Nutritional impact of active hexose-correlated compound for patients with resectable or borderline-resectable pancreatic cancer treated with neoadjuvant therapy.

Active hexose-correlated compound (AHCC) is a standardized extract from cultured Lentinula edodes mycelia, used as a potent biological response modifier in cancer treatment. We evaluated the nutritional effect of AHCC, given during neoadjuvant therapy, to patients with pancreatic ductal adenocarcinoma (PDAC). Thirty patients with resectable or borderline-resectable PDAC received neoadjuvant therapy with gemcitabine plus S-1. We compared, retrospectively, the outcomes of 15 patients who received AHCC combined with neoadjuvant therapy with those of 15 patients who did not receive AHCC combined with neoadjuvant therapy. The median changes of the neutrophil-to-lymphocyte ratio (NLR) and prognostic nutrition index (PNI) were significantly better in the AHCC group. The relative dose intensity of neoadjuvant therapy was also significantly higher in the AHCC group. Thus, AHCC may improve the nutritional status during neoadjuvant therapy of patients with pancreatic ductal adenocarcinoma. To validate these results and examine the long-term impact of AHCC, a prospective phase II study for PDAC is ongoing.

Diet and Exercise Interventions in Patients With Pancreatic Cancer: A Scoping Review.

ABSTRACT: Diet and exercise interventions may help reverse malnutrition and muscle wasting common in pancreatic cancer. We performed a scoping review to identify the knowledge gaps surrounding diet and exercise interventions. We searched PubMed, Scopus, Cumulative Index to Nursing and Allied Health Literature, Embase, ProQuest Theses and Dissertations, and Google Scholar using the umbrella terms of "pancreatic cancer," "diet/nutrition," and "exercise." Included were articles reporting on ambulatory adults with diagnosed pancreatic cancer. Excluded were studies examining prevention and/or risk, animal, or cell lines. Of the 15,708 articles identified, only 62 met the final inclusion criteria. Almost half of the articles were randomized controlled studies (n = 27). Most studies were from the United States (n = 20). The majority examined dietary interventions (n = 41), with 20 assessing the use of omega-3 fatty acids. Exercise interventions were reported in 13 studies, with 8 examining a diet and exercise intervention. Most studies were small and varied greatly in terms of study design, intervention, and outcomes. We identified 7 research gaps that should be addressed in future studies. This scoping review highlights the limited research examining the effect of diet and exercise interventions in ambulatory patients with pancreatic cancer.

Impact of dietary fat composition and quantity in pancreatic carcinogenesis: Recent advances and controversies.

A significant number of pancreatic cancer cases are due to modifiable risk factors, with many being attributed to increased body fatness. This has sparked investigators to examine the role played by high dietary fat intake in pancreatic cancer development and the mechanisms driving this connection. However, there is currently no consensus on how dietary fat quantity and composition specifically affect pancreatic carcinogenesis. The objective of this narrative review is to discuss the link between high total fat consumption and fatty acid composition (saturated, mono-, or poly-unsaturated fats) with pancreatic cancer incidence and progression. Following our detailed analysis of the strengths and weaknesses of recent preclinical and human studies, we discuss existing research gaps and opportunities, and provide recommendations for future studies. Numerous studies suggest that diets high in omega-3 polyunsaturated fatty acids are associated with reduced pancreatic cancer risk. However, the current evidence appears insufficient for a general conclusion regarding the impact of other types of fat in pancreatic carcinogenesis, with many studies providing inconclusive findings due to study limitations. Thus, we recommend future studies to include detailed methodology of the animal experiments, not limited to the diet composition, type of ingredients, formulations, and administration of the diets. Moreover, human studies should include a diverse population and well-characterized biomarkers for accurate determination of dietary fat intake. Ultimately, this will aid the study rigor, and improve our understanding of the impact of fat quantity and composition in pancreatic carcinogenesis.

Heated fennel therapy promotes the recovery of gastrointestinal function in patients after complex abdominal surgery: A single-center prospective randomized controlled trial in China.

