Role of tumor size in the pre-operative management of rectal cancer patients

Clinical management of rectal cancer patients relies on pre-operative staging. Studies however continue to report moderate degrees of over/understaging as well as inter-observer variability. The aim of this study was to determine the sensitivity, specificity and accuracy of tumor size for predicting T and N stages in pre-operatively untreated rectal cancers

Gene expression profiling of mucinous ovarian tumors and comparison with upper and lower gastrointestinal tumors identifies markers associated with adverse outcomes.

PURPOSE: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. EXPERIMENTAL DESIGN: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). RESULTS: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04–7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04–1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01–1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). CONCLUSIONS: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies

Regulation of prolactincytokine receptor signaling by the cytoplasmic protein tyrosine phosphatases, SHP-1 and SHP-2 : by Parham Minoo.

Prolactin (PRL) is a polypeptide hormone that regulates diverse biological processes such as those involved in mammary gland and reproductive organ development. These biological functions are mediated by interaction of PRL with its membrane-bound receptor, a member of the class I cytokine receptor superfamily. Ligand binding to the PRL receptor (PRLR) induces dimerization of the receptor and activation of Janus kinase-2 (Jak2). These events lead to PRLR tyrosine phosphorylation creating binding sites for cellular signaling molecules containing SH2 domains such as the signal transducer and activator of transcription 5 (Stat5). Jak2/Stat5 pathway has emerged as the main signaling pathway mediating many physiological effects of PRL such as the terminal differentiation of mammary epithelial cells and milk protein production.Work in this thesis was performed to understand the molecular mechanisms of PRL actions in target tissues by investigating the role of cytoplasmic protein tyrosine phosphatases containing SH2 domain, SHP-1 and SHP-2, in regulation of PRLR intracellular signaling events. These phosphatases participate in signaling as enzymes and/or adapter proteins. Both SHP-1 and SHP-2 contain specific tyrosine residues at their C-terminal parts that undergo phosphorylation in response to PRLR stimulation. The focus of this doctoral work was to investigate the adapter function of these proteins, which is mediated by their C-terminal tyrosine residues. These studies revealed that these tyrosine residues can function to recruit legitimate substrate(s) for the catalytic domain of SHP-2 including a highly phosphorylated p29 protein. Subsequent studies showed that p29 is growth factor receptor-binding protein-2 (Grb2), suggesting that Grb2 is phosphorylated in response to PRL and the level of phosphorylation is regulated by SHP-2. Grb2 phosphorylation by PRLR was further shown to be a new mechanism by which PRLR inhibits EGFR-induced signaling.In addition, our results indicate that the inhibitory effect of SHP-1 on cytokine-induced Jak/Stat pathway could occur independently of its catalytic activity. Based on our data, SHP-1 C-terminal tyrosine residues contribute to the inhibitory effect of SHP-1 by recruiting inhibitory complex Grb2/SOCS-1 and targeting SOCS-1 to Jak2. Together these findings highlight new mechanisms of PRL/cytokine receptor signaling by the protein tyrosine phosphatases SHP-1 and SHP-2

Characterization of the immunological microenvironment of tumour buds and its impact on prognosis in mismatch repair-proficient and -deficient colorectal cancers

Tumour budding in colorectal cancer is established as a poor prognostic factor. The inverse correlation of tumour buds with peritumoural lymphocytic inflammation suggests an interaction with specific immune responses. The aims of this study were to characterize the immunological microenvironment of tumour buds and its impact on prognosis in mismatch repair (MMR)-proficient and -deficient colorectal cancers

Severe skin disease in lupus associated with hemophagocytic lymphohistiocytosis: case reports and review of the literature

