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Purpose: Distal pancreatectomy (DP) is associated with a high complication rate of 30–50% with postoperative pancreatic fistula (POPF) as a dominant contributor. Adequate risk estimation for POPF enables surgeons to use a tailor-made approach. Assessment of the risk of POPF prior to DP can lead to the application of preventive strategies. The current study aims to validate the recently published preoperative and intraoperative distal fistula risk score (D-FRS) in a nationwide cohort. Methods: This nationwide retrospective Dutch cohort study included all patients after DP for any indication, all of whom were registered in the Dutch Pancreatic Cancer Audit (DPCA) database between 2013 and 2021. The D-FRS was validated by filling in the probability equations with data from this cohort. The predictive capacity of the models was represented by an area under the receiver operating characteristic (AUROC) curve. Results: A total of 896 patients underwent DP of which 152 (17%) developed POPF of whom 144 grade B (95%) and 8 grade C (5%). The preoperative D-FRS, consisting of the variables pancreatic neck thickness and pancreatic duct diameter, showed an AUROC of 0.73 (95%CI 0.68–0.78). The intraoperative D-FRS, comprising pancreatic neck, duct diameter, BMI, operating time, and soft pancreatic aspect, showed an AUROC of 0.69 (95%CI 0.64–0.74). Conclusion: The current study is the first nationwide validation of the preoperative and intraoperative D-FRS showing acceptable distinguishing capacity for only the preoperative D-FRS for POPF. Therefore, the preoperative score could improve prevention and mitigation strategies such as drain management, which is currently investigated in the multicenter PANDORINA trial. [ABSTRACT FROM AUTHOR]

Aim This study used a national registry to compare the outcome after a low Hartmann's procedure ( LHP), defined as removal of most of the rectum to leave a short anorectal stump and an end colostomy, and low anterior resection (LA) with or without a diverting ileostomy ( DI) in rectal cancer patients all of whom had received preoperative neoadjuvant radiotherapy ( RT). Method Patients who underwent LHP or LA with or without DI for rectal cancer after RT between 2009 and 2013 were identified from the Dutch Surgical Colorectal Audit. The postoperative outcome was compared between the three groups and risk of complications, reoperation and mortality were analysed in a multivariable model. Results The study included 4288 patients were included, of whom 27.8% underwent LHP, 20.2% LA and 52.0% LA with DI. Thirty-day mortality was higher after LHP (3.2% vs 1.3% and 1.3% for LA with or without DI, P < 0.001), but LHP was not an independent predictor of mortality in multivariable analysis. LHP and LA with DI were associated with a lower rate of abdominal infective complications (6.5% and 10.1% vs 16.2%, P < 0.001) and reoperation (7.3% and 8.1% vs 16.5%, P < 0.001). In multivariable analysis, LHP ( OR 0.35, 95% CI 0.26-0.47) and LA with DI ( OR 0.43, 95% CI 0.33-0.54) were associated with a lower risk of reoperation than LA alone. LHP was associated with a lower risk of any postoperative complication than LA with or without DI ( OR 0.81, 95% CI 0.66-0.98). Conclusion LHP and LA with DI were associated with fewer infective complications and reoperations than LA alone. The rate of any complication was less after LHR than LA with or without DI. [ABSTRACT FROM AUTHOR]

Background: Different micro-organisms can be cultured from abdominal fluid obtained from patients with intra-abdominal infection resulting from a perforated digestive tract. We evaluated a cohort of patients with abdominal sepsis admitted to the intensive care with the aim of obtaining more insight into the type of microorganisms involved and the efficacy of treatment. A 5-year prospective observational cohort study was performed in patients admitted to the intensive care unit with abdominal sepsis syndrome, defined as a perforation of the digestive tract and inflammatory response with organ failure. Abdominal fluid was obtained for microbial culture during the surgical procedures and from abdominal drains. The initial treatment protocol was cefotaxim, ciprofloxacin, metronidazole, and amphotericin B, tailored according to microbiological results. Selective decontamination of the digestive tract was administered to prevent secondary endogenous infections. Abdominal fluid was taken for microbial culture from 221 of the 239 patients admitted with abdominal sepsis. Aerobic Gram-negative bacteria (AGNB) were found in 52.9% of the cultures of abdominal fluid taken at the time of operation, of which 45% were Escherichia coli; in 36% of patients more than one AGNB was found. The incidence of AGNB was highest in colorectal perforations (68.6%) and perforated appendicitis (77.8%) and lowest in gastroduodenal perforations (20.5%). Gram-positive bacteria were found in 42.5% of the abdominal fluid cultures and most frequently in colorectal perforations (50.0%). Candida was found in 19.9% of patients, with 59.1% of these cultures being Candida albicans. The incidence of Candida was 41.0% in gastroduodenal perforations and 11.8% in colorectal perforation. Anaerobic bacteria were cultured in 77.8% of patients with perforated appendicitis. Over time, the prevalence of AGNB in abdominal fluid decreased from 117 patients (52.9%) in the first culture to one patient (6.7%) in week 4 (efficacy 87%). The prevalence of Grampositive bacteria increased from 42.5% to 86.7% in a 4-week period. The composition of the intra-abdominal flora found in critically ill patients with abdominal sepsis varies depending on the location of the perforation. The efficacy of combined surgical and antibiotic treatment was 87% in 4 weeks for AGNB. [ABSTRACT FROM AUTHOR]

