The possible dual role of Ang-2 in the prognosis of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) features a dense desmoplastic stroma, which raises the intratumoral interstitial pressure leading to vascular collapse and hypoxia, inducing angiogenesis. Vascular growth factors, such as vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2), increase in PDAC. A high VEGF and a high circulating Ang-2 associate with shorter survival in PDAC. In addition to the circulatory Ang-2, PDAC endothelial and epithelial cells express Ang-2. No correlation between tumor epithelial nor endothelial cell Ang-2 expression and survival has been published. We aimed to examine Ang-2 expression and survival. This study comprised PDAC surgical patients at Helsinki University Hospital in 2000-2013. Ang-2 immunohistochemistry staining was completed on 168 PDAC patient samples. Circulating Ang-2 levels were measured using ELISA in the sera of 196 patients. Ang-2 levels were assessed against clinical data and patient outcomes. A low tumor epithelial Ang-2 expression predicted shorter disease-specific survival (DSS) compared with a high expression (p = 0.003). A high serum Ang-2 associated with shorter DSS compared with a low circulating Ang-2 (p = 0.016). Ang-2 seemingly plays a dual role in PDAC survival. Further studies are needed to determine the mechanisms causing tumor cell Ang-2 expression and its positive association with survival.

The impact of implementing current treatment modalities and female sex on gastric cancer outcomes, 2000-2016: a longitudinal nationwide cohort study.

BACKGROUND: The implementation of current treatment modalities and their impact on nationwide gastric cancer outcomes remain poorly understood. Biological differences between females and males could impact survival. We aimed to analyze rates of gastric surgery, chemotherapy, and radiotherapy as well as changes in overall survival among gastric cancer patients diagnosed between 2000-2008 and 2009-2016, respectively, in Finland. MATERIAL AND METHODS: Data on gastric cancer patients were collected from national registries. Cox regression analysis and the Kaplan-Meier method were used to analyze differences in survival. RESULTS: We identified 9223 histologically confirmed gastric cancer patients. The rate of gastric surgery decreased from 44% (n = 2282) to 34% (n = 1368; p < 0.001). The proportion of gastric surgery patients who underwent preoperative oncological treatment increased from 0.5% (n = 12) to 16.2% (n = 222) between the calendar periods (p < 0.001) and stood at 30% in 2016. The median overall survival (OS) improved from 30 months [95% confidence interval (CI) 28-33] to 38 months (95%CI 33-42; p = 0.006) and the period 2009-2016 independently associated with a lower risk of death [hazard ratio (HR) 0.78, 95%CI 0.70-0.87] among patients who underwent gastric surgery. Females exhibited a lower risk of death (HR 0.88, 95%CI 0.81-0.97) among patients who underwent gastric surgery. CONCLUSION: Preoperative oncological treatment was gradually introduced into clinical practice and OS among gastric surgery patients improved. Moreover, female surgical patients exhibited a better survival than male patients.

N-glycosylation in non-invasive and invasive intraductal papillary mucinous neoplasm.

Intraductal papillary mucinous neoplasms (IPMNs), often found incidentally, are potentially malignant cystic tumors of the pancreas. Due to the precancerous nature, IPMNs lacking malignant features should be kept on surveillance. The follow-up relies on magnetic resonance imaging, which has a limited accuracy to define the high-risk patients. New diagnostic methods are thus needed to recognize IPMNs with malignant potential. Here, aberrantly expressed glycans constitute a promising new area of research. We compared the N-glycan profiles of non-invasive IPMN tissues (n = 10) and invasive IPMN tissues (n = 10) to those of non-neoplastic pancreatic controls (n = 5) by matrix-assisted laser desorption-ionization time-of-flight (MALDI-TOF) mass spectrometry. Both IPMN subgroups showed increased abundance of neutral composition H4N4 and decrease in H3N5F1, increase in sialylation, and decrease in sulfation, as compared to the controls. Furthermore, invasive IPMN showed an increase in terminal N-acetylhexosamine containing structure H4N5, and increase in acidic complex-type glycans, but decrease in their complex fucosylation and sulfation, as compared to the controls. In conclusion, the N-glycan profiles differed between healthy pancreatic tissue and non-invasive and invasive IPMNs. The unique glycans expressed in invasive IPMNs may offer interesting new options for diagnostics.

Serum cytokine profiles in patients with pancreatic cancer and chronic pancreatitis.

