Impact of para aortic lymph node removal on survival following resection for pancreatic adenocarcinoma.

INTRODUCTION: For PDAC patients undergoing resection, it remains unclear whether metastases to the paraaortic lymph nodes (PALN+) have any prognostic significance and whether metastases should lead to the operation not being carried out. Our hypothesis is that PALN + status would be associated with short overall survival (OS) compared with PALN-, but longer OS compared with patients undergoing surgical exploration only (EXP). METHODS: Patients with registered PALN removal from the nationwide Danish Pancreatic Cancer Database (DPCD) from May 1st 2011 to December 31st 2020 were assessed. A cohort of PDAC patients who only had explorative laparotomy due to non-resectable tumors were also included (EXP group). Survival analysis between groups were performed with cox-regression in a multivariate approach including relevant confounders. RESULTS: A total of 1758 patients were assessed, including 424 (24.1%) patients who only underwent explorative surgery leaving 1334 (75.8%) patients for further assessment. Of these 158 patients (11.8%) had selective PALN removal, of whom 19 patients (12.0%) had PALN+. Survival analyses indicated that explorative surgery was associated with significantly shorter OS compared with resection and PALN + status (Hazard Ratio 2.36, p < 0.001). No difference between PALN + and PALN- status could be demonstrated in resected patients after controlling for confounders. CONCLUSION: PALN + status in patients undergoing resection offer improved survival compared with EXP. PALN + should not be seen as a contraindication for curative intended resection.

Long-Term Outcomes of Venous Resections in Pancreatic Ductal Adenocarcinoma Patients: A Nationwide Cohort Study.

To investigate whether pancreatic resections (PR) for pancreatic ductal adenocarcinoma (PDAC) is associated with worse survival when resection of the superior mesenteric vein/portal vein (SMV/PV) is required. Background: PR for PDAC with resection of the superior mesenteric vein/portal vein (SMV/PV, PR+V resection) may be associated with inferior overall survival (OS) compared with PR without the need for SMV/PV resection (PR-V). We hypothesized that PR+V results in lower OS compared with PR-V. Method: Retrospective study using data from the nationwide Danish Pancreatic Cancer Database from 2011 to 2020. Data on patients who underwent PR for PDAC were extracted. A group of PR patients found nonresectable on exploratory laparotomy (EXP) was also included. OS was assessed using Kaplan-Meier and Cox proportional hazards models adjusting for confounders (age, sex, R-resection level, chemotherapy, comorbidities, histology T and N classification, procedure subtype as well as tumor distance to the SMV/PV). Results: Overall, 2403 patients were identified. Six hundred two underwent exploration only (EXP group), whereas 412 underwent pancreatic resection with (PR+V group) and 1389 (PR-V) without SMV/PV resection. Five-year OS for the PR+V group was lower (20% vs 30%) compared with PR-V, although multivariate Cox proportional hazards modeling could not associate PR+V status with OS (Hazard ratio 1.11, P = 0.408). Conclusion: When correcting for confounders, PR+V was not associated with lower OS compared with PR-V.

Proteomic Characterization of Colorectal Cancer Tissue from Patients Identifies Novel Putative Protein Biomarkers.

Colorectal cancer (CRC) is one of the leading causes of cancer-related death over the world. There is a great need for biomarkers capable of early detection and as targets for treatment. Differential protein expression was investigated with two-dimensional gel electrophoresis (2D-PAGE) followed by identification with liquid chromatography-tandem mass spectrometry (LC-MS/MS) in CRC patient tissue from (i) the peripheral part of the tumor, (ii) the central part of the tumor as well as from (iii) a non-involved part of the colorectal tissue. The expression patterns of six identified proteins were further evaluated by one-dimensional Western blot (1D-WB) analysis of the CRC tissue. Proteins that were perturbed in expression level in the peripheral or in the central part of the tumor as compared with the non-involved part included S100A11, HNRNPF, HNRNPH1 or HNRNPH2, GSTP1, PKM and FABP1. These identified markers may have future diagnostic potential or may be novel treatment targets after further evaluation in larger patient cohorts.

