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Gallbladder cancer is a rare, aggressive malignancy that has a poor overall prognosis. Effective treatment consists of early detection and surgical treatment. With the wide spread treatment of gallbladder disease with minimally invasive techniques, the rate of incidental gallbladder cancer has seen an equitable rise along with stage migration towards earlier disease. Although the treatment remains mostly surgical, newer modalities such as regional therapy as well as directed therapy based on molecular medicine has led to improved outcomes in patients with advanced disease. We aim to summarize the management of gallbladder cancer along with the newer developments in this formidable disease process.

Background. Anal canal adenocarcinoma (AA) is an uncommon tumor of the gastrointestinal tract. We seek to provide a detailed description of the incidence, demographics, and outcome of this rare tumor in the United States. Methods. The data on anal canal adenocarcinoma from SEER Program, between 1973–2015, were extracted. We analyzed the incidence rates by demographics and tumor characteristics, followed by analysis of its impact on survival. Results. The incidence of AA increased initially by 4.03% yearly from 1973 to 1985 but had a modest decline of 0.32% annually thereafter. The mean age for diagnosis of AA was 68.12 ± 14.02 years. Males outnumbered females by 54.8 to 45.2%. Tumors were mostly localized on presentation (44.4%) and moderately differentiated (41.1%). Age generally correlated with poor overall cancer survival. However, young patients (age p<0.01). Conclusions. Anal canal adenocarcinoma demonstrated a poor bimodal cancer-free survival in both younger and older patient groups. Surgery significantly improves odds of survival and should be offered to patients amenable to intervention.

Objectives Osteoarthritis (OA) is a common degenerative joint disease with the pathological features of the reduced cartilage cellularity. Celastrol, a compound from Tripterygium wilfordii, exerted therapeutic effects on arthritis, but the potential mechanism remains unclear. Methods Tunicamycin was used to establish a model of OA in vitro, and ACLT surgery model in rats was applied to verify the mechanism. Chondrocytes were isolated from the knee articular cartilage of rabbit. MTT and flow cytometry assay were used to detect cell viability and apoptosis rate. Haematoxylin–eosin staining was used to assess for the histopathological changes. The activity and expression of apoptosis-related factors and ERs (endoplasmic reticulum stress)-related factors were detected by ELISA, WB, PCR and IHC, respectively. Key findings Celastrol exhibited significant enhancement on cell viability and reduced the rate of apoptosis in Tm-exposed chondrocytes. Celastrol reduced enzyme activity and protein expression of caspase-3, caspase-6 and caspase-9, decreased Bip, Atf6, Chop and Xbp-1 expression both at protein and mRNA levels. Celastrol showed a more significant effect on cell apoptosis rate and mRNA expression in the combination with 4-PBA. Conclusions This study reveals that celastrol may prevent OA by inhibiting the ERs-mediated apoptosis. All these might supply beneficial hints for celastrol on OA treatment.

Background Parasitic leiomyomas are rare extra-uterine tumors that can be seen in patients after myomectomy or morcellation of leiomyomas. Case A 63-year-old woman with a history of abdominal myomectomy 20 years prior presented with worsening abdominal distension and pain for the past eight months. The patient delayed care due to fear of the COVID-19 pandemic and was found to have a 42 cm parasitic leiomyoma attached to the small bowel causing obstruction and perforation. Conclusion Parasitic leiomyomas can cause small bowel obstruction and perforation., Highlights • Parasitic leiomyomas can range in presentation from asymptomatic to sepsis. • Parasitic leiomyomas can cause small bowel obstruction and perforation. • Care should not be delayed in the setting of the COVID-19 pandemic.

Introduction Simultaneous robot assisted colon and liver resections are being performed more frequently at present due to the expanded adoption of the robotic platform for surgical management of metastatic colon cancer. However, this approach has not been studied in detail with only case series available in the literature. The aim of this systematic review was to evaluate the current body of evidence on the feasibility of performing simultaneous robotic colon and liver resections. Methods A systematic review was performed through PubMed to identify relevant articles describing simultaneous colon and liver resections for metastatic colon cancer. Results A total of 28 patients underwent simultaneous resections robotically with an average operative time of 420.3 minutes and average blood loss of 275.6 ml. Postoperative stay was 8.6 days on average with all cases achieving negative surgical margins. Conclusions Robotic simultaneous resection of colorectal cancer with liver metastases is technically feasible and seems oncologically equivalent to open or laparoscopic surgery. Further studies are urgently needed to assess benefits of robotic surgery in the patient population.

Aminopeptidase N (APN) belongs to the aminopeptidase family, which is widely distributed throughout the animal and plant kingdoms. APN is thought to be a very important target for cancer therapy as it is linked to cancer progression and metastasis. However, bestatin (Ubenimex) is the only approved drug that targets various aminopeptidases for the treatment of acute myelocytic leukemia and lymphedema. A compound 3-amino-2-hydroxy-4-phenylbutanoylvalylisoleucine (also known as LYRM03), isolated from a Streptomyces strain HCCB10043, exhibited more potent inhibitory activity than bestatin. In this work, we applied a chemical synthesis strategy to generate LYRM03 to overcome the low yields typically achieved from fermentation. Finally, we explored a suite of experiments to determine the bioactivity of LYRM03 and revealed that the metastasis of MDA-MB-231 cells was significantly restrained with LYRM03 treatment or injection both in vitro and in vivo. Because of its anti-metastasis capacity, further structure modifications of LYRM03 will be of interest for its use alone or in combination as a therapy in cancer.

