IMARI: multi-Interventional program for prevention and early Management of Anastomotic leakage after low anterior resection in Rectal cancer patIents: rationale and study protocol.

BACKGROUND: Anastomotic leakage (AL) is still a common and feared complication after low anterior resection (LAR) for rectal cancer. The multifactorial pathophysiology of AL and lack of standardised treatment options requires a multi-modal approach to improve long-term anastomotic integrity. The objective of the IMARI-trial is to determine whether the one-year anastomotic integrity rate in patients undergoing LAR for rectal cancer can be improved using a multi-interventional program. METHODS: IMARI is a multicentre prospective clinical effectiveness trial, whereby current local practice (control cohort) will be evaluated, and subsequently compared to results after implementation of the multi-interventional program (intervention cohort). Patients undergoing LAR for rectal cancer will be included. The multi-interventional program includes three preventive interventions (mechanical bowel preparation with oral antibiotics, tailored full splenic flexure mobilization and intraoperative fluorescence angiography using indocyanine green) combined with a standardised pathway for early detection and active management of AL. The primary outcome is anastomotic integrity, confirmed by CT-scan at one year postoperatively. Secondary outcomes include incidence of AL, protocol compliance and association with AL, temporary and permanent stoma rate, reintervention rate, quality of life and functional outcome. Microbiome analysis will be conducted to investigate the role of the rectal microbiome in AL. In a Dutch nationwide study, the AL rate was 20%, with anastomotic integrity of 90% after one year. Based on an expected reduction of AL due to the preventive approaches of 50%, and increase of anastomotic integrity by a standardised pathway for early detection and active management of AL, we hypothesised that the anastomotic integrity rate will increase from 90 to 97% at one year. An improvement of 7% in anastomotic integrity at one year was considered clinically relevant. A total number of 488 patients (244 per cohort) are needed to detect this difference, with 80% statistical power. DISCUSSION: The IMARI-trial is designed to evaluate whether a multi-interventional program can improve long-term anastomotic integrity after rectal cancer surgery. The uniqueness of IMARI lies in the multi-modal design that addresses the multifactorial pathophysiology for prevention, and a standardised pathway for early detection and active treatment of AL. TRIAL REGISTRATION: Trialregister.nl ( NL8261 ), January 2020.

Risk factors for postoperative delirium after elective major abdominal surgery in elderly patients: A cohort study.

BACKGROUND: Prehabilitation programs have recently been suggested as potentially able to lower the incidence of delirium in elderly patients undergoing major abdominal surgery. For these prehabilitation programs to become successful, it is essential to identify those patients who are most likely to develop a delirium. MATERIAL AND METHODS: A single-centre cohort study was conducted. Inclusion criteria were: age ≥70 years and scheduled for abdominal surgery for colorectal cancer or an abdominal aortic aneurysm between January 2013 and June 2018. Baseline patient, surgical, anaesthesiologic and haematological characteristics were collected. A risk factor analysis was conducted, with postoperative delirium as primary outcome, by performing a multivariable logistic regression analysis. RESULTS: In this study, 627 patients were included, of whom 64 (10%) developed a delirium. Variables that differed significantly between delirious and non-delirious patients were age, burden of comorbidity, renal impairment, hypertension, cognitive impairment, history of delirium, physical and nutritional impairment, open surgery, preoperative anaemia and erythrocyte transfusion. After multivariable logistic regression analysis, risk factors for postoperative delirium after major abdominal surgery were renal impairment (OR 2.2; 95%CI 1.2-4.3), cognitive impairment (OR 4.1; 95%CI 1.8-9.2), an ASA score ≥ 3 (OR 2.0; 95% CI 1.0-3.9), being an active smoker (OR 2.7; 95%CI 1.3-5.8), ICU admission (OR 7.1; 95%CI 3.5-14.3), erythrocyte transfusion (OR 2.4; 95%CI 1.2-4.9) and a diagnosis of colorectal cancer (CRC); (OR 4.0; 95% CI 1.7-9.6). Prehabilitation had a protective effect (OR 0.5; 95% CI 0.3-0.9). CONCLUSION: Postoperative delirium is a frequent complication after major abdominal surgery in the elderly, especially in octogenarians and after open procedures. Renal impairment, cognitive impairment, being an active smoker, ICU admission, erythrocyte transfusion and a diagnosis of CRC are important risk factors for the development of delirium. Prehabilitation lowers the risk of developing a delirium.