BACKGROUND: Postoperative gastrointestinal dysfunction remains a major determinant of the duration of stay after complex abdominal surgery. This study was performed to evaluate the effectiveness of heated fennel therapy in accelerating the recovery of gastrointestinal function. METHODS: This surgeon-blinded, prospective randomized controlled study included 381 patients with hepatobiliary, pancreatic, and gastric tumors who were divided into 2 groups. The patients in the experimental groups received heated fennel therapy, and those in the control groups received heated rice husk therapy. We compared the baseline characteristics, time to first postoperative flatus and defecation, fasting time, duration of postoperative hospital stay, grading of abdominal pain, classification of abdominal distension, inflammatory markers, and nutritional status indicators. RESULTS: The time to first flatus and first defecation and the fasting time were statistically significantly less in the heated fennel therapy group than those in the control groups (P < .05 each); and abdominal distension was also relieved in the experimental groups (P < .001). Heated fennel therapy had no obvious beneficial effect on inflammatory markers but improved the serum albumin (ALB) level of the patients at postop day 9 (P < .001). Among the patients with alimentary tract reconstruction, those in the heated fennel therapy group had a clinically important, lesser hospital stay than those in the control group (9.2 5 ± 5.1 versus 11.1 ± 6.4; P < .023). CONCLUSION: Heated fennel therapy facilitated the gastrointestinal motility function of patients early postoperatively.

Physical Inactivity and Pancreatic Cancer Mortality.

OBJECTIVE: To determine the association between pre-diagnostic recreational physical inactivity (RPI) and pancreatic cancer (PC) mortality. METHODS: This analysis included 107 patients seen at Roswell Park Comprehensive Cancer Center diagnosed with PC between 1989 and 1998. Cox proportional hazards models were used to determine hazard ratios (HR) and 95% confidence intervals (CI) for PC mortality associated with self-reported pre-diagnostic RPI. Models were adjusted for known prognostic factors, including age, sex, stage at diagnosis, smoking status, and body mass index (BMI). Results were also stratified by sex, BMI, smoking status, histology, and treatment status. RESULTS: We observed a significant association between RPI and PC mortality in all patients (HR = 1.72, 95% CI = 1.06-2.79), as well as among overweight or obese patients (HR = 2.74, 95% 95% CI = 1.42-5.29), females (HR = 2.63; 95% CI, 1.08-6.39), and non-smokers (HR = 1.72; 95% CI, 1.02-2.89). CONCLUSION: These results suggest that RPI prior to PC diagnosis is associated with a higher risk of death. Future studies with larger sample sizes are needed to explore whether this association varies across tumor histology.

Cordycepin inhibits pancreatic cancer cell growth in vitro and in vivo via targeting FGFR2 and blocking ERK signaling.

Cordycepin (3'-deoxyadenosine) from Cordyceps militaris has been reported to have anti-tumor effects. However, the molecular target and mechanism underlying cordycepin impeding pancreatic cancer cell growth in vitro and in vivo remain vague. In this study, we reported functional target molecule of cordycepin which inhibited pancreatic cancer cells growth in vitro and in vivo. Cordycepin was confirmed to induce apoptosis by activating caspase-3, caspase-9 and cytochrome c. Further studies suggested that MAPK pathway was blocked by cordycepin via inhibiting the expression of Ras and the phosphorylation of Erk. Moreover, cordycepin caused S-phase arrest and DNA damage associated with activating Chk2 (checkpoint kinase 2) pathway and downregulating cyclin A2 and CDK2 phosphorylation. Very interestingly, we showed that cordycepin could bind to FGFR2 (KD = 7.77 × 10-9) very potently to inhibit pancreatic cancer cells growth by blocking Ras/ErK pathway. These results suggest that cordycepin could potentially be a leading compound which targeted FGFR2 to inhibit pancreatic cells growth by inducing cell apoptosis and causing cell cycle arrest via blocking FGFR/Ras/ERK signaling for anti-pancreatic cancer new drug development.

Nutritional and immune impairments and their effects on outcomes in early pancreatic cancer patients undergoing pancreatoduodenectomy.

