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Objective: To determine whether sarcopenia can potentially predict worse survival after resection of pancreatic ductal adenocarcinoma. Background: Sarcopenia is correlated with poor outcomes in hepatopancreatobiliary malignancies, but the relationship of both its qualitative and quantitative features with patient survival after pancreatectomy has not been investigated in a western population. Patients and Methods: Preoperative cross-sectional computed tomography scans of consecutive patients who underwent pancreatectomy in 2005–2017 were evaluated for skeletal muscle index (SMI), intramuscular adipose tissue content (IMAC), and visceral-to-subcutaneous adipose tissue area ratio (VSR). Sex-specific categorical cut-offs were determined. Findings were correlated with outcome. Results: The study included 111 patients, 47% of whom were female, with a median age of 67 years (range: 35–87 years), and median body mass index of 23 kg/m2 (range: 16–40 kg/m2); 77% had a Whipple procedure and 66% received adjuvant chemotherapy. Low SMI correlated with poor overall survival (OS) (P = 0.007), disease-specific survival (DSS) (P = 0.006), and recurrence-free survival (RFS) (P = 0.01). High IMAC correlated with poor OS (P = 0.04). Patients with high IMAC tended to have a shorter DSS (P = 0.09), with no correlation with RFS (P = 0.6). VSR was not associated with survival. Multivariable analysis yielded an independent association of low SMI with OS (HR = 1.7, 95%CI: 1.1–2.8, P = 0.02), DSS (HR = 1.8, 95%CI: 1.03–3.2, P = 0.04), and RFS (HR = 1.8, 95%CI: 1.1–2.8, P = 0.01), and of high IMAC with OS (HR = 1.9, 95%CI: 1.1–3.1, P = 0.01). Conclusion: Both qualitative and quantitative measures of skeletal muscle were independently associated with impaired survival in patients with resectable PDAC. Sarcopenia might serve as an early radiographic surrogate of aggressive tumor behavior, with potential implications for clinical decision-making and future study.

Objective To evaluate the precision and utility of fine-needle aspiration (FNA) in differentiating between benign and malignant parotid tumours, and the implications of FNA results on management and outcomes. Design Retrospective case series. Setting Tertiary medical centre. Participants All adults who underwent preoperative FNA, followed by postoperative histological examination, between 1986 and 2014. Main outcome measures Differences in clinical management and outcomes of patients with parotid masses in light of FNA results. Results We analysed 505 samples from 485 patients. According to histopathological results, preoperative FNA successfully identified benign tumours in 89% of the cases (362/405) and only 59% of malignant tumours (59/100). Overall sensitivity and specificity of FNA in distinguishing between different subtypes of benign lesions were 80% and 99%, respectively, whereas positive predictive value (PPV) and negative predictive value (NPV) were 85% and 98%. Moreover, malignant lesions subtyping had high false-positive and false-negative rates with sensitivity, specificity, PPV and NPV of 44%, 100%, 75% and 99%, respectively. Additionally, when FNA falsely classified malignant tumours as benign, surgeries were inappropriately delayed and the durations of surgeries and hospitalisations were shorter, compared to true malignant FNA results. Interestingly, survival was not affected in falsely benign lesions that were mostly low-grade, conversely non-diagnostic FNA for malignant tumours resulted in decreased survival. Conclusions Our findings highlight the limitations of FNA as a decision-making tool in preoperative evaluation of parotid masses. Clinicians should take into account that FNA is inaccurate for identifying specific subtypes of malignant lesions, which may eventually delay treatment and influence outcome.

Studies have suggested that neutrophil-to-lymphocyte ratio (NLR) has value as a predictor of long-term outcomes in various cancer types. Its prognostic potential in patients with CRLM has not been thoroughly investigated. This original, retrospective study assessed the relationship between the preoperative NLR, survival outcomes, and recurrence patterns in patients after colorectal liver metastasis resection (CRLM). The prospectively maintained database of a tertiary medical center was queried for all patients who underwent CRLM resection between 2005 and 2017. Patients were divided into two groups: NLR 3 (high). Recurrence risk was analysed using Fine and Gray correction for competing risk method and cause specific analyses. The cohort included 231 patients of whom 53 (23%) had a high neutrophil-to-lymphocyte ratio. At presentation, 35% had synchronous disease and 48% had a solitary metastasis; median tumor size was 2 cm. Patients with a high NLR had a significantly higher rate of simultaneous colorectal resection (P = 0.01). A high NLR was independently associated with worse OS (P = 0.02), worse DFS (P = 0.03), and higher risk of recurrence (P = 0.048), specifically recurrence with an extrahepatic pattern (P = 0.03). A high preoperative NLR was independently associated with poorer survival outcomes and extrahepatic recurrence pattern. The NLR appears to have prognostic importance in CRLM and may serve as a surrogate marker of aggressive systemic disease after resection. These findings warrant external validation, preferably in a prospective design.

Objective Gastric cancer (GC) is a leading cause of cancer death, occurs predominantly in older age, with increasing incidence in young patients. The Cancer Genome Atlas indicates four subtypes for GC among which Epstein-Barr virus (EBV) subtype is estimated at 8.7%. We aim to determine the prevalence of EBV subtype in young GC patients (≤45 years) compared with an average-onset cohort (≥55 years) and characterize the clinicopathologic pattern of young-onset GC. Methods Gastric cancer samples of patients of both cohorts were screened for EBV by qPCR. Additional staining was done for Human epidermal growth factor receptor 2 (HER2), microsatellite instability (MSI) status and Programmed death-ligand 1 (PD-L1). Demographics and clinical data were retrieved from the medical records. Results Thirty-nine young-onset and 35 average-onset GC patients were reviewed. There was no apparent difference in tumor location, family history, histology and HER2 status between the cohorts. More young-onset patients were diagnosed with metastatic disease (27% vs 9%, p = 0.0498). EBV was significantly more prevalent in the young-onset cohort (33% vs 11%, p = 0.025). 15/17 EBV positive patients were under the median age of diagnosis for GC in the US (68 years). MSI-H was found only in the average-onset cohort [0% vs 27%, p = 0.001). PD-L1 positivity was higher in the young-onset cohort (31% vs 3%, p = 0.002). Conclusion Our study indicates that EBV subtype is more prevalent in young-onset GC and may play a key role in the pathogenesis. Higher rate of PD-L1 positivity in young-onset GC could change treatment strategies. We are currently evaluating these findings in a prospective trial.

