Does preoperative multidisciplinary team assessment of high-risk patients improve the safety and outcomes of patients undergoing surgery?

BACKGROUND: International guidelines recommend preoperative multidisciplinary team (MDT) assessment for high-risk surgical patients. Preoperative MDT meetings can help to improve surgical care, but there is little evidence on whether they improve patient outcomes. METHODS: This paper aims to share our experience of MDT meetings for high-risk surgical patients to underline their added value to the current standard of care. An observational study of a retrospective cohort of preoperative high-risk MDT meetings of a tertiary referral hospital between January 2015 and December 2020. For 249 patients the outcomes preoperative data, MDT decisions, and patient outcomes were collected from electronic health records. MAIN RESULTS: A total of 249 patients were discussed at high-risk MDT meetings. Most of the patients (97%) were assessed as having an American Society of Anesthesiology score ≥ 3, and 219 (88%) had a European Society of Cardiology and European Society of Anaesthesiology risk score of intermediate or high. After MDT assessment, 154 (62%) were directly approved for surgery, and 39 (16%) were considered ineligible for surgery. The remaining 56 (23%) patients underwent additional assessments before reconsideration at a high-risk MDT meeting. The main reason for patients being discussed at the high-risk MDT meeting was to assess the risk-benefit ratio of surgery. Ultimately, 184 (74%) patients underwent surgery. Of the operated patients, 122 (66%) did not have a major complication in the postoperative period, and 149 patients (81%) were alive after one year. CONCLUSIONS: This cohort study shows the vulnerability and complexity of high-risk patients but also shows that the use of an MDT assessment contributes too improved peri- and postoperative treatment strategies in high-risk patients. Most patients underwent surgery after careful risk assessment and, if deemed necessary, preoperative and perioperative treatment optimization to reduce their risk.

Cost-effectiveness of selective decontamination of the digestive tract to decrease infectious complications in colorectal cancer surgery: An analysis of the SELECT trial.

INTRODUCTION: Selective decontamination of the digestive tract (SDD) is effective in reducing infectious complications in elective colorectal cancer (CRC) surgery. However, it is unclear whether SDD is cost-effective compared to standard antibiotic prophylaxis. MATERIAL & METHODS: Economic evaluation alongside multicenter randomized controlled trial, the SELECT-trial, from a healthcare perspective. Patients included underwent elective surgery for non-metastatic CRC. The intervention group received oral non-absorbable colistin, tobramycin and amphotericin B (SDD) next to standard antibiotic prophylaxis. Both groups received a single shot intravenous cefazolin and metronidazole preoperatively as standard prophylaxis. Occurrence of postoperative infectious complication in the first 30 postoperative days was extracted from medical records, Quality-Adjusted Life-Years (QALYs) based on the ED-5D-3L, and healthcare costs collected from the hospital's financial administration. RESULTS: Of the 455 patients, 228 were randomly assigned to intervention group and 227 patients to the control group. SDD significantly reduced the number of infectious complications compared to control (difference = -0.13, 95 % CI -0.05 to -0.20). No difference was found for QALYs (difference = 0.002, 95 % CI -0.002 to 0.005). Healthcare costs were statistically significantly lower in the intervention group (difference = -€1258, 95 % CI -2751 to -166). The ICER was -9872 €/infectious complication prevented and -820,380 €/QALY gained. For all willingness-to-pay thresholds, the probability that prophylactic SDD was cost-effective compared to standard prophylactic practice alone was 1.0. CONCLUSION: The addition of SDD to the standard preoperative intravenous antibiotic prophylaxis is cost-effective compared to standard prophylactic practice from a healthcare perspective and should be considered as the standard of care.

Selective Decontamination with Oral Antibiotics in Colorectal Surgery: 90-day Reintervention Rates and Long-term Oncological Follow-up.