Multimodal prehabilitation to reduce the incidence of delirium and other adverse events in elderly patients undergoing elective major abdominal surgery: An uncontrolled before-and-after study.

BACKGROUND: Delirium is a common and serious complication in elderly patients undergoing major abdominal surgery, with significant adverse outcomes. Successful strategies or therapies to reduce the incidence of delirium are scarce. The objective of this study was to assess the role of prehabilitation in reducing the incidence of delirium in elderly patients. METHODS: A single-center uncontrolled before-and-after study was conducted, including patients aged 70 years or older who underwent elective abdominal surgery for colorectal carcinoma or an abdominal aortic aneurysm between January 2013 and October 2015 (control group) and between November 2015 and June 2018 (prehabilitation group). The prehabilitation group received interventions to improve patients' physical health, nutritional status, factors of frailty and preoperative anaemia prior to surgery. The primary outcome was incidence of delirium, diagnosed with the DSM-V criteria or the confusion assessment method. Secondary outcomes were additional complications, length of stay, unplanned ICU admission, length of ICU stay, readmission rate, institutionalization, and in-hospital or 30-day mortality. RESULT: A total of 360 control patients and 267 prehabilitation patients were included in the final analysis. The mean number of prehabilitation days was 39 days. The prehabilitation group had a higher burden of comorbidities and was more physically and visually impaired at baseline. At adjusted logistic regression analysis, delirium incidence was reduced significantly from 11.7 to 8.2% (OR 0.56; 95% CI 0.32-0.98; P = 0.043). No statistically significant effects were seen on secondary outcomes. CONCLUSION: Current prehabilitation program is feasible and safe, and can reduce delirium incidence in elderly patients undergoing elective major abdominal surgery. This program merits further evaluation. TRIAL REGISTRATION: Dutch Trial Registration, NTR5932.

Variation in circumferential resection margin: Reporting and involvement in the South-Netherlands.

BACKGROUND: Since the introduction of total mesorectal surgery the outcome of rectal cancer patients has improved significantly. Involvement of the circumferential resection margin (CRM) is an important predictor of increased local recurrence, distant metastases and decreased overall survival. Abdomino perineal excision (APE) is associated with increased risk of CRM involvement. Aim of this study was to analyze reporting of CRM and to identify predictive factors for CRM involvement. METHODS: A population-based dataset was used selecting 2153 patients diagnosed between 2008 and 2013 with primary rectal cancer undergoing surgery. Variation in CRM reporting was assessed and predictive factors for CRM involvement were calculated and used in multivariate analyses. RESULTS: Large variation in CRM reporting was found between pathology departments, with missing cases varying from 6% to 30%. CRM reporting increased from 77% in 2008 to 90% in 2012 (p < 0.001). CRM involvement significantly decreased from 12% to 6% over the years (p < 0.001). In multivariate analysis type of operation, low anterior resection or APE, did not influence the risk of CRM involvement. Clinical T4-stage [odds ratio (OR) = 3.51; 95% confidence interval (CI) = 1.85-6.65) was associated with increased risk of CRM involvement, whereas neoadjuvant treatment (5 × 5 gray radiotherapy [OR 0.39; CI 0.25-0.62] or chemoradiation therapy [OR 0.30; CI 0.17-0.53]) were associated with significant decreased risk of CRM involvement. CONCLUSION: Although significant improvements are made during the last years there still is variation in reporting of CRM involvement in the Southern Netherlands. In multivariate analysis APE was no longer associated with increased risk of CRM involvement.

Postoperative delirium in elderly after elective and acute colorectal surgery: A prospective cohort study.

