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3. Immediate surgery compared with short-course neoadjuvant gemcitabine plus capecitabine, FOLFIRINOX, or chemoradiotherapy in patients with borderline resectable pancreatic cancer (ESPAC5): a four-arm, multicentre, randomised, phase 2 trial

Author

Ghaneh, P., Palmer, D., Cicconi, S., Jackson, R., Halloran, C. M., Rawcliffe, C., Sripadam, R., Mukherjee, S., Soonawalla, Z., Wadsley, J., Al-Mukhtar, A., Dickson, E., Graham, J., Jiao, L., Wasan, H. S., Tait, I. S., Prachalias, A., Ross, P., Valle, J. W., O'Reilly, D. A., Al-Sarireh, B., Gwynne, S., Ahmed, I., Connolly, K., Yim, K. L., Cunningham, D., Armstrong, T., Archer, C., Roberts, K., Ma, Y. T., Springfeld, C., Tjaden, C., Hackert, T., Büchler, M. W., Neoptolemos, J. P., and European Study Group for Pancreatic Cancer

Subjects
Hepatology, Gastroenterology
Abstract

BACKGROUND: Patients with borderline resectable pancreatic ductal adenocarcinoma have relatively low resection rates and poor survival despite the use of adjuvant chemotherapy. The aim of our study was to establish the feasibility and efficacy of three different types of short-course neoadjuvant therapy compared with immediate surgery. METHODS: ESPAC5 (formerly known as ESPAC-5f) was a multicentre, open label, randomised controlled trial done in 16 pancreatic centres in two countries (UK and Germany). Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, biopsy proven pancreatic ductal adenocarcinoma in the pancreatic head, and were staged as having a borderline resectable tumour by contrast-enhanced CT criteria following central review. Participants were randomly assigned by means of minimisation to one of four groups: immediate surgery; neoadjuvant gemcitabine and capecitabine (gemcitabine 1000 mg/m(2) on days 1, 8, and 15, and oral capecitabine 830 mg/m(2) twice a day on days 1-21 of a 28-day cycle for two cycles); neoadjuvant FOLFIRINOX (oxaliplatin 85 mg/m(2), irinotecan 180 mg/m(2), folinic acid given according to local practice, and fluorouracil 400 mg/m(2) bolus injection on days 1 and 15 followed by 2400 mg/m(2) 46 h intravenous infusion given on days 1 and 15, repeated every 2 weeks for four cycles); or neoadjuvant capecitabine-based chemoradiation (total dose 50.4 Gy in 28 daily fractions over 5.5 weeks [1.8 Gy per fraction, Monday to Friday] with capecitabine 830 mg/m(2) twice daily [Monday to Friday] throughout radiotherapy). Patients underwent restaging contrast-enhanced CT at 4-6 weeks after neoadjuvant therapy and underwent surgical exploration if the tumour was still at least borderline resectable. All patients who had their tumour resected received adjuvant therapy at the oncologist's discretion. Primary endpoints were recruitment rate and resection rate. Analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN, 89500674, and is complete. FINDINGS: Between Sept 3, 2014, and Dec 20, 2018, from 478 patients screened, 90 were randomly assigned to a group (33 to immediate surgery, 20 to gemcitabine plus capecitabine, 20 to FOLFIRINOX, and 17 to capecitabine-based chemoradiation); four patients were excluded from the intention-to-treat analysis (one in the capecitabine-based chemoradiotherapy withdrew consent before starting therapy and three [two in the immediate surgery group and one in the gemcitabine plus capecitabine group] were found to be ineligible after randomisation). 44 (80%) of 55 patients completed neoadjuvant therapy. The recruitment rate was 25.92 patients per year from 16 sites; 21 (68%) of 31 patients in the immediate surgery and 30 (55%) of 55 patients in the combined neoadjuvant therapy groups underwent resection (p=0.33). R0 resection was achieved in three (14%) of 21 patients in the immediate surgery group and seven (23%) of 30 in the neoadjuvant therapy groups combined (p=0.49). Surgical complications were observed in 29 (43%) of 68 patients who underwent surgery; no patients died within 30 days. 46 (84%) of 55 patients receiving neoadjuvant therapy were available for restaging. Six (13%) of 46 had a partial response. Median follow-up time was 12.2 months (95% CI 12.0-12.4). 1-year overall survival was 39% (95% CI 24-61) for immediate surgery, 78% (60-100) for gemcitabine plus capecitabine, 84% (70-100) for FOLFIRINOX, and 60% (37-97) for capecitabine-based chemoradiotherapy (p=0.0028). 1-year disease-free survival from surgery was 33% (95% CI 19-58) for immediate surgery and 59% (46-74) for the combined neoadjuvant therapies (hazard ratio 0.53 [95% CI 0.28-0.98], p=0.016). Three patients reported local disease recurrence (two in the immediate surgery group and one in the FOLFIRINOX group). 78 (91%) patients were included in the safety set and assessed for toxicity events. 19 (24%) of 78 patients reported a grade 3 or worse adverse event (two [7%] of 28 patients in the immediate surgery group and 17 [34%] of 50 patients in the neoadjuvant therapy groups combined), the most common of which were neutropenia, infection, and hyperglycaemia. INTERPRETATION: Recruitment was challenging. There was no significant difference in resection rates between patients who underwent immediate surgery and those who underwent neoadjuvant therapy. Short-course (8 week) neoadjuvant therapy had a significant survival benefit compared with immediate surgery. Neoadjuvant chemotherapy with either gemcitabine plus capecitabine or FOLFIRINOX had the best survival compared with immediate surgery. These findings support the use of short-course neoadjuvant chemotherapy in patients with borderline resectable pancreatic ductal adenocarcinoma. FUNDING: Cancer Research UK.

Published
2023

4. Morbus Crohn

Author

Tjaden, C., Hackert, T., Schmidt, J., Siewert, Jörg Rüdiger, editor, Rothmund, Matthias, editor, and Schumpelick, Volker, editor

Published
2011
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5. Morbus Crohn

Author

Tjaden, C., Hackert, T., Schmidt, J., Schumpelick, Volker, editor, Siewert, Jörg Rüdiger, editor, and Rothmund, Matthias, editor

Published
2006
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8. Interpersonal relations within the context of resource groups for people with severe mental illness: A narrative approach

Author

Tjaden, C. D., Boumans, J., Mulder, C. L., Kroon, H., Tjaden, C. D., Boumans, J., Mulder, C. L., and Kroon, H.