Irreversible electroporation of pancreatic cancer - Effect on quality of life and pain perception.

BACKGROUND: Most pancreatic cancer (PC) patients are incurable and may need palliative treatment at some point in time. Irreversible electroporation (IRE) is a novel ablative treatment, which aims to provide local tumor control. The aim of this study was to examine how consolidative treatment with IRE affects quality of life (QOL) and pain perception (PP) in patients with non-metastatic pancreatic cancer. METHODS: Secondary outcomes were extracted from a prospective cohort of non-metastatic PC patients treated with IRE from 2013 to 2019. Patients filled in two questionnaires examining QOL and PP at different timepoints during treatment and follow-up. Data from a selected panel of subscales were extracted and analyzed using a mixed random intercept regression model. RESULTS: Subscales from 41 patients at four different timepoints were included in the model. Global health status, physical functioning, fatigue, nausea and vomiting, appetite loss and mean pain interference were negatively impacted (p < 0.05) in the short- and mid-term, corresponding to a low or moderate clinical effect size. However, all negative effects showed a tendency to dissipate over time. CONCLUSIONS: IRE treatment negatively impacted QOL and PP in the short- and mid-term. No positive long-term effects of IRE were found.

Proteomic Characterization of Colorectal Cancer Cells versus Normal-Derived Colon Mucosa Cells: Approaching Identification of Novel Diagnostic Protein Biomarkers in Colorectal Cancer.

In the western world, colorectal cancer (CRC) is the third most common cause of cancer-related deaths. Survival is closely related to the stage of cancer at diagnosis striking the clinical need for biomarkers capable of early detection. To search for possible biological parameters for early diagnosis of CRC we evaluated protein expression for three CREC (acronym: Cab45, reticulocalbin, ERC-55, calumenin) proteins: reticulocalbin, calumenin, and ERC-55 in a cellular model consisting of a normal derived colon mucosa cell line, NCM460, and a primary adenocarcinoma cell line of the colon, SW480. Furthermore, this cellular model was analyzed by a top-down proteomic approach, 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) for novel putative diagnostic markers by identification of differentially expressed proteins between the two cell lines. A different colorectal carcinoma cell line, HCT 116, was used in a bottom-up proteomic approach with label-free quantification (LFQ) LC-MS/MS. The two cellular models gave sets of putative diagnostic CRC biomarkers. Various of these novel putative markers were verified with increased expression in CRC patient neoplastic tissue compared to the expression in a non-involved part of the colon, including reticulocalbin, calumenin, S100A6 and protein SET. Characterization of these novel identified biological features for CRC patients may have diagnostic potential and therapeutic relevance in this malignancy characterized by a still unmet clinical need.

Treatment of locally advanced pancreatic cancer with irreversible electroporation - a Danish single center study of safety and feasibility.

OBJECTIVES: Irreversible electroporation (IRE) is a novel non-thermal ablative technique applied in the treatment of unresectable locally advanced pancreatic cancer (LAPC). This paper reports on the initial experience with IRE of unresectable LAPC in our institution. METHODS: From October 2013 to March 2018, patients with unresectable LAPC referred for IRE at the Department of Gastrointestinal Surgery, Aalborg University Hospital, were considered for inclusion in the study. Ninety-day morbidity, 30-day mortality, pain score, length of hospital stay (LOS) and overall survival (OS) were recorded. RESULTS: We included 33 patients receiving 40 IRE ablations in total. The median visual analogue scale (VAS)-score was four (range 0-10) two hours after IRE, and one (range 0-8) eight hours after IRE. The median LOS was one day (range 1-13 days). Post-procedural complications occurred in 21 of 40 ablations (53%), of which eight (20%) were major (Clavien-Dindo grade III or more). A proportion of the observed complications might be attributed to disease progression and not IRE per se. Although not statistically significant, we observed increased severity of complications in tumors above 3.5 cm. The 30-day mortality was 5% (2/40). The median OS was 10.7 months (range 0.6-53.8 months) from the initial IRE procedure, and 18.5 months (range 4.9-65.8 months) from time of diagnosis. CONCLUSIONS: In our institution, IRE seems as a feasible consolidative treatment of unresectable LAPC with an acceptable safety profile. The oncological outcome of IRE in patients with unresectable LAPC is to be further evaluated in a planned phase 2 clinical trial (CHEMOFIRE-2).

