Survival of patients with colorectal liver metastases treated with and without preoperative chemotherapy: Nationwide propensity score-matched study.

INTRODUCTION: Routine treatment with preoperative systemic chemotherapy (CTx) in patients with colorectal liver metastases (CRLM) remains controversial due to lack of consistent evidence demonstrating associated survival benefits. This study aimed to determine the effect of preoperative CTx on overall survival (OS) compared to surgery alone and to assess hospital and oncological network variation in 5-year OS. METHODS: This was a population-based study of all patients who underwent liver resection for CRLM between 2014 and 2017 in the Netherlands. After 1:1 propensity score matching (PSM), OS was compared between patients treated with and without preoperative CTx. Hospital and oncological network variation in 5-year OS corrected for case-mix factors was calculated using an observed/expected ratio. RESULTS: Of 2820 patients included, 852 (30.2%) and 1968 (69.8%) patients were treated with preoperative CTx and surgery alone, respectively. After PSM, 537 patients remained in each group, median number of CRLM; 3 [IQR 2-4], median size of CRLM; 28 mm [IQR 18-44], synchronous CLRM (71.1%). Median follow-up was 80.8 months. Five-year OS rates after PSM for patients treated with and without preoperative chemotherapy were 40.2% versus 38.3% (log-rank P = 0.734). After stratification for low, medium, and high tumour burden based on the tumour burden score (TBS) OS was similar for preoperative chemotherapy vs. surgery alone (log-rank P = 0.486, P = 0.914, and P = 0.744, respectively). After correction for non-modifiable patient and tumour characteristics, no relevant hospital or oncological network variation in five-year OS was observed. CONCLUSION: In patients eligible for surgical resection, preoperative chemotherapy does not provide an overall survival benefit compared to surgery alone.

Ferric carboxymaltose infusion versus oral iron supplementation for preoperative iron deficiency anaemia in patients with colorectal cancer (FIT): a multicentre, open-label, randomised, controlled trial.

BACKGROUND: A third of patients with colorectal cancer who are eligible for surgery in high-income countries have concomitant anaemia associated with adverse outcomes. We aimed to compare the efficacy of preoperative intravenous and oral iron supplementation in patients with colorectal cancer and iron deficiency anaemia. METHODS: In the FIT multicentre, open-label, randomised, controlled trial, adult patients (aged 18 years or older) with M0 stage colorectal cancer scheduled for elective curative resection and iron deficiency anaemia (defined as haemoglobin level of less than 7·5 mmol/L (12 g/dL) for women and less than 8 mmol/L (13 g/dL) for men, and a transferrin saturation of less than 20%) were randomly assigned to either 1-2 g of ferric carboxymaltose intravenously or three tablets of 200 mg of oral ferrous fumarate daily. The primary endpoint was the proportion of patients with normalised haemoglobin levels before surgery (≥12 g/dL for women and ≥13 g/dL for men). An intention-to-treat analysis was done for the primary analysis. Safety was analysed in all patients who received treatment. The trial was registered at ClincalTrials.gov, NCT02243735, and has completed recruitment. FINDINGS: Between Oct 31, 2014, and Feb 23, 2021, 202 patients were included and assigned to intravenous (n=96) or oral (n=106) iron treatment. Treatment began a median of 14 days (IQR 11-22) before surgery for intravenous iron and 19 days (IQR 13-27) for oral iron. Normalisation of haemoglobin at day of admission was reached in 14 (17%) of 84 patients treated intravenously and 15 (16%) of 97 patients treated orally (relative risk [RR] 1·08 [95% CI 0·55-2·10]; p=0·83), but the proportion of patients with normalised haemoglobin significantly increased for the intravenous treatment group at later timepoints (49 [60%] of 82 vs 18 [21%] of 88 at 30 days; RR 2·92 [95% CI 1·87-4·58]; p<0·0001). The most prevalent treatment-related adverse event was discoloured faeces (grade 1) after oral iron treatment (14 [13%] of 105), and no treatment-related serious adverse events or deaths were observed in either group. No differences in other safety outcomes were seen, and the most common serious adverse events were anastomotic leakage (11 [5%] of 202), aspiration pneumonia (5 [2%] of 202), and intra-abdominal abscess (5 [2%] 202). INTERPRETATION: Normalisation of haemoglobin before surgery was infrequent with both treatment regimens, but significantly improved at all other timepoints following intravenous iron treatment. Restoration of iron stores was feasible only with intravenous iron. In selected patients, surgery might be delayed to augment the effect of intravenous iron on haemoglobin normalisation. FUNDING: Vifor Pharma.

