The Association Between Inflammation, Epithelial Mesenchymal Transition and Stemness in Colorectal Carcinoma.

BACKGROUND: Inflammation plays an important albeit dual role in carcinogenesis. Survival studies have highlighted the prognostic significance of peritumorous inflammation. Currently, the theoretical background allows inflammation, epithelial mesenchymal transition (EMT) and the closely associated stem cell differentiation in colorectal carcinoma (CRC) to be linked. However, there is scarce direct morphological evidence. PURPOSE AND METHODS: The aim of our study was to investigate the role of inflammation in cancer growth and invasion by analyzing the association between inflammation and known morphological prognostic features of colorectal cancer, EMT, stemness and mismatch repair (MMR) protein expression. The study was designed as a retrospective morphological and immunohistochemical assessment of 553 consecutive cases of surgically treated primary CRC. RESULTS: There were statistically significant associations between high-grade inflammation and lower pT (p = 0.002), absence of lymph node metastases (p < 0.001) and less frequent lymphatic (p = 0.003), venous (p = 0.017), arterial (p = 0.012), perineural (p = 0.001) and intraneural (p = 0.01) invasion. In contrast, Crohn's like reaction (CLR) by density of lymphoid follicles in the invasive front lacked significant differences in regard to pT, pN, tumor invasion into surrounding structures (blood or lymphatic vessels, nerves), grade or necrosis (all p > 0.05). The expression of E-cadherin, CD44 and MMR proteins yielded no statistically significant associations with peritumorous inflammation by Klintrup-Mäkinen score or the density of lymphoid follicles. Nevertheless, E-cadherin levels were significantly associated with the density of eosinophils (p = 0.007). CONCLUSION: High-grade peritumorous inflammation is associated with beneficial morphologic CRC features, including less frequent manifestations of invasion, and is not secondary to tissue damage and necrosis. CLR is not associated with cancer spread by pTN; this finding indirectly suggests an independent role of CLR in carcinogenesis. Further, inflammation by Klintrup-Mäkinen grade and CLR is not dependent on epithelial-mesenchymal transition and stem cell differentiation. Our study highlights the complex associations between inflammation, tumor morphology, EMT, stemness and MMR protein expression in human CRC tissues.

Molecular classification of diffuse gliomas.

In this study we assessed whether gliomas could be subdivided into different molecular subtypes by immunohistochemistry (IHC) reminiscent of those first described by Verhaak et al. in 2010 (classical, proneural, mesenchymal and neural). We also evaluated the prognostic significance of single molecular factors and searched for significant correlations between markers. In this study, we included 146 patients with glioblastomas (GBMs) and 26 with diffuse astrocytomas (DAs). The glioma samples were tested for PDGFRA, IDH1 R132H, CD44, p53, Ki-67, p21 and p27 expression. We found that gliomas could be subdivided into molecular subtypes by IHC. Fifty per cent of GBMs were of the proneural subtype, 18.5% of mesenchymal subtype and 31.5% were not otherwise classified. However, most of the DAs (92.3%) belonged to the proneural subtype. No prognostic role was found for the molecular subtypes, but predictive roles were noted. Both proneural and mesenchymal molecular subtypes showed a benefit from the addition of chemotherapy and radiotherapy; however, the mesenchymal subtype showed a greater response. Interestingly, the mesenchymal subtype did not receive any benefit from the addition of radiotherapy compared with palliative management and surgery alone. Regarding single molecular markers, only IDH1 R132H was found to have a prognostic role for GBMs. There was a trend towards better survival in tumours with lower PDGFRA expression (p = 0.066). In DAs, PDGFRA and Ki-67 expression had prognostic roles. The following statistically significant correlations were found in GBMs: Ki-67/p53, Ki-67/p27 and p53/PDGFRA; in DAs: p53/PDGFRA, CD44/PDGFRA, and p21/PDGFRA.