Background: Genetic factors play an important role in colorectal cancer (CRC) risk, yet the prevalence and spectrum of germline cancer susceptibility gene mutations among unselected Chinese CRC patients is largely undetermined. Methods: We performed next-generation sequencing with a 73-genes panel and analyzed the prevalence and spectrum of germline mutations in 618 unselected Chinese CRC patients. We classified all identified germline alterations for pathogenicity and calculated the frequencies of pathogenic mutations. Clinical characteristics were assessed by age and mutation status. Protein expressions and interactions of MLH1 missense variants were evaluated by western blot and co- immunoprecipitation. Results: Overall, 112 (18.1%) of 618 unselected Chinese CRC patients were found to carry at least one pathogenic or likely pathogenic variant (totaling 97 variants), including 70 (11.3%) Lynch syndrome (LS) mutation carriers and 42 (6.8%) non-LS mutation carriers. LS mutation carriers were significantly younger at CRC diagnosis and were more likely to have right-sided, poorly differentiated, early stage, high-frequency microsatellite instability (MSI-H) or dMMR CRC and a family history of cancer compared with noncarriers. Non-LS mutation carriers were more likely to be proficient mismatch repair (pMMR) than noncarriers (p=0.039). We found four clinical variables (gender, tumor histological stage, cancer stage and mutation status) that showed significant differences between patients younger and older than 50 years old. Higher mutation rates were found in patients under 50 years old (p=0.017). Thirty-three novel variants were discovered and evaluated as pathogenic mutations by our study. Conclusion: Given the high frequency and wide spectrum of mutations, genetic testing with a multigene panel should be considered for all Chinese CRC patients under 50 years old and is also needed to determine whether a gene is associated with CRC susceptibility and to promote clinical translation.

BACKGROUND Studies have shown inconsistent associations of nitrite and nitrate intake with the risk of gastric cancer or its associated mortality. We performed a meta-analysis of observational studies to evaluate the correlation of nitrite and nitrate intake with the risk of gastric cancer. MATERIAL AND METHODS We searched for studies reporting effect estimates and 95% confidence intervals (CIs) of gastric cancer in PubMed, EMBASE, and the Cochrane Library through November 2018. The summary results of the included studies were pooled using a random-effects model. RESULTS Eighteen case-control and 6 prospective cohort studies recruiting 800 321 participants were included in this study. The summary results indicated that the highest (odds ratio [OR], 1.27; 95%CI, 1.03-1.55; P=0.022) or moderate (OR: 1.12; 95%CI, 1.01-1.26; P=0.037) nitrite intake were associated with a higher risk of gastric cancer. However, we noted that high (OR, 0.81; 95%CI, 0.68-0.97; P=0.021) or moderate (OR, 0.86; 95%CI, 0.75-0.99; P=0.036) nitrate intakes were associated with a reduced risk of gastric cancer. These associations differed when stratified by publication year, study design, country, the percentage of male participants, assessment of exposure, adjusted model, and study quality. CONCLUSIONS High or moderate nitrite intake was associated with higher risk of gastric cancer, whereas high or moderate nitrate intake was correlated with lower risk of gastric cancer.

Background: Percutaneous coronary intervention (PCI) has been an effective treatment for acute coronary syndrome (ACS) patients. Acute kidney injury (AKI) is one of the common complications after PCI, which seriously affects the living quality and survival time of patients. The approach followed for the patient with AKI after PCI depends on the clinical context and may vary by resource availability. Summary: This review focuses on the pathophysiologies, influencing factors, and preventive measures of AKI in patients with ACS after PCI. The knowledge may better serve the patients and improve their outcomes. Key Messages: Many studies have been carried out for the definition and standard of AKI in the past few years. Etiologies of AKI after PCI included renal damage of contrast medium and atherosclerotic embolism, cardiac insufficiency and surgical factors on renal function. Basic conditions, treatment modalities, and perioperative changes are major risk factors of AKI. Studies have reported that the prevention of contrast-induced nephropathy, modulating the volume overload, some pharmaceuticals and blood purification treatment are helpful to prevent the occurrence of AKI.

The use of telemedicine for mentoring and proctoring is long-standing, but only in recent years has it been applied to the many specialties in surgery. Despite being relatively new, the concept of telepresence and telesurgery and the new technological advances in robotic surgery have made possible telementoring and teleproctoring in many disciplines including such as e-ICU consultations and advise on how to manage a critically ill patient. This form of telementoring and teleproctoring is probably best known clinically relevant, yet it has been accepted as routine care. Other forms of telementoring and teleproctoring include telemedicine and telepresence applications for trauma, emergency management. In this chapter we will address telementoring, and to a lesser degree teleproctoring in just about all surgical disciplines with exception of gynecology and orthopedics.

With the expected rise in the geriatric patient population, delivery of healthcare for elderly patients will require more resources in the next several decades. The development of cancer is more common in the geriatric population since two-thirds of cancers are typically discovered in the elderly. The elderly often have associated medical comorbidities. Treatment of the geriatric patient population will encompass more personalized approaches based on their functional status. Surgical management of elderly cancer patients is complex. Not only does it require incorporation of multimodality care, the treating physician needs to balance risks and benefits from options available due to patient medical comorbidities leading to posttreatment debilitation and side effect profiles. Furthermore, there are also insufficient studies in the elderly population in terms of long-term oncologic follow-up as many studies frequently exclude the elderly in their study designs. With the development of newer modalities of treatment such as ablative procedures, minimally invasive approaches, and immunotherapy, the selection of treatment methods will need to balance optimal oncologic outcome with expected patient survival.

