstrated excellent capture efficiency (95.6%) and high release efficiency (92.6%). The good purity (28.5%) and cell viability (93.5%) of CTCs could be obtained through specific capture and biological release by using Pe-SiNWS. The good purity of CTCs facilitated precise and quick biological analysis, and five types of KRAS mutation were detected in 16 pancreatic cancer patients but not in healthy donors. Conclusion: The results proved that the effective capture, minor damage release, and precise analysis of CTCs could be realized simultaneously by our novel strategy. The successful clinical application indicated that our work was anticipated to open up new opportunities for the design of CTC microfluidic device. Keywords: circulating tumor cells, Pe-SiNWS, biological release, pancreatic cancers

In pancreatic cancer (PC), surgical resection remains the sole curative option, albeit patients undergoing resection are susceptible to postoperative pancreatic fistula (PF) formation and tumor recurrence. An unmet need exists for a unified strategy capable of concomitantly averting PF and tumor relapse to mitigate morbidity in PC patients after surgery. Herein, an original dual crosslinked biological sealant hydrogel (methacrylate-hyaluronic acid-dopamine (MA-HA-DA) and sulfhydryl-hyaluronic acid-dopamine (SH-HA-DA)) was engineered as a drug depot and loaded with polydopamine-cloaked cytokine interleukin-15 and platelets conjugated with anti-TIGIT. In vitro analyses validated favorable tissue adhesion, cytocompatibility, and stability of the hydrogels. In a PF rodent model, the hydrogel effectively adhered to the pancreatic stump, sealing the severed pancreatic end and impeding post-operative elevations in amylase and lipase. In PC murine models, hydrogels potently stimulated CD8+ T and NK cells to deter residual tumor re-growth and distant metastasis. This innovative hydrogel strategy establishes a new framework for concomitant prevention of PF and PC recurrence. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM), one of the metabolic diseases which is characterized by sustained hyperglycemia, is a life-threatening disease. The global prevalence of DM is on the rise, mainly in low- and middle-income countries. Diabetes is a major cause of blindness, heart attacks, kidney failure, stroke, and lower limb amputation. Type 2 diabetes mellitus (T2DM) is a form of diabetes that is characterized by high blood sugar and insulin resistance. T2DM can be prevented or delayed by a healthy diet, regular physical activity, maintaining normal body weight, and avoiding alcohol and tobacco use. Ethanol and its metabolites can cause differentiation defects in stem cells and promote inflammatory injury and carcinogenesis in several tissues. Recent studies have suggested that diabetes can be treated, and its consequences can be avoided or delayed with proper management. DM has a greater risk for several cancers, such as breast, colorectal, endometrial, pancreatic, gallbladder, renal, and liver cancer. The incidence of cancer is significantly higher in patients with DM than in those without DM. In addition to DM, alcohol abuse is also a risk factor for many cancers. We present a review of the recent studies investigating the association of both DM and alcohol abuse with cancer incidence.

Abstract Background Pancreatic cancer has a dismal prognosis with 5-year overall survival rate of around 5%. Although surgery is still the best option in operable cases, majority of the patients who present in locally advanced stages are deemed inoperable. Novel approaches are therefore needed for the management of around 80% of these inoperable locally advanced pancreatic cancers (LAPC). Hyperthermia (39–43 °C) is a potent radiosensitizer and further enhances the action of gemcitabine, also a known radiosensitizer. Thus through triple sensitization, a combination of hyperthermia, radiotherapy and gemcitabine could be expected to improve the therapeutic outcomes in LAPC. Methods This phase II randomized trial, HEATPAC in unresectable LAPC, explores the feasibility and efficacy of concurrent thermochemoradiotherapy (HTCTRT) over chemoradiotherapy (CTRT) alone with pre- and post-intervention FOLFIRINOX at standard dosage and schedule. Following 4 cycles of neoadjuvant FOLFIRINOX, patients with no metastasis and absence of gross peritoneal carcinomatosis would be randomized to either (a) control arm: concurrent CTRT with gemcitabine (400 mg/m2, weekly ×6) or (b) study arm: locoregional hyperthermia (weekly ×6 during radiotherapy) with concurrent CTRT (same as in control arm). All patients would receive simultaneous-integrated boost intensity-modulated radiation therapy to doses of 56Gy and 50.4Gy to the gross and clinical target volumes respectively delivered in 28 fractions over 5.5 weeks. Deep locoregional hyperthermia would be administered weekly and monitored with real-time intraduodenal multisensor thermometry probe. A temperature of 40–43 °C for 60 min would be aimed for each hyperthermia session. On completion of CTRT/HTCTRT, patients of both groups would receive an additional 8 cycles of FOLFIRINOX. Discussion The expected 1-year baseline overall survival with CTRT alone is considered as 40%. With HTCTRT, a survival advantage of +20% is expected. Considering α = 0.05 and β = 0.80 for sample size computation, a total of 86 patients would be equally randomized into the two treatment groups. This phase II study if found to be safe and effective, would form the basis of a future phase III randomized study. Trial registration The trial has been registered with the ClinicalTrials.gov ( NCT02439593 ). The study has been approved by the Ethical Commissions of Basel and Zurich and is open for patient recruitment.

