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Self-sustained quiescence (SSQ) has been characterized as a stable but reversible non-proliferative cellular state that limits the cloning of cultured cancer cells. By developing refined clonogenic assays, we showed here that cancer cells in SSQ can be selected with anticancer agents and that culture at low cell density induced SSQ in pancreas and prostate adenocarcinoma cells. Pre-culture of cells in 3D or their pretreatment with pharmacological inhibitors of mechanistic target of rapamycin (mTOR) synergize with low cell density for induction of SSQ in a Beclin-1-dependent manner. Dissociated pancreatic adenocarcinoma (PAAD) cells rendered defective for SSQ by down-regulating Beclin-1 expression exhibit higher tumor growth rate when injected subcutaneously into mice. Conversely, dissociated PAAD cells in SSQ promote the formation of small indolent tumors that eventually transitioned to a rapid growth phase. Ex vivo clonogenic assays showed that up to 40% of clonogenic cancer cells enzymatically dissociated from resected fast-growing tumors could enter SSQ, suggesting that SSQ could significantly impact the proliferation of cancer cells that are naturally dispersed from tumors. Remarkably, the kinetics of clinical metastatic recurrence in 124 patients with pancreatic adenocarcinoma included in the TGCA-PAAD project could be predicted from Beclin-1 and Cyclin-A2 mRNA levels in their primary tumor, Cyclin A2 mRNA being a marker of both cell proliferation and mTOR complex 1 activity. Overall, our data show that SSQ is likely to promote the late development of clinical metastases and suggest that identifying new agents targeting cancer cells in SSQ could help improve patient survival. [ABSTRACT FROM AUTHOR]

Simple Summary: Treatment of pancreas ductal adenocarcinoma (PDAC) remains challenging due to the late stage of presentation, limited efficacy of cytotoxic chemotherapies, and aggressive tumor biology. Novel therapeutic targets are desperately needed. The voltage-gated potassium channel, Kv1.3, is one such unique target. It has been extensively studied in many cancers but less is known in pancreas cancer. In this study, we evaluated the tissue expression of Kv1.3 in resected PDAC and tumor inhibition using novel Kv1.3 inhibitors developed by our group (PCARBTP and PAPTP) with cytotoxic chemotherapies. We found that Kv1.3 is expressed in early stage, non-metastatic, resectable pancreas cancer specimens. Treatment with novel mitochondrial Kv1.3 inhibitors resulted in 95% reduced tumor growth when combined with cytotoxic chemotherapies. This near complete eradication of tumors using this treatment strategy shows that Kv1.3 represents an innovative therapeutic target for pancreas cancer therapy. Pancreas ductal adenocarcinoma (PDAC) is one the most aggressive cancers and associated with very high mortality, requiring the development of novel treatments. The mitochondrial voltage-gated potassium channel, Kv1.3 is emerging as an attractive oncologic target but its function in PDAC is unknown. Here, we evaluated the tissue expression of Kv1.3 in resected PDAC from 55 patients using immunohistochemistry (IHC) and show that all tumors expressed Kv1.3 with 60% of tumor specimens having high Kv1.3 expression. In Pan02 cells, the recently developed mitochondria-targeted Kv1.3 inhibitors PCARBTP and PAPTP strongly reduced cell survival in vitro. In an orthotopic pancreas tumor model (Pan02 cells injected into C57BL/6 mice) in immune-competent mice, injection of PAPTP or PCARBTP resulted in tumor reductions of 87% and 70%, respectively. When combined with clinically used Gemcitabine plus Abraxane (albumin-bound paclitaxel), reduction reached 95% and 80% without resultant organ toxicity. Drug-mediated tumor cell death occurred through the p38-MAPK pathway, loss of mitochondrial membrane potential, and oxidative stress. Resistant Pan02 clones to PCARBTP escaped cell death through upregulation of the antioxidant system. In contrast, tumor cells did not develop resistance to PAPTP. Our data show that Kv1.3 is highly expressed in resected human PDAC and the use of novel mitochondrial Kv1.3 inhibitors combined with cytotoxic chemotherapies might be a novel, effective treatment for PDAC. [ABSTRACT FROM AUTHOR]

