Salmonella enterica Outbreaks Linked to the Consumption of Tahini and Tahini-Based Products

Salmonella is a leading cause of bacterial foodborne illness in the world. Although typically associated with foods of animal origin, low-moisture foods, such as tahini, are quickly gaining recognition as an important vehicle of Salmonella exposure. This review offers the Canadian perspective on the issue of Salmonella in tahini and tahini-based products. A summary of several recent food product recalls and foodborne outbreaks related to the presence of Salmonella in tahini and tahini-based products such as halva are presented. The properties of the food vehicles, their production practices, and potential routes of contamination are discussed. Particular focus is placed on the ecology of Salmonella in the tahini production continuum, including its survival characteristics and response to intervention technologies.

Quality of Life: A Prospective Randomized Trial of Palliative Volumetric Arc Therapy Versus 3-Dimensional Conventional Radiation Therapy.

PURPOSE: Volumetric arc therapy (VMAT) is a radiation therapy (RT) technique that spares normal tissues from high and intermediate RT doses but increases the volume of tissues receiving low doses of RT compared with 3-dimensional conformal RT (3DCRT). We hypothesized that palliative VMAT would reduce the detriment to patient quality of life (QOL) compared with palliative 3DCRT. METHODS AND MATERIALS: This phase 2 trial randomized patients to palliative RT using VMAT or 3DCRT to 1 painful site of metastatic disease in the trunk. Treating physicians could choose 8 Gy in 1 fraction or 20 Gy in 5 fractions to stratify randomization. The primary endpoint was the change in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0 (EORTC QLQ-C30) global health status QOL subscale at 1 week after RT. Repeated measures analysis of variance was used to assess the relationship of patient QOL over time with other factors. RESULTS: From July 2014 to November 2017, 37 patients who underwent 3DCRT and 32 patients who underwent VMAT were randomized into the study. Median overall survival was 9 months. Overall pain responses to RT were equivalent (P = .53) between the techniques. Patient compliance in returning QOL questionnaires was 94%, 81%, and 69% at baseline, 1 week after RT, and 1 month after RT, respectively. At 1 week after RT, change in global QOL was not significantly (P = .31) different between VMAT versus 3DCRT. At 4 weeks after RT, VMAT induced significantly (P = .049) less global QOL deterioration than 3DCRT did. Patients who underwent VMAT maintained better physical (P = .012), role (P = .041), and social (P = .025) functioning, but they reported more diarrhea symptoms (P = .017) than in the 3DCRT group. CONCLUSIONS: Palliative VMAT and 3DCRT did not differ in their ability to control pain; however, palliative VMAT induced fewer QOL detriments than 3DCRT did at 4 weeks after RT.

Use of Intraoperative Radioguidance in Recurrent Merkel Carcinoma.

Merkel cell carcinoma is a rapidly progressive nonmelanoma skin cancer with a high risk of recurrence. When recurrence occurs, it is associated with poor prognosis and there is a lack of guidelines for the management of such cases. This article describes a challenging case in which the innovative use of iodine-125 radioactive seeds permitted us to precisely identify and resect two nonpalpable recurrent nodules. The safety and accuracy of the surgical procedure were compromised by the presence of scar tissue following two past resections and two courses of radiotherapy. Radioactive seed localization is a well-known procedure in breast cancer, demonstrating potential for an extended application in other cancer types and in complex clinical situations.

Outbreaks of Escherichia coli O157:H7 Infections Linked to Romaine Lettuce in Canada from 2008 to 2018: An Analysis of Food Safety Context.