Abstract This phase I clinical trial (NCT01935843) is to evaluate the safety, feasibility, and activity of chimeric antigen receptor-engineered T cell (CART) immunotherapy targeting human epidermal growth factor receptor 2 (HER2) in patients with advanced biliary tract cancers (BTCs) and pancreatic cancers (PCs). Eligible patients with HER2-positive (>50%) BTCs and PCs were enrolled in the trial. Well cultured CART-HER2 cells were infused following the conditioning treatment composed of nab-paclitaxel (100–200 mg/m2) and cyclophosphamide (15–35 mg/kg). CAR transgene copy number in the peripheral blood was serially measured to monitor the expansion and persistence of CART-HER2 cells in vivo. Eleven enrolled patients received 1 to 2-cycle CART-HER2 cell infusion (median CAR+ T cell 2.1 × 106/kg). The conditioning treatment resulted in mild-to-moderate fatigue, nausea/vomiting, myalgia/arthralgia, and lymphopenia. Except one grade-3 acute febrile syndrome and one abnormal elevation of transaminase (>9 ULN), adverse events related to the infusion of CART-HER2 cells were mild-to-moderate. Post-infusion toxicities included one case of reversible severe upper gastrointestinal hemorrhage which occurred in a patient with gastric antrum invaded by metastasis 11 days after the CART-HER2 cell infusion, and 2 cases of grade 1–2 delayed fever, accompanied by the release of C-reactive protein and interleukin-6. All patients were evaluable for assessment of clinical response, among which 1 obtained a 4.5-months partial response and 5 achieved stable disease. The median progression free survival was 4.8 months (range, 1.5–8.3 months). Finally, data from this study demonstrated the safety and feasibility of CART-HER2 immunotherapy, and showed encouraging signals of clinical activity.

The development of surface-enhanced Raman scattering (SERS) probes with high sensitivity and stability is imminent to improve the accuracy of cancer diagnosis. Here, an exclusive core-Janus satellite (CJS) assembly was constructed by a hierarchical assembly strategy in which the Au-Ag Janus satellite is vertically self-aligned on the core surface. In the process, a silica shell template was ingeniously employed to asymmetrically mask the presatellites for the in situ formation of the Janus structure, and a series of Janus satellites with different morphologies were developed by regulating the encapsulated area of the presatellites. The ordered-oriented arrangement of Au-Ag Janus and unique heterojunction morphology permit CJS assemblies, featuring two types of plasmonic nanogaps, including intrananocrevices for individual Janus and internanogaps between neighboring Janus, thereby multiplying the "hotspots" compared to conventional core-monotonous satellites, which contributes to superior SERS activity. As anticipated, the enhancement factor of CJS assemblies was as high as 3.8 × 10 8 . Moreover, it is intriguing that the directional distribution and head physically immobilized by Janus provided uniform and stable SERS signals. The SERS probe based on the CJS assembly for the detection of carbohydrate antigen 19-9 resulted in an ultrahigh sensitivity with a limit of detection of 3.7 × 10 -5 IU·mL -1 , which is nearly 10 times lower than other SERS probes, and a wide detection range of 3 × 10 -5 to 1 × 10 4 IU·mL -1 . The CJS assembly with excellent SERS performance is promising to advance further development of the early diagnosis of pancreatic cancer.