Systemic and local inflammation in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer in the world. The cornerstone of CRC treatment is surgical resection. However, patients in the same TNM stage show different recurrence rates and survival. Of patients with a local disease without lymph node or a distant metastasis, 20-25% still develop recurrence. There is evidence that inflammatory reaction is one of the key elements in tumour development. MATERIALS AND METHODS: We reviewed literature on colorectal cancer and its relationships with the immune system, with special focus on local and systemic inflammatory reaction. The Pubmed and ClinicalKey databases were searched using the key words colorectal cancer, local inflammation, systemic inflammation, markers of inflammation. The relevant literature was reviewed and included in the article. RESULTS: The immune system has two-sided relationships with cancer, so it not only performs anti-tumour activities, but can also promote tumour growth and spread. Research has shown that signs of local inflammation are associated with a better prognosis in CRC. Systemic inflammation has been associated with more aggressive behaviour and a worse prognosis for patients with several cancers, including CRC. CONCLUSIONS: Recent findings in tumour biology have improved our understanding of colorectal cancer and of the natural course of this disease. Several markers of local and systemic inflammatory reaction have been identified. The next step is to find the most accurate and applicable marker, so that this promising tool can be used in clinical practice and aid in decision making.

Laparoscopic Cholecystectomy for a Patient with a Lumboperitoneal Shunt: A Rare Case.

A rare factor that can complicate the perioperative course of laparoscopic cholecystectomy is previous placement of a lumboperitoneal (LP) shunt. Thus far, only two articles describing this situation have been published. Here, we report on a 41-year-old female patient with gallstone disease and a LP shunt placement in the preceding year due to idiopathic intracranial hypertension. It is a syndrome of increased intracranial pressure without any known cause that mainly affects young obese women. The patient was operated upon using standard port placement and peritoneal insufflation. The postoperative period was uneventful and the patient was discharged shortly after the procedure. Due to the increasing incidence and prevalence of obesity, the number of general surgical patients with a LP shunt will likely increase. Based on our experience and evidence in the literature, we conclude that performing a laparoscopy for a patient with a LP shunt is safe.

Evaluation of malignant parathyroid tumours in two European cohorts of patients with sporadic primary hyperparathyroidism.

PURPOSE: Parathyroid carcinoma (PC) is remarkable for its rare occurrence and challenging diagnostics. PC accounts for 0.1-5 % cases of primary hyperparathyroidism (PHPT). The differentiation from benign tumours is difficult even by morphological criteria. To address these issues, we assessed the PC frequency in two separate European PHPT cohorts and evaluated the demographic, clinical, morphological and molecular background. METHODS: A retrospective study was carried out, using continuously maintained database (2005-2014) of PHPT patients from two tertiary referral university hospitals in Europe. The demographic, clinical data and frequency of PC among surgically treated PHPT was detected. Immunohistochemistry (IHC) was performed to detect parafibromin, representing protein product of HRPT2 gene and proliferation marker Ki-67. RESULTS: Both PHPT cohorts were characterised by close mean age values (58.6 and 58.0 years) and female predominance. The frequency of PC differed significantly between the cohorts: 2.1 vs. 0.3 %; p = 0.004. PC was characterised by invariable complete loss of parafibromin contrasting with parathyroid adenomas. The proliferation fraction was similar in both PC cohorts (10.6 and 11.0 %). PC showed significantly higher proliferation fraction than typical parathyroid adenomas (1.6 %), atypical adenomas (1.6 %) or adenomas featuring focal loss of parafibromin (2.2 %). CONCLUSIONS: PC frequency can range significantly between the two European cohorts. The differences can be attributable to selection bias of patients referred for surgery and are not caused by discordant definition of malignant parathyroid histology. Diffuse loss of parafibromin and increased proliferation fraction by Ki-67 are valuable adjuncts in PC diagnostics due to significant differences with various clinical and morphological subtypes of adenoma.

Morphological and immunohistochemical profile of pancreatic neuroendocrine neoplasms.

