Exploring Pain, Quality of Life, and Emotional Well-Being in Patients with Advanced Pancreatic Cancer Practicing Spiritual Meditation: A Pilot Study.

INTRODUCTION: Studies on mind-body approaches in patients with advanced pancreatic ductal adenocarcinoma (PDAC) are rare. We performed a pilot study with follow-up until 1 year to explore changes in pain, quality of life (QoL), stress, and negative emotions in patients with advanced PDAC, who regularly practiced a standardized form of spiritual meditation in addition to standard medical care. METHODS: At baseline and every 2 months for a maximum of 1 year, global pain, QoL (global, SEIQoL, FACT-G), spiritual well-being (FACIT-Sp), perceived stress (PSQ-20), anxiety and depression (HADS), and diurnal cortisol secretion (cortisol slope) were assessed. Changes from baseline were explored by pairwise comparisons of available cases. RESULTS: Twenty participants (11 women, 62 ± 9.9 SD years) participated in the study, of whom 9 patients survived the study year. Pairwise comparisons revealed transient improvements of pain after 4 and 6 months (both p values < 0.05), of global QoL after 4, 6, 8, 10 months (all p values < 0.05), of SeiQoL scores after 4 months (p < 0.05), of FACT-G scores after 6 months (p < 0.05), and of FACIT-Sp scores after 2 and 6 months (both p values < 0.05). Furthermore, overall stress levels (PSQ-20) decreased from baseline to 2, 6, and 8 months (all p values < 0.05), and anxiety declined from baseline to 6 months (p < 0.05). Depression scores and the cortisol slope did not change. CONCLUSION: This pilot study demonstrated the acceptability and feasibility of studies on spiritual meditation in patients with advanced PDAC. Randomized controlled trials are warranted to study the effects of spiritual meditation and other mind-body interventions on pain, QoL, and emotional well-being in this patient population.Bislang gibt es kaum Studien zu Mind-Body-Ansätzen bei Patienten mit fortgeschrittenem duktalem Adenokarzinom der Bauchspeicheldrüse (PDAC). Wir führten eine explorative Pilotstudie mit einer einjährigen Nachbe- obachtungszeit durch, um Veränderungen von Schmerzen, Lebensqualität, Stress und negativen Emotionen bei Patienten mit fortgeschrittenem PDAC zu untersuchen, die zusätzlich zur medizinischen Standardversorgung regelmäßig eine standardisierte Form der spirituellen Meditation praktizierten.Zu Beginn der Studie und alle zwei Monate wurden über einen Zeitraum von maximal einem Jahr die globalen Schmerzen, die Lebensqualität (global, SEIQoL, FACT-G), das psychologische Wohlbefinden (FACIT-Sp), Stress (PSQ-20), Angst und Depression (HADS) sowie die circadiane Cortisolausschüttung (Cortisolabfall) untersucht. Die Änderungen gegenüber dem Ausgangswert wurden mit paarweisen Vergleichen der jeweils verfügbaren Fälle auf Signifikanz getestet.20 Patienten (11 Frauen, 62 ± 9.9 SD Jahre) nahmen an der Studie teil, von denen 9 das Studienjahr überlebten. Paarweise Vergleiche zeigten vorübergehende Verbesserungen der Schmerzen nach 4 und 6 Monaten (beide p-Werte < 0.05), der globalen Lebensqualität nach 4, 6, 8 und 10 Monaten (alle p-Werte < 0.05), der SeiQoL-Werte nach 4 Monaten (p < 0.05), der FACT-G-Werte nach 6 Monaten (p < 0.05) und der FACIT-Sp-Werte nach 2 und 6 Monaten (beide p-Werte < 0.05). Außerdem war der Gesamtstress (PSQ-20) nach 2, 6 und 8 Monaten (alle p-Werte < 0.05) sowie die Ängstlichkeit nach 6 Monaten (p < 0.05) signifikant gesunken. Die Depressionswerte und der circadiane Cortisolabfall änderten sich nicht.Diese Pilotstudie weist auf die Akzeptanz und Durchführbarkeit von Studien zu spiritueller Meditation bei Patienten mit fortgeschrittenem PDAC hin. Randomisierte kontrollierte Studie sollten folgen, um die Effekte von spiritueller Meditation und anderen Mind-Body-Interventionen auf Schmerzen, Lebensqualität und emotionales Wohlbefinden in dieser Patientengruppe zu untersuchen.

