The natural history of intraductal papillary mucinous neoplasms (IPMNs) remains uncertain. The inconsistencies among published guidelines preclude accurate decision-making. The outcomes and potential ...risks of a conservative watch-and-wait approach vs a surgical approach must be compared.
To provide an overview of the surgical management of IPMNs, focusing on the time of resection.
This cohort study was conducted in a single referral center; all patients with pathologically proven IPMN who received a pancreatic resection at the institution between October 2001 and December 2019 were analyzed. Preoperatively obtained images and the medical history were scrutinized for signs of progression and/or malignant features. The timeliness of resection was stratified into too early (adenoma and low-grade dysplasia), timely (intermediate-grade dysplasia and in situ carcinoma), and too late (invasive cancer). The perioperative characteristics and outcomes were compared between these groups.
Timeliness of resection according to the final pathological findings.
The risk of malignant transformation at the final pathology.
Of 1439 patients, 438 (30.4%) were assigned to the too early group, 504 (35.1%) to the timely group, and 497 (34.5%) to the too late group. Radiological criteria for malignant conditions were detected in 53 of 382 patients (13.9%), 149 of 432 patients (34.5%), and 341 of 385 patients (88.6%) in the too early, timely, and too late groups, respectively (P < .001). Patients in the too early group underwent more parenchyma-sparing resections (too early group, 123 of 438 28.1%; timely group, 40 of 504 7.9%; too late group, 5 of 497 1.0%; P < .001), while morbidity (too early group, 112 of 438 25.6%; timely group, 117 of 504 23.2%; too late group, 158 of 497 31.8%; P = .002) and mortality (too early group, 4 patients 0.9%; timely, 4 0.8%; too late, 13 2.6%; P = .03) were highest in the too late group. Of the 497 patients in the too late group, 124 (24.9%) had a previous history of watch-and-wait care.
Until the biology and progression patterns of IPMN are clarified and accurate guidelines established, a watch-and-wait policy should be applied with caution, especially in IPMN bearing a main-duct component. One-third of IPMNs reach the cancer stage before resection. At specialized referral centers, the risks of surgical morbidity and mortality are justifiable.
Loss of body weight is often seen in pancreatic cancer and also predicts poor prognosis. Thus, maintaining muscle mass is an essential treatment goal. The primary aim was to investigate whether ...progressive resistance training impacts muscle and adipose tissue compartments. Furthermore, the effect of body composition on overall survival (OS) was investigated.
In the randomized SUPPORT-study, 65 patients were assigned to 6-month resistance training (2x/week) or a usual care control group. As secondary endpoint, muscle strength of the upper and lower extremities was assessed before and after the intervention period. Routine CT scans were assessed on lumbar L3/4 level for quantification of total-fat-area, visceral-fat-area, subcutaneous-fat-area, intramuscular-fat-area, visceral-to-subcutaneous fat ratio (VFR), muscle-area (MA), muscle-density and skeletal-muscle-index (SMI). OS data were retrieved.
Of 65 patients, 53 had suitable CT scans at baseline and 28 completed the intervention period with suitable CT scans. There were no significant effects observed of resistance training on body composition (p>0.05; effect sizes ω2p <0.02). Significant moderate to high correlations were found between MA and muscle strength parameters (r = 0.57-0.85; p<0.001). High VFR at baseline was a predictor of poor OS (VFR≥1.3 vs. <1.3; median OS 14.6 vs. 45.3 months; p = 0.012). Loss of muscle mass was also a predictor of poor OS (loss vs. gain of SMI; median OS 24.6 vs. 50.8 months; p = 0.049).
There is anabolic potential in patients with resectable pancreatic cancer. A progressive resistance training may help patients to maintain their muscle mass and avoid muscle depletion. CT-quantified muscle mass at the level of L3/4 showed a good correlation to muscle strength. Therefore, maintaining muscle mass and muscle strength through structured resistance training could help patients to maintain their physical functioning. A high VFR at baseline and a high loss of muscle mass are predictors of poor OS. Registered on ClinicalTrials.gov (NCT01977066).