Abstract

Objective: The resource group method intends to promote patients' agency and self-management and to organize meaningful partnerships between patients and their informal and formal support systems. The aim of this study was to enhance the understanding of interpersonal dynamics that arise within resource groups for people with severe mental illness. Insight into these unfolding processes would enable improved implementation of the resource group method so that it contributes to establishing a positive social environment, which can lead to more enduring recovery. Methodology: We performed a narrative analysis of transcripts and field notes obtained in a longitudinal, qualitative study on the resource group method. The stories of four different resource groups were reconstructed and analyzed in depth. Data included a total of 36 interviews (with patients, significant others, and mental health professionals) and 18 observations of resource group meetings. Results: The degree to which the resource group method actually contributes to recovery was based on the extent to which the existing roles of and patterns between the patient and his/her resource group members were altered. Breaking through old patterns of inequality and the joint search for a new balance in relationships proved to be crucial processes for establishing an empowering resource group. The four cases showed that it takes time, patience, and small steps back and forth to overcome the struggles and fears related to finding new ways of relating to each other. An honest and reflective atmosphere in which all participants are encouraged to participate and be curious about themselves and each other is essential for changes in interpersonal dynamics to emerge. Such changes pave the way for individuals with SMI to find their own voices and pursue their unique recovery journeys. Conclusions: The functioning of the resource group and the ability of the involved members

Published
2021

9. Attachment as a framework to facilitate empowerment for people with severe mental illness

Author

Tjaden, C. D., Mulder, C. L., Delespaul, A. E. G., Arntz, A. R., Kroon, H., Tjaden, C. D., Mulder, C. L., Delespaul, A. E. G., Arntz, A. R., and Kroon, H.

Abstract

Objectives: Recovery and empowerment have evolved into key objectives in the treatment and care of people with severe mental illness (SMI), and interest has grown in the role of social relationships in recovery. This study is the first to explore whether attachment styles are related to levels of empowerment, and secondly, whether attachment anxiety and attachment avoidance are associated with lower empowerment levels, independently of quality and frequency of social contact. Design: We used a cross-sectional design. Methods: In a sample of 157 participants with SMI in outpatient care, associations between attachment (Revised Adult Attachment Scale), self-reported social functioning, and empowerment (Netherlands Empowerment List) were assessed. Results: Attachment anxiety and attachment avoidance were both associated with lower levels of empowerment. A stepwise multiple regression analysis showed that the prediction of empowerment was significantly improved by adding attachment anxiety and attachment avoidance to quality and frequency of social contact. Attachment anxiety, attachment avoidance, and quality of social contact were significant predictors; frequency of social contact was not. Conclusions: Although our design does not allow causal conclusions, our results highlight the importance of interpersonal processes and behaviours as routes to improving empowerment for people with SMI. A promising approach might thus consist of securing attachment bonds with significant others so that the self and the other are perceived as reliable resources. Our findings also feature the importance of reciprocity and equality in social relationships. Taken together, our study emphasizes the value of social, contextualized interventions in recovery work for people with SMI. Practitioner points: Working towards attachment safety in interpersonal relations may be important in recovery-oriented treatment and care for

Published
2021

11. ESPAC-5F: Four arm, international randomised phase II trial of immediate surgery compared with neoadjuvant gemcitabine plus capecitabine (GEMCAP) or FOLFIRINOX or chemoradiotherapy (CRT) in patients with borderline resectable pancreatic cancer

Author

Ghaneh, P., primary, Palmer, D., additional, Cicconi, S., additional, Halloran, C., additional, Psarelli, E., additional, Rawcliffe, C., additional, Sripadam, R., additional, Mukherjee, S., additional, Wadsley, J., additional, Al-Mukhtar, A., additional, Jiao, L., additional, Wasan, H., additional, Carter, R., additional, Graham, J., additional, Ammad, F., additional, Evans, J., additional, Tjaden, C., additional, Hackert, T., additional, Buchler, M., additional, and Neoptolemos, J., additional

Published
2020
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12. Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma

Author

Obazee, O., Archibugi, L., Andriulli, A., Soucek, P., Malecka-Panas, E., Ivanauskas, A., Johnson, T., Gazouli, M., Pausch, T., Lawlor, R. T., Cavestro, G. M., Milanetto, A. C., Di Leo, M., Pasquali, C., Hegyi, P., Szentesi, A., Radu, C. E., Gheorghe, C., Theodoropoulos, G. E., Bergmann, F., Brenner, H., Vodickova, L., Katzke, V., Campa, D., Strobel, O., Kaiser, J., Pezzilli, R., Federici, F., Mohelnikova-Duchonova, B., Boggi, U., Lemstrova, R., Johansen, J. S., Bojesen, S. E., Chen, I., Jensen, B. V., Capurso, G., Pazienza, V., Dervenis, C., Sperti, C., Mambrini, A., Hackert, T., Kaaks, R., Basso, D., Talar-Wojnarowska, R., Maiello, E., Izbicki, J. R., Cuk, K., Saum, K. U., Cantore, M., Kupcinskas, J., Palmieri, O., Delle Fave, G., Landi, S., Salvia, R., Fogar, P., Vashist, Y. K., Scarpa, A., Vodicka, P., Tjaden, C., Iskierka-Jazdzewska, E., Canzian, F., Obazee, O., Archibugi, L., Andriulli, A., Soucek, P., Malecka-Panas, E., Ivanauskas, A., Johnson, T., Gazouli, M., Pausch, T., Lawlor, R. T., Cavestro, G. M., Milanetto, A. C., Di Leo, M., Pasquali, C., Hegyi, P., Szentesi, A., Radu, C. E., Gheorghe, C., Theodoropoulos, G. E., Bergmann, F., Brenner, H., Vodickova, L., Katzke, V., Campa, D., Strobel, O., Kaiser, J., Pezzilli, R., Federici, F., Mohelnikova-Duchonova, B., Boggi, U., Lemstrova, R., Johansen, J. S., Bojesen, S. E., Chen, I., Jensen, B. V., Capurso, G., Pazienza, V., Dervenis, C., Sperti, C., Mambrini, A., Hackert, T., Kaaks, R., Basso, D., Talar-Wojnarowska, R., Maiello, E., Izbicki, J. R., Cuk, K., Saum, K. U., Cantore, M., Kupcinskas, J., Palmieri, O., Delle Fave, G., Landi, S., Salvia, R., Fogar, P., Vashist, Y. K., Scarpa, A., Vodicka, P., Tjaden, C., Iskierka-Jazdzewska, E., and Canzian, F.

