Konstantinos P. Economopoulos

Treatment and Prognosis for Patients With Intrahepatic Cholangiocarcinoma: Systematic Review and Meta-analysis

IMPORTANCE Data on outcomes following surgical management of intrahepatic cholangiocarcinoma (ICC) are limited. The incidence of ICC is increasing and it has a poor prognosis. No consensus has been reached regarding the optimal treatment modalities. OBJECTIVE To systematically review and synthesize the available evidence regarding treatment and prognosis in patients with ICC. DATA SOURCES The PubMed database was searched for relevant articles published between January 1, 2000, and April 1, 2013. STUDY SELECTION Only studies assessing predictors of survival or recurrence in patients undergoing curative-intent surgical treatment of ICC were included. Small series, studies reporting on mixed types of cholangiocarcinoma, or exclusively on hepatolithiasis-associated cholangiocarcinoma, and those published in a language other than English, French, German, Italian, or Greek, were excluded. Fifty-seven of 960 articles were therefore analyzed. DATA EXTRACTION AND SYNTHESIS Data on preoperative, intraoperative, and postoperative variables were extracted by 3 independent reviewers. Multiple studies reporting on the same population were excluded. Data were pooled using a random-effects model. MAIN OUTCOMES AND MEASURES We hypothesized that preoperative variables and tumor characteristics affect patient survival. The outcomes of the study were overall survival and recurrence-free survival. The hypothesis was formulated before data collection. RESULTS Fifty-seven studies (4756 patients) were included in the review. Median patient age ranged from 49 to 67 years, and 57% were male. Most patients had a solitary (69%), large (median size, 4.5-8.0 cm) tumor of the mass-forming type (86%). Approximately one-third of the patients had lymph node metastasis (34%) or vascular (38%), perineural (29%), or biliary invasion (29%). Most underwent a major hepatectomy (82%), often accompanied by lymphadenectomy (67%) and sometimes by extrahepatic bile duct resection (23%). Median and 5-year overall survival (OS) generally were approximately 28 months (range, 9-53 months) and 30% (range, 5%-56%), respectively; factors predicting shorter OS included large tumor size, multiple tumors, lymph node metastasis, and vascular invasion. Adjuvant chemotherapy or radiotherapy did not appear to be beneficial. Seven studies (2132 patients) provided data for the meta-analysis. Factors associated with shorter OS included older age (pooled hazard ratio, 1.10; 95% CI, 1.03-1.17), larger tumor size (1.09; 1.02-1.16), presence of multiple tumors (1.70; 1.43-2.02), lymph node metastasis (2.09; 1.80-2.43), vascular invasion (1.87; 1.44-2.42), and poor tumor differentiation (1.41; 1.17-1.71). CONCLUSIONS AND RELEVANCE The prognosis of ICC is dictated mainly by tumor factors. Future research could focus on the usefulness of adjuvant treatment as well as other multidisciplinary treatment modalities.

Carotid Artery Stenting Versus Carotid Endarterectomy A Comprehensive Meta-Analysis of Short-Term and Long-Term Outcomes

Background and Purpose— The comparison between carotid endarterectomy and carotid artery stenting (CAS) remains a debated field, especially in the context of long-term outcomes. Methods— Concerning the short-term (30-day) analysis, the numbers of outcomes per arm were abstracted, whereas outcomes per arm and hazard ratios were abstracted for long-term (≥1-year) results. Results— Thirteen randomized trials (3723 carotid endarterectomy and 3754 CAS patients) were eligible. Regarding short-term outcomes, CAS was associated with elevated risk for stroke and “death or stroke.” CAS also exhibited a marginal trend toward higher death and “death or disabling stroke” rates. Carotid endarterectomy presented with higher rates of myocardial infarction and cranial nerve injury. Concerning long-term outcomes, CAS was associated with higher rates of stroke (pooled OR, 1.37; 95% CI, 1.13 to 1.65) and “death or stroke” (pooled OR, 1.25; 95% CI, 1.06 to 1.48). These findings were replicated at the level of pooled hazard ratios and marginally regarding secondary preventive efficacy. The difference in long-term stroke rates was particularly sizeable in patients >68 years, but little difference in rates was observed in those <68 years. No statistically significant heterogeneity became evident. Metaregression did not reveal any significant modifying effect mediated by symptomatic/asymptomatic status, distal protection, early termination of trials, area of study origin, or CAS learning curve. Conclusions— This meta-analysis points to the significantly less frequent stroke events after carotid endarterectomy at the long-term context. The outcomes of carotid endarterectomy seem superior to CAS, but there may be subgroups, particularly younger patients, in whom the results seem equivalent.