Background and Aims: Pancreatic ductal adenocarcinoma has one of the worst prognosis of all malignancies. This investigated the relationship between the preoperative serum carbohydrate antigen 19-9 and surgical resectability.Methods: A systematic search was performed in three databases (MEDLINE, EMBASE, and Web of Science) to compare the surgical resectability of pancreatic ductal adenocarcinoma in patients with high and low preoperative serum carbohydrate antigen 19-9 values. The receiving operating characteristic curves were constructed and the weighted mean differences for preoperative serum carbohydrate antigen 19-9 levels of resectable and unresectable groups of patients were calculated. The PROSPERO registration number is CRD42019132522.Results: Results showed that there was a significant difference in resectability between the low and high carbohydrate antigen 19-9 groups. Six out of the eight studies utilised receiver operating characteristic curves in order to find the cut-off preoperative carbohydrate antigen 19-9 levels marking unresectability. The overall result from the pooled area under curve values from the receiver operating characteristic curves was 0.794 (CI: 0.694–0.893), showing that the preoperative carbohydrate antigen 19-9 level is a “fair” marker of resectability. The result of the pooled weighted mean differences was 964 U/ml (p < 0.001) showing that there is a significant carbohydrate antigen 19-9 difference between the resectable and unresectable groups. Based on the results of the I-squared test, the result was 87.4%, accounting for “considerable” heterogeneity within the population.Conclusion: Carbohydrate antigen 19-9 is not a reliable marker of unresectability, it should not be used on its own in surgical decision-making.

Pancreatic cancer has one of the highest mortality rates among cancers, and a combination of nab-paclitaxel with gemcitabine remains the cornerstone of first-line therapy. However, major advances are required to achieve improvements in patient outcomes. For this reason, several research groups have proposed supplementing treatment with other therapeutic agents. Ongoing studies are being conducted to find the optimal treatment in a first-line setting. In this work, we used a search strategy to compare studies on the efficacy and safety of nab-paclitaxel with gemcitabine in combination with other therapeutic agents based on the criteria of the Preferred Reporting Items for Systematic Reviews. We found seven studies in different clinical phases that met the inclusion criteria. The seven therapeutic agents were ibrutinib, necuparanib, tarextumab, apatorsen, cisplatin, enzalutamide, and momelotinib. Although these therapeutic agents have different mechanisms of action, and molecular biology studies are still needed, the present review was aimed to answer the following question: which formulations of the nab-paclitaxel/gemcitabine regimen in combination with other therapeutic agents are safest for patients with previously untreated metastatic pancreas ductal adenocarcinoma? The triple regimen is emerging as the first-line option for patients with pancreatic cancer, albeit with some limitations. Thus, further studies of this regimen are recommended. [ABSTRACT FROM AUTHOR]

Background: Ovarian metastases (OM) of pancreatic adenocarcinoma (PA) (OM-PA) can mimic primary ovarian mucinous carcinoma (POMC) on imaging and histology. These metastases are often symptomatic and not highly chemosensitive, so that oophorectomy may be considered. Aims: The aims of this study were to compare the characteristics of OM-PA and POMC, and discuss the role of surgery. Patients and Methods: Clinical, imaging, and histological data of patients with OM-PA and POMC (2000–2017) in three tertiary centers were reviewed. Twenty-six genes were analyzed by next generation sequencing (NGS) on both primary PA and OM-PA. Results: Twenty-two women with OM-PA (n = 13, 11 with surgical resection) or POMC (n = 9) were selected. OM-PA were smaller than POMC (p = 0.02); imaging, histological, and immunohistochemistry data did not clearly differentiate OM-PA from POMC in 12 of 22 cases (54%). Seven PA/OM-PA pairs were analyzed, and a concordant KRAS mutation was identified in all cases. In four OM-PA, concordant mutations were also found in TP53 (n = 3), SMAD4 (n = 1), MET (n = 1), and PDGFRA (n = 1) genes. The aim of oophorectomy in 11 OM-PA was for antalgic (n = 6) or curative (n = 5) intent. Pain improved in 4/6 of the former patients, but 2/6 had significant morbidity, and 2/6 died of rapid tumor progression. After oophorectomy, median progression-free and overall survivals were 6 (0–11) and 8 months (1–131), respectively. Conclusion: Analysis of mutation profiles in both primary PA and ovarian tumors, especially KRAS, can help to determine the pancreatic origin of OM-PA. Surgical resection of OM-AP in highly selected patients may improve pelvic symptoms but may also cause significant morbidity. The benefit to survival requires further studies. [ABSTRACT FROM AUTHOR]

Purpose: To clarify the prognostic value of the preoperative nutrition status of patients undergoing conversion surgery (CS) for initially unresectable pancreatic adenocarcinoma (UR-PA). Methods: The subjects of this retrospective study were 41 consecutive patients with initially UR-PA treated with chemo-/radiotherapy and subsequent CS between 2007 and 2014, at Tohoku University Hospital. The preoperative Glasgow Prognostic Score (GPS) was 0, conveying normal nutrition, in 25 patients (N group) and 1–2, conveying malnutrition, in 16 patients (M group). The clinicopathological factors influencing overall survival were defined by uni- and multivariate analyses. Results: The M group had a significantly worse prognosis than the N group (median overall survival (mOS) 9.6 vs 40.7 months, p = 0.001). Multivariate analysis identified a GPS of 1–2 as an independent predictor of worse prognosis [hazard ratio (HR)3.437, p = 0.032], followed by CA19-9 elevation before CS (HR4.089, p = 0.012) and pathological lymph node metastases (HR2.314, p = 0.046). Patients who maintained a favorable nutritional status (GPS 0) during preoperative treatment had a significantly better prognosis, whereas those whose nutritional status deteriorated (elevated to GPS 1–2) had poorer survival (mOS 40.7 vs. 9.7 months, p = 0.003) Conclusion: Preoperative malnutrition status (GPS 1–2) is considered an independent predictor of a worse prognosis for patients undergoing CS for initially UR-PA. [ABSTRACT FROM AUTHOR]