BACKGROUND Our study aimed to explore the levels of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) in healthy participants, type 2 diabetes mellitus (T2DM) patients, and diabetic peripheral neuropathy (DPN) patients in order to find their effects on DPN. MATERIAL AND METHODS The clinical data of 110 healthy participants (age: 57.3±8.2 year, height: 165.4±5.5 cm, weight: 64.1±7.5 kg), 83 T2DM patients (age: 56.5±7.9 year, height: 164.8±6.2 cm, and weight: 63.6±6.6 kg), and 65 DPN patients (age: 58.2±7.3 year, height: 166.7±6.7 cm, weight: 63.1±5.8 kg) were observed. ELISA was applied to detect serum NGF and BDNF levels. Receiver operating characteristic (ROC) curve analysis was performed to evaluate diagnostic value of serum NGF and BDNF levels in DPN. Logistic regression analysis was performed to analyze risk factors for DPN. RESULTS Serum NGF and BDNF levels decreased most in DPN patients. Subsequently, we determined that serum NGF and BDNF levels were correlated with: the course of disease for patients, fasting C-peptide (FCP), 2-hour postprandial C-peptide level (2-h PCP), glycosylated hemoglobin level (HbAlc), and 24-hour urinary microalbumin excretion (24-h UME). ROC curve analysis identified high sensitivity, specificity, and accuracy of NGF and BDNF levels on DPN. Serum levels of NGF and BDNF, course of disease, 2-h PCP level, and postprandial blood glucose level were determined to be risk factors for DPN. CONCLUSIONS Our study highlights that serum levels of NGF and BDNF might be associated with the occurrence and development of DPN.

TPS10607 Background: Pancreatic adenocarcinoma (PC) has a persistently high mortality as it presents in the advanced stages and has largely not benefited from the genomic and immunotherapeutic revolutions in oncology. Improvements in screening to detect early stage cancers are therefore urgently needed. Screening studies such as those from the International CAPS Consortium have demonstrated improved survivals in hereditary high risk individuals. In the sporadic population, individuals with new-onset diabetes (NOD) or long-standing deteriorating diabetes (DD) are at substantially increased risk of PC in the 12 months following these diagnoses and have been proposed as target populations for screening efforts. This trial will study the benefits of PC screening in the latter populations in a community setting. Methods: Individuals ≥ 50 years of age with either NOD or DD will be eligible. Criteria for NOD (within the past 12 months) include: fasting blood glucose ≥ 126 mg/dL, random blood glucose ≥ 200 mg/dL, or HbA1c ≥ 6.5%, with confirmed prior normal values. For those without prior glycemic values, a HbA1c ≥ 7.0% is required. Transition from pre-diabetes requires an increase in HgA1c of ≥ 0.5%. DD is defined by an increase in HbA1c of ≥ 2% within the past six months that is not associated with medication non-compliance or weight gain. Study participants will undergo every 6 months: evaluation by an APRN, testing for anxiety and depression and blood donation for biobanking purposes. High resolution MRI/MRCP with gadolinium will be performed at study entry and annually for 2 years. Images will be reviewed at a multi-disciplinary tumor board consisting of body-image certified radiologists, interventional gastroenterologists, hepatobiliary surgeons and medical oncologists. MRI results will be classified according to a novel PANC-RADS system. High-risk pancreatic findings will be further interrogated by endoscopic ultrasound (EUS). Study endpoints include detection rate of high-risk lesions, referrals for EUS and surgery and detection of incidental findings leading to unnecessary procedures. Adverse psychological impacts will be assessed through HADS testing. Target accrual: 500 patients within 3 years. Clinical trial information: NCT03937453 .

Inflammation is associated with atrial fibrillation (AF), and peroxisome proliferator-activated receptor-gamma (PPARγ) agonists have anti-inflammatory properties. We tested whether pioglitazone reduced AF recurrence after electrical cardioversion (EC) by modifying systemic inflammation. In this randomized and prospective trial, patients with persistent AF and type 2 diabetes mellitus were randomized into a pioglitazone group (n=48) or a control group (n=49) before EC. Treatment was continued for 3 months or until AF recurred. Serum inflammatory markers [high sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α)] were measured at baseline and follow-up. During the 3-month follow-up, AF recurred in 22 (45.8%) patients of the pioglitazone-treated and 24 (49.0%) patients of the control group (P=0.756). However, the 3 inflammatory markers were significantly lowered with pioglitazone treatment during follow-up. Cox proportional hazards regression models showed that the predictors of recurrence included AF history (relative risk RR 1.002, 95% CI 1.003–1.061, P =0.037) and the left atrial diameter (RR 1.131, 95% CI 1.029–1.242, P = 0.010). In conclusion, while reducing some inflammatory markers, the PPARγ agonist pioglitazone did not affect the recurrence of AF after EC.

Activation of the Akt pathway has been shown to protect the heart from ischaemia/reperfusion (I/R) injury. NEDD4-1 has been shown to positively regulate nuclear trafficking of the activated form of Akt. However, the role of NEDD4-1 in cardiac I/R injury remains to be elucidated. In the present study, Lentiviral vectors were constructed to overexpress or knockdown NEDD4-1 in H9c2 cardiomyocytes subjected to I/R injury or ischemic preconditioning (IPC). The results indicated that NEDD4-1 levels were decreased after I/R and increased after IPC in rat heart tissue and in H9c2 cardiomyocytes. Overexpression of NEDD4-1 activated the Akt pathway and regulated apoptosis-related proteins in H9c2 cardiomyocytes, attenuating SI/R-induced cell apoptosis and caspase 3/7 activities. Furthermore, in vivo overexpression of NEDD4-1 attenuated myocardial apoptosis following myocardial I/R. Our results demonstrated that NEDD4-1 protects the myocardium from I/R induced apoptosis by activating PI3K/Akt signaling.