Validating registry data on statins prescriptions by blood measurements.

PURPOSE: To validate prescription registry data as a measurement of adherence to statins through a direct method using assays for selected statins in serial blood samples collected from two prospective cohorts of Danish colorectal cancer patients. METHODS: We linked information on statin prescriptions from the Aarhus University Prescription Database with the cancer cohorts from Aalborg University Hospital. For statin-prescribed patients, we calculated a prescription window covering the anticipated duration of the prescription. For each statin-prescribed patient with at least one blood sample in a prescription window, we selected without replacement a never-statin-prescribed patient matched on sex, age, and calendar year of surgery. Each of the selected blood samples were analyzed using assays to detect statins. We calculated the positive and negative predictive value of the prescription registry reporting using the assay result as the gold standard. RESULTS: We identified 73 ever-statin-prescribed patients with a total of 253 blood samples and 74 blood samples among never-statin-prescribed patients. The positive predictive value for prescribed patients, with presence of statins in at least one blood sample as the gold standard, was 93% (95% CI, 86%-97%) and the negative predictive value was 93% (95% CI, 86%-97%). Stratified results did not reveal substantial differences in predictive values. Fifty-two (71%) of the statin-prescribed patients had statins in every blood sample, suggesting continuous adherence. CONCLUSION: This study showed a high adherence with treatment with statins among colorectal cancer patients.

The prognostic efficacy of cell-free DNA hypermethylation in colorectal cancer.

Epigenetic alterations in colorectal cancer (CRC) cause important differences in the underlying tumor biology and aggressiveness. DNA hypermethylation is central for the development of CRC but the prognostic impact remains elusive. We aimed to assess the association between cell-free hypermethylated DNA and stage and survival in colorectal cancer (CRC). We analyzed pre-treatment plasma samples from 193 patients with CRC. Thirty gene-promoter regions were analyzed using methylation specific PCR. We compared the median number (range) of hypermethylated promoter regions with CRC stage, and constructed a multivariable Cox-regression model adjusted for stage, to evaluate the added prognostic information. The median number of hypermethylated promoter regions was nine (0-28) in patients with distant metastasis compared to five (0-19) in patients without metastatic disease (p < 0.0001). The majority of the hypermethylated promoter regions inferred a poor prognosis. Cox-regression analysis adjusted for patient age, sex, pre-treatment CEA-levels, and disease stage, showed that RARB (HR = 1.99, 95% CI [1.07, 3.72]) and RASSF1A (HR = 3.35, 95% CI [1.76, 6.38]) hypermethylation inferred a significant effect on survival. The risk of metastasis increase with the number of cell-free hypermethylated promoter regions. The presence of RARB and RASSF1A hypermethylation indicated aggressive disease, regardless of stage at the time of diagnosis.

Hypermethylated DNA, a circulating biomarker for colorectal cancer detection.

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers in the western world. Screening is an efficient method of reducing cancer-related mortality. Molecular biomarkers for cancer in general and CRC in particular have been proposed, and hypermethylated DNA from stool or blood samples are already implemented as biomarkers for CRC screening. We aimed to evaluate the performance of proven hypermethylated DNA promoter regions as plasma based biomarkers for CRC detection. METHODS: We conducted a cross-sectional case-control study of 193 CRC patients and 102 colonoscopy-verified healthy controls. Using methylation specific polymerase chain reaction, we evaluated 30 DNA promoter regions previously found to be CRC specific. We used multivariable logistic regression with stepwise backwards selection, and subsequent leave-pair-out cross validation, to calculate the optimism corrected area under the receiver operating characteristics curve (AUC) for all stage as well as early stage CRC. RESULTS: None of the individual DNA promoter regions provided an overall sensitivity above 30% at a reasonable specificity. However, seven hypermethylated promoter regions (ALX4, BMP3, NPTX2, RARB, SDC2, SEPT9, and VIM) along with the covariates sex and age yielded an optimism corrected AUC of 0.86 for all stage CRC and 0.85 for early stage CRC. Overall sensitivity for CRC detection was 90.7% at 72.5% specificity using a cut point value of 0.5. CONCLUSIONS: Individual hypermethylated DNA promoter regions have limited value as CRC screening markers. However, a panel of seven hypermethylated promoter regions show great promise as a model for CRC detection.