The role of (chemo) radiation in the perioperative management of patients with resectable and borderline resectable pancreatic ductal adenocarcinoma is controversial. Herein, we review and interpret existing data relating to the ability of (chemo) radiation to "downstage" pancreatic tumors, delay recurrence, and prolong patients' survival. In sum, the evidence suggests that while neoadjuvant (chemo) radiation may impact pathologic metrics favorably, it rarely converts anatomically unresectable tumors to resectable ones. And while data do support the ability of (chemo)radiation to delay cancer progression, its ability to prolong longevity has not been confirmed. It is possible that (chemo)radiation is effective in prolonging the survival of select patients, but to date, this cohort remains undefined due to heterogeneity in both the populations studied and the regimens used to treat them. Based on our interpretation of existing data, we currently administer neoadjuvant and adjuvant (chemo)radiation selectively to patients with localized pancreatic cancer who we consider at highest risk for local progression. We may also use it as an alternative to pancreatectomy in patients who are poor candidates for surgery. Ultimately, the role of (chemo)radiation in these settings is evolving. Better studies of patients most likely to benefit from its local effects are necessary to clearly define its place within the perioperative treatment algorithms used for patients with localized pancreatic cancer. [ABSTRACT FROM AUTHOR]

Pancreatic cancer has one of the highest mortality rates among cancers, and a combination of nab-paclitaxel with gemcitabine remains the cornerstone of first-line therapy. However, major advances are required to achieve improvements in patient outcomes. For this reason, several research groups have proposed supplementing treatment with other therapeutic agents. Ongoing studies are being conducted to find the optimal treatment in a first-line setting. In this work, we used a search strategy to compare studies on the efficacy and safety of nab-paclitaxel with gemcitabine in combination with other therapeutic agents based on the criteria of the Preferred Reporting Items for Systematic Reviews. We found seven studies in different clinical phases that met the inclusion criteria. The seven therapeutic agents were ibrutinib, necuparanib, tarextumab, apatorsen, cisplatin, enzalutamide, and momelotinib. Although these therapeutic agents have different mechanisms of action, and molecular biology studies are still needed, the present review was aimed to answer the following question: which formulations of the nab-paclitaxel/gemcitabine regimen in combination with other therapeutic agents are safest for patients with previously untreated metastatic pancreas ductal adenocarcinoma? The triple regimen is emerging as the first-line option for patients with pancreatic cancer, albeit with some limitations. Thus, further studies of this regimen are recommended.

Background and Objective: Pancreas adenocarcinoma is a disease with dire prognosis. Imaging is pivotal to the diagnosis, staging, reassessment, surgical planning, and surveillance of pancreas cancer. The purpose of this paper is to provide the reader an overview of current imaging practices for pancreas adenocarcinoma., Methods: A literature search of original papers and reviews through 2022 was performed using the PubMed database. The most current American College of Radiology Appropriateness Criteria and National Comprehensive Cancer Network guidelines on pancreas cancer imaging were also included., Key Content and Findings: Multidisciplinary team care at a high-volume institution is instrumental to optimal patient management and outcomes. It is therefore important for all team members to be aware of imaging modality options, strengths, and challenges. Additionally, a high-level understanding of imaging findings is useful clinically. This manuscript provides a current overview of imaging modalities used in the identification and assessment of pancreas adenocarcinoma, including ultrasound, computed tomography, magnetic resonance imaging, and positron emission tomography. Imaging findings, including the expected and unexpected, are reviewed to give the novice imager a better understanding., Conclusions: This review provides a current overview of imaging for pancreas adenocarcinoma, including strengths and weakness of various imaging modalities; therefore, providing the reader with a robust resource when considering imaging in the management of this disease., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-1044/coif). JS serves as an unpaid editorial board member of Journal of Gastrointestinal Oncology from January 2022 to December 2024. The other authors have no conflicts of interest to declare., (2023 Journal of Gastrointestinal Oncology. All rights reserved.)