Lynch syndrome is an autosomal dominant disorder in which one's DNA mismatch repair mechanism is impaired, resulting in an increased risk of developing colon and endometrial cancers, as well as other malignancies. With such an increased risk of colorectal cancer, patients diagnosed with Lynch syndrome should undergo colonoscopy screening every 1–2 years beginning at ages 20 to 25 or two to five years prior to earliest diagnosis of colorectal cancer in their family members. In patients with Lynch syndrome, colorectal cancer usually presents after the fourth decade of life. Few cases have been reported in pediatric patients with early onset colorectal cancer. We report here a 16-year-old patient who presented initially with symptoms characteristic of appendicitis. Following a CT scan suggesting perforated appendicitis, the patient was treated with intravenous antibiotics with a scheduled interval appendectomy three months later. Pathology reports from the interval appendectomy showed that the specimen contained a well-to-moderately differentiated adenocarcinoma. The patient then underwent robot assisted right hemicolectomy as definitive management, which demonstrated that the tumor originated in the cecum with invasion into the submucosa and focally infiltrating the muscularis propria. This case illustrates the need to be cognizant that cancer can present similarly to appendicitis, to be aware of the increasing incidence of colon cancer in younger patients, and to catalyze the acceptability of robotics for minimally invasive surgery. Keywords: Lynch syndrome, Pediatric colon cancer, Robotic colectomy

The volume of a disease treated by a hospital and the quality of care delivered by a hospital have a known proportionate relationship. In the design of a new hospital, or the addition of new clinical services to an existing hospital, one of the central tenets is the ability to provide high-quality care that hopefully is combined with excellent outcomes. There are certain high-risk procedures known to require high-volume multimodality care to produce quality outcomes. Best examples of quality healthcare that are related to volume are high-risk surgical cases such as coronary artery bypass grafting, abdominal aortic aneurysm repair, liver transplantation, esophagectomy, pancreatectomy, and other high-risk oncologic procedures. As a result, when creating or advancing new clinical programs, the need to research the regional patient population and to concentrate on the regional patient needs is crucial to the success of the new hospital. The ability to understand the critical clinical and organizational differences between low- and high-volume hospitals may help implement changes to improve care. Therefore, in this rapidly evolving environment with introduction of new medical and surgical technologies, implementation of electronic medical records, adherence to regulatory measures such as the Joint Commission and the Hospital Quality Alliance public reporting, changing needs of the resident patient population, the building of new clinical programs capable of adapting to the changing environment may be the best solution.

Background: Duodenal gastrointestinal stromal tumors (GISTs) are uncommon, making up only 3–5% of all GISTs. [ 1 , 2 ] Historically, the treatment of choice for duodenal GIST tumors was pancreaticoduodenectomy. [3]Currently, newer surgical intervention methods including local resection via laparotomy, endoscopic resection, and robotic resection are feasible. When doing a local resection, the defect can be closed either primarily or via a Roux-en-Y duodenojejunostomy. [ 3 ] Case presentation: Our patient is a 64-year- old female who presented initially with shortness of breath and was found to have a pulmonary embolism. She then developed upper GI bleeding from anticoagulation and was found to have an ulcerated GIST tumor in the anti-mesenteric border of the third portion of the duodenum (D3). Initial surgery was postponed due to high pulmonary artery pressure from the pulmonary embolism. The patient underwent argon beam coagulation of the bleeding mass to control the bleeding, followed by localized radiotherapy plus Gleevec. Unfortunately, the tumor grew in size during follow-up. The patient was then taken to the OR for a robot-assisted partial duodenal resection (D3) with Roux-en-Y duodenojejunostomy to reconstruct the large defect. She did well post operatively and her final pathology showed a GIST tumor, c-kit and DOG1 positive, 3.5 cm in size, with negative margins. Conclusion: Robotic duodenal resection is a new technique currently being used to resect duodenal GIST tumors. Our video demonstrates the feasibility of D3 partial resection with Roux-en-Y duodenojejunostomy. Duodenal GIST tumor robotic resection offers both decreased morbidity and adequate oncologic outcomes.

Background Although catheter ablation can effectively eliminate atrial fibrillation (AF), the progression of atrial remodeling increases the risk of recurrence. We, therefore, examined the possibility of determining the postablation prognosis of patients with AF using biomarkers of atrial structural remodeling and serum connective tissue growth factor (CTGF) level, and measured its changes after catheter ablation. Methods Subjects were 400 consecutive patients (308 with paroxysmal AF and 92 with nonparoxysmal AF [persistent and long-standing persistent AF]) who underwent catheter ablation for drug-resistant AF. Serum CTGF levels were measured before and 2 months after ablation. Results During the follow-up period of 20.5 ± 6.9 (8–30) months, 61 patients (66%) with nonparoxysmal AF and 95 patients (31%) with paroxysmal AF had recurrence after catheter ablation. Recurrence was associated with higher “baseline CTGF level” in patients with nonparoxysmal AF (936.5 ± 93.1 ng/mL vs 746.3 ± 56.9 ng/mL, P = 0.007) instead of patients with paroxysmal AF (851.6 ± 97.6 ng/mL vs 807.6 ± 99.1 ng/mL, P = 0.921). In nonparoxysmal AF, the recurrence subgroup also had larger left atrial diameter (LAD; 47.1 ± 5.2 mm vs 39.5 ± 4.3 mm, P = 0.035) compared with the nonrecurrence subgroup, and “baseline serum CTGF” and LAD were shown to be independent predictors for postablation recurrence by a Cox proportional hazards model. However, the 2-month postablation elevations of CTGF in patients with recurrence were not significantly different from that in patients without recurrence in nonparoxysmal AF. Conclusion Our finding indicates that “baseline serum CTGF level” is an independent predictor for recurrence in patients with nonparoxysmal AF following catheter ablation. Two-month postablation elevation in CTGF has no association with recurrence.