Introduction: Early and accurate diagnosis is paramount for improving the therapeutic efficacy of pancreatic cancers. Endoscopic ultrasonography-- fine needle aspiration (EUS-FNA) cytology has come up with the advantage of an early and accurate diagnosis of pancreatic cancers. This study was conducted to analyze the spectrum of pancreatic lesions cytology, and appraise the diagnostic accuracy of EUS-FNA cytology for pancreatic solid and cystic lesions. Materials and Methods: This retrospective study includes 288 EUS-guided pancreatic FNA cases. Clinical data, laboratory tests, cytopathology, histopathology, and imaging reports were retrieved. The final diagnosis was based on EUS-FNA cell block and/or pathology in surgical specimens, with immunohistochemistry support. The results of EUS-guided FNA were compared with the final diagnoses to calculate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results: Among 288 EUS-guided pancreatic FNA cases, 175 (62.0%) were malignant. The mean age was 57.8 ± 13.5 years and 50.1 ± 13.7 years, and the mean size of the lesion was 4.1 ± 1.8 cm and 2.2 ± 1.1 cm in malignant and benign groups, respectively. Sensitivity, specificity, PPV, and NPV of EUS-FNA cytology for solid malignant lesions were 98.3%, 95.1%, 98.3%, and 95.1%, and those for cystic lesions were 88%, 92.3%, 100%, and 100%. Diagnostic accuracy of EUS-FNA cytology for solid and cystic pancreatic lesions is 97.4% and 95.0%, respectively. In conclusion of the above; diagnosis of pancreatic solid and cystic malignancy can be assigned from a composite of the EUS-FNA cytology, cell block preparation and immunohistochemistry Diagnosis of pancreatic solid and cystic malignancy can be assigned from a composite of the EUS-FNA cytology, cell block preparation, and immunohistochemistry. [ABSTRACT FROM AUTHOR]

GI cancer is not one cancer but is a term for the group of cancers that affect the digestive system including gastric cancer (GC), colorectal cancer (CRC), hepatocellular carcinoma (HCC), esophageal cancer (EC), and pancreatic cancer (PC). Overall, the GI cancers are responsible for more cancers and more deaths from cancer than any other organ. 5 year survival of these cancers remains low compared to western world. Unlike the rest of the world where organ based specialities hepatobiliary, pancreatic, colorectal and esophagogastric exist , these cancers are managed in India by either a gastrointestinal surgeons, surgical oncologist, or a general surgeon with varying outcomes.The aim of this review was to collate data on GI cancers in indian continent. In colorectal cancers, data from tertiary care centres identifies the unique problem of mucinous and signet colorectal cancer. Results of rectal cancer resection in terms of technique (intersphincteric resection, extralevator aper, minimal invasive approach ) to be comparable with world literature. However long term outcome and data regarding colon cancers and nationally is needed. Gastric cancer at presentation are advanced and in surgically resected patients, there is need for a trial to compare chemoradiation vs chemotherapy alone to prevent loco regional recurrence. Data on minimal invasive gastric cancer surgery may be sparse for the same reason. Theree is a lot of data on surgical techniques and perioperatve outcomes in pancreatic cancer. There is a high volume of locally advanced gallbladder cancers with efforts on to decide whether neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy is better for down staging. Considering GI cancers, a heterogeneous disease with site specific treatment options and variable outcomes, the overall data and outcomes are extremely variable. Young patients with pathology unique to the Indian subcontinent (for example, signet ring rectal cancer, GBCs) need focussed attention. Solution for such pathology needs to come from the Indian continent itself. Joint efforts to improve outcomes for GI cancer can be integrated under the national cancer grid program.

This phase I clinical trial (NCT01935843) is to evaluate the safety, feasibility, and activity of chimeric antigen receptor-engineered T cell (CART) immunotherapy targeting human epidermal growth factor receptor 2 (HER2) in patients with advanced biliary tract cancers (BTCs) and pancreatic cancers (PCs). Eligible patients with HER2-positive (>50%) BTCs and PCs were enrolled in the trial. Well cultured CART-HER2 cells were infused following the conditioning treatment composed of nab-paclitaxel (100-200 mg/m2) and cyclophosphamide (15-35 mg/kg). CAR transgene copy number in the peripheral blood was serially measured to monitor the expansion and persistence of CART-HER2 cells in vivo. Eleven enrolled patients received 1 to 2-cycle CART-HER2 cell infusion (median CAR+ T cell 2.1 × 106/kg). The conditioning treatment resulted in mild-to-moderate fatigue, nausea/vomiting, myalgia/arthralgia, and lymphopenia. Except one grade-3 acute febrile syndrome and one abnormal elevation of transaminase (>9 ULN), adverse events related to the infusion of CART-HER2 cells were mild-to-moderate. Post-infusion toxicities included one case of reversible severe upper gastrointestinal hemorrhage which occurred in a patient with gastric antrum invaded by metastasis 11 days after the CART-HER2 cell infusion, and 2 cases of grade 1-2 delayed fever, accompanied by the release of C-reactive protein and interleukin-6. All patients were evaluable for assessment of clinical response, among which 1 obtained a 4.5-months partial response and 5 achieved stable disease. The median progression free survival was 4.8 months (range, 1.5-8.3 months). Finally, data from this study demonstrated the safety and feasibility of CART-HER2 immunotherapy, and showed encouraging signals of clinical activity. [ABSTRACT FROM AUTHOR]

