Two Days Versus Five Days of Postoperative Antibiotics for Complex Appendicitis: Cost Analysis of a Randomized, Noninferiority Trial.

OBJECTIVE: To compare costs for 2 days versus 5 days of postoperative antibiotics within the antibiotics after an aPPendectomy In Complex appendicitis trial.Background:Recent studies suggest that restrictive antibiotic use leads to a significant reduction in hospital stays without compromising patient safety. Its potential effect on societal costs remains underexplored. METHODS: This was a pragmatic, open-label, multicenter clinical trial powered for noninferiority. Patients with complex appendicitis (age ≥ 8 years) were randomly allocated to 2 days or 5 days of intravenous antibiotics after appendectomy. Patient inclusion lasted from June 2017 to June 2021 in 15 Dutch hospitals. The final follow-up was on September 1, 2021. The primary trial endpoint was a composite endpoint of infectious complications and mortality within 90 days. In the present study, the main outcome measures were overall societal costs (comprising direct health care costs and costs related to productivity loss) and cost-effectiveness. Direct health care costs were recorded based on data in the electronic patient files, complemented by a telephone follow-up at 90 days. In addition, data on loss of productivity were acquired through the validated Productivity Cost Questionnaire at 4 weeks after surgery. Cost estimates were based on prices for the year 2019. RESULTS: In total, 1005 patients were evaluated in the "intention-to-treat" analysis: 502 patients were allocated to the 2-day group and 503 to the 5-day group. The mean difference in overall societal costs was - €625 (95% CI: -€ 958 to -€ 278) to the advantage of the 2-day group. This difference was largely explained by reduced hospital stay. Productivity losses were similar between the study groups. Restricting postoperative antibiotics to 2 days was cost-effective, with estimated cost savings of €31,117 per additional infectious complication. CONCLUSIONS: Two days of postoperative antibiotics for complex appendicitis results in a statistically significant and relevant cost reduction, as compared with 5 days. Findings apply to laparoscopic appendectomy in a well-resourced health care setting.

2 days versus 5 days of postoperative antibiotics for complex appendicitis: a pragmatic, open-label, multicentre, non-inferiority randomised trial.

BACKGROUND: The appropriate duration of postoperative antibiotics for complex appendicitis is unclear. The increasing global threat of antimicrobial resistance warrants restrictive antibiotic use, which could also reduce side-effects, length of hospital stay, and costs. METHODS: In this pragmatic, open-label, non-inferiority trial in 15 hospitals in the Netherlands, patients with complex appendicitis (aged ≥8 years) were randomly assigned (1:1) to receive 2 days or 5 days of intravenous antibiotics after appendicectomy. Randomisation was stratified by centre, and treating physicians and patients were not masked to treatment allocation. The primary endpoint was a composite endpoint of infectious complications and mortality within 90 days. The main outcome was the absolute risk difference (95% CI) in the primary endpoint, adjusted for age and severity of appendicitis, with a non-inferiority margin of 7·5%. Outcome assessment was based on electronic patient records and a telephone consultation 90 days after appendicectomy. Efficacy was analysed in the intention-to-treat and per-protocol populations. Safety outcomes were analysed in the intention-to-treat population. This trial was registered with the Netherlands Trial Register, NL5946. FINDINGS: Between April 12, 2017, and June 3, 2021, 13 267 patients were screened and 1066 were randomly assigned, 533 to each group. 31 were excluded from intention-to-treat analysis of the 2-day group and 30 from the 5-day group owing to errors in recruitment or consent. Appendicectomy was done laparoscopically in 955 (95%) of 1005 patients. The telephone follow-up was completed in 664 (66%) of 1005 patients. The primary endpoint occurred in 51 (10%) of 502 patients analysed in the 2-day group and 41 (8%) of 503 patients analysed in the 5-day group (adjusted absolute risk difference 2·0%, 95% CI -1·6 to 5·6). Rates of complications and re-interventions were similar between trial groups. Fewer patients had adverse effects of antibiotics in the 2-day group (45 [9%] of 502 patients) than in the 5-day group (112 [22%] of 503 patients; odds ratio [OR] 0·344, 95% CI 0·237 to 0·498). Re-admission to hospital was more frequent in the 2-day group (58 [12%] of 502 patients) than in the 5-day group (29 [6%] of 503 patients; OR 2·135, 1·342 to 3·396). There were no treatment-related deaths. INTERPRETATION: 2 days of postoperative intravenous antibiotics for complex appendicitis is non-inferior to 5 days in terms of infectious complications and mortality within 90 days, based on a non-inferiority margin of 7·5%. These findings apply to laparoscopic appendicectomy conducted in a well resourced health-care setting. Adopting this strategy will reduce adverse effects of antibiotics and length of hospital stay. FUNDING: The Netherlands Organization for Health Research and Development.

