A functional microRNA library screen reveals miR-410 as a novel anti-apoptotic regulator of cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma is characterized by late diagnosis and a poor survival rate. MicroRNAs have been involved in the pathogenesis of different cancer types, including cholangiocarcinoma. Our aim was to identify novel microRNAs regulating cholangiocarcinoma cell growth in vitro and in vivo. METHODS: A functional microRNA library screen was performed in human cholangiocarcinoma cells to identify microRNAs that regulate cholangiocarcinoma cell growth. Real-time PCR analysis evaluated miR-9 and XIAP mRNA levels in cholangiocarcinoma cells and tumors. RESULTS: The screen identified 21 microRNAs that regulated >50 % cholangiocarcinoma cell growth. MiR-410 was identified as the top suppressor of growth, while its overexpression significantly inhibited the invasion and colony formation ability of cholangiocarcinoma cells. Bioinformatics analysis revealed that microRNA-410 exerts its effects through the direct regulation of the X-linked inhibitor of apoptosis protein (XIAP). Furthermore, overexpression of miR-410 significantly reduced cholangiocarcinoma tumor growth in a xenograft mouse model through induction of apoptosis. In addition, we identified an inverse relationship between miR-410 and XIAP mRNA levels in human cholangiocarcinomas. CONCLUSIONS: Taken together, our study revealed a novel microRNA signaling pathway involved in cholangiocarcinoma and suggests that manipulation of the miR-410/XIAP pathway could have a therapeutic potential for cholangiocarcinoma.

Tumor infiltration by FcγRIII (CD16)+ myeloid cells is associated with improved survival in patients with colorectal carcinoma.

The prognostic significance of macrophage and natural killer (NK) cell infiltration in colorectal carcinoma (CRC) microenvironment is unclear. We investigated the CRC innate inflammatory infiltrate in over 1,600 CRC using two independent tissue microarrays and immunohistochemistry. Survival time was assessed using the Kaplan-Meier method and Cox proportional hazards regression analysis in a multivariable setting. Spearman's rank correlation tested the association between macrophage and lymphocyte infiltration. The Basel study included over 1,400 CRCs. The level of CD16+ cell infiltration correlated with that of CD3+ and CD8+ lymphocytes but not with NK cell infiltration. Patients with high CD16+ cell infiltration (score 2) survived longer than patients with low (score 1) infiltration (p = 0.008), while no survival difference between patients with score 1 or 2 for CD56+ (p = 0.264) or CD57+ cell (p = 0.583) infiltration was detected. CD16+ infiltrate was associated with improved survival even after adjusting for known prognostic factors including pT, pN, grade, vascular invasion, tumor growth and age [(p = 0.001: HR (95% CI) = 0.71 (0.6-0.9)]. These effects were independent from CD8+ lymphocyte infiltration [(p = 0.036: HR (95% CI) = 0.81 (0.7-0.9)] and presence of metastases [(p = 0.002: HR (95% CI) = 0.43 (0.3-0.7)]. Phenotypic studies identified CD16+ as CD45+CD33+CD11b+CD11c+ but CD64- HLA-DR-myeloid cells. Beneficial effects of CD16+ cell infiltration were independently validated by a study carried out at the University of Athens confirming that patients with CD16 score 2 survived longer than patients with score 1 CRCs (p = 0.011). Thus, CD16+ cell infiltration represents a novel favorable prognostic factor in CRC.

Systematic assessment of protein phenotypes characterizing high-grade tumour budding in mismatch repair-proficient colorectal cancer.