Hartmann's procedure versus sigmoidectomy with primary anastomosis for perforated diverticulitis with purulent or faecal peritonitis (LADIES): a multicentre, parallel-group, randomised, open-label, superiority trial.

BACKGROUND: Previous studies have suggested that sigmoidectomy with primary anastomosis is superior to Hartmann's procedure. The likelihood of stoma reversal after primary anastomosis has been reported to be higher and reversal seems to be associated with lower morbidity and mortality. Although promising, results from these previous studies remain uncertain because of potential selection bias. Therefore, this study aimed to assess outcomes after Hartmann's procedure versus sigmoidectomy with primary anastomosis, with or without defunctioning ileostomy, for perforated diverticulitis with purulent or faecal peritonitis (Hinchey III or IV disease) in a randomised trial. METHODS: A multicentre, randomised, open-label, superiority trial was done in eight academic hospitals and 34 teaching hospitals in Belgium, Italy, and the Netherlands. Patients aged between 18 and 85 years who presented with clinical signs of general peritonitis and suspected perforated diverticulitis were eligible for inclusion if plain abdominal radiography or CT scan showed diffuse free air or fluid. Patients with Hinchey I or II diverticulitis were not eligible for inclusion. Patients were allocated (1:1) to Hartmann's procedure or sigmoidectomy with primary anastomosis, with or without defunctioning ileostomy. Patients were enrolled by the surgeon or surgical resident involved, and secure online randomisation software was used in the operating room or by the trial coordinator on the phone. Random and concealed block sizes of two, four, or six were used, and randomisation was stratified by age (<60 and ≥60 years). The primary endpoint was 12-month stoma-free survival. Patients were analysed according to a modified intention-to-treat principle. The trial is registered with the Netherlands Trial Register, number NTR2037, and ClinicalTrials.gov, number NCT01317485. FINDINGS: Between July 1, 2010, and Feb 22, 2013, and June 9, 2013, and trial termination on June 3, 2016, 133 patients (93 with Hinchey III disease and 40 with Hinchey IV disease) were randomly assigned to Hartmann's procedure (68 patients) or primary anastomosis (65 patients). Two patients in the Hartmann's group were excluded, as was one in the primary anastomosis group; the modified intention-to-treat population therefore consisted of 66 patients in the Hartmann's procedure group (46 with Hinchey III disease, 20 with Hinchey IV disease) and 64 in the primary anastomosis group (46 with Hinchey III disease, 18 with Hinchey IV disease). In 17 (27%) of 64 patients assigned to primary anastomosis, no stoma was constructed. 12-month stoma-free survival was significantly better for patients undergoing primary anastomosis compared with Hartmann's procedure (94·6% [95% CI 88·7-100] vs 71·7% [95% CI 60·1-83·3], hazard ratio 2·79 [95% CI 1·86-4·18]; log-rank p<0·0001). There were no significant differences in short-term morbidity and mortality after the index procedure for Hartmann's procedure compared with primary anastomosis (morbidity: 29 [44%] of 66 patients vs 25 [39%] of 64, p=0·60; mortality: two [3%] vs four [6%], p=0·44). INTERPRETATION: In haemodynamically stable, immunocompetent patients younger than 85 years, primary anastomosis is preferable to Hartmann's procedure as a treatment for perforated diverticulitis (Hinchey III or Hinchey IV disease). FUNDING: Netherlands Organisation for Health Research and Development.

The ladies trial: laparoscopic peritoneal lavage or resection for purulent peritonitis and Hartmann's procedure or resection with primary anastomosis for purulent or faecal peritonitis in perforated diverticulitis (NTR2037).

BACKGROUND: Recently, excellent results are reported on laparoscopic lavage in patients with purulent perforated diverticulitis as an alternative for sigmoidectomy and ostomy.The objective of this study is to determine whether LaparOscopic LAvage and drainage is a safe and effective treatment for patients with purulent peritonitis (LOLA-arm) and to determine the optimal resectional strategy in patients with a purulent or faecal peritonitis (DIVA-arm: perforated DIVerticulitis: sigmoidresection with or without Anastomosis). METHODS/DESIGN: In this multicentre randomised trial all patients with perforated diverticulitis are included. Upon laparoscopy, patients with purulent peritonitis are treated with laparoscopic lavage and drainage, Hartmann's procedure or sigmoidectomy with primary anastomosis in a ratio of 2:1:1 (LOLA-arm). Patients with faecal peritonitis will be randomised 1:1 between Hartmann's procedure and resection with primary anastomosis (DIVA-arm). The primary combined endpoint of the LOLA-arm is major morbidity and mortality. A sample size of 132:66:66 patients will be able to detect a difference in the primary endpoint from 25% in resectional groups compared to 10% in the laparoscopic lavage group (two sided alpha = 5%, power = 90%). Endpoint of the DIVA-arm is stoma free survival one year after initial surgery. In this arm 212 patients are needed to significantly demonstrate a difference of 30% (log rank test two sided alpha = 5% and power = 90%) in favour of the patients with resection with primary anastomosis. Secondary endpoints for both arms are the number of days alive and outside the hospital, health related quality of life, health care utilisation and associated costs. DISCUSSION: The Ladies trial is a nationwide multicentre randomised trial on perforated diverticulitis that will provide evidence on the merits of laparoscopic lavage and drainage for purulent generalised peritonitis and on the optimal resectional strategy for both purulent and faecal generalised peritonitis. TRIAL REGISTRATION: Nederlands Trial Register NTR2037.