BACKGROUND: Chronic pancreatitis (CP) may cause tumor-like lesions, creating a challenge in distinguishing between CP and pancreatic ductal adenocarcinoma (PDAC) in a patient. Given that invasive surgery is a standard cancer treatment, we aimed to examine whether a noninvasive diagnostic tool utilizing serum cytokines could safely differentiate between PDAC and CP. METHODS: A pre-operative serum panel comprising 48 inflammatory cytokines, CA19-9, and C-reactive protein (CRP) was analyzed, consisting of 231 patients, 186 with stage I-III PDAC and 45 with CP. We excluded PDAC patients who underwent neoadjuvant therapy and those CP patients with other active malignancies. The laboratory variables most associated with PDAC diagnosis were assessed using logistic regression and selected using the lasso method. RESULTS: The cytokines CTACK, GRO-α, and ß-NGF were selected alongside CA19-9 and CRP for our differential diagnostic model. The area under the curve (AUC) for our differential diagnostic model was 0.809 (95% confidence interval [CI] 0.738-0.880), compared with 0.791 (95% CI 0.728-0.854) for CA19-9 alone (not significant). CONCLUSIONS: We found that inflammatory cytokines CTACK, GRO-α, and ß-NGF alongside CA19-9 and CRP may help distinguish PDAC from CP.

Transient Changes in Serum CEA, CA19-9, CRP, YKL-40, and IL-6 during Adjuvant Chemotherapy and Survival of Patients with Colorectal Cancer.

Serum carcinoembryonic antigen (CEA) is frequently monitored to detect colorectal cancer (CRC) recurrence after surgery. The clinical significance of transiently increased CEA during adjuvant chemotherapy is poorly understood. Serum CEA, CA19-9, CRP, YKL-40, and IL-6 were measured before, during, and after adjuvant 5-fluorouracil-based chemotherapy in the randomised LIPSYT study population. The biomarker kinetic patterns were classified into three groups: no increase, a transient increase (≥10% increase followed by a decrease), and a persistent increase during the adjuvant treatment, and the associations of these patterns with disease free-survival (DFS) and overall survival (OS) were investigated by using Cox regression analyses. The findings were validated in two single-centre cohorts that received modern adjuvant chemotherapy. A transient increase in CEA occurred in about a half of the patients during chemotherapy, in all the cohorts. The patients with a transient increase had a roughly similar DFS and OS to the patients with no increase, and a more favourable survival compared to the patients with a persistent increase. In the LIPSYT cohort, the hazard ratio was 0.21 for DFS (CI95% 0.07-0.66) and 0.24 for OS (CI95% 0.08-0.76). Transient increases in CA19-9 and YKL-40 tended to be associated with a favourable survival. A transient increase in CEA during adjuvant chemotherapy is associated with a favourable survival when compared with a persistent increase.

Optimal Perioperative Fluid Therapy Associates with Fewer Complications After Pancreaticoduodenectomy.

BACKGROUND: Optimal fluid management in pancreaticoduodenectomy patients remains contested. We aimed to examine the association between perioperative fluid administration and postoperative complications. METHODS: We studied 168 pancreaticoduodenectomy patients operated in 2015 (n = 93) or 2017 (n = 75) at Helsinki University Hospital. In 2015, patients received intraoperative fluids following a goal-directed approach and, in 2017, according to anesthesiologist's clinical practice (conventional fluid management). We analyzed the differences in perioperative fluid administration between the groups, specifically examining the occurrence of severe complications (Clavien-Dindo ≥ III), pancreatic fistulas, cardiovascular complications, and the length of hospital stay. RESULTS: The goal-directed group received more intraoperative fluids than the conventional fluid management group (12.0 ml/kg/h vs. 8.3 ml/kg/h, p < 0.001). Urine output (770 ml vs. 575 ml, p = 0.004) and intraoperative fluid balance (9.4 ml/kg/h vs. 6.3 ml/kg/h, p < 0.001) were higher in the goal-directed group than in the conventional fluid management group. Severe surgical complications (19.4% vs. 38.7%, p = 0.009) as well as clinically relevant pancreatic fistulas (1.1% vs. 10.7%, p = 0.011) occurred more frequently in patients receiving conventional fluid management. Moreover, the conventional fluid management group experienced longer hospital stays (9.0 vs. 11.5 days, p = 0.02). Lower intraoperative fluid volume accompanying conventional fluid management was associated with a higher risk of severe postoperative complications compared with higher volume in the goal-directed group (odds ratio 2.58 (95% confidence interval 1.04-6.42), p = 0.041). CONCLUSIONS: The goal-directed group experienced severe complications less frequently. Our findings indicate that optimizing the intraoperative fluid administration benefits patients, while adopting a too-restrictive approach represents an inferior choice.