Objectives
To evaluate IVIM DW-MRI for changes in IVIM-derived parameters during steroid treatment of autoimmune pancreatitis (AIP) and for the differentiation from pancreatic cancer (PC).
Methods
...Fifteen AIP-patients, 11 healthy patients and 20 PC-patients were examined with DWI-MRI using eight b-values (50, 100, 150, 200, 300, 400, 600, 800). 12 AIP-patients underwent follow-up examinations during treatment. IVIM-parameters and ADC
800
-values were tested for significant differences and an ROC analysis was performed.
Results
The perfusion fraction
f
was significantly lower in patients with AIP at the time of diagnosis (10.5 ± 4.3 %) than in patients without AIP (20.7 ± 4.3 %). In AIP follow-up,
f
increased significantly to 17.1 ± 7.0 % in the first and 21.0 ± 4.1 % in the second follow up. In PC, the
f
-values were lower (8.2 ± 4.0 %, n.s.) compared to initial AIP and were significantly lower compared to first and second follow-up examination. In the ROC-analysis AUC-values for
f
were 0.63, 0.88 and 0.98 for differentiation of PC from initial, first and second follow up AIP-examination.
Conclusions
The found differences in
f
between AIP, AIP during steroid treatment and pancreatic cancer suggest that IVIM-diffusion MRI could serve as imaging biomarker during treatment in AIP-patients and as a helpful tool for differentiation between PC and AIP.
Key Points
•
MRI is used for follow-up examinations during therapy in AIP-patients
•
IVIM-DWI-MRI offers parameters which reflect perfusion and true diffusion
•
IVIM-parameters are helpful for differentiation between AIP and pancreatic cancer
•
IVIM-parameters could serve as an imaging biomarker during steroid treatment
Purpose
Cancer patients frequently experience reduced physical fitness due to the disease itself as well as treatment-related side effects. However, studies on physical fitness in pancreatic cancer ...patients are missing. Therefore, we assessed cardiorespiratory fitness and muscle strength of pancreatic cancer patients.
Methods
We included 65 pancreatic cancer patients, mostly after surgical resection. Cardiorespiratory fitness was assessed using cardiopulmonary exercise testing (CPET) and 6-min walk test (6MWT). Hand-held dynamometry was used to evaluate isometric muscle strength. Physical fitness values were compared to reference values of a healthy population. Associations between sociodemographic and clinical variables with patients’ physical fitness were analyzed using multiple regression models.
Results
Cardiorespiratory fitness (VO
2
peak, 20.5 ± 6.9 ml/min/kg) was significantly lower (−24%) compared to healthy reference values. In the 6MWT pancreatic cancer patients nearly reached predicted values (555 vs. 562 m). Maximal voluntary isometric contraction (MVIC) of the upper (−4.3%) and lower extremities (−13.8%) were significantly lower compared to reference values. Overall differences were larger in men than those in women. Participating in regular exercise in the year before diagnosis was associated with greater VO
2
peak (
p
< .05) and MVIC of the knee extensors (
p
< .05).
Conclusions
Pancreatic cancer patients had significantly impaired physical fitness with regard to both cardiorespiratory function and isometric muscle strength, already in the early treatment phase (median 95 days after surgical resection). Our findings underline the need to investigate exercise training in pancreatic cancer patients to counteract the loss of physical fitness.
Improving quality of life (QoL) is an important treatment goal in pancreatic cancer patients. Although the beneficial effects of exercise on QoL are well understood, few studies have investigated ...more aggressive cancers such as pancreatic cancer.
Within a randomized trial, we assessed the efficacy of 6-month resistance training on physical functioning (primary outcome) and further QoL-related outcomes. 65 pancreatic cancer patients were assigned to home-based training, supervised training, or a usual care control group. Analysis-of-covariance models on changes from baseline to 6 and 3 months were ap- plied.
47 patients completed the intervention period. After 6 months, no effects of resistance training were observed. However, after 3 months, explorative analyses showed significant between-group mean differences (MD) in favor for resistance training for physical functioning (pooled group: MD=11.0; p=0.016; effect sizeES=0.31), as well as for global QoL (MD=12.1; p=0.016; effect size=0.56), and other outcomes, such as sleep problems and fatigue. Multiple imputation analyses yielded similar results. Home-based and supervised training performed similarly.