Subjects
Male, Cancer Research, pancreatic cancer, Genes, BRCA2, I157T, Polymorphism, Single Nucleotide, Humans, Genetic Predisposition to Disease, Germ-Line Mutation, Aged, BRCA2 Protein, K3326X, PANDoRA consortium, rs11571833, rs17879961, Oncology, Pancreatic cancer, Middle Aged, Pancreatic Neoplasms, Checkpoint Kinase 2, Case-Control Studies, Female, Carcinoma, Pancreatic Ductal
Abstract

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values

Published
2018

13. Embracing the social nature of recovery: A longitudinal, qualitative, multi-perspective study on the resource group method for people with severe mental illness

Author

Tjaden, C. T., Boumans, J., Mulder, C. L., Kroon, H., Geestelijke Gezondheidszorg, and Tranzo, Scientific center for care and wellbeing

Abstract

Objective: The resource group method for people with severe mental illness might provide a useful framework to facilitate patient's empowerment and systematically engage significant others. However, no research has explored the perspectives and experiences of patients and their significant others. This is crucial for better adjustment to the needs of the people using the method. The aim of this study was to develop a useful framework for a deeper understanding of the resource group method and its outcomes. Method: The study used a longitudinal, qualitative multiple case-study design based on grounded theory methodology. During a period of 2 years, the developments and processes in eight resource groups were explored by conducting a total of 74 interviews (e.g., with patients, significant others, and mental health professionals) and 26 observations of resource group meetings. Results: Analysis showed that a well-functioning resource group set the stage for five processes to unfold: (i) experience of support; (ii) acknowledgment of significant others; (iii) activation; (iv) openness; and (v) integration. These processes facilitated recovery both in terms of an arousing curiosity within the patient as well as increasing reciprocity and equality in their social relations. In addition, the method emphasized the uniqueness of each recovery journey, thereby providing a framework to shape recovery-oriented care. The analysis also revealed three hindering factors: (i) embedding and implementation issues; (ii) predominant network; and (iii) tensions inherent in the resource group setting. Conclusion: Working according to the resource group method involves that the person's recovery work becomes a social process that takes place in relation to the social environment and everyday life in which it is important to acknowledge and integrate the needs of significant others in treatment and care. This study provides a first step toward a multidimensional comprehension of the resource group method, the working mechanisms and its influence on recovery for people with severe mental illness.

Published
2020

16. Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma

Author

Obazee, O. Archibugi, L. Andriulli, A. Soucek, P. Małecka-Panas, E. Ivanauskas, A. Johnson, T. Gazouli, M. Pausch, T. Lawlor, R.T. Cavestro, G.M. Milanetto, A.C. Di Leo, M. Pasquali, C. Hegyi, P. Szentesi, A. Radu, C.E. Gheorghe, C. Theodoropoulos, G.E. Bergmann, F. Brenner, H. Vodickova, L. Katzke, V. Campa, D. Strobel, O. Kaiser, J. Pezzilli, R. Federici, F. Mohelnikova-Duchonova, B. Boggi, U. Lemstrova, R. Johansen, J.S. Bojesen, S.E. Chen, I. Jensen, B.V. Capurso, G. Pazienza, V. Dervenis, C. Sperti, C. Mambrini, A. Hackert, T. Kaaks, R. Basso, D. Talar-Wojnarowska, R. Maiello, E. Izbicki, J.R. Cuk, K. Saum, K.U. Cantore, M. Kupcinskas, J. Palmieri, O. Delle Fave, G. Landi, S. Salvia, R. Fogar, P. Vashist, Y.K. Scarpa, A. Vodicka, P. Tjaden, C. Iskierka-Jazdzewska, E. Canzian, F.

Abstract

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values

Published
2019

18. Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma

Author

Obazee, O, Archibugi, L, Andriulli, A, Soucek, P, Małecka-Panas, E, Ivanauskas, A, Johnson, T, Gazouli, M, Pausch, T, Lawlor, R T, Cavestro, G M, Milanetto, A C, Di Leo, M, Pasquali, C, Hegyi, P, Szentesi, A, Radu, C E, Gheorghe, C, Theodoropoulos, G E, Bergmann, F, Brenner, H, Vodickova, L, Katzke, V, Campa, D, Strobel, O, Kaiser, J, Pezzilli, R, Federici, F, Mohelnikova-Duchonova, B, Boggi, U, Lemstrova, R, Johansen, J S, Bojesen, S E, Chen, I, Jensen, B V, Capurso, G, Pazienza, V, Dervenis, C, Sperti, C, Mambrini, A, Hackert, T, Kaaks, R, Basso, D, Talar-Wojnarowska, R, Maiello, E, Izbicki, J R, Cuk, K, Saum, K U, Cantore, M, Kupcinskas, J, Palmieri, O, Delle Fave, G, Landi, S, Salvia, R, Fogar, P, Vashist, Y K, Scarpa, A, Vodicka, P, Tjaden, C, Iskierka-Jazdzewska, E, Canzian, F, Obazee, O, Archibugi, L, Andriulli, A, Soucek, P, Małecka-Panas, E, Ivanauskas, A, Johnson, T, Gazouli, M, Pausch, T, Lawlor, R T, Cavestro, G M, Milanetto, A C, Di Leo, M, Pasquali, C, Hegyi, P, Szentesi, A, Radu, C E, Gheorghe, C, Theodoropoulos, G E, Bergmann, F, Brenner, H, Vodickova, L, Katzke, V, Campa, D, Strobel, O, Kaiser, J, Pezzilli, R, Federici, F, Mohelnikova-Duchonova, B, Boggi, U, Lemstrova, R, Johansen, J S, Bojesen, S E, Chen, I, Jensen, B V, Capurso, G, Pazienza, V, Dervenis, C, Sperti, C, Mambrini, A, Hackert, T, Kaaks, R, Basso, D, Talar-Wojnarowska, R, Maiello, E, Izbicki, J R, Cuk, K, Saum, K U, Cantore, M, Kupcinskas, J, Palmieri, O, Delle Fave, G, Landi, S, Salvia, R, Fogar, P, Vashist, Y K, Scarpa, A, Vodicka, P, Tjaden, C, Iskierka-Jazdzewska, E, and Canzian, F

Abstract

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values <0.05 considered significant. K3326X and I157T were associated with increased risk of developing sporadic PDAC (odds ratio (ORdom ) = 1.78, 95% confidence interval (CI) = 1.26-2.52, p = 1.19 × 10-3 and ORdom = 1.74, 95% CI = 1.15-2.63, p = 8.57 × 10-3 , respectively). Neither mutation was significantly associated with risk of developing early-onset PDAC. This retrospective study demonstrates novel risk estimates of K3326X and I157T in sporadic PDAC which suggest that upon validation and in combination with other established genetic and non-genetic risk factors, these mutations may be used to improve pancreatic cancer risk assessment in European populations. Identification of carriers of these risk alleles as high-risk groups may also facilitate screening or prevention strategies for such individuals, regardless of family history.

Published
2019

19. The resource group method in severe mental illness: Study protocol for a randomized controlled trial and a qualitative multiple case study

Author

Tjaden, C., Mulder, C. L., van Weeghel, J., Delespaul, P., Keet, R., Tjaden, C., Mulder, C. L., van Weeghel, J., Delespaul, P., and Keet, R.