In this study, we have developed an antibody fragment (AF)-conjugated gemcitabine (GEM) and paclitaxel (PTX)-loaded liposome (AF-GPL) to enhance the therapeutic efficacy in pancreatic cancer treatment. The maleimide-thiol chemistry was utilized to conjugate AF on the liposome surface. The dual-drug loaded liposome was nanosized and exhibited a controlled release of both the drugs. Importantly, two drugs have different release pattern over a period of time. The AF-conjugated liposome showed enhanced cellular uptake in pancreatic cancer cells compared to that of non-targeted liposome. Two-fold higher internalization of particles might increase the intracellular concentration of anticancer drugs that might further increase the therapeutic efficacy in pancreatic cancer cells. AF-GPL showed significantly higher cytotoxic effect in pancreatic cancer cell compared to that of non-targeted GPL. The IC50 value of GEM, PTX, GPL and AF-GPL were 5.9 μg/ml, 4.2 μg/ml, 1.92 μg/ml, and 0.45 μg/ml, respectively. Consistently, AF-GPL (4.12) showed significantly higher ratio of Bax/Bcl-2 compared to that of non-targeted GPL (2.8). Importantly, AF-GPL induced a significant apoptosis of cancer cells with predominant amount of cells in late apoptosis cells. Overall, AF-conjugated nanosystem could potentially improve the therapeutic efficacy in pancreatic cancers. [ABSTRACT FROM AUTHOR]