Two versus five days of antibiotics after appendectomy for complex acute appendicitis (APPIC): study protocol for a randomized controlled trial.

BACKGROUND: Acute appendicitis is one of the most common indications for emergency surgery. In patients with a complex appendicitis, prolonged antibiotic prophylaxis is recommended after appendectomy. There is no consensus regarding the optimum duration of antibiotics. Guidelines propose 3 to 7 days of treatment, but shorter courses may be as effective in the prevention of infectious complications. At the same time, the global issue of increasing antimicrobial resistance urges for optimization of antibiotic strategies. The aim of this study is to determine whether a short course (48 h) of postoperative antibiotics is non-inferior to current standard practice of 5 days. METHODS: Patients of 8 years and older undergoing appendectomy for acute complex appendicitis - defined as a gangrenous and/or perforated appendicitis or appendicitis in presence of an abscess - are eligible for inclusion. Immunocompromised or pregnant patients are excluded, as well as patients with a contraindication to the study antibiotics. In total, 1066 patients will be randomly allocated in a 1:1 ratio to the experimental treatment arm (48 h of postoperative intravenously administered (IV) antibiotics) or the control arm (5 days of postoperative IV antibiotics). After discharge from the hospital, patients participate in a productivity-cost-questionnaire at 4 weeks and a standardized telephone follow-up at 90 days after appendectomy. The primary outcome is a composite endpoint of infectious complications, including intra-abdominal abscess (IAA) and surgical site infection (SSI), and mortality within 90 days after appendectomy. Secondary outcomes include IAA, SSI, restart of antibiotics, length of hospital stay (LOS), reoperation, percutaneous drainage, readmission rate, and cost-effectiveness. The non-inferiority margin for the difference in the primary endpoint rate is set at 7.5% (one-sided test at ɑ 0.025). Both per-protocol and intention-to-treat analyses will be performed. DISCUSSION: This trial will provide evidence on whether 48 h of postoperative antibiotics is non-inferior to a standard course of 5 days of antibiotics. If non-inferiority is established, longer intravenous administration following appendectomy for complex appendicitis can be abandoned, and guidelines need to be adjusted accordingly. TRIAL REGISTRATION: Dutch Trial Register, NTR6128 . Registered on 20 December 2016.

Adrenal Incidentalomas During Diagnostic Work-up of Colorectal Cancer Patients: What is the Risk of Metastases?

BACKGROUND: Adrenal incidentalomas (AIs) are regularly discovered on staging computed tomography (CT) of patients with colorectal cancer (CRC). Although CRC is considered unlikely to metastasize to the adrenal gland, it is not known how often an AI appears to be a CRC metastasis. This causes a diagnostic dilemma for many patients with newly diagnosed CRC. This study aimed primarily to describe the incidence of AIs and adrenal metastases in CRC patients. METHODS: A single-center cohort of 475 consecutive patients with newly diagnosed CRC was defined. Retrospectively, all radiology reports and multidisciplinary team meeting reports were assessed for the presence of adrenal abnormalities. All AIs shown on staging CT were reevaluated for the purpose of this study, and the sizes of these adrenal glands were determined. Based on the CT reevaluation, follow-up imaging, and clinical follow-up assessment, conclusions on the presence or absence of adrenal metastases were drawn. RESULTS: The incidence of AIs in this CRC patient cohort was 10.5% (50/475). In 96% (48/50) of the patients with AIs, adrenal metastases could be ruled out. No solitary adrenal metastases were encountered. In two patients who had widespread systemic disease without curative treatment options, the AIs were considered to be adrenal metastases (cohort incidence, 0.4%). CONCLUSION: This is the first study to report on adrenal incidentalomas in CRC patients. In newly diagnosed CRC patients without disseminated disease, AIs can be considered benign, and no additional imaging is indicated to rule out adrenal metastases in this group.

Accuracy of MRI in Restaging Locally Advanced Rectal Cancer After Preoperative Chemoradiation.