Abstract

Background The resource group method provides a structure to facilitate patients’ empowerment and recovery processes, and to systematically engage significant others in treatment and care. A patient chooses members of a resource group (RG) that will work together on fulfilling patients’ recovery plan. By adopting shared decision-making processes and stimulating collaboration of different support systems, a broad and continuous support of patients’ chosen goals and wishes is preserved and problem solving and communication skills of the RG members are addressed. Objective The objectives of this study are (1) to establish the effectiveness of the RG method in increasing empowerment in patients with severe mental illnesses (SMI) in the Netherlands; (2) to investigate the cost-effectiveness and cost utility of the RG method; and (3) to qualitatively explore its dynamics and processes. Methods/design This multisite randomized controlled trial will compare the effects of the RG-method integrated in Flexible Assertive Community Treatment (FACT) (90 patients) with those of standard FACT (90 patients). Baseline assessments and 9-month and 18-month follow-up assessments will be conducted in face-to-face home visits. The primary outcome measure, empowerment, will be assessed using the Netherlands Empowerment List (NEL). The secondary outcomes will be quality of life (MANSA); personal, community and clinical recovery (I.ROC); general, social and community functioning (WHODAS 2.0); general psychopathological signs and symptoms (BSI-18); and societal costs (TiC-P). An economic evaluation of the cost-effectiveness and cost utility of the RG method will also be conducted. A qualitative multiple case-study will be added to collect patients’, RG members’ and professionals’ perspectives by in-depth interviews, observations and focus groups. Discussion This trial will be the first to study the effects of the RG method on empowerment in patients

Published
2019

20. Predictive performance of factors associated with malignancy in intraductal papillary mucinous neoplasia of the pancreas

Author

Heckler, M., Brieger, L., Heger, U., Pausch, T., Tjaden, C., Kaiser, J., Tanaka, M., Hackert, T., and Michalski, C. W.

Subjects
Systematic Reviews, Systematic Review
Abstract

Background Estimation of the risk of malignancy in intraductal papillary mucinous neoplasia (IPMN) of the pancreas is a clinical challenge. Several routinely used clinical factors form the basis of the current consensus guidelines. This study aimed to determine the predictive values of the most commonly assessed risk factors. Methods A meta‐analysis of individual risk factors of malignancy in IPMN was performed. Contingency tables were derived from these data, and sensitivity, specificity, negative and positive predictive values, and diagnostic odds ratios (DOR) were determined. Hierarchical summary receiver operating characteristic (HSROC) curves for each factor were calculated and the respective area under the curve (AUC) was assessed. Results A total of 3443 studies were screened initially. Analysis of recent literature revealed 60 studies with 13 relevant risk factors including clinical, serological and radiological parameters. The largest area under the HSROC curve was found for weight loss (0·84) and jaundice/raised bilirubin level (0·80), followed by increased carcinoembryonic antigen (CEA) (0·79) or carbohydrate antigen (CA) 19‐9 (0·78) levels. The most sensitive factors were patient age (71 per cent) and mural nodules (65 per cent), and jaundice/raised bilirubin level (97 per cent) and increased CEA level (95 per cent) were most specific. None of the analysed factors reached a positive or negative level of prediction beyond 90 per cent. Conclusion None of the established criteria safely distinguishes malignant from non‐malignant lesions.

Published
2017

21. Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma

Author

Obazee, O., primary, Archibugi, L., additional, Andriulli, A., additional, Soucek, P., additional, Małecka-Panas, E., additional, Ivanauskas, A., additional, Johnson, T., additional, Gazouli, M., additional, Pausch, T., additional, Lawlor, R. T., additional, Cavestro, G. M., additional, Milanetto, A. C., additional, Di Leo, M., additional, Pasquali, C., additional, Hegyi, P., additional, Szentesi, A., additional, Radu, C. E., additional, Gheorghe, C., additional, Theodoropoulos, G. E., additional, Bergmann, F., additional, Brenner, H., additional, Vodickova, L., additional, Katzke, V., additional, Campa, D., additional, Strobel, O., additional, Kaiser, J., additional, Pezzilli, R., additional, Federici, F., additional, Mohelnikova-Duchonova, B., additional, Boggi, U., additional, Lemstrova, R., additional, Johansen, J. S., additional, Bojesen, S. E., additional, Chen, I., additional, Jensen, B. V., additional, Capurso, G., additional, Pazienza, V., additional, Dervenis, C., additional, Sperti, C., additional, Mambrini, A., additional, Hackert, T., additional, Kaaks, R., additional, Basso, D., additional, Talar-Wojnarowska, R., additional, Maiello, E., additional, Izbicki, J. R., additional, Cuk, K., additional, Saum, K. U., additional, Cantore, M., additional, Kupcinskas, J., additional, Palmieri, O., additional, Delle Fave, G., additional, Landi, S., additional, Salvia, R., additional, Fogar, P., additional, Vashist, Y. K., additional, Scarpa, A., additional, Vodicka, P., additional, Tjaden, C., additional, Iskierka-Jazdzewska, E., additional, and Canzian, F., additional

Published
2019
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24. Association of genetic polymorphisms with survival of pancreatic ductal adenocarcinoma patients

Author

Rizzato, C. Campa, D. Talar-Wojnarowska, R. Halloran, C. Kupcinskas, J. Butturini, G. Mohelníková-Duchoňová, B. Sperti, C. Tjaden, C. Ghaneh, P. Hackert, T. Funel, N. Giese, N. Tavano, F. Pezzilli, R. Pedata, M. Pasquali, C. Gazouli, M. Mambrini, A. Souček, P. di Sebastiano, P. Capurso, G. Cantore, M. Oliverius, M. Offringa, R. Małecka-Panas, E. Strobel, O. Scarpa, A. Canzian, F.

Abstract

Germline genetic variability might contribute, at least partially, to the survival of pancreatic ductal adenocarcinoma (PDAC) patients. Two recently performed genome-wide association studies (GWAS) on PDAC overall survival (OS) suggested (P < 10-5) the association between 30 genomic regions and PDAC OS. With the aim to highlight the true associations within these regions, we analyzed 44 single-nucleotide polymorphisms (SNPs) in the 30 candidate regions in 1722 PDAC patients within the PANcreatic Disease ReseArch (PANDoRA) consortium. We observed statistically significant associations for five of the selected regions. One association in the CTNNA2 gene on chromosome 2p12 [rs1567532, hazard ratio (HR) = 1.75, 95% confidence interval (CI) 1.19-2.58, P = 0.005 for homozygotes for the minor allele] and one in the last intron of the RUNX2 gene on chromosome 6p21 (rs12209785, HR = 0.88, 95% CI 0.80-0.98, P = 0.014 for heterozygotes) are of particular relevance. These loci do not coincide with those that showed the strongest associations in the previous GWAS. In silico analysis strongly suggested a possible mechanistic link between these two SNPs and pancreatic cancer survival. Functional studies are warranted to confirm the link between these genes (or other genes mapping in those regions) and PDAC prognosis in order to understand whether these variants may have the potential to impact treatment decisions and design of clinical trials. © The Author 2016. Published by Oxford University Press. All rights reserved.

