Benefits on quality of life concomitant to metabolic improvement in intervention program for prevention of diabetes mellitus

To evaluate whether an interdisciplinary intervention program on lifestyle results in better quality of life (QoL) and lower frequencies of depression and binge eating disorder (BED) in individuals at risk for type 2 diabetes mellitus. A total of 177 individuals (32.2% men, age 55.4 +/- A 12.5 years) at risk for diabetes were allocated to a 9-month traditional (TI) or intensive interdisciplinary intervention (II) on dietary habits and physical activity including psychoeducative groups. They were submitted to questionnaires and clinical and laboratory examinations. Predictors of non-adherence were analyzed by logistic regression. Only individuals submitted to II had blood pressure and plasma glucose levels reduced. Frequencies of depression reduced in both interventions but of BED only in II (28.0-4.0%, P < 0.001). Increments in the scores of SF-36 domains (physical functioning: 11.1 +/- A 14.0 vs. 5.3 +/- A 13.0, role-emotional: 20.4 +/- A 40.2 vs. 6.2 +/- A 43.8, P = 0.05) were greater in the II than in TI, respectively. Changes in SF-36 correlated with decreases in anthropometry, blood pressure and glucose levels, depression and BED scores. Male gender was independently associated with non-adherence to the II. In addition to metabolic benefits, an interdisciplinary approach may induce desirable extrametabolic effects, favoring the control of psychiatric disorders and improving the QoL of individuals at risk for diabetes.

Measures of quality of life in children with cochlear implant: systematic review

The use of cochlear implant (CI) in children enables the development of listening and communication skills, allowing the child's progress in school and to be able to obtain, maintain and carry out an occupation. However, the progress after the CI has different results in some children, because many children are able to interact and participate in society, while others develop limited ability to communicate verbally. The need for a better understanding of CI outcomes, besides hearing and language benefits, has spurred the inclusion of quality of life measurements (QOL) to assess the impact of this technology. OBJECTIVE: Identify the key aspects of quality of life assessed in children with cochlear implant. METHOD: Through a systematic literature review, we considered publications from the period of 2000 to 2011. CONCLUSION: We concluded that QOL measurements in children include several concepts and methodologies. When referring to children using CI, results showed the challenges in broadly conceptualizing which quality of life domains are important to the child and how these areas can evolve during development, considering the wide variety of instruments and aspects evaluated.

Questionnaire for monitoring auditory and language development in the first year of life

Purpose: To validate a monitoring questionnaire about hearing and language development applied by community health agents in the first year of life. Methods: Seventy six community health agents, previously trained on infant hearing health, administered a questionnaire to the families of 304 children with ages from 0 to 1 year. The questionnaire contains questions regarding hearing and language development and, for all age groups, the question “Does your child hear well?” was presented. The validity of the questionnaire was assessed by analyzing false positive and false negative rates of the identified children. A double-blind study was conducted so that all children assessed by the questionnaire were submitted to hearing evaluation performed by audiologists. Results: Four children (1.32%) were diagnosed with sensorineural hearing loss (two unilateral), and 69 (22.7%) with conductive hearing loss. The monitoring questionnaire showed specificity of 96% and sensitivity of 67%, with a false-negative rate of 33% for not identifying the unilateral hearing loss, and a false-positive rate of 4%. Conclusion: The questionnaire used has shown to be feasible and relevant to actions of the community health agents of the Family Health Strategy program, with high specificity and moderate sensitivity. The use of the validated instrument should be considered to complement Newborn Hearing Screening Programs, in order to identify late onset or acquired hearing loss.

