Clinical added value of MRI to CT in patients scheduled for local therapy of colorectal liver metastases (CAMINO): study protocol for an international multicentre prospective diagnostic accuracy study.

BACKGROUND: Abdominal computed tomography (CT) is the standard imaging method for patients with suspected colorectal liver metastases (CRLM) in the diagnostic workup for surgery or thermal ablation. Diffusion-weighted and gadoxetic-acid-enhanced magnetic resonance imaging (MRI) of the liver is increasingly used to improve the detection rate and characterization of liver lesions. MRI is superior in detection and characterization of CRLM as compared to CT. However, it is unknown how MRI actually impacts patient management. The primary aim of the CAMINO study is to evaluate whether MRI has sufficient clinical added value to be routinely added to CT in the staging of CRLM. The secondary objective is to identify subgroups who benefit the most from additional MRI. METHODS: In this international multicentre prospective incremental diagnostic accuracy study, 298 patients with primary or recurrent CRLM scheduled for curative liver resection or thermal ablation based on CT staging will be enrolled from 17 centres across the Netherlands, Belgium, Norway, and Italy. All study participants will undergo CT and diffusion-weighted and gadoxetic-acid enhanced MRI prior to local therapy. The local multidisciplinary team will provide two local therapy plans: first, based on CT-staging and second, based on both CT and MRI. The primary outcome measure is the proportion of clinically significant CRLM (CS-CRLM) detected by MRI not visible on CT. CS-CRLM are defined as liver lesions leading to a change in local therapeutical management. If MRI detects new CRLM in segments which would have been resected in the original operative plan, these are not considered CS-CRLM. It is hypothesized that MRI will lead to the detection of CS-CRLM in ≥10% of patients which is considered the minimal clinically important difference. Furthermore, a prediction model will be developed using multivariable logistic regression modelling to evaluate the predictive value of patient, tumor and procedural variables on finding CS-CRLM on MRI. DISCUSSION: The CAMINO study will clarify the clinical added value of MRI to CT in patients with CRLM scheduled for local therapy. This study will provide the evidence required for the implementation of additional MRI in the routine work-up of patients with primary and recurrent CRLM for local therapy. TRIAL REGISTRATION: The CAMINO study was registered in the Netherlands National Trial Register under number NL8039 on September 20th 2019.

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.

Prognostic implications of occult nodal tumour cells in stage I and II colon cancer: The correlation between micrometastasis and disease recurrence.

INTRODUCTION: Occult nodal tumour cells should be categorised as micrometastasis (MMs) and isolated tumour cells (ITCs). A recent meta-analysis demonstrated that MMs, but not ITCs, are prognostic for disease recurrence in patients with stage I/II colon cancer. AIMS & METHODS: The objective of this retrospective multicenter study was to correlate MMs and ITCs to characteristics of the primary tumour, and to determine their prognostic value in patients with stage I/II colon cancer. RESULTS: One hundred ninety two patients were included in the study with a median follow up of 46 month (IQR 33-81 months). MMs were found in eight patients (4.2%), ITCs in 37 (19.3%) and occult tumour cells were absent in 147 patients (76.6%). Between these groups, tumour differentiation and venous or lymphatic invasion was equally distributed. Advanced stage (pT3/pT4) was found in 66.0% of patients without occult tumour cells (97/147), 72.9% of patients with ITCs (27/37), and 100% in patients with MMs (8/8), although this was a non-significant trend. Patients with MMs showed a significantly reduced 3 year-disease free survival compared to patients with ITCs or patients without occult tumour cells (75.0% versus 88.0% and 94.8%, respectively, p = 0.005). When adjusted for T-stage, MMs independently predicted recurrence of cancer (OR 7.6 95% CI 1.5-37.4, p = 0.012). CONCLUSION: In this study, the incidence of MMs and ITCs in patients with stage I/II colon cancer was 4.2% and 19.3%, respectively. MMs were associated with an reduced 3 year disease free survival rate, but ITCs were not.

Single-port laparoscopic appendectomy in children: single center experience in 50 patients.