Published
2016

29. Die Bedeutung einer Spezialambulanz für die Betreuung chirurgischer Pankreaspatienten

Author

Tjaden, C, Hackert, T, Fritz, S, Büchler, MW, and Werner, J

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Einleitung: Operative Eingriffe am Pankreas erfordern sowohl von chirurgischer Seite als auch von seiten der Patientenbetreuung eine spezialisierte Versorgung um optimale Ergebnisse zu erzielen. Ziel der Studie war die Auswertung der Patientenversorgung über die Pankreassprechstunde der Chirurgischen[for full text, please go to the a.m. URL], 128. Kongress der Deutschen Gesellschaft für Chirurgie

Published
2011
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30. Inzidenz von Zweittumoren bei Patienten mit Pankreascarcinomen

Author

Hackert, T., Tjaden, C., Hinz, U., Hartwig, W., Büchler, M.W., and Werner, J.

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Einleitung: Tumorsyndrome sind v.a. bei colorektalen Karzinomen und endokrinen Neoplasien bekannt. Das duktale Pankreascarcinom (PDAC) ist bislang nicht mit anderen Tumorentitäten assoziiert. Ziel der Studie war die Untersuchung von PDAC Patienten im Hinblick auf Häufigkeit, Risikofaktoren[for full text, please go to the a.m. URL], 126. Kongress der Deutschen Gesellschaft für Chirurgie

Published
2009
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41. Genetic variability of the ABCC2 gene and clinical outcomes in pancreatic cancer patients

Author

Rita T. Lawlor, Raffaele Pezzilli, Péter Hegyi, Andrea Szentesi, Eithne Costello, Paula Puchalt García, John P. Neoptolemos, Alice Alessandra Galeotti, Cosimo Sperti, Giulia Martina Cavestro, Pavel Vodicka, Federico Canzian, Thilo Hackert, Renata Talar-Wojnarowska, Daniele Campa, Oliver Strobel, Francesca Tavano, Martin Lovecek, Gabriele Capurso, Christine Tjaden, Pavel Soucek, Manuel Gentiluomo, Anna Caterina Milanetto, Juozas Kupcinskas, Gentiluomo, M., Garcia, P. P., Galeotti, A. A., Talar-Wojnarowska, R., Tjaden, C., Tavano, F., Strobel, O., Kupcinskas, J., Neoptolemos, J., Hegyi, P., Costello, E., Pezzilli, R., Sperti, C., Lawlor, R. T., Capurso, G., Szentesi, A., Soucek, P., Vodicka, P., Lovecek, M., Hackert, T., Cavestro, G. M., Milanetto, A. C., Canzian, F., and Campa, D.

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, medicine.medical_specialty, Pancreatic disease, Genotype, alleles polymorphism gemcitabine genes single nucleotide polymorphism genetics treatment outcome pancreatic cancer mrp2 protein, human pancreatic ductal adenocarcinoma, Single-nucleotide polymorphism, Disease, Polymorphism, Single Nucleotide, 03 medical and health sciences, human pancreatic ductal adenocarcinoma, 0302 clinical medicine, alleles polymorphism gemcitabine genes single nucleotide polymorphism genetics treatment outcome pancreatic cancer mrp2 protein, Pancreatic cancer, Internal medicine, Biomarkers, Tumor, Medicine, Humans, Genetic variability, Allele, Aged, business.industry, Hazard ratio, General Medicine, Middle Aged, medicine.disease, Prognosis, Combined Modality Therapy, Gemcitabine, Multidrug Resistance-Associated Protein 2, Gene Expression Regulation, Neoplastic, Pancreatic Neoplasms, Survival Rate, 030104 developmental biology, 030220 oncology & carcinogenesis, Case-Control Studies, Female, Multidrug Resistance-Associated Proteins, business, medicine.drug, Carcinoma, Pancreatic Ductal, Follow-Up Studies
Abstract

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis, caused by various factors, such as the aggressiveness of the disease, the limited therapeutic options and the lack of early detection and risk markers. The ATP binding cassette subfamily C member 2 (ABCC2) protein plays a critical role in response to various drugs and is differentially expressed in gemcitabine sensitive and resistant cells. Moreover, single nucleotide polymorphisms (SNPs) in the gene have been associated with differential outcomes and prognosis in several tumour types. The aim of this study was to investigate the possible association between SNPs in the ABCC2 gene and overall survival (OS) in PDAC patients. We analysed 12 polymorphisms, including tagging-SNPs covering all the genetic variability of the ABCC2 gene and genotyped them in 1415 PDAC patients collected within the Pancreatic Disease ReseArch (PANDoRA) consortium. We tested the association between ABCC2 SNPs and PDAC OS using Cox proportional hazard models. We analysed PDAC patients dividing them by stage and observed that the minor alleles of three SNPs showed an association with worse OS [rs3740067: hazard ratio (HR) = 3.29, 95% confidence interval (CI) = 1.56-6.97, P = 0.002; rs3740073: HR = 3.11, 95% CI = 1.52-6.38, P = 0.002 and rs717620: HR = 2.90, 95% CI = 1.41-5.95, P = 0.004, respectively] in stage I patients. In patients with more advanced PDAC, we did not observe any statistically significant association. Our results suggest that rs3740067, rs3740073 and rs717620 could be promising prognostic markers in stage I PDAC patients.

Published
2019

42. The PAncreatic Surgery Composite Endpoint (PACE): Development and Validation of a Clinically Relevant Endpoint Requiring Lower Sample Sizes.

Author

Nickel F, Kuemmerli C, Müller PC, Schmidt MW, Schmidt LP, Wise P, Klotz R, Tjaden C, Diener M, Probst P, Hackert T, and Büchler MW

Subjects
Humans, Female, Male, Middle Aged, Aged, Sample Size, Prospective Studies, Postoperative Complications epidemiology, Postoperative Complications mortality, Pancreatic Fistula etiology, Reoperation statistics & numerical data, Postoperative Hemorrhage epidemiology, Endpoint Determination, Pancreatectomy methods, Length of Stay statistics & numerical data
Abstract

Objective: To provide a composite endpoint in pancreatic surgery., Background: Single endpoints in prospective and randomized studies have become impractical due to their low frequency and the marginal benefit of new interventions., Methods: Data from prospective studies were used to develop (n=1273) and validate (n=544) a composite endpoint based on postoperative pancreatic fistula, postpancreatectomy hemorrhage, as well as reoperation and reinterventions. All patients had pancreatectomies of different extents. The association of the developed PAncreatic surgery Composite Endpoint (PACE) with prolonged length of hospital stay >75th percentile and mortality was assessed. A single-institution database was used for external validation (n=2666). Sample size calculations were made for single outcomes and the composite endpoint., Results: In the internal validation cohort, the PACE demonstrated an area under the curve of 78.0%, a sensitivity of 90.4%, and a specificity of 67.6% in predicting a prolonged length of hospital stay. In the external cohort, the area under the curve was 76.9%, a sensitivity of 73.8%, and a specificity of 80.1%. The 90-day mortality rate was significantly different for patients with a positive versus a negative PACE both in the development and internal validation cohort (5.1% vs 0.9%; P < 0.001), as well as in the external validation cohort (8.5% vs 1.2%, P < 0.001). The PACE enabled sample size reductions of up to 80.5% compared to single outcomes., Conclusions: The PACE performed well in predicting prolonged hospital stays and can be used as a standardized and clinically relevant endpoint for future prospective trials enabling lower sample sizes and therefore improved feasibility compared to single outcome parameters., Competing Interests: The authors report no conflicts of interest, (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Published
2025
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43. Pancreatic Adenocarcinoma: Long-Term Outcomes of Adjuvant Therapy in the ESPAC4 Phase III Trial.