ABSTRACT: Foodborne diseases are a major cause of illness in Canada. One of the main pathogens causing cases and outbreaks of foodborne illness in Canada is Escherichia coli O157:H7. From 2008 to 2018, 11 outbreaks of E. coli O157:H7 infection in Canada were linked to leafy greens, including 7 (63.6%) linked to romaine lettuce, 2 (18.2%) linked to iceberg lettuce, and 2 (18.2%) linked to other or unspecified types of leafy greens. The consumption of lettuce in Canada, the behavior of E. coli O157:H7 on lettuce leaves, and the production practices used for romaine and iceberg lettuce do not seem to explain why a higher number of outbreaks of E. coli O157:H7 infection were linked to romaine than to iceberg lettuce. However, the difference in the shape of iceberg and romaine lettuce heads could be an important factor. Among the seven outbreaks linked to romaine lettuce in Canada between 2008 and 2018, an eastern distribution of cases was observed. Cases from western provinces were reported only twice. The consumption of romaine and iceberg lettuce by the Canadian population does not seem to explain the eastern distribution of cases observed, but the commercial distribution, travel distances, and the storage practices used for lettuce may be important factors. In the past 10 years, the majority of the outbreaks of E. coli O157:H7 infection linked to romaine lettuce occurred during the spring (March to June) and fall (September to December). The timing of these outbreaks may be explained by the availability of lettuce in Canada, the growing region transition periods in the United States, and the seasonality in the prevalence of E. coli O157:H7. The consumption of romaine lettuce by the Canadian population does not explain the timing of the outbreaks observed.

The tyrosine phosphatase Shp-2 confers resistance to colonic inflammation by driving goblet cell function and crypt regeneration.

The Src homology-2 domain-containing tyrosine phosphatase 2 (SHP-2) regulates many cellular processes, including proliferation, differentiation and survival. Polymorphisms in the gene encoding SHP-2 are associated with an increased susceptibility to develop ulcerative colitis. We recently reported that intestinal epithelial cell (IEC)-specific deletion of Shp-2 in mice (Shp-2IEC-KO ) leads to chronic colitis and colitis-associated cancer. This suggests that SHP-2-dependent signaling protects the colonic epithelium against inflammation and colitis-associated cancer development. To verify this hypothesis, we generated mice expressing the Shp-2 E76K activated form specifically in IEC. Our results showed that sustained Shp-2 activation in IEC increased intestine and crypt length, correlating with increased cell proliferation and migration. Crypt regeneration capacity was also markedly enhanced, as revealed by ex vivo organoid culture. Shp-2 activation alters the secretory cell lineage, as evidenced by increased goblet cell numbers and mucus secretion. Notably, these mice also demonstrated elevated ERK signaling in IEC and exhibited resistance against both chemical- and Citrobacter rodentium-induced colitis. In contrast, mice with IEC-specific Shp-2 deletion displayed reduced ERK signaling and rapidly developed chronic colitis. Remarkably, expression of an activated form of Braf in Shp-2-deficient mice restored ERK activation, goblet cell production and prevented colitis. Altogether, our results indicate that chronic activation of Shp-2/ERK signaling in the colonic epithelium confers resistance to mucosal erosion and colitis. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Patient Reported Outcomes After Radiation Therapy for Bone Metastases as a Function of Age: A Secondary Analysis of the NCIC CTG SC-Twenty-Three Randomized Trial.

PURPOSE: To explore the age difference in response and patient-reported outcomes in patients with cancer having bone metastases undergoing palliative radiotherapy. METHODS: Patients completed the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life (QOL) Bone Metastases module (QLQ-BM22), EORTC QOL Core-15-Palliative (QLQ-C15-PAL), and Dexamethasone Symptom Questionnaire (DSQ) before a single 8-Gy radiation treatment, on days 10 and 42 after treatment. Patient demographics, performance status, analgesic consumption, BM22, C15, and DSQ were compared with multivariant analysis between patients under 75 years and 75 years and older. Multiple linear regression models were used to assess the differences between age-groups, adjusting for baseline demographics and primary disease sites. RESULTS: There were 298 patients (170 male) with 209 (70%) less than 75 years of age. Most common primary cancer sites include lung, prostate, and breast. At baseline, younger patients had better performance status, consumed more analgesic, and reported worse scores in nausea, insomnia, and functional interference, while older patients more commonly had prostate cancer. There were no significant differences in the incidence of radiation-induced pain flare; response to radiation; changes from baseline for BM22, C15-PAL; and DSQ, nor overall survival at day 42 between the 2 groups. Responders to radiation in the elderly group reported better improvement in physical and emotional domains when compared with nonresponders. CONCLUSIONS: In patients with cancer having bone metastases undergoing palliative radiotherapy, there was no significant difference in general with age in response to radiation and patient-reported outcomes. Palliative radiotherapy should be offered to elderly patients when needed.