AIMS: A tumour bud is defined as a single tumour cell or tumour cell cluster of up to five cells at the invasive tumour front. Significant differences in survival have been detected in colorectal cancer patients with low- compared to high-grade budding. The aim of this study was to identify potential multi-marker phenotypes characterizing low- and high-grade budding in mismatch repair (MMR)-proficient colorectal cancer. METHODS AND RESULTS: Established and promising prognostic proteins such as epidermal growth factor receptor (EGFR), pERK, RHAMM, RKIP, beta-catenin, E-cadherin, pAKT, p16, p21, Ki67, Bcl-2, vascular endothelial growth factor (VEGF), apoptotic protease activating factor-1 (APAF-1), MUC1, EphB2, matrix metalloproteinase 7, pSMAD2, CDX2, laminin5gamma2 and MST1 were analysed on 208 MMR-proficient colorectal cancers with complete clinicopathological data. The most accurate markers for predicting high-grade budding (more than six tumour buds) were EphB2 (P < 0.001), Bcl-2 (P < 0.001), RKIP (P < 0.001), E-cadherin (P = 0.004), laminin5gamma2 (P = 0.004) and APAF-1 (P = 0.005). On multivariable analysis, only loss of Bcl-2 (P < 0.001) and EphB2 (P < 0.001) were independent predictors of high-grade budding. Bcl-2-/EphB2- tumours were more frequently poorly differentiated (P < 0.001), of advanced pT stage (P = 0.002), lymph node positive (P = 0.023), presented vascular (P = 0.053) and lymphatic invasion (P = 0.005) and had a negative impact on patient survival (P = 0.012). CONCLUSIONS: The multi-marker phenotype EphB2-/Bcl-2- is an independent predictor of high-grade budding and implies increased aggressive behaviour in MMR-proficient colorectal cancer.

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

BACKGROUND: 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. METHODS: We examined a test cohort of 418 well-documented patients with pre-operatively untreated rectal cancer admitted to the University Hospital of Basel between 1987 and 1996. Classification and regression tree (CART) and logistic regression analysis were carried out to determine the ability of tumor size to discriminate between early (pT1-2) and late (pT3-4) T stages and between node-negative (pN0) and node-positive (pN1-2) patients. Results were validated by an external patient cohort (n = 28). RESULTS: A tumor diameter threshold of 34 mm was identified from the test cohort resulting in a sensitivity and specificity for late T stage of 76.3%, and 67.4%, respectively and an odds ratio (OR) of 6.67 (95%CI:3.4-12.9). At a threshold value of 29 mm, sensitivity and specificity for node-positive disease were 94% and 15.5%, respectively with an OR of 3.02 (95%CI:1.5-6.1). Applying these threshold values to the validation cohort, sensitivity and specificity for T stage were 73.7% and 77.8% and for N stage 50% and 75%, respectively. CONCLUSIONS: Tumor size at a threshold value of 34 mm is a reproducible predictive factor for late T stage in rectal cancers. Tumor size may help to complement clinical staging and further optimize the pre-operative management of patients with rectal cancer.

Successful pancreaticoduodenectomy with immediate vascular reconstruction in a patient with cancer of the pancreatic head and celiac artery stenosis. A case report.

CONTEXT: Celiac artery stenosis is observed in a significant percentage of individuals in the general population. Although usually clinically silent and insignificant, due to the presence of extensive collaterals between the celiac artery and the superior mesenteric artery, celiac artery stenosis may be associated with potentially catastrophic ischemic complications in patients undergoing pancreaticoduodenectomy, due to the abrupt interruption of the collateral pathways. Therefore, revascularization may be indicated in selected patients with celiac artery stenosis undergoing a PD. CASE REPORT: We present a patient with celiac artery stenosis diagnosed intraoperatively during a PD, who underwent vascular reconstruction at the time of the PD. In the immediate postoperative period, he developed hepatic ischemia due to stenosis at the anastomosis of the stent with the hepatic artery. He was subsequently treated successfully with the endovascular placement of a stent. In retrospect, a careful reevaluation of the preoperative abdominal CT scan showed the stenosis at the origin of celiac artery. CONCLUSION: A careful evaluation of abdominal CT scan is required to preoperatively identify this not uncommon vascular obstructive disease, especially in asymptomatic patients. Otherwise, the astute surgeon should suspect celiac artery stenosis based on intraoperative findings/changes immediately following ligation of the gastroduodenal artery during a PD.

Initial ultrasonographic assessment for blunt abdominal trauma: is it a reliable diagnostic modality for emergency laparotomy?