BACKGROUND: Oral antibiotics (OAB) in colorectal surgery have been shown to reduce surgical site infections (SSIs) and possibly anastomotic leakage. However, evidence on long-term follow-up, reintervention rates and 5-year oncological follow-up is lacking. The current study aims at elucidating this knowledge gap. METHODS: This study evaluated the long-term effectiveness of perioperative 'Selective decontamination of the digestive tract' (SDD) in colorectal cancer surgery. The primary outcome was anastomotic leakage within 90 days, secondary outcomes included infectious complications, reinterventions, readmission, hospital stay, and 5-year overall and disease-free-survival. Statistical analysis including univariate and multivariate analysis was performed to identify predictors of 90-day outcomes, and Kaplan-Meier survival analysis was used for the 5-year survival outcomes. RESULTS: In total 455 patients were analyzed, 228 participants in the SDD group and 227 in the control group. Anastomotic leakage rate was not statistically different between the SDD and control group (6.6% versus 9.7%). One or more infectious complications occurred in 15.4% of patients in the SDD group and in 28.2% in the control group (OR 0.46, 95% C.I. 0.29 - 0.73). In the SDD group 8,8% of patients required a reintervention compared to 16,3% of patients in the control group (OR 0.47, 95% C.I. 0.26 - 0.84). After multivariable analysis SDD remained significant in reducing both infectious complications and reinterventions after 90-days follow-up. There was no difference between SDD and control group in 5-year overall survival and disease-free-survival. CONCLUSION: SDD as OAB is effective in reducing 90-days postoperative infectious complications and reinterventions. As such, SDD as standard OAB in elective colorectal surgery is highly recommended.

Optimizing patient selection for stereotactic ablative radiotherapy in patients with locally advanced pancreatic cancer after initial chemotherapy - a single center prospective cohort.

Background: The role of stereotactic ablative radiation therapy (SABR) as local treatment option after chemotherapy for locally advanced pancreatic cancer (LAPC) is evolving. However adequate patient selection criteria for SABR in patients with LAPC are lacking. Methods: A prospective institutional database collected data of patients with LAPC treated with chemotherapy, mainly FOLFIRINOX, followed by SABR, which was delivered using magnetic resonance guided radiotherapy, 40 Gy in 5 fractions within two weeks. Primary endpoint was overall survival (OS). Cox regression analyses were performed to identify predictors for OS. Results: Overall, 74 patients were included, median age 66 years, 45.9% had a KPS score of ≥90. Median OS was 19.6 months from diagnosis and 12.1 months from start of SABR. Local control was 90% at one year. Multivariable Cox regression analyses identified KPS ≥90, age <70, and absence of pain prior to SABR as independent favorable predictors for OS. The rate of grade ≥3 fatigue and late gastro-intestinal toxicity was 2.7%. Conclusions: SABR is a well-tolerated treatment in patients with unresectable LAPC following chemotherapy, with better outcomes when applied in patients with higher performance score, age <70 years and absence of pain. Future randomized trials will have to confirm these findings.

Perspectives of patients with colorectal cancer liver metastases on e-consultation in transmural care: a qualitative study : Is privacy really an issue?

BACKGROUND: Comprehensive cancer networks have been established to deliver high-quality care for patients with cancer. Logistic challenges are faced, when patients need to be referred for specialized treatments. Despite strengthened privacy legislations, digital platforms are increasingly used to consult specialists from dedicated liver centers or refer patients with colorectal cancer liver metastases (CRLM) for local treatment strategies. This qualitative study aimed to explore the perspectives of patients with CRLM regarding e-consultation of transmural specialists. METHODS: A focus group study was conducted. Patients referred from regional hospitals to an academic liver center for treatment of CRLM were asked to participate. Focus group discussions were audio-recorded and transcribed verbatim. A thematic content analysis of data was conducted, comprising open, axial, and selective coding of the transcripts. The consolidated criteria for reporting qualitative research (COREQ) were used. RESULTS: Two focus groups were held, involving 11 patients and 8 relatives. Three major themes were identified with regard to e-consultation in transmural care: 'data management', 'expertise', and 'information and coordination'. Confidence in the expertise of physicians appeared most important during the course of treatment, as patients experienced uncertainty after diagnosis of cancer. Despite the privacy risks, use of digital communication platforms to contact experts in the field were strongly endorsed to improve eligibility for potentially curative treatment. Moreover, e-consultation of specialists may reduce waiting times, due to effective coordination of care. CONCLUSION: Initiatives to improve medical data transfer between care providers were encouraged to achieve effective coordination of oncological care. The potential hazard of privacy violation associated with digital data exchange is accepted by patients and their relatives, provided that use of digital data improves patient's own health care, research or education.