Effect of loss of CDKL5 on brain development in a new Cdkl5 knockout mouse model

Rett's Syndrome (RTT) is a severe neurodevelopmental disorder, characterized by cognitive disability that appears in the first months/years of life. Recently, mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been detected in RTT patients characterized by early-onset seizures. CDKL5 is highly expressed in the brain starting from early postnatal stages to adulthood, suggesting the importance of this kinase for proper brain maturation and function. However, the role/s of CDKL5 in brain development and the molecular mechanisms whereby CDKL5 exerts its effects are still largely unknown. In order to characterize the role of CDKL5 on brain development, we created a mice carrying a targeted conditional knockout allele of Cdkl5. A first behavioral characterization shows that Cdkl5 knockout mice recapitulate several features that mimic the clinical features described in CDKL5 patients and are a useful tool to investigate phenotypic and functional aspects of Cdkl5 loss. We used the Cdkl5 knockout mouse model to dissect the role of CDKL5 on hippocampal development and to establish the mechanism/s underlying its actions. We found that Cdkl5 knockout mice showed increased precursor cell proliferation in the hippocampal dentate gyrus. Interestingly, this region was also characterized by an increased rate of apoptotic cell death that caused a reduction in the final neuron number in spite of the proliferation increase. Moreover, loss of Cdkl5 led to decreased dendritic development of new generated granule cells. Finally, we identified the Akt/GSK3-beta signaling as a target of Cdkl5 in the regulation of neuronal precursor proliferation, survival and maturation. Overall our findings highlight a critical role of CDKL5/AKT/GSK3-beta signaling in the control of neuron proliferation, survival and differentiation and suggest that CDKL5-related alterations of these processes during brain development underlie the neurological symptoms of the CDKL5 variant of RTT.

Prosthetic Rehabilitation, Implant Survival and Quality of Life 2 to 5 Years after Resection of Oral Tumors

Background: After oral tumor resection, structural and functional rehabilitation by means of dental prostheses is complex, and positive treatment outcome is not always predictable. Purpose: The objective of the study was to report on oral rehabilitation and quality of life 2-5 years after resection of malignant oral tumors. Materials and Methods: Data of 46 patients (57 ± 7 years) who underwent oral tumor surgery were available. More than 50% of tumors were classified T3 or T4. Open oro-nasal defects resulted in 12 patients and full mandibulary block resections in 23 patients. Comprehensive planning, implant placement, and prosthetic rehabilitation followed an interdisciplinary protocol. Analysis comprised tumor location, type of prostheses, implant survival, and quality of life. Results: Because of advanced tumor status, resections resulted in marked alteration of the oral anatomy requiring complex treatment procedures. Prosthetic rehabilitation comprised fixed and removable prostheses, with 104 implants placed in 28 patients (60%). Early implant loss was high (13%) and cumulative survival rate of loaded implants was <90% after 5 years. Prosthetic plans had to be modified because of side effects of tumor therapy, complications with implants and tumor recurrence. The majority of patients rated quality of life favorable, but some experienced impaired swallowing, dry mouth, limited mouth opening, appearance, and soreness. Conclusions: Some local effects of tumor therapy could not be significantly improved by prosthetic rehabilitation leading to functional and emotional disability. Many patients had passed away or felt too ill to fill the questionnaires. This case series confirms the complex anatomic alterations after tumor resection and the need for individual treatment approaches especially regarding prosthesis design. In spite of disease-related local and general restrictions, most patients gave a positive assessment of quality of life.

[On quality of life after surgical therapy of oral cancer - a retrospective multi-center study: the connection between dedentition, denture, quality of life, and dysphagia, and the resulting rehabilitation schemes]

PURPOSE: The surgical treatment of oral cancer results in functional and aesthetical impairments. Patients' quality of life is considerably impaired by oral symptoms resulting from therapy of oral cancer. In many cases the inevitable resection of the tumor, as well as the adjuvant radiochemotherapy will cause the destruction of physiologically and anatomically important structures. One focus of research was the specific rehabilitation of dental loss by functional dentures. Another was the course of 19 impairments (comprehension of speech for unknown others, comprehension of speech for familiar others, eating/swallowing, mobility of the tongue, opening range of the mouth, mobility of lower jaw, mobility of neck, mobility of arms and shoulders, sense of taste, sense of smell, appearance, strength, appetite, respiration, pain, swelling, xerostomia, halitosis). METHODS: Commissioned by the German, Austrian and Swiss cooperative group on tumors of the maxillofacial region (DOSAK), data were collected in 3.894 questionnaires at 43 hospitals in Germany, Austria and Switzerland. The catalogue comprised 147 items in 9 chapters. At the end of the enquiry, 1.761 anonymous questionnaires were returned by 38 hospitals. 1.652 of these could be evaluated regarding the question. RESULTS: The sum score of the 19 impairments was highly increased immediately after the operation and recovered over the next 6 months, without, however, reaching the pre-surgery level. Of 1.652 patients, only 35% did not lose any teeth during therapy. 23% lost up to 5, 17% up to 10 teeth. A quarter of the patients lost more than 10 teeth. The more teeth were lost, the greater the decline of quality of life (p < or = 0.001), although this could be allayed by the functionality of the dentures (p < or = 0.001). There is a reciprocal dependence between the functionality of dental prosthetics and impairment by eating/swallowing (p < or = 0.001). CONCLUSIONS: Patients' quality of life after radical surgery of a carcinoma of the oral cavity depends not only on the functionality of dentures and the specificity of rehabilitation, but also from the initial findings, the extent and location of the resection, the chosen therapy, the general circumstances of the patient's life as well as their strategies of coping. These factors, however, unlike those of functionality of dental prosthesis and rehabilitation, are not modifiable.