Venous thromboembolism is one of the most common complications of cancer, which also contributes to mortality in cancer patients. Venous thromboembolism can be observed as the first manifestation of occult cancer. We present the case of a 54-year-old woman with deep vein thromboembolism and pulmonary embolism as the first signs of cancer, who was subsequently diagnosed with disseminated adenocarcinoma, most likely originated from the pancreatico-biliary system. [ABSTRACT FROM AUTHOR]

Background. In neoplastic diseases, quality of life often has to be balanced against duration of life, therefore adequate psychological support and optimal pain management are extremely important. The QLQ-C15 PAL questionnaire is recommended to be used for patients with advanced, incurable and symptomatic cancer, with an expected survival time of a few months, not undergoing anti-cancer treatment. Objectives. The aim of the study was to define, using the QLQ-C15 PAL questionnaire, the quality of life related needs of a group of patients with pancreas adenocarcinoma and to evaluate the questionnaire’s practical usefulness for palliative care monitoring and its ongoing improvement. Material and methods. A Polish translation of the QLQ-C15 PAL questionnaire was used in the year 2010 to estimate the quality of life of 26 patients with advanced stage pancreas adenocarcinoma, subjected to palliative care outside hospitals in the Lower Silesia region of Poland. Results. The majority of patients in the surveyed group considered their quality of life to be quite good, but the study pointed out 2 patients complaining of very poor quality of life, thus requiring a reevaluation of their needs and the strategy of their palliative support. Conclusions. The QLQ-C15 PAL questionnaire is a rapid and effective means to find out both the needs of particular patients and the characteristics of palliative care-covered patients groups. Its use enabled quick identification of those patients needing care adjustment. In cases when the questionnaire is filled in repeatedly over a longer period of time by the same patients, it can be useful in tracing the effectiveness of palliative care as measured by the patient's quality of life. [ABSTRACT FROM AUTHOR]

The aim of the present research is to increase lipid solubility, metabolic stability and therapeutic efficacy of water soluble gemcitabine (GEM) via phospholipid complex (PC) formation. A novel phospholipid complex of GEM was successfully prepared and optimized. Physical interaction of GEM with phospholipid was evaluated by DSC, FT-IR, 1 H NMR, 31 P-NMR and P-XRD. SEM images of GEM-PC showed rough structure and TEM images of diluted aqueous dispersion of GEM-PC showed micellar structure. In silico study also revealed the significant interaction between drug and phospholipid. GEM-PC demonstrated sustained drug release pattern and high plasma stability (∼2.2 fold) in vitro as compared to GEM. Increased in vitro cytotoxicity and apoptosis were observed with GEM-PC, when incubated with human pancreas adenocarcinoma cell lines. In vivo pharmacokinetics showed the almost 2 fold increase in AUC 0-∞ (area under curve) with phospholipid complex (8983.26 ng h/ml) as compared with GEM (4371.18 ng h/ml) and GEMITA (4689.29 ng h/ml). Toxicity studies signify the safety of GEM-PC over GEMITA. Pharmacodynamics studies in pancreatic tumor model further revealed higher efficacy of GEM-PC than GEMITA. These findings suggested the higher potential of phospholipid based technology for the enhancement of metabolic stability and therapeutic efficacy of GEM. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is an aggressive malignancy with a poor prognosis. The disease and its treatment can cause significant nutritional impairments that often adversely impact patient quality of life (QOL). The pancreas has both exocrine and endocrine functions and, in the setting of cancer, both systems may be affected. Pancreatic exocrine insufficiency (PEI) manifests as weight loss and steatorrhea, while endocrine insufficiency may result in diabetes mellitus. Surgical resection, a central component of pancreatic cancer treatment, may induce or exacerbate these dysfunctions. Nutritional and metabolic dysfunctions in patients with pancreatic cancer lack characterization, and few guidelines exist for nutritional support in patients after surgical resection. We reviewed publications from the past two decades (1995-2016) addressing the nutritional and metabolic status of patients with pancreatic cancer, grouping them into status at the time of diagnosis, status at the time of resection, and status of nutritional support throughout the diagnosis and treatment of pancreatic cancer. Here, we summarize the results of these investigations and evaluate the effectiveness of various types of nutritional support in patients after pancreatectomy for pancreatic adenocarcinoma (PDAC). We outline the following conservative perioperative strategies to optimize patient outcomes and guide the care of these patients: (1) patients with albumin <2.5 mg/dL or weight loss > 10% should postpone surgery and begin aggressive nutrition supplementation; (2) patients with albumin < 3 mg/dL or weight loss between 5% and 10% should have nutrition supplementation prior to surgery; (3) enteral nutrition (EN) should be preferred as a nutritional intervention over total parenteral nutrition (TPN) postoperatively; and, (4) a multidisciplinary approach should be used to allow for early detection of symptoms of endocrine and exocrine pancreatic insufficiency alongside implementation of appropriate treatment to improve the patient's quality of life. [ABSTRACT FROM AUTHOR]