Abstract Background The CARTS study is a multicenter feasibility study, investigating the role of rectum saving surgery for distal rectal cancer. Methods/Design Patients with a clinical T1-3 N0 M0 rectal adenocarcinoma below 10 cm from the anal verge will receive neoadjuvant chemoradiation therapy (25 fractions of 2 Gy with concurrent capecitabine). Transanal Endoscopic Microsurgery (TEM) will be performed 8 - 10 weeks after the end of the preoperative treatment depending on the clinical response. Primary objective is to determine the number of patients with a (near) complete pathological response after chemoradiation therapy and TEM. Secondary objectives are the local recurrence rate and quality of life after this combined therapeutic modality. A three-step analysis will be performed after 20, 33 and 55 patients to ensure the feasibility of this treatment protocol. Discussion The CARTS-study is one of the first prospective multicentre trials to investigate the role of a rectum saving treatment modality using chemoradiation therapy and local excision. The CARTS study is registered at clinicaltrials.gov (NCT01273051)

Abstract Background In predicted severe acute pancreatitis, infections have a negative effect on clinical outcome. A start of enteral nutrition (EN) within 24 hours of onset may reduce the number of infections as compared to the current practice of starting an oral diet and EN if necessary at 3-4 days after admission. Methods/Design The PYTHON trial is a randomised controlled, parallel-group, superiority multicenter trial. Patients with predicted severe acute pancreatitis (Imrie-score ≥ 3 or APACHE-II score ≥ 8 or CRP > 150 mg/L) will be randomised to EN within 24 hours or an oral diet and EN if necessary, after 72 hours after hospital admission. During a 3-year period, 208 patients will be enrolled from 20 hospitals of the Dutch Pancreatitis Study Group. The primary endpoint is a composite of mortality or infections (bacteraemia, infected pancreatic or peripancreatic necrosis, pneumonia) during hospital stay or within 6 months following randomisation. Secondary endpoints include other major morbidity (e.g. new onset organ failure, need for intervention), intolerance of enteral feeding and total costs from a societal perspective. Discussion The PYTHON trial is designed to show that a very early (< 24 h) start of EN reduces the combined endpoint of mortality or infections as compared to the current practice of an oral diet and EN if necessary at around 72 hours after admission for predicted severe acute pancreatitis. Trial Registration ISRCTN: ISRCTN18170985

The article reports on a trial comparing early nasoenteric tube feeding (ENTF) in acute pancreatic patients at 72 hours after emergency department presentation in 2014. Topics discussed include the 30% primary end point in the early group and 27% in the on-demand group, and the absence of significant differences in major infection rates between the two groups. The article states that ENTF showed no superiority over an oral diet in reducing infection or death rate in patients.