Intermediate results of health related quality of life after vertical banded gastroplasty

OBJECTIVES: The purpose of this study is to evaluate (a) health-related quality of life (HRQL) after vertical banded gastroplasty (VBG) (Mason) and (b) predictors of HRQL. SUBJECTS: Eighty-two consecutive patients were assessed preoperatively and then after 6, 12 and 24 months. Patients filled out questionnaires for subjective appraisal of HRQL (physical well-being, mood, physical performance, perceived health, social support and coping/adjustment). RESULTS: The greatest improvement in weight and HRQL was seen within 6 months of surgery. Twenty-four months after VBG weight reduction (P<0.05), perceived health (P<0.05), physical well-being (P<0.05), physical performance (P<0.05), mood (P<0.05), coping/adjustment (P<0.05) continued to be better than before surgery. Preoperative binge eating was the most important predictor of HRQL. CONCLUSION: Two years after VBG weight loss and a significant improvement of HRQL can be found. HRQL and weight loss are not associated in terms of outcome, indicating that weight loss alone may not be enough to improve HRQL.

Temporary neurological dysfunction after surgery of the thoracic aorta: a predictor of poor outcome and impaired quality of life

BACKGROUND: Transient neurological dysfunction (TND) consists of postoperative confusion, delirium and agitation. It is underestimated after surgery on the thoracic aorta and its influence on long-term quality of life (QoL) has not yet been studied. This study aimed to assess the influence of TND on short- and long-term outcome following surgery of the ascending aorta and proximal arch. METHODS: Nine hundred and seven patients undergoing surgery of the ascending aorta and the proximal aortic arch at our institution were included. Two hundred and ninety patients (31.9%) underwent surgery because of acute aortic dissection type A (AADA) and 617 patients because of aortic aneurysm. In 547 patients (60.3%) the distal anastomosis was performed using deep hypothermic circulatory arrest (DHCA). TND was defined as a Glasgow coma scale (GCS) value <13. All surviving patients had a clinical follow up and QoL was assessed with an SF-36 questionnaire. RESULTS: Overall in-hospital mortality was 8.3%. TND occurred in 89 patients (9.8%). As compared to patients without TND, those who suffered from TND were older (66.4 vs 59.9 years, p<0.01) underwent more frequently emergent procedures (53% vs 32%, p<0.05) and surgery under DHCA (84.3% vs 57.7%, p<0.05). However, duration of DHCA and extent of surgery did not influence the incidence of TND. In-hospital mortality in the group of patients with TND compared to the group without TND was similar (12.0% vs 11.4%; p=ns). Patients with TND suffered more frequently from coronary artery disease (28% vs 20.8%, p=ns) and were more frequently admitted in a compromised haemodynamic condition (23.6% vs 9.9%, p<0.05). Postoperative course revealed more pulmonary complications such as prolonged mechanical ventilation. Additional to their transient neurological dysfunction, significantly more patients had strokes with permanent neurological loss of function (14.6% vs 4.8%, p<0.05) compared to the patients without TND. ICU and hospital stay were significantly prolonged in TND patients (18+/-13 days vs 12+/-7 days, p<0.05). Over a mean follow-up interval of 27+/-14 months, patients with TND showed a significantly impaired QoL. CONCLUSION: The neurological outcome following surgery of the ascending aorta and proximal aortic arch is of paramount importance. The impact of TND on short- and long-term outcome is underestimated and negatively affects the short- and long-term outcome.