Epithelial Src homology region 2 domain-containing phosphatase-1 restrains intestinal growth, secretory cell differentiation, and tumorigenesis.

Shp-1 (Src homology region 2 domain-containing protein tyrosine phosphatase-1) is a phosphatase that is highly expressed in hematopoietic and epithelial cells. Whereas its function is largely characterized in hematopoietic cells, its role in epithelial cells, such as intestinal epithelial cells (IECs), is not well known. Here, we generated mice with an IEC-specific knockout of Shp-1 (Src homology region 2 domain-containing phosphatase-1; Shp-1IEC-KO). We showed that the loss of epithelial Shp-1 leads to an intestinalomegaly that is associated with an increase in epithelial cell proliferation and size. Histologic analysis demonstrates significant perturbation of the crypt-villus architecture with an apparent increase in the number of goblet and Paneth cells and increased expression of their respective markers {Muc2 (mucin 2), αDef, and Sox9 [SRY (sex determining region Y)-box 9]}. Expansion of intermediate cells-common progenitors of goblet and Paneth cell lineages-is also observed in Shp-1IEC-KO mice. Although sustained activation of Wnt/ß-catenin and PI3K/Akt/mammalian target of rapamycin signaling is observed, Shp-1IEC-KO mice fail to develop any intestinal tumors after 15 mo; however, the loss of Shp-1 in IECs markedly enhances tumor load ApcMin/+ mice. These findings show a novel role for Shp-1 in the regulation of IEC growth and secretory lineage allocation, possibly via modulation of PI3K/Akt-dependent signaling pathways. Finally, Shp-1 does not function as a classic tumor suppressor gene in the intestinal epithelium.-Leblanc, C., Langlois, M.-J., Coulombe, G., Vaillancourt-Lavigueur, V., Jones, C., Carrier, J. C., Boudreau, F., Rivard, N. Epithelial Src homology region 2 domain-containing phosphatase-1 restrains intestinal growth, secretory cell differentiation, and tumorigenesis.

Adjuvant Radiotherapy for Thymic Neuroendocrine Tumors: A Case Report and Review of the Literature.

Thymic carcinoid tumors are very rare. Between two and four percent of carcinoids originate from the thymus with an estimated incidence of 1.5 to 3 per 10,000,000 persons per year. Thymic carcinoids can be associated with the multiple endocrine neoplasia (MEN) type 1. The principal treatment is surgical resection. The potential roles of systemic and radiation treatments are a matter of debate. We describe the successful multidisciplinary treatment of a case of thymic carcinoid associated with MEN and review the literature pertaining to the use of adjuvant thoracic radiation.

Effect of Radiotherapy on Painful Bone Metastases: A Secondary Analysis of the NCIC Clinical Trials Group Symptom Control Trial SC.23.

IMPORTANCE: Many studies that found improved quality of life (QOL) after radiotherapy of bone metastases have small sample sizes and do not use specific questionnaires. How soon after radiotherapy one can expect an improvement in QOL is unknown. OBJECTIVE: To investigate QOL at days 10 and 42 after radiotherapy with a bone metastases-specific QOL tool. DESIGN, SETTING, AND PARTICIPANTS: In this secondary analysis of the NCIC Clinical Trials Group Symptom Control Trial SC.23, a double-blind randomized clinical trial that investigated dexamethasone for the prophylaxis of pain flare after radiotherapy, patients were accrued from 23 Canadian centers from May 30, 2011, to December 11, 2014, and were followed up for 42 days after treatment. Participants referred for radiotherapy for bone metastases were required to have a pain score at the site(s) of treatment of at least 2 (range, 0-10). INTERVENTIONS: Patients were treated with a single 8-Gy radiotherapy dose for 1 or 2 bone metastases. MAIN OUTCOMES AND MEASURES: Patients reported their worst pain score and analgesic intake at baseline and days 10 and 42 after treatment. Pain response was assessed with International Bone Metastases Consensus Endpoint Definitions. Self-reported QOL was completed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Bone Metastases Module (QLQ-BM22) and the European Organisation for Research and Treatment of Cancer Quality of Life Core 15 Palliative (QLQ-C15-PAL) at the same time points. RESULTS: A total of 298 patients were accrued (median age, 68.8 [range, 32-94] years at day 10 and 68.0 [range, 34-90] years at day 42). A total of 122 patients (40.9%) responded to radiotherapy at day 10 and 116 patients (38.9%) at day 42. At day 10, compared with nonresponders, patients with a pain response had a greater reduction in pain (mean reduction, 17.0 vs 1.8; P = .002) and pain characteristics (mean reduction, 12.8 vs 1.1; P = .002), as well as greater improvements in functional interference (mean increase, 11.6 vs 3.6; P = .01) and psychosocial aspects (mean increase, 1.2 points in responders vs mean decrease of 2.2 points in nonresponders, P = .04). Comparing changes in QOL from baseline to day 42, responders had significantly greater improvements in the physical (mean increase, 6.2 vs -9.0; P < .001), emotional (mean increase, 12.3 vs -5.5; P < .001), and global domains (mean increase, 10.3 vs -4.5; P < .001) of the QLQ-C15-PAL compared with nonresponders. CONCLUSIONS AND RELEVANCE: Forty percent of patients experienced pain reduction and better QOL at day 10 after radiotherapy with further improvements in QOL at day 42 in responders. A single 8-Gy radiotherapy dose for bone metastases should be offered to all patients, even those with poor survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01248585.