This first randomized resistance training trial in pancreatic cancer patients indicated clinically relevant improve- ments in QoL after 3 but not after 6 months. Given the severity of pancreatic cancer, exercise recommendations may already commence at surgery.
Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions of pancreatic cancer, which is characterized by an immunosuppressive microenvironment. Yet, the spatial distribution of the ...immune infiltrate and how it changes during IPMN progression is just beginning to be understood.
We obtained tissue samples from patients who underwent pancreatic surgery for IPMN, and performed comprehensive immunohistochemical analyses to investigate the clinical significance, composition and spatial organization of the immune microenvironment during progression of IPMNs. Survival analysis of pancreatic cancer patients was stratified by tumour infiltrating immune cell subtypes.
The immune microenvironment evolves from a diverse T cell mixture, comprising CD8+ T cells, Th/c1 and Th/c2 as major players combined with Th9, Th/c17, Th22, and Treg cells in low-grade IPMN, to a Treg dominated immunosuppressive state in invasive pancreatic cancer. Organized lymphoid clusters formed in IPMN surrounding stroma and accumulated immunosuppressive cell types during tumour progression. Survival of pancreatic cancer patients correlated with Th2 signatures in the tumour microenvironment.
The major change with regards to T cell composition during IPMN progression occurs at the step of tissue invasion, indicating that malignant transformation only occurs when tumour immune surveillance is overcome. This suggests that novel immunotherapies that would boost spontaneous antitumor immunity at premalignant states could prevent pancreatic cancer development.
The present work was supported by German Cancer Aid grants (70,112,720 and 70,113,167) to S. R., and the Olympia Morata Programme of the Medical Faculty of Heidelberg University to S. R.
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).
Lesion imaging features of 39 patients with SPNs and 127 patients with pNENs were retrospectively extracted from 104 CT and 91 MRI scans.
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.
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.
Display omitted
•Solid pseudopapillary neoplasms (SPNs) are often larger and rounder than pancreatic neuroendocrine neoplasms (pNENs).•The presence of a fibrous capsule is a strong imaging predictor of SPNs compared to pNENs.•Arterial hyperenhancement is rare in SPNs, but present in over half of pNENs.•Upstream dilatation of the pancreatic or bile duct almost never occurs in SPNs, but can occur in pNENs.
IntroductionPostoperative pancreatic fistula (POPF) is still the most frequently occurring and clinically relevant complication after distal pancreatectomy (DP). Preoperative endoscopic injection of ...botulinum toxin (BTX) into the sphincter of Oddi represents an innovative approach to prevent POPF. The aim of this project (PREBOTPilot) is to generate the first randomised controlled trial data on the safety, feasibility and efficacy of preoperative endoscopic BTX injection into the sphincter of Oddi to prevent clinically relevant POPF following DP.Methods and analysisPREBOTPilot is an investigator-initiated, single-centre, randomised, controlled, open-label, phase II clinical trial with two parallel study groups and an exploratory study design. 60 patients scheduled for DP will be randomised to intervention and control group. In the intervention group, patients will undergo preoperative endoscopic injection of BTX into the sphincter of Oddi, whereas in the control group no preoperative endoscopy will be performed. The combined primary endpoint is the occurrence of clinically relevant POPF and/or death within 30 days after DP. The secondary endpoints comprise further postoperative outcome parameters and quality of life up to 3 months after DP as well as safety and feasibility of the procedure. Statistical analysis is based on the modified intention-to-treat population, excluding patients without status post DP. For safety analysis, rates of adverse events (AEs) and serious AEs will be calculated with 95% CIs for group comparisons.Ethics, funding and disseminationPREBOTPilot has been approved by the German Federal Institute for Drugs and Medical Devices (reference number 4043654) and the Ethics Committee of Heidelberg University (reference number AFmo-523/2019). This trial is supported by the German Federal Ministry of Education and Research (BMBF). The results of the trial will be presented at national and international conferences and published in a peer-reviewed journal.Trial registration numberDRKS00020401.