BACKGROUND: Recent years evolution of minimal invasive laparoscopic procedures led to new techniques, like single-port laparoscopy (SPL), resulting in nearly-scarless procedures. The purpose of this study is to evaluate that SPL appendectomy is a safe and feasible procedure using a commercially available trocar (LESS: Laparo Endoscopic Single Site trocar; Olympus TriPort+) in pediatric patients. METHODS: From July 2011 to March 2014 all patients undergoing SPL appendectomy under 18 years were included in this retrospective study. Per- en postoperative data were collected in a prospective database. RESULTS: A total of 50 children (mean age 12 years) diagnosed as acute appendicitis underwent SPL appendectomy. SPL appendectomy was feasible and safe in all cases, both in non-perforated and perforated appendicitis. In one procedure (2%) an extra trocar was placed. Seven patients (14%) were readmitted to the hospital after initial uncomplicated postoperative course. One patient (2%) needed reoperation due to a wound abscess. Three patients (6%) were readmitted due to intra-abdominal abscesses for which antibiotics were given. CONCLUSIONS: SPL appendectomy is a safe and feasible procedure in children with acute appendicitis.

The diagnostic value of one-step nucleic acid amplification (OSNA) for sentinel lymph nodes in colon cancer patients.

BACKGROUND: Lymph node status in colon cancer is critical for prognosis estimation and treatment allocation. The purpose of this study was to compare the performance of one-step nucleic acid amplification (OSNA) through detection of cytokeratin 19 mRNA levels with routine pathological examination (RP) and multilevel fine pathological examination (FP) in sentinel lymph nodes (SLN), detected using the ex vivo SLN mapping (SLNM) procedure, in presurgically defined nonmetastatic colon cancer patients. METHODS: In this prospective study, 325 SLNs of 128 patients from the Jeroen Bosch Hospital in 's-Hertogenbosch and the Leiden University Medical Center were investigated by RP (H&E), FP (H&E and Keratin Pan immunohistochemical staining), and OSNA. The SLNs were harvested by the SLNM procedure, using Patent blue or Indocyanine green. SLNs were divided and separate parts were used for RP, FP, and the OSNA assay. RESULTS: The diagnostic value of OSNA was 82.1 and 100 % for both FP and combined method (OSNA and FP) compared with RP. An upstaging rate of 20.2 % was obtained with the use of OSNA only and 36.4 % with the use of FP only. An upstaging rate of 46.5 % was obtained by combining the two methods together. CONCLUSIONS: OSNA and FP appeared to be promising tools for the detection of lymph node micro- and macrometastases in SLNs after SLNM. The performances of OSNA and FP in this study were superior to RP. Because OSNA allows analysis of the whole lymph node, sampling bias can be avoided. OSNA therefore may improve tumor staging.

Results of construction of protective loop ileostomies and reversal surgery for colorectal surgery.

BACKGROUND: Protective loop ileostomies in colorectal surgery are constructed to reduce morbidity and reinterventions related to the primary operation. However, ileostomies are associated with stoma-related morbidity and postoperative complications following reversal surgery. Dutch national data show increased use of loop ileostomies in colorectal surgery for cancer justifying an adequate assessment of its morbidity. This study was undertaken to investigate morbidity associated with protective loop ileostomies in colorectal surgery. METHODS: Retrospectively, 118 consecutive patients undergoing left-sided colonic or rectal resection with protective loop ileostomy were included. Primary outcome was 30-day mortality. Secondary endpoints included total complication rate (including stoma-related morbidity), total reintervention risk, anastomotic leakage risk and total length of stay. RESULTS: No mortality was observed. Overall major complication, reintervention and anastomotic leakage risk for colorectal surgery were 20, 20 and 3.9%, respectively. Combined length of stay for stoma-related morbidity and reversal surgery was 12.7 days. The risk for stoma-related morbidity was 35%, and the risk for nonelective reversal was 12%. Closure rate (mean follow-up of 15 months) was 87% with a mean interval of 125 days. Reversal surgery was not correlated with mortality but with major complications (11%) and reintervention risk, anastomotic leakage risk (3.8%) and a mean length of stay of 9 days. CONCLUSION: Construction of loop ileostomies in left-sided colonic or rectal resection is associated with a low risk for anastomotic leakage at the expense of substantial stoma-related morbidity and morbidity related to reversal surgery. More accurate identification of colorectal cancer patients benefitting from protective loop ileostomy seems to be warranted.