OBJECTIVE: To assess the frailty and the incidence of delirium in elderly patients undergoing elective and acute colorectal surgery in correlation with morbidity and mortality. METHODS: Patients aged 65 years and older having elective and acute colorectal surgery, between April 2013 and December 2013 were included in a prospective database. Patients diagnosed with a colorectal carcinoma or diverticulitis who were operated on were included. Factors that characterize frailty of patients were noted. The incidence rates of delirium after elective and acute surgery were recorded. Delirium was diagnosed using the Delirium Observation Screening Scale (DOSS). Preoperative evaluation, surgical outcome including morbidity, hospital stay and mortality were analyzed. RESULTS: Patients ≥ 65 years were included, 83 (75%) received elective and 28 (25%) acute surgery. The overall incidence of delirium was 21%, 18% for elective and 29% for patients having urgent surgery (p = 0.24). Patients with delirium were older than the non-delirious patients (median 82 years vs. 74 years; p < 0.001). Delirious patients showed higher incidence of adverse events. Hospital stay, mortality and discharge to a nursing home were significant higher in the delirious compared to the non-delirious group (p = 0.01; 0.01; 0.02 respectively). CONCLUSION: High incidence of delirium was found in both acute and elective colorectal surgery. Delirium was associated with adverse outcomes.

A close look at postoperative fluid management and electrolyte disorders after gastrointestinal surgery in a teaching hospital where patients are treated according to the ERAS protocol.

PURPOSE: To evaluate the routine postoperative fluid management in relation to the British Consensus Guidelines on Intravenous Fluid Therapy for Adult Surgical Patients 2008 by the assessment of the fluid overload and electrolyte disorders in patients who were postoperatively treated according to an 'enhanced recovery after surgery' (ERAS) protocol. METHODS: All liver, pancreatic and gastrointestinal surgical patients treated during a 10-week period were consecutively included in this analysis. All patients were treated according to a fast track protocol. Fluid balance charts and electrolyte disorders were recorded. Electrolyte disorders were reported based on the laboratory results. RESULTS: A total of 71 patients with an uncomplicated postoperative course were analysed. Even with restrictive fluid management performed as part of the ERAS protocol, hypervolemia developed in 54 % of all patients on the first postoperative day. There were no cases of excessive peripheral or pulmonary oedema in cases with excessive fluid administration. Twenty-six percent of the patients had electrolyte imbalances, euvolaemia was seen in 22 %, and 85 % of these patients had hypokalemia. CONCLUSION: Postoperative registration of fluid charts is difficult, which results in incomplete charts. This has resulted in more attention being paid to recording the fluid balance at our institution. Concerning electrolyte disorders, we recommend prophylactic potassium administration. However, there is no reason to replace standard 0.9 % NaCl/glucose 5 % by Ringer's lactate, as the British guidelines advice.

"Axillary recurrences after sentinel lymph node biopsy: a multicentre analysis and follow-up of sentinel lymph node negative breast cancer patients".

INTRODUCTION: The objective of this study was to conduct a multicentre data analysis to identify prognostic factors for developing an axillary recurrence (AR) after negative sentinel lymph node biopsy (SLNB) in a large cohort of breast cancer patients with long follow-up. PATIENTS AND METHODS: The prospective databases from different hospitals of clinically node negative breast cancer patients operated on between, 2000 and 2002 were analyzed. SLNB was performed and pathological analysis done by local pathologists according to national guidelines. Adjuvant treatment was given according to contemporary guidelines. Multivariate analysis was performed using all available variables, a p-value of <0,05 was considered to be significant. RESULTS: A total of 929 patients who did not undergo axillary lymph node dissection were identified. After a median follow up of 77 (range 1-106) months, fifteen patients developed an isolated AR (AR rate 1,6%). Multivariate analysis showed that young age (p = 0.007) and the absence of radiotherapy (p = 0.010) significantly increased the risk of developing an AR. Distant metastasis free survival (DMFS) was significantly worse for patients with an AR compared to all other breast cancer patients (p < 0,0001). CONCLUSION: Even after long-term follow up, the risk of developing an AR after a negative SLN in breast cancer is low. Young age and absence of radiation therapy are highly significant factors for developing an axillary recurrence. DMFS is worse for AR patients compared to patients initially diagnosed with N0 or N1 disease.

ARM: axillary reverse mapping - the need for selection of patients.