BACKGROUND: Patients with a locally advanced rectal carcinoma benefit from preoperative chemoradiotherapy. MRI is considered the first choice imaging modality after preoperative chemoradiation, although its reliability for restaging is debatable. OBJECTIVE: The purpose of this study was to determine the accuracy of MRI in restaging locally advanced rectal cancer after preoperative chemoradiation. DESIGN: This was a retrospective study. SETTINGS: The study was conducted in a Dutch high-volume rectal cancer center. PATIENTS: A consecutive cohort of 48 patients with locally advanced rectal cancer treated with a curative intent was identified. MAIN OUTCOME MEASURES: Three readers independently evaluated the MRI both for primary staging and for restaging after preoperative chemoradiation and were blinded to results from the other readers as well as histological results. Interobserver variability was determined. Accuracy of the restaging MRI was assessed through the comparison of tumor characteristics on MRI with histopathologic outcomes. RESULTS: T stage was correctly predicted by the 3 readers in 47% to 68% and N stage in 68% to 70%. Overstaging was more common than understaging. Positive predictive values (PPV) among the 3 readers for T0 were 0%, and negative predictive values (NPVs) varied from 84% to 85%. For T1/2, PPVs and NPVs were 50% to 67% and 72% to 90%, and for T3/4 they were 54% to 62% and 33% to 78%. PPVs and NPVs for N0 stage were 81% to 95% and 58% to 73%. Tumor regression grade on MRI did not correspond with histopathologic tumor regression grade; PPVs for good response (tumor regression grade on MRI 1-2) were 48% to 61%, and NPVs were 42% to 58%. Interobserver agreement was fair to moderate for T stage, N stage, and tumor response (κ = 0.20-0.41) and fair to substantial for the relation with the mesorectal fascia (κ = 0.33-0.77). In none of the patients was the surgical plan changed after the restaging MRI. LIMITATIONS: This study was limited by its small sample size and retrospective nature. CONCLUSIONS: MRI has low accuracy for restaging locally advanced rectal cancer after preoperative chemoradiation, and the interobserver variability is significant.

Long-term Outcome of an Organ Preservation Program After Neoadjuvant Treatment for Rectal Cancer.

BACKGROUND: The aim of this study was to establish the oncological and functional results of organ preservation with a watch-and-wait approach (W&W) and selective transanal endoscopic microsurgery (TEM) in patients with a clinical complete or near-complete response (cCR) after neoadjuvant chemoradiation for rectal cancer. METHODS: Between 2004 and 2014, organ preservation was offered if response assessment with digital rectal examination, endoscopy, and MRI showed (near) cCR. Watch-and-wait was offered for cCR, and two options were offered for near cCR: TEM or reassessment after three months. Follow-up included endoscopy and MRIs every three months during the first year, and every six months thereafter. Long-term outcome was assessed with Kaplan-Meier curves. Functional outcome was assessed with colostomy-free survival and Vaizey incontinence score (0 = perfect continence, 24 = totally incontinent). RESULTS: One hundred patients were included, with median follow-up of 41.1 months. Sixty-one had cCR at initial response assessment. Thirty-nine had near cCR, of whom 24 developed cCR at the second assessment and 15 patients underwent TEM (9 ypT0, 1 ypT1, 5 ypT2). Fifteen patients developed a local regrowth (12 luminal, 3 nodal), all salvageable and within 25 months. Five patients developed metastases, and five patients died. Three-year overall survival was 96.6% (95% confidence interval [CI] = 89.9% to 98.9%), distant metastasis-free survival was 96.8% (95% CI = 90.4% to 99.0%), local regrowth-free survival was 84.6% (95% CI = 75.8% to 90.5%), and disease-free survival was 80.6% (95% CI = 70.9% to 87.4%). Colostomy-free survival was 94.8% (95% CI = 88.0% to 97.8%), with a good continence after watch-and-wait (Vaizey = 3.4, SD = 3.9) and moderate after TEM (Vaizey = 9.7, SD = 5.1). CONCLUSIONS: Organ preservation appears oncologically safe for selected rectal cancer patients with a cCR or near cCR after neoadjuvant chemoradiation when applying strict selection criteria and frequent follow-up, including endoscopy and MRI. The low colostomy rate and the good long-term functional outcome warrant discussing this option with the patient as an alternative to major surgery.

CT texture analysis in colorectal liver metastases: A better way than size and volume measurements to assess response to chemotherapy?

BACKGROUND: Response Evaluation Criteria In Solid Tumors (RECIST) are known to have limitations in assessing the response of colorectal liver metastases (CRLMs) to chemotherapy. OBJECTIVE: The objective of this article is to compare CT texture analysis to RECIST-based size measurements and tumor volumetry for response assessment of CRLMs to chemotherapy. METHODS: Twenty-one patients with CRLMs underwent CT pre- and post-chemotherapy. Texture parameters mean intensity (M), entropy (E) and uniformity (U) were assessed for the largest metastatic lesion using different filter values (0.0 = no/0.5 = fine/1.5 = medium/2.5 = coarse filtration). Total volume (cm(3)) of all metastatic lesions and the largest size of one to two lesions (according to RECIST 1.1) were determined. Potential predictive parameters to differentiate good responders (n = 9; histological TRG 1-2) from poor responders (n = 12; TRG 3-5) were identified by univariable logistic regression analysis and subsequently tested in multivariable logistic regression analysis. Diagnostic odds ratios were recorded. RESULTS: The best predictive texture parameters were Δuniformity and Δentropy (without filtration). Odds ratios for Δuniformity and Δentropy in the multivariable analyses were 0.95 and 1.34, respectively. Pre- and post-treatment texture parameters, as well as the various size and volume measures, were not significant predictors. Odds ratios for Δsize and Δvolume in the univariable logistic regression were 1.08 and 1.05, respectively. CONCLUSIONS: Relative differences in CT texture occurring after treatment hold promise to assess the pathologic response to chemotherapy in patients with CRLMs and may be better predictors of response than changes in lesion size or volume.