Abdominal ultrasound has been proposed as a tool for the evaluation of blunt abdominal trauma. The aim of this study was to evaluate ultrasound's ability to identify intraabdominal injuries that require surgical treatment. Data from 1463 patients were examined retrospectively during a 2-year time period, which were ultrasonographically evaluated for blunt abdominal injury. Hemoperitoneum and abdominal visceral injury were correctly detected by ultrasound with 88% sensitivity and 96.8% specificity. The results are in accordance with the international literature.

Telecytology: a tool for quality assessment and improvement in the evaluation of thyroid fine-needle aspiration specimens.

The objective of this study was to investigate the role of telecytology as a tool with increased quality standards in the optimal evaluation of thyroid fine-needle aspiration specimens prepared by the ThinPrep(R) technique (Cytyc Co., Boxborough, MA). The study was performed on 252 adequate specimens of 157 patients referred to the Cytopathology Department of University Hospital "Attikon" for preoperative evaluation of thyroid nodules. In all cases, surgical excision followed the initial cytological diagnosis. Three diagnostic categories of cytological reports were used. All cases were confirmed by histological diagnosis of surgical specimens. Ten characteristic images from each case were transferred via file transfer protocol to password-protected accounts for remote review by four independent cytopathologists. In addition to diagnosis, reviewers also commented on overall digital image quality. Contributor's and reviewer's diagnoses were collected, recorded and statistically evaluated. No significant difference in diagnostic accuracy could be detected between the diagnoses proffered on the basis of digitized images and conventional slides. Telecytology is a prompt and valid method for quality assessment and proficiency testing and can be integrated into daily workflow. The use of liquid-based cytology ensures that additional material is preserved for ancillary studies (if necessary) and that a sufficient number of replicate microscope slides can be produced. The use of telecytology in the daily workflow will ensure the reproducibility of cytological diagnoses and make feasible the production of digital educational material. Besides diagnostic accuracy, the implementation of a diagnostic telecytology system requires consideration of numerous financial, legal, professional, and ethical issues.

TYMS/KRAS/BRAF molecular profiling predicts survival following adjuvant chemotherapy in colorectal cancer.

BACKGROUND: Patients with stage II-III colorectal cancer (CRC) treated with adjuvant chemotherapy, gain a 25% survival benefit. In the context of personalized medicine, there is a need to identify patients with CRC who may benefit from adjuvant chemotherapy. Molecular profiling could guide treatment decisions in these patients. Thymidylate synthase (TYMS) gene polymorphisms, KRAS and BRAF could be included in the molecular profile under consideration. AIM: To investigate the association of TYMS gene polymorphisms, KRAS and BRAF mutations with survival of CRC patients treated with chemotherapy. METHODS: A retrospective study studied formalin-fixed paraffin-embedded tissues (FFPEs) of consecutive patients treated with adjuvant chemotherapy during January/2005-January/2007. FFPEs were analysed with PCR for the detection of TYMS polymorphisms, mutated KRAS (mKRAS) and BRAF (mBRAF). Patients were classified into three groups (high, medium and low risk) according to 5'UTR TYMS polymorphisms Similarly, based on 3'UTR polymorphism ins/loss of heterozygosity (LOH) patients were allocated into two groups (high and low risk of relapse, respectively). Cox regression models examined the associated 5-year survival outcomes. RESULTS: One hundred and thirty patients with early stage CRC (stage I-II: 55 patients; stage III 75 patients; colon: 70 patients; rectal: 60 patients) were treated with surgery and chemotherapy. The 5-year disease free survival and overall survival rate was 61.6% and 73.9% respectively. 5'UTR polymorphisms of intermediate TYMS polymorphisms (2RG/3RG, 2RG/LOH, 3RC/LOH) were associated with lower risk for relapse [hazard ratio (HR) 0.320, P = 0.02 and HR 0.343, P = 0.013 respectively] and death (HR 0.368, P = 0.031 and HR 0.394, P = 0.029 respectively). The 3'UTR polymorphism ins/LOH was independently associated with increased risk for disease recurrence (P = 0.001) and death (P = 0.005). mBRAF (3.8% of patients) was associated with increased risk of death (HR 4.500, P = 0.022) whereas mKRAS (39% of patients) not. CONCLUSION: Prospective validating studies are required to confirm whether 2RG/3RG, 2RG/LOH, 3RC/LOH, absence of ins/LOH and wild type BRAF may indicate patients at lower risk of relapse following adjuvant chemotherapy.