Objective: To measure the rate of LTS in resected PDAC and determine the association between predictors of OS and LTS., Summary Background Data: Long-term survival (>5 y, LTS) remains rare in pancreatic ductal adenocarcinoma (PDAC). Multiple predictors of overall survival (OS) are known but their association with LTS remains unclear., Methods: An international, multicenter retrospective study was conducted. Included were patients from 2012-2019 with resected PDAC. Excluded were those with metastases at diagnosis or resection, R2 resections, and 90-day mortality. Predictors of OS were identified using multivariable Cox regression and their prevalence in patients with LTS assessed. LTS was calculated by excluding patients with shorter follow-up and predictors of LTS were identified using multivariable logistic regression., Results: 3,003 patients were included (27.4% received neoadjuvant chemotherapy). Elevated baseline CA19-9, high tumor grade, nodal disease, and perineural and lymphovascular invasion were negative independent predictors of OS, while receipt of adjuvant chemotherapy predicted improved OS (all P<0.05). LTS was observed in 220/2,436 patients (9.0%), of whom 198 (90%) harbored poor prognostic factors: elevated baseline CA19-9 (58.1%), poor tumor differentiation (51.0%), nodal disease (46.8%), and perineural invasion (76.0%). Of those without any of these four features, 50.0% achieved LTS as compared to 21.3%, 13.3%, 5.2%, and 3.5% in those with 1, 2, 3, or 4 features., Conclusions: This bi-national cohort demonstrates a true LTS rate of 9.0% in resected PDAC. Clinicians should remain aware that presence of poor prognostic factors does not preclude LTS., Competing Interests: Conflicts of Interest: The authors declare that there are no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To assess nationwide surgical outcome after pancreatoduodenectomy (PD) in patients at very high risk for postoperative pancreatic fistula (POPF), categorized as ISGPS-D., Summary Background Data: Morbidity and mortality after ISGPS-D PD is perceived so high that a recent randomized trial advocated prophylactic total pancreatectomy (TP) as alternative aiming to lower this risk. However, current outcomes of ISGPS-D PD remain unknown as large nationwide series are lacking., Methods: Nationwide retrospective analysis including consecutive patients undergoing ISGPS-D PD (i.e., soft texture and pancreatic duct ≤3 mm), using the mandatory Dutch Pancreatic Cancer Audit (2014-2021). Primary outcome was in-hospital mortality and secondary outcomes included major morbidity (i.e., Clavien-Dindo grade ≥IIIa) and POPF (ISGPS grade B/C). The use of prophylactic TP to avoid POPF during the study period was assessed., Results: Overall, 1402 patients were included. In-hospital mortality was 4.1% (n=57), which decreased to 3.7% (n=20/536) in the last 2 years. Major morbidity occurred in 642 patients (45.9%) and POPF in 410 (30.0%), which corresponded with failure to rescue in 8.9% (n=57/642). Patients with POPF had increased rates of major morbidity (88.0% vs. 28.3%; P<0.001) and mortality (6.3% vs. 3.5%; P=0.016), compared to patients without POPF. Among 190 patients undergoing TP, prophylactic TP to prevent POPF was performed in 4 (2.1%)., Conclusion: This nationwide series found a 4.1% in-hospital mortality after ISGPS-D PD with 45.9% major morbidity, leaving little room for improvement through prophylactic TP. Nevertheless, given the outcomes in 30% of patients who develop POPF, future randomized trials should aim to prevent and mitigate POPF in this high-risk category., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Unlabelled: This population-based study evaluates the association between hospital volume and CRM (circumferential resection margin) involvement, adjusted for other confounders, in rectal cancer surgery. A low hospital volume (<20 cases/year) was independently associated with a higher risk of CRM involvement (odds ratio=1.54; 95% CI: 1.12-2.11)., Objective: To evaluate the association between hospital volume and CRM (circumferential resection margin) involvement in rectal cancer surgery., Background: To guarantee the quality of surgical treatment of rectal cancer, the Association of Surgeons of the Netherlands has stated a minimal annual volume standard of 20 procedures per hospital. The influence of hospital volume has been examined for different outcome variables in rectal cancer surgery. Its influence on the pathological outcome (CRM) however remains unclear. As long-term outcomes are best predicted by the CRM status, this parameter is of essential importance in the debate on the justification of minimal volume standards in rectal cancer surgery., Methods: Data from the Dutch Surgical Colorectal Audit (2011-2012) were used. Hospital volume was divided into 3 groups, and baseline characteristics were described. The influence of hospital volume on CRM involvement was analyzed, in a multivariate model, between low- and high-volume hospitals, according to the minimal volume standards., Results: This study included 5161 patients. CRM was recorded in 86% of patients. CRM involvement was 11% in low-volume group versus 7.7% and 7.9% in the medium- and high-volume group (P≤0.001). After adjustment for relevant confounders, the influence of hospital volume on CRM involvement was still significant odds ratio (OR) = 1.54; 95% CI: 1.12-2.11)., Conclusions: The outcomes of this pooled analysis support minimal volume standards in rectal cancer surgery. Low hospital volume was independently associated with a higher risk of CRM involvement (OR = 1.54; 95% CI: 1.12-2.11).

