Epithelial-Mesenchymal Transition in Cancer: Parallels Between Normal Development and Tumor Progression

From the earliest stages of embryonic development, cells of epithelial and mesenchymal origin contribute to the structure and function of developing organs. However, these phenotypes are not always permanent, and instead, under the appropriate conditions, epithelial and mesenchymal cells convert between these two phenotypes. These processes, termed Epithelial-Mesenchymal Transition (EMT), or the reverse Mesenchymal-Epithelial Transition (MET), are required for complex body patterning and morphogenesis. In addition, epithelial plasticity and the acquisition of invasive properties without the full commitment to a mesenchymal phenotype are critical in development, particularly during branching morphogenesis in the mammary gland. Recent work in cancer has identified an analogous plasticity of cellular phenotypes whereby epithelial cancer cells acquire mesenchymal features that permit escape from the primary tumor. Because local invasion is thought to be a necessary first step in metastatic dissemination, EMT and epithelial plasticity are hypothesized to contribute to tumor progression. Similarities between developmental and oncogenic EMT have led to the identification of common contributing pathways, suggesting that the reactivation of developmental pathways in breast and other cancers contributes to tumor progression. For example, developmental EMT regulators including Snail/Slug, Twist, Six1, and Cripto, along with developmental signaling pathways including TGF-β and Wnt/β-catenin, are misexpressed in breast cancer and correlate with poor clinical outcomes. This review focuses on the parallels between epithelial plasticity/EMT in the mammary gland and other organs during development, and on a selection of developmental EMT regulators that are misexpressed specifically during breast cancer.     

The role of pre-operative B mode ultrasound in the evaluation of the axillary lymph node metastases in the initial staging of breast carcinoma

The lymph node status of a breast cancer is one of the main prognostic criterias. This status is very important to determine the therapeutic approach. Physical examination alone is not sufficient to assess axillary metastases. Mammographic examination can give us an idea about breast cancer and axillary involvement. Ultrasonographic evaluation can improve the sensitivity of clinical and mammographic examination in assessing axillary lymph node status. 42 patients operated on for breast cancer between January 2000-January 2003 were included in this prospective study. In the study, we used axillary B mode ultrasound to evaluate the axillary lymph nodes. There are several sonographic features to categorize them. Axillary B mode ultrasound was performed to evaluate the axillary lymph nodes for metastatic involvement. In the evaluation of lymph nodes, the sonographic criteria were centric echogenity, thickening of cortex, length/width ratio (L/W) and the diameter of lymph nodes. Hyperechogenic hilus was accepted as a benign finding. The thickening of the cortex less than 50% of the thickening of the centric echogenic hilus was also accepted as a benign finding. L/W ratio below 2 and parameters above 2 cm were accepted as malignant findings. 168 lymph nodes in 42 patients were evaluated pre-operatively with axillary B mode ultrasound. As a result, these lymph nodes were defined as benign in 19 patients (45.2%) and malignant in 23 patients (54.8%). Axillary lymph node status was found as benign in 18 patients (42.9%) and malignant in 24 patients (57.1%) pathologically . Comparative results of ultrasound and axillary lymph node status can be seen on Table III. As a result, the sensitivity of axillary B mode ultrasound to show the metastases was found as 79.1%, specificity was 77.7%, positive predictive value 82.6% and negative predictive value 73.6%. We think some better results may be obtained in the future and these developments may affect the surgeon's decisions concerning axillary dissection for breast cancer operations.     