Prognostic Role of Porphyromonas gingivalis Gingipain Rgp and Matrix Metalloproteinase 9 in Oropharyngeal Squamous Cell Carcinoma.

BACKGROUND/AIM: The oral bacteria involved in the development of periodontitis alter the tissue conditions and modify immune responses in a way that may also influence tumor development. We investigated the prevalence of R gingipain (Rgp), a key virulence factor of the oral pathobiont Porphyromonas gingivalis, and the tissue-destructive enzymes matrix metalloproteinase 8 (MMP-8) and 9 (MMP-9) in 202 unselected consecutive oropharyngeal squamous cell carcinoma (OPSCC) samples. We further investigated the relationships between these factors and human papillomavirus (HPV) status, Treponema denticola chymotrypsin-like proteinase (Td-CTLP) immunoexpression, clinical parameters, and patient outcome. PATIENTS AND METHODS: Clinicopathological data were derived from university hospital records. Rgp, MMP-8, and MMP-9 immunoexpression was evaluated by immunohistochemistry; the immunohistochemistry of Td-CTLP and HPV has been described earlier for this patient series. Cox regression analysis including death by causes other than OPSCC as a competing risk served to assess sub distribution hazard ratios. RESULTS: In multivariable survival analysis, positive tumoral MMP-9 immunoexpression predicted poor prognosis among all patients [sub distribution hazard ratio (SHR)=2.4; confidence interval (CI)=1.2-4.4, p=0.008], and especially among those with HPV-negative OPSCC (SHR=3.5; CI=1.7-7.3, p=0.001). Positive immunoexpression of Rgp in inflammatory cells was associated with favorable outcome among all patients (SHR=0.5, CI=0.2-0.9, p=0.021) and among those with HPV-negative disease (SHR=0.4, CI=0.2-0.9, p=0.022). CONCLUSION: Our results suggest that tumoral MMP-9 may be related to poor outcome in OPSCC, especially in HPV-negative disease, while Rgp immunoexpression in inflammatory cells is associated here with better disease-specific survival (DSS).

Anatomical pancreatic variants in intraductal papillary mucinous neoplasm patients: a cross-sectional study.

BACKGROUND: No previous studies have examined the possible relationship between intraductal papillary mucinous neoplasm (IPMN) and the developmental ductal variations of the pancreas, such as an ansa pancreatica and a meandering main pancreatic duct (MMPD). METHODS: This retrospective cross-sectional study enrolled 214 patients, 108 with IPMN disease and 106 subjects from a community at the tertiary care unit. The main pancreatic duct (MPD) was evaluated in the head of the pancreas by its course, which were non-MMPD: descending, vertical, and sigmoid, or MMPD including loop types, reverse-Z subtypes, and an N-shape, which was identified for the first time in this study. IPMN patients were also evaluated for worrisome features (WF) or high-risk stigmata (HRS), and the extent of IPMN cysts. RESULTS: Among IPMN patients, 18.4% had MMPD, which we observed in only 3.0% of the control group (P < 0.001). Patients with MMPD were more likely to belong to the IPMN group compared with non-MMPD patients [odds ratio (OR) 6.4, 95% confidence interval (CI) 2.2-24.9]. Compared with a descending shape MPD, IPMN patients with an N-shaped MPD were more likely to have a cystic mural nodule (OR 5.9, 95% CI 1.02-36.0). The presence of ansa pancreatica associated with more extent IPMN disease (OR 12.8, 95% CI 2.6-127.7). CONCLUSIONS: IPMN patients exhibited an MMPD more often than control patients. Ansa pancreatica associated with multiple cysts. Furthermore, an N-shape in IPMN patients associated with cystic mural nodules, suggesting that this shape serves as a risk factor for more severe IPMN.