BACKGROUND & AIMS: Nutritional impairments are highly frequent in pancreatic cancer even in the early stages and have a significant impact on outcomes. The aim of this prospective study was to investigate immune and nutritional impairments, their interrelations and impacts on outcomes in an unselected cohort of patients scheduled for pancreatoduodenectomy due to suspicion of pancreatic cancer. METHODS: All consecutive patients scheduled for pancreatoduodenectomy at Vilnius University Hospital Santaros Klinikos between January 2016 and November 2018 were recruited into the study according to the inclusion/exclusion criteria. Patients were randomly allocated into the groups of nutritional intervention with immunonutrition vs. control and stratified into the groups of pancreatic ductal adenocarcinoma (PDAC) vs. other pancreatic tumors. Nutritional evaluation included screening (NRS 2002), anthropometric measurements, bioelectrical impedance analysis and lumbar skeletal muscle index (LSMI). Inflammatory indicators were measured before and after surgery. Surgical outcomes were assessed 30 days postoperatively using Comprehensive Complication Index (CCI). RESULTS: Although increased nutritional risk was identified in 22.4% of patients, 41.4% were finally diagnosed with cachexia. While cachexia was predominantly diagnosed in underweight patients, sarcopenia was detected across all BMI categories and 11.7% of obese patients had sarcopenia. Decreased LSMI was identified in 52.5% of patients as compared to decreased phase angle in 39% of patients and decreased fat free mass index in only 3.4% of patients. Regression model indicate a large effect of nutritional indicators on CCI (R2 coefficient 71.1%). In comparison to patients with other pancreatic tumors, patients with PDAC had a characteristic pattern of increased systemic inflammation prior to surgery and decreased inflammation postoperatively (p = 0.02). CONCLUSIONS: A high rate of nutritional impairments was identified in our cohort of patients with early pancreatic cancer, including abnormal body composition phenotypes. They produced negative effects on postoperative outcomes. The highest diagnostic rates were obtained with LSMI measurement, while the highest value for prognostication was attained with the inclusion of multiple objective nutritional state indicators.

Metabolic syndrome, metabolic components, and their relation to the risk of pancreatic cancer.

BACKGROUND: Components of the metabolic syndrome (MetS), such as elevated fasting glucose levels and abdominal obesity, have been suggested as potential risk factors for pancreatic cancer. However, data are still insufficient to assure the influence of MetS on incident pancreatic cancer. The objective of the current study was to investigate the association between MetS, metabolic components, and the risk of pancreatic cancer. METHODS: In the Korea National Health Information Database, 223,138 individuals who were without pancreatic cancer in 2009 were enrolled and followed until 2013. They were categorized into 4 groups according to the number of baseline metabolic components (0, 1, 2, 3, and 4-5). A multivariate Cox proportional hazard model was used to calculate the adjusted hazard ratios (HRs) and 95% CIs for incident pancreatic cancer according to the presence of MetS and the number of metabolic components. In addition, the risk of pancreatic cancer was evaluated in individuals who had a single metabolic component. RESULTS: The presence of MetS was significantly associated with incident pancreatic cancer (adjusted HR, 1.47; 95% CI, 1.19-1.81). The group with 4 or 5 baseline metabolic components had a higher risk of pancreatic cancer than the other groups (0 components: reference category; 1 component: adjusted HR, 0.94 [95% CI, 0.61-1.45]; 2 components: adjusted HR, 1.03 [95% CI, 0.68-1.56]; 3 components: adjusted HR, 1.35 [95% CI, 0.89-2.04]; 4-5 components: adjusted HR, 1.64 [95% CI, 1.06-2.51]). Regarding associations between the individual metabolic components and pancreatic cancer, no metabolic component alone had a statistically significant association with pancreatic cancer. CONCLUSIONS: MetS is a potential risk factor for pancreatic cancer. The presence of ≥4 metabolic components leads to a higher risk of pancreatic cancer even within categories of the MetS.

Home-Based Exercise Prehabilitation During Preoperative Treatment for Pancreatic Cancer Is Associated With Improvement in Physical Function and Quality of Life.

Purpose: To investigate relationships among physical activity, changes in physical function, and health-related quality of life (HRQOL) among patients with pancreatic adenocarcinoma enrolled in a home-based exercise prehabilitation program. Methods: Patients with resectable pancreatic adenocarcinoma receiving preoperative chemotherapy and/or chemoradiation were enrolled on this prospective, single-arm trial and were advised to perform ≥60 minutes each of moderate-intensity aerobic exercise and strengthening exercise weekly. Activity was measured via self-report and accelerometers, including moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), and sedentary activity (SA). Physical function measures at baseline and restaging follow-up included 6-minute walk test (6MWT), 5 times sit-to-stand (5×STS), handgrip strength (HGS), 3-m walk for gait speed (GS), and the PROMIS Physical Function Short Form. HRQOL was measured via the FACT-Hep questionnaire. Results: Fifty participants with mean age 66 years (standard deviation = 8 years) were enrolled. The 6MWT, 5×STS, and GS significantly improved from baseline to restaging follow-up (P=.001, P=.049, and P=.009, respectively). Increases in self-reported aerobic exercise, weekly MVPA, and LPA were associated with improvement in 6MWT (ß=.19, P=.048; ß=.18, P=.03; and ß=.08, P=.03, respectively) and self-reported physical functioning (ß=.02, P=.03; ß=.03, P=.005; and ß=.01, P=.02, respectively). Increased weekly LPA was associated with increased HRQOL (ß=.03, P=.02). Increased SA was associated with decreased HRQOL (ß=-.02,P=.01). Conclusions: Patients with potentially resectable pancreatic cancer exhibit meaningful improvement in physical function with prehabilitation; physical activity was associated with improved physical function and HRQOL. These data highlight the importance of physical activity during treatment for pancreatic cancer.