The study represents a comprehensive retrospective morphological and immunohistochemical profiling of pancreatic neuroendocrine neoplasms (PNENs) in order to reveal the associations between morphological and molecular parameters. The local tumour spread (T), presence of metastases in regional lymph nodes (N) and distant organs (M), tumour grade (G) and resection line status (R) by pathology findings (pTNMGR), mitotic activity, perineural, vascular and lymphatic invasion were assessed in 16 surgically resected PNENs. By immunohistochemistry, expression of Ki-67, p53, p27, p21, cyclin D1, Bcl-2, E-cadherin, CD44, vimentin, cyclooxygenase 2 (COX-2), microvascular density, and cytokeratin (CK) spectrum, along with neuroendocrine, intestinal and squamous markers were detected. Descriptive statistics, Chi-square test, Spearman's rank correlation, Mann-Whitney and Kruskal-Wallis methods were applied; p<0.05 was considered significant. Ki-67, CK19, p63, vimentin and COX-2 were significantly up-regulated in PNENs in comparison to benign pancreatic islets. A complex network of morphological and molecular associations was identified. Ki-67 correlated with PNEN size (p=0.022), the World Health Organization 2004 and 2010 classification grades (p=0.021 and p=0.002), stage (p=0.028) and mitotic count (p=0.007) but among molecular markers--with CK19 (p=0.033) and vimentin (p=0.045). CK19 was significantly up-regulated in PNENs, having higher pT (p=0.018), pR (p=0.025), vascular (p=0.020), perineural (p=0.026) and lymphatic invasion (p=0.043). In conclusion, proliferation activity (by Ki-67), E-cadherin, vimentin and CK19 are important molecular characteristics of PNENs due to significant associations with morphological tumour characteristics, pTNMGR and invasive growth.

The first evidence of hereditary and familial gastric cancer in Latvia: implications for prevention.

BACKGROUND AND OBJECTIVE: Gastric cancer is a frequent cause of cancer mortality. The prognosis of established tumor is unfavorable due to the propensity to spread and limited treatment efficiency. Therefore, prevention has a high significance. We tested a population screening approach in order to identify families with an increased gastric cancer load for further surveillance. MATERIAL AND METHODS: Population screening was performed by questionnaire reaching 76.6% of the population. Hereditary gastric cancer (HGC) syndrome was diagnosed if 3 mutually first-degree relatives with gastric cancer were reported in the kindred. Additional group (HGC2) of families with 2 first-degree relatives affected by gastric cancer was identified. RESULTS: The HGC syndrome was diagnosed in 0.11%, but HGC2 syndrome, in 0.4% probands. The gastric cancer frequency among blood relatives was 25.2% (95% CI, 20.6%-30.4%) in HGC, but 16.0% (95% CI, 13.8%-18.5%) in HGC2 families. The mean age at diagnosis of cancer was 56.9 years (95% CI, 53.4-60.3) in HGC and 62.5 years (95% CI, 60.1-64.8) in HGC2. The mean survival was 2.6 years (95% CI, 1.2-4.0). CONCLUSIONS: Population screening identifies reasonable number of families with a high frequency of gastric cancer. The frequency of gastric cancer and an unfavorable course characterized by low survival justify surveillance in families with 2 or 3 first-degree relatives affected by gastric cancer. Population screening provides the age characteristics of the respective tumors in order to adjust the surveillance schedule.

Molecular subtype shift in breast cancer upon trastuzumab treatment: a case report.

Breast cancer is the most common cancer in women. The mortality remains significant despite advanced treatment possibilities. The management of breast cancer is guided by immunohistochemical data that are summarized into molecular subtypes, namely, luminal A, luminal B, HER2 positive and triple negative. HER2 positive and triple negative subtypes of breast cancer are considered to be biologically distinct. We present a case of clinically aggressive breast cancer in a 58-year-old female. Along the course of the disease, the molecular type switched from HER2 positive to triple negative. The patient deteriorated despite combined therapy. We recommend making a possible change of the molecular subtype and employing repeated immunohistochemical investigation in case of relapse.

Population screening for hereditary and familial cancer syndromes in Valka district of Latvia.