Long-term outcome of convulsive status epilepticus: a 10-year follow-up

Objective: This study aimed to determine the mortality, causes of death and factors affecting the outcome of convulsive status epilepticus (CSE) at 10 years. Method: This retrospective study consisted of 62 consecutive adult patients diagnosed with CSE at the Helsinki University Hospital (HUS) emergency department during 2002-2003. Patients were followed for up to 10 years or up to the time of death. Data on patient demographics, CSE characteristics, treatment, complications, and outcome from the time of CSE were collected. The Official Statistics of Finland provided the information on mortality and causes of death. Survival analysis was conducted using Cox proportional hazards regression analysis. Results: In-hospital mortality was 8.1%, and mortality was 25.8% at one year, 51.6% at five years and 64.5% at 10 years. Estimated standardized mortality ratio (SMR) was 5.3 and the deceased patients lost 20.9 potential years of life, on average. The leading causes of death were disorders of the brain or the circulatory system, epilepsy-related conditions or intracranial tumours. The univariable survival analysis demonstrated that age ≥65 (HR=2.8, p=0.001), Charlson Comorbidity Index (CCI)>0 (CCI=1-3: HR=3.0, p=0.009; CCI>3: HR=8.4, p<0.001), Status Epilepticus Severity Score (STESS)>4 (HR=5.3, p<0.001) and Epidemiology-Based Mortality Score (EMSE-EAC)>15 (HR=2.2, p=0.036) were risk factors and a Glasgow outcome scale (GOS) of 5 at discharge (HR=0.14, p=0.025) was a protective factor for survival. The multivariable analysis established STESS>4 (HR=5.0, p=0.002) and CCI>0 (CCI=1-3: HR=2.9, p=0.015;CCI>3: HR=6.3, p=0.006) as independent risk factors and GOS>3 (time-dependent) (GOS=4: HR=0.33, p=0.048;GOS=5: HR=0.13, p=0.019) as a protective factor for survival. Significance: The rate of long-term mortality and number of potential years of life lost were high. Factors demonstrative of the overall situation of the patients, such as comorbidities, functional state after CSE and age, were significant predictors for long-term outcome.

ß-catenin plus PROX1 immunostaining stratifies disease progression and patient survival in neoadjuvant-treated pancreatic cancer.

BACKGROUND: Wnt/ß-catenin signaling is a highly conserved signaling pathway that regulates the transcription factor PROX1. The role of ß-catenin and PROX1 in pancreatic cancer is ambiguous, as some studies have associated their expression with tumor regression and some with tumor progression. OBJECTIVE: We have investigated their expression in surgically treated pancreatic cancer patients receiving neoadjuvant therapy (NAT), and patients treated upfront with surgery (US). We furthermore compared the expression of ß-catenin and PROX1 between patients who had a good or poor response to NAT. METHODS: We evaluated ß-catenin and PROX1 expression through immunohistochemistry in 88 neoadjuvant and 144 upfront surgery patients by scoring the intensity of the immunopositivity as 0-3, corresponding to negative, weak, moderate, or strong. We developed a six-tier grading scheme for the neoadjuvant responses by analyzing the remaining tumor cells in surgical specimen histological sections. RESULTS: Strong ß-catenin immunopositivity associated with improved survival in the patients with good NAT-response (≤10% residual tumor cells) (Hazard ratio [HR] 0.26 95%, confidence interval [CI] 0.07-0.88 p = 0.030). Additionally, the combined moderate ß-catenin and PROX1 expression associated with improved survival (HR 0.20 95% CI 0.05-0-76 p = 0.018) among the good responders. Among the patients with a poor NAT-response (> 10% residual tumor cells), both strong ß-catenin immunopositivity and strong combined ß-catenin and PROX1 associated with shorter survival (HR 2.03 95% CI 1.16-3.55 p = 0.013, and HR 3.1 95% CI 1.08-8.94 p = 0.03, respectively). PROX1 alone was not associated with survival. CONCLUSIONS: Strong ß-catenin immunopositivity and combined strong or moderate ß-catenin and PROX1 immunopositivity associated with improved survival among the good NAT-responders and worse survival among the poor NAT-responders.

The expression and prognostic value of toll-like receptors (TLRs) in pancreatic cancer patients treated with neoadjuvant therapy.

OBJECTIVES: Toll-like receptors (TLRs) play a pivotal role in the immune system and carcinogenesis. There is no research on TLR expression and association with survival among preoperatively treated pancreatic cancer patients. We studied the expression intensity and prognostic value of TLRs in pancreatic cancer patients treated with neoadjuvant therapy (NAT) and compared the results to patients undergoing upfront surgery (US). METHOD: Between 2000 and 2015, 71 borderline resectable patients were treated with NAT and surgery and 145 resectable patients underwent upfront surgery at Helsinki University Hospital, Finland. We immunostained TLRs 1-5, 7, and 9 on sections of tissue-microarray. We classified TLR expression as 0 (negative), 1 (mild), 2 (moderate), or 3 (strong) and divided into high (2-3) and low (0-1) expression for statistical purposes. RESULTS: Among TLRs 1, 3, and 9 (TLR1 81% vs 70%, p = 0.008; TLR3 92% vs 68%, p = 0.001; TLR9 cytoplasmic 83% vs 42%, p<0.001; TLR9 membranous 53% vs 25%, p = 0.002) NAT patients exhibited a higher immunopositivity score more frequently than patients undergoing upfront surgery. Among NAT patients, a high expression of TLR1 [Hazards ratio (HR) 0.48, p<0.05] associated with a longer postoperative survival, whereas among US patients, high expression of TLR5 (HR 0.64, p<0.05), TLR7 (HR 0.59, p<0.01, and both TLR7 and TLR9 (HR 0.5, p<0.01) predicted a favorable postoperative outcome in separate analysis adjusted for background variables. CONCLUSIONS: We found higher immunopositive intensities among TLRs 1, 3, and 9 in NAT patients. A high TLR1 expression associated with a longer survival among NAT patients, however, among US patients, high expression intensity of TLR5 and TLR7 predicted a favorable postoperative outcome in the adjusted analysis.