Introduction: In 2009, the nationwide Dutch Surgical Colorectal Audit (DSCA) was initiated by the Association of Surgeons of the Netherlands (ASN) to monitor, evaluate and improve colorectal cancer care. The DSCA is currently widely used as a blueprint for the initiation of other audits, coordinated by the Dutch Institute for Clinical Auditing (DICA). This article illustrates key elements of the DSCA and results of three years of auditing., Methods: Key elements include: a leading role of the professional association with integration of the audit in the national quality assurance policy; web-based registration by medical specialists; weekly updated online feedback to participants; annual external data verification with other data sources; improvement projects., Results: In two years, all Dutch hospitals participated in the audit. Case-ascertainment was 92% in 2010 and 95% in 2011. External data verification by comparison with the Netherlands Cancer Registry (NCR) showed high concordance of data items. Within three years, guideline compliance for diagnostics, preoperative multidisciplinary meetings and standardised reporting increased; complication-, re-intervention and postoperative mortality rates decreased significantly., Discussion: The success of the DSCA is the result of effective surgical collaboration. The leading role of the ASN in conducting the audit resulted in full participation of all colorectal surgeons in the Netherlands. By integrating the audit into the ASNs' quality assurance policy, it could be used to set national quality standards. Future challenges include reduction of administrative burden; expansion to a multidisciplinary registration; and addition of financial information and patient reported outcomes to the audit data., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the potential of isolated limb perfusion (ILP) for efficient and tumor-specific adenovirus-mediated gene transfer in sarcoma-bearing rats., Summary Background Data: A major concern in adenovirus-mediated gene therapy in cancer is the transfer of genes to organs other than the tumor, especially organs with a rapid cell turnover. Adjustment of the vector delivery route might be an option creating tumor specificity in therapeutic gene expression., Methods: Rat hind limb sarcomas (5-10 mm) were transfected with recombinant adenoviruses. Intratumoral luciferase expression after ILP was compared with systemic administration, regional infusion, or intratumoral injection using a similar dose of adenoviruses carrying the luciferase marker gene. Localization studies using lacZ as a marker gene were performed to evaluate the intratumoral distribution of transfected cells after both ILP and intratumoral injection., Results: Intratumoral luciferase activity after ILP or intratumoral administration was significantly higher compared with regional infusion or systemic administration. After ILP, luciferase gene expression was minimal in extratumoral organs, whether outside or inside the isolated circuit. Localization studies demonstrated that transfection was confined to tumor cells lying along the needle track after intratumoral injection, whereas after ILP, lacZ expression was found in viable tumor cells and in the tumor-associated vasculature., Conclusions: Using ILP, efficient and tumor-specific gene transfection can be achieved. The ILP technique might be useful for the delivery of recombinant adenoviruses carrying therapeutic gene constructs to enhance tumor control.

Aims: Isolated limb perfusion (ILP) with recombinant tumour necrosis factor-alpha (rTNF-alpha) and melphalan has recently been reported to induce major tumour responses and permit limb salvage in over 80% of patients with unresectable soft-tissue sarcomas of the extremities. We investigated whether TNF-based ILP could allow limb-sparing surgery in patients with primary, recurrent or metastatic bone sarcoma to the lower extremity who met the criteria for an amputation and had failed or refused chemotherapy., Methods: From August 1992 to December 1997, we employed ILP with rTNF-alpha and melphalan in 13 patients with unresectable bone sarcoma of the lower extremity, all of whom were candidates for amputation. The aim was to reduce tumour size and allow the performance of a limb-sparing surgery (LSS)., Results: Following ILP, none of the patients had severe local toxicity and only one patient experienced significant systemic side-effects. LSS was subsequently performed in nine of the 13 patients. LSS was feasible in an additional three patients but was not performed because of the emergence of diffused metastatic disease., Conclusions: ILP with rTNF-alpha and melphalan can allow limb salvage in patients wih locally advanced bone sarcomas who had failed standard treatment options. Its potential role in the treatment of unresectable bone sarcomas of the extremities merits further evaluation.

An isolated limb perfusion (ILP) model using soft tissue sarcoma-bearing rats was used to study prerequisites for an effective ILP, such as oxygenation of the perfusate, temperature of the limb, duration of the perfusion and concentration of tumour necrosis factor (TNF). Combination of 50 microg TNF and 40 microg melphalan demonstrated synergistic activity leading to a partial and complete response rate of 71%. In comparison to oxygenated ILP, hypoxia was shown to enhance anti-tumour activity of melphalan alone and TNF alone but not of their combined use. Shorter perfusion times decreased anti-tumour responses. At a temperature of 24-26 degrees C, anti-tumour effects were lost, whereas temperatures of 38-39 degrees C or 42-43 degrees C resulted in higher response rates. However, at 42-43 degrees C, local toxicity impaired limb function dramatically. Synergy between TNF and melphalan was lost at a dose of TNF below 10 microg in 5 ml perfusate. We conclude that the combination of TNF and melphalan has strong synergistic anti-tumour effects in our model, just as in the clinical setting. Hypoxia enhanced activity of melphalan and TNF alone but not the efficacy of their combined use. For an optimal ILP, minimal perfusion time of 30 min and minimal temperature of 38 degrees C was mandatory. Moreover, the dose of TNF could be lowered to 10 microg per 5 ml perfusate, which might allow the use of TNF in less leakage-free or less inert perfusion settings.