Tissue-transglutaminase antibodies (TGA) may be used to diagnose celiac disease (CD) without biopsy in selected cases. We aimed to investigate real-life performance of a CD serology automated analyzer (Bioplex2200), and to explore the correlation between TGA levels and intestinal biopsies in children.A retrospective review was performed in 2 pediatric gastroenterological centers, between November 1, 2018 and April 1, 2020 and included patients with both TGA serology testing and duodenal biopsies. Retrieved data included patients' demographics, medical background, TGA levels, and biopsy results.Overall, 538 children were evaluated, 256 with positive TGA (68.4% girls, median age 6.4 years), and 282 with negative TGA (53.9% girls, median age 13.4 years). Among patients with positive TGA, intestinal biopsies confirmed CD in 219 (85.5%). Overall, positive serology with normal histology was found in 14.5% of the cohort, with 52%; 21.6%; 21.1%; and 4.2% in TGA ranges of 1 to 3 times upper limit of normal (ULN); 3 to 5 ULN; 5 to 10 ULN; and above 10 times ULN, respectively, P 0.001. Area under the receiver-operating characteristic curve (AUC) was 0.963 (95% CI 0.947-0.980). Among patients with positive TGA, 216 (84.4%) had positive anti-endomysial antibodies. In this sub-group, the overall diagnostic performance was inferior, with AUC of 0.737 (95% CI 0.834-0.839).The Multiplex TGA assay had a very high diagnostic accuracy in real-life. Among patients with positive TGA, adding EMA did not improve the diagnostic performance of the test. False-positive rates differed between different ranges of TGA and were low with TGA above 10 times ULN.

Background and aims The primary clinical characteristics of Fanconi Anemia (FA) include typical physical features, progressive bone marrow failure, and an increased incidence of neoplasms, including esophageal carcinoma. Currently, there are no data regarding endoscopic findings or the interval time to malignancy in these patients. Data about the contribution of Human Papilloma Virus (HPV) to esophageal carcinoma is conflicting. Our objective is to document the upper gastrointestinal (GI) findings at baseline, document cancer incidence, and evaluate the role of HPV among these cancers. Methods We reviewed endoscopic and clinical data of FA subjects who participated in active surveillance before cancer diagnosis. Incident esophageal cancers were stained for HPV p16 protein. Results Eight FA patients were included (men 62.5%; median age at first endoscopy 20 years, median endoscopies number: 5.5). At baseline, 8/8 had endoscopic evidence for reflux esophagitis. In 3/8 the reflux esophagitis was mild and in 5/8 it was moderate or severe. During the follow up time (median time 4.5 years 2/8 developed Barrett’s esophagus and 2/8 patients had incident esophageal squamous cell carcinoma during follow up, at intervals of eight and eighteen months from the previous upper endoscopy. Both cancers stained negative for HPV P16. Conclusions FA subjects have both an extremely high risk for esophageal cancer within short intervals and a very high prevalence of reflux esophagitis with various severities. Active surveillance programs in specialized centers including annual upper endoscopies should be considered in these patients.

To determine whether sarcopenia can potentially predict worse survival after resection of pancreatic ductal adenocarcinoma.Sarcopenia is correlated with poor outcomes in hepatopancreatobiliary malignancies, but the relationship of both its qualitative and quantitative features with patient survival after pancreatectomy has not been investigated in a western population.Preoperative cross-sectional computed tomography scans of consecutive patients who underwent pancreatectomy in 2005-2017 were evaluated for skeletal muscle index (SMI), intramuscular adipose tissue content (IMAC), and visceral-to-subcutaneous adipose tissue area ratio (VSR). Sex-specific categorical cut-offs were determined. Findings were correlated with outcome.The study included 111 patients, 47% of whom were female, with a median age of 67 years (range: 35-87 years), and median body mass index of 23 kg/mBoth qualitative and quantitative measures of skeletal muscle were independently associated with impaired survival in patients with resectable PDAC. Sarcopenia might serve as an early radiographic surrogate of aggressive tumor behavior, with potential implications for clinical decision-making and future study.

Intestinal metaplasia (IM) is an intermediate step in the progression from premalignant to malignant stages of gastric cancer (GC). The Popeye domain containing (POPDC) gene family encodes three transmembrane proteins, POPDC1, POPDC2, and POPDC3, initially described in muscles and later in epithelial and other cells, where they function in cell–cell interaction, and cell migration. POPDC1 and POPDC3 downregulation was described in several tumors, including colon and gastric cancers. We questioned whether IM-to-GC transition involves POPDC gene dysregulation. Gastric endoscopic biopsies of normal, IM, and GC patients were examined for expression levels of POPDC1-3 and several suggested IM biomarkers, using immunohistochemistry and qPCR. Immunostaining indicated lower POPDC1 and POPDC3 labeling in IM compared with normal tissues. Significantly lower POPDC1 and POPDC3 mRNA levels were measured in IM and GC biopsies and in GC-derived cell lines. The reduction in focal IM was smaller than in extensive IM that resembled GC tissues. POPDC1 and POPDC3 transcript levels were highly correlated with each other and inversely correlated with LGR5, OLFM4, CDX2, and several mucin transcripts. The association of POPDC1 and POPDC3 downregulation with IM-to-GC transition implicates a role in tumor suppression and highlights them as potential biomarkers for GC progression and prospective treatment targets.