BACKGROUND: Axillary reverse mapping (ARM) is a technique that discerns axillary lymphatic drainage of the arm from the breast. This study was performed to evaluate both the feasibility of this technique and the proportion of metastatic involvement of ARM-nodes. PATIENTS AND METHODS: Patients with invasive breast cancer and an indication for axillary lymph node dissection (ALND) were enrolled in the study: patients with a tumor-positive sentinel lymph node (SLN(+)-group) and patients who had axillary metastases proven by preoperative cytology (CP-N(+)-group) were distinguished. ARM was performed in all patients by injecting blue dye. During surgery ARM-nodes were identified and removed first, followed by ALND. RESULTS: Between October 2009 and June 2011 93 patients underwent ARM. There were 43 patients in the SLN(+)-group and 50 patients in the CP-N(+)-group. No significant differences in visualization rate of ARM-nodes between the groups (86 vs 94% respectively, P = 0.196) were identified. In the SLN(+)-group none of the ARM-nodes contained metastases versus 11 patients (22%) in the CP-N(+)-group (P = 0.001). Patients receiving neoadjuvant systemic therapy had a significantly lower risk of additional axillary lymph node metastases (24.6 vs 44.4%, P = 0.046). DISCUSSION: The ARM procedure is technically feasible with a high visualization rate. The proportion of patients with metastases in the ARM-nodes was significantly higher in patients with proven axillary metastases than in patients with a positive SLN. Patients with SLN metastases appear to be good candidates for the ARM technique and possibly also patients with proven axillary metastases receiving neoadjuvant chemotherapy.

The incidence and significance of micrometastases in lymph nodes of patients with ductal carcinoma in situ and T1a carcinoma of the breast.

AIM: To report the incidence and predictive value of positive axillary nodes in ductal carcinoma in situ (DCIS) and T1a carcinoma of the breast. METHODS: Cases from The Netherlands Cancer Institute were used to determine the incidence of lymph-node metastases. All consecutive patients with primary breast cancer that were treated between 1989 and 1998 and who had undergone axillary dissection were selected. Patients were identified with pure DCIS (n = 71), DCIS with small invasion (n = 12), invasive ductal/lobular carcinoma (IDC/ILC) < or =5 mm (n = 18) or tubular carcinoma < or =10 mm (n = 17). All archived lymph nodes of these patients were re-evaluated using immunohistochemistry (IHC). RESULTS: In DCIS the incidence increased from 1.4% with routine staining to 11% with IHC. For DCIS with small invasion it was 0 vs 27%, respectively. In IDC/ILC sized 2-5 mm the incidence rose from 6 to 12% and in tubular carcinoma < or =10 mm from 0 to 12%. All but one of the immunohistochemically detected metastases were isolated tumour cells (n = 9) or small (micro)metastases (n = 4). Maximally two nodes per patient were affected. None of the patients with positive lymph nodes died during follow-up (mean 102 months). CONCLUSIONS: Survival of our patients appeared not to be influenced by the finding of micrometastases in the lymph nodes by IHC. Immunohistochemistry of the sentinel node seems not contributive to further treatment in these patients.

[The para-esophageal hernia: a rare hiatal hernia requiring a specific approach]. / De para-oesofageale hernia: een zeldzame hiatushernia die een eigen aanpak vereist.

In three patients, a woman aged 87 years who presented with signs indicating a myocardial infarction, a man aged 31 suffering from postprandial epigastric pain that suddenly worsened, and a woman aged 60 years with longstanding postprandial pain and recent fatigue due to anaemia, a para-oesophageal hernia was diagnosed. Para-oesophageal herniation is an uncommon disorder accounting for approximately 5% of all hernias at the oesophageal hiatus. They are distinguished from the more common sliding hiatal hernia by a relative preservation of the intra-abdominal fixation of the gastro-oesophageal junction. These patients show that the clinical presentation of para-oesophageal rolling hernias is different from that of sliding hernias. Pathological reflux may occur; though symptoms associated with a relative obstruction of the stomach within the hernia sac, such as dysphagia, are more common. Rare non-specific symptoms such as anaemia and loss of weight are also seen. Adequate therapy differs from that of a sliding hernia and should be individualized: surgical correction is indicated in a healthy patient with a symptomatic para-oesophageal hernia, such as in the last patient. However, when the hernia is incidentally diagnosed or when comorbidity is present, such as in the first patient, a wait-and-see policy is recommended. Only in case of a threatening incarceration, such as in the second patient, is an emergency operation indicated.

Effect of hormone depletion on cell survival in the EMR-86 rat mammary carcinoma.