Reproducibility of a Noninvasive System for Eye Positioning and Monitoring in Stereotactic Radiotherapy of Ocular Melanoma.

PURPOSE: Our preferred treatment for juxtapapillary choroidal melanoma is stereotactic radiotherapy. We aim to describe our immobilization system and quantify its reproducibility. MATERIALS AND METHODS: Patients were identified in our radiosurgery database. Patients were imaged at computed tomography simulator with an in-house system which allows visual monitoring of the eye as the patient fixates a small target. All patients were reimaged at least once prior to and/or during radiotherapy. The patients were treated on the CyberKnife system, 60 Gy in 10 daily fractions, using skull tracking in conjunction with our visual monitoring system. In order to quantify the reproducibility of the eye immobilization system, computed tomography scans were coregistered using rigid 6-dimensional skull registration. Using the coregistered scans, x, y, and z displacements of the lens/optic nerve insertion were measured. From these displacements, 3-dimensional vectors were calculated. RESULTS: Thirty-four patients were treated from October 2010 to September 2015. Thirty-nine coregistrations were performed using 73 scans (2-3 scans per patient). The mean displacements of lens and optic nerve insertion were 0.1 and 0.0 mm. The median 3-dimensional displacements (absolute value) of lens and nerve insertion were 0.8 and 0.7 mm (standard deviation: 0.5 and 0.6 mm). Ninety-eight percent of 3-dimensional displacements were below 2 mm (maximum 2.4 mm). The calculated planning target volume (PTV) margins were 0.8, 1.4, and 1.5 mm in the anterior-posterior, craniocaudal, and right-left axes, respectively. Following this analysis, no further changes have been applied to our planning margin of 2 to 2.5 mm as it is also meant to account for uncertainties in magnetic resonance imaging to computed tomography registration, skull tracking, and also contouring variability. CONCLUSION: We have found our stereotactic eye immobilization system to be highly reproducible (<1 mm) and free of systematic error.

SHP-2 phosphatase contributes to KRAS-driven intestinal oncogenesis but prevents colitis-associated cancer development.

A major risk factor of developing colorectal cancer (CRC) is the presence of chronic inflammation in the colon. In order to understand how inflammation contributes to CRC development, the present study focused on SHP-2, a tyrosine phosphatase encoded by PTPN11 gene in which polymorphisms have been shown to be markers of colitis susceptibility. Conversely, gain-of-function mutations in PTPN11 gene (E76 residue) have been found in certain sporadic CRC. Results shown herein demonstrate that SHP-2 expression was markedly increased in sporadic human adenomas but not in advanced colorectal tumors. SHP-2 silencing inhibited proliferative, invasive and tumoral properties of both intestinal epithelial cells (IECs) transformed by oncogenic KRAS and of human CRC cells. IEC-specific expression of a SHP-2E76K activated mutant in mice was not sufficient to induce tumorigenesis but markedly promoted tumor growth under the ApcMin/+ background. Conversely, mice with a conditional deletion of SHP-2 in IECs developed colitis-associated adenocarcinomas with age, associated with sustained activation of Wnt/ß-catenin, NFκB and STAT3 signalings in the colonic mucosae. Moreover, SHP-2 epithelial deficiency considerably increased tumor load in ApcMin/+ mice, shifting tumor incidence toward the colon. Overall, these results reveal that SHP-2 can exert opposing functions in the large intestine: it can promote or inhibit tumorigenesis depending of the inflammatory context.