The genetic basis of hereditary medullary thyroid cancer: clinical implications for the surgeon, with a particular emphasis on the role of prophylactic thyroidectomy.

Medullary thyroid cancer (MTC) may occur either sporadically or on a hereditary basis. Hereditary MTC may be observed with either multiple endocrine neoplasia syndromes (MEN 2A and MEN 2B) or as familial MTC (FMTC). Despite the rarity of these syndromes, early diagnosis is especially important, since MTC is a lethal disease if not promptly and appropriately treated. Recently, the development of genetic testing and direct DNA analysis allows the identification of asymptomatic patients. Surgical prophylaxis should be considered in these cases, ideally to prevent the development of MTC. During the recent decade, the concept of 'codon-directed' timing of prophylactic surgery emerged as a reasonable strategy in the management of these patients. Currently, genetic analysis offers the possibility to define genotype-phenotype correlations and to adjust the time of prophylactic surgery. Hereditary MTC is a model of genetically determined cancer in which both diagnostic and therapeutic strategies rely on the identification of specific mutations.

Recent advances and current controversies in the management of DCIS of the breast.

Ductal carcinoma in situ (DCIS) is commonly diagnosed today, mainly due to widespread use of screening mammography. Despite a better understanding of its biological behavior, many issues regarding its optimal management remain controversial. The biological behavior of DCIS has been associated with distinct molecular and histological features (such as expression of COX2, Ki67, c-erbB2, p53 mutation, presence or absence of comedonecrosis, nuclear grade, hormone receptor status, etc.). Recent advances in the diagnosis of DCIS include using magnetic resonance imaging, and the use of stereotactic-guided directional vacuum-assisted biopsy (DVAB). Ductoscopy and ductal lavage have a limited role in the management of DCIS. Surgical treatment of DCIS includes simple local excision to various forms of wider excision (segmental resection or quadrantectomy), or even mastectomy (either simple or skin-sparing). Radiotherapy following breast-conserving surgery significantly reduces local recurrence rates. Axillary lymph node dissection is not required for the management of DCIS; however, during the last decade, sentinel lymph node biopsy is increasingly used to exclude the presence of axillary metastases (when invasive disease is present within the DCIS). This approach has many advantages (including the avoidance of a second surgery if invasive disease is diagnosed within the DCIS) and should be considered when there is an increased probability for the presence of invasive breast cancer within the DCIS. The role of other minimally invasive methods (such as the "therapeutic" application of the DVAB technique, radiofrequency ablation, laser therapy, cryotherapy and brachytherapy) in the management of small DCIS remains unproven. Tamoxifen should be considered in the management of selected patients with DCIS, such as patients with hormone receptor positive DCIS, young patients, and patients without risk factors for potential side effects. Additionally, and controversial, there is evidence that aromatase inhibitors may be better than tamoxifen in the management of DCIS.

The expression of matrix metalloproteinases-2 and -9 and their tissue inhibitor 2 in pancreatic ductal and ampullary carcinoma and their relation to angiogenesis and clinicopathological parameters.