The number of high-risk factors is related to outcome in stage II colonic cancer patients.

BACKGROUND: A subgroup of stage II colonic cancer patients are considered to be at high-risk for recurrent/metastatic disease based on 1) tumour obstruction/perforation 2) <10 lymph nodes 3) T4 lesions and 4) lymphangio-invasion. Their prognosis is regarded as comparable to stage III (T1-4N+M0) colonic cancer and it is therefore strongly advised to treat them with adjuvant chemotherapy. The purpose of this study was i) to determine the magnitude of prognostic significance of the conventional high-risk factors and ii) to determine whether the number of high-risk factors influences outcome. METHODS: We retrospectively analyzed 212 stage II colonic cancer patients undergoing surgery between January 2002 and December 2008. No adjuvant chemotherapy was given. Survival analyses were performed. RESULTS: 154/212 (73%) patients were considered to be high-risk patients based on conventional high-risk factors. 58 patients did not meet any high-risk factor, 125 patients met 1 high-risk factor and 29 patients met ≥2 high-risk factors. Median follow up was 40 months. Multivariate analysis identified four independent risk factors for recurrent/metastatic disease: age, obstruction, perforation and lymphangio-invasion. The three-year-DFS-rates for the low-risk group, the high-risk group with 1 high-risk factor and the high-risk group with ≥2 high-risk criteria are 90.4%, 87.6% and 75.9% respectively. Patients meeting ≥2 conventional high-risk criteria had a significantly worse three-year disease free survival (p < 0.002). CONCLUSIONS: Four independent high-risk factors were identified. The number of high-risk factors does influence outcome. More attention should be given to the definition and treatment of high-risk stage II colonic cancer patients.

Sentinel lymph node biopsy to direct treatment in gastric cancer. A systematic review of the literature.

Gastric cancer is one of the main causes of cancer-related deaths around the world. The prevalence of early gastric cancer (EGC) among all gastric cancers of 45-51% in Japan, but only 7-28% in Western countries. The prevalence of EGC is growing partly because of better diagnostics and screening programmes. Possible treatment options for EGC treatment are expanded by the introduction of endoscopic mucosal resection and endoscopic submucosal dissection Therefore, detailed knowledge about nodal metastatic risk is warranted. We performed a systematic review of the literature concerning studies investigating the role of sentinel lymph node biopsy in EGCr and whether there is enough proof to introduce SLN as a part of treatment for EGC in the Netherlands. Several detection substances (dye or radiocolloid) and injection methods (submucosal or subserosal) are investigated. An overall sensitivity percentage of 85.4% was found. In comparison, high and clinically sufficient percentages were observed for specificity (98.2%), negative predictive value (90.7%) and accuracy (94%). Subgroup analyses showed that the combination of dye and radiocolloid detection substances is the best method for sentinel lymph node detection in early gastric cancer. However, the precise method of sentinel lymph node biopsy in EGC has to be determined further. Large, randomized series should be initiated in Europe to address this issue.

Trends in incidence, treatment and survival of gastric adenocarcinoma between 1990 and 2007: a population-based study in the Netherlands.

BACKGROUND: Survival of gastric cancer in the Western world remains poor. We conducted a retrospective population-based study to evaluate trends in incidence, treatment and outcome of gastric adenocarcinoma. METHODS: All patients diagnosed with gastric adenocarcinoma during 1990-2007 in the Dutch Eindhoven Cancer Registry area were included (n=4,797). Trend analyses were conducted for incidence, mortality, tumour and patient characteristics, treatment and crude overall survival, according to tumour location (cardia versus non-cardia). Temporal changes in the odds of undergoing surgery and the risk of death were analysed by means of multivariable regression methods. RESULTS: Age-standardised incidence decreased among males (24-12 per 100,000 inhabitants) and females (10-6); mortality rates decreased at a similar pace. The proportion of cardia tumours remained stable. Stage distribution worsened over time among patients with cardia (stages I and II: 32% in 1990-1993 and 22% in 2006-2007, p=0.005) and non-cardia (stage IV: 33% in 1990-1993 and 40% in 2006-2007, p=0.0003) cancer. Chemotherapy rates increased in all settings. Five-year survival worsened over time for patients with non-cardia tumours. Age and stage had significant influence on survival after stratification for tumour localisation. After adjustments for relevant factors (i.e. stage), the risk of death decreased since the late 90s for patients with a cardia tumour (hazard ratio 0.8, p=0.01). CONCLUSION: The absence of improvement in survival rates indicates the need for earlier detection and prospective studies to evaluate new therapy regimens with standardised surgery and pathology.