Abstract Background Hemophagocytic lymphohistiocytosis (HLH) is a severe clinical entity associated with high mortality in the adult population. HLH has been associated with infections, malignancy and autoimmune conditions such as Systemic Lupus Erythematosus (SLE), however this is often in the context of a disease flare. Currently, there are limited reports of inaugural SLE manifesting as HLH with a lack of consensus on treatment and management of these patients. Case presentation Here, we present two rare case reports of severe cutaneous manifestation of lupus associated with HLH. Both patients presented with sinister clinical courses with primarily rheumatologic complaints including malaise, arthralgia, and myalgia with biochemical abnormalities. Both patients were diagnosed with HLH as a result of first presentation from cutaneous lupus. A comprehensive literature review using the PubMed database with cases comprising keywords of HLH and SLE up to September 2017 was conducted, with an emphasis on inaugural cutaneous SLE cases. Conclusions Ultimately, we highlight that a keen clinical acumen is required as misdiagnosis may lead to insufficient treatment with adverse clinical outcomes with the unique presentation of HLH from inaugural cases of SLE

Tumor border configuration added to TNM staging better stratifies stage II colorectal cancer patients into prognostic subgroups

BACKGROUND: Reproducible and well characterized prognostic histomorphologic criteria added to current pathological staging could have an immediate effect on refining prognosis in colorectal cancer. The aim of this study was to determine the additive effect of tumor border configuration and peritumoral lymphocytic infiltration on the selection of patients for adjuvant therapy classified by TNM. METHODS: A total of 1420 primary colorectal cancers with complete clinicopathological data from multiple treatment centers were analyzed. The prognostic effect of tumor border configuration (pushing or infiltrating) and peritumoral lymphocytic infiltration was assessed, validated by resampling of the data, and compared with TNM staging. All P values were 2-sided. RESULTS: Multivariate analysis confirmed the adverse prognostic value of the tumor border configuration (P > .001), but not of peritumoral lymphocytic infiltration. The addition of tumor border configuration to T and N category identified 2 major prognostic subgroups (relative risk of death, 4.75; 95% confidence interval [CI], 2.53-8.94). Moreover, stage II patients with a pushing border had a 5-year survival rate of 82.1% (95% CI, 71.8%-90.3%), whereas an infiltrating border resulted in a significantly more adverse outcome (5-year survival rate, 62.7%; 95% CI, 48.0-76.2%), closely resembling that of stage III patients. Similar results were obtained after adjusting for adjuvant therapy (P > .001). CONCLUSIONS: The classification of patients into prognostic subgroups is improved with the addition of tumor border configuration to TNM stage. In particular, patients with stage II disease characterized by an infiltrating tumor border have poor clinical outcome and represent a subset of lymph node-negative patients who could be considered for adjuvant therapy

Urokinase-type plasminogen activator is a marker of aggressive phenotype and an independent prognostic factor in mismatch repair-proficient colorectal cancer

The aim of this study was to determine the prognostic significance of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) in colorectal cancer stratified by mismatch repair status and to determine their contribution to the aggressive phenotype predicted by loss of E-cadherin and apoptosis protease activating factor-1 (APAF-1). Immunohistochemistry for uPA and uPAR was performed on a tissue microarray comprising 811 mismatch repair-proficient and 164 mismatch repair-deficient colorectal cancers. Immunoreactivity was scored semiquantitatively and the interobserver agreement between multiple pathologists was determined. Optimal cutoff scores for uPA and uPAR positivity were obtained by receiver operating characteristic curve analysis. Agreement between pathologists was excellent for uPA and uPAR. Cutoff scores of 60% for uPA and 75% for uPAR were validated by resampling of the data. In mismatch repair-proficient colorectal cancer, overexpression of uPA and uPAR was associated with advanced pT stage (P = .009, both), an infiltrating margin (P = .009 and P = .033, respectively), and poor prognosis (P = .002 and P > .001, respectively). uPA, but not uPAR, maintained its significant prognostic effect in multivariable analysis (P = .037). In addition to loss of APAF-1 (P = .002) and E-cadherin (P > .001), uPA independently predicted an infiltrating margin (P = .016). Our findings suggest that uPA, but not uPAR, is an independent prognostic factor and that this negative effect on survival is relevant specifically for mismatch repair-proficient colorectal cancers. Moreover, the combination of uPA with E-cadherin and APAF-1 is linked to an aggressive tumor phenotype and highly predictive of an infiltrating growth pattern