The synergism of Clinacanthus nutans Lindau extracts with gemcitabine: downregulation of anti-apoptotic markers in squamous pancreatic ductal adenocarcinoma.

BACKGROUND: Clinacanthus nutans extracts have been consumed by the cancer patients with the hope that the extracts can kill cancers more effectively than conventional chemotherapies. Our previous study reported its anti-inflammatory effects were caused by inhibiting Toll-like Receptor-4 (TLR-4) activation. However, we are unsure of its anticancer effect, and its interaction with existing chemotherapy. METHODS: We investigated the anti-proliferative efficacy of polar leaf extracts (LP), non-polar leaf extracts (LN), polar stem extract (SP) and non-polar stem extracts (SN) in human breast, colorectal, lung, endometrial, nasopharyngeal, and pancreatic cancer cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT assay. The most potent extracts was tested along with gemcitabine using our established drug combination analysis. The effect of the combinatory treatment in apoptosis were quantified using enzyme-linked immunosorbent assay (ELISA), Annexin V assay, antibody array and immunoblotting. Statistical significance was analysed using one-way analysis of variance (ANOVA) and post hoc Dunnett's test. A p-value of less than 0.05 (p < 0.05) was considered statistical significance. RESULTS: All extracts tested were not able to induce potent anti-proliferative effects. However, it was found that pancreatic ductal adenocarcinoma, PDAC (AsPC1, BxPC3 and SW1990) were the cell lines most sensitive cell lines to SN extracts. This is the first report of C. nutans SN extracts acting in synergy with gemcitabine, the first line chemotherapy for pancreatic cancer, as compared to conventional monotherapy. In the presence of SN extracts, we can reduce the dose of gemcitabine 2.38-5.28 folds but still maintain the effects of gemcitabine in PDAC. SN extracts potentiated the killing of gemcitabine in PDAC by apoptosis. Bax was upregulated while bcl-2, cIAP-2, and XIAP levels were downregulated in SW1990 and BxPC3 cells treated with gemcitabine and SN extracts. The synergism was independent of TLR-4 expression in pancreatic cancer cells. CONCLUSION: These results provide strong evidence of C. nutans extracts being inefficacious as monotherapy for cancer. Hence, it should not be used as a total substitution for any chemotherapy agents. However, SN extracts may synergise with gemcitabine in the anti-tumor mechanism.

Anti-tumor effect and mechanistic study of elemene on pancreatic carcinoma.

BACKGROUND: Elemene is an effective anticancer component extracted from Zingiberaceae plants. This work was aimed to evaluate the anti-tumor effect and mechanism actions of elemene on pancreatic carcinoma in vitro and in vivo. METHODS: The anti-proliferation experiment was measured by Methylthiazolyldiphenyl-tetrazolium bromide (MTT) method in the time of 24, 48 and 72 h in three different dosages. The cell cycle was detected by flow cytometer after 12 h treatment. Forty-eight nude mice were subcutaneously xenograft with BxPC-3 pancreatic cancer cells and divided into four groups: Control group and high, medium, low dosage of elemene (20, 40 and 60 mg/kg) treatment groups. Immunoblot and immunohistochemical methods were applied to detect the protein expression of P53 and Bcl-2 in the tumor of pancreatic cancer xenografts. H & E staining was used to detect the histopathological changes in each group. RESULTS: A significant inhibition effect was observed in the anti-proliferation of BxPC-3 and Panc-1 cells in vitro in the time course of 24, 48 and 72 h with a dose dependent manner. The cell cycle results showed that elemene could arrest pancreatic cancer cells in the S phase after 12 h treatment in BxPC-3 and Panc-1 cell line. The in vivo BxPC-3 xenografts study exhibited that elemene was significantly decreased the tumor size in the high dosage group, compared to control group. And there is no any significant change in body weight of all animals. H&E pathology section result showed that treatment with elemene significantly decreased the inflammation cells and reduced the histopathological changes with a dose-dependent manner. Meanwhile, treatment with elemene significantly up-regulates the protein expression of P53, while down-regulate the protein expression of Bcl-2 in the tumor tissues, respectively. Furthermore, the western blot result showed that treatment with elemene increased the expression of P53 and decreased the expression of Bcl-2, compared with the control group, which is similar to the results of immunohistochemical staining. CONCLUSIONS: This study suggests that elemene has a potential anti pancreatic cancer effect, down-regulation the protein expression of Bcl-2 and up-regulation the protein expression of P53 in a dose dependent manner may be is the anti-tumor mechanism.