CSPG4 marks pericytes, undifferentiated precursors and tumor cells. We assessed whether the shed ectodomain of CSPG4 (sCSPG4) might circulate and reflect potential changes in CSPG4 tissue expression ...(pCSPG4) due to desmoplastic and malignant aberrations occurring in pancreatic tumors. Serum sCSPG4 was measured using ELISA in test (n = 83) and validation (n = 221) cohorts comprising donors (n = 11+26) and patients with chronic pancreatitis (n = 11+20) or neoplasms: benign (serous cystadenoma SCA, n = 13+20), premalignant (intraductal dysplastic IPMNs, n = 9+55), and malignant (IPMN-associated invasive carcinomas, n = 4+14; ductal adenocarcinomas, n = 35+86). Pancreatic pCSPG4 expression was evaluated using qRT-PCR (n = 139), western blot analysis and immunohistochemistry. sCSPG4 was found in circulation, but its level was significantly lower in pancreatic patients than in donors. Selective maintenance was observed in advanced IPMNs and PDACs and showed a nodal association while lacking prognostic relevance. Pancreatic pCSPG4 expression was preserved or elevated, whereby neoplastic cells lacked pCSPG4 or tended to overexpress without shedding. Extreme pancreatic overexpression, membranous exposure and tissue(high)/sera(low)-discordance highlighted stroma-poor benign cystic neoplasm. SCA is known to display hypoxic markers and coincide with von-Hippel-Lindau and Peutz-Jeghers syndromes, in which pVHL and LBK1 mutations affect hypoxic signaling pathways. In vitro testing confined pCSPG4 overexpression to normal mesenchymal but not epithelial cells, and a third of tested carcinoma cell lines; however, only the latter showed pCSPG4-responsiveness to chronic hypoxia. siRNA-based knockdowns failed to reduce the malignant potential of either normoxic or hypoxic cells. Thus, overexpression of the newly established conditional hypoxic indicator, CSPG4, is apparently non-pathogenic in pancreatic malignancies but might mark distinct epithelial lineage and contribute to cell polarity disorders. Surficial retention on tumor cells renders CSPG4 an attractive therapeutic target. Systemic 'drop and restoration' alterations accompanying IPMN and PDAC progression indicate that the interference of pancreatic diseases with local and remote shedding/release of sCSPG4 into circulation deserves broad diagnostic exploration.
IntroductionPancreatic cancer is a devastating disease with an exceptionally poor prognosis. Complete resection of the primary tumour followed by adjuvant chemotherapy is the current standard ...treatment for patients with resectable disease and the only curative treatment option. However, long-term survival remains rare. Tumour cell dissemination due to manipulation during surgery may increase the rate of future metastases and local recurrence, and perioperative chemotherapy might diminish local, distant and circulating minimal residual disease. Yet, safety and feasibility of systemic chemotherapeutic treatments during pancreatic cancer resection have to be evaluated in a first instance.Methods and analysisThis is a prospective, single-centre phase I/II feasibility study to investigate the safety and tolerability of a combination of intraoperative chemotherapy and surgical resection in pancreatic cancer. Forty patients with locally confined or borderline resectable pancreatic cancer, meeting all proposed criteria will be included. Participants will receive 400 mg/m2 calcium folinate over 2 hours and 2000 mg/m2 5-fluorouracil over 48 hours, started on the day before pancreatic surgery and thus continuing during surgery. Participants will be followed until 60 days after surgery. The primary endpoint is the 30-day overall complication rate according to the Clavien-Dindo classification. Secondary endpoints comprise toxicity and treatment associated complications. Patients receiving perioperative chemotherapy will be compared with a propensity score matched contemporary control group of 70 patients with pancreatic cancer receiving the standard treatment. This trial also contains an ancillary translational study to analyse disseminated tumour cells and effects of pharmacological interventions in pancreatic cancer.Ethics and disseminationCombiCaRe has been approved by the German Federal Institute for Drugs and Medical Devices (reference number 4042787) and the Medical Ethics Committee of Heidelberg University (reference number AFmo-269/2018). The results of this trial will be presented at national and international conferences and published in peer-reviewed journals.Trial registration numberGerman Clinical Trials Register (DRKS00015766).
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