AIM: To investigate the expression of metalloproteinase (MMP) -2, MMP-9 and tissue inhibitor of MMP (TIMP) -2 in pancreatic ductal and ampullary carcinoma and to test the findings for correlation with angiogenesis and several clinicopathological parameters. PATIENTS AND METHODS: Paraffin sections from 32 pancreatic ductal adenocarcinomas and 17 ampullary carcinomas were assessed for the expression of MMP-2, MMP-9 and TIMP-2 by immunohistochemistry. Stromal and epithelial staining was evaluated separately. Moreover, sections stained immunohistochemically with anti-CD34 antibody were evaluated by image analysis for the quantification of microvessel density (MVD). RESULTS: In pancreatic ductal adenocarcinoma, lower levels of glandular TIMP-2 were found in poorly differentiated tumors, while high glandular TIMP-2 expression was significantly associated with better survival. The age of the patients and the degree of differentiation of the tumor were identified as independent prognostic parameters. No relation was found between the expression of MMPs, TIMP or angiogenesis and the parameters under consideration. In ampullary adenocarcinoma, strong expression of glandular MMP-2 was associated with higher MVD values. Moreover, lymph vessel invasion was associated with higher stromal TIMP-2. CONCLUSION: In pancreatic ductal adenocarcinoma, TIMP-2 may have a more crucial role in prognosis than MMP-2, MMP-9 or angiogenesis. In ampullary adenocarcinoma, MMP-2 expression correlated with MVD, supporting its postulated role in angiogenesis.

P53Arg72 homozygosity and its increased incidence in left-sided sporadic colorectal adenocarcinomas, in a Greek-Caucasian population.

BACKGROUND: The current case-control study was conducted in order to elucidate any possible association of the single nucleotide polymorphism (SNP) of codon 72 of the p53 gene (Arg72Pro) and sporadic colorectal adenocarcinoma development in a Caucasian population in Greece. The distribution of its alleles, in relation to many clinical parameters of the cancer group, was also investigated. MATERIALS AND METHODS: Genomic DNA samples from 93 sporadic colorectal adenocarcinoma cases and 95 healthy controls (age and ethnicity matched) were used to genotype the p53 codon 72 polymorphism. RESULTS: A strong association of the homozygous 72Arg allele with the development of colorectal cancer was observed (Chi-Square = 11,212, p = 0.001, O.R = 2.902, 95% (CI) = 1.540-5.469, for Arg/Arg vs. Arg/Pro and Pro/Pro). When tumor location was accounted for, the Arg/Arg carrier genotypes were associated with an increased incidence of left colon cancer (Chi-Square = 5.256, p = 0.026, OR = 2.975, 95% (CI) = 1.150-7.699). CONCLUSION: p53Arg homozygosity is associated with the development of sporadic colorectal adenocarcinoma, in the Greek-Caucasian population studied and this polymorphism may have a significant prognostic value, where tumor location is concerned.

Large somatostatin-producing endocrine carcinoma of the ampulla of vater in association with GIST in a patient with von Recklinghausen's disease. Case report and review of the literature.

CONTEXT: Somatostatin-producing endocrine tumors of the duodenum are very rare neoplasms of the gastrointestinal tract. These tumors may be associated with von Recklinghausen's disease. CASE REPORT: We present the case of a 49-year-old female patient with von Recklinghausen's disease and an incidentally diagnosed ampullary neoplasm. The patient was treated with a classical pancreaticoduodenectomy. At surgery, a mass was found in the greater curve of the stomach which was resected using the classic Whipple procedure. Histology and immunohistochemistry showed that the duodenal tumor was an ampullary somatostatin-producing endocrine carcinoma while the gastric tumor was a gastrointestinal stromal tumor (GIST). The postoperative course was uneventful and the patient is alive, without tumor recurrence, six years after surgery. CONCLUSION: Somatostatin-producing endocrine tumors of the duodenum are rare tumors, often associated with von Recklinghausen's disease; these neoplasms should be treated aggressively using radical surgical resection. Although local resection may be appropriate for small duodenal somatostatin-producing tumors, a pancreaticoduodenectomy is usually required for larger tumors.

Principles of war surgery: current concepts and future perspectives.

Medical support is an important part of military operations. The aim of war surgery is to achieve the return of the greatest number of injured to combat and the preservation of life, limb, and eyesight. War surgery is different from current traumatology because of many reasons. Because hemorrhage is the most common cause of death in military trauma, airway preservation and effective control of bleeding represent the highest priorities in war injuries. Wound excision (the so-called debridement) is a significant part in the management of war injuries. It involves excision of all foreign objects and contaminants and dead/nonviable tissue that--if not removed--would become a medium for infection. Broad-spectrum antibiotics should be administered and tetanus prophylaxis measures should be taken, as indicated. Delayed wound closure (usually after 4-5 days) is the standard procedure after wound excision. Recently, changes in the dogma of war necessitated significant changes in the organization schema of military services supporting modern military operations. The concept of highly mobile, easily deployed, forward surgical facilities is the most important change in the philosophy of modern war injury. Military surgeons are now facing new challenges; appropriate education is required to achieve success in their mission.