A multicenter randomized clinical trial investigating the cost-effectiveness of treatment strategies with or without antibiotics for uncomplicated acute diverticulitis (DIABOLO trial).

BACKGROUND: Conservative treatment of uncomplicated or mild diverticulitis usually includes antibiotic therapy. It is, however, uncertain whether patients with acute diverticulitis indeed benefit from antibiotics. In most guidelines issued by professional organizations antibiotics are considered mandatory in the treatment of mild diverticulitis. This advice lacks evidence and is merely based on experts' opinion. Adverse effects of the use of antibiotics are well known, including allergic reactions, development of bacterial resistance to antibiotics and other side-effects. METHODS: A randomized multicenter pragmatic clinical trial comparing two treatment strategies for uncomplicated acute diverticulitis. I) A conservative strategy with antibiotics: hospital admission, supportive measures and at least 48 hours of intravenous antibiotics which subsequently are switched to oral, if tolerated (for a total duration of antibiotic treatment of 10 days). II) A liberal strategy without antibiotics: admission only if needed on clinical grounds, supportive measures only. Patients are eligible for inclusion if they have a diagnosis of acute uncomplicated diverticulitis as demonstrated by radiological imaging. Only patients with stages 1a and 1b according to Hinchey's classification or "mild" diverticulitis according to the Ambrosetti criteria are included. The primary endpoint is time-to-full recovery within a 6-month follow-up period. Full recovery is defined as being discharged from the hospital, with a return to pre-illness activities, and VAS score below 4 without the use of daily pain medication. Secondary endpoints are proportion of patients who develop complicated diverticulitis requiring surgery or non-surgical intervention, morbidity, costs, health-related quality of life, readmission rate and acute diverticulitis recurrence rate. In a non-inferiority design 264 patients are needed in each study arm to detect a difference in time-to-full recovery of 5 days or more with a power of 85% and a confidence level of 95%. With an estimated one percent of patients lost to follow up, a total of 533 patients will be included. CONCLUSION: A clinically relevant difference of more than 5 days in time-to-full recovery between the two treatment strategies is not expected. The liberal strategy without antibiotics and without the strict requirement for hospital admission is anticipated to be more a more cost-effective approach. TRIAL REGISTRATION NUMBER: NCT01111253.

The influence of brain death on liver function.

BACKGROUND: In this study, we investigated the influence of brain death on inflammatory response and the effects of brain death on liver function both directly after explantation and after reoxygenation. METHODS: The influence of brain death on liver function was studied in rats using a brain death model and the liver slice model to mimic reoxygenation. Liver function was assessed by measuring the ATP content and the ATP-driven urea synthesis. The activation of non-parenchymal cells was studied by measuring mRNA levels of IL-10, cytokine production (IL-10 and IL-1 beta) and inducible nitric oxide synthases (iNOS) upregulation (mRNA) and protein level. RESULTS: Brain death had no direct influence on the ATP content of the liver. However, it led to induction of several cytokines because of activation of non-parenchymal cells, which led to upregulation of iNOS and to nitric oxide metabolites production. It is known that cytokine production may influence the drug metabolism capacity; however, no influence of brain death on drug metabolism was observed. An explanation may be the relatively short experimental period. CONCLUSIONS: Kupffer cells seem to be activated during the onset of brain death induction; however, they become quiescent when liver slices of brain dead rats were reoxygenated during incubation. Other non-parenchymal cells, possibly the endothelial cells, remain activated during incubation and reoxygenation in slices from brain death donors but not in slices from control livers. Future experiments in our rat liver transplantation model need to elucidate the implications of these findings.

Distinct transcriptional changes in donor kidneys upon brain death induction in rats: insights in the processes of brain death.