Nodal staging in rectal cancer: why is restaging after chemoradiation more accurate than primary nodal staging?

PURPOSE: This study aims to explore the influence of chemoradiation treatment (CRT) on rectal cancer nodes and to generate hypotheses why nodal restaging post-CRT is more accurate than at primary staging. METHODS: Thirty-nine patients with locally advanced rectal cancer underwent MRI pre- and post-CRT. All visible mesorectal nodes were measured on a 3D T1-weighted gradient echo (3D T1W GRE) sequence with 1-mm(3) voxels and matched between pre- and post-CRT-MRI and with histology by lesion-by-lesion matching. Change in number and size of nodes was compared between pre- and post-CRT-MRI. ROC curves were constructed to assess diagnostic performance of size. RESULTS: Eight hundred ninety-five nodes were found pre-CRT: 44 % disappeared and 40 % became smaller post-CRT. Disappearing nodes were initially significantly smaller than nodes that remained visible post-CRT: 2.9 mm vs. 3.8 mm. cN+ stage was predicted in 97 % pre-CRT and 36 % of patients had ypN+ post-CRT. ypN+ patients had significantly larger nodes than ypN0 patients both pre- and post-CRT. Optimal size cutoff for post-CRT ypN stage prediction was 2.5 mm (area under the curve (AUC) of 0.78) at MRI. CONCLUSIONS: After CRT, most lymph nodes become smaller, and many disappear. Size predicts disappearance and node positivity. Together with a low prevalence of ypN+, this can explain the higher accuracy of nodal staging after CRT than in a primary staging setting, possibly of use when considering organ-preserving strategies after CRT.

Good and complete responding locally advanced rectal tumors after chemoradiotherapy: where are the residual positive nodes located on restaging MRI?

PURPOSE: Aim of this study was to evaluate the distribution of persistent mesorectal lymph node metastases on restaging MRI in patients with a good or complete response of their primary tumor (ypT0-2) after CRT for locally advanced rectal cancer. METHODS: Two hundred and twenty eight locally advanced rectal cancer patients underwent CRT, which resulted in a good response (downstaging to yT0-2) in 144 patients. Forty-nine patients were excluded (no surgery/insufficient follow-up or lacking lesion-by-lesion histology results). This resulted in a final study group of 95 yT0-2 patients. For the patients with a yN(+)-status, a detailed lesion-by-lesion comparison between restaging MRI and histology was performed to evaluate the characteristics and distribution of the individual N(+)-nodes. RESULTS: 7/95 patients (7%) had a yT0-2N(+) status (11/880 (1%) N(+) nodes): no N(+) were found below the tumor level, 55% of the N(+) nodes were located at the level of the tumor, and 45% proximal to the tumor (at a median distance of 1.4 cm above the tumor level). In axial plane, 82% of the nodes were located at the ipsilateral circumference of the tumor, at a median distance of 0.9 cm from the tumor/rectal wall. CONCLUSIONS: The incidence of persistent metastatic mesorectal nodes after CRT in patients with a good tumor response after CRT is very low. No N(+) nodes are found below the tumor level. All N(+) nodes are located at the level of or proximal to the primary tumor, of which the majority very close to the tumor/lumen.

MRI and diffusion-weighted MRI to diagnose a local tumour regrowth during long-term follow-up of rectal cancer patients treated with organ preservation after chemoradiotherapy.

OBJECTIVES: To assess the value of MRI and diffusion-weighted imaging (DWI) for diagnosing local tumour regrowth during follow-up of organ preservation treatment after chemoradiotherapy for rectal cancer. METHODS: Seventy-two patients underwent organ preservation treatment (chemoradiotherapy + transanal endoscopic microsurgery or "wait-and-see") and were followed with MRI including DWI (1.5 T) every 3 -months during the first year and 6 months during following years. Two readers scored each MRI for local regrowth using a confidence level, first on standard MRI, then on standard MRI+DWI. Histology and clinical follow-up were the standard reference. Receiver operating characteristic curves were constructed and areas under the curve (AUC) and corresponding accuracy figures calculated on a per-scan basis. RESULTS: Four hundred and forty MRIs were assessed. Twelve patients developed local regrowth. AUC/sensitivity/specificity for standard MRI were 0.95/58 %/98 % (R1) and 0.96/58 % /100 % (R2). For standard MRI+DWI, these numbers were 0.86/75 %/97 % (R1) and 0.98/75 %/100 % (R2). After adding DWI, the number of equivocal scores decreased from 22 to 7 (R1) and from 40 to 20 (R2). CONCLUSIONS: Although there was no overall improvement in diagnostic performance in terms of AUC, adding DWI improved the sensitivity of MRI for diagnosing local tumour regrowth and lowered the rate of equivocal MRIs. KEY POINTS: • DWI improves sensitivity for detecting local tumour regrowth after organ preservation treatment. • In particular, DWI can aid in detecting small local recurrence. • DWI reduces the number of equivocal scores.