Intestinal metaplasia (IM) is an intermediate step in the progression from premalignant to malignant stages of gastric cancer (GC). The Popeye domain containing (POPDC) gene family encodes three transmembrane proteins, POPDC1, POPDC2, and POPDC3, initially described in muscles and later in epithelial and other cells, where they function in cell–cell interaction, and cell migration. POPDC1 and POPDC3 downregulation was described in several tumors, including colon and gastric cancers. We questioned whether IM-to-GC transition involves POPDC gene dysregulation. Gastric endoscopic biopsies of normal, IM, and GC patients were examined for expression levels of POPDC1-3 and several suggested IM biomarkers, using immunohistochemistry and qPCR. Immunostaining indicated lower POPDC1 and POPDC3 labeling in IM compared with normal tissues. Significantly lower POPDC1 and POPDC3 mRNA levels were measured in IM and GC biopsies and in GC-derived cell lines. The reduction in focal IM was smaller than in extensive IM that resembled GC tissues. POPDC1 and POPDC3 transcript levels were highly correlated with each other and inversely correlated with LGR5, OLFM4, CDX2, and several mucin transcripts. The association of POPDC1 and POPDC3 downregulation with IM-to-GC transition implicates a role in tumor suppression and highlights them as potential biomarkers for GC progression and prospective treatment targets.

Studies have suggested that neutrophil-to-lymphocyte ratio (NLR) has value as a predictor of long-term outcomes in various cancer types. Its prognostic potential in patients with CRLM has not been thoroughly investigated. This original, retrospective study assessed the relationship between the preoperative NLR, survival outcomes, and recurrence patterns in patients after colorectal liver metastasis resection (CRLM).The prospectively maintained database of a tertiary medical center was queried for all patients who underwent CRLM resection between 2005 and 2017. Patients were divided into two groups: NLR3 (normal) or3 (high). Recurrence risk was analysed using Fine and Gray correction for competing risk method and cause specific analyses.The cohort included 231 patients of whom 53 (23%) had a high neutrophil-to-lymphocyte ratio. At presentation, 35% had synchronous disease and 48% had a solitary metastasis; median tumor size was 2 cm. Patients with a high NLR had a significantly higher rate of simultaneous colorectal resection (P = 0.01). A high NLR was independently associated with worse OS (P = 0.02), worse DFS (P = 0.03), and higher risk of recurrence (P = 0.048), specifically recurrence with an extrahepatic pattern (P = 0.03).A high preoperative NLR was independently associated with poorer survival outcomes and extrahepatic recurrence pattern. The NLR appears to have prognostic importance in CRLM and may serve as a surrogate marker of aggressive systemic disease after resection. These findings warrant external validation, preferably in a prospective design.

While the prognosis of patients with locoregional esophageal adenocarcinoma (EAC) has improved in the neoadjuvant treatment (NAT) era, high-grade histology (G3) is still associated with a limited treatment response. We sought to investigate oncologic outcomes in patients after esophagectomy for G3 EAC and to identify predictors of poor survival among these patients.Patients with EAC who underwent resection with curative intent in 2011-2018 were divided by histologic grade (G3, G1/2) and compared for overall survival (OS). Cox regression was performed to analyze the response to NAT and the predictive role of signet ring cell (SRC) features.The cohort included 163 patients, 94 (57.7%) with G3 histology. NAT was administered to 69 (73.4%) patients. Following resection, OS in the G3 EAC group was 30 months (95% confidence interval [CI] 23.9-36.1). On univariate analysis, G3 disease (p = 0.050) and SRC features (p = 0.019) predicted low OS. Median survival in the G3 EAC group was worse in patients with SRC histology (18 months, 95% CI 8.6-27.4) than those without (30 months, 95% CI 23.8-36.1; p = 0.041). No patients with SRC histology were alive at 5 years of follow-up. Among all patients administered NAT, 88.2% of those with SRC showed minimal or no pathologic response and only 27.8% were downstaged.High-grade histology was found in most patients with EAC and predicted poor survival and treatment response. SRC features in patients with G3 disease were associated with lower OS. The benefit of NAT for G3 EAC in patients with SRC histology appears limited.

Objectives The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) 2012 guidelines, enabled for the first time, a nonbiopsy approach in the diagnosis of celiac disease (CD). We aimed to prospectively assess 4 tissue-transglutaminase (tTg) IgA assays of 4 random-access analyzers and examine their accuracy in diagnosing CD without a biopsy. Methods We enrolled 186 consecutive children referred to upper endoscopy and intestinal biopsy. One group included 109 patients with positive tTg that was referred for suspected CD. Another group included 77 patients with negative tTg referred because of other indications. All participants had a blood sample taken at the time of endoscopy. Samples were tested with 4 tTg IgA assays on automated analyzers and 1 Elisa kit. All intestinal biopsies were evaluated by a local pathologist, a central pathologist, and a CD expert blinded to each other. CD was diagnosed when full agreement was reached. Analytical performance of the assays included precision with controls and samples, lot to lot variation, and carryover. Results In our cohort, all tested tTg IgA-automated assays showed sensitivities above 98% and specificities above 99%. ROC analysis demonstrated AUC (area under the curve) >0.99 for all 4 analyzers. The positive-predictive values (PPV) were all >0.99 and negative-predictive values (NPV) were >0.97. The Elisa kit had sensitivity of 95%, specificity of 96%, AUC of 0.96, PPV of 0.98 and NPV of 0.93. Conclusion CD can be accurately diagnosed without biopsy based on tTg IgA levels at least 10 times the ULN using the 4 high-volume random-access analyzers used in our study.

INTRODUCTION Breast and chest wall desmoid tumours can cause debilitating symptoms and deformity. The mutilating effects of surgical treatment have prompted a shift to medical treatments and even to a wait-and-see approach. This study sought to highlight specific characteristics of breast and chest wall desmoid tumours on long-term follow-up by sequential MRI scans. METHODS Thirty-two breast MRI scans from six patients with chest wall or breast desmoid tumours followed up for up to 6 years were retrospectively reviewed. RESULTS All patients underwent breast surgery prior to the development of the desmoid tumour. Five of the patients had reconstruction or augmentation using silicone implants. Two desmoids were treated primarily with surgery, three with medical means and one is under wait-and-see approach. On MRI, tumours appeared either oval and lobulated (chest wall) or spiculated with architectural distortion (breast). Chest wall desmoids demonstrated both an enhancing high-T2-signal component and a non-enhancing low-T2- signal component. The histologically defined phases during the course of desmoid tumours (progression, regression, residual disease) could be demonstrated by corresponding MRI changes in each of the components. CONCLUSIONS Magnetic resonance imaging delineates the complex infiltrative features of chest wall and breast desmoid tumours. In tumours with a bright cellular enhancing and dark collagenous non-enhancing component, treatment response may be predicted by changes on serial T2-weighted sequences, beyond the tumour-dimension-based RECIST assessment alone.

