Prognostic Significance of Synchronous Colorectal Adenocarcinoma: A Matched-Pair Analysis.

OBJECTIVE: To determine the prognostic significance of the synchronous colorectal cancer (S-CRC) on survival and recurrence rate. METHODS: Authors conducted an analysis of 90 colorectal adenocarcinoma patients who received a curative (R0) resection with a full course of standard adjuvant treatment. A total of 45 patients diagnosed with S-CRC at the time of initial presentation were individually matched to a group of 45 solitary CRC patients in pair at a ratio of 1:1. The case-matched criteria included age (± 5 years), gender, tumor location, and tumor stage. For S-CRC, the most advanced pathologic lesion was defined as the index lesion, and the matching cancer stage was categorized according to the index lesion. The N-stage was determined based on all lymph nodes. RESULT: There were a higher number of retrieved nodes in patients with S-CRC than those with solitary CRC. The median (min, max) of the total number of retrieved nodes for S-CRC was 18 (3, 53) nodes, compared to 14 (4, 45) nodes for solitary CRC (p < 0.01). All patients were without distant metastasis (stage I to III). The total accumulative number of patients experiencing tumor recurrence was 9 (20%) amongst the solitary CRC patients and 18 (40%) amongst the S-CRC patients at the 15-year surveillance period (p<0.05). The disease-free survival (DFS) (mean + SD) was 147.6 + 9.3 months in the solitary CRC group, compared to 110.5 + 11.7 months in the S-CRC group (p<0.05). Amongst S-CRC patients, those having primary and synchronous tumors located across anatomical segments had poorer DFS (70.5 months) and higher 15-year tumor recurrence rate (17.8%) than those with all tumors in the same or contiguous anatomical segments. In addition, the S-CRC patients with all tumors located in contiguous segment had a longer DFS (123.7 months) than the other types of anatomical correlation. CONCLUSION: Patients with S-CRC had worse prognosis than those with solitary CRC. For S-CRC, the anatomical correlation between the primary and the synchronous tumors may influence DFS and recurrence rate.

Tissue Microvessel Density as a Potential Predictive Marker for Vascular Invasion in Colorectal Cancer.

OBJECTIVE: This study aimed to determine whether microvessel density (MVD) in the tumor tissues could be a potential predictive marker for vascular invasion (VI). METHODS: Surgical specimens of 73 patients with colorectal adenocarcinoma in Phramongkutklao Hospital were analyzed. Tissues of patients receiving preoperative radiation or prior anti-angiogenic therapy were excluded. Tumor MVD was determined using the average number of counted CD34-stained endothelial cells from two selected fields at 200x magnification in each slide. The presence of VI was defined by tumor involvement of endothelial cell-lined spaces. The optimal cut-off value of MVD to predict VI was examined using receiver operating characteristic analysis to assess the area under the curve and accuracy. RESULT: VI was detected in 17 of 73 specimens (23.3%). Colorectal cancer (CRC) specimens were classified according to MVD as low (61 specimens, 83.6%) and high density (12 specimens, 16.4%). Average MVD was slightly higher in specimens with VI (81.3±9.3) than those without VI (76.3±7.6), but without statistical significance (p = 0.736). The MVD's cut-off value of 60 vessels/200x field provided 88% sensitivity, 40% specificity, and 57.5% accuracy, with the area under the ROC curve of 0.5788. Patients with CRC having MVD of > 60 vessels/200x field were at significantly higher risk of VI than those with CRC having MVD of <60 vessels/200x field (P=0.009, Fisher's exact test). Univariate analysis revealed that MVD, nodal involvement and AJCC tumor stage were associated with the presence of VI (p <0.05). Further multivariate analysis of these three potential variables demonstrated MVD (OR, 11.994; 95% CI, 2.197 to 65.483; p <0.01) and nodal involvement (OR, 10.767; 95% CI, 1.973 to 58.748; p <0.05) as independent prognostic factors associated with VI. CONCLUSION: Based on our study, MVD immunostaining was an angiogenic marker that potentially be a predictive marker for VI.

Pretreatment Microvessel Density for Predicting of Tumor Responsiveness to Neoadjuvant Chemoradiotherapy of Locally Advanced Rectal Cancer.