Classification of painful bone metastases as mild, moderate, or severe using both EORTC QLQ-C15-PAL and EORTC QLQ-BM22.

PURPOSE: Previous studies have determined optimal cut points (CPs) for the classification of pain severity as mild, moderate, or severe using only the Brief Pain Inventory (BPI) or the BPI in conjunction with a quality of life (QOL) tool. The purpose of our study was to determine the optimal CPs based on correlation with only QOL outcomes. METHODS: We conducted an analysis of 298 patients treated with radiation therapy for painful bone metastases on a phase III randomized trial. Prior to treatment, patients provided their worst pain score on a scale of 0 (no pain) to 10 (worst possible pain), as well as completed the European Organization of Cancer Research and Treatment (EORTC) QOL Questionnaire Bone Metastases module (QLQ-BM22) and the EORTC QOL Questionnaire Core-15 Palliative (QLQ-C15-PAL). Optimal CPs were determined to be those that yielded the largest F ratio for the between category effect on each subscale of the QLQ-BM22 and QLQ-C15-PAL using the multivariate analysis of variance (MANOVA). RESULTS: The two largest F ratios for Wilk's λ, Pillai's Trace, and Hotelling's Trace were for CPs 5,6 and 5,7. Combining both, the optimal CPs to differentiate between mild, moderate, and severe pain were 5 and 7. Pain scores of 1-5, 6, and 7-10 were classified as mild, moderate, and severe, respectively. Patients with severe pain experienced greater functional interference and poorer QOL when compared to those with mild pain. CONCLUSION: Our results suggest that, based on the impact of pain on QOL measures, pain scores should be classified as follows: 1-5 as mild pain, 6 as moderate pain, and 7-10 as severe pain. Optimal CPs vary depending on the type of outcome measurement used.

Minimal clinically important differences in the EORTC QLQ-BM22 and EORTC QLQ-C15-PAL modules in patients with bone metastases undergoing palliative radiotherapy.

PURPOSE: Validated tools for evaluating quality of life (QOL) in patients with bone metastases include the EORTC QLQ-BM22 and QLQ-C15-PAL modules. A statistically significant difference in metric scores may not be clinically significant. To aid in their interpretation, we performed analyses to determine the minimal clinically important differences (MCID) for these QOL instruments. METHODS: Both anchor-based and distribution-based methods were used to determine the MCID among patients with bone metastases enrolled in a randomized phase III trial. For the anchor-based approach, overall QOL as measured by the QLQ-C15-PAL module was used as the anchor and only the subscales with moderate or better correlation were used for subsequent MCID analysis. In the anchor-based approach, patients were classified as improved, stable or deteriorated by the change in the overall QOL score from baseline to follow-up after 42 days. The MCID and confidence interval was then calculated for all subscales. In the distribution-based approach, the MCID was expressed as a proportion of the standard deviation and standard error measurement from the subscale score distribution. RESULTS: A total of 204 patients completed the questionnaires at baseline and follow-up. Only the dyspnea and insomnia subscales did not have at least moderate correlation with the overall QOL anchor. Using the anchor-based approach, 10/11 subscales had an MCID score significantly different than 0 for improvement and 3/11 subscales had a significant MCID score for deterioration. The magnitude of MCID scores was higher for improvement in comparison with deterioration. For improvement, the anchor-based approach showed good agreement with the distribution-based approach when using 0.5 SD as the MCID. However, there was greater lack of agreement between these approaches for deterioration. CONCLUSION: We present the MCID scores for the EORTC QLQ-BM22 and QLQ-C15-PAL QOL instruments. The results of this study can guide clinicians in the interpretation of these instruments. CLINICAL TRIALS REGISTRY: NCT01248585.