Intestinal alkaline phosphatase prevents metabolic syndrome in mice

Metabolic syndrome comprises a cluster of related disorders that includes obesity, glucose intolerance, insulin resistance, dyslipidemia, and fatty liver. Recently, gut-derived chronic endotoxemia has been identified as a primary mediator for triggering the low-grade inflammation responsible for the development of metabolic syndrome. In the present study we examined the role of the small intestinal brush-border enzyme, intestinal alkaline phosphatase (IAP), in preventing a high-fat-diet–induced metabolic syndrome in mice. We found that both endogenous and orally supplemented IAP inhibits absorption of endotoxin (lipopolysaccharides) that occurs with dietary fat, and oral IAP supplementation prevents as well as reverses metabolic syndrome. Furthermore, IAP supplementation improves the lipid profile in mice fed a standard, low-fat chow diet. These results point to a potentially unique therapy against metabolic syndrome in at-risk humans.

GSTM1, GSTT1, GSTP1, GSTA1 and colorectal cancer risk: A comprehensive meta-analysis

Glutathione S-transferases (GSTs) catalyse reactions between glutathione and lipophilic compounds with electrophilic centres, leading to neutralisation of toxic compounds, xenobiotics and products of oxidative stress. Controversy exists about whether GST polymorphisms (GSTM1 null/present genotype, GSTT1 null/present genotype, GSTP1 Ile105Val and GSTA1 *A/*B) represent risk factors for colorectal cancer. This meta-analysis aims to examine the associations between the above-mentioned polymorphisms and colorectal cancer risk. Forty-four studies were eligible for GSTM1 (11,998 colorectal cancer cases, 17,552 controls), 34 studies for GSTT1 (8596 cases, 13,589 controls), 19 studies for GSTP1 (5421 cases, 7671 controls) and four studies for GSTA1 polymorphism (1648 cases, 2039 controls). Pooled odds ratios (ORs) were appropriately derived from fixed-effects or random-effects models. Separate analyses were conducted on Caucasian and Chinese populations. Where appropriate, sensitivity analysis concerning the deviation of genotype frequencies in controls from the Hardy-Weinberg equilibrium was performed. GSTM1 null allele carriers exhibited increased colorectal cancer risk in Caucasian populations (pooled OR=1.150, 95% confidence interval (CI): 1.060-1.248, random effects); no significant association was detected for Chinese subjects (pooled OR=1.025, 95% CI: 0.903-1.163, fixed effects). Similarly, GSTT1 null allele carriers exhibited increased colorectal cancer risk in Caucasian populations (pooled OR=1.312, 95% CI: 1.119-1.538, random effects); the association in Chinese subjects was not significant (pooled OR=1.068, 95% CI: 0.788-1.449, random effects). Concerning GSTP1 Ile105Val no significant associations were demonstrated in either race. GSTA1 *A/*B polymorphism was not associated with colorectal cancer risk. GSTM1 and GSTT1 null genotypes confer additional risk for colorectal cancer in Caucasian populations.