Eosinophils are implicated in the pathogenesis of ulcerative colitis.To evaluate the magnitude of mucosal and blood eosinophils in newly diagnosed pediatric ulcerative colitis patients and its significance in predicting disease outcomes.We retrospectively evaluated colorectal biopsies of 96 pediatric patients with ulcerative colitis and 50 age- and sex-matched controls. Samples were taken from diseased areas of the colon and examined by a gastrointestinal pathologist. The most inflamed site was used for assessment of mucosal eosinophils.Samples from 96 diagnostic and 70 follow-up colonoscopies were evaluated. Median age was 13.3 years (IQR 10.1-15.3). Median duration of follow-up was 12.8 years (IQR 7.2-17.1). Median number of tissue eosinophils at diagnosis was 45 (IQR 22-73) compared to 10 eosinophils (IQR 8-25) during histologic remission (p0.0001). Peripheral absolute eosinophil counts correlated with tissue inflammation and eosinophilia (p=0.001). Mucosal eosinophilic infiltration (p=0.02) and peripheral eosinophilia (p=0.04) was associated with clinical severity at diagnosis. Multivariate analysis showed that severe eosinophilic infiltration is associated with corticosteroid therapy following diagnosis (p=0.04) but not with long-term risk for step-up therapy or colectomy.Tissue and peripheral eosinophilia correlate with ulcerative colitis severity at diagnosis and with short-term corticosteroid requirement but not with long-term outcomes.

Background Anatomic location of primary tumors across the colon correlate with survival in the metastatic setting, whereas left-sided tumors may exhibit superior survival compared with right-sided tumors. The Oncotype Recurrence Score (RS) assay is a clinically validated predictor of recurrence risk in patients with stage II colorectal cancer (CRC). Previous studies had indicated that without adjuvant chemotherapy, CDX2-negative stage II CRC tumors are associated with a lower rate of disease-free survival than CDX2-positive stage II CRC tumors. We aimed to evaluate whether these two validated prognostic biomarkers may correlate with primary tumor location, and whether tumor location may reflect differential prognosis in stage II CRC. Materials and Methods We retrospectively analyzed patients with T3 mismatch repair-proficient (MMR-P) stage II CRC for whom RS assay was performed. Pathological report was reviewed for exact primary tumor location and CDX2 immunostaining. RS and CDX2 expression were correlated with primary tumor location. Results The analysis included 1,147 patients with MMR-P stage II CRC (median age 69 years [range 29–93]). Tumor distribution across the colon was as follows: 46% (n = 551) were right-sided and 54% (n = 596) were left-sided. RS was higher in right-sided tumors (p = .01). The RS results gradually decreased across the colon (cecum, highest score; sigmoid, lowest score; p = .04). Right-sided tumors exhibited more CDX2-negative tumors (p = .07). Conclusion Our study indicates that right-sided colorectal tumors may display worse prognosis compared with left-sided tumors in MMR-P stage II CRC. Primary tumor location may serve as a prognostic factor that should be taken into account for recurrence risk assessment and consideration of adjuvant treatment.

Aims The distinction between benign and malignant thyroid nodules has important therapeutic implications. Our objective was to develop an assay that could classify indeterminate thyroid nodules as benign or suspicious, using routinely prepared fine needle aspirate (FNA) cytology smears. Methods A training set of 375 FNA smears was used to develop the microRNA-based assay, which was validated using a blinded, multicentre, retrospective cohort of 201 smears. Final diagnosis of the validation samples was determined based on corresponding surgical specimens, reviewed by the contributing institute pathologist and two independent pathologists. Validation samples were from adult patients (≥18 years) with nodule size >0.5 cm, and a final diagnosis confirmed by at least one of the two blinded, independent pathologists. The developed assay, RosettaGX Reveal, differentiates benign from malignant thyroid nodules, using quantitative RT-PCR. Results Test performance on the 189 samples that passed quality control: negative predictive value: 91% (95% CI 84% to 96%); sensitivity: 85% (CI 74% to 93%); specificity: 72% (CI 63% to 79%). Performance for cases in which all three reviewing pathologists were in agreement regarding the final diagnosis (n=150): negative predictive value: 99% (CI 94% to 100%); sensitivity: 98% (CI 87% to 100%); specificity: 78% (CI 69% to 85%). Conclusions A novel assay utilising microRNA expression in cytology smears was developed. The assay distinguishes benign from malignant thyroid nodules using a single FNA stained smear, and does not require fresh tissue or special collection and shipment conditions. This assay offers a valuable tool for the preoperative classification of thyroid samples with indeterminate cytology.

Background Surgical resection is considered to be the best treatment for gastrointestinal stromal tumor (GIST), the most common mesenchymal tumor of the gastrointestinal tract. Tumor size, mitotic rate, and anatomic locations are directly related to the potential malignancy, surgical approach, oncological treatment, and recurrence rate. Materials and methods This was a retrospective study of 40 patients who underwent surgical resection of histologically or immunohistochemistry-proven GIST of the stomach at the Rabin and Kaplan Medical Center between 2004 and 2013. Tumor size, location, margin status, pathologic characteristics, surgical approach, surgical outcome, and long-term follow-up were analyzed from hospital records. Results The most common presentation was upper gastrointestinal bleeding (40%), although 30% of cases were asymptomatic. A laparoscopic approach was the preferred technique whenever feasible; 85% of tumors were localized in the proximal stomach, with a median size of 5.6 cm. Most of the resected tumors revealed a low mitotic rate and thus had low-moderate risks of malignancy. All tumors were completely resected with free surgical margins. The median follow-up period was 40 months with 93% disease-free survival. Conclusions Gastric GIST is a snake in the grass and its diagnosis is often incidental to endoscopy and computed tomographic scan. The most important technical point is to avoid tumor rupture during removal.