Long Term Results of Pancreatectomy With and Without Venous Resection: A Comparison of Safety and Complications of Spiral Graft, End-to-End and Tangential/Patch Reconstruction Techniques.

OBJECTIVE: Roughly 10% - 20% of pancreatic cancer patients are candidates for curative intent surgical treatment. In the 2000s, many studies showed similar survival rates comparing pancreatic surgery with or without vein resection and reconstruction. The aim was to identify the best method of venous reconstruction. METHODS: This was a retrospective cohort study. A total of 1 375 patients undergoing pancreatectomy between 2005 and 2018 were identified. Patients undergoing a combined pancreatic resection and venous reconstruction were included retrospectively. When tumour infiltration to the portal/superior mesenteric vein was detected, excision and reconstruction with tangential suturing/patch, end to end anastomosis, or a spiral graft from the great saphenous vein was performed. Next, 90 day and long term survival and outcomes across reconstruction techniques were analysed. RESULTS: Overall, 198 patients had venous involvement visible in pre-operative scans or detected during surgery, broken down as follows: 171 (86%) pancreaticoduodenectomy, 12 (6%) total pancreatectomy, and 15 (8%) distal pancreatectomy. In total, 69 (35%) spiral graft reconstructions, 77 (39%) end to end anastomoses, and 52 (26%) tangential/patch reconstructions were performed. Tumour histology revealed pancreatic adenocarcinomas in 162 (82%) patients, intraductal mucinous pancreatic neoplasia in 14 (7%), cholangiocarcinoma in five (3%), neuro-endocrine neoplasia in nine (5%), and eight other diagnoses. Overall, 183 (92%) were malignant and 15 (8%) benign. Two patients died within 90 days, one in hospital and one on post-operative day 38 due to thrombosis of the superior mesenteric vein and intestinal necrosis, a Clavien-Dindo grade 5 complication. In addition, 50 (23%) patients had Clavien-Dindo grade 3 - 4 complications. No differences in complications comparing vein reconstruction techniques or in the long term survival of pancreatectomy patients with or without venous reconstruction were detected. CONCLUSION: The spiral graft technique, used when more advanced venous infiltration occurs, does not increase complications, with outcomes mirroring those accompanying shorter venous resections.

Single-operator peroral pancreatoscopy in the preoperative diagnostics of suspected main duct intraductal papillary mucinous neoplasms: efficacy and novel insights on complications.

BACKGROUND: Distinguishing intraductal papillary mucinous neoplasms (IPMNs) from other pancreatic cystic lesions is essential since IPMNs carry the risk of becoming malignant. Differentiating the main pancreatic duct involving IPMNs (MD-IPMNs) through conventional imaging is deficient. Single-operator peroral pancreatoscopy (SOPP) represents a promising method offering additional information on suspected lesions in the pancreatic main duct (MD). We aimed to determine the role of SOPP in the preoperative diagnostics of suspected MD-IPMNs and identify factors contributing to SOPP-related complications. MATERIALS AND METHODS: In this primarily retrospective study, SOPPs were performed at three high-volume centers on suspected MD-IPMNs. Primary outcome was the clinical impact of SOPP to subsequent patient care. Additionally, we documented post-SOPP complications and analyzed several assumed patient- and procedure-related risk factors. RESULTS: One hundred and one (101) SOPPs were performed. Subsequent clinical management was affected due to the findings in 86 (85%) cases. Surgery was planned for 29 (29%) patients. A condition other than IPMN explaining MD dilatation was found in 28 (28%) cases. In 35 (35%) cases, follow-up with MRI was continued. Post-SOPP pancreatitis occurred in 20 (20%) patients and one of them was fatal. A decrease in odds of post-SOPP pancreatitis was seen as the MD diameter increases (OR 0.714 for 1.0 mm increase in MD diameter, CI 95% 0.514-0.993, p = 0.045). Furthermore, a correlation between lower MD diameter values and higher severity post-SOPP pancreatitis was seen (TJT = 599, SE = 116.6, z = - 2.31; p = 0.020). History of pancreatitis after endoscopic retrograde cholangiopancreatography was a confirmed risk factor for post-SOPP pancreatitis. Conclusions between complications and other risk factors could not be drawn. CONCLUSION: SOPP aids clinical decision-making in suspected MD-IPMNs. Risk for post-SOPP pancreatitis is not negligible compared to non-invasive imaging methods. The risk for pancreatitis decreases as the diameter of the MD increases.