Inflammatory Potential of Diet, Inflammation-Related Lifestyle Factors, and Risk of Pancreatic Cancer: Results from the NIH-AARP Diet and Health Study.

BACKGROUND: Chronic inflammation is implicated in pancreatic cancer, and can be modulated by diet and other lifestyle factors. We examined the association between Dietary Inflammatory Index (DII) scores and pancreatic cancer risk in the NIH-AARP Diet and Health Study, and examined effect modification by inflammation-related lifestyle factors, including body mass index, cigarette smoking, diabetes, alcohol drinking, and use of non-steroidal anti-inflammatory drugs. METHODS: Energy-adjusted DII scores (E-DII) were computed on the basis of food frequency questionnaire responses for foods and dietary supplements. Cox proportional hazards models were fitted and effect modification was examined by adding a cross-product of each effect modifier with E-DII quintile in the multivariable-adjusted model. RESULTS: There were 2,824 primary incident pancreatic cancers diagnosed during a median of 13.4 years follow-up, and there was no association between E-DII scores and pancreatic cancer risk among either men [HRQ5vsQ1, 1.00; 95% confidence interval (CI), 0.86-1.16] or women (HRQ5vsQ1, 1.00; 95% CI, 0.82-1.21) in the multivariable-adjusted model, and no association was detected by any cancer stage. The E-DII and pancreatic cancer association was not modified by any of the inflammation-related lifestyle factors examined. CONCLUSIONS: Results from this large prospective study did not support an association between inflammatory potential of diet and pancreatic cancer, or effect modification by other inflammation-related lifestyle factors. IMPACT: Inflammatory potential of diet may not be related to pancreatic cancer risk. Future cohort studies with more frequent dietary measures could be useful in determining the appropriate timing of dietary intake in relation to pancreatic cancer etiology.

Ixocarpalactone A from dietary tomatillo inhibits pancreatic cancer growth by targeting PHGDH.

3-Phosphoglycerate dehydrogenase (PHGDH) catalyzes the first rate-limiting step for the synthesis of glucose-derived serine by converting 3-phosphoglycerate (3-PG) to phosphohydroxypyruvate (p-Pyr), which has been reported to associate with tumorigenesis in many cancers. Iox A, a natural withanolide obtained from dietary tomatillo (Physalis ixocarpa), showed significant PHGDH inhibitory activity with an IC50 value of 1.66 ± 0.28 µM, and it was further confirmed to bind directly to PHGDH by the MST assay. Molecular docking demonstrated that Iox A coordinated at the allosteric site of PHGDH, which was consistent with the non-competitive kinetics. Meanwhile, Iox A selectively inhibited the proliferation of high PHGDH-expressing cancer cell lines (SW1990, MCF-7 and HeLa) and showed no obvious cytotoxicities on normal human cells (LO2, L929 and HPDE6-C7). In particular, Iox A showed a dose-dependent proapoptotic activity against SW1990 cells in a micromolar concentration as detected by flow cytometry and western blot analysis. DARTS and siRNA assays further demonstrated that Iox A directly targets at PHGDH to inhibit the proliferation of SW1990 cells. Furthermore, Iox A significantly inhibited the tumor growth in a SW1990 xenograft mouse model with low toxicities, suggesting its potential therapeutic application in pancreatic cancer treatment. Therefore, Iox A was identified as a novel natural PHGDH inhibitor with high targeting and low toxicities for the treatment of pancreatic cancers.

Anacardic acid inhibits pancreatic cancer cell growth, and potentiates chemotherapeutic effect by Chmp1A - ATM - p53 signaling pathway.