Impact of merging two university hospitals on surgical outcome after esophagogastric and hepato-pancreato-biliary surgery: Results from a retrospective study.

Background: Due to centralization and super-specialization in medicine, hospital mergers are increasingly common. Their effect on postoperative outcomes in highly specialized surgical departments is unclear. As quality metrics often worsen after major organizational changes, preservation of quality of care during an hospital merge is of the utmost importance. Objective: To evaluate the effect of a merger of two Dutch university hospitals on quality of surgical care, volume, and timeliness of care. Methods: The upper gastro-intestinal and hepato-biliary-pancreatic sections merged on the 27th of January 2020 and the 31th of May 2021 respectively. Outcomes of all adult surgical patients were compared six months before and six months after the merger. Short-term quality metrics, volume, and timeliness of care were assessed. Results: Overall, a cohort of 631 patients were included of whom 195 were upper gastro-intestinal (97 prior to the merger, 98 after the merger) and 436 (223 prior to the merger, 213 after) hepato-biliary-pancreatic patients. There were no differences in mortality, readmission, number and severity of complications, volume, and timeliness of care six months post-merger as compared to before merger. Conclusion: This study shows that a hospital merger of two university hospitals can be performed without jeopardizing patient safety and while benefitting from centralization of highly specialized care and enhancement of medical research. Key message: This study investigated the impact of a merger of two Dutch university hospitals on quality of care, timeliness of care, and volume. It showed no deterioration in the evaluated short-term quality metrics, volume or timeliness for upper GI and HPB surgery, suggesting that a hospital merger of two university hospitals can be performed safely, while benefitting from centralization of highly specialized care and enhancement of medical research.

Impact of shifting from laparoscopic to robotic surgery during 600 minimally invasive pancreatic and liver resections.

BACKGROUND: Many centers worldwide are shifting from laparoscopic to robotic minimally invasive hepato-pancreato-biliary resections (MIS-HPB) but large single center series assessing this process are lacking. We hypothesized that the introduction of robot-assisted surgery was safe and feasible in a high-volume center. METHODS: Single center, post-hoc assessment of prospectively collected data including all consecutive MIS-HPB resections (January 2010-February 2022). As of December 2018, all MIS pancreatoduodenectomy and liver resections were robot-assisted. All surgeons had participated in dedicated training programs for laparoscopic and robotic MIS-HPB. Primary outcomes were in-hospital/30-day mortality and Clavien-Dindo ≥ 3 complications. RESULTS: Among 1875 pancreatic and liver resections, 600 (32%) were MIS-HPB resections. The overall rate of conversion was 4.3%, Clavien-Dindo ≥ 3 complications 25.7%, and in-hospital/30-day mortality 1.8% (n = 11). When comparing the period before and after the introduction of robotic MIS-HPB (Dec 2018), the overall use of MIS-HPB increased from 25.3 to 43.8% (P < 0.001) and blood loss decreased from 250 ml [IQR 100-500] to 150 ml [IQR 50-300] (P < 0.001). The 291 MIS pancreatic resections included 163 MIS pancreatoduodenectomies (52 laparoscopic, 111 robotic) with 4.3% conversion rate. The implementation of robotic pancreatoduodenectomy was associated with reduced operation time (450 vs 361 min; P < 0.001), reduced blood loss (350 vs 200 ml; P < 0.001), and a decreased rate of delayed gastric emptying (28.8% vs 9.9%; P = 0.009). The 309 MIS liver resections included 198 laparoscopic and 111 robotic procedures with a 3.6% conversion rate. The implementation of robotic liver resection was associated with less overall complications (24.7% vs 10.8%; P = 0.003) and shorter hospital stay (4 vs 3 days; P < 0.001). CONCLUSION: The introduction of robotic surgery was associated with greater implementation of MIS-HPB in up to nearly half of all pancreatic and liver resections. Although mortality and major morbidity were not affected, robotic surgery was associated with improvements in some selected outcomes. Ultimately, randomized studies and high-quality registries should determine its added value.