Matrix Metalloproteinase 8 Expression in a Tumour Predicts a Favourable Prognosis in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer-related death globally, and, despite improvements in diagnostics and treatment, survival remains poor. Matrix metalloproteinases (MMPs) are enzymes involved in stroma remodelling in inflammation and cancer. MMP-8 plays a varied prognostic role in cancers of the gastrointestinal tract. We examined the prognostic value of MMP-8 immunoexpression in tumour tissue and the amount of MMP-8-positive polymorphonuclear cells (PMNs) in PDAC and their association with immune responses using C-reactive protein (CRP) as a marker of systemic inflammation. Tumour samples from 141 PDAC patients undergoing surgery in 2002−2011 at the Department of Surgery, Helsinki University Hospital were stained immunohistochemically, for which we evaluated MMP-8 expression in cancer cells and the amount of MMP-8-positive PMNs. We assessed survival using the Kaplan−Meier analysis while uni- and multivariable analyses relied on the Cox proportional hazards model. A negative MMP-8 stain and elevated CRP level predicted a poor prognosis (hazard ratio [HR] = 6.95; 95% confidence interval (CI) 2.69−17.93; p < 0.001) compared to a positive stain and low CRP level (<10 mg/L). The absence of PMNs together with an elevated CRP level also predicted an unfavourable outcome (HR = 3.17; 95% CI 1.60−6.30; p = 0.001). MMP-8 expression in the tumour served as an independent positive prognostic factor (HR = 0.33; 95% CI 0.16−0.68; p = 0.003). Tumour MMP-8 expression and a low CRP level may predict a favourable outcome in PDAC with similar results for MMP-8-positive PMNs and low CRP levels. Tumoural MMP-8 expression represents an independent positive prognostic factor in PDAC.

Preoperative oncologic therapy and the prolonged risk of venous thromboembolism in resectable pancreatic cancer.

BACKGROUND: Pancreatic cancer is one of the most prothrombotic cancers. Among patients receiving preoperative chemotherapy followed by surgery, chemotherapy and surgery represent a compound risk for venous thromboembolism (VTE), rendering the postoperative time a period of interest. We aimed to analyze whether preoperative oncologic therapy increases the risk for VTE after surgery and identify which characteristics associate with VTE. METHODS: We first identified patients surgically treated for pancreatic cancer at Helsinki University Hospital between 2000 and 2017, collecting the following data: gender, age at surgery, preoperative medication, body mass index (BMI), preoperative chemo(radio)therapy, tumor size, positive node ratio, perineural and perivascular invasion, tumor grade, surgical technique, postoperative anticoagulation, adjuvant therapy, time of VTE, time of local disease recurrence, time of distant metastasis, and time of death. With a follow-up period of at least 2 years or until death, we compared a total of 93 preoperative oncologic therapy and 291 upfront surgery patients (n = 384, median age 66.5 years). RESULTS: Preoperative oncologic therapy increased the risk for thrombosis after surgery (hazard ratio [HR] 1.61; 95% confidence interval [CI] 1.03-2.53). The VTE incidence rate remained high for up to 2 years after surgery. BMI ≥30 kg/m2 , prior anticoagulation, and disease recurrence (p < 0.05, respectively) associated with VTE. VTE is also associated with shorter overall survival (HR 3.25; 95% CI 2.36-4.44). In 71.6% (95% CI 60.5-81.1) of patients, VTE was diagnosed after disease recurrence. CONCLUSIONS: Preoperative oncologic therapy represents an independent risk factor for VTE, not only during the immediate postoperative period but up to 2 years after surgery. VTE is associated with obesity, prior anticoagulation, and disease recurrence and diminishes overall survival.

Pancreatic Cancer Organoids in the Field of Precision Medicine: A Review of Literature and Experience on Drug Sensitivity Testing with Multiple Readouts and Synergy Scoring.