This work was to determine threshold values for accurate measurements of left ventricular end-diastolic volume (EDV), end-systolic volume (ESV), and ejection fraction (EF) from electrocardiography-gated myocardial perfusion imaging (MPI) in Chinese, and these data were compared with those of echocardiography. A total of 110 patients with definite or suspected coronary artery disease were referred for both gated MPI and echocardiography within 1 week. The EDV, ESV, and EF automatically measured by MyoMetrix and echocardiography were analyzed using Bland–Altman plot correlation and paired t test. The results showed that these parameters quantified by MyoMetrix software were correlated, moderately to highly, with those on echocardiography (ρ, r ≥ 0.75, P

Peritoneal carcinomatosis is a late manifestation of colon cancer. Patients with right sided colon cancer have increased incidence of peritoneal carcinomatosis compared to those with left sided colon cancers. Conventional intravenous chemotherapy has traditionally been less effective in management of colorectal cancer with peritoneal carcinomatosis. Mucinous histology of the primary colon cancer, more commonly seen with right sided colon cancers, is resistant to chemotherapy and showed more favorable response with aggressive cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC). With appropriate preoperative planning, patients that can be treated with complete tumor debulking with CRS have the most favorable outcomes. Development of CRS along with HIPEC in recent years yielded another potential therapy in addition to systemic chemotherapy for management of this disease. Potentially, metastatic peritoneal carcinomatosis can now be treated with CRS and HIPEC in order to achieve long-term survival in carefully selected individuals.

The objective of this study was to study the effect of diabetic hyperglycemia on astrocytes after forebrain ischemia. Streptozotocin (STZ)-injected hyperglycemic and vehicle-injected normoglycemic rats were subjected to 15 minutes of forebrain ischemia. The brains were harvested in sham-operated controls and in animals with 1 and 6 h of recirculation following ischemia. Brain damage was accessed by haematoxylin and eosin (H&E) staining, cleaved caspase-3 immunohistochemistry and TdT-mediated-dUTP nick end labeling (TUNEL). Anti-GFAP antibody was employed to study astrocytes. The results showed that the 15-minute ischemia caused neuronal death after 1 and 6 h of reperfusion as revealed by increased numbers of karyopyknotic cells, edema, TUNEL-positive and active caspase-3-positive cells. Ischemia also activated astrocytes in the cingulated cortex as reflected by astrocyte stomata hypertrophy, elongated dendrites and increases in the number of dendrites, and immunoreactivity of GFAP. Diabetic hyperglycemia further enhanced neuronal death and suppressed ischemia-induced astrocyte activation. Further, diabetes-damaged astrocytes have increased withdrawal of the astrocyte end-foot from the cerebral blood vessel wall. It is concluded that diabetes-induced suppression and damages to astrocytes may contribute to its detrimental effects on recovery from cerebral ischemia.

To evaluate the safety and efficacy of Ex-PRESS (R50) implantation combined with phacoemulsification in primary angle-closure glaucoma (PACG) patients with cataract. Twenty-four eyes of 24 patients with unregulated PACG underwent combined cataract and glaucoma surgery. After phacoemulsification and intraocular lens implantation, the Ex-PRESS (R-50) was inserted into the anterior chamber under a scleral flap. The intraocular pressure (IOP), best corrected visual acuity (BCVA), number of medications, and complications were recorded preoperatively as well as postoperatively on day 7 and at 1, 3, 6, and 12 months. The mean follow-up was 16.4 ± 2.5 months (range 14–21 months) and the mean age of the patients was 64.7 ± 6.8 years (range 56–78 years). The mean IOP was 20.4 ± 5.4 mm Hg preoperatively and decreased to 10.2 ± 2.8, 13.1 ± 2.7, 14.9 ± 4.1, 14.3 ± 3.9, and 14.0 ± 3.6 mm Hg on day 7 and at 1, 3, 6, and 12 months after surgery (all P

Objectives As a parenchymal cell, the photoreceptor is more susceptible to alterations in outer micro-environmental conditions than other cells. In the present study, we aimed to investigate inhibitory effects of zinc oxide (ZnO) nanoparticles on expression of manganese superoxide dismutase (MnSOD) in murine photoreceptor-derived cells. Materials and methods We investigated effects of ZnO nanoparticles on murine photoreceptor cell viability and on expression and activity of MnSOD using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, immunofluorescence analysis, flow cytometry, quantitative real-time PCR and enzyme-linked immunosorbent assay (ELISA). Results ZnO nanoparticles were found to have higher cytotoxic effects in concentration- and time-dependent manners, to elevate intracellular levels of hydrogen peroxide and hydroxyl radicals, and thus to induce overproduction of reactive oxygen species (ROS) and collapse of mitochondrial membrane potential, leading to cell damage. Moreover, ZnO nanoparticles also significantly reduced expression of MnSOD at both the mRNA and protein levels, reduced its activity, and further aggravated oxidative stress-mediated cell damage. Conclusion Overall, ZnO nanoparticle-induced cytotoxicity was associated with elevated levels of oxidative stress due to overproduction of ROS and reduced expression and activity of MnSOD.

Introduction Consistent definitions of congenital syphilis are critical for determining true incidences and setting up targets of elimination. This study aimed to assess the evaluation and management of infants at high risk of congenital syphilis with an antenatal syphilis-screening programme in the Shenzhen SEZ and to develop feasible definitions for the detection of congenital syphilis in China. Methods A retrospective study was conducted of all standardised records of pregnant women with positive syphilis between 2003 and 2007. Infants at high risk of congenital syphilis were evaluated by laboratory tests at birth and longitudinal follow-up. A screening test-positive congenital syphilis case was defined based on a positive 19S-IgM-FTA-ABS result at birth. Assuming that 19S-IgM-FTA-ABS was the gold standard, the sensitivity and specificity of the ascertainment methods were calculated. Results During the study period, 1010 live infants were born to women with active syphilis during pregnancy. 19S-IgM-FTA-ABS detected 42 screening-positive congenital syphilis cases and another nine cases were identified by longitudinal follow-up only. Using 19S-IgM-FTA-ABS as the gold standard, ‘fourfold rapid plasma reagin (RPR) titres’ had the highest sensitivity and specificity compared with the other two follow-up methods. Discussion 19S-IgM-FTA-ABS makes congenital syphilis case classification simpler and faster for newborns. In areas where 19S-IgM-FTA-ABS is not available, comparing newborn RPR titres with maternal titres can be an alternative method. Meanwhile, positive follow-up results act as treatment indicators for older infants. As congenital syphilis definitions vary over the country, the Shenzhen programme suggested a practical model for surveillance and treatment in areas with or without available 19S-IgM-FTA-ABS testing.