Long term follow-up of a simplified and less burdened pancreatic duct ligation model of exocrine pancreatic insufficiency in Goettingen Minipigs.

BACKGROUND: Pancreatic duct ligation in a minipig model leads to exocrine pancreatic insufficiency (EPI). This allows the study of digestive processes and pancreatic enzyme replacement therapies. However, detailed descriptions of the surgical procedure, perioperative management, a determination of exocrine pancreatic insufficiency are scarce in the literature. Data of the long-term health status of minipigs upon EPI induction are still not available. Therefore, the present study describes in detail an experimental approach to the induction of exocrine pancreatic insufficiency via pancreatic duct ligation in minipigs and the long term follow up of the animal's health state. METHODS: 14 Goettingen minipigs underwent pancreatic duct ligation via midline laparotomy for the induction of exocrine pancreatic insufficiency. Fecal fat content, fat absorption, chymotrypsin levels, body weight and blood vitamin and glucose levels were determined. RESULTS: Exocrine pancreatic insufficiency was successfully induced in 12 Goettingen minipigs. Two minipigs failed to develop exocrine insufficiency most likely due to undetected accessory pancreatic ducts. All animals tolerated the procedure very well and gained weight within 8 weeks after surgery without requiring pancreatic enzyme replacement therapy. The follow up for approx. 180 weeks showed a stable body weight and health state of the animals with normal blood glucose levels (Table 1). From approx. 130 weeks post pancreatic duct ligation, all animals were supplemented with pancreatic enzymes and vitamins resulting in blood concentrations almost within the reference range. CONCLUSIONS: Pancreatic duct ligation in minipigs is an excellent method of inducing exocrine pancreatic insufficiency. It is important to identify and ligate accessory pancreatic ducts since persistence of accessory ducts will lead to maintenance of exocrine pancreatic function. The EPI model caused no persistent side effects in the animals and has the potential to be used in long-term EPI studies with up to 100 weeks post-OP without supplementation with enzymes and vitamins.

Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer - the NEONAX trial (AIO-PAK-0313), a prospective, randomized, controlled, phase II study of the AIO pancreatic cancer group.