Growth of the transplantable EMR-86 rat mammary carcinoma depends on elevated prolactin levels which are induced by oestrogenic stimulation of the pituitary. We investigated histological and cell kinetic changes during tumour regression after removal of implanted oestrogen pellets (EP), and we especially focused on the role of apoptosis. After EP removal, serum prolactin decreased to basal levels in 5 days, reaching its largest depletion during the first day. Similarly, S-phase cell fractions, assessed by bromodeoxyuridine (BrdUrd) incorporation, decreased to half the initial value during the first day and developed into a gradual decrease to basal levels thereafter. Within 10 days, tumour volumes were reduced to 20% without striking changes in tissue architecture. To quantify apoptosis, we applied a method that stains DNA breaks in tissue sections and subsequently measured the stained area by automated image cytometry. This procedure was necessary, as the subtle changes could not be detected by histological examination alone. One day after the rapid decline of the S-phase fraction, a 3-fold increase in apoptotic area was observed that remained for about 3 days and then gradually decreased. This correlated with the histologically observed reduction of tumour cells. In spite of the major cell loss, regression came to a halt after about 10 days. The surviving cell fraction is discussed within the context of a stem cell hypothesis, in which tumour cells with stem cell characteristics are less susceptible to hormone-induced apoptosis than their (non-stem) daughter cells. This notion has implications for the eradication of residual tumour cells, because a diminished susceptibility might also apply to apoptosis induced by radio- or chemotherapy.

A new method to detect apoptosis in paraffin sections: in situ end-labeling of fragmented DNA.

Apoptosis (programmed cell death) can be difficult to detect in routine histological sections. Since extensive DNA fragmentation is an important characteristic of this process, visualization of DNA breaks could greatly facilitate the identification of apoptotic cells. We describe a new staining method for formalin-fixed, paraffin-embedded tissue sections that involves an in situ end-labeling (ISEL) procedure. After protease treatment to permeate the tissue sections, biotinylated nucleotides are in situ incorporated into DNA breaks by polymerase and subsequently stained with DAB via peroxidase-conjugated avidin. Staining of cells with the morphological characteristics of apoptosis was demonstrated in tissues known to exhibit programmed cell death, i.e., prostate and uterus after castration, tumors, lymph node follicles, and embryos. Apoptotic cells could be discriminated morphologically from areas of labeled necrotic cells, in which DNA degradation also occurs. Because apoptosis is relatively easily recognized in H&E-stained sections of involuting prostates of castrated rats, we used this model system to validate the ISEL method for the quantification of apoptotic cells. A high correlation was found between the fractions of ISEL-labeled cells and the fractions of apoptotic cells that were morphologically determined in adjacent sections. We conclude that ISEL is a useful technique for quantification of apoptosis in paraffin sections, especially for those tissues in which morphological determination is difficult. Furthermore, this new staining method enables the use of automated image cytometry for evaluating apoptosis.

Immunoreactivity of proliferating cell nuclear antigen compared with bromodeoxyuridine incorporation in normal and neoplastic rat tissue.

Monoclonal antibodies (MoAbs) against proliferating cell nuclear antigen (PCNA) represent a potentially useful tool for cell kinetic analysis of tumours. Because in paraffin-embedded tissue the relationship between PCNA immunoreactivity and tumour cell proliferation is not well characterized, we have compared PCNA positivity as detected by the PC10 MoAb with the bromodeoxyuridine labelling index (BrdUrd-LI) in two different transplantable hormone-dependent rat mammary tumours. Together, these two tumour models (MCR-83 and EMR-86) cover a wide range of S-phase fractions. Evaluating 31 methacarn-fixed tumours, a strong but non-linear relationship (r = 0.98) was obtained. PCNA-positive fractions were invariably higher than corresponding BrdUrd-LIs and also higher than the estimated growth faction: growth fractions as determined by continuous BrdUrd labelling of the tumour and stromal cell population in EMR-86 carcinomas were 12 and 26 per cent lower than PCNA-positive fractions, implying that a certain fraction of non-cycling cells can also express PCNA. A dramatic disturbance in the relationship of PCNA positivity and the BrdUrd-LI was observed in the EMR-86 model after growth arrest induced by hormonal ablation: PCNA immunoreactivity remained detectable for at least 3 days, whereas the BrdUrd-LI decreased almost immediately. In comparison, PCNA immunoreactivity persisted for a much shorter period in small intestinal cells that had stopped DNA replication when moving from the crypt towards the villus. It is concluded that although differences in PCNA expression exist between various tissues, PCNA as detected by the PC10 MoAb may be used in tumours as an operational marker for the growth fraction.(ABSTRACT TRUNCATED AT 250 WORDS)

A prolactin-dependent, metastasising rat mammary carcinoma as a model for endocrine-related tumour dormancy.