FDG-PET has no definite role in preoperative imaging in gastric cancer.

BACKGROUND: Gastric cancer is fourth on the incidence list of cancers worldwide with a high disease-related mortality rate. Curation can only be achieved by a radical resection including an adequate lymphadenectomy. However, prognosis remains poor and cancer recurrence rates are high, also due to lymph node metastases. To improve outcome, (neo)adjuvant treatment strategies with chemo- and/or radiotherapy regimes are employed. AIMS: Accurate staging of gastric cancer at primary diagnosis is essential for adequate treatment. In this non-systematic review the role 18-F-Fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) in preoperative staging is investigated. Furthermore, the results of neoadjuvant chemotherapy-induced tumour response monitoring by FDG-PET are discussed. RESULTS AND CONCLUSION: It is concluded that currently FDG-PET has no role in the primary detection of gastric cancer due to its low sensitivity. FDG-PET shows, however, slightly better results in the evaluation of lymph node metastases in gastric cancer compared to CT and could have therefore a role in the preoperative staging. Improvement in accuracy could be achieved by using PET/CT or other PET tracers than FDG, but these modalities need further investigation. FDG-PET, however, adequately detects therapy responders at an early stage following neoadjuvant chemotherapy.

The role of APC and beta-catenin in the aetiology of aggressive fibromatosis (desmoid tumors).

BACKGROUND: Aggressive fibromatosis (syn. desmoid tumor) is a sporadically occurring neoplastic proliferation of fibroblasts originating from musculoaponeurotic planes, forming invasively growing masses without the capability to metastasize. The choice of treatment remains surgical resection with or without radiotherapy, and is characterized by high recurrence rates. Better understanding of the aetiology of aggressive fibromatosis is needed to be able to develop new treatment strategies to cope with the high recurrence rates. METHODS: Relevant studies were identified through a search of the electronic databases PubMed/ Medline. The following search terms were used: 'aggressive fibromatosis', 'desmoid tumor', 'adenomatous polyposis coli', 'APC', 'beta-catenin', 'Wnt', 'Wingless' and 'Wnt/Wingless'. Studies were selected for review on the basis of abstract reading. A hand search was performed by checking reference lists in selected articles. RESULTS: The neoplastic nature of aggressive fibromatosis and the role of the adenomatous polyposis coli (APC) and beta-catenin signaling cascade in driving the onset and progression of this disease are discussed. CONCLUSION: Mutations in either the APC or beta-catenin genes are likely to be a major driving force in the formation of these desmoid tumors. More research is needed to develop new treatment strategies.

[Lower leg amputation due to critical limb ischaemia: morbidity, mortality and rehabilitation potential]. / Onderbeenamputatie wegens kritieke ischemie: morbiditeit, sterfte en mogelijkheden tot revalidatie.

A total of 3 patients, a female aged 66 years, a male aged 67 years and a female aged 82 years, presented with rest pain or gangrene of their lower extremities as a result of critical limb ischemia (CLI). Radiographic studies showed non-reconstructable arterial obstructive disease in the 66-year-old female patient, who underwent an uncomplicated primary amputation and subsequent rehabilitation. Bypass surgery was initially performed in the male patient. However, failed reconstruction and progression of ischaemia necessitated transfemoral amputations to be performed, which was followed by impaired rehabilitation. In the 82-year-old female patient gangrene was the indication for primary amputation. She died due to progressive sepsis following surgery. In about 40% of patients with CLI, major lower extremity amputation is the ultimate solution. The morbidity, mortality and rehabilitation potential in CLI and the factors that influence these outcomes are discussed. The most clinically relevant determinants of morbidity, mortality and rehabilitation following major lower extremity amputation are comorbidity, age, preoperative mobility and amputation level.

Oestrogen modulates cardiac ischaemic remodelling through oestrogen receptor-specific mechanisms.