BACKGROUND: Even clearly resectable pancreatic cancer still has an unfavorable prognosis. Neoadjuvant or perioperative therapies might improve the prognosis of these patients. Thus, evaluation of perioperative chemotherapy in resectable pancreatic cancer in a prospective, randomized trial is warranted. A substantial improvement in overall survival of patients with metastatic pancreatic cancer with FOLFIRINOX and nab-paclitaxel/gemcitabine vs standard gemcitabine has been demonstrated in phase III-trials. Indeed nab-paclitaxel/gemcitabine has a more favorable toxicity profile compared to the FOLFIRINOX protocol and appears applicable in a perioperative setting. METHODS: NEONAX is an interventional, prospective, randomized, controlled, open label, two sided phase II study with an unconnected analysis of the results in both experimental arms against a fixed survival probability (38% at 18 months with adjuvant gemcitabine), NCT02047513. NEONAX will enroll 166 patients with resectable pancreatic ductal adenocarcinoma (≤ cT3, N0 or N1, cM0) in two arms: Arm A (perioperative arm): 2 cycles nab-paclitaxel (125 mg/m2)/gemcitabine (1000 mg/m2, d1, 8 and 15 of an 28 day-cycle) followed by tumor surgery followed by 4 cycles nab-paclitaxel/gemcitabine, Arm B (adjuvant arm): tumor surgery followed by 6 cycles nab-paclitaxel/gemcitabine. The randomization (1:1) is eminent to avoid allocation bias between the groups. Randomization is stratified for tumor stage (ct1/2 vs. cT3) and lymph node status (cN0 vs. cN1). Primary objective is disease free survival (DFS) at 18 months after randomization. Key secondary objectives are 3-year overall survival (OS) rate and DFS rate, progression during neoadjuvant therapy, R0 and R1 resection rate, quality of life and correlation of DFS, OS and tumor regression with pharmacogenomic markers, tumor biomarkers and molecular analyses (ctDNA, transcriptome, miRNA-arrays). In addition, circulating tumor-DNA will be analyzed in patients with the best and the worst responses to the neoadjuvant treatment. The study was initiated in March 2015 in 26 centers for pancreatic surgery in Germany. DISCUSSION: The NEONAX trial is an innovative study on resectable pancreatic cancer and currently one of the largest trials in this field of research. It addresses the question of the role of intensified perioperative treatment with nab-paclitaxel plus gemcitabine in resectable pancreatic cancers to improve disease-free survival and offers a unique potential for translational research. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02047513, 08/13/2014.

Resveratrol induces apoptosis and alters gene expression in human fibrosarcoma cells.

BACKGROUND/AIM: Metastatic fibrosarcomas still represent a therapeutic dilemma. Commonly used chemotherapeutic agents such as doxorubicin have been proven effective in fewer than 30% of all cases disseminated of fibrosarcoma. Elderly patients with cardiac disease are not suitable for systemic chemotherapy with doxorubicin. We therefore tested the apoptotic effects of the natural and well-tolerated compound resveratrol on human fibrosarcoma cells (HT1080). MATERIALS AND METHODS: Vital, apoptotic and necrotic cells were quantified using flow cytometric analysis. Gene expression was analyzed by RNA microarrays. RESULTS: Application of resveratrol induced apoptotic cell death and significantly reduced proliferation of HT1080 cells. Correspondingly, expression of apoptosis-associated genes was altered in microarray analysis. CONCLUSION: This in vitro study demonstrates the anticancer activity of resveratrol against human fibrosarcoma cells. These results provide experimental support for in vivo trials assessing the effect of the natural polyphenol resveratrol.

Pro­apoptotic effects of pycnogenol on HT1080 human fibrosarcoma cells.

Complete surgical resection with clear margins remains the mainstay of therapy for localised fibrosarcomas. Nevertheless, metastatic fibrosarcomas still represent a therapeutic dilemma. Commonly used chemotherapeutic agents like doxorubicin have proven to be effective in <30% of all cases of disseminated fibrosarcoma. Especially elderly patients with cardiac subdisease are not suitable for systemic chemotherapy with doxorubicin. Therefore we tested the apoptotic effects of the well-tolerated pine bark extract pycnogenol and its constituents on human fibrosarcoma cells (HT1080). Ten healthy subjects (six females, four males, mean age 24.8 ± 6 years) received a single dose of 300 mg pycnogenol orally. Blood plasma samples were obtained before and 6 h after intake of pycnogenol. HT1080 cells were treated with these plasma samples. Additionally, HT1080 were incubated separately with catechin, epicatechin and taxifolin that are known as the main constituents of pycnogenol. Vital, apoptotic and necrotic cells were quantified using flow cytometric analysis. Gene expression was analyzed by RNA microarray. The results showed that single application of taxifolin, catechin and epicatechin reduced cell viability of HT1080 cells only moderately. A single dose of 300 mg pycnogenol given to 10 healthy adults produced plasma samples that led to significant apoptotic cell death ex vivo whereas pycnogenol-negative serum displayed no apoptotic activity. Microarray analysis revealed remarkable expression changes induced by pycnogenol in a variety of genes, which are involved in different apoptotic pathways of cancer cells [Janus kinase 1 (JAK1), DUSP1, RHOA, laminin γ1 (LAMC1), fibronectin 1 (FN1), catenin α1 (CTNNA1), ITGB1]. In conclusion, metabolised pycnogenol induces apoptosis in human fibrosarcoma cells. Pycnogenol exhibits its pro-apoptotic activity as a mixture and is more effective than its main constituents catechin, epicatechin and taxifolin indicating that the metabolised components interact synergistically. These results provide experimental support for in vivo trials assessing the effect of the pine bark extract pycnogenol.