Background: The aim of this study was to characterize the signs of invasive lobular carcinoma of the breast on digital breast tomosynthesis (DBT) imaging. Patients and Methods: The study group included 23 women with pathologically proven invasive lobular carcinoma of the breast for whom both digital mammography (DM) and DBT images were available. The images were read jointly by 2 experienced breast radiologists. Findings were recorded according to the descriptors in the Breast Imaging and Reporting Data System lexicon and correlated with the detailed pathology results. Results: In 21 of the 23 patients, the combination of DM and DBT yielded pathologic findings (91%). Architectural distortions or spiculations were demonstrated in 87% of cases. The addition of DBT to DM improved lesion detection by more clearly depicting both the lesion margins and architectural distortions. Only 2 lesions were occult by both DM and DBT, including 1 lesion in a peripheral location that was not incorporated in the standard mediolateral oblique and craniocaudal views. Conclusion: DBT improves the detection of invasive lobular carcinoma lesions by more clearly depicting architectural distortions and spiculations.

Immunohistochemistry (IHC) testing for mismatch repair proteins (MMRP) in patients with colorectal cancer can be performed on endoscopic biopsy material or the surgical resection material. Data are continuing to accumulate regarding the deleterious effect of neoadjuvant chemoradiation on MMRP expression. However, despite continuing rise in the use of endoscopic biopsies for IHC, most pathology departments still use mainly the surgical materials for IHC testing. In this study we compared the quality of stains among 96 colon cancer subjects with paired endoscopic and surgical material available for MLH1, MSH2, MSH6, and PMS2 stains (96 × 4, yielding 384 paired stains). Each slide received both a quantitative score (immunoreactivity [0-3] × percent positivity [0-4]) and a qualitative score (absent; weak and focal; strong). The quantitative scores of all MMRP were significantly higher among the endoscopic material (P

Malignant mesothelioma is an uncommon tumor that usually arises in the pleural cavity of adults with a history of asbestos exposure. Less frequently, it appears in the peritoneum or other mesothelial surfaces. Deciduoid mesothelioma is a rare subtype that has been found at both sites. Of the 3 reported cases in children, 2 originated in the mesenterium and 1 in the pleura. We describe a 4th case of pediatric, malignant, deciduoid mesothelioma and a third case in the mesenteric cavity. The patient was an 8-year-old girl who presented with abdominal pain and fullness. Workup revealed extensive involvement of the abdomen by a serosa-based tumor. The clinical and pathologic findings are described, and the pertinent literature is reviewed.

OBJECTIVE Salivary gland neoplasms are rare tumours, with most arising in the parotid gland. Fine-needle aspiration cytology (FNAC) is a common method for preoperative evaluation of parotid masses, although its usefulness is controversial. This study was designed to evaluate the accuracy of FNAC in a large cohort of patients, with emphasis on diagnosis of benign tumours and especially Warthin tumour which can be managed conservatively. STUDY DESIGN Retrospective case series with chart review. SETTING Tertiary medical centre. SUBJECTS AND METHODS From 1991 to 2014, all patients 18 or older with both preoperative FNAC and postoperative pathology report were included. Patients with a history of head and neck malignancy or chronic sialoadenitis and patients who had undergone prior oncological treatment were excluded. RESULTS 470 patients were available for analysis. Overall accuracy was 82.6%. Positive predictive value (PPV) varied between 88.6% and 94.3% for pleomorphic adenoma and 77.1%-100% for Warthin tumour, with values varying depending on different characteristics of patients (eg age, smoking status). For pathologically proven malignant tumours, the FNAC diagnosis was benign or non-diagnostic in 26% of the cases. CONCLUSION Fine-needle aspiration cytology has limited utility in confirming a benign diagnosis of a parotid mass for most patients, although for some subpopulations, the PPV may be high enough to defer surgery.

Background & Aims The guidelines of the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition allow for diagnosis of celiac disease without biopsies in children with symptoms and levels of immunoglobulin A against tissue-transglutaminase (TGA-IgA) 10-fold or more the upper limit of normal (ULN), confirmed by detection of endomysium antibodies (EMA) and positivity for HLA-DQ2/DQ8. We performed a large, international prospective study to validate this approach. Methods We collected data from consecutive pediatric patients (18 years or younger) on a gluten-containing diet who tested positive for TGA-IgA from November 2011 through May 2014, seen at 33 pediatric gastroenterology units in 21 countries. Local centers recorded symptoms; measurements of total IgA, TGA, and EMA; and histopathology findings from duodenal biopsies. Children were considered to have malabsorption if they had chronic diarrhea, weight loss (or insufficient gain), growth failure, or anemia. We directly compared central findings from 16 antibody tests (8 for TGA-IgA, 1 for TGA-IgG, 6 for IgG against deamidated gliadin peptides, and 1 for EMA, from 5 different manufacturers), 2 HLA-DQ2/DQ8 tests from 2 manufacturers, and histopathology findings from the reference pathologist. Final diagnoses were based on local and central results. If all local and central results were concordant for celiac disease, cases were classified as proven celiac disease. Patients with only a low level of TGA-IgA (threefold or less the ULN) but no other results indicating celiac disease were classified as no celiac disease. Central histo-morphometry analyses were performed on all other biopsies and cases were carefully reviewed in a blinded manner. Inconclusive cases were regarded as not having celiac disease for calculation of diagnostic accuracy. The primary aim was to determine whether the nonbiopsy approach identifies children with celiac disease with a positive predictive value (PPV) above 99% in clinical practice. Secondary aims included comparing performance of different serological tests and to determine whether the suggested criteria can be simplified. Results Of 803 children recruited for the study, 96 were excluded due to incomplete data, low level of IgA, or poor-quality biopsies. In the remaining 707 children (65.1% girls; median age, 6.2 years), 645 were diagnosed with celiac disease, 46 were found not to have celiac disease, and 16 had inconclusive results. Findings from local laboratories of TGA-IgA 10-fold or more the ULN, a positive result from the test for EMA, and any symptom identified children with celiac disease (n = 399) with a PPV of 99.75 (95% confidence interval [CI], 98.61–99.99); the PPV was 100.00 (95% CI, 98.68–100.00) when only malabsorption symptoms were used instead of any symptom (n = 278). Inclusion of HLA analyses did not increase accuracy. Findings from central laboratories differed greatly for patients with lower levels of antibodies, but when levels of TGA-IgA were 10-fold or more the ULN, PPVs ranged from 99.63 (95% CI, 98.67–99.96) to 100.00 (95% CI, 99.23–100.00). Conclusions Children can be accurately diagnosed with celiac disease without biopsy analysis. Diagnosis based on level of TGA-IgA 10-fold or more the ULN, a positive result from the EMA tests in a second blood sample, and the presence of at least 1 symptom could avoid risks and costs of endoscopy for more than half the children with celiac disease worldwide. HLA analysis is not required for accurate diagnosis. Clinical Trial Registration no: DRKS00003555.