A prospective study validating the EORTC QLQ-BM22 bone metastases module in patients with painful bone metastases undergoing palliative radiotherapy.

PURPOSE: Quality of life (QOL) can be compromised in patients with bone metastases, and validated QOL instruments are required to accurately measure QOL outcomes in this population. This study investigated the validity, reliability and responsiveness of the EORTC QLQ-BM22 module with the EORTC QLQ-C15-PAL instrument in bone metastases. METHODS: The studied patients underwent palliative radiotherapy to bone metastases in the randomized NCIC CTG SC 23 trial. Multi-trait scaling analysis was performed to determine convergent and divergent validity among scales. Pearson coefficients were calculated to determine the correlation between items of the two instruments. The clinical validity and responsiveness of the QLQ-BM22 was tested by known group comparisons of different performance status and response to radiotherapy. RESULTS: 204 patients completed both questionnaires at baseline and 42day follow-up. On multi-trait scaling analysis, there was mixed evidence of construct validity (explained by the questionnaire format and population characteristics). There was little correlation between most QLQ-BM22 and QLQ-C15-PAL items (except for conceptually related scales) validating their complementary nature. There were statistically significant differences in all QLQ-BM22 scale scores in groups with KPS<80 vs. KPS⩾80 and three out of four QLQ-BM22 scale scores in "responders" vs. "non-responders" to radiotherapy. In patients who responded to radiotherapy, there were statistically significant differences in all QLQ-BM22 scale scores between baseline and follow-up. CONCLUSION: This study further validates the use of the QLQ-BM22 as a robust and sensitive instrument to assess QOL in patients with bone metastases treated with palliative radiotherapy.

SHP-2 Phosphatase Prevents Colonic Inflammation by Controlling Secretory Cell Differentiation and Maintaining Host-Microbiota Homeostasis.

Polymorphisms in the PTPN11 gene encoding for the tyrosine phosphatase SHP-2 were described in patients with ulcerative colitis. We have recently demonstrated that mice with an intestinal epithelial cell-specific deletion of SHP-2 (SHP-2(IEC-KO) ) develop severe colitis 1 month after birth. However, the mechanisms by which SHP-2 deletion induces colonic inflammation remain to be elucidated. We generated SHP-2(IEC-KO) mice lacking Myd88 exclusively in the intestinal epithelium. The colonic phenotype was histologically analyzed and cell differentiation was determined by electron microscopy and lysozyme or Alcian blue staining. Microbiota composition was analyzed by 16S sequencing. Results show that innate defense genes including those specific to Paneth cells were strongly up-regulated in SHP-2-deficient colons. Expansion of intermediate cells (common progenitors of the Goblet and Paneth cell lineages) was found in the colon of SHP-2(IEC-KO) mice whereas Goblet cell number was clearly diminished. These alterations in Goblet/intermediate cell ratio were noticed 2 weeks after birth, before the onset of inflammation and were associated with significant alterations in microbiota composition. Indeed, an increase in Enterobacteriaceae and a decrease in Firmicutes were observed in the colon of these mice, indicating that dysbiosis also occurred prior to inflammation. Importantly, loss of epithelial Myd88 expression inhibited colitis development in SHP-2(IEC-KO) mice, rescued Goblet/intermediate cell ratio, and prevented NFκB hyperactivation and inflammation. These data indicate that SHP-2 is functionally important for the maintenance of appropriate barrier function and host-microbiota homeostasis in the large intestine. J. Cell. Physiol. 231: 2529-2540, 2016. © 2016 The Authors. Journal of Cellular Physiology published by Wiley Periodicals, Inc.

New and Unexpected Biological Functions for the Src-Homology 2 Domain-Containing Phosphatase SHP-2 in the Gastrointestinal Tract.