Predictive Value of Sonographic Features in Preoperative Evaluation of Malignant Thyroid Nodules in a Multinodular Goiter

BACKGROUND: The primary goal of ultrasonography (US) in the evaluation of a thyroid nodule is to determine its malignancy, although the diagnosis of a malignant nodule on the basis of US alone is nearly impossible. The aim of this prospective study was to evaluate the predictive value of sonographic features in the preoperative diagnosis of malignant thyroid nodules, and to determine the important features of sonography. METHODS: This prospective study included 550 consecutive patients with , thyroid nodules. Nodules were divided into two groups on the basis of pathological diagnosis: group 1 consisted of 1,633 nodules with a benign pathology, and group 2 consisted of 293 nodules with a malignant pathology. RESULTS: Microcalcifications, blurred nodular margins, and solid and hypoechoic appearance were more common in malignant nodules compared to benign nodules (89.1% versus 5%; 64.5% versus 4.7%; 81.6% versus 30.6% ; and 62.5% versus 43.1%, respectively; p < 0.001). There was a positive correlation between the detection of malignant thyroid nodules and microcalcification (rs = 0.791, p = 0.0001), blurred nodular margin (rs = 0.625, p = 0.0001), solid appearance (rs = 0.376, p = 0.0001), and hypoechoic appearance (rs = 0.141, p = 0.0001). Microcalcifications, blurred nodular margins, and solid and hypoechoic appearance were independent determinants of malignancy upon US examination of thyroid nodules (OR: 159, OR: 37, OR: 9.9, and OR: 2.2, respectively). CONCLUSION: Although we did not identify a single feature indicative of malignancy in the sonographic examination of nodules, microcalcification and blurred margin were the strongest correlates for malignancy.     

Glycemic Control after Sleeve Gastrectomy and Roux-En-Y Gastric Bypass in Obese Subjects with Type 2 Diabetes Mellitus

Background

Roux-en-Y gastric bypass (LRYGB) has weight-independent effects on glycemia in obese type 2 diabetic patients, whereas sleeve gastrectomy (LSG) is less well characterized. This study aims to compare early weight-independent and later weight-dependent glycemic effects of LRYGB and LSG.

Methods

Eighteen LRYGB and 15 LSG patients were included in the study. Glucose, insulin, GLP-1, and GIP levels were monitored during a modified 30 g oral glucose tolerance test before surgery and 2 days, 3 weeks, and 12 months after surgery. Patients self-monitored glucose levels 2 weeks before and after surgery.

Results

Postoperative fasting blood glucose decreased similarly in both groups (LRYGB vs. SG; baseline—8.1?±?0.6 vs. 8.2?±?0.4 mmol/l, 2 days—7.8?±?0.5 vs. 7.4?±?0.3 mmol/l, 3 weeks—6.6?±?0.4 vs. 6.6?±?0.3 mmol/l, respectively, P <?0.01 vs. baseline for both groups; 12 months—6.6?±?0.4 vs. 5.9?±?0.4, respectively, P <?0.05 for LRYGB and P <?0.001 for LSG vs. baseline, P =?ns between the groups at all times). LSG, but not LRYGB, showed increased peak insulin levels 2 days postoperatively (mean?±?SEM; LSG +?58?±?14%, P <?0.01; LRYGB ??8?±?17%, P =?ns). GLP-1 levels increased similarly at 2 days, but were higher in LRYGB at 3 weeks (AUC; 7525?±?1258 vs. 4779?±?712 pmol?×?min, respectively, P <?0.05). GIP levels did not differ. Body mass index (BMI) decreased more after LRYGB than LSG (??10.1?±?0.9 vs. ??7.9?±?0.5 kg/m², respectively, P <?0.05).

Conclusion

LRYGB and LSG show very similar effects on glycemic control, despite lower GLP-1 levels and inferior BMI decrease after LSG.

     

Predicting Individual Survival After Hepatectomy for Hepatocellular Carcinoma: a Novel Nomogram from the “HCC East &amp; West Study Group”

Introductions

Different staging systems have been devised for patients undergoing resection for hepatocellular carcinoma (HCC) with disparate results. The aim of this study was to create a new nomogram to predict individual survival after hepatectomy for HCC.

Methods

Based on the “Hepatocellular Carcinoma: Eastern & Western Experiences Network,” data from 2046 patients who underwent HCC resections at ten centers were reviewed. Patient survival was analyzed with Cox-regression analysis to construct a unique nomogram and contour plots to predict survival.