Adjuvant chemotherapy for resected duodenal adenocarcinoma: a case-matched analysis in nation wide cohort.

BACKGROUND: Duodenal adenocarcinoma (DA) is a rare tumor for which survival data on adjuvant chemotherapy in patients after surgical treatment are unclear. This case-matched study in a nationwide cohort aims to investigate the benefit of adjuvant chemotherapy for patients with resectable DA on overall survival. METHODS: All patients diagnosed with DA and intestinal type periampullary adenocarcinoma (PVA) in the Netherlands between 2000 and 2015 were included (n = 1316). Patients with disease stages II and III who underwent resection and adjuvant chemotherapy were matched (1:2), based on identified covariates associated with OS, with patients who underwent surgery alone. Overall survival was compared using Kaplan-Meier estimates. RESULTS: The median OS was 49.9 months in patients who underwent curative resection (n = 649). Univariate and multivariate analysis showed a significant influence of age, lymph node involvement, and T- stage on survival. The group of patients receiving adjuvant treatment consisted of 43 patients and the non-adjuvant group of 83 case-matched patients. The median OS of the complete matched cohort (n = 126) was 26.9 months. No statistically significant survival benefit was found for the adjuvant group as compared to the group treated with surgery alone (median OS = 34.4 months and 23.0 months, p = 0.20). CONCLUSION: This population-based, case-matched analysis demonstrates no statistically significant survival benefit for adjuvant chemotherapy after curative resection in stages II and III patients. Future studies with specified treatment regimens as well as thorough stratification for prognostic factors will be required in order to more definitively determine the role of adjuvant therapy.

Stereotactic ablative radiotherapy or best supportive care in patients with localized pancreatic cancer not receiving chemotherapy and surgery (PANCOSAR): a nationwide multicenter randomized controlled trial according to a TwiCs design.

BACKGROUND: Significant comorbidities, advanced age, and a poor performance status prevent surgery and systemic treatment for many patients with localized (non-metastatic) pancreatic ductal adenocarcinoma (PDAC). These patients are currently treated with 'best supportive care'. Therefore, it is desirable to find a treatment option which could improve both disease control and quality of life in these patients. A brief course of high-dose high-precision radiotherapy i.e. stereotactic ablative body radiotherapy (SABR) may be feasible. METHODS: A nationwide multicenter trial performed within a previously established large prospective cohort (the Dutch Pancreatic cancer project; PACAP) according to the 'Trial within cohorts' (TwiCs) design. Patients enrolled in the PACAP cohort routinely provide informed consent to answer quality of life questionnaires and to be randomized according to the TwiCs design when eligible for a study. Patients with localized PDAC who are unfit for chemotherapy and surgery or those who refrain from these treatments are eligible. Patients will be randomized between SABR (5 fractions of 8 Gy) with 'best supportive care' and 'best supportive care' only. The primary endpoint is overall survival from randomization. Secondary endpoints include preservation of quality of life (EORTC-QLQ-C30 and -PAN26), NRS pain score response and WHO performance scores at baseline, and, 3, 6 and 12 months. Acute and late toxicity will be scored using CTCAE criteria version 5.0: assessed at baseline, day of last fraction, at 3 and 6 weeks, and 3, 6 and 12 months following SABR. DISCUSSION: The PANCOSAR trial studies the added value of SBRT as compared to 'best supportive care' in patients with localized PDAC who are medically unfit to receive chemotherapy and surgery, or refrain from these treatments. This study will assess whether SABR, in comparison to best supportive care, can relieve or delay tumor-related symptoms, enhance quality of life, and extend survival in these patients. TRIAL REGISTRATION: Clinical trials, NCT05265663 , Registered March 3 2022, Retrospectively registered.