THE USE OF LIFE-CYCLE ANALYSIS TO REDUCE THE ENVIRONMENTAL IMPACT OF MATERIALS IN MANUFACTURING

This thesis is composed of three life-cycle analysis (LCA) studies of manufacturing to determine cumulative energy demand (CED) and greenhouse gas emissions (GHG). The methods proposed could reduce the environmental impact by reducing the CED in three manufacturing processes. First, industrial symbiosis is proposed and a LCA is performed on both conventional 1 GW-scaled hydrogenated amorphous silicon (a-Si:H)-based single junction and a-Si:H/microcrystalline-Si:H tandem cell solar PV manufacturing plants and such plants coupled to silane recycling plants. Using a recycling process that results in a silane loss of only 17 versus 85 percent, this results in a CED savings of 81,700 GJ and 290,000 GJ per year for single and tandem junction plants, respectively. This recycling process reduces the cost of raw silane by 68 percent, or approximately $22.6 and $79 million per year for a single and tandem 1 GW PV production facility, respectively. The results show environmental benefits of silane recycling centered around a-Si:H-based PV manufacturing plants. Second, an open-source self-replicating rapid prototype or 3-D printer, the RepRap, has the potential to reduce the environmental impact of manufacturing of polymer-based products, using distributed manufacturing paradigm, which is further minimized by the use of PV and improvements in PV manufacturing. Using 3-D printers for manufacturing provides the ability to ultra-customize products and to change fill composition, which increases material efficiency. An LCA was performed on three polymer-based products to determine the CED and GHG from conventional large-scale production and are compared to experimental measurements on a RepRap producing identical products with ABS and PLA. The results of this LCA study indicate that the CED of manufacturing polymer products can possibly be reduced using distributed manufacturing with existing 3-D printers under 89% fill and reduced even further with a solar photovoltaic system. The results indicate that the ability of RepRaps to vary fill has the potential to diminish environmental impact on many products. Third, one additional way to improve the environmental performance of this distributed manufacturing system is to create the polymer filament feedstock for 3-D printers using post-consumer plastic bottles. An LCA was performed on the recycling of high density polyethylene (HDPE) using the RecycleBot. The results of the LCA showed that distributed recycling has a lower CED than the best-case scenario used for centralized recycling. If this process is applied to the HDPE currently recycled in the U.S., more than 100 million MJ of energy could be conserved per annum along with significant reductions in GHG. This presents a novel path to a future of distributed manufacturing suited for both the developed and developing world with reduced environmental impact. From improving manufacturing in the photovoltaic industry with the use of recycling to recycling and manufacturing plastic products within our own homes, each step reduces the impact on the environment. The three coupled projects presented here show a clear potential to reduce the environmental impact of manufacturing and other processes by implementing complimenting systems, which have environmental benefits of their own in order to achieve a compounding effect of reduced CED and GHG.

Health-related quality of life in rural children living in four European countries: the GABRIEL study

OBJECTIVE Measuring children's health-related quality of life (HRQOL) is of growing importance given increasing chronic diseases. By integrating HRQOL questions into the European GABRIEL study, we assessed differences in HRQOL between rural farm and non-farm children from Germany, Austria, Switzerland and Poland to relate it to common childhood health problems and to compare it to a representative, mostly urban German population sample (KIGGS). METHODS The parents of 10,400 school-aged children answered comprehensive questionnaires including health-related questions and the KINDL-R questions assessing HRQOL. RESULTS Austrian children reported highest KINDL-R scores (mean: 80.9; 95 % CI [80.4, 81.4]) and Polish children the lowest (74.5; [73.9, 75.0]). Farm children reported higher KINDL-R scores than non-farm children (p = 0.002). Significantly lower scores were observed in children with allergic diseases (p < 0.001), with sleeping difficulties (p < 0.001) and in overweight children (p = 0.04). The German GABRIEL sample reported higher mean scores (age 7-10 years: 80.1, [79.9, 80.4]; age 11-13 years: 77.1, [74.9, 79.2]) compared to the urban KIGGS study (age 7-10 years: 79.0, [78.7-79.3]; age 11-13 years: 75.1 [74.6-75.6]). Socio-demographic or health-related factors could not explain differences in HRQOL between countries. CONCLUSIONS Future increases in chronic diseases may negatively impact children's HRQOL.