Background: Pancreatic cancer has a dismal prognosis with 5-year overall survival rate of around 5%. Although surgery is still the best option in operable cases, majority of the patients who present in locally advanced stages are deemed inoperable. Novel approaches are therefore needed for the management of around 80% of these inoperable locally advanced pancreatic cancers (LAPC). Hyperthermia (39-43 °C) is a potent radiosensitizer and further enhances the action of gemcitabine, also a known radiosensitizer. Thus through triple sensitization, a combination of hyperthermia, radiotherapy and gemcitabine could be expected to improve the therapeutic outcomes in LAPC.Methods: This phase II randomized trial, HEATPAC in unresectable LAPC, explores the feasibility and efficacy of concurrent thermochemoradiotherapy (HTCTRT) over chemoradiotherapy (CTRT) alone with pre- and post-intervention FOLFIRINOX at standard dosage and schedule. Following 4 cycles of neoadjuvant FOLFIRINOX, patients with no metastasis and absence of gross peritoneal carcinomatosis would be randomized to either (a) control arm: concurrent CTRT with gemcitabine (400 mg/m2, weekly ×6) or (b) study arm: locoregional hyperthermia (weekly ×6 during radiotherapy) with concurrent CTRT (same as in control arm). All patients would receive simultaneous-integrated boost intensity-modulated radiation therapy to doses of 56Gy and 50.4Gy to the gross and clinical target volumes respectively delivered in 28 fractions over 5.5 weeks. Deep locoregional hyperthermia would be administered weekly and monitored with real-time intraduodenal multisensor thermometry probe. A temperature of 40-43 °C for 60 min would be aimed for each hyperthermia session. On completion of CTRT/HTCTRT, patients of both groups would receive an additional 8 cycles of FOLFIRINOX.Discussion: The expected 1-year baseline overall survival with CTRT alone is considered as 40%. With HTCTRT, a survival advantage of +20% is expected. Considering α = 0.05 and β = 0.80 for sample size computation, a total of 86 patients would be equally randomized into the two treatment groups. This phase II study if found to be safe and effective, would form the basis of a future phase III randomized study.Trial Registration: The trial has been registered with the ClinicalTrials.gov ( NCT02439593 ). The study has been approved by the Ethical Commissions of Basel and Zurich and is open for patient recruitment. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is a lethal malignancy and only around 4% of patients will live 5 years post-diagnosis. Photodynamic therapy (PDT) is a promising strategy for treating malignant tumors because of its high selectivity. Through the colocalization of light, oxygen and photosensitizer, a large number of reactive oxygen species (ROS) are generated under excitation at a specific wavelength of a laser, which can induce DNA damage and destroy cancer cells. However, the repair mechanism of cell will repair part of the damaged DNA, which could reduce the efficiency of PDT. The poly (ADP-Ribose) polymerase (PARP) plays a wide and multifaceted role in the cellular response to DNA damage, with growing evidence for participation in multiple pathways of DNA damage repair and genome maintenance. Cells require PARP to resolve single-strand DNA breaks (SSBs) induced by chemotherapy agents. Its inhibition is thought to result in the accumulation of damage in DNA, which may eventually lead to cell death. The combination therapy of PDT and PARP inhibitors may benefit patients. In this study, we design and synthesize a zeolitic imidazolate framework-8 (ZIF-8) to co-deliver DNA damaging agent Chlorin e6 (Ce6) and PARP inhibitor Olaparib (Ola). Ce6 and Ola demonstrate strong synergistic actions, providing a novel approach for the treatment of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is drawing widespread attention in treating pancreatic ductal adenocarcinoma (PDAC) as a safe and therapeutically efficient technique through modulating the dense fibrotic stroma in the tumor microenvironment to enhance drug penetration. Considerable NO nanogenerators and NO releasing molecules have been developed to shield the systemic toxicity caused by free diffusion of NO gas. However, on-demand controlled release of NO and chemotherapy drugs at tumor sites remains a problem limited by the complex and dynamic tumor microenvironment. Herein, we present an ultrasound-responsive nanoprodrug of CPT-t-R-PEG 2000 @BaTiO 3 (CRB) which encapsulates piezoelectric nanomaterials barium titanate nanoparticle (BaTiO 3 ) with amphiphilic prodrug molecules that consisted of thioketal bond (t) linked chemotherapy drug camptothecin (CPT) and NO-donor l-arginine (R). Based on ultrasound-triggered piezocatalysis, BaTiO 3 can continuously generate ROS in the hypoxic tumor environment, which induces a cascade of reaction processes to break the thioketal bond to release CPT and oxidize R to release NO, simultaneously delivering CPT and NO to the tumor site. It is revealed that CRB shows a uniform size distribution, prolonged blood circulation time, and excellent tumor targeting ability. Moreover, controlled release of CPT and NO were observed both in vitro and in vivo under the stimulation of ultrasound, which is beneficial to the depletion of dense stroma and subsequently enhanced delivery and efficacy of CPT. Taken together, CRB significantly increased the antitumor efficacy against highly malignant Panc02 tumors in mice through inhibiting chemoresistance, representing a feasible approach for targeted therapies against Panc02 and other PDAC.

The aim of this study was to determine the therapeutic effects of adoptive immunotherapy following dendritic cell (DC) vaccine and cytokine-induced killer (CIK) cell therapy and evaluate its cytotoxicity, survival benefits and quality of life (QOL) changes in patients with hepatobiliary and pancreatic cancer (HPC). We performed a retrospective analysis of 407 clinical cases, including 77 patients with HPC who received immunotherapy with DC vaccine and CIK cells (I group) and 330 patients with similar characteristics who underwent baseline treatment but did not receive immunotherapy [non-immunotherapy (NI) group)] as the control group. After a follow-up period of 294±207.5 days, the median survival time (MST) of the two groups was compared using the Kaplan-Meier method. In the I group, 61% of the patients developed a positive, delayed-type hypersensitivity response and 65% of the patients exhibited an improvement in QOL. The most notable adverse events included fever (28%), insomnia (25%), anorexia (17%), skin rash (12%) and arthralgia (31%). No severe toxicities were observed in patients in the I group; in addition, the MST was significantly longer in the I group compared with that in the NI group (P=0.014). Thus, the DC vaccine and CIK cell therapy was associated with mild adverse effects, but was able to induce an immune response and effectively eliminate tumor cells, thereby improving the QOL and prolonging the MST of the patients. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is one of the most dangerous cancers and is associated with a grave prognosis. Despite increased knowledge of the complex signaling networks responsible for progression of pancreatic cancer, many challenging therapies have fallen short of expectations. In this study, we examined the anti-migratory effect of quercetin 3-O-glucoside in epidermal growth factor-induced cell migration by inhibiting EGF receptor (EGFR) signaling in several human pancreatic cancer cell lines. Treatment with quercetin, quercetin 3-O-glucoside, and quercetin 7-O-glucoside differentially suppressed epidermal growth factor-induced migration activity of human pancreatic cancer cells. In particular, quercetin 3-O-glucoside strongly inhibited the infiltration activity of pancreatic cancer cells in a dose-dependent manner. Furthermore, quercetin 3-O-glucoside exerted the anti-migratory effect even at a relatively low dose compared with other forms of quercetin. The anti-tumor effects of quercetin 3-O-glucoside were mediated by selectively inhibiting the EGFR-mediated FAK, AKT, MEK1/2, and ERK1/2 signaling pathway. Combinatorial treatment with quercetin 3-O-glucoside plus gemcitabine showed the synergistic anti-migratory effect on epidermal growth factor-induced cell migration in human pancreatic cancer cell lines. These results suggest that quercetin 3-O-glucoside has potential for anti-metastatic therapy in human pancreatic cancer. [ABSTRACT FROM AUTHOR]