Detection of non-metastatic non-small-cell lung cancer in urine by methylation-specific PCR analysis: A feasibility study.

BACKGROUND: Lung cancer has the highest cancer-related mortality worldwide and earlier detection could improve outcomes. Urine circulating tumor DNA (ctDNA) represents a true non-invasive means for ambulant sample collection. In this prospective study, the potential of urine for perioperative detection of non-metastatic non-small cell lung cancer (NSCLC) using ctDNA methylation analysis is evaluated. METHODS: Preoperative urine samples of 46 surgical NSCLC patients and 50 sex and age-matched controls were analyzed for DNA methylation of NSCLC-associated methylation markers CDO1, SOX17, and TAC1, using quantitative methylation-specific PCR (qMSP). The accuracy for NSCLC detection was determined by univariable and multivariable logistic regression analysis, followed by leave-one-out cross-validation. Fourteen additional urine samples were collected postoperatively to evaluate whether DNA methylation levels alter after surgery with curative intent. RESULTS: Methylation levels of CDO1 and SOX17 were significantly elevated in patients compared to controls (P =.016 and P <.001, respectively). This marker combination yielded an area under the receiver operating curve (AUC) value of 0.71 upon leave-one-out cross-validation for non-metastatic NSCLC detection in urine. Stage I patients tended to have higher methylation levels of SOX17 as compared to stage III patients. Similar methylation levels were found across the different histological subtypes of NSCLC. In some patients with preoperative elevated methylation levels, reduced methylation levels were found in post-operative urine samples. CONCLUSIONS: Urine CDO1 and SOX17 showed increased methylation levels in NSCLC patients as compared to sex- and age-matched controls. This demonstrates that urine ctDNA methylation analysis may provide an interesting non-invasive means to detect non-metastatic NSCLC. Further studies are needed to validate the clinical usefulness of this approach and to assess the potential of post-operative monitoring.

Value of routine intraoperative frozen sections of proximal bile duct margins in perihilar cholangiocarcinoma, a retrospective multicenter and matched case-control study.

BACKGROUND: Currently, the potential benefits of additional resection after positive proximal intraoperative frozen sections (IFS) in perihilar cholangiocarcinoma (pCCA) on residual disease and oncological outcome remain uncertain. Therefore, the aim of this study is to investigate the number of R0 resections after additional resection of a positive proximal IFS and the influence of additional resections on overall survival (OS) in patients with pCCA. MATERIALS AND METHODS: A retrospective, multicenter, matched case-control study was performed, including patients undergoing resection for pCCA between 2000 and 2019 at three tertiary centers. Primary outcome was the number of achieved 'additional' R0 resections. Secondary outcomes were OS, recurrence, severe morbidity and mortality. RESULTS: Forty-four out of 328 patients undergoing resection for pCCA had a positive proximal IFS. An additional resection was performed in 35 out of 44 (79.5%) patients, which was negative in 24 (68.6%) patients. Nevertheless, seven out of these 24 patients were eventually classified as R1 resection due to other positive resection margins. Therefore, 17 (48.6%) patients could be classified as "true" R0 resection after additional resection. Ninety-day mortality after R1 resections was high (25%) and strongly influenced OS. After correction for 90-day mortality, median OS after negative additional resection was 33 months (95%CI:29.5-36.5) compared to 30 months (95%CI:24.4-35.6) after initial R1 (P = 0.875) and 46 months (95%CI:32.7-59.3) after initial R0 (P = 0.348). CONCLUSION: There were only 17 patients (out of a total of 328 patients) that potentially benefitted from routine IFS. Additional resection for a positive IFS leading to R0 resection was not associated with improved long-term survival.