BACKGROUND: The growing possibilities of cancer prevention and treatment as well as the increasing knowledge about hereditary cancers require proper identification of the persons at risk. The aim of this study was to test the outcome of population screening in the scientific and practical evaluation of hereditary cancer. METHODS: Population screening for hereditary cancer was carried out retrospectively in a geographic area of Latvia. Family cancer histories were collected from 18642 adults representing 76.6% of the population of this area. Hereditary cancer syndromes were diagnosed clinically. Molecular testing for BRCA1 founder mutations 300 T/G, 4153delA and 5382insC was conducted in 588 persons who reported at least one case of breast or ovary cancer among blood relatives. RESULTS: Clinically, 74 (0.40%; 95% confidence interval (CI): 0.32 - 0.50%) high-risk and 548 (2.94%, 95% CI: 2.71 - 3.19) moderate-risk hereditary cancer syndromes were detected covering wide cancer spectrum. All syndromes were characterised by high cancer frequency among blood relatives ranging 8.6 - 46.2% in contrast to spouse correlation of 2.5 - 3.6%. The mean age of cancer onset ranged 38.0 - 72.0 years in different syndromes. The BRCA1 gene mutations were identified in 10 (1.7%; 95% CI: 0.9 - 3.1%) probands. Families with established BRCA1 gene founder mutations were identified with the frequency 1:2663 clinically screened persons. CONCLUSIONS: Population screening is a useful practical tool for the identification of persons belonging to families with high frequency of malignant tumours. The whole hereditary and familial cancer spectrum along with the age structure was identified adjusting follow-up guidelines. Another benefit of the population screening is the possibility to identify oncologically healthy persons belonging to hereditary and familial cancer families so that appropriate surveillance can be offered. Clinical diagnostics is appropriate for population screening purposes; molecular investigation provides additional information. In collaboration with family doctors, the screening is technically manageable as characterised by high compliance.

Initial results of colorectal polyposis research in Latvia.

AIM: Patients suffering from colorectal polyps are more likely to develop a malignant condition with poor prognosis. The aim of the study is to investigate clinical and molecular features of colorectal polyposis syndromes in Latvia in order to offer and provide predictive genetic testing for the affected families, as well as to evaluate the frequency of familial adenomatous polyposis (FAP) in Latvia. PATIENTS AND METHODS: Six polyposis patients along with three of their relatives were included in this study. Two patients were selected from the colorectal cancer database (from a total of 2,552), and four patients not affected with colorectal cancer (CRC) were referred from the endoscopic facility of our hospital. All the patients were examined during the period from January 1st, 2000 until June 30th, 2007. Clinical data, histological examinations and family cancer histories of the respective patients were evaluated. Screening for germline APC mutations was performed in five patients and their relatives. In addition, all patients underwent genetic counseling. RESULTS: Two patients out of 2,552 from the CRC Hereditary Cancer Institute database fulfilled the clinical criteria for FAP. Thus, the frequency of FAP is 0.08% (2/2,552) of all CRC cases, and comprises approximately 0.0003% of the population of Latvia (7/22 million inhabitants). Unknown polyposis was identified in two cases. Pathogenic APC gene mutations were detected in five out of seven examined patients and their relatives. Two of the mutations (c.3942delG:p.Arg1314SerfsX7 and c.3286C > T;p.Gln1096X) are novel. CONCLUSION: In this study, we report the first four APC mutation-positive FAP cases in Latvia. The present frequency of FAP is lower than that reported in Finland, Lithuania, and other neighbouring countries, but the numbers might increase if a more systematic identification approach is used. Initial molecular examinations reveal partially unique spectrum of APC gene mutations.

Pilot study on low penetrance breast and colorectal cancer predisposition markers in latvia.