Assessment of Clinical Complete Response After Chemoradiation for Rectal Cancer with Digital Rectal Examination, Endoscopy, and MRI: Selection for Organ-Saving Treatment.

BACKGROUND: The response to chemoradiotherapy (CRT) for rectal cancer can be assessed by clinical examination, consisting of digital rectal examination (DRE) and endoscopy, and by MRI. A high accuracy is required to select complete response (CR) for organ-preserving treatment. The aim of this study was to evaluate the value of clinical examination (endoscopy with or without biopsy and DRE), T2W-MRI, and diffusion-weighted MRI (DWI) for the detection of CR after CRT. METHODS: This prospective cohort study in a university hospital recruited 50 patients who underwent clinical assessment (DRE, endoscopy with or without biopsy), T2W-MRI, and DWI at 6-8 weeks after CRT. Confidence levels were used to score the likelihood of CR. The reference standard was histopathology or recurrence-free interval of >12 months in cases of wait-and-see approaches. Diagnostic performance was calculated by area under the receiver operator characteristics curve, with corresponding sensitivities and specificities. Strategies were assessed and compared by use of likelihood ratios. RESULTS: Seventeen (34 %) of 50 patients had a CR. Areas under the curve were 0.88 (0.78-1.00) for clinical assessment and 0.79 (0.66-0.92) for T2W-MRI and DWI. Combining the modalities led to a posttest probability for predicting a CR of 98 %. Conversely, when all modalities indicated residual tumor, 15 % of patients still experienced CR. CONCLUSIONS: Clinical assessment after CRT is the single most accurate modality for identification of CR after CRT. Addition of MRI with DWI further improves the diagnostic performance, and the combination can be recommended as the optimal strategy for a safe and accurate selection of CR after CRT.

Whole-liver diffusion-weighted MRI histogram analysis: effect of the presence of colorectal hepatic metastases on the remaining liver parenchyma.

OBJECTIVES: To explore whether whole-liver diffusion-weighted MRI analysis (of the apparently normal liver parenchyma) can help differentiate between patients with colorectal liver metastasis and controls without liver disease. MATERIALS AND METHODS: Ten patients with colorectal liver metastasis and 10 controls with no focal/diffuse liver disease underwent liver MRI at 1.5 T including diffusion-weighted imaging (DWI; b-values 0, 50, 100, 500, 750, 1000). Apparent diffusion coefficient (ADC) maps were calculated from the DWI images to carry out quantitative diffusion analyses. An experienced reader performed segmentation of the apparently nondiseased liver (excluding metastases/focal liver lesions) on the ADC maps. Histogram ADC parameters were calculated and compared between the patients and the controls. RESULTS: The mean liver ADC was 0.95×10⁻³ mm²/s for the patients versus 1.03×10⁻³ mm²/s for the controls (P=0.42). The fifth percentile of the ADC was significantly lower for the patients compared with the controls (0.45 vs. 0.69 10⁻³ mm²/s, P=0.01). The SD was significantly higher in the patient group (0.30 vs. 0.22, P<0.001). Median, skewness, kurtosis, and 30th-95th percentile were not significantly different between the two groups. Areas under the receiver operator characteristics curves to differentiate patients with metastatic liver involvement from healthy controls without liver disease were 0.79 for the fifth percentile and 0.95 for the SD. CONCLUSION: Whole-liver diffusion-weighted MRI histogram analysis showed a significant shift towards lower fifth percentile ADC values and higher SD in patients with colorectal liver metastasis compared with controls without liver disease.

MRI and Diffusion-weighted MRI Volumetry for Identification of Complete Tumor Responders After Preoperative Chemoradiotherapy in Patients With Rectal Cancer: A Bi-institutional Validation Study.