Ductal pancreatic adenocarcinoma.

BACKGROUND: Ductal adenocarcinoma of the pancreas is the fourth most common cause of death from cancer in men and women in Germany: about 15 000 persons die of this disease each year. METHOD: The S3 guideline on exocrine pancreatic carcinoma was updated with the aid of systematic literature reviews on the surgical, neoadjuvant, and adjuvant treatment of ductal pancreatic carcinoma, and on treatment in the metastatic stage. These reviews covered the periods 2002 to February 2012 (for radiotherapy) and 2006 to August 2011 (for all other topics). RESULTS: The criteria for borderline resectable pancreatic tumors are the same as those of the guidelines of the National Comprehensive Cancer Network. Preoperative biliary drainage with a stent is recommended only if cholangitis is present or if a planned operation cannot be performed soon after the diagnosis is made. When a pancreatic carcinoma is resected, at least 10 regional lymph nodes should be excised, and the ratio of affected to excised nodes should be documented in the pathology report. Gemcitabine and 5-fluorouracil are recommended for adjuvant therapy. Neither of these drugs is preferred over the other; if the one initially given is poorly tolerated, the other one should be given instead. When gemcitabine and erlotinib are given for palliative treatment, erlotinib should be given for no longer than 8 weeks if no skin rash develops. In selected patients, the folfirinox protocol yields markedly better results than gemcitabin. Moreover, the new combination of nab-paclitaxel and gemcitabine can be used as first-line treatment. In the event of disease progression under first-line treatment, second-line treatment should be initiated. CONCLUSION: In recent years, new chemotherapeutic protocols have brought about marked improvement in palliative care. Further trials are needed to determine whether the perioperative or adjuvant use of these protocols might also improve the outcome of surgical treatment with curative intent.

Sustained partial remission of metastatic pancreatic cancer following systemic chemotherapy with gemcitabine and oxaliplatin plus adjunctive treatment with mistletoe extract.

BACKGROUND: The clinical prognosis of metastatic pancreatic cancer is very poor, with a median survival time of such patients ranging from 3 to 6 months. Current chemotherapy regimens include the combination of oxaliplatin and gemcitabine. CASE REPORT: A 43-year-old woman was diagnosed with pancreatic adenocarcinoma spreading into the regional lymph nodes and into multiple liver segments (pT3, pN1, pM1). Upon diagnosis, she underwent a pylorus-preserving pancreatic head resection, including dissection of regional lymph nodes and atypical resection of a single liver segment, followed by 9 cycles of palliative chemotherapy with gemcitabine and oxaliplatin. 37 weeks after surgery, the patient demonstrated a sustained partial remission, and the chemotherapy was stopped. Surprisingly, 10 months later, she still showed no evidence of tumor progression. Since the time of pancreatic surgery, the patient had taken mistletoe extracts and this adjunctive treatment has been continued until now. CONCLUSIONS: Cases of sustained long-term remission of metastatic pancreatic cancer are extremely rare. Although this single case observation does not allow for firm conclusions regarding potential mechanisms, the adjunctive therapy with mistletoe extracts might have played a role. Therefore, the clinical effects of such treatment in patients with pancreatic cancer warrant further investigation.

Selective amino acid deficiency in patients with impaired glucose tolerance and type 2 diabetes.