Pancreatic ductal adenocarcinoma (PDAC) is a silent killer, often diagnosed late. However, it is also dishearteningly resistant to nearly all forms of treatment. New therapies are urgently needed, and with the advent of organoid culture for pancreatic cancer, an increasing number of innovative approaches are being tested. Organoids can be derived within a short enough time window to allow testing of several anticancer agents, which opens up the possibility for functional precision medicine for pancreatic cancer. At the same time, organoid model systems are being refined to better mimic the cancer, for example, by incorporation of components of the tumor microenvironment. We review some of the latest developments in pancreatic cancer organoid research and in novel treatment design. We also summarize our own current experiences with pancreatic cancer organoid drug sensitivity and resistance testing (DSRT) in 14 organoids from 11 PDAC patients. Our data show that it may be necessary to include a cell death read-out in ex vivo DSRT assays, as metabolic viability quantitation does not capture actual organoid killing. We also successfully adapted the organoid platform for drug combination synergy discovery. Lastly, live organoid culture 3D confocal microscopy can help identify individual surviving tumor cells escaping cell death even during harsh combination treatments. Taken together, the organoid technology allows the development of novel precision medicine approaches for PDAC, which paves the way for clinical trials and much needed new treatment options for pancreatic cancer patients.

Pancreatic fibrosis, acinar atrophy and chronic inflammation in surgical specimens associated with survival in patients with resectable pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies, is increasing in incidence. However, the stromal reaction pathophysiology and its role in PDAC development remain unknown. We, therefore, investigated the potential role of histological chronic pancreatitis findings and chronic inflammation on surgical PDAC specimens and disease-specific survival (DSS). METHODS: Between 2000 and 2016, we retrospectively enrolled 236 PDAC patients treated with curative-intent pancreatic surgery at Helsinki University Hospital. All pancreatic transection margin slides were re-reviewed and histological findings were evaluated applying international guidelines. RESULTS: DSS among patients with no fibrosis, acinar atrophy or chronic inflammation identified on pathology slides was significantly better than DSS among patients with fibrosis, acinar atrophy and chronic inflammation [median survival: 41.8 months, 95% confidence interval (CI) 26.0-57.6 vs. 20.6 months, 95% CI 10.3-30.9; log-rank test p = 0.001]. Multivariate analysis revealed that Ca 19-9 > 37 kU/l [hazard ratio (HR) 1.48, 95% CI 1.02-2.16], lymph node metastases N1-2 (HR 1.71, 95% CI 1.16-2.52), tumor size > 30 mm (HR 1.47, 95% CI 1.04-2.08), the combined effect of fibrosis and acinar atrophy (HR 1.91, 95% CI 1.27-2.88) and the combined effect of fibrosis, acinar atrophy and chronic inflammation (HR 1.63, 95% CI 1.03-2.58) independently served as unfavorable prognostic factors for DSS. However, we observed no significant associations between tumor size (> 30 mm) and the degree of perilobular fibrosis (p = 0.655), intralobular fibrosis (p = 0.587), acinar atrophy (p = 0.584) or chronic inflammation (p = 0.453). CONCLUSIONS: Our results indicate that the pancreatic stroma is associated with PDAC patients' DSS. Additionally, the more severe the fibrosis, acinar atrophy and chronic inflammation, the worse the impact on DSS, thereby warranting further studies investigating stroma-targeted therapies.

Pancreatic cancer survival prediction via inflammatory serum markers.

BACKGROUND: For prognostic evaluation of pancreatic ductal adenocarcinoma (PDAC), the only well-established serum marker is carbohydrate antigen CA19-9. To improve the accuracy of survival prediction, we tested the efficacy of inflammatory serum markers. METHODS: A preoperative serum panel comprising 48 cytokines plus high-sensitivity CRP (hs-CRP) was analyzed in 173 stage I-III PDAC patients. Analysis of the effect of serum markers on survival utilized the Cox regression model, with the most promising cytokines chosen with the aid of the lasso method. We formed a reference model comprising age, gender, tumor stage, adjuvant chemotherapy status, and CA19-9 level. Our prognostic study model incorporated these data plus hs-CRP and the cytokines. We constructed time-dependent ROC curves and calculated an integrated time-averaged area under the curve (iAUC) for both models from 1 to 10 years after surgery. RESULTS: Hs-CRP and the cytokines CTACK, MIF, IL-1ß, IL-3, GRO-α, M-CSF, and SCF, were our choices for the prognostic study model, in which the iAUC was 0.837 (95% CI 0.796-0.902), compared to the reference model's 0.759 (95% CI 0.691-0.836, NS). These models divided the patients into two groups based on the maximum value of Youden's index at 7.5 years. In our study model, 60th percentile survival times were 4.5 (95% CI 3.7-NA) years (predicted high-survival group, n = 34) and 1.3 (95% CI 1.0-1.7) years (predicted low-survival group, n = 128), log rank p < 0.001. By the reference model, the 60th percentile survival times were 2.8 (95% CI 2.1-4.4) years (predicted high-survival group, n = 44) and 1.3 (95% CI 1.0-1.7) years (predicted low-survival group, n = 118), log rank p < 0.001. CONCLUSION: Hs-CRP and the seven cytokines added to the reference model including CA19-9 are potential prognostic factors for improved survival prediction for PDAC patients.