Loss of TRAIL-receptors is a recurrent feature in pancreatic cancer and determines the prognosis of patients with no nodal metastasis after surgery

INTRODUCTION Agonistic antibodies targeting TRAIL-receptors 1 and 2 (TRAIL-R1 and TRAIL-R2) are being developed as a novel therapeutic approach in cancer therapy including pancreatic cancer. However, the cellular distribution of these receptors in primary pancreatic cancer samples has not been sufficiently investigated and no study has yet addressed the issue of their prognostic significance in this tumor entity. AIMS AND METHODS Applying tissue microarray (TMA) analysis, we performed an immunohistochemical assessment of TRAIL-receptors in surgical samples from 84 consecutive patients affected by pancreatic adenocarcinoma and in 26 additional selected specimens from patients with no lymph nodes metastasis at the time of surgery. The prognostic significance of membrane staining and staining intensity for TRAIL-receptors was evaluated. RESULTS The fraction of pancreatic cancer samples with positive membrane staining for TRAIL-R1 and TRAIL-R2 was lower than that of cells from surrounding non-tumor tissues (TRAIL-R1: p<0.001, TRAIL-R2: p = 0.006). In addition, subgroup analyses showed that loss of membrane staining for TRAIL-R2 was associated with poorer prognosis in patients without nodal metastases (multivariate Cox regression analysis, Hazard Ratio: 0.44 [95% confidence interval: 0.22-0.87]; p = 0.019). In contrast, analysis of decoy receptors TRAIL-R3 and -R4 in tumor samples showed an exclusively cytoplasmatic staining pattern and no prognostic relevance. CONCLUSION This is a first report on the prognostic significance of TRAIL-receptors expression in pancreatic cancer showing that TRAIL-R2 might represent a prognostic marker for patients with early stage disease. In addition, our data suggest that loss of membrane-bound TRAIL-receptors could represent a molecular mechanism for therapeutic failure upon administration of TRAIL-receptors-targeting antibodies in pancreatic cancer. This hypothesis should be evaluated in future clinical trials.

Loss of p53 in enterocytes generates an inflammatory microenvironment enabling invasion and lymph node metastasis of carcinogen-induced colorectal tumors

Loss of p53 is considered to allow progression of colorectal tumors from the adenoma to the carcinoma stage. Using mice with an intestinal epithelial cell (IEC)-specific p53 deletion, we demonstrate that loss of p53 alone is insufficient to initiate intestinal tumorigenesis but markedly enhances carcinogen-induced tumor incidence and leads to invasive cancer and lymph node metastasis. Whereas p53 controls DNA damage and IEC survival during the initiation stage, loss of p53 during tumor progression is associated with increased intestinal permeability, causing formation of an NF-κB-dependent inflammatory microenvironment and the induction of epithelial-mesenchymal transition. Thus, we propose a p53-controlled tumor-suppressive function that is independent of its well-established role in cell-cycle regulation, apoptosis, and senescence.

Loss of Cdx2 Expression in Primary Tumors and Lymph Node Metastases is Specific for Mismatch Repair-Deficiency in Colorectal Cancer

Background: Approximately 20% of all colorectal cancers are hypothesized to arise from the "serrated pathway" characterized by mutation in BRAF, high-level CpG Island Methylator Phenotype, and microsatellite instability/mismatch repair (MMR)-deficiency. MMR-deficient cancers show frequent losses of Cdx2, a homeodomain transcription factor. Here, we determine the predictive value of Cdx2 expression for MMR-deficiency and investigate changes in expression between primary cancers and matched lymph node metastases. Methods: Immunohistochemistry for Cdx2, Mlh1, Msh2, Msh6, and Pms2 was performed on whole tissue sections from 201 patients with primary colorectal cancer and 59 cases of matched lymph node metastases. Receiver operating characteristic curve analysis and Area under the Curve (AUC) were investigated; association of Cdx2 with clinicopathological features and patient survival was carried out. Results: Loss of Cdx2 expression was associated with higher tumor grade (p = 0.0002), advanced pT (p = 0.0166), and perineural invasion (p = 0.0228). Cdx2 loss was an unfavorable prognostic factor in univariate (p = 0.0145) and multivariate [p = 0.0427; HR (95% CI): 0.58 (0.34-0.98)] analysis. The accuracy (AUC) for discriminating MMR-proficient and - deficient cancers was 87% [OR (95% CI): 0.96 (0.95-0.98); p < 0.0001]. Specificity and negative predictive value for MMR-deficiency was 99.1 and 96.3%. One hundred and seventy-four patients had MMR-proficient cancers, of which 60 (34.5%) showed Cdx2 loss. Cdx2 loss in metastases was related to MMR-deficiency (p < 0.0001). There was no difference in expression between primary tumors and matched metastases. Conclusion: Loss of Cdx2 is a sensitive and specific predictor of MMR-deficiency, but is not limited to these tumors, suggesting that events "upstream" of the development of microsatellite instability may impact Cdx2 expression.

Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors

BACKGROUND & AIMS Sporadic pancreatic neuroendocrine tumors (pNETs) are rare and genetically heterogeneous. Chromosome instability (CIN) has been detected in pNETs from patients with poor outcomes, but no specific genetic factors have been associated with CIN. Mutations in death domain-associated protein gene (DAXX) or ATR-X gene (ATRX) (which both encode proteins involved in chromatin remodeling) have been detected in 40% of pNETs, in association with activation of alternative lengthening of telomeres. We investigated whether loss of DAXX or ATRX, and consequent alternative lengthening of telomeres, are related to CIN in pNETs. We also assessed whether loss of DAXX or ATRX is associated with specific phenotypes of pNETs. METHODS We collected well-differentiated primary pNET samples from 142 patients at the University Hospital Zurich and from 101 patients at the University Hospital Bern (both located in Switzerland). Clinical follow-up data were obtained for 149 patients from general practitioners and tumor registries. The tumors were reclassified into 3 groups according to the 2010 World Health Organization classification. Samples were analyzed by immunohistochemistry and telomeric fluorescence in situ hybridization. We correlated loss of DAXX, or ATRX, expression, and activation of alternative lengthening of telomeres with data from comparative genomic hybridization array studies, as well as with clinical and pathological features of the tumors and relapse and survival data. RESULTS Loss of DAXX or ATRX protein and alternative lengthening of telomeres were associated with CIN in pNETs. Furthermore, loss of DAXX or ATRX correlated with tumor stage and metastasis, reduced time of relapse-free survival, and decreased time of tumor-associated survival. CONCLUSIONS Loss of DAXX or ATRX is associated with CIN in pNETs and shorter survival times of patients. These results support the hypothesis that DAXX- and ATRX-negative tumors are a more aggressive subtype of pNET, and could lead to identification of strategies to target CIN in pancreatic tumors.

Loss of Raf-1 kinase inhibitor protein (RKIP) is strongly associated with high-grade tumor budding and correlates with an aggressive phenotype in pancreatic ductal adenocarcinoma (PDAC)

BACKGROUND Raf-1 kinase inhibitor protein (RKIP) has emerged as a significant metastatic suppressor in a variety of human cancers and is known to inhibit Ras/Raf/MEK/ERK signaling. By suppressing the activation of the NFkB/SNAIL circuit, RKIP can regulate the induction of epithelial-mesenchymal transition (EMT). The aim of this study was to evaluate RKIP expression and to determine its association with clinicopathological features, including EMT in form of tumor budding in pancreatic ductal adenocarcinoma (PDAC). METHODS Staining for RKIP was performed on a multipunch Tissue Microarray (TMA) of 114 well-characterized PDACs with clinico-pathological, follow-up and adjuvant therapy information. RKIP-expression was assessed separately in the main tumor body and in the tumor buds. Another 3 TMAs containing normal pancreatic tissue, precursor lesions (Pancreatic Intraepithelial Neoplasia, PanINs) and matched lymph node metastases were stained in parallel. Cut-off values were calculated by receiver operating characteristic (ROC) curve analysis. RESULTS We found a significant progressive loss of RKIP expression between normal pancreatic ductal epithelia (average: 74%), precursor lesions (PanINs; average: 37%), PDAC (average 20%) and lymph node metastases (average 8%, p<0.0001). RKIP expression was significantly lower in tumor buds (average: 6%) compared to the main tumor body (average 20%; p<0.005). RKIP loss in the tumor body was marginally associated with advanced T-stage (p=0.0599) as well as high-grade peritumoral (p=0.0048) and intratumoral budding (p=0.0373). RKIP loss in the buds showed a clear association with advanced T stage (p=0.0089). CONCLUSIONS The progressive loss of RKIP seems to play a major role in the neoplastic transformation of pancreas, correlates with aggressive features in PDAC and is associated with the presence of EMT in form of tumor budding.