INTRODUCTION: Amino acids are important modulators of glucose metabolism, insulin secretion and insulin sensitivity. However, little is known about the changes in amino acid metabolism in patients with diabetes. PATIENTS AND METHODS: The circulating amino acid levels were determined in 17 patients with type 2 diabetes, 17 individuals with impaired glucose tolerance (IGT), and 14 control subjects. RESULTS: Total amino acid concentrations were 2850+/-57micromol/l in patients with type 2 diabetes, 2980+/-77micromol/l in individuals with IGT, and 2886+/-74micromol/l in control subjects (p=0.38). Patients with type 2 diabetes exhibited significant reductions in the concentrations of gamma-aminobutyric acid (GABA), arginine, glutamine and phosphoethanolamine (p<0.05), whereas valine levels were higher than in controls (p=0.008). In IGT subjects, GABA levels were reduced, while tyrosine concentrations were increased (p<0.05). The plasma levels of essential amino acids were positively related to fasting and post-challenge glucose levels, fasting C-peptide, HOMA insulin resistance and fasting glucagon levels (p<0.05). CONCLUSIONS: Total amino acid levels are similar in patients with diabetes, IGT subjects and controls, but the individual levels of several amino acids differ significantly between these groups. These alterations may contribute to the disturbances in insulin secretion and action in diabetic patients and may provide a rationale for offering specific amino acid supplementations to diabetic patients.

Amino acid malnutrition in patients with chronic pancreatitis and pancreatic carcinoma.

OBJECTIVES: Chronic pancreatitis (CP) and pancreatic cancer (CA) have been associated with intestinal malabsorption and inflammation. However, little is known about the changes in amino acid metabolism in such patients. METHODS: The circulating amino acid levels were determined in 12 patients with CP, 12 CA patients, and 12 controls. RESULTS: Total amino acid concentrations were 2850 +/- 71 micromol/L in controls, 2640 +/- 96 micromol/L in CP patients, and 2210 +/- 123 micromol/L in CA patients (P < 0.001). In CP patients, significant reductions in the concentrations of citrulline, gamma-aminobutyric acid, taurine, and aspartic acid were found (P < 0.05), whereas in CA patients, the levels of phosphoethanolamine, gamma-aminobutyric acid, aspartic acid, taurine, arginine, threonine, alanine, citrulline, and tryptophan were reduced. There was a significant inverse relationship between the total amino acid levels and the white blood cell counts (r = -0.44, P = 0.008). CONCLUSIONS: Both patients with CP and with CA exhibit alterations in amino acid levels. The mechanisms underlying these defects may involve intestinal malabsorption as well as systemic inflammation. Providing selective amino acid supplementation to such patients may minimize the excess morbidity and mortality associated with protein malnutrition.

The effect of synacthen on acute necrotizing pancreatitis in rats.

OBJECTIVES: This study investigates the hypothesis that an adrenocorticotropic hormone-analog therapy may ameliorate relative adrenal insufficiency in the early phase of acute necrotizing pancreatitis (NP) by boosting endogenous glucocorticoid production. METHODS: Forty Wistar rats with taurocholate-induced NP were divided into 5 groups: the first group received low-dose Synacthen (0.5 mg/kg); the second, high-dose Synacthen (5mg/kg); the third,low-dose cortisol (10 mg/kg); the fourth, high-dose cortisol (100 mg/kg); and the fifth, the control group, received no treatment. All animals were killed after 6 hours: concentrations of plasma corticosterone, interleukin 1 (IL-1), IL-6, IL-10, tumor necrosis factor alpha, amylase, and lipase in ascites, myeloperoxidase activity in the pancreas, and a histological score were evaluated. RESULTS: Corticosterone increased neither in the low-dose nor in the high-dose Synacthen group. Synacthen did not improve the early course of NP in terms of laboratory and histological results. A reduction of pancreatic necrosis and inflammation was observed in the low-dose cortisol group. CONCLUSIONS: Endogenous glucocorticoid release seemed to be at its maximum during the early stage of NP and could not be further increased by Synacthen. Low-dose exogenous cortisol ameliorated the disease. These findings support the existence of relative adrenal insufficiency in the early phase of acute NP.