Comparing practice and outcome of laparoscopic liver resection between high-volume expert centres and nationwide low-to-medium volume centres.

BACKGROUND: Based on excellent outcomes from high-volume centres, laparoscopic liver resection is increasingly being adopted into nationwide practice which typically includes low-medium volume centres. It is unknown how the use and outcome of laparoscopic liver resection compare between high-volume centres and low-medium volume centres. This study aimed to compare use and outcome of laparoscopic liver resection in three leading European high-volume centres and nationwide practice in the Netherlands. METHOD: An international, retrospective multicentre cohort study including data from three European high-volume centres (Oslo, Southampton and Milan) and all 20 centres in the Netherlands performing laparoscopic liver resection (low-medium volume practice) from January 2011 to December 2016. A high-volume centre is defined as a centre performing >50 laparoscopic liver resections per year. Patients were retrospectively stratified into low, moderate- and high-risk Southampton difficulty score groups. RESULTS: A total of 2425 patients were included (1540 high-volume; 885 low-medium volume). The median annual proportion of laparoscopic liver resection was 42.9 per cent in high-volume centres and 7.2 per cent in low-medium volume centres. Patients in the high-volume centres had a lower conversion rate (7.4 versus 13.1 per cent; P < 0.001) with less intraoperative incidents (9.3 versus 14.6 per cent; P = 0.002) as compared to low-medium volume centres. Whereas postoperative morbidity and mortality rates were similar in the two groups, a lower reintervention rate (5.1 versus 7.2 per cent; P = 0.034) and a shorter postoperative hospital stay (3 versus 5 days; P < 0.001) were observed in the high-volume centres as compared to the low-medium volume centres. In each Southampton difficulty score group, the conversion rate was lower and hospital stay shorter in high-volume centres. The rate of intraoperative incidents did not differ in the low-risk group, whilst in the moderate-risk and high-risk groups this rate was lower in high-volume centres (absolute difference 6.7 and 14.2 per cent; all P < 0.004). CONCLUSION: High-volume expert centres had a sixfold higher use of laparoscopic liver resection, less conversions, and shorter hospital stay, as compared to a nationwide low-medium volume practice. Stratification into Southampton difficulty score risk groups identified some differences but largely outcomes appeared better for high-volume centres in each risk group.

Advanced image analytics predicting clinical outcomes in patients with colorectal liver metastases: A systematic review of the literature.

BACKGROUND: To better select patients with colorectal liver metastases (CRLM) for an optimal selection of treatment strategy (i.e. local, systemic or combined treatment) new prognostic models are warranted. In the last decade, radiomics has emerged as a field to create predictive models based on imaging features. This systematic review aims to investigate the current state and potential of radiomics to predict clinical outcomes in patients with CRLM. METHODS: A comprehensive literature search was conducted in the electronic databases of PubMed, Embase, and Cochrane Library, according to PRISMA guidelines. Original studies reporting on radiomics predicting clinical outcome in patients diagnosed with CRLM were included. Clinical outcomes were defined as response to systemic treatment, recurrence of disease, and survival (overall, progression-free, disease-free). Primary outcome was the predictive performance of radiomics. A narrative synthesis of the results was made. Methodological quality was assessed using the radiomics quality score. RESULTS: In 11 out of 14 included studies, radiomics was predictive for response to treatment, recurrence of disease, survival, or a combination of outcomes. Combining clinical parameters and radiomic features in multivariate modelling often improved the predictive performance. Different types of individual features were found prognostic. Noticeable were the contrary levels of heterogeneous and homogeneous features in patients with good response. The methodological quality as assessed by the radiomics quality score varied considerably between studies. CONCLUSION: Radiomics appears a promising non-invasive method to predict clinical outcome and improve personalized decision-making in patients with CRLM. However, results were contradictory and difficult to compare. Standardized prospective studies are warranted to establish the added value of radiomics in patients with CRLM.