Immunohistochemistry (IHC) testing for mismatch repair proteins (MMRP) is currently being used primarily in colorectal cancer resection specimens. We aimed to compare the results of IHC staining performed on biopsy specimens obtained at endoscopy with that performed on surgical specimens after neoadjuvant therapy. Thirty-two rectal cancer subjects had paired preneoadjuvant and postneoadjuvant tissue available for IHC staining (MLH1, MSH2, MSH6, and PMS2), whereas 39 rectosigmoid cancer patients who did not receive neoadjuvant treatment served as controls. Each slide received a qualitative (absent, focal, and strong) and quantitative score (immunoreactivity [0-3] × percent positivity [0-4]). The quantitative scores of MMRP from the operative material were significantly lower in the neoadjuvant group than in the control (P < .05 for all).The scores of all MMRP from endoscopic biopsies were not significantly different between the neoadjuvant and the control groups. Disagreement between the endoscopic biopsy and the operative material was evident in 23 of 128 stains (18.5%) in the neoadjuvant group and in 12 of 156 stains (7.7%) in the control group (P = .009). In the neoadjuvant group, a disagreement pattern of "endoscopic strong operative focal" was observed in 28.1% for PMS2, 12.5% for MSH6, 12.5% for MLH1, and 6.3% for MSH2, and in the control group, this same disagreement pattern was found in 12.8% for PMS2, 7.7% for MSH6, 7.7% for MLH1, and 0% for MSH2. Based on our findings, we suggest that for rectal cancer, the endoscopic material rather than the operative material should serve as the primary material for IHC staining.

There are currently no accepted clinical guidelines for the surveillance of first-degree relatives (FDRs) of gastric cancer patients. The existence of intestinal metaplasia, as well as altered mucin expression, might be associated with an increased risk for gastric cancer. In the present study we aimed to investigate the mucin phenotype of individuals with a family history of gastric cancer.We included FDRs of gastric cancer patients. Individuals with functional chest pain served as controls. Upper endoscopy including extensive biopsy according to the Olga protocol was performed. Immunohistochemical staining for MUC1, MUC2, MUC5AC, and MUC6 was performed. Sera were assayed for pepsinogen I and II. Helicobacter status was determined through Giemsa staining and serological tests.Forty FDRs and eight controls were included; the mean age was 46.7 ± 12.0 years. In both the study group and the control group there were no gross endoscopic findings and no histological evidence of intestinal metaplasia. Superficial MUC1 expression was significantly increased in the study group (47.5 vs. 0%; P=0.01). There was no difference in the expression of deep MUC1, MUC2, MUC5AC, or MUC6 between the groups, nor was there a difference in pepsinogen I/II levels or Helicobacter pylori exposure (35.0 vs. 25.0%; P=0.46).Despite normal appearing mucosa and the absence of intestinal metaplasia according to histological analysis, FDRs of gastric cancer patients show increased expression of MUC1, which may serve as a predictor of future intestinal metaplasia, dysplasia, and cancer. Further studies are needed to verify these findings and their implications.

Summary Background Increased numbers of duodenal intraepithelial lymphocytes (IELs) characterise coeliac disease (CD) but have also been described in noncoeliacs. Controversy exists regarding an association between increased IELs and infection with Helicobacter pylori, which is commonly found in children. Aim To assess the relationship between H. pylori infection and duodenal IELs in a large cohort of children, with and without CD. Methods We reviewed gastric and duodenal biopsies of children who underwent esophagogastroduodenoscopy between January 2006 and February 2013 because of either recurrent abdominal pain (RAP) or suspected CD at Schneider Children's Medical Center of Israel, a referral centre for Israel's largest Health Maintenance Organization. The duodenal IEL count and H. pylori presence in antral biopsies were determined for each specimen. Results Children with RAP (n = 693) or CD (n = 306) were included. Among children with RAP, H. pylori was present in 33.8%. The mean IEL count in the H. pylori positive RAP group was 17.8(±8.8)/100 enterocytes, vs. 15.8(±8.3) in the H. pylori negative patients (P = 0.004). Increased IEL counts (≥25 IELs/100 enterocytes) were found in 15.7% of H. pylori negative, noncoeliac children. Among children with CD, there was no significant difference in IEL counts according to H. pylori status: 73.1(±26.1) vs. 72.6 (±26.5) in H. pylori positive and negative patients respectively. Conclusions Our study suggests that slightly elevated duodenal intraepithelial lymphocyte counts are common in the paediatric population. Helicobacter pylori infection has no major influence on the intraepithelial lymphocyte counts in children with recurrent abdominal pain or children with coeliac disease.

Objective The aim of this study was to describe the radiographic findings in stercoral colitis. Methods The computed tomographic scans and abdominal radiographs of 13 patients with surgically and pathologically confirmed stercoral colitis from 4 affiliated hospitals were reviewed by a board-certified abdominal radiologist blinded to the official imaging, surgical, and pathologic findings. Results The median age was 66 years. The patients presented mainly with constipation (100%) and an acute inflammatory process (85%); 5 patients (38%) had frank septic shock. Mortality was 46%. Imaging scans showed that the colon dilated proximally to the impaction site in 6 patients (50%). Other findings included fat stranding (100%), mucosal sloughing (58%), mesenteric hyperemia (58%), and extraluminal gas (17%). Conclusions Computed tomography is an important diagnostic modality for stercoral colitis. The presence of a large fecaloma with distention of the affected colon and wall thickening and pericolonic fat stranding should alert radiologists and surgeons to the presence of this potentially fatal condition.