BACKGROUND: Retrospective single-center studies have shown that diffusion-weighted magnetic resonance imaging (DWI) is promising for identification of patients with rectal cancer with a complete tumor response after neoadjuvant chemoradiotherapy (CRT), using certain volumetric thresholds. OBJECTIVE: This study aims to validate the diagnostic value of these volume thresholds in a larger, independent, and bi-institutional patient cohort. METHODS: A total of 112 patients with locally advanced rectal cancer (2 centers) treated with a long course of CRT were enrolled. Patients underwent standard T2W-magnetic resonance imaging and DWI, both pre- and post-CRT. Two experienced readers independently determined pre-CRT and post-CRT tumor volumes (cm) on T2W-magnetic resonance image and diffusion-weighted magnetic resonance image by means of freehand tumor delineation. Tumor volume reduction rates (Δvolume) were calculated. Previously determined T2W and DWI threshold values for prevolume, postvolume, and Δvolume were tested to "prospectively" assess their respective diagnostic value in discriminating patients with a complete tumor response from patients with residual tumor. RESULTS: Twenty patients had a complete response. Using the average measurements between the 2 readers, areas under the curve for the pre-/post-/Δvolumes was 0.73/0.82/0.78 for T2W-magnetic resonance imaging and 0.77/0.92/0.86 for DWI, respectively. For T2W-volumetry, sensitivity and specificity using the predefined volume thresholds were 55% and 74% for pre-, 60% and 89% for post-, and 60% and 86% for Δvolume. For DWI volumetry, sensitivity and specificity were 65% and 76% for pre-, 70% and 98% for post-, and 70% and 93% for Δvolume. CONCLUSIONS: Previously established DWI volume thresholds can be reproduced with good results. Post-CRT DWI volumetry offers the best results for the detection of patients with a complete response after CRT with an area under the curve of 0.92, sensitivity of 70%, and specificity of 98%.

Can perfusion MRI predict response to preoperative treatment in rectal cancer?

BACKGROUND AND PURPOSE: Dynamic contrast-enhanced MRI (DCE-MRI) provides information on perfusion and could identify good prognostic tumors. Aim of this study was to evaluate whether DCE-MRI using a novel blood pool contrast-agent can accurately predict the response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. MATERIALS AND METHODS: Thirty patients underwent DCE-MRI before and 7-10weeks after chemoradiotherapy. Regions of interest were drawn on DCE-MRI with T2W-images as reference. DCE-MRI-based kinetic parameters (initial slope, initial peak, late slope, and AUC at 60, 90, and 120s) determined pre- and post-CRT and their Δ were compared between good (TRG1-2) and poor (TRG3-5) responders. Optimal thresholds were determined and sensitivities, specificities, positive predictive values (PPV), and negative predictive values (NPV) were calculated. RESULTS: Pre-therapy, the late slope was able to discriminate between good and poor responders (-0.05×10(-3) vs. 0.62×10(-3), p<0.001) with an AUC of 0.90, sensitivity 92%, specificity 82%, PPV 80%, and NPV 93%. Other pre-CRT parameters showed no significant differences, nor any post-CRT parameters or their Δ. CONCLUSIONS: The kinetic parameter 'late slope' derived from DCE-MRI could potentially be helpful to predict before the onset of neoadjuvant chemoradiotherapy which tumors are likely going to respond. This could allow for personalized treatment-options in rectal cancer patients.

Whole-liver CT texture analysis in colorectal cancer: Does the presence of liver metastases affect the texture of the remaining liver?

BACKGROUND: Liver metastases limit survival in colorectal cancer. Earlier detection of (occult) metastatic disease may benefit treatment and survival. OBJECTIVE: The objective of this article is to evaluate the potential of whole-liver CT texture analysis of apparently disease-free liver parenchyma for discriminating between colorectal cancer (CRC) patients with and without hepatic metastases. METHODS: The primary staging CT examinations of 29 CRC patients were retrospectively analysed. Patients were divided into three groups: patients without liver metastases (n = 15), with synchronous liver metastases (n = 10) and metachronous liver metastases within 18 months following primary staging (n = 4). Whole-liver texture analysis was performed by delineation of the apparently non-diseased liver parenchyma (excluding metastases or other focal liver lesions) on portal phase images. Mean grey-level intensity (M), entropy (E) and uniformity (U) were derived with no filtration and different filter widths (0.5 = fine, 1.5 = medium, 2.5 = coarse). RESULTS: Mean E1.5 and E2.5 for the whole liver in patients with synchronous metastases were significantly higher compared with the non-metastatic patients (p = 0.02 and p = 0.01). Mean U1.5 and U2.5 were significantly lower in the synchronous metastases group compared with the non-metastatic group (p = 0.04 and p = 0.02). Texture parameters for the metachronous metastases group were not significantly different from the non-metastatic group or synchronous metastases group (p > 0.05), although - similar to the synchronous metastases group - there was a subtle trend towards increased E1.5, E2.5 and decreased U1.5, U2.5 values. Areas under the ROC curve for the diagnosis of synchronous metastatic disease based on the texture parameters E1.5,2.5 and U1.5,2.5 ranged between 0.73 and 0.78. CONCLUSION: Texture analysis of the apparently non-diseased liver holds promise to differentiate between CRC patients with and without metastatic liver disease. Further research is required to determine whether these findings may be used to benefit the prediction of metachronous liver disease.