BACKGROUND: Pancreatic cancer is one of the leading causes of cancer related death and its incidence has risen steadily. Although anticancer drugs have been developed based on the new molecular findings, the drugs have produced unsatisfactory results due to toxicity and resistance. Thus, a complementary therapeutic intervention is urgently needed for pancreatic cancer patients. METHODS: The aim of this study was to assess the potential therapeutic effect of Anacardic acid on pancreatic cancer in vitro and elucidate its underlying mechanisms. Human pancreatic cancer cells were treated with Anacardic acid and assessed for the cytotoxic effect using MTT and spheroid formation assays. Using the same methods, the synergy between Anacardic acid and 5-Fluorouracil or Gemcitabine was determined. To elucidate the underlying molecular mechanisms, Western blot analysis and immunocytochemistry were performed on cancer cells treated with Anacardic acid alone or in combination with 5-Fluorouracil or Gemcitabine. Chromatin Modifying Protein 1A (Chmp1A), Ataxia Telangiectasia Mutated (ATM), and p53 were the primary signaling molecules examined. In addition, Chmp1A was silenced with shRNA to examine the necessity of Chmp1A for the anticancer effect of Anacardic acid, 5-Fluorouracil, or Gemcitabine. RESULTS: Anacardic acid induced an anticancer effect in pancreatic cancer cell lines in a dose dependent manner, and increased the cytotoxicity of 5-Fluorouracil or Gemcitabine in MTT cell viability assays. In spheroid formation assays, spheroids formed were smaller in size and in number upon Anacardic acid treatment compared to control. Mechanistically, Anacardic acid exerted its anticancer activity via the activation of Chmp1A, ATM, and p53. Interestingly, 5-Fluorouracil and Gemcitabine also induced an increase in Chmp1A protein level, suggesting that Chmp1A might mediate the cytotoxic action of chemotherapeutics. Silencing experiments indicate that Chmp1A is required for the action of Anacardic acid, but not for 5-Fluorouracil or Gemcitabine. CONCLUSIONS: Our data suggests that Anacardic Acid might be a promising complementary supplement to slow the initiation or progression of pancreatic cancer.

Fermented Extraction of Citrus unshiu Peel Inhibits Viability and Migration of Human Pancreatic Cancers.

Pancreatic cancer is one of the most dangerous cancers with high mortality rates. Despite continuous efforts, there has been limited improvement in its prognosis. In this study, we prepared fermented extract of Citrus unshiu peel (fCUP) from the by-product after juice processing and then examined the anticancer effects of fCUP on human pancreatic cancer cells. Treatment with fCUP inhibited the growth of human pancreatic cancer cells through induction of caspase-3 cleavage both in vitro and in vivo. Treatment with fCUP also blocked the migration of human pancreatic cancer cells through activation of intracellular signaling pathways such as MKK3/6 and P38. In contrast, treatment with fCUP did not inhibit growth and migration of human umbilical vein endothelial cells. In addition, we found that fCUP mainly consisted of aboriginal compounds, narirutin and hesperidin, as well as newly generated compounds, naringenin and hesperetin. In silico analysis showed that naringenin and hesperetin were the unique modules related to anticancer effect. Furthermore, fCUP exhibited the anticancer effects in in vivo xenograft models. Collectively, these results suggest that fCUP might have the potential to be developed into an effective anticancer drug for pancreatic cancers without causing adverse side-effects.

Predictors of Pancreatic Cancer-Associated Weight Loss and Nutritional Interventions.

OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is often accompanied by weight loss. We sought to characterize factors associated with weight loss and observed nutritional interventions, as well as define the effect of weight loss on survival. METHODS: Consecutive subjects diagnosed with PDAC (N = 123) were retrospectively evaluated. Univariate analysis was used to compare subjects with and without substantial (>5%) weight loss. Multivariate logistic regression was performed to identify factors associated with weight loss, and survival analyses were performed using Kaplan-Meier curves and Cox survival models. RESULTS: Substantial weight loss at diagnosis was present in 71.5% of subjects and was independently associated with higher baseline body mass index, longer symptom duration, and increased tumor size. Recommendations for nutrition consultation and pancreatic enzyme replacement therapy occurred in 27.6% and 36.9% of subjects, respectively. Weight loss (>5%) was not associated with worse survival on multivariate analysis (hazard ratio, 1.32; 95% confidence interval, 0.76-2.30), unless a higher threshold (>10%) was used (hazard ratio, 1.77; 95% confidence interval, 1.09-2.87). CONCLUSIONS: Despite the high prevalence of weight loss at PDAC diagnosis, there are low observed rates of nutritional interventions. Weight loss based on current criteria for cancer cachexia is not associated with poor survival in PDAC.