In order to study the growth kinetics of breast tumours during long-term hormonal withdrawal, we developed a transplantable, invasive mammary carcinoma EMR-86 that originated in a female WAG/Olac rat bearing a subcutaneously implanted oestrogen pellet (EP). Outgrowth of transplanted tumours occurs only in the presence of an EP, and metastases are formed in lungs and regional lymph nodes. Subsequent EP removal induces rapid regression. However, tumours do not disappear completely, as small nodules persist. These dormant tumour remnants can be restimulated even after long periods. Because EP-stimulated tumours regressed after treatment with bromocriptine and dormant tumours in non-oestrogenized rats grew out after treatment with perphenazine, prolactin is the major growth-stimulating hormone in this model. Cell kinetics in the growing, regressing and dormant phase were studied by immunocytochemical detection of DNA-incorporated bromodeoxyuridine (BrdUrd) in tissue sections. BrdUrd labelling indices decreased from 21.6 +/- 3.0% to less than 1% within 7 days after EP removal. After prolonged hormonal withdrawal (up to 90 days) BrdUrd-labelled tumour cells could always be demonstrated (range 0.4-0.8%), without a concomitant increase in tumour volume. Additional treatment either with bromocriptine or with ovariectomy could not significantly reduce this residual proliferative activity, as demonstrated by continuous BrdUrd labelling experiments. The results indicate that in vivo dormancy may represent a steady state of cell division and cell loss, rather than an accumulation of cells in a non-cycling G0 state.

Cell-cycle-related staining patterns of anti-proliferating cell nuclear antigen monoclonal antibodies. Comparison with BrdUrd labeling and Ki-67 staining.

Monoclonal antibodies (MAbs) to nuclear antigens are increasingly used as tools to obtain valuable information concerning the proliferative characteristics of various types of cancer. Prerequisite for the application of these MAbs in surgical pathology is establishment of the level of expression and/or cellular distribution of the antigens in relation to distinct cell-cycle compartments. In this study the topologic distribution of proliferating cell nuclear antigen (PCNA), an auxiliary protein of DNA polymerase delta, as recognized by human autoantiserum (AK) and two recently developed MAbs (19A2 and 19F4), was evaluated. Using cultured human cancer cells as a model system, and providing optimal fixation/permeation procedures are applied, these antibodies display a high affinity for PCNA bound to nuclear replicon clusters, resulting in distinct granular staining patterns. A more diffuse nucleoplasmic PCNA staining was mainly restricted to non-S-phase cells; in methanol-fixed cells, staining intensity of this form relative to the replicon-bound form appeared higher after staining with 19A2 than with 19F4 or AK. Comparing PCNA expression (detected with 19A2) with the expression of the Ki-67 antigen, PCNA-negative cells are also Ki-67 negative. In MCF-7 human breast cancer cells treated with 10(-6) mol/l (molar) tamoxifen, the fraction of nuclei showing replication patterns decreased from 42% to 8% within 8 days, but PCNA and Ki-67 antigens remained detectable in most cells during this interval, indicating a relatively slow decrease of antigen expression in cells that have entered a quiescent state. Treatment of MCF-7 cells with 10(-6) mol/l methotrexate resulted in a rapid accumulation of cells with an early S-phase DNA content; PCNA replication patterns showing a frequency distribution reflecting this DNA content were observed up to 48 hours after treatment. This indicates that the presence of replication patterns as visualized with anti-PCNAs is not a measure of replicative activity per se. It is concluded that, providing nuclear non-S-phase PCNA staining is faint relative to staining of replicon clusters, anti-PCNA antibodies may be excellent markers to detect in situ cells with S-phase DNA contents.