Fenestrated and Branched Endografts for the Treatment of Thoracoabdominal Aortic Aneurysms: A Systematic Review

Purpose: To offer a critical review of the current literature on the use of fenestrated and branched stent-grafts in patients with thoracoabdominal aortic aneurysms (TAAA). Methods: A thorough search of the English-language literature published between January 2000 and September 2009 identified reports of endovascular procedures using fenestrated and/or branched endografts as the intended repair strategy in patients with TAAA. Studies were selected based on specific inclusion criteria: (1) >3 high-risk patients with preoperative diagnosis of TAAA, (2) the intended treatment strategy was an endovascular repair using a fenestrated or branched endograft or both, and (3) patient demographics and outcome data (technical success rate, 30-day mortality, and follow-up length) were clearly stated. From 47 articles initially identified, 7 studies were included in the statistical analysis encompassing 155 patients (mean age 74.4 years, range 41–86) with TAAA averaging 69.2 mm in diameter. The mean follow-up was 11.8 months, and the majority of patients had Crawford type IV aneurysms. Outcome measures of eligible studies were tabulated and then analyzed cumulatively. Results: Technical success was achieved in 94.2% (n = 146) of the 155 patients. Twenty-three (18.4%) primary endoleaks were reported. The 30-day mortality was 7.1% (n = 11), while the 1-year survival rate was 82.6% (n = 128). Three (1.9%) patients developed permanent paraplegia and 2 (1.3%) developed permanent paraparesis; renal failure was reported in 9 (5.8%). Overall follow-up mortality was 16.1% (n=25). Conclusion: Endovascular treatment with fenestrated or/and branched stent-grafts is a new therapeutic option with encouraging results for patients considered unfit for conventional open repair. However, prolonged follow-up studies are needed in order to draw robust conclusions.

Annual Financial Impact of Well-Differentiated Thyroid Cancer Care in the United States

Well‐differentiated thyroid cancer (WDTC) is a prevalent disease, which is increasing in incidence faster than any other cancer. Substantial direct medical care costs are related to the diagnosis and treatment of newly diagnosed patients as well as the ongoing surveillance of patients who have a long life expectancy. Prior analyses of the aggregate health care costs attributable to WDTC in the United States have not been reported.

PTH/PTHrP Receptor Mediates Cachexia in Models of Kidney Failure and Cancer

Cachexia is a wasting syndrome associated with elevated basal energy expenditure and loss of adipose and muscle tissues. It accompanies many chronic diseases including renal failure and cancer and is an important risk factor for mortality. Our recent work demonstrated that tumor-derived PTHrP drives adipose tissue browning and cachexia. Here, we show that PTH is involved in stimulating a thermogenic gene program in 5/6 nephrectomized mice that suffer from cachexia. Fat-specific knockout of PTHR blocked adipose browning and wasting. Surprisingly, loss of PTHR in fat tissue also preserved muscle mass and improved muscle strength. Similarly, PTHR knockout mice were resistant to cachexia driven by tumors. Our results demonstrate that PTHrP and PTH mediate wasting through a common mechanism involving PTHR, and there exists an unexpected crosstalk mechanism between wasting of fat tissue and skeletal muscle. Targeting the PTH/PTHrP pathway may have therapeutic uses in humans with cachexia.

Endometriosis, in vitro fertilisation and the risk of gynaecological malignancies, including ovarian and breast cancer.

There is evidence that endometriosis as well as drugs used in the process of in vitro fertilisation appear to associate with increased risk for gynaecological cancer. In this review, we attempt to describe this relationship according to the most recent epidemiologic data and to present the possible mechanisms on the molecular level that could potentially explain this correlation. There are data to support that ovarian endometriosis could have the potential for malignant transformation. Epidemiologic and genetic studies support this notion. It seems that endometriosis is associated with specific types of ovarian cancer (endometrioid and clear cell). There is no clear association between endometriosis and breast or endometrial cancer. More studies are needed to establish the risk factors that may lead to malignant transformation of this condition and to identify predisposed individuals who may require closer surveillance. Currently, there is no proven relationship between any type of gynaecological cancer and drugs used for infertility treatment. In principle, infertile women have increased risk for gynaecologic malignancies. Nulligravidas who received treatment are at increased risk for malignancy compared with women who had conceived after treatment. There is limited evidence that clomiphene citrate use for more than six cycles or 900mg or treatment of women over the age of 40 could increase their risk for ovarian and breast cancer. More studies with the appropriate statistical power and follow-up time are required to evaluate accurately the long-term effects of these drugs and procedures.