Synergistic apoptotic effects of taurolidine and TRAIL on squamous carcinoma cells of the esophagus.

The treatment of choice for esophageal cancer is considered surgical resection, but a median survival of around 20 months after treatment is still discouraging. The value of adjuvant or neoadjuvant radiation or chemotherapy is limited and to date, benefits have only been described for certain tumor stages. Therefore, new therapeutic options are required. As alternative chemotherapeutics, we tested the antibiotic taurolidine (TRD) on KYSE 270 human esophageal carcinoma cells alone and in combination with rhTRAIL (TNF related apoptosis-inducing ligand). Viability, apoptosis and necrosis were visualized by TUNEL assay and quantitated by FACS analysis. Gene expression was analysed by RNA microarray. The most effective concentration of TRD as single substance (250 micromol/l) induced apoptosis to a maximum of 40% after 12-h dose dependently, leaving 4% viable cells after 48 h; by comparison, rhTRAIL did not have a significant effect. The combination of both substances doubled the effect of TRD alone. Gene expression profiling revealed that TRD downregulated endogenous TRAIL, TNFRSF1A, TRADD, TNFRSF1B, TNFRSF21, FADD, as well as MAP2K4, JAK2 and Bcl2, Bcl2l1, APAF1 and caspase-3. TNFRSF25, cytochrome-c, caspase-1, -8, -9, JUN, GADD45A and NFKBIA were upregulated. TRAIL reduced endogenous TRAIL, Bcl2l1 and caspase-1 expression. BIRC2, BIRC3, TNFAIP3, and NFKBIA were upregulated. The combined substances upregulated endogenous TRAIL, NFKBIA and JUN, whereas DFFA and TRAF3 were downregulated compared to TRD as single substance. We conclude that TRD overcomes TRAIL resistance in KYSE 270 cells. Synergistic effects are dependent on the same and on distinct apoptotic pathways which, jointly triggered, result in an amplified response. Several apoptotic pathways, including the TNF-receptor associated and the mitochondrial pathway, were differentially regulated by the substances on gene expression level. Additionally transcription factors seem to be influenced, NFKB in particular. Endogenous TRAIL expression is increased by the combination of substances, whereas it is reduced by each single substance. Taking into consideration that the non-toxic TRD was able to reduce rhTRAIL toxicity and dose, combined therapy with TRD and rhTRAIL may offer new options for treatment in esophageal cancer.

Fecal incontinence: an up-to-date critical overview of surgical treatment options.

BACKGROUND: Surgery is the last resort for patients suffering from severe fecal incontinence. The armamentarium of surgical options for this condition has increased impressively during the last decade. Nevertheless, this fact seems to make neither patients nor surgeons feel more comfortable. Treatment of fecal incontinence still remains a challenge to modern medicine due to many specific sides of this problem. AIMS: This article gives an up-to-date overview of existing operative treatment options. METHODS: An unbiased review of relevant literature was performed to assess the role of all methods of surgical treatment for fecal incontinence available nowadays. RESULTS: Recent studies have shown poor late results after primary sphincter repair and low predictive value for most preoperative diagnostic tests. New surgical options such as artificial devices and electrically stimulated muscle transpositions are doomed by low success rates and unacceptably frequent complications. That is why current attention has focused on non- or minimally invasive therapies such as sacral nerve stimulation and temperature-controlled radio-frequency energy delivery to the anal canal. However, all these innovative techniques remain experimental till enough high-evidence data are gathered for their objective evaluation. CONCLUSION: Careful and detailed preoperative assessment to exactly determine the etiology of incontinence and individual approach remain the cornerstones of surgical treatment of fecal incontinence nowadays.