Long-term nationwide trends in the treatment of and outcomes among pancreatic cancer patients.

Whilst treatment modalities for pancreatic cancer patients have evolved in recent years, their impact on outcomes remains relatively unexamined on a national scale. We aimed to analyse changes in overall survival and trends in surgical and oncological treatments in pancreatic cancer patients diagnosed in the periods 2000 through 2008 and 2009 through 2016 in Finland. We collected data for pancreatic cancer patients diagnosed between 2000 and 2016, gathering data from the Finnish national registries on surgeries, oncological treatments and time of death. Follow-up continued through the end of 2018. We compared patients diagnosed between 2000 and 2008 to those diagnosed between 2009 through 2016. Our study comprised 14 712 pancreatic cancer patients. There was no significant change in the national resection rate (8.1% vs 8.0%, p = 0.690). In radical surgery patients, median survival improved from 20 months (95% confidence interval (CI) 18-22) to 28 months (CI 25-31) (p < 0.001), with 1-year survival ranging from 70% to 81%. In the no-surgery group, median survival slightly improved from 3.1 months (CI 3.0-3.3) to 3.3 months (CI 3.1-3.4) (p < 0.001). The proportion of radical surgery patients receiving preoperative oncological treatment increased from 4% to 13% (p < 0.001) and only postoperative treatment from 25% to 47% (p < 0.001). Whilst the resection rate did not increase, the prognosis of pancreatic cancer patients improved, particularly amongst radical surgery patients resulting most likely from the fact that a larger proportion of patients receive more effective oncological treatments.

Use of self-expandable metallic stents for endoscopic biliary decompression decreases stent complications in pancreatic cancer patients receiving chemotherapy.

BACKGROUND: Both plastic stents and self-expandable metallic stents (SEMSes) are used for endoscopic biliary decompression (BD) among patients with pancreatic cancer (PAC). Cholangitis or stent occlusion often interrupts or ends chemotherapy. We investigated cholangitis, stent occlusion, and chemotherapy interruption rates for SEMSes and plastic stents among patients receiving chemotherapy for PAC. MATERIALS AND METHODS: We retrospectively analyzed data for 293 PAC patients who received a biliary stent at Helsinki University Hospital during 2000-2017. Patients received chemotherapy as palliative treatment (PT: n = 187) or neoadjuvant treatment (NAT: n = 106). Among participants, 229 had a plastic stent (PT: n = 138, NAT: n = 91) and 64 had a SEMS (PT: n = 49, NAT: n = 15). RESULTS: Overall, 15.6% (n = 10) of patients with SEMSes (PT: 20.4%, n = 10, NAT: 0%) and 53.0% (n = 121) of patients with plastic stents (PT: 69.3%, n = 95, NAT: 28.5%, n = 26) experienced one or more stent complications (p < 0.001). Cholangitis developed in 6.3% (n = 8) of PT patients with SEMSes. No patients with SEMSes receiving NAT (n = 15) experienced cholangitis. However, 31.9% (PT: 42.8%, n = 59, p = 0.001; NAT: 15.4%, n = 14, p = 0.211) of patients with plastic stents developed cholangitis. Among all patients receiving NAT or PT, cholangitis interrupted chemotherapy 6 times (9.4%) in SEMS patients and 61 times (26.6%) in plastic stent patients (p = 0.004). Stent occlusion without cholangitis interrupted NAT or PT 2 times (2.1%) in SEMS patients and 31 times (13.5%) in plastic stent patients (p = 0.023). CONCLUSIONS: SEMS is recommended for BD among patients with PAC receiving chemotherapy. Among both PT and NAT patients, patients with SEMS experience a lower stent failure rate, lower rate of cholangitis, and fewer chemotherapy interruptions than patients with plastic stents.