Intestinal alkaline phosphatase promotes gut bacterial growth by reducing the concentration of luminal nucleotide triphosphates

The intestinal microbiota plays a pivotal role in maintaining human health and well-being. Previously, we have shown that mice deficient in the brush-border enzyme intestinal alkaline phosphatase (IAP) suffer from dysbiosis and that oral IAP supplementation normalizes the gut flora. Here we aimed to decipher the molecular mechanism by which IAP promotes bacterial growth. We used an isolated mouse intestinal loop model to directly examine the effect of exogenous IAP on the growth of specific intestinal bacterial species. We studied the effects of various IAP targets on the growth of stool aerobic and anaerobic bacteria as well as on a few specific gut organisms. We determined the effects of ATP and other nucleotides on bacterial growth. Furthermore, we examined the effects of IAP on reversing the inhibitory effects of nucleotides on bacterial growth. We have confirmed that local IAP bioactivity creates a luminal environment that promotes the growth of a wide range of commensal organisms. IAP promotes the growth of stool aerobic and anaerobic bacteria and appears to exert its growth promoting effects by inactivating (dephosphorylating) luminal ATP and other luminal nucleotide triphosphates. We observed that compared with wild-type mice, IAP-knockout mice have more ATP in their luminal contents, and exogenous IAP can reverse the ATP-mediated inhibition of bacterial growth in the isolated intestinal loop. In conclusion, IAP appears to promote the growth of intestinal commensal bacteria by inhibiting the concentration of luminal nucleotide triphosphates.

Hobnail Variant of Papillary Thyroid Carcinoma: An Institutional Case Series and Molecular Profile

BACKGROUND Papillary thyroid carcinoma (PTC) is increasing in incidence while mortality is unchanged. Identifying patients with higher risk of recurrence and death is essential. Case series identify the hobnail variant of PTC (HVPTC), which is characterized by micropapillary architecture, apocrine features, and loss of cellular polarity. Herein, we describe the clinical course, pathologic features, and mutational profile of patients at our institution with HVPTC. METHODS A query into the surgical pathologic database (2009-2012) was performed, and clinicopathologic data were collected on all patients carrying the diagnosis of HVPTC. BRAF(V600E) testing was performed on paraffin-embedded blocks using SNaPshot mutational analysis. RESULTS Twelve patients with HVPTC were identified, with an average age of 54.1±18.8 years. Seven patients (63.6%) were AJCC Stage III or IV at presentation. Tumors were large (3.7±2.0 cm), some were multifocal (33.3%), and frequently with extrathyroidal extension (58.3%), lymphovascular invasion (41.7%), and lymph node metastasis (75%). Forty percent of the patients had concomitant tall cell features (TCF), and two had small foci of undifferentiated (anaplastic) thyroid carcinoma (ATC). Eighty percent of tumors undergoing mutational analysis had the BRAF(V600E) mutation, and the remaining 20% harbored a RET/PTC1 gene rearrangement. No other known thyroid cancer mutations were identified on SNaPshot analysis. At median follow-up of 26 months, four patients had recurrent or persistent disease, one of whom died from the disease one year after surgery. CONCLUSIONS The hobnail variant of PTC has an aggressive behavior, with a high incidence of infiltrative tumors and metastatic disease. Strikingly, all tumors in our series harbored a PTC-associated genetic abnormality, either a BRAF(V600E) mutation (80%) or a RET/PTC1 rearrangement (20%). This histologic variant warrants further study, and patients with this diagnosis should be observed closely for recurrence.