We histologically investigated the cause of failed endoscopic treatment of vesicoureteral reflux with dextranomer/hyaluronic acid injections in children.A total of 192 children underwent dextranomer/hyaluronic acid injection at our institution between January 2008 and September 2010. The study population consisted of 13 children (22 ureters) with vesicoureteral reflux who underwent ureteroneocystostomy following failed endoscopic injections (1 to 2) of dextranomer/hyaluronic acid. In all cases the dextranomer/hyaluronic acid was implanted in the mucosa of the mid to distal ureteral tunnel following hydrodistention of the ureter. The medical records were reviewed, and specimens of the archived distal ureters removed during surgery were examined histologically.Mean patient age was 4.1 years. Mean dose of dextranomer/hyaluronic acid was 0.9 ml (both treatments) and mean lag between treatments was 13.4 months. Indications for open surgery were recurrent urinary tract infections and/or residual or aggravated reflux grade IV or higher. Histological study revealed that the dextranomer/hyaluronic acid was malpositioned in 21 of 22 ureters, residing in the muscle fibers in 2, adventitia in 14 and periureteral space in 5.This is the first known study to provide a histologically proved cause of failure of endoscopic treatment of vesicoureteral reflux with dextranomer/hyaluronic acid injections in children. Malpositioning of the material outside the submucosal ureter was identified in a high percentage of cases. Larger studies are needed to corroborate these findings.

Background The ratio of Helicobacter pylori/NSAID-negative gastric ulcers is increasing. Idiopathic gastric ulcers have unique clinical and endoscopic features, and are associated with more bleeding complications and a higher mortality. Alterations in gastric mucin expression and sialylation pattern may be important in ulcer pathogenesis.

The type of pathological response to neoadjuvant chemoradiation in patients with locally advanced esophageal cancer predicts overall survival (OS). We aimed to assess early 18F-FDG positron emission tomography/computed tomography parameters in predicting the pathological response to neoadjuvant treatment. The cohort included consecutive patients with locally advanced esophageal cancer who underwent baseline 18F-FDG positron emission tomography/computed tomography between September 2006 and February 2015. Positron emission tomography variables of maximum and average standardized uptake values (SUVmax, SUVaverage), metabolic tumor volume (MTV), and total lesion glycolysis were recorded in addition to computed tomography volume. MTV was calculated using cut-off values of 42%, 50% and 60% (MTV 0.42, 0.5, and 0.6) of the tumoral SUVmax. Receiver operating characteristic (ROC) analysis was used to determine sensitivity and specificity. Sixty-one patients (44 male, 17 female) fulfilled the inclusion criteria. Only MTV values of 13.6 mL (MTV 0.42) and 7.4 mL (MTV 0.5) remained significant on ROC analysis, with an area under the curve of 0.690 (confidence interval 0.557–0.823, p = .02] and 0.664 (confidence interval 0.527–0.802, P = .048), respectively in differentiating patients with a complete (n = 44) or incomplete (n = 17) pathological response. MTV at presentation is associated with the pathological response to neoadjuvant chemoradiation in patients with locally advanced esophageal cancer.

The definitive identification of malignant pleural mesothelioma (MPM) has significant clinical implications, yet other malignancies often involve the lung pleura, confounding the diagnosis of MPM. In the absence of accurate markers, MPM can be difficult to distinguish from peripheral lung adenocarcinoma and metastatic epithelial cancers. MicroRNA expression is tissue-specific and highly informative for identifying tumor origin. We identified microRNA biomarkers for the differential diagnosis of MPM and developed a standardized microRNA-based assay. Formalin-fixed, paraffin-embedded samples of 33 MPM and 210 carcinomas were used for assay development. Using microarrays, we identified microRNAs differentially expressed between MPM and various carcinomas. Hsa-miR-193–3p was overexpressed in MPM, while hsa-miR-200c and hsa-miR-192 were overexpressed in peripheral lung adenocarcinoma and carcinomas that frequently metastasize to lung pleura. We developed a standardized diagnostic assay based on the expression of these microRNAs. The assay reached a sensitivity of 100% and a specificity of 94% in a blinded validation set of 68 samples from the lung and pleura. This diagnostic assay can provide a useful tool in the differential diagnosis of MPM from other malignancies in the pleura.

The objective of this study is to examine the expression of matrix metalloproteinase 1 (MMP-1) in invasive well-differentiated thyroid carcinoma (WDTC) and its relation to clinicopathological features. This retrospective case study group included 26 patients with invasive WDTC who were treated at our center between January 1985 and May 2007. Clinical data were collected from the medical files. MMP-1 expression was tested in samples from paraffin-embedded tumor by immunohistochemical staining. MMP-1 expression correlated with laryngotracheal invasion (p = 0.032), multifocality of the tumor (p = 0.044), and presence of regional (p = 0.034) and distant metastases (p = 0.048). In conclusion, the expression of MMP-1 in invasive WDTC is consistent with tumor aggressiveness, manifested by laryngotracheal invasion, multifocality, and regional and distant metastases. MMP-1 expression may serve as a prognostic marker and an indicator for the need for more aggressive surgical treatment.

Background Patients infected by Helicobacter pylori who have first-degree relatives with gastric cancer have an 8-fold increased risk of developing gastric cancer themselves. Mucins are high-molecular-weight glycoproteins that play a cardinal role in the protective mechanism of the gastric epithelium. Aim To study gastric acid and mucin secretion in dyspeptic patients with and without a family history of gastric cancer and H. pylori infection. Materials and methods Twenty-six dyspeptic patients underwent esophago-gastro-duodenoscopy, gastric biopsies, and acid and mucin secretory tests. The sample was divided by family history of gastric cancer and H. pylori status. Results Patients who were infected by H. pylori had a significantly higher degree of inflammation than those who were not. H. pylori-positive patients with a positive family history had a lower basal and maximal gastric acid output than infected patients with no family history and noninfected controls, and a higher basal and maximal mucin output than infected patients with no family history. MUC5AC was the major mucin species expressed in gastric juice. Conclusions In patients with relatives with gastric cancer, H. pylori infection is associated with a more severe inflammatory reaction consisting of decreased gastric acid secretion and increased mucin secretion.