Clinical relevant pancreatic fistula after pancreatoduodenectomy: when negative amylase levels tell the truth.

Drain Amylase level are routinely determined to diagnose pancreatic fistula after Pancreatocoduodenectomy. Consensus is lacking regarding the cut-off value of amylase to diagnosis clinically relevant postoperative pancreatic fistulae (POPF). The present study proposes a model based on Amylase Value in the Drain (AVD) measured in the first three postoperative days to predict a POPF. Amylase cut-offs were selected from a previous published systematic review and the accuracy were validated in a multicentre database from 12 centres in 2 countries. The present study defined POPF the 2016 ISGPS criteria (3 times the upper limit of normal serum amylase). A learning machine method was used to correlate AVD with the diagnosis of POPF. Overall, 454 (27%) of 1638 patients developed POPF. Machine learning excluded a clinically relevant postoperative pancreatic fistulae with an AUC of 0.962 (95% CI 0.940-0.984) in the first five postoperative days. An AVD at a cut-off of 270 U/L in 2 days in the first three postoperative days excluded a POPF with an AUC of 0.869 (CI 0.81-0.90, p < 0.0001). A single AVD in the first three postoperative days may not exclude POPF after pancreatoduodenectomy. The levels should be monitored until day 3 and have two negative values before removing the drain. In the group with a positive level, the drain should be kept in and AVD monitored until postoperative day five.

Focal adhesion kinase inhibition synergizes with nab-paclitaxel to target pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a very lethal disease, with minimal therapeutic options. Aberrant tyrosine kinase activity influences tumor growth and is regulated by phosphorylation. We investigated phosphorylated kinases as target in PDAC. METHODS: Mass spectrometry-based phosphotyrosine proteomic analysis on PDAC cell lines was used to evaluate active kinases. Pathway analysis and inferred kinase activity analysis was performed to identify novel targets. Subsequently, we investigated targeting of focal adhesion kinase (FAK) in vitro with drug perturbations in combination with chemotherapeutics used against PDAC. Tyrosine phosphoproteomics upon treatment was performed to evaluate signaling. An orthotopic model of PDAC was used to evaluate the combination of defactinib with nab-paclitaxel. RESULTS: PDAC cell lines portrayed high activity of multiple receptor tyrosine kinases to various degree. The non-receptor kinase, FAK, was identified in all cell lines by our phosphotyrosine proteomic screen and pathway analysis. Targeting of this kinase with defactinib validated reduced phosphorylation profiles. Additionally, FAK inhibition had anti-proliferative and anti-migratory effects. Combination with (nab-)paclitaxel had a synergistic effect on cell proliferation in vitro and reduced tumor growth in vivo. CONCLUSIONS: Our study shows high phosphorylation of several oncogenic receptor tyrosine kinases in PDAC cells and validated FAK inhibition as potential synergistic target with Nab-paclitaxel against this devastating disease.

Exocrine pancreatic insufficiency after esophagectomy: a systematic review of literature.

Complaints of maldigestion, malabsorption, and unintended weight loss after esophagectomy are often attributed to an impaired exocrine pancreatic function. This review systematically summarizes all literature reporting on the presence of exocrine pancreatic insufficiency (EPI) after esophagectomy and the effect of treatment with pancreatic enzymes on gastrointestinal complaints, body weight, and quality of life. Databases of PubMed, Embase, and Wiley/Cochrane Library were searched systematically until July 2020. Studies reporting on EPI and pancreatic enzyme replacement therapy after esophagectomy were included. The Newcastle-Ottawa scale was used to assess study quality. Four studies, including 158 patients, were selected. The maximum score for study quality was six (range 4-6). Exocrine pancreatic function was investigated in three studies, measured by fecal elastase-1 and 72-hour fecal fat excretion. Fecal elastase-1 levels <200 µg/g were reported in 16% of patients at 4 months, 18% at 6 months, and 31% at 18-24 months postoperatively. A decreased fecal fat absorption was noticed in 57% 1 month postoperatively. Treatment with pancreatic enzymes was reported in two studies. In patients with fecal elastase-1 levels <200 µg/g, 90% of patients reported improvement in symptoms and 70% reported improvement in weight. In patients with complaints of steatorrhea, 87% noticed settlement of symptoms. Based on current literature, complaints of maldigestion, malabsorption, and unintended weight loss after esophagectomy are common and can be related to an impaired exocrine pancreatic function. High-quality studies evaluating the presence of EPI and the effect of treatment with pancreatic enzymes after esophagectomy are needed to verify this conclusion.