Results

The nomograms built on the multivariate analyses, which showed that the independent predictors were tumor size, tumor number, vascular invasion, cirrhosis, preoperative bilirubin value, and esophageal varices, showed good calibration and discriminatory abilities with C-index value of 0.62 (95 % CI, 0.59–0.69) and 0.61 (95 % CI, 0.56–0.64) for overall and disease-free survival, respectively. The 5-year survival contour plots showed that the presence of vascular invasion was associated with decreased survival, regardless of the tumor number or size. Cirrhosis and varices were equally associated with decreased survival, according to the tumor number or size.

Conclusions

These nomograms accurately predict individual prognosis after HCC resection and support an expansion of the selection criteria for resection. They offer useful guidance to clinicians for individual survival prediction.

     

Comparison of surgical and conservative treatment outcomes for type a aortic dissection in elderly patients

Background

In recent years, surgical outcomes have improved, and positive reports on surgery for type A aortic dissection (AAD) in the elderly are increasing. However, the difference between surgical and conservative treatments in the elderly remains unclear. Therefore, we conducted this study to determine whether surgery should be performed for Stanford (AAD) in elderly patients.

Methods

Data of patients aged 80?years or older who were hospitalized for AAD from April 2014 to March 2016 were extracted from the Japanese national inpatient database. Outcome measures were all-cause in-hospital death, stroke, acute kidney injury and tracheotomy, and composite adverse events (consisting of all-cause in-hospital death, stroke, acute kidney injury, and tracheotomy), and we compared them between surgical and conservative treatments using propensity score matching.

Results

The study cohort included 3258 patients, with 845 matched pairs (1690 patients) in the propensity score matching. All-cause in-hospital death was significantly lower in the surgical treatment group than in the conservative treatment group before and after matching (15.6% vs. 51.1%, p?<?0.001; 16.7% vs. 31.6%, p?<?0.001, respectively); however, there was no significant difference in composite adverse events after matching (36.0%, conservative vs. 37.2%, surgical; p?=?0.65), and adjusted odds ratio was 1.06 and 95% confidence interval was 0.86–1.29 (p?=?0.61) with reference to conservative treatment.

Conclusions

All-cause in-hospital death among elderly patients with AAD was significantly lower in patients treated surgically than in those undergoing conservative treatment. However, there was no significant difference between the two groups in the event-free survival, which is important for the elderly. These findings may be used in the consideration of treatment course for elderly patients with AAD.

     

Noninvasive Pancreatic Cystic Neoplasms can be Safely and Effectively Treated by Limited Pancreatectomy

Background Appropriate management of cystic lesions of the pancreas is controversial. Major pancreatectomies (pancreaticoduodenectomy or distal pancreatectomy with splenectomy) are the commonly used procedures, even though most cystic lesions are noninvasive neoplasms. We tested the adequacy of limited pancreatectomies in the treatment of pancreatic cystic lesions. Methods Data from 109 patients who underwent surgical resection of a pancreatic cystic lesion at National Taiwan University Hospital from 2001 to 2007 were retrospectively reviewed. Major pancreatomies (n = 79) constituted pancreaticoduodenectomy and total/distal pancreatectomies, while other resection procedures (n = 30) represented limited pancreatectomies. Clinicopathologic features were compared between the major and limited groups. Results There were no statistically significant differences in sex, age, presence of symptoms, cyst diameter, minor or major treatment complications, or pancreatic leakage between the two groups. Cystic lesions located in the neck/body/tail rather than in the head/uncinate process were significantly more often treated with limited pancreatectomy (P = .02). Both groups had similar pathologic distribution of cystic lesions, with the exception of nine invasive neoplasms. The latter were treated with major pancreatectomy. No recurrence was noted in 100 patients with noninvasive cystic neoplasms after major or limited pancreatectomy. Conclusions Noninvasive pancreatic cystic neoplasms can be safely and effectively treated by limited pancreatectomy.     