Currently, the most examinations and markers are of limited diagnostic and prognostic value in chronic inflammation of the pancreas and its malignant tumorous disease. The purpose of this pilot study was to measure thermal changes of blood plasma by differential scanning calorimetry (DSC) method on patients with chronic pancreatitis, and with operable or inoperable pancreatic adenocarcinoma. The study involved chronic pancreatitis patients ( n = 5), in whom had to perform surgery due to any complications. In malignant pancreatic cancer group, according to resectability of the tumors, patients were divided into operable (curative R0 resection, n = 11) and inoperable (palliative double bypass, n = 5) subgroups. Peripheral blood samples were collected from the patients preoperatively and from healthy controls ( n = 5). Denaturation of plasma components was detected in Setaram Micro DSC-II calorimeter. DSC results showed decrease of T (48.8 °C) and T (61.8 °C) and increase of T (68 °C) in chronic pancreatitis group compared to healthy controls (56.2, 63.1 and 68 °C). Similar tendencies were in patients with operable (48.2, 61.5, 67.6 °C) and inoperable (48.1, 62.4, 69 °C) pancreas adenocarcinoma. Calorimetric enthalpy mildly decreased in each group except for operable group (1.3 J g ∆ H) compared to controls (1.2 J g ∆ H). This research confirmed that DSC parameters of blood plasma on patients with chronic pancreatitis and pancreatic adenocarcinoma are clearly distinct from thermodynamical data of healthy controls. After better validation of calorimetric data, it can be a noninvasive tool for diagnostic and monitoring of pancreatic diseases. [ABSTRACT FROM AUTHOR]

Purpose: Hemolytic-uremic syndrome (HUS) is a rare side effect of gemcitabine, which is reported as having a high morbidity and mortality despite interventions with standard HUS therapies including plasmapheresis. The purpose of this report was to describe the successful treatment of gemcitabine-induced HUS (G-HUS) with rituximab. It also aims to summarize the literature regarding the morbidity and mortality of G-HUS in pancreatic adenocarcinoma depending on the treatment given, ultimately providing some guidance for beneficial therapies.Methods: This is a retrospective report of three patients with pancreatic adenocarcinoma who developed G-HUS and were treated with a combination of therapies including rituximab.Results: All three patients received a combination of therapies to treat their HUS. One patient appeared to have some benefit with plasmapheresis. Resolution occurred following one course of rituximab for all three patients. This resolution has been long lasting with a minimum of eighteen month's follow-up. Similarly, in our literature review a variety of therapies were utilized, but immune therapies appear to reverse HUS if other therapies are failing.Conclusion: Rituximab can be an effective therapy for reversal of hemolysis and stabilization of renal function in G-HUS when other therapies fail. [ABSTRACT FROM AUTHOR]

Background: Prior to withdrawing the EUS-FNA needle from the lesion, the stopcock of the suction syringe is closed to reduce contamination. Residual negative pressure (RNP) may persist in the needle despite closing the stopcock.Aims: To determine whether neutralizing RNP before withdrawing the needle will improve the cytology yield.Methods: Bench-top testing was done to confirm the presence of RNP followed by a prospective, randomized, cross-over study on patients with pancreas mass. Ten milliliters of suction was applied to the FNA needle. Before withdrawing the needle from the lesion, the stopcock was closed. Based on randomization, the first pass was done with the stopcock either attached to the needle (S+) or disconnected (S-) to allow air to enter and neutralize RNP and accordingly the second pass was crossed over to S+ or S-. On-site cytopathologist was blinded to S+/S-.Results: Bench tests confirmed the presence of RNP which was successfully neutralized by disconnecting the syringe (S-) from the needle. Sixty patients were enrolled, 120 samples analyzed. S+ samples showed significantly greater GI tract contamination compared to S- samples (16.7 vs. 6.7%, p = 0.03). Of the 53 patients confirmed to have pancreas adenocarcinoma, FNA using S- approach was positive in 49 (93%) compared to 40 using the S+ approach (76%, p = 0.02).Conclusions: Despite closing the stopcock of the suction syringe, RNP is present in the FNA needle. Neutralizing RNP prior to withdrawing the needle from the target lesion significantly decreased GI tract contamination of the sample thereby improving the FNA cytology yield.Clinical Trials Registration Number: NCT01995474. [ABSTRACT FROM AUTHOR]