Brain death affects hormone regulation, inflammatory reactivity and hemodynamic stability. In transplant models, donor organs retrieved from brain dead (BD) rats suffer from increased rates of primary non-function and lower graft survival. To unravel the mechanisms behind brain death we have performed DNA microarray studies with kidney-derived RNA from normo- and hypotensive BD rats, corresponding with optimal and marginal BD donors, respectively. In kidneys from normotensive donors 63 genes were identified as either up- (55) or down-regulated (8), while 90 genes were differentially expressed (67 up-regulated) in hypotensive BD donor kidneys. Most genes were categorized in different functional groups: metabolism/transport (including the down-regulated water channel Aqp-2), inflammation/coagulation (containing the largest number (16) of up-regulated genes including selectins, Il-6, alpha- and beta-fibrinogen), cell division/fibrosis (including KIM-1 involved in tubular regeneration) and defense/repair (with the cytoprotective genes HO-1, Hsp70, MnSOD2). Also, genes encoding transcription factors (including immediate early genes as Atf-3, Egr-1) and proteins involved in signal transduction (Pik3r1) were identified. Summarizing, the use of DNA microarrays has clarified parts of the process of brain death: Brain-death-induced effects ultimately lead, via activation of transcription factors and signal transduction cascades, to differential expression of different "effector" genes. Not only deleterious processes such as inflammation and fibrosis occur in brain dead donor kidneys but genes involved in protection and early repair processes are activated as well. These findings can be used to introduce specific cytoprotective interventions in the brain dead donor to better maintain or even increase organ viability.

Donor brain death aggravates chronic rejection after lung transplantation in rats.

BACKGROUND: Many recipients of lung transplants from brain-dead donors develop bronchiolitis obliterans, a manifestation of chronic rejection. It has been shown that brain death increases inflammatory mediators and accelerates acute rejection in kidney, liver, and heart transplants. In this study, the authors investigated the hypothesis that brain death increases inflammatory mediators in the donor lung and subsequently aggravates chronic rejection of the lungs after transplantation in rats. METHODS: Brain death was induced in F344 rats by inflation of a subdurally placed balloon catheter. After 6 hr, donor lungs were assessed for influx of leukocytes, expression of cell adhesion molecules, and cytokine mRNA expression. For assessment of the lung after transplantation, lungs from brain-dead F344 rats were transplanted into WKY rats. Lung function after transplantation was monitored by chest radiographs during an observation period of 100 days. At the end of this period, the lungs were histologically examined; also, cytokine mRNA expression was measured. Lungs from ventilated living donors and living donors served as controls. RESULTS: After 6 hr of brain death, influx of polymorphonuclear cells and macrophages and expression of vascular cell adhesion molecule-1 in the donor lungs was increased. After transplantation at postoperative day 100, the lung function was significantly decreased compared with allografts from living donors. In the lung allografts from brain-dead donors, histologic symptoms of chronic rejection were obvious, including severe intimal hyperplasia but without bronchiolitis obliterans. Interleukin-2 mRNA was significantly increased in allografts from brain-dead donors compared with living donors. CONCLUSIONS: This study shows that brain death induces an inflammatory response in the donor lung and subsequently aggravates chronic rejection after transplantation. This may explain the clinical difference in long-term function between lungs from cadaveric donors and living donors.

Effect of brain death on gene expression and tissue activation in human donor kidneys.

BACKGROUND: After kidney transplantation, decreased graft survival is seen in grafts from brain dead (BD) donors compared with living donors. This might result partly from a progressive nonspecific inflammation in the graft. In this study, we focused on the effects of BD on inflammatory response (adhesion molecules, leukocyte invasion, gene expression) and stress-related heat shock proteins in the human kidney. Research outcomes and clinical donor parameters were then linked to outcome data after transplantation. METHODS: Kidney biopsy specimens and serum were obtained during organ retrieval from BD and living organ donor controls. Immunohistochemistry and semiquantitative reverse transcriptase-polymerase chain reaction were performed on the biopsy specimens. Clinical and laboratory parameters from BD donors were recorded and connected to outcome data of the recipients of the kidneys studied. RESULTS: After brain death, immunohistochemistry showed an increase of E-selectin (P<0.01) and interstitial leukocyte invasion (P<0.05) compared with controls. Also, reverse transcriptase-polymerase chain reaction showed a threefold increased heme oxygenase-1 (P<0.05) and Hsp70 (P<0.01) gene expression after BD. Levels of monocyte chemotactic protein-1 and transforming growth factor-beta were twice as high after brain death but did not reach significance. Transplantation outcome was influenced by several donor variables: positively most notably by donor treatment with desmopressin and negatively by high serum urea levels during brain death and by high intercellular adhesion molecule and vascular cell adhesion molecule expression in the kidney. Heme oxygenase-1 proved to have a protective function, but only in kidneys from living donors. CONCLUSIONS: The presence of interstitial leukocytes and the early adhesion molecule E-selectin in BD donor kidneys indicates an early-phase inflammatory process during organ retrieval. Elevated levels of monocyte chemotactic protein-1 and transforming growth factor-beta suggest a role for monocytes/macrophages in this phase. We suggest that BD causes a stress-related response against which protective heat shock proteins are formed in the future graft. This stress response may be too severe to be fully counteracted by elevated heat shock proteins. Which systemic and/or local factors trigger brain death-related graft injury is currently under investigation.