SHP-2 is a tyrosine phosphatase expressed in most embryonic and adult tissues. SHP-2 regulates many cellular functions including growth, differentiation, migration, and survival. Genetic and biochemical evidence show that SHP-2 is required for rat sarcoma viral oncogene/extracellular signal-regulated kinases mitogen-activated protein kinase pathway activation by most tyrosine kinase receptors, as well as by G-protein-coupled and cytokine receptors. In addition, SHP-2 can regulate the Janus kinase/signal transducers and activators of transcription, nuclear factor-κB, phosphatidyl-inositol 3-kinase/Akt, RhoA, Hippo, and Wnt/ß-catenin signaling pathways. Emerging evidence has shown that SHP-2 dysfunction represents a key factor in the pathogenesis of gastrointestinal diseases, in particular in chronic inflammation and cancer. Variations within the gene locus encoding SHP-2 have been associated with increased susceptibility to develop ulcerative colitis and gastric atrophy. Furthermore, mice with conditional deletion of SHP-2 in intestinal epithelial cells rapidly develop severe colitis. Similarly, hepatocyte-specific deletion of SHP-2 induces hepatic inflammation, resulting in regenerative hyperplasia and development of tumors in aged mice. However, the SHP-2 gene initially was suggested to be a proto-oncogene because activating mutations of this gene were found in pediatric leukemias and certain forms of liver and colon cancers. Moreover, SHP-2 expression is up-regulated in gastric and hepatocellular cancers. Notably, SHP-2 functions downstream of cytotoxin-associated antigen A (CagA), the major virulence factor of Helicobacter pylori, and is associated with increased risks of gastric cancer. Further compounding this complexity, most recent findings suggest that SHP-2 also coordinates carbohydrate, lipid, and bile acid synthesis in the liver and pancreas. This review aims to summarize current knowledge and recent data regarding the biological functions of SHP-2 in the gastrointestinal tract.

Should women younger than 40 years of age with invasive breast cancer have a mastectomy? 15-year outcomes in a population-based cohort.

PURPOSE: Optimal local management for young women with early-stage breast cancer remains controversial. This study examined 15-year outcomes among women younger than 40 years treated with breast-conserving surgery plus whole-breast radiation therapy (BCT) compared with those treated with modified radical mastectomy (MRM). METHODS AND MATERIALS: Women aged 20 to 39 years with early-stage breast cancer diagnosed between 1989 and 2003 were identified in a population-based database. Primary outcomes of breast cancer-specific survival (BCSS), overall survival (OS) and secondary outcomes of local relapse-free survival (LRFS), locoregional relapse-free survival (LRRFS), and distant relapse-free survival (DRFS) were calculated using Kaplan-Meier methods and compared between BCT and MRM cohorts using log-rank tests. A planned subgroup analysis was performed on patients considered "ideal" for BCT (ie, T1N0, negative margins and no extensive ductal carcinoma in situ) and in whom local therapy may have the largest impact on survival because of low systemic risk. RESULTS: 965 patients were identified; 616 had BCT and 349 had MRM. The median follow-up time was 14.4 years (range, 8.4-23.3 years). Overall, 15-year rates of BCSS (76.0% vs 74.1%, P=.62), OS (74.2% vs 73.0%, P=.75), LRFS (85.4% vs 86.5%, P=.95), LRRFS (82.2% vs 81.6%, P=.61), and DRFS (74.4% vs 71.6%, P=.40) were similar between the BCT and MRM cohorts. In the "ideal" for BCT subgroup, there were 219 BCT and 67 MRM patients with a median follow-up time of 15.5 years. The 15-year BCSS (86.1% vs 82.9%, P=.57), OS (82.6% vs 82.9%, P=.89), LRFS (86.2% vs 84.2%, P=.50), LRRFS (83.1% vs 78.3%, P=.24), and DRFS (84.8% vs 79.1%, P=.17) were similar in the BCT and MRM cohorts. CONCLUSIONS: This population-based analysis with long-term follow-up confirmed that women younger than 40 years treated with BCT had similar 15-year outcomes compared with MRM. Young age alone is not a contraindication to BCT.

Epithelial tyrosine phosphatase SHP-2 protects against intestinal inflammation in mice.