Objective The precise cause of congenital sensorineural hearing loss (CSNHL) is unclear in many cases. In a previous study we found that offspring from guinea pigs with autoimmune sensorineural hearing loss (ASNHL) exhibited signs of SNHL. Here we studied women with autoimmune inner ear diseases (AIED) and their offspring. Our aim was to determine if autoimmune damage may be one of the causes of CSNHL. Methods Thirty-eight pregnant women with AIED were recruited. Thirty-three had ASNHL; one with autoimmune delayed endolymphatic hydrops (ADEH) and four with autoimmune Meniere's disease (AIMD). The following were assessed in all women: audiogram, auditory brain stem response (ABR), otoacoustic emission (OAE), vestibular function test and presence of inner ear antigens. The following were assessed in offspring from these women: OAE, ABR and presence of inner ear antigens. Results Five of the 38 children born to women with AIED had SNHL (an incidence much higher than normal). OAEs were not inducible in these children shortly after birth or within 46–100 days after birth. Abnormal ABR findings were apparent in these five children and inner ear antigens were detected in three of the five children (the mother's of these children were also positive for inner ear antigens). Conclusions These preliminary findings suggest that the prevalence of congenital ASNHL may be increased in offspring born to women with AIED.

In this study, we have fabricated the functionalized nickel nanoparticles and investigated their effects on cellular uptake of quercetin in leukemia K562 cancer cells by using electrochemical assay. The results indicate that nickel nanoparticles could efficiently enhance the quercetin uptake and increase the intracellular accumulation in cancer cells, implying the great potential of functionalized nickel nanoparticles in target cancer therapy.

MicroRNAs are endogenous short chain nucleotide RNAs that regulate gene function by direct binding of target mRNAs. In this study, we investigated the effects of microRNA-206 (miR-206) on the development of gastric cancer. miR-206 was first confirmed to be downregulated in gastric cancer specimens. Conversely, upregulation of c-Met was confirmed in tissue samples of human gastric cancer, with its level inversely correlated with miR-206 expression. Introduction of miR-206 inhibited cellular proliferation by inducing G1 cell cycle arrest, as well as migration and invasion. Moreover, important proliferation and/or migration related molecules such as c-Met, CDK4, p-Rb, p-Akt and p-ERK were confirmed to be downregulated by Western blot analysis. Targeting of c-Met also directly affected AGS cell proliferation, migration and invasion. In vivo, miR-206 expressing tumor cells also displayed growth delay in comparison to unaffected tumor cells. Our results demonstrated that miR-206 suppressed c-Met expression in gastric cancer and could function as a potent tumor suppressor in c-Met overexpressing tumors. Inhibition of miR-206 function could contribute to aberrant cell proliferation and migration, leading to gastric cancer development.

Oxidative stress contributes to the formation of cataracts. The leucine rich repeat containing G protein-coupled receptor 4 (LGR4, also known as GPR48), is important in many developmental processes. Since deletion of Lgr4 has previously been shown to lead to cataract formation in mice, we sought to determine the specific role that Lgr4 plays in the formation of cataracts. Initially, the lens opacities of Lgr4(-/-) mice at different ages without ocular anterior segment dysgenesis (ASD) were evaluated with slit-lamp biomicroscopy. Lenses from both Lgr4(-/-) and wild-type mice were subjected to oxidation induced protein denaturation to assess the ability of the lens to withstand oxidation. The expression of antioxidant enzymes was evaluated with real-time quantitative PCR. Phenotypically, Lgr4(-/-) mice showed earlier onset of lens opacification and higher incidence of cataract formation compared with wild-type mice of similar age. In addition, Lgr4(-/-) mice demonstrated increased sensitivity to environmental oxidative damage, as evidenced by altered protein expression. Real-time quantitative PCR showed that two prominent antioxidant defense enzymes, catalase (CAT) and superoxidase dismutase-1 (SOD1), were significantly decreased in the lens epithelial cells of Lgr4(-/-) mice. Our results suggest that the deletion of Lgr4 can lead to premature cataract formation, as well as progressive deterioration with aging. Oxidative stress and altered expression of several antioxidant defense enzymes contribute to the formation of cataracts.

Background Hyperglycemia exacerbates brain damage caused by cerebral ischemia. Neuroinflammation may play a role in mediating such enhanced damage. The objectives of this study were to examine the mRNA and protein levels and cell type distribution of ICAM-1 after cerebral ischemia in normo-and diabetic hyperglycemic rats. Results Compared to normoglycemic ischemia animals, diabetes aggravated neuronal death, decreased Nissl body staining, and increased ICAM-1 mRNA and protein levels in the frontal cortex. The increased ICAM-1 was located not only in vascular endothelial cells but also in cortical neurons. Conclusions Our results suggest that exacerbated neuro-inflammation in the brain may mediate the detrimental effects of diabetes on the ischemic brain.