OBJECTIVE: This study aimed to assess whether pretreatment tumor tissue microvessel density (MVD) could be a potential predictive marker for Mandard response in LARC treated with nCRT. METHODS: A retrospective analysis was performed in pretreatment paraffin-embedded specimens of 31 pathologically confirmed rectal adenocarcinoma. All patients received nCRT and subsequent total mesorectal resection. Tumor MVD was determined by an average number of counted CD34-stained endothelial cells from two selected fields at 200x magnification in each slide and categorized into two groups: low MVD ( 60). The tumor response was determined using the Mandard tumor regression grading system. The subjects were grouped according to their TRG into responder (TRG 1-3) and non-responder (TRG 4-5). RESULT: Twenty out of thirty-one patients (64.5%) were defined as responders. Eleven patients (35.5%) were defined as non-responders. MVD was significantly associated with tumor responsiveness to nCRT (p < 0.05). High MVD was shown to be an independent risk factor associated with tumor resistance to nCRT (OR, 22.58; 95% CI, 1.943-262.34; p = 0.013). A strong correlation was found between MVD and TRG (correlation coefficient value of 0.642, p <0.01), between MVD and vascular invasion (correlation coefficient value of 0.618, p <0.01), and between nodal involvement and vascular invasion (correlation coefficient value of 0.521, p <0.01). A moderate correlation was found between nodal involvement and vascular invasion (correlation coefficient value of 0.406, p <0.05). CONCLUSION: High MVD in pretreatment tumor tissue was significantly associated with the tumor resistance to nCRT.

Synchronous Advanced Colorectal Neoplasia: Clinicopathologic Features and Prognostic Significance.

OBJECTIVE: This study aimed to compare the clinico-pathologic features, recurrence rate and disease-free survival between colorectal cancers (CRCs) with synchronous advanced colorectal neoplasia (SCN) and solitary CRCs to determine the prognostic significance of SCN. METHODS: A retrospective review of prospectively collected data of patients with CRCs was conducted in Phramongkutklao Hospital from January 2009 to December 2014. Patients were categorized in 3 groups: 1) solitary CRCs, 2) CRCs with advanced colorectal adenomas (ACAs) but having no another cancer and 3) synchronous colorectal cancers (S-CRCs) with or without ACAs. Patients undergoing curative resection and complete standard adjuvant treatment were recruited to evaluate the prognostic significance of SCN.  Clinicopathologic features, recurrence rate and disease-free survival were analyzed to compare among different groups.  Result: Among 328 recruited patients, 282 were classified as solitary CRCs (86%), 23 as CRCs with ACAs (7%) and 23 as S-CRCs (7%). Patients with CRCs with SCN (groups 2 and 3) were significantly older than patients with solitary CRCs (p <0.01), and SCN was found more commonly among males (15.2%) than females (12.3%) (p=0.045). In all, 288 patients achieved a curative resection and accomplished complete standard postoperative adjuvant treatment. Of these, the accumulative number of patients experiencing tumor recurrence was 11.8, 21.2, 24.6, 26.4 and 26.7% at the 1-, 3-, 5-, 7- and 10-year surveillance period, respectively. The disease-free survival of the groups with SCN was marginally higher than that of solitary CRCs groups (p=0.72) (solitary CRCs, 120.7±4.4 months; CRCs/ACAs, 127.4±13.9 months and S-CRCs: 126.2±13.6 months). CONCLUSION: CRCs with SCN were found at a more advanced age than those with solitary CRCs. SCN was found more often among males than females. After achieving curative resection and complete adjuvant treatment, the recurrence rate and disease-free survival of CRCs with SCN did not significantly differ from those of solitary CRCs.

Diagnostic potential of Type VII Collagen during oral carcinogenesis.

Type VII collagen (Col7) is a major component of anchoring fibrils. Col7 plays a role in tumor development and aggressiveness of cutaneous squamous cell carcinoma of recessive dystrophic epidermolysis bullosa. However, the role of Col7 in oral squamous cell carcinoma (OSCC) and oral leukoplakia (OL) remains largely unknown. To elucidate the role of Col7 and its diagnostic potential during oral carcinogenesis. Col7 expression was immunohistochemically studied in 254 samples, including normal oral mucosa (NM), OL without dysplasia, OL with dysplasia, and OSCC. The correlation between Col7 expression and clinicopathologic parameters of OSCC was also determined. Col7 was present as a linear deposit at the basement membrane of NM, OL without dysplasia and OL with dysplasia, and at the tumor-stromal junction around tumor islands in OSCC. Discontinuity of expression was frequently observed in OL with dysplasia and OSCC. OSCC had the significantly lowest Col7 expression (p<0.0001). Compared with OL without dysplasia, OL with dysplasia showed significantly reduced Col7 expression. Patients in clinical stage 4 with positive nodes had low Col7 expression compared with those in clinical stage 1 and negative nodes, respectively. Loss of Col7 is associated with tumorigenesis and aggressiveness in OSCC. A significantly reduced Col7 expression in OSCC implies that Col7 may be a useful marker for diagnosis and therapeutic targets.