Recognition of skin changes connected with neoplasm is important because it allows early treatment of the disease. Necrolytic migratory erythema is a paraneoplastic marker which in 80% of cases shows the presence of pancreatic cancer, originating from alpha cells which produce glucagon. The presence of the neoplasm is connected with weight loss, erythematous and vesicular skin changes of limbs, trunk and face as well as glossitis, cheilitis, diffuse alopecia and paronychia. There is usually mild diabetes with markedly increased level of glucagon, lower level of amino acids and zinc in the sera, anemia and increased sedimentation rate. In 42-year-old male patient erythematous skin changes, pustules, erosions and ecchymoses appeared 2 years ago and were localized on his face, trunk, genitalia and limbs. At first the diagnosis of disseminated eczema were made. After 2 years, on abdominal ultrasound examination metastases to liver were found and during laparotomy tuberous changes of pancreas were observed. The histopathology confirmed the diagnosis of endocrine carcinoma of the pancreas with liver metastases. [ABSTRACT FROM AUTHOR]

Abstract: The majority of cancers are caused by mutations of a few signal transducers such as the GTPase RAS, the kinase Src and the tumor suppressor p53. Thus, a group of specific chemical compounds called ‘signal therapeutics’, that block or reverse selectively these abnormally activated signaling pathways would be very useful for the treatment of these signally disordered cancers. More than 90% of human pancreatic cancers are associated with oncogenic mutations of RAS, in particular K-RAS at codon 12. We have previously shown that, PAK1, the Rac/CDC42-dependent Ser/Thr kinase, is essential for RAS/estrogen-induced transformation and neurofibromatosis (NF). Furthermore, we and others have demonstrated that the growth of mouse RAS-induced sarcomas allografts in mice is almost completely suppressed by either FK228 or a combination of two complimentary Tyr-kinase inhibitors, PP1 and AG 879, all of which block the RAS-induced activation of PAK1. Since, so far no effective therapeutic is available for the treatment of pancreatic cancer patients, we have examined the therapeutic potential of either FK228, the combination of these two Tyr-kinase inhibitors or GL-2003, a water-soluble derivative of AG 879, on human pancreatic cancer (Capan-1) xenograft in mice. Among these PAK1-blocking approaches, the PP1/GL-2003 combination is the most effective in the therapy of this cancer xenograft model. Its therapeutic potential is equivalent to those of gemcitabine and kigamicin D which suppress by 70–80% the growth of a similar human pancreatic cancer xenograft model. Also, this PP1/GL-2003 combination therapy has been proven to be very effective to suppress the estrogen-independent growth of an NF1-deficient multidrug/FK228-resistant human breast cancer (MDA-MB-231) xenograft in mice. [Copyright &y& Elsevier]