Esophageal squamous cell carcinomas and expression of p53, Bcl-2, and Bcl-X(L).

p53 protein promotes apoptosis, whereas Bcl-2 family proteins have an antiapoptotic function. This study determines the predictive value of selected clinical and histopathological factors in correlation with the expression of p53, Bcl-2, and Bcl-X(L) proteins in esophageal squamous cell carcinomas (SCCs). Paraffin-embedded sections from 19 surgically resected primary esophageal SCCs were examined by immunohistochemistry. p53 expression was related to degree of tumor differentiation (P = 0.044). Bcl-2 expression was associated with regional lymph node metastasis (P = 0.053), whereas Bcl-X(L) expression was correlated with distant metastasis (P = 0.060) and with the expression of Bcl-2 protein (P = 0.068). p53 and Bcl-2 family proteins may help to estimate the properties of esophageal SCCs and provide useful information to the oncologist for the selection of patients for intensive combined therapy modalities with curative intention or for palliative therapy.

Apoptosis and adenocarcinoma of the cardia: expression of p53, Bcl-2, Bcl-XL, WAF1, and fas proteins and association with characteristics of the tumors.

Our knowledge regarding the biology of the gastroesophageal junction adenocarcinomas is still incomplete. Paraffin-embedded sections from 31 surgically resected primary cardia adenocarcinomas were examined by immunohistochemistry. Statistical analysis showed that Bcl-2 expression was significantly correlated with the age of the patients (P = 0.043), whereas Bcl-X(L) expression was inversely correlated with Bcl-2 expression (P = 0.021). An inverse correlation of high statistical significance was also found between p53 and Bcl-2 expression (P = 0.000). Fas expression was highly correlated with tumor stage (P = 0.006), degree of differentiation (P = 0.044), and the stage of the disease (P = 0.029). A significant correlation was also observed between the expression levels of WAF1 and Fas (P = 0.037), Fas and Bcl-X(L) (P = 0.018), and WAF1 and p53 (P = 0.018). These proteins may contribute to the estimation of the properties of adenocarcinomas of the gastroesophageal junction, facilitating prognosis of cancer patients treated by multimode therapy.

Abdominal desmoid tumors.

Desmoid tumors are rare, benign, fibromatous lesions that are the result of abnormal proliferation of myofibroblasts. Desmoid tumors can be classified as extra-abdominal and abdominal. Abdominal desmoid tumors are either superficial or intraabdominal. These tumors are associated with a high recurrence rates, even if their microscopic characters indicate a benign disease; their biologic behavior often indicates rather a "malignant" disease, which can cause even the death. Intraabdominal desmoid tumors can engulf surrounding viscera and vessels, thereby greatly complicating their surgical treatment. Management is multidisciplinary. Simple observation is a reasonable management option for asymptomatic patients; spontaneous regression of these tumors may be observed. Complete excision is the treatment of choice for tumors causing symptoms or complications. Surgery should be minimized as much as feasible, while at the same time achieving free margins. Adjuvant therapy should be considered in selected cases; the role of other management options (including gene transfer therapy) is currently under intensive investigation.

The role of surgery in the management of septic shock--extra-abdominal causes of sepsis.

Septic shock is a severe inflammatory response to one or more pathogenic micro-organisms. When a person's immune response is excessively intense, a cascade of phenomena may be activated that ultimately is harmful. Appropriate management of septic shock may include surgical intervention to remove or neutralize the septic focus in an effort to treat the inflammatory response cascade. This is the first of two articles presenting current information on the role of surgery in the management of a patient with septic shock. This article describes extra-abdominal sources of sepsis.

Integrating TYMS, KRAS and BRAF testing in patients with metastatic colorectal cancer.

