Differentiating between segmental arterial mediolysis and other arterial vasculopathies to establish an early diagnosis - a systematic literature review and proposal of new diagnostic criteria.

Segmental arterial mediolysis (SAM) is a rare vascular disease, characterized by acute but transient vulnerability of the wall of medium-sized arteries. The most characteristic feature of SAM is its biphasic course: an injurious phase marked by acute weakness of the arterial wall leading to acute dissection and/or hemorrhage, followed by a reparative phase in which granulation tissue and fibrosis restore the injured arterial wall. Residual stenosis, aneurysms, and/or arterial wall irregularities may remain visible on future imaging studies. Differentiating between SAM and other arterial vasculopathies is difficult due to its similarities with many other vascular diseases, such as vasculitis, fibromuscular dysplasia, inherited connective tissue disorders, and isolated visceral artery dissection. In this systematic review, we provide an overview on SAM, with an emphasis on the differential diagnosis and diagnostic work-up. We propose new diagnostic criteria to help establish a prompt diagnosis of SAM, illustrated by case examples from our multidisciplinary vascular clinic.

Abdominal inflammatory myofibroblastic tumour: Clinicopathological and molecular analysis of 20 cases, highlighting potential therapeutic targets.

AIMS: Inflammatory myofibroblastic tumour (IMT) is a rare mesenchymal neoplasm of intermediate malignant potential, occurring at any age and at multiple sites. Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is an aggressive subtype of IMT, typically involving the abdomen. Most IMTs harbour kinase gene fusions, especially involving ALK and ROS1, but 20-30% of IMTs show no detectable translocations. The aim of this study is to further delineate clinicopathological and molecular characteristics of abdominal IMT and discover potential new therapeutic targets. METHODS AND RESULTS: In 20 IMTs, including four EIMS, RNA fusion analysis was performed, followed by multiplex DNA analysis if no ALK or ROS1 fusion was detected. Fourteen IMTs (70.0%) had an ALK translocation and the fusion partner was identified in 11, including a RRBP1::ALK fusion, not previously described in classical (non-EIMS) IMT. RANBP2::ALK fusion was demonstrated in all EIMS. One IMT had a ROS1 fusion. In all ALK/ROS1 translocation-negative IMTs mutations or fusions - as yet unreported in primary IMT - were found in genes related to the receptor tyrosine kinase (RTK)/PI3K/AKT pathway. Three of four patients with EIMS died of disease [mean survival 8 months (4-15 months)], whereas only one of 14 classical IMT patients succumbed to disease [mean follow-up time 52 months (2-204 months); P < 0.01]. CONCLUSION: This study shows the wide clinical spectrum of abdominal IMTs and affirms the poor prognosis of EIMS, raising discussion about its status as IMT subtype. Furthermore, the newly detected alterations of the RTK/PI3K/AKT pathway expand the molecular landscape of IMTs and provide potential therapeutic targets.

Bite-on-bite biopsies for the detection of residual esophageal cancer after neoadjuvant chemoradiotherapy.

BACKGROUND: Active surveillance after neoadjuvant treatment is increasingly implemented. The success of this strategy relies on the accurate detection of residual cancer. This study aimed to assess the diagnostic value of a second (bite-on-bite) biopsy for the detection of residual esophageal cancer and to correlate outcomes to the distribution of residual cancer found in the resection specimen. METHODS: A multicenter prospective study of esophageal cancer patients undergoing active surveillance after neoadjuvant chemoradiotherapy was performed. At clinical response evaluations, an upper gastrointestinal (GI) endoscopy was performed with at least four bite-on-bite biopsies of the primary tumor site. First and second biopsies were analyzed separately. Patients with histopathological evidence of residual cancer were included in the primary analysis. Two pathologists blinded for biopsy outcome examined all resection specimens. RESULTS: Between October 2017 and July 2020, 626 upper GI endoscopies were performed in 367 patients. Of 138 patients with residual cancer, 112 patients (81 %) had at least one positive biopsy. In 14 patients (10 %) only the first biopsy was positive and in 25 patients (18 %) only the second biopsy (P = 0.11). Remarkably, the rates of patients with tumor-free mucosa and deeper located tumors were higher in patients detected by the first biopsy. The second biopsy increased the false-positive rate by 3 percentage points. No adverse events occurred. CONCLUSIONS: A second (bite-on-bite) biopsy improves the detection of residual esophageal cancer by almost 20 percentage points, at the expense of increasing the false-positive rate by 3 percentage points. The higher detection rate is explained by the higher number of biopsies obtained rather than by the penetration depth.

LIM and SH3 protein 1 (LASP1) differentiates malignant chordomas from less malignant chondrosarcomas.

PURPOSE: Chordomas are malignant tumors that develop along the neuraxis between skull-base and sacrum. Chondrosarcomas show similarities with chordomas, yet show less malignant behavior. LIM and SH3 protein 1 (LASP1) is a cytoskeletal protein known to promote the malignant behavior of tumors. LASP1 was previously identified as a possibly overexpressed protein in a chordoma proteomics experiment. In this study we compare LASP1 expression in chordoma and chondrosarcoma tissue. METHODS: Biopsies of primary tumors were collected from surgically treated chordoma (n = 6) and chondrosarcoma (n = 6) patients, flash-frozen upon collection and collectively analyzed for LASP1 RNA (real-time PCR) and protein expression (western blotting). Additionally, tissue micro array (TMA)-based immunohistochemistry was applied to an archive of 31 chordoma and 1 chondrosarcoma specimen. RESULTS: In chordoma samples, LASP1 mRNA was detected in 4/6 cases and a strong 36 kDa immunoreactive protein band was observed in 4/5 cases. In contrast, 0/6 chondrosarcoma samples showed detectable levels of LASP1 mRNA and only a weak 36 kDa band was observed in 4/5 cases. Immunohistochemical analysis showed LASP1 expression in all chordoma samples, whereas chondrosarcoma specimen did not show immunoreactivity. CONCLUSION: LASP1 is strongly expressed in the majority of chordoma cases and shows low expression in chondrosarcoma tissue. Since LASP1 is known to function as oncogene and regulate cell proliferation in other tumor types, this study implicates a role for LASP1 in chordoma biology. Further studies are warranted to improve understanding of LASP1's expression and functioning within chordoma, both in vitro and in vivo.

Molecular pathways in post-colonoscopy versus detected colorectal cancers: results from a nested case-control study.

BACKGROUND: Post-colonoscopy colorectal cancers (PCCRCs) pose challenges in clinical practice. PCCRCs occur due to a combination of procedural and biological causes. In a nested case-control study, we compared clinical and molecular features of PCCRCs and detected CRCs (DCRCs). METHODS: Whole-genome chromosomal copy number changes and mutation status of genes commonly affected in CRC were examined by low-coverage WGS and targeted sequencing, respectively. MSI and CIMP status was also determined. RESULTS: In total, 122 PCCRCs and 98 DCRCs with high-quality DNA were examined. PCCRCs were more often located proximally (P < 0.001), non-polypoid appearing (P = 0.004), early stage (P = 0.009) and poorly differentiated (P = 0.006). PCCRCs showed significantly less 18q loss (FDR < 0.2), compared to DCRCs. No significant differences in mutations were observed. PCCRCs were more commonly CIMP high (P = 0.014) and MSI (P = 0.029). After correction for tumour location, only less 18q loss remained significant (P = 0.005). CONCLUSION: Molecular features associated with the sessile serrated lesions (SSLs) and non-polypoid colorectal neoplasms (CRNs) are more commonly seen in PCCRCs than in DCRCs. These together with the clinical features observed support the hypothesis that SSLs and non-polypoid CRNs are contributors to the development of PCCRCs. The future focus should be directed at improving the detection and endoscopic removal of these non-polypoid CRN and SSLs. CLINICAL TRIAL REGISTRATION: NTR3093 in the Dutch trial register ( www.trialregister.nl ).

High CD8+ tumour-infiltrating lymphocyte density associates with unfavourable prognosis in oesophageal adenocarcinoma following poor response to neoadjuvant chemoradiotherapy.

AIMS: Determining prognosis following poor response to neoadjuvant chemoradiotherapy (nCRT) in oesophageal adenocarcinoma (OAC) remains challenging. An immunosuppressive tumour microenvironment (TME) as well as immune infiltrate density and composition are considered to play a critical role in the immune interaction between host and tumour and can predict therapy response and survival in many cancers, including gastrointestinal malignancies. The aim of this study was to establish the TME characteristics associated with survival following a poor response to nCRT. METHODS AND RESULTS: The prognostic significance of OAC-associated CD3+ , CD4+ , CD8+ , forkhead box protein 3 (FoxP3+ ) and programmed cell death ligand 1 (PD-L1) expression was studied by immunohistochemistry and quantified by automated image analysis in 123 patients who underwent nCRT and curative resection. Results from good and poor responders were contrasted and immune infiltration was related to disease course in both groups. Subsequently a cohort of 57 patients with a moderate response to nCRT was analysed in a similar fashion. Tumour cell percentage positively correlated to immune infiltration markers. In good and moderate responders, none of the immune infiltrate parameters was associated with survival; in poor responders CD8+ was an independent negative predictor of OS in univariate analysis (P = 0.03) and high CD8+ infiltration was associated with worse OS (15 versus 32 months, P = 0.042). CONCLUSION: A high CD8+ density is an independent biomarker of poor OS in poor responders to nCRT, but not in good and moderate responders. Our results suggest that patients with a poor response to nCRT but concomitant high CD8+ counts in the resection specimen require adjuvant therapy.

Active Surveillance Versus Immediate Surgery in Clinically Complete Responders After Neoadjuvant Chemoradiotherapy for Esophageal Cancer: A Multicenter Propensity Matched Study.

OBJECTIVE: This study compared outcomes of patients with esophageal cancer and clinically complete response (cCR) after neoadjuvant chemoradiotherapy (nCRT) undergoing active surveillance or immediate surgery. BACKGROUND: Since nearly one-third of patients with esophageal cancer show pathologically complete response after nCRT according to CROSS regimen, the oncological benefit of immediate surgery in cCR is topic of debate. METHODS: Patients with cCR based on endoscopic biopsies and endoscopic ultrasonography with fine-needle aspiration initially declining or accepting immediate surgery after nCRT were identified between 2011 and 2018. Primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), rate and timing of distant dissemination, and postoperative outcomes. RESULTS: Some 98 patients with cCR were identified: 31 in the active surveillance- and 67 in the immediate surgery group with median followup of survivors of 27.7 and 34.8 months, respectively. Propensity score matching resulted in 2 comparable groups (n = 29 in both groups). Patients undergoing active surveillance or immediate surgery had a 3-year OS of 77% and 55% (HR 0.41; 95% CI 0.14-1.20, P = 0.104), respectively. The 3-year PFS was 60% and 54% (HR 1.08; 95% CI 0.44-2.67, P = 0.871), respectively. Patients undergoing active surveillance or immediate surgery had a comparable distant dissemination rate (both groups 28%), radical resection rate (both groups 100%), and severity of postoperative complications (Clav- ien-Dindo grade ≥ 3: 43% vs 45%, respectively). CONCLUSION: In this retrospective study, OS and PFS in patients with cCR undergoing active surveillance or immediate surgery were not significantly different. Active surveillance with postponed surgery for recurrent disease was not associated with a higher distant dissemination rate or more severe adverse postoperative outcomes.

Lymph node response to chemoradiotherapy in oesophageal cancer patients: relationship with radiotherapy fields.

BACKGROUND: The presence of lymph node metastasis (LNmets) is a poor prognostic factor in oesophageal cancer (OeC) patients treated with neoadjuvant chemoradiotherapy (nCRT) followed by surgery. Tumour regression grade (TRG) in LNmets has been suggested as a predictor for survival. The aim of this study was to investigate whether TRG in LNmets is related to their location within the radiotherapy (RT) field. METHODS: Histopathological TRG was retrospectively classified in 2565 lymph nodes (LNs) from 117 OeC patients treated with nCRT and surgery as: (A) no tumour, no signs of regression; (B) tumour without regression; (C) viable tumour and regression; and (D) complete response. Multivariate survival analysis was used to investigate the relationship between LN location within the RT field, pathological TRG of the LN and TRG of the primary tumour. RESULTS: In 63 (54%) patients, viable tumour cells or signs of regression were seen in 264 (10.2%) LNs which were classified as TRG-B (n = 56), C (n = 104) or D (n = 104) LNs. 73% of B, C and D LNs were located within the RT field. There was a trend towards a relationship between LN response and anatomical LN location with respect to the RT field (p = 0.052). Multivariate analysis showed that only the presence of LNmets within the RT field with TRG-B is related to poor overall survival. CONCLUSION: Patients have the best survival if all LNmets show tumour regression, even if LNmets are located outside the RT field. Response in LNmets to nCRT is heterogeneous which warrants further studies to better understand underlying mechanisms.

Electron microscopic observations in perfusion-fixed human non-alcoholic fatty liver disease biopsies.

Non-alcoholic fatty liver disease (NAFLD) is a widespread liver disease in Western society, but its multifactorial pathogenesis is not yet fully understood. Ultrastructural analysis of liver sinusoidal endothelial cells (LSECs) in animal models and in vitro studies shows defenestration early in the course of NAFLD, promoting steatosis. LSECs and fenestrae are important in the transport of lipids across the sinusoids. However, human ultrastructural data, especially on LSECs and fenestrae, are scarce. This study aimed to explore the ultrastructural changes in perfusion type fixed liver biopsies of NAFLD patients with and without non-alcoholic steatohepatitis (NASH), with a special focus on LSECs and their fenestration. Liver biopsies from patients with NAFLD were fixed using two perfusion techniques, jet and injection fixation, for needle and wedge biopsies, respectively. Ultrastructural changes were studied using transmission electron microscopy. NASH was diagnosed by bright-field microscopy using the SAF score (steatosis, activity, fibrosis). Thirty-seven patients were included, of which 12 (32.4%) had NASH. Significantly less defenestration was found in NASH compared to noNASH samples (p=0.002). Other features, i.e., giant mitochondria and fenestrae size did not differ between groups. Furthermore, we described new structures, i.e., single cell steatonecrosis and inflammatory fat follicles (IFF) that were observed in both groups. Concluding, defenestration was more common in noNASH compared to NASH in human liver samples. Defenestration was not related to the degree of steatosis or fibrosis. We speculate that defenestration can be a protective mechanism in simple steatosis which is lacking in NASH.

Appendiceal neurofibroma and diverticula in a neurofibromatosis type 1 patient with chronic right lower quadrant pain.

Neurofibromatosis type 1 (NF1, Von Recklinghausen disease) is an autosomal dominant disease with a birth incidence of 1/2500-3000. The most common presentations of NF1 are cutaneous presentations like café-au-lait spots and neurofibromas. 5%-25% of patients with NF1 have gastrointestinal manifestations of the disease. Appendiceal neurofibroma are extremely rare and only a few cases are described in literature. An appendectomy is indicated because of high risk of appendicitis and malignant transformation. We report the case of a 74-year-old male patient with a history of NF1 with chronic right lower quadrant pain. Successive imaging scans showed suspicion of chronic appendicitis. A diagnostic laparoscopy, resulting in a laparoscopic appendectomy was performed without complications. Histopathology showed appendiceal neurofibroma and diverticula. The postoperative course was uneventful. In patients with NF1 with right lower quadrant pain benign appendiceal neurofibroma should be included in the differential diagnosis. A diagnostic laparoscopy should be performed followed by an appendectomy.

The IGF pathway is activated in insulinomas but downregulated in metastatic disease.

Clinical and molecular studies have implicated epidermal growth factor receptor (EGFR), insulin-like growth factor (IGF) and target of rapamycin (mTOR) signaling pathways in the regulation of pancreatic neuroendocrine tumor (PanNET) growth. Interpretation and comparison of these studies is complex due to clinical and molecular tumor heterogeneity. We therefore focused in this study on insulinomas, which we examined for mRNA and protein expression of EGFR, IGF and mTOR signaling pathway components by quantitative real-time PCR (n=48) and immunohistochemistry (n=86). Findings were compared with normal pancreatic islets and correlated with histopathological data and clinical outcome. Insulinomas showed low EGFR and high IGF2 expression. IGFBP2, IGFBP3 and IGFBP6 mRNA levels were 2-4 folds higher than in islets. High protein expression of IGF2, IGF1R and INSR (in 51-92% of the tumors) and low to moderate expression of mTORC1 pathway proteins p-PS6k and p-4EBP1 (7-28% of the tumors) were observed. Correlations were found between 1) ERK1 mRNA expression and that of numerous IGF pathway genes, 2) p-ERK and IGF1R protein expression and 3) decrease of IGF pathway components and both metastatic disease and shorter 10 years disease free survival. In conclusion, our observations suggest that high expression of IGF signaling pathway components is a hallmark of insulinomas, but does not necessarily lead to increased mTOR signaling. Reduced expression of IGF pathway components may be an adverse prognostic factor in insulinomas.

Significantly higher rates of multiple and proximally located adenomas among patients with diabetes mellitus: A cross-sectional population-based study.

BACKGROUND: Diabetes mellitus (DM) is associated with a greater risk for colorectal cancer (CRC). OBJECTIVE: The objective of this article is to examine the endoscopic phenotype and histopathology of colorectal polyps in patients with vs without DM. METHODS: We conducted a cross-sectional study of patients who underwent colonoscopy at our university hospital and who completed a questionnaire. We collected endoscopy and histopathology data regarding colorectal adenomas and serrated polyps. Cox regression analyses were used to estimate adjusted prevalence ratios (PRs). RESULTS: We examined a total of 3654 patients (mean age (SD): 62 (12) years, 47% males). Of them, 360 (9.9%) had DM. Overall, the prevalence of colorectal adenomas (42% vs 32%, p < 0.01), multiple (≥3) adenomas (12% vs 7%, p = 0.01) and proximal adenomas (30% vs 19%, p < 0.01) was higher in patients with vs without DM. Multivariable analysis showed that the prevalence of adenomas (PR 1.17, 95% CI; 1.02-1.34), multiple (PR 1.37, 95% CI; 1.00-1.86) and proximal (PR 1.37, 95% CI; 1.16-1.62) adenomas was higher in patients with vs without DM, especially in men. CONCLUSION: Patients with DM harbor more frequently multiple and proximal adenomas than those without DM. Close colonoscopic surveillance of DM patients is important to maximize the effectiveness of colonoscopic CRC prevention.

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.

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.

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.

Magnetization transfer imaging to assess tumour response after chemoradiotherapy in rectal cancer.

PURPOSE: Single-slice magnetization transfer (MT) imaging has shown promising results for evaluating post-radiation fibrosis. The study aim was to evaluate the value of multislice MT imaging to assess tumour response after chemoradiotherapy by comparing magnetization transfer ratios (MTR) with histopathological tumour regression grade (TRG). MATERIALS AND METHODS: Thirty patients with locally advanced rectal cancer (cT3-4 and/or cN2) underwent routine restaging MRI 8 weeks post-chemoradiotherapy, including multislice MT-sequence, covering the entire tumour bed. Two independent readers delineated regions of interest on MTR maps, covering all potential remaining tumour and fibrotic areas. Mean MTR and histogram parameters (minimum, maximum, median, standard deviation, skewness, kurtosis, and 5-30-70-95th percentiles) were calculated. Reference standard was histological TRG1-2 (good response) and TRG3-5 (poor response). RESULTS: 24/30 patients were male; mean age was 67.7 ± 10.8 years. Mean MTR rendered AUCs of 0.65 (reader1) and 0.87 (reader2) to differentiate between TRG1-2 versus TRG3-5. Best results were obtained for 95(th) percentile (AUC 0.75- 0.88). Interobserver agreement was moderate (ICC 0.50) for mean MTR and good (ICC 0.80) for 95(th) percentile. CONCLUSIONS: MT imaging is a promising tool to assess tumour response post-chemoradiotherapy in rectal cancer. Particularly, 95(th) percentile results in AUCs up to 0.88 to discriminate a good tumour response. KEY POINTS: • The mean MTR can differentiate between good and poor responders after chemoradiation. • In addition to measurement of the mean value, histogram analyses can be beneficial. • The histogram parameter 95 (th) percentile can reach AUCs of 0.75-0.88.

Non-invasive MR assessment of macroscopic and microscopic vascular abnormalities in the rectal tumour-surrounding mesorectum.

OBJECTIVES: To evaluate the MRI macroscopic and microscopic parameters of mesorectal vasculature in rectal cancer patients. METHODS: Thirteen patients with rectal adenocarcinoma underwent a dynamic contrast-enhanced MRI at 1.5 T using a blood pool agent at the primary staging. Mesorectal macrovascular features, i.e., the number of vascular branches, average diameter and length, were assessed from baseline-subtracted post-contrast images by two independent readers. Mesorectal microvascular function was investigated by means of area under the enhancement-time curve (AUC). Histopathology served as reference standard of the tumour response to CRT. RESULTS: The average vessel branching in the mesorectum around the tumour and normal rectal wall was 8.2 ± 3.8 and 1.7 ± 1.3, respectively (reader1: p = 0.001, reader2: p = 0.002). Similarly, the tumour-surrounding mesorectum displayed circa tenfold elevated AUC (p = 0.01). Interestingly, patients with primary node involvement had a twofold higher number of macrovascular branches compared to those with healthy nodes (reader1: p = 0.005 and reader2: p = 0.03). A similar difference was observed between good and poor responders to CRT, whose tumour-surrounding mesorectum displayed 10.7 ± 3.4 and 5.6 ± 1.5 vessels, respectively (reader1/reader2: p = 0.02). CONCLUSIONS: We showed at baseline MRI of rectal tumours a significantly enhanced macrovascular structure and microvascular function in rectal tumour-surrounding mesorectum, and the association of primary mesorectal macrovascular parameters with node involvement and therapy response. KEY POINTS: • Vascular MRI reveals macrovascular and microvascular abnormalities in the rectal tumour-surrounding mesorectum. • Formation of highly vascular stroma precedes the actual tumour invasion. • High macrovascular parameters are associated with node involvement. • Mesorectal vascular network differs for good and poor responders.

A phase I-II study on the combination of rapamycin and short course radiotherapy in rectal cancer.

PURPOSE: This phase I/II study sought to determine the safety and maximum tolerated dose (MTD) of the combination of rapamycin, an mTOR inhibitor, with short-course radiotherapy in rectal cancer patients. Antitumor activity, changes in metabolic activity and perfusion on imaging, and changes in phosphorylation status of the mTOR pathway were also assessed. MATERIALS AND METHODS: Patients with primary resectable rectal cancer were treated with short-course hypofractionated radiotherapy (5×5 Gy) combined with oral rapamycin 1 week before and during radiotherapy, followed by surgical resection. RESULTS: Thirteen patients were entered in phase I. One patient developed a dose-limiting toxicity, consisting of a grade 4 leak and grade 4 bleeding. Because of an unexpected high rate of grade 3 postoperative toxicity, it was decided to treat patients with delayed surgery in phase II. Primary endpoint for phase II was tumor blood flow (K(trans)) assessed by perfusion CT. Thirty-one patients were treated with the MTD of 6 mg rapamycin daily. One patient (3%) developed a pathological complete response (pCR) and 3 patients (10%) had a ypT1N0 tumor at the time of resection. No change in tumor perfusion was observed on perfusion CT, but a significant decrease of metabolic activity was found on PET-scan. CONCLUSIONS: The combination of short-course radiotherapy and rapamycin turned out to be feasible, provided that the interval between neo-adjuvant treatment and surgical resection is at least 6 weeks. Although from this cohort no clear increase in pCR could be observed, a clear metabolic response after rapamycin run-in was observed, indicating a biological activity of this drug in rectal cancer.

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.