The basal nutritional state of PDAC patients is the dominant factor for completing adjuvant chemotherapy.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is highly lethal, and several clinical trials have shown that adjuvant chemotherapy after curative resection can improve the prognosis of these patients. However, the adjuvant chemotherapy completion rate is less than satisfactory. If this rate could be increased then the overall prognosis of PDAC might be improved; however, reports addressing this problem are insufficient. To elucidate the factors, we retrospectively investigated PDAC patients. METHODS: Various factors of 121 PDAC patients undergoing R0 resection, including preoperatively treated patients, were investigated. Univariate and multivariate analyses were performed to investigate the factors that were associated with the completion of adjuvant chemotherapy. RESULTS: The analysis identified age and the prognostic nutritional index (PNI) as significant independent factors. A receiver operating characteristic curve analysis of age yielded a cutoff value of 67 years (sensitivity, 64%; specificity, 78%). Univariate and multivariate analyses of the 61 patients who were over 67 years of age revealed that the PNI (odds ratio, 0.85; P = 0.048) and Evans grade (odds ratio, 0.041; P = 0.0010) were significant factors for the completion of chemotherapy. CONCLUSIONS: The results of our investigation suggest that nutrition should be controlled in older PDAC patients to facilitate the completion of adjuvant chemotherapy.

Transcriptome Analysis of Piperlongumine-Treated Human Pancreatic Cancer Cells Reveals Involvement of Oxidative Stress and Endoplasmic Reticulum Stress Pathways.

Piperlongumine (PL), an alkaloid obtained from long peppers, displays antitumorigenic properties for a variety of human cell- and animal-based models. The aim of this study was to identify the underlying molecular mechanisms for PL anticancer effects on human pancreatic cancer cells. RNA sequencing (RNA-seq) was used to identify the effects of PL on the transcriptome of MIA PaCa-2 human pancreatic cancer cells. PL treatment of pancreatic cancer cells resulted in differential expression of 683 mRNA transcripts with known protein functions, 351 of which were upregulated and 332 of which were downregulated compared to control-treated cells. Transcripts associated with oxidative stress, endoplasmic reticulum (ER) stress, and unfolded protein response pathways were significantly overexpressed with PL treatment. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to validate the RNA-seq results, which included upregulation of HO-1, IRE1α, cytochrome c, and ASNS. The results provide key insight into the mechanisms by which PL alters cancer cell physiology and identify that activation of oxidative stress and ER stress pathways is a critical avenue for PL anticancer effects.

Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro- and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations.

The effects of curcumin (diferuloylmethane) on body composition of patients with advanced pancreatic cancer.

BACKGROUND: Curcumin is a natural product that is often explored by patients with cancer. Weight loss due to fat and muscle depletion is a hallmark of pancreatic cancer and is associated with worse outcomes. Studies of curcumin's effects on muscularity show conflicting results in animal models. METHODS AND RESULTS: Retrospective matched 1:2 case-control study to evaluate the effects of curcumin on body composition (determined by computerized tomography) of 66 patients with advanced pancreatic cancer (22 treated,44 controls). Average age (SEM) was 63(1.8) years, 30/66(45%) women, median number of prior therapies was 2, median (IQR) time from advanced pancreatic cancer diagnosis to baseline image was 7(2-13.5) months (p>0.2, all variables). All patients lost weight (3.3% and 1.3%, treated vs. control, p=0.13). Treated patients lost more muscle (median [IQR] percent change -4.8[-9.1,-0.1] vs. -0.05%[-4.2, 2.6] in controls,p<0.001) and fat (median [IQR] percent change -6.8%[-15,-0.6] vs. -4.0%[-7.6, 1.3] in controls,p=0.04). Subcutaneous fat was more affected in the treated patients. Sarcopenic patients treated with curcumin(n=15) had survival of 169(115-223) days vs. 299(229-369) sarcopenic controls(p=0.024). No survival difference was found amongst non-sarcopenic patients. CONCLUSIONS: Patients with advanced pancreatic cancer treated with curcumin showed significantly greater loss of subcutaneous fat and muscle than matched untreated controls.