Value of gadofosveset-enhanced MRI and multiplanar reformatting for selecting good responders after chemoradiation for rectal cancer.

OBJECTIVES: Our primary objective was to evaluate diagnostic performance of gadofosveset T1-weighted magnetic resonance imaging (T1W MRI) for discriminating between ypT0-2 and ypT3-4 tumours after chemoradiation therapy (CRT) for rectal cancer compared with T2W MRI for a general and expert reader. Second objectives included assessing the value of multiplanar reformatting (MPR) and interobserver agreement. METHODS: A general and expert reader evaluated 49 patients for likelihood of ypT0-2 tumour after CRT on T2W, gadofosveset T1W MRI, and gadofosveset T1W MRI + T2W MRI. The general reader scored with and without MPR. Confidence level scores were used to construct receiver-operating characteristic (ROC) curves. Area under the curve (AUC) values and diagnostic parameters were calculated and compared. RESULTS: Gadofosveset T1W MRI + T2W MRI showed slightly superior sensitivity than T2W MRI for the general but not the expert reader. Specificity was higher for the expert on gadofosveset T1W MRI only compared with T2W MRI only (100% vs. 82%). MPR did not increase diagnostic performance. Interobserver agreement was highest for the combination of gadofosveset-enhanced T1W imaging plus T2W MRI. CONCLUSIONS: The sole use or addition of gadofosveset-enhanced T1W MRI to T2W MRI did not increase significantly diagnostic performance for assessing ypT0-2 tumours. Adding gadofosveset-enhanced T1W MRI slightly increased sensitivity for the general reader and specificity for the expert reader, but this increase was not significant for more accurate clinical decision making. MPR did not improve diagnostic performance. KEY POINTS: • ycT restaging with MRI in rectal cancer is challenging. • Gadofosveset-enhanced T1W MRI has shown promise for nodal restaging. • Gadofosveset-enhanced T1W MRI did not significantly increase diagnostic performance for assessing ypT0-2-tumours. • Addition of the gadofosveset sequence to T2W MRI slightly increased sensitivity for the general reader. • MPR did not improve diagnostic performance of ycT staging.

Magnetization transfer ratio: a potential biomarker for the assessment of postradiation fibrosis in patients with rectal cancer.

OBJECTIVES: Magnetization transfer-magnetic resonance imaging (MT-MRI) uses differences in the magnetization interaction of the free "unbound" water protons and the macromolecular-bound protons. The aim of this study was to evaluate whether the magnetization transfer ratio (MTR) may be used to identify fibrosis in patients with rectal cancer treated with chemoradiotherapy. MATERIALS AND METHODS: This study was part of a rectal cancer imaging study, which was approved by the local institutional review board. Twenty-six patients, treated with neoadjuvant chemoradiotherapy, underwent a standard MRI including T2-weighted sequences and a diffusion-weighted sequence. An axially oriented MT sequence was performed at the center of the (former) tumor location. Regions of interest were manually drawn on the MT-MRI (with reference to the T2-weighted and diffusion-weighted images), covering areas of residual tumor, fibrosis, or the normal or edematous rectal wall. The results were compared with that of the histopathological examination. Differences in MTR between the 4 tissue types were analyzed, and a receiver operating characteristic (ROC) curve was generated to assess the diagnostic potential. RESULTS: Thirty-eight regions of interest were analyzed on the MT-MRI. The mean (SD) MTR of the fibrosis was 37.7% (2.7%), which was significantly higher than that of the residual tumor (29.6% [4.2%]; P < 0.001), the normal rectal wall (30.3% [4.7%]; P = 0.003), and the edematous rectal wall (18.2% [4.0%]; P < 0.001). The use of MTR resulted in an area under the ROC-curve of 0.96, a sensitivity of 88%, and a specificity of 90% for the diagnosis of fibrosis. CONCLUSIONS: Magnetization transfer ratio can be used to discriminate postradiation fibrosis from residual tumor and the normal rectal wall after chemoradiotherapy. Magnetization transfer imaging can thus be a promising tool for the unsolved dilemma of interpreting postradiation fibrosis in rectal cancer.

Performance of gadofosveset-enhanced MRI for staging rectal cancer nodes: can the initial promising results be reproduced?