Author

Palmer DH, Jackson R, Springfeld C, Ghaneh P, Rawcliffe C, Halloran CM, Faluyi O, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Lind P, Glimelius B, Falk S, Ma YT, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Hammel P, Borg D, Sothi S, Valle JW, Mehrabi A, Bailey P, Tjaden C, Michalski C, Hackert T, Büchler MW, and Neoptolemos JP

Abstract

Purpose: The ESPAC4 trial showed that adjuvant chemotherapy with gemcitabine plus capecitabine (GemCap) produced longer overall survival (OS) than gemcitabine monotherapy. Subsequently, the PRODIGE24-CCTG PA.6 trial showed even longer survival for modified fluorouracil, folinic acid, irinotecan, and oxaliplatin (mFOLFIRINOX) than gemcitabine but had more restrictive eligibility criteria. Our aim was to analyze the ESPAC4 survival on long-term follow-up., Methods: The OS of 732 ESPAC4 patients comparing 367 randomly assigned to gemcitabine and 365 to GemCap was previously reported after a median follow-up time of 43.2 months (95% CI, 39.7 to 45.5) and 458 deaths. Analysis was now carried out after a median follow-up of 104 months (101-108) and 566 deaths., Results: The median OS was 29.5 months (27.5-32.1) for all patients, 28.4 months (25.2-32.0) in the gemcitabine group and 31.6 months (26.5-38.0) in the GemCap group (hazard ratio [HR], 0.83 [0.71 to 0.98]; P = .031). R0 patients given gemcitabine had a median survival of 32.2 months (27.9-41.6) compared with 49.9 months (39.0-82.3) for those given GemCap (HR, 0.63 [0.47 to 0.84]; P = .002). Lymph node-negative patients had significantly higher 5 year OS rates on GemCap (59% [49%-71%]) than gemcitabine (53% [42%-66%]; HR, 0.63 [0.41 to 0.98]; P = .04) but not those with positive lymph nodes ( P = .225). The OS advantage for GemCap was retained in the PRODIGE24 subgroup of 193 (26.4%) ESPAC4 patients not eligible for PRODIGE24 with a median survival of 20.7 (16.2-27.3) months in patients allocated to gemcitabine compared with 25.9 (22.3-30.2) months for ineligible patients allocated to GemCap (HR, 0.71 [95% CI, 0.52 to 0.98]; χ 2 log-rank-1df = 4.31; P = .038)., Conclusion: GemCap is a standard option for patients not eligible for mFOLFIRINOX. Exploratory evidence suggests that GemCap may be particularly efficacious in R0 patients and also in lymph node-negative patients.

Published
2024
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44. Combined analysis of a serum mRNA/miRNA marker signature and CA 19-9 for timely and accurate diagnosis of recurrence after resection of pancreatic ductal adenocarcinoma: A prospective multicenter cohort study.

Author

Buchholz M, Lausser L, Schenk M, Earl J, Lawlor RT, Scarpa A, Sanjuanbenito A, Carrato A, Malats N, Tjaden C, Giese NA, Büchler M, Hackert T, Kestler HA, and Gress TM

Abstract

Background and Aims: Timely and accurate detection of tumor recurrence in pancreatic ductal adenocarcinoma (PDAC) patients is an urgent and unmet medical need. This study aimed to develop a noninvasive molecular diagnostic procedure for the detection of recurrence after PDAC resection based on quantification of circulating mRNA and miRNA biomarkers in serum samples., Methods: In a multicentric study, serum samples from a total of 146 patients were prospectively collected after resection. Samples were classified into a "No Evidence of Disease" and a "Recurrence" group based on clinical follow-up data. A multianalyte biomarker panel was composed of mRNAs and miRNA markers and simultaneously analyzed in serum samples using custom microfluidic qPCR arrays (TaqMan array cards). A diagnostic algorithm was developed combining a 7-gene marker signature with CA19-9 data., Results: The best-performing marker combination achieved 90% diagnostic accuracy in predicting the presence of tumor recurrence (98% sensitivity; 84% specificity), clearly outperforming the singular CA 19-9 analysis. Moreover, time series data obtained by analyzing successively collected samples from 5 patients during extended follow-up suggested that molecular diagnosis has the potential to detect recurrence earlier than routine clinical procedures., Conclusions: TaqMan array card measurements were found to be biologically valid and technically reproducible. The BioPac multianalyte marker panel is capable of sensitive and accurate detection of recurrence in patients resected for PDAC using a simple blood test. This could allow a closer follow-up using shorter time intervals than currently used for imaging, thus potentially prompting an earlier work-up with additional modalities to allow for earlier therapeutic intervention. This study provides a promising approach for improved postoperative monitoring of resected PDAC patients, which is an urgent and unmet clinical need., (© 2024 The Author(s). United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Published
2024
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45. Imaging differentiation of solid pseudopapillary neoplasms and neuroendocrine neoplasms of the pancreas.

Author

Khristenko E, Gaida MM, Tjaden C, Steinle V, Loos M, Krieger K, Weber TF, Kauczor HU, Klauß M, and Mayer P

Abstract

Purpose: The present study aimed to compare the computed tomography (CT) and magnetic resonance imaging (MRI) features of solid pseudopapillary neoplasms (SPNs) and pancreatic neuroendocrine neoplasms (pNENs)., Method: Lesion imaging features of 39 patients with SPNs and 127 patients with pNENs were retrospectively extracted from 104 CT and 91 MRI scans., Results: Compared to pNEN patients, SPN patients were significantly younger (mean age 51.8 yrs versus 32.7 yrs) and more often female (female: male ratio, 5.50:1 versus 1.19:1). Most SPNs and pNENs presented as well-defined lesions with an expansive growth pattern. SPNs more often appeared as round or ovoid lesions, compared to pNENs which showed a lobulated or irregular shape in more than half of cases (p<0.01). A surrounding capsule was detected in the majority of SPNs, but only in a minority of pNENs (<0.01). Hemorrhage occurred non-significantly more often in SPNs (p=0.09). Signal inhomogeneity in T1-fat-saturated (p<0.01) and T2-weighted imaging (p=0.046) as well as cystic degeneration (p<0.01) were more often observed in SPNs. Hyperenhancement in the arterial and portal-venous phase was more common in pNENs (p<0.01). Enlargement of locoregional lymph nodes (p<0.01) and liver metastases (p=0.03) were observed in some pNEN patients, but not in SPN patients. Multivariate logistic regression identified the presence of a capsule (p<0.01), absence of arterial hyperenhancement (p<0.01), and low patient age (p<0.01), as independent predictors for SPN., Conclusions: The present study provides three key features for differentiating SPNs from pNENs extracted from a large patient cohort: presence of a capsule, absence of arterial hyperenhancement, and low patient age., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Published
2024
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46. Immunohistochemical FAP Expression Reflects 68 Ga-FAPI PET Imaging Properties of Low- and High-Grade Intraductal Papillary Mucinous Neoplasms and Pancreatic Ductal Adenocarcinoma.