Surgical Complications and the Risk Factors of Laparoscopy-Assisted Distal Gastrectomy in Early Gastric Cancer

Background Information on surgical complications of laparoscopy-assisted distal gastrectomy (LADG) and their risk factors is limited in the literature despite increasing popularity of this procedure. This study was performed to identify the surgical complications and their associated risk factors of LADG in early gastric cancer. Methods LADG was performed in 347 gastric cancer patients from January 2002 to December 2006 at the Korean National Cancer Center by four surgeons with ample experience of open gastric surgery before LADG. LADG indications for cases of gastric cancer at our institution are preoperatively diagnosed cT1N0 or cT1N1, except in cases with an absolute indication for endoscopic resection. Lymph node dissection of more than D1 + β was performed in all patients. Intraoperative and postoperative complications were reviewed and their risk factors were retrospectively analyzed by prospective database information. Results Forty complications occurred in 34 patients (9.8%), but there was no mortality. Intraoperative complications occurred in nine patients (2.6%), and open conversion was performed in eight (2.3%) of these patients. Early and late postoperative complications occurred in 21 (6.1%) and 10 (2.9%) patients, respectively. The most serious complication was vascular injury resulting in bleeding or organ ischemia, which occurred in seven patients. Degree of lymph node dissection and surgical inexperience were found to be risk factors of surgical complication (P = .023, odds ratio 2.832, 95% confidence interval 1.155–6.946 vs. P = .028, odds ratio 2.975, 95% confidence interval 1.127–7.854). Conclusions Lymph node dissection during LADG should be performed cautiously to prevent surgical complications like vascular injuries, especially during the surgeon’s early learning period.     

Preoperative Serum Carcinoembryonic Antigen Level as a Predictive Factor of Recurrence After Curative Resection of Colorectal Cancer

Background  We evaluated the prognostic value of the preoperative serum carcinoembryonic antigen (CEA) level in patients with colorectal cancer (CRC). Patients and Methods  The study group comprised 638 patients. The optimal cutoff value for the preoperative serum CEA level was determined. Predictive factors of recurrence were evaluated using multivariate analyses. The relapse-free time was investigated according to the CEA level. Results  All patients underwent potentially curative resection for CRC without distant metastasis, classified as stage I, II, or III. The optimal cutoff value for preoperative serum CEA level was 10 ng/ml. Elevated preoperative serum CEA level was observed in 92 patients. Multivariate analysis identified tumor–node–metastasis (TNM) stage and preoperative serum CEA level as independent predictive factors of recurrence. The relapse-free survival between CEA levels >10 ng/ml and <10 ng/ml significantly differed in patients with stage II and III. However, there was no significant difference in relapse-free survival between CEA levels >10 ng/ml and <10 ng/ml in patients with stage I. Conclusion  Preoperative serum CEA is a reliable predictive factor of recurrence after curative surgery in CRC patients and a useful indicator of the optimal treatment after resection, particularly for cases classified as stage II or stage III.     

Prevalence and Severity of Sleep Apnea in a Group of Morbidly Obese Patients

Background Obesity is the most important risk factor for obstructive sleep apnea. It is estimated that 70% of sleep apnea patients are obese. In the morbidly obese, the prevalence may reach 80% in men and 50% in women. The aim of this study was to determine the prevalence and severity of sleep apnea in a group of morbidly obese patients, leading to bariatric surgery. Methods In a cross-sectional study developed in Bahia, northeastern Brazil. 108 patients (78 women and 30 men) from the Obesity Treatment and Surgery Center - “Núcleo de Tratamento e Cirurgia da Obesidade” underwent standard polysomnography. Patients with an apnea-hypopnea index (AHI) ≥ 5 events/hour were considered apneic. Results Mean ± SD for age and BMI were 37.1 ± 10.2 years and 45.2 ± 5.4 kg/m2, respectively. The calculated AHI ranged widely from 2.5 to 128.9 events/hour. Sleep apnea was detected in 93.6% of the sample, wherein 35.2% had mild, 30.6% moderate and 27.8% severe apnea. Oxyhemoglobin desaturation was directly related to the AHI and was more severe in men. Conclusion There was a high frequency of sleep apnea in this group of morbidly obese patients, for whom it was very important to request polysomnography, thus enabling therapeutic management and prognostication.