OBJECTIVES: A previous study showed promising results for gadofosveset-trisodium as a lymph node magnetic resonance imaging (MRI) contrast agent in rectal cancer. The aim of this study was to prospectively confirm the diagnostic performance of gadofosveset MRI for nodal (re)staging in rectal cancer in a second patient cohort. METHODS: Seventy-one rectal cancer patients were prospectively included, of whom 13 (group I) underwent a primary staging gadofosveset MRI (1.5-T) followed by surgery (± preoperative 5 × 5 Gy) and 58 (group II) underwent both primary staging and restaging gadofosveset MRI after a long course of chemoradiotherapy followed by surgery. Nodal status was scored as (y)cN0 or (y)cN+ by two independent readers (R1, R2) with different experience levels. Results were correlated with histology on a node-by-node basis. RESULTS: Sensitivity, specificity and area under the receiver operating characteristics curve (AUC) were 94%, 79% and 0.89 for the more experienced R1 and 50%, 83% and 0.74 for the non-experienced R2. R2's performance improved considerably after a learning curve, to an AUC of 0.83. Misinterpretations mainly occurred in nodes located in the superior mesorectum, nodes located in between vessels and nodes containing micrometastases. CONCLUSIONS: This prospective study confirms the good diagnostic performance of gadofosveset MRI for nodal (re)staging in rectal cancer. KEY POINTS: • Gadofosveset-enhanced MRI shows high performance for nodal (re)staging in rectal cancer. • Gadofosveset MRI may facilitate better selection of patients for personalised treatment. • Results can be reproduced by non-expert readers. • Experience of 50-60 cases is required to achieve required expertise level. • Main pitfalls are nodes located between vessels and nodes containing micrometastases.

Diffusion-weighted MR imaging in primary rectal cancer staging demonstrates but does not characterise lymph nodes.

OBJECTIVES: To evaluate the performance of diffusion-weighted MRI (DWI) for the detection of lymph nodes and for differentiating between benign and metastatic nodes during primary rectal cancer staging. METHODS: Twenty-one patients underwent 1.5-T MRI followed by surgery (± preoperative 5 × 5 Gy). Imaging consisted of T2-weighted MRI, DWI (b0, 500, 1000), and 3DT1-weighted MRI with 1-mm isotropic voxels. The latter was used for accurate detection and per lesion histological validation of nodes. Two independent readers analysed the signal intensity on DWI and measured the mean apparent diffusion coefficient (ADC) for each node (ADCnode) and the ADC of each node relative to the mean tumour ADC (ADCrel). RESULTS: DWI detected 6 % more nodes than T2W-MRI. The signal on DWI was not accurate for the differentiation of metastatic nodes (AUC 0.45-0.50). Interobserver reproducibility for the nodal ADC measurements was excellent (ICC 0.93). Mean ADCnode was higher for benign than for malignant nodes (1.15 ± 0.24 vs. 1.04 ± 0.22 *10(-3) mm(2)/s), though not statistically significant (P = 0.10). Area under the ROC curve/sensitivity/specificity for the assessment of metastatic nodes were 0.64/67 %/60 % for ADCnode and 0.67/75 %/61 % for ADCrel. CONCLUSIONS: DWI can facilitate lymph node detection, but alone it is not reliable for differentiating between benign and malignant lymph nodes.

Gadofosveset-enhanced MRI for the assessment of rectal cancer lymph nodes: predictive criteria.

PURPOSE: To confirm the use of the nodal signal intensity (SI) and the 'chemical shift' artefact as diagnostic criteria for detecting nodal metastases from rectal cancer on gadofosveset contrast-enhanced MRI. METHODS: Thirty-three patients underwent a non-enhanced and gadofosveset-enhanced 3D-T1W GRE-MRI at 1.5T. For each lymph node, the SI of the middle part of the node (mSI) and white rim of the chemical shift artefact encircling the node (wSI) were measured on the non-enhanced and gadofosveset-enhanced images. Second, the aspect of the chemical shift artefact encircling the nodes was scored using a 4-point scale. Results were compared with histology on a node-by-node basis. RESULTS: 289 nodes (55 N+) were analysed. On gadofosveset-MRI, mSI and wSI were significantly higher for the benign than for the metastatic lymph nodes (p < 0.001). Areas under the ROC curve (AUC) for identification of metastases were 0.74 (mSI) and 0.73 (wSI). The chemical shift criterion rendered an AUC of 0.85. The combination of mSI and the chemical shift criterion resulted in an AUC of 0.88 and the rendered an AUC of 0.86-0.92 when subjectively (visually) assessed by two independent readers. CONCLUSIONS: Benign lymph nodes show significant contrast enhancement after gadofosveset injection, while metastatic nodes do not. The uptake of gadofosveset in the nodes also affects the chemical shift artefact encircling the nodes. Combined assessment of these two features on gadofosveset-enhanced MRI provides a high diagnostic performance for diagnosing metastatic lymph nodes in patients with rectal cancer.