Objective: Fibronectin (FN),vitronectin (VTN), and tip IV kollagen (Kol IV) are the important components of the extracellular matrix (ECM) proteins. The objective of this study was to determine the clinical significance of serum levels of these molecules in pancreas adenocarcinoma (PA) patients. Material and Methods: A total of 33 patients with a pathologically confirmed diagnosis of PA and age- and sex-matched 30 healthy controls were enrolled into this study. Serum FN, VTN, and Kol IV concentrations were determined by the enzyme-linked immuno-sorbent assay (ELISA) method. Results: The median age at diagnosis was 59 years, range 32 to 84 years where 61% of the patients were male. Majority of the patients (70%) had good performance status (0-1). The most common tumor localization was head of pancreas (68%). Of the 9 patients who undergone surgical intervention, 5 patients (15%) had pancreaticoduodenectomy, while palliative surgery was performed in the remaining 4 (12%) patients. The baseline serum FN, VTN, and Kol IV levels were significantly higher in patients with PA than in the healthy control group (p=0.001, p=0.007 and p<0.001, respectively). Additionally, serum FN levels of the patients with jaundice (p=0.02), serum VTN levels of older patients - (p=0.03), and serum Kol IV levels of older patients, patients with metastasis and liver metastasis presence were detected to be significantly higher compared with others (p=0.009, p=0.05 and p=0.04, respectively). However, serum FN, VTN, and Kol IV levels had no prognostic role for outcome in PA patients (p=0.45, p=0.69 and p=0.11, respectively). Conclusions: Serum levels of ECM proteins were diagnostic markers in PA patients. However, their predictive and prognostic values were not determined. [ABSTRACT FROM AUTHOR]

Background: Adequate lymph node evaluation (LNE) is recommended for surgically treated pancreatic adenocarcinoma because studies have shown an association between improved survival and adequate LNE. This study aimed to understand the mechanism of this association and determine whether LNE is a valuable quality metric.Methods: Using the linked Surveillance Epidemiology End Results Medicare database, we identified patients with surgically treated pancreatic adenocarcinoma from 2000 to 2010. Adequate LNE was defined as evaluation of ≥15 nodes. Survival was determined using Kaplan-Meier and Cox proportional hazards.Results: We identified 2629 patients who underwent resection for pancreatic adenocarcinoma. Overall, 33 % had adequate LNE. Adequate LNE was significantly associated with receipt of postoperative chemotherapy. A significant decrease in hazard of death was associated with adequate LNE (HR 0.86, p < 0.05). Receipt of postoperative chemotherapy was also significantly associated with decreased hazard of death (HR 0.77, p < 0.05). On unadjusted analysis, the survival benefit associated with adequate LNE was lost when stratified by receipt of postoperative chemotherapy.Conclusion: The survival benefit associated with LNE is in part derived from the fact that patients who receive adequate LNE are also more likely to receive chemotherapy. Thus, the use of lymph node counts has limitations as a quality metric. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is an aggressive malignancy with a poor prognosis. The disease and its treatment can cause significant nutritional impairments that often adversely impact patient quality of life (QOL). The pancreas has both exocrine and endocrine functions and, in the setting of cancer, both systems may be affected. Pancreatic exocrine insufficiency (PEI) manifests as weight loss and steatorrhea, while endocrine insufficiency may result in diabetes mellitus. Surgical resection, a central component of pancreatic cancer treatment, may induce or exacerbate these dysfunctions. Nutritional and metabolic dysfunctions in patients with pancreatic cancer lack characterization, and few guidelines exist for nutritional support in patients after surgical resection. We reviewed publications from the past two decades (1995–2016) addressing the nutritional and metabolic status of patients with pancreatic cancer, grouping them into status at the time of diagnosis, status at the time of resection, and status of nutritional support throughout the diagnosis and treatment of pancreatic cancer. Here, we summarize the results of these investigations and evaluate the effectiveness of various types of nutritional support in patients after pancreatectomy for pancreatic adenocarcinoma (PDAC). We outline the following conservative perioperative strategies to optimize patient outcomes and guide the care of these patients: (1) patients with albumin < 2.5 mg/dL or weight loss > 10% should postpone surgery and begin aggressive nutrition supplementation; (2) patients with albumin < 3 mg/dL or weight loss between 5% and 10% should have nutrition supplementation prior to surgery; (3) enteral nutrition (EN) should be preferred as a nutritional intervention over total parenteral nutrition (TPN) postoperatively; and, (4) a multidisciplinary approach should be used to allow for early detection of symptoms of endocrine and exocrine pancreatic insufficiency alongside implementation of appropriate treatment to improve the patient’s quality of life.