Author

Spektor AM, Gutjahr E, Lang M, Glatting FM, Hackert T, Pausch T, Tjaden C, Schreckenberger M, Haberkorn U, and Röhrich M

Subjects
Humans, Gallium Radioisotopes, Positron Emission Tomography Computed Tomography, Pancreatic Ducts metabolism, Pancreatic Ducts pathology, Positron-Emission Tomography, Pancreatic Intraductal Neoplasms diagnostic imaging, Pancreatic Intraductal Neoplasms pathology, Adenocarcinoma, Mucinous diagnosis, Adenocarcinoma, Mucinous pathology, Adenocarcinoma, Mucinous surgery, Pancreatic Neoplasms metabolism, Carcinoma, Pancreatic Ductal diagnostic imaging, Carcinoma, Pancreatic Ductal metabolism
Abstract

Pancreatic intraductal papillary mucinous neoplasms (IPMNs) are grossly visible (typically > 5 mm) intraductal epithelial neoplasms of mucin-producing cells, arising in the main pancreatic duct or its branches. According to the current 2-tiered grading scheme, these lesions are categorized as having either low-grade (LG) dysplasia, which has a benign prognosis, or high-grade (HG) dysplasia, which formally represents a carcinoma in situ and thus can transform to pancreatic ductal adenocarcinoma (PDAC). Because both entities require different treatments according to their risk of becoming malignant, a precise pretherapeutic diagnostic differentiation is inevitable for adequate patient management. Recently, our group has demonstrated that 68 Ga-fibroblast activation protein (FAP) inhibitor (FAPI) PET/CT shows great potential for the differentiation of LG IPMNs, HG IPMNs, and PDAC according to marked differences in signal intensity and tracer dynamics. The purpose of this study was to biologically validate FAP as a target for PET imaging by analyzing immunohistochemical FAP expression in LG IPMNs, HG IPMNs, and PDAC and comparing with SUV and time to peak (TTP) measured in our prior study. Methods: To evaluate the correlation of the expression level of FAP and α-smooth muscle actin (αSMA) in neoplasm-associated stroma depending on the degree of dysplasia in IPMNs, 98 patients with a diagnosis of LG IPMN, HG IPMN, PDAC with associated HG IPMN, or PDAC who underwent pancreatic surgery at the University Hospital Heidelberg between 2017 and 2023 were identified using the database of the Institute of Pathology, University Hospital Heidelberg. In a reevaluation of hematoxylin- and eosin-stained tissue sections of formalin-fixed and paraffin-embedded resection material from the archive, which was originally generated for histopathologic routine diagnostics, a regrading of IPMNs was performed by a pathologist according to the current 2-tiered grading scheme, consequently eliminating the former diagnosis of "IPMN with intermediate-grade dysplasia." For each case, semithin tissue sections of 3 paraffin blocks containing neoplasm were immunohistologically stained with antibodies directed against FAP and αSMA. In a masked approach, a semiquantitative analysis of the immunohistochemically stained slides was finally performed by a pathologist by adapting the immunoreactive score (IRS) and human epidermal growth factor receptor 2 (Her2)/neu score to determine the intensity and percentage of FAP- and αSMA-positive cells. Afterward, the IRS of 14 patients who underwent 68 Ga-FAPI-74 PET/CT in our previous study was compared with their SUV max , SUV mean , and TTP for result validation. Results: From 98 patients, 294 specimens (3 replicates per patient) were immunohistochemically stained for FAP and αSMA. Twenty-three patients had LG IPMNs, 11 had HG IPMNs, 10 had HG IPMNs plus PDAC, and 54 had PDAC. The tumor stroma was in all cases variably positive for FAP. The staining intensity, percentage of FAP-positive stroma, IRS, and Her2/neu score increased with higher malignancy. αSMA expression could be shown in normal pancreatic stroma as well as within peri- and intraneoplastic desmoplastic reaction. No homogeneous increase in intensity, percentage, IRS, and Her2/neu score with higher malignancy was observed for αSMA. The comparison of the mean IRS of FAP with the mean SUV max , SUV mean , and TTP of 68 Ga-GAPI-74 PET/CT showed a matching value increasing with higher malignancy in 68 Ga-FAPI-74 PET imaging and immunohistochemical FAP expression. Conclusion: The immunohistochemical staining of IPMNs and PDAC validates FAP as a biology-based stromal target for in vivo imaging. Increasing expression of FAP in lesions with a higher degree of malignancy matches the expectation of a stronger FAP expression in PDAC and HG IPMNs than in LG IPMNs and corroborates our previous findings of higher SUVs and a longer TTP in PDAC and HG IPMNs than in LG IPMNs., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Published
2024
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47. DNA-methylation signature accurately differentiates pancreatic cancer from chronic pancreatitis in tissue and plasma.

Author

Wu Y, Seufert I, Al-Shaheri FN, Kurilov R, Bauer AS, Manoochehri M, Moskalev EA, Brors B, Tjaden C, Giese NA, Hackert T, Büchler MW, and Hoheisel JD

Subjects
Humans, DNA Methylation, DNA, Biomarkers, Tumor genetics, Pancreatic Neoplasms diagnosis, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Pancreatitis, Chronic diagnosis, Pancreatitis, Chronic genetics, Carcinoma, Pancreatic Ductal diagnosis, Carcinoma, Pancreatic Ductal genetics
Abstract

Objective: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Differentiation from chronic pancreatitis (CP) is currently inaccurate in about one-third of cases. Misdiagnoses in both directions, however, have severe consequences for patients. We set out to identify molecular markers for a clear distinction between PDAC and CP., Design: Genome-wide variations of DNA-methylation, messenger RNA and microRNA level as well as combinations thereof were analysed in 345 tissue samples for marker identification. To improve diagnostic performance, we established a random-forest machine-learning approach. Results were validated on another 48 samples and further corroborated in 16 liquid biopsy samples., Results: Machine-learning succeeded in defining markers to differentiate between patients with PDAC and CP, while low-dimensional embedding and cluster analysis failed to do so. DNA-methylation yielded the best diagnostic accuracy by far, dwarfing the importance of transcript levels. Identified changes were confirmed with data taken from public repositories and validated in independent sample sets. A signature of six DNA-methylation sites in a CpG-island of the protein kinase C beta type gene achieved a validated diagnostic accuracy of 100% in tissue and in circulating free DNA isolated from patient plasma., Conclusion: The success of machine-learning to identify an effective marker signature documents the power of this approach. The high diagnostic accuracy of discriminating PDAC from CP could have tremendous consequences for treatment success, once the result from still a limited number of liquid biopsy samples would be confirmed in a larger cohort of patients with suspected pancreatic cancer., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2023
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48. Persister cell phenotypes contribute to poor patient outcomes after neoadjuvant chemotherapy in PDAC.