INTRODUCTION: It has not been established whether CHEK2 and NOD2 variants are present in Latvia and whether inherited variation in these genes influences cancer risk in this population. AIM OF THE STUDY: To evaluate the role of CHEK2 and NOD2 mutations in breast and colorectal cancers in the population of Latvia. MATERIALS AND METHODS: Peripheral venous blood samples were collected from 185 breast cancer and 235 colorectal cancer consecutive hospital-based cases from 11/2003 to 06/2005. The population control group included blood samples from the clamped distal part of the umbilical cord from 978 consecutive anonymous newborns born between 03/2005 and 08/2005. All cases and controls were tested for the presence of NOD2 3020insC mutation and CHEK2 I157T mutation. RESULTS: NOD2 3020insC was present in 7.7% (18/235) of CRC cancers, in 9.2% (17/185) of breast cancers and in 7.7% (75/974) of controls. CHEK2 I157T variant was found in 7.6% (14/185) of breast cancer cases, 10.2% (24/235) of colon cancer cases and in 6.4% (63/978) of population controls. NOD2 3020insC variant was associated with increased risk of breast cancer (OR = 2.5, p < 0.05) for cases diagnosed at age between 51 and 60 years. CHEK2 I157T variant was associated with increased risk of colorectal cancer (OR = 1.7, p < 0.05) with the highest OR = 2.0 for cases diagnosed at age >70 yrs. CONCLUSIONS: NOD2 3020insC, CHEK2 I157T variants may be associated with increased risk of colorectal and breast cancers in Latvia.

Clinical, molecular and geographical features of hereditary breast/ovarian cancer in latvia.

INTRODUCTION: The aim of the study is to evaluate the incidence and phenotype-genotype characteristics of hereditary breast and ovarian cancer syndromes in Latvia in order to develop the basis of clinical management for patients and their relatives affected by this syndrome. MATERIALS AND METHODS: In 2002-2004 in two Latvian oncology hospitals (Liepãja Oncology Hospital and Daugavpils Oncology Hospital) cancer family histories were collected from 287 consecutive patients with breast and ovarian cancer. In all cases, when it was possible to obtain the blood sample, DNA testing for founder mutations in the BRCA1 gene was performed. RESULTS: Among 287 family cancer histories analysed in 8 (2.8%) cases criteria of hereditary breast cancer (HBC) were fulfilled and in 5 (1.7%) cases hereditary breast and ovarian cancer (HBOC) was diagnosed. In 50 (17.4%) cases we have suspicion of hereditary breast cancer (HBC susp.) and in 8 (2.8%) cases - suspicion of hereditary breast and ovarian cancer (HBOC susp.). We have one (0.3%) case with hereditary ovarian cancer (HOC). DNA testing of founder mutations in the BRCA1 gene (exon 20 (5382 insC) exon 5 (300T/G), exon 11, 17 (4153delA)) for 178/287 (62%) patients was performed. In 9/287 (4.9%) cases we found a mutation in the BRCA1 gene. 4 mutations were detected in exon 11, 17 (4153delA) and 4 mutations in exon 20 (5382 insC) and 1 in exon 5. CONCLUSIONS: Existing pedigree/clinical data suggest that in Latvia the clinical frequency of hereditary breast and ovarian cancer is around 5% of consecutive breast and ovarian cancer patients and suspicion of the syndrome is observed in another 20% of cases. Frequency of BRCA1 founder mutations is 5% of all consecutive breast and ovarian cancers. Considerable geographical differences in the clinical and molecular frequency of hereditary breast ovarian cancer have been observed in Latvia.

Biomechanical properties of oesophagus wall under loading.

In this investigation, firstly, the biomechanical properties of different parts of oesophagus were determined. Oesophagus stress and strain are the greatest in the cervical part for all age groups. The human oesophagus deforms unevenly, depending on the direction of load in relation to the organ's axis, it exhibits anisotropical behaviour. With the age the values of mechanical parameters of the oesophagus wall reduce, in particular beginning from 45 years of age, but the modulus of elasticity increases. Biomechanical properties of the oesophagus depend on the architecture of its structure. By loading the organ in the circumferential direction, microfibrilae rupture and deformation of the muscular fibres occurs. With increase of load, collagenous fibres straighten and microruptures in collagenous fibrilae occur. With stretching of oesophagus longitudinally, collagenous fibres partially preserve their wavy and helical configuration. Therefore, higher resistance of the oesophageal wall occurs in the longitudinal direction.