Polymorphisms of PTPN11 encoding SHP-2 are biomarkers for ulcerative colitis (UC) susceptibility. However, their functional relevance is unknown. We thus investigated the role of epithelial SHP-2 in the control of intestinal homeostasis. Mice with an intestinal epithelial cell-specific SHP-2 deletion (SHP-2(IEC-KO) mice) were generated. Control and SHP-2(IEC-KO) mice were monitored for clinical symptoms and sacrificed for histological staining and Western blot analyses. Cytokines and chemokines, as well as intestinal permeability, were quantified. SHP-2 mRNA expression was evaluated in control and UC patients. SHP-2(IEC-KO) mice showed growth retardation compared to control littermates and rapidly developed severe colitis. Colon architecture was markedly altered with infiltration of immune cells, crypt abscesses, neutrophil accumulation, and reduced goblet cell numbers. Decreased expression of claudins was associated with enhanced intestinal permeability in mutant SHP-2(IEC-KO) mice. Inflammatory transcription factors Stat3 and NF-κB were hyperactivated early in the mutant colonic epithelium. Levels of several epithelial chemokines and cytokines were markedly enhanced in SHP-2(IEC-KO) mice. Of note, antibiotic treatment remarkably impaired the development of colitis in SHP-2(IEC-KO) mice. Finally, SHP-2 mRNA levels were significantly reduced in intestinal biopsy specimens from UC patients. Our results establish intestinal epithelial SHP-2 as a critical determinant for prevention of gut inflammation.

Successful treatment of anaplastic meningioma metastatic to cervical lymph nodes.

BACKGROUND: Cervical lymph node metastases of meningioma represent an important diagnostic and treatment challenge. Not only has this entity been rarely described, but successful treatment has never been reported in the literature. METHODS AND RESULTS: This case report was conducted using reviews of the literature. A 58-year-old man with a history of resected anaplastic meningioma was referred for a right neck mass. Excisional biopsy revealed metastatic meningioma, and a metastatic workup was negative. Modified radical neck dissection showed positivity in 5 lymph nodes. The patient received adjuvant intensity-modulated radiation therapy (IMRT), for a mean target dose of 60 Gray (Gy). Two years after treatment, the patient was disease free. Eleven cases of cervical lymph node metastasis of meningioma were identified in our literature search, and none described successful treatment of this entity. CONCLUSION: Cervical lymph node metastasis of anaplastic meningioma is potentially treatable with surgical resection and IMRT, although further studies with long-term follow-up are necessary.

¹8F-FDG-PET imaging in radiotherapy tumor volume delineation in treatment of head and neck cancer.

PURPOSE: To determine the impact of (18)F-fluorodeoxyglucose positron emission tomography (PET) in radiotherapy target delineation and patient management for head and neck squamous cell carcinoma (HNSCC) compared to computed tomography (CT) alone. MATERIALS AND METHODS: Twenty-nine patients with HNSCC were included. CT and PET/CT obtained for treatment planning purposes were reviewed respectively by a neuroradiologist and a nuclear medicine specialist who were blinded to the findings from each other. The attending radiation oncologist together with the neuroradiologist initially defined all gross tumor volume of the primary (GTVp) and the suspicious lymph nodes (GTVn) on CT. Subsequently, the same radiation oncologist and the nuclear medicine specialist defined the GTVp and GTVn on (18)F-FDG-PET/CT. Upon disagreement between CT and (18)F-FDG-PET on the status of a particular lymph node, an ultrasound-guided fine needle aspiration was performed. Volumes based on CT and (18)F-FDG-PET were compared with a paired Student's t-test. RESULTS: For the primary disease, four patients had previous diagnostic tonsillectomy and therefore, FDG uptake occurred in 25 patients. For these patients, GTVp contoured on (18)F-FDG-PET (GTVp-PET) were smaller than the GTVp contoured on CT (GTVp-CT) in 80% of the cases, leading to a statistically significant volume difference (p=0.001). Of the 60 lymph nodes suspicious on PET, 55 were also detected on CT. No volume change was observed (p=0.08). Ten biopsies were performed for lymph nodes that were discordant between modalities and all were of benign histology. Distant metastases were found in two patients and one had a newly diagnosed lung adenocarcinoma. CONCLUSIONS: GTVp-CT was significantly larger when compared to GTVp-PET. No such change was observed for the lymph nodes. (18)F-FDG-PET modified treatment management in three patients, including two for which no curative radiotherapy was attempted. Larger multicenter studies are needed to ascertain whether combined (18)F-FDG-PET/CT in target delineation can influence the main clinical outcomes.