Detection of colorectal cancer in urine using DNA methylation analysis.

Colorectal cancer (CRC) is the second leading cause for cancer-related death globally. Clinically, there is an urgent need for non-invasive CRC detection. This study assessed the feasibility of CRC detection by analysis of tumor-derived methylated DNA fragments in urine. Urine samples, including both unfractioned and supernatant urine fractions, of 92 CRC patients and 63 healthy volunteers were analyzed for DNA methylation levels of 6 CRC-associated markers (SEPT9, TMEFF2, SDC2, NDRG4, VIM and ALX4). Optimal marker panels were determined by two statistical approaches. Methylation levels of SEPT9 were significantly increased in urine supernatant of CRC patients compared to controls (p < 0.0001). Methylation analysis in unfractioned urine appeared inaccurate. Following multivariate logistic regression and classification and regression tree analysis, a marker panel consisting of SEPT9 and SDC2 was able to detect up to 70% of CRC cases in urine supernatant at 86% specificity. First evidence is provided for CRC detection in urine by SEPT9 methylation analysis, which combined with SDC2 allows for an optimal differentiation between CRC patients and controls. Urine therefore provides a promising liquid biopsy for non-invasive CRC detection.

Microscopic resection margin status in pancreatic ductal adenocarcinoma - A nationwide analysis.

INTRODUCTION: First, this study aimed to assess the prognostic value of different definitions for resection margin status on disease-free survival (DFS) and overall survival (OS) in pancreatic ductal adenocarcinoma (PDAC). Second, preoperative predictors of direct margin involvement were identified. MATERIALS AND METHODS: This nationwide observational cohort study included all patients who underwent upfront PDAC resection (2014-2016), as registered in the prospective Dutch Pancreatic Cancer Audit. Patients were subdivided into three groups: R0 (≥1 mm margin clearance), R1 (<1 mm margin clearance) or R1 (direct margin involvement). Survival was compared using multivariable Cox regression analysis. Logistic regression with baseline variables was performed to identify preoperative predictors of R1 (direct). RESULTS: 595 patients with a median OS of 18 months (IQR 10-32 months) months were analysed. R0 (≥1 mm) was achieved in 277 patients (47%), R1 (<1 mm) in 146 patients (24%) and R1 (direct) in 172 patients (29%). R1 (direct) was associated with a worse OS, as compared with both R0 (≥1 mm) (hazard ratio (HR) 1.35 [95% and confidence interval (CI) 1.08-1.70); P < 0.01) and R1 (<1 mm) (HR 1.29 [95%CI 1.01-1.67]; P < 0.05). No OS difference was found between R0 (≥1 mm) and R1 (<1 mm) (HR 1.05 [95% CI 0.82-1.34]; P = 0.71). Preoperative predictors associated with an increased risk of R1 (direct) included age, male sex, performance score 2-4, and venous or arterial tumour involvement. CONCLUSION: Resection margin clearance of <1 mm, but without direct margin involvement, does not affect survival, as compared with a margin clearance of ≥1 mm. Given that any vascular tumour involvement on preoperative imaging was associated with an increased risk of R1 (direct) resection with upfront surgery, neoadjuvant therapy might be considered in these patients.