Author

Zhou X, An J, Kurilov R, Brors B, Hu K, Peccerella T, Roessler S, Pfütze K, Schulz A, Wolf S, Hohmann N, Theile D, Sauter M, Burhenne J, Ei S, Heger U, Strobel O, Barry ST, Springfeld C, Tjaden C, Bergmann F, Büchler M, Hackert T, Fortunato F, Neoptolemos JP, and Bailey P

Subjects
Humans, Cytochrome P-450 CYP3A, Adjuvants, Immunologic, Keratin-17, Phenotype, Neoadjuvant Therapy, Adenocarcinoma
Abstract

Neoadjuvant chemotherapy can improve the survival of individuals with borderline and unresectable pancreatic ductal adenocarcinoma; however, heterogeneous responses to chemotherapy remain a significant clinical challenge. Here, we performed RNA sequencing (n = 97) and multiplexed immunofluorescence (n = 122) on chemo-naive and postchemotherapy (post-CTX) resected patient samples (chemoradiotherapy excluded) to define the impact of neoadjuvant chemotherapy. Transcriptome analysis combined with high-resolution mapping of whole-tissue sections identified GATA6 (classical), KRT17 (basal-like) and cytochrome P450 3A (CYP3A) coexpressing cells that were preferentially enriched in post-CTX resected samples. The persistence of GATA6 hi and KRT17 hi cells post-CTX was significantly associated with poor survival after mFOLFIRINOX (mFFX), but not gemcitabine (GEM), treatment. Analysis of organoid models derived from chemo-naive and post-CTX samples demonstrated that CYP3A expression is a predictor of chemotherapy response and that CYP3A-expressing drug detoxification pathways can metabolize the prodrug irinotecan, a constituent of mFFX. These findings identify CYP3A-expressing drug-tolerant cell phenotypes in residual disease that may ultimately inform adjuvant treatment selection., (© 2023. The Author(s).)

Published
2023
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49. Surgery for intraductal papillary mucinous neoplasms in young patients: High-risk population.

Author

Kaiser J, Hackert T, Hinz U, Mayer P, Tjaden C, Roth S, Pausch TM, Heger U, Heckler M, Al-Saeedi M, Büchler MW, and Loos M

Subjects
Humans, Retrospective Studies, Prospective Studies, Neoplasm Recurrence, Local epidemiology, Neoplasm Recurrence, Local pathology, Carcinoma, Pancreatic Ductal, Pancreatic Neoplasms, Neoplasms, Cystic, Mucinous, and Serous
Abstract

Background: Intraductal papillary mucinous neoplasms of the pancreas are uncommon in young individuals. Management of these patients is challenging because the risk of malignancy and recurrence after surgery remains unclear. The aim of the present study was to assess the long-term risk for intraductal papillary mucinous neoplasm recurrence after surgery for intraductal papillary mucinous neoplasms in patients ≤50 years of age., Methods: Perioperative and long-term follow-up data of patients who had undergone surgery for intraductal papillary mucinous neoplasms between 2004 and 2020 were extracted from a prospective unicentric database and retrospectively analyzed., Results: Seventy-eight patients underwent surgical treatment for benign intraductal papillary mucinous neoplasms (low-grade n = 22 and intermediate-grade n = 21) and malignant intraductal papillary mucinous neoplasms (high-grade n = 16 and intraductal papillary mucinous neoplasm-associated carcinoma n = 19). Severe postoperative morbidity (Clavien-Dindo ≥III) was found in 14 patients (18%). The median length of hospital stay was 10 days. No perioperative mortality was observed. The median length of follow-up was 72 months. Recurrence of intraductal papillary mucinous neoplasm-associated carcinoma was found in 6 patients (19%) with malignant intraductal papillary mucinous neoplasm and 1 patient (3%) with benign intraductal papillary mucinous neoplasm., Conclusion: Surgery for intraductal papillary mucinous neoplasm is safe and can be performed with low morbidity and potentially no mortality in young patients. Given the high rate of malignancy (45%), these patients with intraductal papillary mucinous neoplasms represent a high-risk population, and prophylactic surgical treatment should be considered in these patients with long life expectancies. Regular clinical and radiologic follow-up examinations are important to rule out disease recurrence, which is high, especially in patients with intraductal papillary mucinous neoplasm-associated carcinoma., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Published
2023
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50. Central pancreatectomy prevents postoperative diabetes.

Author

Klotz R, Schilling C, Kuner C, Hinz U, Klaiber U, Holze M, Tjaden C, Loos M, Büchler MW, and Hackert T

Subjects
Humans, Pancreatectomy methods, Prospective Studies, Treatment Outcome, Postoperative Complications, Retrospective Studies, Pancreatic Neoplasms pathology, Diabetes Mellitus epidemiology, Diabetes Mellitus prevention & control, Diabetes Mellitus etiology
Abstract

Background: Central pancreatectomy (CP) can be performed as an alternative surgical approach to distal pancreatectomy (DP) in the treatment of benign or low-grade malignant lesions located in the neck and body of the pancreas, aiming to reduce loss of parenchyma and therefore organ failure. The objective of this study was to evaluate the short- and long-term outcome of CP in comparison to DP., Methods: Patients who received CP in a large tertiary care pancreatic surgery center between 2001 and 2020 were identified from a prospectively maintained database and compared via propensity score matching with patients receiving DP during the same time period. Perioperative rate of complications and long-term outcome of pancreatic endocrine and exocrine function were evaluated., Results: One hundred and seven patients undergoing open CP were compared to 107 patients with open DP. No significant difference in rates or severity of most surgical complications could be found including postoperative pancreatic fistula, intraabdominal fluid collection, delayed gastric emptying and wound infection. However, patients receiving CP had a significantly higher risk of grade C postpancreatectomy hemorrhage (PPH) (CP: 10 patients, 9.3% versus DP: 1 patient, 0.9%; p = .0019). Perioperative mortality was comparable. Long-term follow-up of 60 matched pairs revealed significantly less patients with new-onset diabetes after CP (eight patients, 13.3%) compared to DP (22 patients, 36.7%, p = .0056)., Conclusion: CP offers an improved endocrine long-term outcome at the expense of a higher risk of PPH without increased perioperative mortality. As evidence on this parenchyma sparing surgical technique is sparse, more prospective data are needed., (© 2022 The Authors. Journal of Hepato-Biliary-Pancreatic Sciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Published
2023
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