The aim of this study was to elucidate cytogenetic changes in pancreatic cancers (PCs) and to examine their clinical implications. We screened for genetic alterations in 32 primary PCs including 4 cases with distant organ metastasis using comparative genomic hybridization coupled with tissue microdissection and degenerate oligonucleotide primed polymerase chain reaction (DOP-PCR). The present study revealed frequent gains of chromosomes 13q and 15q and a loss of Xq in addition to a high prevalence of chromosomal imbalances. The average number of total genetic alterations and gains tended to be higher in N1 tumors (TNM classification) than in N0 tumors. The average number of amplifications was significantly higher in M1 tumors than in M0 tumors (p = 0.024). Gain/amplification of 20q was more frequently observed in M1 tumors than in M0 tumors (p = 0.016), and this change was also detected in all of 4 distant metastatic lesions. Losses of 6q, 8p, 9p, 17p, and 18q were recurrent in N0 and M0 tumors, and these alterations were also retained in N1 and M1 tumors. These observations suggest that these genetic losses contribute to the development of PCs and that increases in the DNA copy number confer an aggressive character on cancer cells. Especially, gain/amplification of 20q was associated with the potential of distant organ metastasis of tumor cells.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Others have suggested that in certain technically challenging operations, outcome and experience are related. Because pancreaticoduodenectomy is a technically complex procedure, this study was undertaken to evaluate mortality, length of hospital stay, and hospital charges when compared to volume of experience. The database of the State of Florida Agency for Health Care Administration was queried for pancreaticoduodenectomies undertaken during a recent 33-month period. Length of stay, hospital charges, and inhospital mortality were stratified by the frequency of pancreaticoduodenectomy. A total of 282 surgeons performed 698 pancreaticoduodenectomies over 33 months. Eighty-nine percent of surgeons performed one pancreaticoduodenectomy per year or less and accounted for 52% of the procedures. Overall mortality rate was 5.1%. Average hospital charges were $72,171.64. The more frequently pancreaticoduodenectomy was undertaken, the shorter the hospital stay ( P = 0.025, regression analysis) and the lower the hospital charges ( P = 0.008, regression analysis) and in-hospital mortality ( P = 0.036, log likelihood ratio test). Surgeons who undertake pancreaticoduodenectomy more frequently have patients with shorter hospital stays, lower hospital charges, and lower in-hospital mortality rates, independent of hospital volume. Variations exist among surgeons and among different areas of the state. Data regarding cost and mortality are available for use in programs of cost and quality improvement. [ABSTRACT FROM AUTHOR]

The immune system plays a vital role in maintaining the delicate balance between immune recognition and tumor development. Regardless, it is not uncommon that cancerous cells can intelligently acquire abilities to bypass the antitumor immune responses, thus allowing continuous tumor growth and development. Immune evasion has emerged as a significant factor contributing to the progression and immune resistance of pancreatic cancer. Compared with other cancers, pancreatic cancer has a tumor microenvironment that can resist most treatment modalities, including emerging immunotherapy. Sadly, the use of immunotherapy has yet to bring significant clinical breakthrough among pancreatic cancer patients, suggesting that pancreatic cancer has successfully evaded immunomodulation. In this review, we summarize the impact of genetic alteration and epigenetic modification (especially histone deacetylases, HDAC) on immune evasion in pancreatic cancer. HDAC overexpression significantly suppresses tumor suppressor genes, contributing to tumor growth and progression. We review the evidence on HDAC inhibitors in tumor eradication, improving T cells activation, restoring tumor immunogenicity, and modulating programmed death 1 interaction. We provide our perspective in targeting HDAC as a strategy to reverse immune evasion in pancreatic cancer., Competing Interests: Conflict-of-interest statement: There is no conflict of interest with any authors contributed to this manuscript., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Diabetes mellitus (DM), one of the metabolic diseases which is characterized by sustained hyperglycemia, is a life-threatening disease. The global prevalence of DM is on the rise, mainly in low- and middle-income countries. Diabetes is a major cause of blindness, heart attacks, kidney failure, stroke, and lower limb amputation. Type 2 diabetes mellitus (T2DM) is a form of diabetes that is characterized by high blood sugar and insulin resistance. T2DM can be prevented or delayed by a healthy diet, regular physical activity, maintaining normal body weight, and avoiding alcohol and tobacco use. Ethanol and its metabolites can cause differentiation defects in stem cells and promote inflammatory injury and carcinogenesis in several tissues. Recent studies have suggested that diabetes can be treated, and its consequences can be avoided or delayed with proper management. DM has a greater risk for several cancers, such as breast, colorectal, endometrial, pancreatic, gallbladder, renal, and liver cancer. The incidence of cancer is significantly higher in patients with DM than in those without DM. In addition to DM, alcohol abuse is also a risk factor for many cancers. We present a review of the recent studies investigating the association of both DM and alcohol abuse with cancer incidence. [ABSTRACT FROM AUTHOR]