Diagnostic potential of Type VII Collagen during oral carcinogenesis

Abstract Type VII collagen (Col7) is a major component of anchoring fibrils. Col7 plays a role in tumor development and aggressiveness of cutaneous squamous cell carcinoma of recessive dystrophic epidermolysis bullosa. However, the role of Col7 in oral squamous cell carcinoma (OSCC) and oral leukoplakia (OL) remains largely unknown. Objective To elucidate the role of Col7 and its diagnostic potential during oral carcinogenesis. Methodology Col7 expression was immunohistochemically studied in 254 samples, including normal oral mucosa (NM), OL without dysplasia, OL with dysplasia, and OSCC. The correlation between Col7 expression and clinicopathologic parameters of OSCC was also determined. Results Col7 was present as a linear deposit at the basement membrane of NM, OL without dysplasia and OL with dysplasia, and at the tumor-stromal junction around tumor islands in OSCC. Discontinuity of expression was frequently observed in OL with dysplasia and OSCC. OSCC had the significantly lowest Col7 expression (p<0.0001). Compared with OL without dysplasia, OL with dysplasia showed significantly reduced Col7 expression. Patients in clinical stage 4 with positive nodes had low Col7 expression compared with those in clinical stage 1 and negative nodes, respectively. Conclusion Loss of Col7 is associated with tumorigenesis and aggressiveness in OSCC. A significantly reduced Col7 expression in OSCC implies that Col7 may be a useful marker for diagnosis and therapeutic targets.

The importance of targeting signalling mechanisms of the SLC39A family of zinc transporters to inhibit endocrine resistant breast cancer.

Aim: Zinc is a key secondary messenger that can regulate multiple signalling pathways within cancer cells, thus its levels need to be strictly controlled. The Zrt, Irt-like protein (ZIP, SLC39A) family of zinc transporters increase cytosolic zinc from either extracellular or intracellular stores. This study examines the relevance of zinc transporters ZIP7 and ZIP6 as therapeutic targets in tamoxifen resistant (TAMR) breast cancer. Methods: A series of in vitro assays, including immunohistochemistry, immunofluorescence, flow cytometry, and western blotting were used to evaluate levels and activity of ZIP7 and ZIP6 in models of TAMR and sensitive (MCF-7) breast cancer. Analyses of these transporters in the clinical setting were performed using publicly available online resources: Gene Expression Profiling Interactive Analysis (GEPIA)2 and Kaplan-Meier Plotter (KmPlot). Results: Both total and activated levels of ZIP7 were significantly elevated in TAMR cells versus responsive MCF-7 cells. This was accompanied by an associated increase in free cytoplasmic zinc leading to amplification of downstream signals. Consistent with our proposed model, activated ZIP6 levels correlated with mitotic cells, which could be efficiently inhibited through use of our anti-ZIP6 monoclonal antibody. Mitotic inhibition translated to impaired proliferation in both models, with TAMR cells displaying increased sensitivity. Analysis of matched tumour and normal breast samples from patients revealed significant increases in both ZIP7 and ZIP6 in tumours, as well as family member ZIP4. Kaplan-Meier analysis revealed that high ZIP7 levels correlated with decreased overall and relapse-free survival (RFS) of patients, including patient groups who had received systemic endocrine therapy or tamoxifen only. In contrast, high ZIP6 levels were significantly linked to improved overall and RFS in all patients, as well as RFS in patients that received systemic endocrine therapy. Conclusions: TAMR cells displayed increased activity of both ZIP7 and ZIP6 transporters compared to anti-hormone responsive cells, suggesting their potential as novel therapeutic targets following development of resistant disease.

The ZIP6/ZIP10 heteromer is essential for the zinc-mediated trigger of mitosis.

Zinc has been known to be essential for cell division for over 40 years but the molecular pathways involved remain elusive. Cellular zinc import across biological membranes necessitates the help of zinc transporters such as the SLC39A family of ZIP transporters. We have discovered a molecular process that explains why zinc is required for cell division, involving two highly regulated zinc transporters, as a heteromer of ZIP6 and ZIP10, providing the means of cellular zinc entry at a specific time of the cell cycle that initiates a pathway resulting in the onset of mitosis. Crucially, when the zinc influx across this heteromer is blocked by ZIP6 or ZIP10 specific antibodies, there is no evidence of mitosis, confirming the requirement for zinc influx as a trigger of mitosis. The zinc that influxes into cells to trigger mitosis additionally changes the phosphorylation state of STAT3 converting it from a transcription factor to a protein that complexes with this heteromer and pS38Stathmin, the form allowing microtubule rearrangement as required in mitosis. This discovery now explains the specific cellular role of ZIP6 and ZIP10 and how they have special importance in the mitosis process compared to other ZIP transporter family members. This finding offers new therapeutic opportunities for inhibition of cell division in the many proliferative diseases that exist, such as cancer.