Introduction: Isolated limb perfusion (ILP) with TNFalpha in combination with melphalan and IFNgamma has resulted in an immediate and dramatic tumor response in patients. Such an effect was also noted following ILP in a rat sarcoma model. This model enables us to investigate several factors responsible for the TNFalpha-induced tumor responses. We applied total body irradiation (TBI) to reduce white blood cell count, to investigate the contribution of leukocytes to the anti-tumor effect of TNFalpha., Methods: Small fragments of the nonimmunogenic BN 175 sarcoma were implanted sc in the lower hind leg. A 5 Gy TBI was performed before ILP at a tumor diameter of approximately 15 mm. The hind limbs of 63 rats were perfused and were divided into 6 groups: group 1, sham perfusion, n = 9; group 2, TBI + sham perfusion, n = 6; group 3, TNFalpha 50 microgram, n = 9; group 4, melphalan 40 microgram, n = 9; group 5, TNFalpha 50 microgram + melphalan 40 microgram, n = 22; group 6, TBI + TNFalpha + melphalan ILP, n = 8. In addition, 10 rats were perfused for histological analysis at 24 h post-ILP., Results: We observed in Group 1: 9/9 progressive disease (PD); Group 2: 6/6 PD; Group 3: 9/9 PD; Group 4: 9/9 no change (NC) of tumor diameter for at least 4 days; Group 5: 6/22 NC, 16/22 complete remission (CR), 12/16 of which showed skin necrosis at the tumor site; and Group 6: 7/8 NC and 1/8 CR (without skin necrosis). After TBI, WBC reduction of 80-95% was observed, while the number of platelets was not significantly reduced and platelet aggregation was maintained at 72 %. Histological analysis revealed decreased hemorrhagic necrosis associated with the absence of PMN infiltration at the tumor margins in the TBI rats., Conclusion: TBI and the associated reduction in WBC count decreased the tumor response by TNFalpha and melphalan significantly and abrogated the immediate response of skin necrosis at the tumor site, as found in rats treated with TNFalpha and melphalan without TBI. These data strongly suggest that leukocytes play an important role in the hemorrhagic effects of TNFalpha., (Copyright 1998 Academic Press.)

The clinical success of the application of tumor necrosis factor-alpha (TNFalpha) in isolated limb perfusions in patients with advanced sarcomas, melanomas and other tumors has renewed the interest in this agent as an anticancer drug. At the Rotterdam Cancer Center, we have developed an interactive preclinical-clinical TNFalpha program that explores new methods to use TNFalpha in various settings. Regional organ perfusion models were developed and the effectivity of targeting of TNFalpha to the tumor by means of systemic administration of liposomes are tested. Furthermore various drugs and mechanisms that may enhance the activity of TNFalpha are under investigation. A summary of this comprehensive program is presented here.

Isolated limb perfusion (ILP) with TNF alpha, IFN gamma and melphalan causes impressive tumour reduction in patients with irresectable soft tissue sarcomas with a high limb salvage rate. Since this therapy could be of value in patients with progressive osteosarcoma, we performed a study in an osteosarcoma tumour model in the rat. The ROS-1 osteosarcoma was implanted s.c. in the hind leg of WAG rats. Rats were divided in four groups: rats that underwent ILP with perfusate alone, TNF alpha alone, melphalan alone or their combination. Almost all rats, treated with a sham ILP or a perfusion with 40 micrograms melphalan, showed progressive disease (PD) (6/6 and 5/6). After perfusion with 50 micrograms TNF alpha alone a varied response was observed: 2/6 PD, 2/6 no change (NC) and 2/6 a complete remission (CR). After combined perfusion: 3/6 rats had a partial remission and 3/6 a CR. The best and most consistent responses are obtained by combining TNF alpha and melphalan. The discrepancy with the in vitro sensitivity of ROS-1 indicates that indirect effects are important in this tumour model.

The clinical success of the application of TNF-alpha in the setting of isolated limb perfusions in patients with advanced sarcomas, melanomas and other tumors has renewed the interest in TNF alpha as an anticancer drug in man. We have developed an interactive preclinical-clinical TNF alpha program that explores new methods to use TNF alpha in various settings or enhance its activity. Thus we have developed regional organ perfusion models and are testing the effectivity of targeting of TNF to the tumor by means systemic administration of long circulating liposomes. Furthermore various drugs and mechanisms that may enhance the activity of TNF alpha are under investigation. An overview of this comprehensive program is presented here.