AIM: Observational and clinical studies suggest different responses upon sex hormone replacement therapy in ischaemic heart disease. Few studies, however, have examined the impact of oestrogen receptor-dependent mechanisms on the extent of injury after myocardial infarction (MI). Therefore, we set out to evaluate the effect of oestrogen (E2) replacement on infarct size and remodelling, and the respective role of the oestrogen receptors (ER)alpha and -beta in this process, using ERalpha- and ERbeta-deficient mice. METHODS: Wild type (WT) (ERalpha(+/+) and ERbeta(+/+)), ERalpha-deficient (ERalpha(-/-)) and ERbeta-deficient (ERbeta(-/-)) mice were ovariectomized and subsequently supplemented with E2 or placebo using subcutaneous 60-day release pellets. MI was induced by left coronary artery ligation. Two weeks following MI, haemodynamic function was assessed and infarct size was determined. RESULTS: There was no significant difference in infarct size between E2- or placebo-treated WT (ERalpha(+/+) and ERbeta(+/+)) mice. Surprisingly, E2 treatment did result in smaller infarct sizes in ERalpha(-/-) mice, but increased the infarct size in ERbeta(-/-) mice. Increase of the left ventricular mass post-MI was significantly larger in the E2-treated ERalpha(-/-) animals compared with placebo-treated animals. E2 treatment also significantly increased post-MI mortality in ERalpha(+/+), ERbeta(+/+) and ERalpha(-/-) animals, but not in ERbeta(-/-) mice. CONCLUSIONS: Although E2 modulates the infarct size in ERalpha(-/-), it also appears to be responsible for the higher mortality following MI. ERbeta appears to be the receptor involved in the modulating effects of E2 in the infarcted heart.

Early and transient gene expression changes in pressure overload-induced cardiac hypertrophy in mice.

Cardiac hypertrophy is an important risk factor for cardiac morbidity and mortality. To unravel the underlying pathogenic genetic pathways, we hybridized left ventricular RNA from Transverse Aortic Constriction mice at 48 h, 1 week, and 2, 3, and 8 weeks after surgery to microarrays containing a 15K fetal cDNA collection. Key processes involved an early restriction in the expression of metabolic genes, accompanied by increased expression of genes related to growth and reactivation of fetal genes. Most of these genes returned to basal expression levels during the later, compensated hypertrophic phase. Our findings suggest that compensated hypertrophy in these mice is established by rapid adaptation of the heart at the cost of gene expression associated with metabolic activity, with only temporary expression of possible maladaptive processes. Therefore, the transient early changes may reflect a beneficial response to pressure overload, as deterioration of cardiac hemodynamic function or heart failure does not occur.

Diagnosis and treatment of levothyroxine pseudomalabsorption.

Many causes of malabsorption of levothyroxine in patients with hypothyroidism have been thoroughly described in literature. Pseudomalabsorption, poor compliance of the patient with the therapy regime, is the most common cause of failure of levothyroxine therapy. Pseudomalabsorption is characterised by a deficient diagnostic process, patient denial and difficulties in treatment. The present article provides guidelines in diagnosing and treating pseudomalabsorption in hypothyroidism.

Diagnosing diastolic heart failure.

BACKGROUND: increasing evidence supports the existence of left ventricular diastolic dysfunction as an important cause of congestive heart failure, present in up to 40% of heart failure patients. AIM: to review the pathophysiology of LV diastolic dysfunction and diastolic heart failure and the currently available methods to diagnose these disorders. RESULTS: for diagnosing LV diastolic dysfunction, invasive hemodynamic measurements are the gold standard. Additional exercise testing with assessment of LV volumes and pressures may be of help in detecting exercise-induced elevation of filling pressures because of diastolic dysfunction. However, echocardiography is obtained more easily, and will remain the most often used method for diagnosing diastolic heart failure in the coming years. MRI may provide noninvasive determination of LV three-dimensional motion during diastole, but data on correlation of MRI data with clinical findings are scant, and possibilities for widespread application are limited at this moment. CONCLUSIONS: in the forthcoming years, optimal diagnostic and therapeutic strategies for patients with primary diastolic heart failure have to be developed. Therefore, future heart failure trials should incorporate patients with diastolic heart failure, describing precise details of LV systolic and diastolic function in their study populations.