AIM: To investigate the impact of thymidylate synthase (TYMS), KRAS and BRAF in the survival of metastatic colorectal cancer (mCRC) patients treated with chemotherapy. METHODS: Clinical data were collected retrospectively from records of consecutive patients with mCRC treated with fluoropyrimidine-based chemotherapy from 1/2005 to 1/2007. Formalin-fixed paraffin-embedded tissues were retrieved for analysis. TYMS genotypes were identified with restriction fragment analysis PCR, while KRAS and BRAF mutation status was evaluated using real-time PCR assays. TYMS gene polymorphisms of each of the 3' untranslated region (UTR) and 5'UTR were classified into three groups according to the probability they have for high, medium and low TYMS expression (and similar levels of risk) based on evidence from previous studies. Univariate and multivariate survival analyses were performed. RESULTS: The analysis recovered 89 patients with mCRC (46.1% de novo metastatic disease and 53.9% relapsed). Of these, 46 patients (51.7%) had colon cancer and 43 (48.3%) rectal cancer as primary. All patients were treated with fluoropyrimidine-based chemotherapy (5FU or capecitabine) as single-agent or in combination with irinotecan or/and oxaliplatin or/and bevacizumab. With a median follow-up time of 14.8 mo (range 0-119.8), 85 patients (95.5%) experienced disease progression, and 63 deaths (70.8%) were recorded. The 3-year and 5-year OS rate was 25.4% and 7.7% while the 3-year progression-free survival rate was 7.1%. Multivariate analysis of TYMS polymorphisms, KRAS and BRAF with clinicopathological parameters indicated that TYMS 3'UTR polymorphisms are associated with risk for disease progression and death (P < 0.05 and P < 0.03 respectively). When compared to tumors without any del allele (genotypes ins/ins and ins/loss of heterozygosity (LOH) linked with high TYMS expression) tumors with del/del genotype (low expression group) and tumors with ins/del or del/LOH (intermediate expression group) have lower risk for disease progression (HR = 0.432, 95%CI: 0.198-0.946, P < 0.04 and HR = 0.513, 95%CI: 0.287-0.919, P < 0.03 respectively) and death (HR = 0.366, 95%CI: 0.162-0.827, P < 0.02 and HR = 0.559, 95%CI: 0.309-1.113, P < 0.06 respectively). Additionally, KRAS mutation was associated independently with the risk of disease progression (HR = 1.600, 95%CI: 1.011-2.531, P < 0.05). The addition of irinotecan in 1st line chemotherapy was associated independently with lower risk for disease progression and death (HR = 0.600, 95%CI: 0.372-0.969, P < 0.04 and HR = 0.352, 95%CI: 0.164-0.757, P < 0.01 respectively). CONCLUSION: The TYMS genotypes ins/ins and ins/LOH associate with worst prognosis in mCRC patients under fluoropyrimidine-based chemotherapy. Large prospective studies are needed for validation of our findings.

Thyroid nodule: a potentially malignant lesion; optimal management from a surgical perspective.

Thyroid nodules are very common lesions, frequently detected by modern imaging methods (mainly ultrasonography). Despite that most thyroid nodules represent benign lesions, a small but significant percentage of them are malignant. Surgery is indicated when there is underlying malignancy (or suspicion for), pressure symptoms, or for cosmetic reasons. Total/near total thyroidectomy is the most radical procedure, which achieves cure, avoids the possibility of reoperation in the future (completion thyroidectomy), and facilitates postoperative management of the patient with underlying malignancy. Simple observation and thyroid hormone suppressive therapy are acceptable management options for patients with presumably benign thyroid nodules. Radioiodine therapy may be used for the management of patients with hyperfunctioning ("hot") thyroid nodules. Ablation of thyroid nodules (sclerosing therapy [alcohol injection] and laser photocoagulation) have been used for the in situ destruction of thyroid nodules; ablation therapy is currently viewed as experimental therapeutic method. Careful evaluation is required in order to avoid both overtreatment (mainly unnecessary surgery) as well as undertreatment of these potentially malignant, but highly curable lesions.