Background Stanniocalcin-1 (STC1) and stanniocalcin-2 (STC2) are secreted glycoprotein hormones involved in various types of human malignancies. The roles of STC1 and STC2 in laryngeal squamous cell carcinoma (LSCC) remain unknown. We investigated correlations between STC1 and STC2 expression and clinicopathological or prognostic factors in LSCC. Methods Pre-surgical peripheral blood samples were collected between 2012 and 2013 from 62 patients with LSCC. Quantitative RT-PCR analysis was performed to examine mRNA levels of STC1 and STC2. Immunohistochemistry was performed to retrospectively analyze 90 paraffin-embedded LSCC tissue samples, which were obtained from patients who received surgery between 2006 and 2009. These patients did not have histories of treatment or malignancies. Univariate analysis of patient survival was performed by the Kaplan–Meier method. Multivariate analyses were performed with the Cox proportional hazards model. Results The relative mRNA levels of STC1 and STC2 in peripheral blood were significantly greater in LSCC patients than those of healthy volunteers (both P

Background and Objectives Vaccination with cytokine gene-modified tumor cells augments the immune response against established tumors and protects against tumor challenges. In this study, we investigated the vaccine potential of GM-CSF–transduced MCA106 fibrosarcoma (MCA-GMCSF) cells in the C57BL/6 (B6) murine hepatic metastasis model. Methods Experimental mice received one to three weekly vaccines (subcutaneous/intramuscular, s.c./i.m.) of irradiated, parental, or GM-CSF–transduced MCA106 tumor cells. One week after the last immunization, hepatic metastases were established through the intrasplenic injection of live MCA106 parental (MCA106P) tumor cells. The animals were then sacrificed 3–4 weeks after surgery for evaluation of hepatic tumor burden. Results Based on in vivo experiments, both GM-CSF–modified and parental MCA106 tumor cell vaccines induced strong protection against hepatic tumor growth with grossly visible tumors rarely identified. This protection was evident even at a single vaccine dose of as low as 1 × 105 irradiated cells. Unimmunized control mice, on the other hand, consistently developed substantial hepatic tumors. Cytotoxicity assays on splenocytes (cultured in vitro for 4–5 days) showed that both groups of vaccinated mice developed strong tumor-specific cytotoxic T-lymphocyte (CTL) responses. Immunohistochemical analysis of injection sites showed infiltration of dendritic cells (DCs) and macrophages into subcutaneously injected MCA-GMCSF cells. Mostly macrophages, however, were seen at the injection site of MCA106P cells. Furthermore, the MCA106P cells expressed high levels of MHC class I antigens and the level of expression was not significantly altered by transduction with the GM-CSF gene. The high expression of MHC class I antigens probably contributed to the strong immunogenicity of the MCA106P cell vaccine. Conclusions This study demonstrates that MCA106 parental cells are as effective as the GM-CSF–transduced cells in suppressing the growth of hepatic metastases. The cellular immune responses induced by these two vaccines, however, are probably mediated by different subsets of host effector cells. These results have important implications for the use of GM-CSF–transduced cell vaccines in the immunotherapy of tumors that have the propensity to metastasize through the lymphatic channels and the circulatory system. J. Surg. Oncol. 1999;71:36–45. © 1999 Wiley-Liss, Inc.

Objectives. We aimed to investigate the impact of intravascular ultrasound (IVUS)-guided stent implantation on the 6-month restenosis rate, which has not yet been fully established in randomized trials.Background. The 6-month angiographic restenosis rate was compared in patients with symptomatic ischemic heart disease who were randomly allocated to angioplasty and stent deployment, with versus without IVUS guidance.Methods. After successful stent implantation, patients were randomized into two groups: Group A had no further dilation, and Group B had additional balloon dilation until achievement of IVUS criterion for stent expansion. The study group consisted of 164 patients, assuming a 50% reduction of the restenosis rate in Group B (15% vs. 30%) (alpha = 10%, beta = 20%).Results. We enrolled 155 patients. Overdilation was carried out in 31 (39%) of 79 Group B patients, with the IVUS criterion being achieved in 63 (80%) of 79. No significant difference was observed in the minimal luminal diameter (MLD), but the stent lumen cross-sectional area (CSA) was significantly larger in Group B (mean ± SD) (7.16 ± 2.48 vs. 7.95 ± 2.21 mm2, p = 0.04). At 6 months, there was no significant difference in the restenosis rate, (28.8% [21 of 73] in Group A vs. 22.5% [16 of 71] in Group B, p = 0.25), but according to the observed difference in the restenosis rate, the power of the study was only 40%. The difference in MLD was also nonsignificant (1.60 ± 0.65 mm in Group A vs. 1.70 ± 0.64 mm in Group B, p = 0.20), whereas the lumen CSA was 20% larger in the IVUS-guided group (4.47 ± 2.59 vs. 5.36 ± 2.81 mm2, p = 0.03). Lumen CSA was the only predictor of restenosis by multivariate logistic regression analysis.Conclusions. A nonsignificant 6.3% absolute reduction in the restenosis rate and a nonsignificant difference in MLD were observed in this study. Nonetheless, we still cannot rule out a beneficial effect of IVUS guidance, although this may have gone undetected owing to a lack of statistical power. A significant increase was observed in immediate and 6-month lumen size, as detected by IVUS, indicating that ultrasound guidance in stent deployment may be beneficial.

Recent studies have identified a class of small non-coding RNA molecules, named microRNA (miRNA), that is dysregulated in malignant brain glioblastoma. Substantial data have indicated that miRNA-16 (miR-16) plays a significant role in tumors of various origins. This miRNA has been linked to various aspects of carcinogenesis, including cell apoptosis and migration. However, the molecular functions of miR-16 in gliomagenesis are largely unknown. We have shown that the expression of miR-16 in human brain glioma tissues was lower than in non-cancerous brain tissues, and that the expression of miR-16 decreased with increasing degrees of malignancy. Our data suggest that the expression of miR-16 and nuclear factor (NF)-κB1 was negatively correlated with glioma levels. MicroRNA-16 decreased glioma malignancy by downregulating NF-κB1 and MMP9, and led to suppressed invasiveness of human glioma cell lines SHG44, U87, and U373. Our results also indicated that upregulation of miR-16 promoted apoptosis by suppressing BCL2 expression. Finally, the upregulation of miR-16 in a nude mice model of human glioma resulted in significant suppression of glioma growth and invasiveness. Taken together, our experiments have validated the important role of miR-16 as a tumor suppressor gene in glioma growth and invasiveness, and revealed a novel mechanism of miR-16-mediated regulation in glioma growth and invasiveness through inhibition of BCL2 and the NF-κB1/MMP-9 signaling pathway. Therefore, our experiments suggest the possible future use of miR-16 as a therapeutic target in gliomas.