Background This trial was designed to study performance of a novel handheld probe (Dune Medical Devices, Caesarea, Israel) in intraoperative detection of positive margins and its potential benefit toward minimizing the positive margin rate. Methods The probe was intraoperatively applied to 57 lumpectomy specimens. Surgeons were blinded to device output, and surgical decisions were not affected by probe data. Probe readings were compared with histological analysis per margin and per patient. Results Nineteen of 22 (86%) pathology-positive patients were intraoperatively detected with device use. Per-margin sensitivity was .71, and specificity was .68, maintained within a range of positive margin definitions (0–.4 cm). Conclusions The device is an effective tool for intraoperative detection of positive margins with the potential for significant positive margin rate reduction.

Mucin is a high molecular weight glycoprotein that plays an important role in protecting the gallbladder epithelium from the detergent effect of bile. However, it also participates in gallstone formation. There is little information about a possible relationship between gallbladder inflammation and mucin expression or gallbladder stones' characteristics. The aims of this study were to investigate stone characteristics and patterns of mucin expression in the gallbladder epithelium and bile of gallstone patients, in relation to inflammation. Gallbladder bile and tissue samples from 21 patients were obtained at surgery. Mucin content was evaluated by gel filtration on a Sepharose CL-4B column. Dot blot for bile mucin apoproteins and immunohistochemistry staining for gallbladder mucosal mucin apoproteins were performed with antibodies to MUC2, MUC3, MUC5AC, MUC5B and MUC6. Staining intensity score (0-3) was used for assessment of antigen expression and the level of inflammation. Gallstone cholesterol content was determined in 16 patients. MUC 5AC and MUC 5B were demonstrated in 95.4 and 100% of gallbladder bile samples, respectively. Immunohistochemistry staining with antibodies to MUC 2, MUC 3, MUC 5AC, MUC 5B and MUC 6 were positive in 0, 100, 85.7, 100 and 95.4% of the gallbladder mucosal samples, respectively. Pigmented brown stones were associated with a higher level of gallbladder inflammation. Mucin species expressed in gallbladder epithelium are MUC3, MUC5AC, MUC5B and MUC6. MUC5AC and MUC5B are secreted into bile. Inflammation of the gallbladder is accompanied by a higher level of MUC5AC expression and is associated with pigmented brown stones.

BAT monoclonal antibody exhibited anti-tumor activity mediated by T and NK cells. We have evaluated the efficacy of murine and humanized BAT for the treatment of human colorectal carcinoma liver metastases in nude mice. HM7, a human colorectal carcinoma was injected into the spleen to colonize the liver. A single intravenous administration of both BAT antibodies significantly reduced the number of metastases and liver weights. Histological examinations demonstrated lymphocyte accumulation near remnant tumors and in tumor-free tissues of BAT treated mice. The efficacy of humanized BAT in the regression of hepatic metastases in human colorectal carcinoma has potential clinical use.

To determine the expression of membrane-bound mucins and glycan side chain sialic acids in Helicobacter pylori (H. pylori)-associated, non-steroidal inflammatory drug (NSAID)-associated and idiopathic-gastric ulcers.We studied a cohort of randomly selected patients with H. pylori (group 1, n = 30), NSAID (group 2, n = 18), combined H. pylori and NSAID associated gastric ulcers (group 3, n = 24), and patients with idiopathic gastric ulcers (group 4, n = 20). Immunohistochemistry for MUC1, MUC4, MUC17, and staining for Erythrina cristagalli agglutinin and Sambucus nigra agglutinin (SNA) lectins was performed on sections from the ulcer margins.Staining intensity of MUC17 was higher in H. pylori ulcers (group 1) than in idiopathic ulcers (group 4), 11.05 ± 3.67 vs 6.93 ± 4.00 for foveola cells, and 10.29 ± 4.67 vs 8.00 ± 3.48 for gland cells, respectively (P0.0001). In contrast, MUC1 expression was higher in group 4 compared group 1, 9.89 ± 4.17 vs 2.93 ± 5.13 in foveola cells and 7.63 ± 4.60 vs 2.57± 4.50 for glands, respectively (P0.0001). SNA lectin staining was increased in group 4, in parallel to elevated MUC1 expression, indicating more abundant α2-6 sialylation in that group.Cytoplasmic MUC17 staining was significantly decreased in the cases with idiopathic ulcer. The opposite was observed for both MUC1 and SNA lectin. This observation may reflect important pathogenic mechanisms, since different mucins with altered sialylation patterns may differ in their protection efficiency against acid and pepsin.

We report a case of primary, high-grade non-Hodgkin B-cell lymphoma in the breast of a young woman. The clinical and sonographic presentation was not of a mass but of an infiltrating anechoic process mimicking mastitis. Primary breast lymphoma is a rare entity, especially in young females. Early detection and treatment are crucial because the results of salvage treatment are generally poor. In previous imaging reports of breast lymphoma, it has always been considered as a mass, though the presence of markedly hypoechoic regions that look like fluid collections is a well known sonographic characteristic of lymphoma. © 2005 Wiley Periodicals, Inc. J Clin Ultrasound 33:140–142, 2005

Immunomodulator therapy with thiopurine analogues azathioprine or 6-mercaptopurine is commonly prescribed for the treatment of organ transplantation, inflammatory bowel disease, autoimmune diseases and malignancies. Hepatotoxicity due to thiopurine analogues usually presents as an increase in serum transaminase levels. Toxicity is usually not severe, and a dose reduction is effective in most patients. Nodular regenerative hyperplasia (NRH) is a very rare but potentially severe complication of thiopurine-containing therapy. NRH is often asymptomatic, neither biochemical nor molecular markers are indicative for NRH. The suspicion rises when there are clinical symptoms of portal hypertension or increases in transaminases levels orthrombocytopenia. Liver biopsy is essential for definitive diagnosis. This is a case report of a 40-year-old male patient with Crohn's disease who developed increased serum levels of liver enzymes and thrombocytopenia following the administration of thiopurine. Although treatment with thiopurine was discontinued, he has further progressed and presented with acute variceal bleeding due to portal hypertension. The diagnosis of nodular regenerative hyperplasia was proven by a liver biopsy. In conclusion, NRH is a very rare but potentially severe complication of thiopurine-containing immunosuppressive therapy for IBD.