Zinc transporter ZIP10 forms a heteromer with ZIP6 which regulates embryonic development and cell migration.

There is growing evidence that zinc and its transporters are involved in cell migration during development and in cancer. In the present study, we show that zinc transporter ZIP10 (SLC39A10) stimulates cell motility and proliferation, both in mammalian cells and in the zebrafish embryo. This is associated with inactivation of GSK (glycogen synthase kinase)-3α and -3ß and down-regulation of E-cadherin (CDH1). Morpholino-mediated knockdown of zip10 causes delayed epiboly and deformities of the head, eye, heart and tail. Furthermore, zip10 deficiency results in overexpression of cdh1, zip6 and stat3, the latter gene product driving transcription of both zip6 and zip10 The non-redundant requirement of Zip6 and Zip10 for epithelial to mesenchymal transition (EMT) is consistent with our finding that they exist as a heteromer. We postulate that a subset of ZIPs carrying prion protein (PrP)-like ectodomains, including ZIP6 and ZIP10, are integral to cellular pathways and plasticity programmes, such as EMT.

Study of the vascular endothelial growth factor (VEGF) expression and microvascular density (MVD) in primary colorectal cancer specimens.

OBJECTIVE: Determine the relationship between vascular endothelial growth factor (VEGF) expression and microvascular density (MVD) in primary colorectal cancer specimens including the prognostic value by evaluating the correlation between various common reported prognostic histopathologic indictors and these two angiogenic parameters. The Inter-observer reliability on VEGF and MVD measurement was also determined. MATERIAL AND METHOD: Anti-VEGF and anti-factor CD34 monoclonal antibodies immunohistochemical staining was performed in 40 randomly selected formalin-fixed paraffin-embedded colorectal cancer specimens of non-stage-IV patients who underwent curative resection using. Immunoreactive in 25% or more carcinoma cells was categorized as positive. The intensity of VEGF expression was graded in a semiquantitative fashion, ranging from 0 to 2 Tumor MVD was determined by counting any endothelial cells stained with CD34 per two randomly selected fields at x200 magnification in each slide. The correlation between VEGF expression and MVD was evaluated. Inter-observer agreement was assessed by comparing the results of VEGF and MVD measurements made by two pathologists. RESULTS: A moderate correlation was found between the percentage of positive immunoreactive cells and the intensity of VEGF immunoreactive staining (correlation value of 0.436, p < 0.05). MVD was found having no correlation with both the percentage of positive immunoreactive cells and intensity of VEGF immunoreactive staining (the correlation value of -0.056, p = 0.732 and 0.108, p = 0.506, respectively). Neither MVD nor VEGF expression in primary colorectal cancer tissue was found having a significant correlation with any common reported prognostic histopathologic indictors. In counting CD34-stained endothelial cells, this study revealed a high intra-observer correlation coefficient of 0.886 (95% CI: 0.715-0.955) for the first pathologist and 0.913 (95% CI: 0.782-0.965) for the second. High inter-observer reliability was found in both MVD and VEGF measurement with a substantial agreement (agreement: 95%, kappa = 0.643) between the two pathologists. CONCLUSION: In primary colorectal cancer tissues, there was no significant relationship between MVD and VEGF expression. This study revealed a high intra and inter-observer reliability on VEGF and MVD measurement. Neither MVD nor VEGF expression provided predictive value of advanced or aggressiveness of disease. Further studies on larger sample size would help validate these results.

Malignant fibrous histiocytoma of the urinary bladder as a post-radiation secondary cancer: a case report.

INTRODUCTION: Malignant fibrous histiocytomas have been periodically reported as the primary tumor in various organs including the urinary bladder, and is the second most frequent sarcoma of the urinary tract in adults. This report discusses a case of the well established diagnosis of a malignant fibrous histiocytoma of the bladder occurring as a post-radiation cancer after the treatment of a cervical carcinoma. Our findings support those of many previous studies and make the view of the nature of the disease clearer. CASE PRESENTATION: We report the case of a 54-year-old Thai woman who had been treated with radiation therapy for cervical cancer, who presented to our facility with urinary incontinence. Initially, our patient was diagnosed as having a high-grade urothelial carcinoma. Subsequent radical surgery rendered the final pathological diagnosis, confirmed histologically and immunohistochemically as malignant fibrous histiocytoma, with clinical and pathological staging of T4b N0 M0. Adjuvant chemotherapy was provided for our patient. CONCLUSIONS: This type of malignancy is very aggressive and easily misdiagnosed due to its rarity. Therefore, in a patient with a prior history of irradiation in the pelvic area, this should be considered as a differential diagnosis to ensure early correct diagnosis and treatment.