Purpose MicroRNA-124a (miR-124a), an abundant microRNA in the central neuron system, has been linked to tumor progression. Here, we investigated the role of miR-124a in uveal melanoma development. Methods Expression of miR-124a in uveal melanoma cells was examined using real time RT-PCR. The effect of miR-124a on cell proliferation, migration, and invasion was analyzed using MTS assay, flow cytometry, and transwell experiments. The ability of miR-124a to repress tumor growth was tested in vivo. Target genes of miR-124a were first predicted by bioinformatics, confirmed using a luciferase assay, and their expression determined by Western blotting. DNA methylation and histone modification of miR-124a was analyzed by methylation-specific PCR and ChIP assay. Finally, epigenetic drugs were used to alter the expression of miR-124a. Results miR-124a expression was downregulated in both uveal melanoma cells and clinical specimens. Transient transfection of miR-124a into uveal melanoma cells inhibited cell growth, migration, and invasion. Moreover, introduction of miR-124a suppressed in vivo growth of tumor. Potential targets of miR-124a were found to include CDK4, CDK6, cyclin D2, and EZH2. Knockdown of EZH2 by siRNA resulted in inhibition of uveal melanoma cell migration and invasion. In addition, miR-124a expression was found to be regulated via epigenetic mechanisms, with its expression restored when cells were treated with a DNA hypomethylating agent, 5-aza-2'-deoxycytidine, and a histone deacetylase inhibitor, trichostatin A. Conclusions Our results demonstrated that miR-124a could function as a potent tumor suppressor by regulation of multiple targets, and was epigenetically silenced in the development of uveal melanoma.

PURPOSE To describe prevalence and associations of anisometropia in children. METHODS The cross-sectional school-based study included children aged 4 to 18 years. RESULTS The study included 6025 (94.7%) of 6364 eligible children. Mean refractive anisometropia was 0.37 ± 0.57 diopters (median: 0.25 diopters; range: 0-7.88 diopters; prevalence [≥1 diopter]: 7.0% ± 0.3%). In multivariate analysis (regression coefficient r: 0.66), higher refractive anisometropia was associated with older age (P < 0.001; β: 0.07; B: 0.01; 95% CI: 0.01-0.02), higher maternal education level (P < 0.001; β: 0.04; B: 0.02; 95% CI: 0.01-0.03), more total time spent indoors reading or writing (P = 0.001; β: 0.04; B: 0.01; 95% CI: 0.01-0.02), larger intereye difference in axial length (P < 0.001; β: 0.57; B: 1.20; 95% CI: 1.15-1.24), shorter mean axial length of both eyes (P = 0.03; β: -0.03; B: -0.02; 95% CI: -0.03 to -0.001), larger intereye difference in best corrected visual acuity (BCVA) (P < 0.001; β: 0.14; B: 1.83; 95% CI: 1.54-2.12), and lower stereoacuity (P < 0.001; β: 0.08; B: 0.31; 95% CI: 0.22-0.39). Refractive anisometropia showed a U-shaped correlation with refractive error. Higher anisomyopia was associated (r: 0.57) with older age (P = 0.001; β: 0.05; B: 0.006; 95% CI: 0.002-0.009), higher level of paternal education (P = 0.001; β: 0.01; B: 0.01; 95% CI: 0.01-0.02), more total time spent indoors reading or writing (P = 0.01; β: 0.03; B: 0.01; 95% CI: 0.00-0.01), larger intereye difference in axial length (P < 0.001; β: 0.22; B: 0.26; 95% CI: 0.23-0.29), greater myopic refractive error (P < 0.001; β: -0.46; B: -0.07; 95% CI: -0.08 to -0.07), and lower corneal astigmatism (P < 0.001; β: -0.10; B: -0.06; 95% CI: -0.08 to -0.05). In the same multivariate model, hyperopic anisometropia was not significantly associated with time spent indoors with reading (P = 0.18). Cylindrical anisometropia (mean: 0.30 ± 0.32 diopters; prevalence [≥1 diopter]: 3.7% ± 0.2%) increased with higher refractive anisometropia (P < 0.001; β: 0.16; B: 0.09; 95% CI: 0.08-0.11), greater myopic refractive error (P < 0.001; β: -0.06; B: -0.01; 95% CI: -0.01 to -0.01), higher corneal astigmatism (P < 0.001; β: -0.22; B: -0.15; 95% CI: -0.17 to -0.13), and lower mean BCVA (P < 0.001; β: 0.11; B: 0.90; 95% CI: 0.68-1.17). CONCLUSIONS In 4- to 18-year-old children, refractive anisometropia and anisomyopia increased with systemic parameters such as age, parental education level, and lifestyle of the children, for example, more time spent indoors reading or writing. In contrast, hyperopic anisometropia and cylindrical anisometropia were not related with lifestyle parameters.

Gallbladder cancer (GBC), although considered as a relatively rare malignancy, is the most common neoplasm of the biliary tract system. The late diagnosis and abysmal prognosis present challenges to treatment. The overall 5-year survival rate for metastatic GBC patients is extremely low. BRCA1 and BRCA2 are the breast cancer susceptibility genes and their mutation carriers are at a high risk for cancer development, both in men and women. Olaparib, an oral poly ADP-ribose polymerase inhibitor, has been approved by the Food and Drug Administration and the European Commission for the treatment of ovarian cancer with any BRCA1/2 mutations. The first case of a BRCA1-mutated GBC patient who responded to olaparib treatment is reported here.

MicroRNAs (miRNAs) are endogenous small non-coding RNAs that play central roles in diverse pathological processes. In this study, we investigated the effect of microRNA-182 (miR-182) on the development of posterior uveal melanomas. Initially, we demonstrated that miR-182 expression was dependent on p53 induction in uveal melanoma cells. