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.

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 ).

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.

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.

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.

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.

Endoscopic characterization of sessile serrated adenomas/polyps with and without dysplasia.

BACKGROUND AND STUDY AIMS: Sessile serrated adenomas/polyps (SSA/Ps) are precursors of colorectal cancer (CRC), but their endoscopic detection can be difficult. We therefore examined the endoscopic characteristics of SSA/Ps with and without dysplasia in a cross-sectional study. PATIENTS AND METHODS: We reviewed clinical, endoscopic, and histopathologic data from patients undergoing colonoscopy between February 2008 and February 2012. We categorized colorectal polyps according to anatomic site, size, and shape, and classified serrated polyps using the World Health Organization (WHO) classification. Multiple logistic regression analyses examined potential differences regarding site, size, and shape between SSA/Ps and colorectal adenomas (overall and advanced only). RESULTS: We examined 7433 patients (mean age 59 years, 45.9 % men) with 5968 colorectal polyps. In total, we found 170 SSA/Ps (170/5968, 2.9 %), including 63 SSA/Ps with dysplasia (1.1 %) and 107 SSA/Ps without dysplasia (1.8 %). Compared with SSA/Ps with dysplasia, SSA/Ps without dysplasia were more often proximally located (odds ratio [OR] 3.3, 95 % confidence interval [95 %CI] 1.7 - 6.4), but less often < 6 mm in size (OR 0.6, 95 %CI 0.3 - 1.1). No significant differences were found regarding location between SSA/Ps with dysplasia and advanced adenomas (proximal colon, 47.6 % vs. 40.1 %). However, SSA/Ps with dysplasia were more often < 6 mm in size than advanced adenomas (OR 0.3, 95 %CI 0.2 - 0.5). Of the 63 dysplastic SSA/Ps, 6 (9.5 %) contained high grade dysplasia, but none invasive carcinoma. CONCLUSIONS: SSA/Ps with dysplasia are frequently < 6 mm in size, located throughout the colon and 9.5 % of them contain high grade dysplasia. These findings underscore the importance of high quality colonoscopic examination to maximize protection against CRC.

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.

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.

Aggressive behavior and poor prognosis of endometrial stromal sarcomas with YWHAE-FAM22 rearrangement indicate the clinical importance to recognize this subset.

OBJECTIVES: Although the World Health Organization (WHO) in 2003 defined endometrial stromal sarcomas (ESSs) in general have a good prognosis, considerable differences in clinical behavior and prognosis may exist between different patients with ESS. The ESSs of the type associated with YWHAE-NUTM2 (previously named YWHAE-FAM22) fusion have a more aggressive clinical behavior and poorer prognosis than conventional ESS. Recently, the WHO 2014 classification recognizes this subset of ESS as a separate entity and classifies these as high-grade ESSs. Recognition of this subset has therefore an important clinical impact. We performed a review of the literature to delineate the clinicopathologic features of ESS patients with an YWHAE-NUTM2 rearrangement, with the goal to recognize this subset of ESS. METHODS: We report a case of a woman with WHO 2014-defined high-grade ESS. Furthermore, published English literature was reviewed for YWHAE-FAM22 ESS and uterus. RESULTS: Twenty patients were identified, with a median age of 50 (range, 28-67) years. There were no clinical features able to recognize YWHAE-NUTM2 ESS. However, they characteristically contain specific histopathological features. Furthermore, YWHAE-NUTM2 ESSs are strongly cyclin D1 positive in contrast to conventional low-grade ESSs. CONCLUSIONS: YWHAE-NUTM2 ESSs represent a subset of ESSs with an aggressive clinical behavior and poor prognosis. Specific histopathological features may indicate the presence of YWHAE-NUTM2 rearrangement, which subsequently can be confirmed by cyclin D1 immunostaining.

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.

Endoscopic appearance of proximal colorectal neoplasms and potential implications for colonoscopy in cancer prevention.