Brain death induces apoptosis in donor liver of the rat.

BACKGROUND: A difference in short- and long-term function between living-related and cadaveric donor organs is consistently shown in kidney- and liver-transplant studies. We hypothesize that this is caused by induction of apoptosis and inflammation of the potential graft because of the phase of brain death (BD) in the cadaveric donor that predisposes for additional transplant injury. Previously, we have shown inflammation in the liver of brain-dead donors by increased expression of cell adhesion molecules and influx of leukocytes. The key inflammatory mediator in inflammation is tumor necrosis factor (TNF)-alpha. In addition to being involved in inflammation, TNF-alpha also activates the potential detrimental process of apoptosis and, on the other hand, activates an antiapoptotic survival pathway by way of NF-kB. The aim of the present study was to investigate whether the inflammatory response in the liver of brain-dead donors is accompanied by changes in apoptosis and in expression of apoptosis-related proteins, in particular those regulated by NF-kB. METHODS: BD was induced by inflation of an intracranially placed balloon. Apoptosis was assessed by caspase-3 enzyme activity and terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) assay. Changes in expression of proteins involved in pathways leading to apoptosis were studied by determination of mRNA levels using semiquantitative reverse-transcriptase polymerase chain reaction followed by image analysis. TNF-receptor (TNFR), Fas, and Fas-ligand (FasL) were used as indicators for activation of the death receptor mediated pathway. Bcl-2, Bax, Bak, Bid, and A1 were used as indicators for activation of the mitochondrial pathway. RESULTS: After 6 hours of normotensive BD, the number of apoptotic cells and caspase-3 activity were significantly increased compared with non-brain-dead control rats. TUNEL staining revealed that the apoptotic cells were primarily hepatocytes. mRNA levels of all NF-kappaB induced activators (Fas, bid) and inhibitors (A1, BCl-xl, cIAP2) of both apoptotic pathways were significantly increased in liver tissue of BD donors versus non-BD controls. CONCLUSIONS: The phase of BD in the donor induces increased apoptosis of hepatocytes despite an enhanced expression of NF-kB-dependent antiapoptotic genes.

Relationship between duration of brain death and hemodynamic (in)stability on progressive dysfunction and increased immunologic activation of donor kidneys.

BACKGROUND: Consistent difference in graft survival after renal transplantation has been shown when cadaveric transplants are compared to the living related donor situation, in favor of the latter. Recently, evidence has been put forward that brain death has significant effects on the donor organ quality. In this study, we aimed to assess the relation between brain death-induced hemodynamic instability in combination with the duration of brain death on the function and immunogenicity status of potential donor kidneys. METHODS: In Wistar rats, short-term (1 hour) or long-term (6 hours) brain death in the presence or absence of hemodynamic stability was applied. Sham-operated rats served as controls (1 hour and 6 hours). Organ function was studied by monitoring serum creatinine, lactate dehydrogenase (LDH), lactate, and total protein content. Expression of cell adhesion molecules [intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)] and the influx of leukocytes in the kidney assessed the immunologic status of the kidney. RESULTS: Progressive organ dysfunction was most pronounced in hemodynamically unstable brain-dead donors reflected by increased serum creatinine levels. Regardless of hemodynamic status, a progressive inflammatory activation by cell adhesion molecule expression and an influx of leukocytes could be observed in kidneys of brain-dead rats compared with nonbrain-dead controls. CONCLUSION: Brain death causes progressive kidney dysfunction. Also, inflammatory responses reflecting tissue injury are caused by brain death. When hemodynamic instability in the brain-dead donor is not corrected, kidney dysfunction is enhanced and immune activation occurs faster and is more profound. The observed changes may predispose the graft for additional ischemia/reperfusion injury during the transplant process and hence accelerate rejection of the graft after transplantation.