[Display omitted] • Prostaglandin E2 (PGE2) molecule and its receptors play an important role in malignancies and metastases. • Prostaglandin E2 form complexes with randomly-methylated-beta-cyclodextrin (RAMEB) with high affinity. • RAMEB can be labeled with diagnostic and therapeutic isotopes and binds to PGE2-positive tumors. • Radiolabeled RAMEB may play a role in the diagnosis and radionuclide therapy of PGE2-positive tumors. Prostaglandin E2 (PGE2) molecule and its receptors play an important role in the development of malignancies and metastases therefore PGE2 may play a crucial role in the diagnosis and a new therapeutic target in the field of radionuclide therapy of PGE2-positive tumors. PGE2 form complexes with RAMEB (randomly-methylated-beta-cyclodextrin) with high affinity therefore the aim of this present study was to synthesize a PGE2-specific DOTAGA-RAMEB, which can be labeled with diagnostic and therapeutic isotopes also and binds to PGE2-positive tumors. DOTAGA-RAMEB was labeled with 68Ga and 205/206Bi radionuclides and their radiochemical purity (RCP%), partition coefficient (log P values), and in vitro and in vivo stability were determined. For the assessment of the biological properties and the PGE2 specificity of [68Ga]Ga-DOTAGA-RAMEB and [205/206Bi]Bi-DOTAGA-RAMEB in vivo PET imaging and ex vivo biodistribution studies were performed using healthy control and PGE2-positive BxPC-3 tumor-bearing CB17 SCID mice. The RCP% of the newly synthesized [68Ga]Ga-DOTAGA-RAMEB and [205/206Bi]Bi-DOTAGA-RAMEB was higher than 98 %. In vivo studies showed that the tumor-to-background ratio of [68Ga]Ga-DOTAGA-RAMEB was 2.5 ± 0.2 as a result BxPC-3 tumors were clearly identified on PET images. Beside this the ex vivo biodistribution studies showed that the accumulation rate of [68Ga]Ga-DOTAGA-RAMEB and [205/206Bi]Bi-DOTAGA-RAMEB was similar in the PGE2-positive BxPC-3 tumors. [ABSTRACT FROM AUTHOR]

Background: In patients with adenocarcinoma of the pancreas, there are no standard second-line regimens. Many pre-clinical studies have shown that metformin alone or when combined with paclitaxel has antitumour effects on this tumour. We have tested here the combination of paclitaxel and metformin for patients with gemcitabine-refractory pancreatic cancer. Methods: An uncontrolled phase II trial was carried out based on a two-stage Simon's design, with metformin and paclitaxel for patients with locally advanced or metastatic pancreatic cancer whose disease had progressed during first line treatment with a gemcitabine-based regimen. The primary endpoint was the disease control rate at eight weeks as per response evaluation criteria in solid tumours (RECIST) 1.1. Patients received paclitaxel 80 mg/m2 weekly for three weeks every 28 days and metformin 850 mg p.o. t.i.d. continuously until progression or intolerance state was reached. Results: Twenty patients were enrolled from July 2011 to January 2014: N = 6 (31.6%) achieved the primary endpoint, with all presenting stable disease. Median overall survival (OS) was 128 days (range 17-697) and the median progression free survival (PFS) was 44 days (range 14-210). Eight patients (40%) presented treatment-related G3-4 toxicities with the most common one being diarrhoea. Conclusions: Despite the encouraging pre-clinical evidence of the antitumour activity of metformin in adenocarcinoma of the pancreas, the primary endpoint of the disease control rate was not met. Besides, the treatment combination was poorly tolerated and could not be studied further. This study highlights the importance of performing clinical trials to reassure preclinical or observational data. [ABSTRACT FROM AUTHOR]

Background Nucleotide transporters such as human equilibrative nucleoside transporter-1 (hENT1) play a major role in transporting gemcitabine into cells. CO-1.01 (gemcitabine-5′-elaidate) is a novel cytotoxic agent consisting of a fatty acid derivative of gemcitabine, which is transported intracellularly independent of hENT1. CO-1.01 was postulated to have efficacy as a second-line treatment in gemcitabine-refractory pancreatic adenocarcinoma in patients with negative tumor hENT1 expression. Methods Eligibility criteria included patients with either a newly procured or archival biopsy tumor confirming the absence of hENT1 and either gemcitabine-refractory metastatic pancreas adenocarcinoma or with progression of disease following resection during or within 3 months of adjuvant gemcitabine therapy. Patients were treated with intravenous infusion of CO-1.01 dosed at 1250 mg/m 2 on Days 1, 8, and 15 of a 4-week cycle. The primary end point was disease control rate (DCR). Results Nineteen patients were enrolled of which 18 patients were evaluable for efficacy assessment. Thirteen patients (68%) had liver metastases, 6 (32%) had lymph node metastases, and 10 (53%) had lung metastases. Two of 18 patients (11%) achieved disease control. The median survival time was 4.3 (95% CI 2.1–8.1) months. All patients experienced at least one treatment-related adverse event with the majority of events being mild or moderate. Conclusion This study did not meet its primary endpoint and no efficacy signal was identified for CO-1.01 in treating progressive metastatic pancreas adenocarcinoma. [ABSTRACT FROM AUTHOR]