BACKGROUND: In everyday practice, the use of colonoscopy for the prevention of colorectal cancer (CRC) is less effective in the proximal than the distal colon. A potential explanation for this is that proximal neoplasms have a more subtle endoscopic appearance, making them more likely to be overlooked. OBJECTIVE: To investigate the differences in endoscopic appearance, ie, diminutive size and nonpolypoid shape, of proximal compared with distal colorectal neoplasms. DESIGN: Cross-sectional, single-center study. SETTING: Endoscopists at the Maastricht University Medical Center in the Netherlands who were previously trained in the detection and classification of nonpolypoid colorectal lesions. PATIENTS: Consecutive patients undergoing elective colonoscopy. MAIN OUTCOME MEASUREMENTS: Endoscopic appearance, ie, diminutive size (<6 mm) or nonpolypoid shape (height less than half of the diameter) of colorectal adenomas and serrated polyps (SPs), with a focus on adenomas with advanced histology, ie, high-grade dysplasia or early CRC and SPs with dysplasia or large size. RESULTS: We included 3720 consecutive patients with 2106 adenomas and 941 SPs. We found that in both men and women, proximal adenomas with high-grade dysplasia/early CRC (n = 181) were more likely to be diminutive or nonpolypoid than distal ones (76.3% vs 26.2%; odds ratio [OR] 9.24; 95% CI, 4.45-19.2; P < .001). Of the proximal adenomas, 84.4% were diminutive or nonpolypoid compared with 68.0% of the distal ones (OR 2.66; 95% CI, 2.14-3.29; P < .001). Likewise, large/dysplastic SPs in the proximal colon were more often nonpolypoid than distal ones (66.2% vs 27.8%; OR 5.51; 95% CI, 2.79-10.9; P < .001). LIMITATIONS: Inclusion of both symptomatic and asymptomatic patients. CONCLUSIONS: Proximal colorectal neoplasms with advanced histology frequently are small or have a nonpolypoid appearance. These findings support careful inspection of the proximal colon, if quality of cancer prevention with the use of colonoscopy is to be optimized.

Among B cell non-Hodgkin's lymphomas, MALT lymphomas express a unique antibody repertoire with frequent rheumatoid factor reactivity.

We analyzed the structure of antigen receptors of a comprehensive panel of mature B non-Hodgkin's lymphomas (B-NHLs) by comparing, at the amino acid level, their immunoglobulin (Ig)V(H)-CDR3s with CDR3 sequences present in GenBank. Follicular lymphomas, diffuse large B cell lymphomas, Burkitt's lymphomas, and myelomas expressed a CDR3 repertoire comparable to that of normal B cells. Mantle cell lymphomas and B cell chronic lymphocytic leukemias (B-CLLs) expressed clearly restricted albeit different CDR3 repertoires. Lymphomas of mucosa-associated lymphoid tissues (MALTs) were unique as 8 out of 45 (18%) of gastric- and 13 out of 32 (41%) of salivary gland-MALT lymphomas expressed B cell antigen receptors with strong CDR3 homology to rheumatoid factors (RFs). Of note, the RF-CDR3 homology without exception included N-region-encoded residues in the hypermutated IgV(H) genes, indicating that they were stringently selected for reactivity with auto-IgG. By in vitro binding studies with 10 MALT lymphoma-derived antibodies, we showed that seven of these cases, of which four with RF-CDR3 homology, indeed possessed strong RF reactivity. Of one MALT lymphoma, functional proof for selection of subclones with high RF affinity was obtained. Interestingly, RF-CDR3 homology and t(11;18) appeared to be mutually exclusive features and RF-CDR3 homology was not encountered in any of the 19 pulmonary MALT lymphomas studied.

Value of ADC measurements for nodal staging after chemoradiation in locally advanced rectal cancer-a per lesion validation study.

OBJECTIVES: To evaluate the performance of diffusion-weighted MRI (DWI) in addition to T2-weighted (T2W) MRI for nodal restaging after chemoradiation in rectal cancer. METHODS: Thirty patients underwent chemoradiation followed by MRI (1.5 T) and surgery. Imaging consisted of T2W-MRI and DWI (b0, 500, 1000). On T2W-MRI, nodes were scored as benign/malignant by two independent readers (R1, R2). Mean apparent diffusion coefficient (ADC) was measured for each node. Diagnostic performance was compared for T2W-MRI, ADC and T2W+ADC, using a per lesion histological validation. RESULTS: ADC was higher for the malignant nodes (1.43 ± 0.38 vs 1.19 ± 0.27 *10⁻³ mm²/s, p < 0.001). Area under the ROC curve/sensitivity/specificity were 0.88/65%/93% (R1) and 0.95/71%/91% (R2) using T2W-MRI; 0.66/53%/82% using ADC (mean of two readers); and 0.91/56%/98% (R1) and 0.96/56%/99% (R2) using T2W+ADC. There was no significant difference between T2W-MRI and T2W+ADC. Interobserver reproducibility was good for T2W-MRI (κ0.73) and ADC (intraclass correlation coefficient 0.77). CONCLUSIONS: After chemoradiation, ADC measurements may have potential for nodal characterisation, but DWI on its own is not reliable. Addition of DWI to T2W-MRI does not improve accuracy and T2W-MRI is already sufficiently accurate.

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.