[Splenic injury after sigmoidoscopy]. / Miltlæsion efter sigmoideoskopi.

Endoscopy of colon and rectum is a commonly used diagnostic and therapeutic procedure, which is generally safe although complications such as bleeding and perforation occur. There is, however, a small risk of splenic injury with potentially lethal outcome. We describe a case of splenic injury after sigmoidoscopy in a 48-year-old male.

Prognostic value of preoperative D-dimer and carcinoembryonic antigen levels in patients undergoing intended curative resection for colorectal cancer: a prospective cohort study.

PURPOSE: Carcinoembryonic antigen (CEA) has limited value as an isolated predictor for survival among colorectal cancer (CRC) patients. D-dimer (DD) is a strong predictor of survival among metastatic CRC patients, but the prognostic value in non-metastatic CRC patients remains controversial. We examined the prognostic value of preoperative DD levels in relation to CEA levels in non-metastatic, resectable CRC patients. METHODS: Between October 2003 and November 2005, 166 patients were included. We used the Kaplan-Meier method to compute 5-year mortality rates, stratified by preoperative DD and CEA levels. Adjusted Cox regression analysis was used to compute mortality rate ratios (MRRs) during postoperative years 0-1 and 1-5 based on the preoperative CEA and DD levels. RESULTS: The cumulative 5-year mortality rate was 15 % (95 % confidence interval [CI], 9-25 %) in patients with normal DD and CEA levels, 30 % (CI, 16-53 %) in patients with isolated elevated CEA levels, 37 % (CI, 25-53 %) in patients with isolated elevated DD levels, and 60 % (CI, 37-83 %) in patients with elevated CEA and DD levels. Elevated CEA was associated with an approximately ten-fold increase in mortality within the first postoperative year (adjusted MRR 9.8, CI 2.5-38.3); this association was lost during postoperative years 1-5 (adjusted MRR 1.1, CI 0.5-2.7). Elevated DD was associated with a greater than two-fold increase in mortality during postoperative years 0-1 (adjusted MRR 2.8, CI 0.7-11.0) and 1-5 (adjusted MRR 2.2, CI 1.1-4.8). CONCLUSION: DD is a strong predictor of survival among non-metastatic curatively resected CRC patients, particularly in combination with CEA.

Combined use of clinical pre-test probability and D-dimer test in the diagnosis of preoperative deep venous thrombosis in colorectal cancer patients.

The preoperative prevalence of deep venous thrombosis (DVT) in patients with colorectal cancer may be as high as 8%. In order to minimize the risk of pulmonary embolism, it is important to rule out preoperative DVT. A large study has confirmed that a negative D-dimer test in combination with a low clinical pre-test probability (PTP) can be safely used to rule out the tentative diagnosis of DVT in cancer patients. However, the accuracy in colorectal cancer patients is uncertain. This study assessed the diagnostic accuracy of a quantitative D-dimer assay in combination with the PTP score in ruling out preoperative DVT in colorectal cancer patients admitted for surgery. Preoperative D-dimer test and compression ultrasonography for DVT were performed in 193 consecutive patients with newly diagnosed colorectal cancer. Diagnostic accuracy indices of the D-dimer test were assessed according to the PTP score. The negative predictive value, positive predictive value, sensitivity and specificity were 99% (95% confidence interval (CI), 95-100%), 17% (95% CI, 9-26), 93% (95% CI, 68-100%) and 61% (95% CI, 53-68%), respectively. In conclusion, the combined use of pre-test probability and D-dimer test may be useful in ruling out preoperative DVT in colorectal cancer patients admitted for surgery.