Several tumor markers have been studied for early diagnosis of gastrointestinal tumors. While some of them are used in clinical practice, most are not cancer specific. CEA, AFP and CA 19-9 are most commonly used markers for gastrointestinal tumors. Pancreas adenocarcinoma is one of the serious malignities with a bad prognosis among gastrointestinal tumors. Most of the patients present with distant metastasis in time of diagnosis. Therefore, early diagnosis is still an important problem. CA 19-9 is most commonly used tumor marker in clinical practice. CA 19-9 is not specific for pancreas cancer and also increased in other gastrointestinal malignities and benign pathologies. New tumor markers have been researched for early diagnosis of pancreas cancer in last years. Beside CA 19-9, some oncogens and micro RNA's are also still investigated. We aimed to summarize the diagnostic value of CA 19-9 and other tumor markers in pancreas adenocarcinoma with literature review. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the use of pretreatment carbohydrate antigen (CA) 19-9 and carcinoembryonic antigen (CEA) as prognostic factors to determine survival in pancreatic adenocarcinoma. Materials and Methods: A retrospective review of the medical records of patients who were diagnosed with pancreatic adenocarcinoma and received surgery, chemoradiotherapy or chemotherapy was performed. Factors, including CA 19-9 and CEA, associated with the survival of pancreatic cancer patients were analyzed. Results: Patients with the median age of 65 years were included (n=187). Elevated serum CA 19-9 levels and CEA levels were observed in 75.4% and 39% of patients at diagnosis, respectively. CEA was correlated with tumor stages (p=0.005), but CA 19-9 was not. CA 19-9 and CEA were elevated in 69.0% and 33.3% of patients with resectable pancreatic cancer, and elevated in 72.9% and 47.2% of patients with advanced pancreatic cancer, respectively. The median overall survival of the normal serum CEA group was longer than that of the elevated serum CEA group (16.3 months vs. 10.2 months, p=0.004). However, the median overall survival of the normal serum CA 19-9 group was not different from that of the elevated serum CA 19-9 group (12.4 months vs. 13.5 months, p=0.969). The independent factors associated with overall survival were advanced pancreatic cancer [harzard ratio (HR) 4.33, p=0.001] and elevated serum CEA level (HR 1.52, p=0.032). Conclusion: Patients with elevated serum CEA level at diagnosis demonstrated poor overall survival. Pretreatment CEA level may predict the prognosis of patients with pancreatic adenocarcinoma. [ABSTRACT FROM AUTHOR]

Background. BRCA1 and BRCA2 germline mutations are associated with an elevated risk for pancreas adenocarcinoma (PAC). Other BRCA-associated cancers have been shown to have greater sensitivity to platinum and poly-(ADP-ribose) polymerase (PARP) inhibitors with better clinical outcomes than in sporadic cases; however, outcomes in BRCA-associated PAC have not been reported. Methods. Patients with a known BRCA1 or BRCA2 mutation and a diagnosis of PAC were identified from the Gastrointestinal Oncology Service, Familial Pancreas Cancer Registry, and Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center. Results. Fifteen patients, five male, with aBRCA1(n=4) or BRCA2 (n =11) mutation and PAC and one patient with a BRCA1 mutation and acinar cell carcinoma of the pancreas were identified. Seven female patients (70%) had a prior history of breast cancer. Four patients received a PARP inhibitor alone or in combination with chemotherapy; three demonstrated an initial radiographic partial response by Response Evaluation Criteria in Solid Tumors whereas one patient had stable disease for 6 months. Six patients received platinum-based chemotherapy first line for metastatic disease; five of those patients had a radiographic partial response. Conclusion. BRCA mutation-associated PAC represents an underidentified, but clinically important, subgroup of patients. This is of particular relevance given the ongoing development of therapeutic agents targeting DNA repair, which may potentially offer a significant benefit to a genetically selected population. We anticipate that further study and understanding of the clinical and biologic features of BRCA-mutant PAC will aid in the identification of tissue biomarkers indicating defective tumor DNA repair pathways in sporadic PAC. [ABSTRACT FROM AUTHOR]

Pancreatic adenocarcinoma has the worst prognosis of any major malignancy, with <5% of patients surviving five years. This can be contributed to the often late diagnosis, lack of sufficient treatment and metastatic spread. Heterogeneity within tumors is increasingly becoming a focus in cancer research, as novel therapies are required to target the most aggressive subpopulations of cells that are frequently termed cancer stem cells (CSCs). In the current study, we describe the identification of a slow-cycling cancer stem-like population of cells in vivo in BxPC-3 and Panc03.27 xenografts. A distinct slow-cycling label-retaining population of cells (DiI+/SCC) was found both at the edge of tumors, and in small circumscribed areas within the tumors. DiI+/SCC in these areas display an epithelial-to-mesenchymal transition (EMT) fingerprint, including an upregulation of the mesenchymal markers vimentin and N-cadherin and a loss of the epithelial marker E-cadherin. DiI+/SCC also displayed a critical re-localization of beta-catenin from the membrane to the nucleus. Additionally, the DiI+/SCC population was found to express the developmental signaling molecule sonic hedgehog. This study represents a novel step in defining the biological activities of a tumorigenic subpopulation within the heterogeneous tumor microenvironment in vivo. Understanding the interactions and functions of a CSC population within the context of the tumor microenvironment is critical to design targeted therapeutics. [ABSTRACT FROM AUTHOR]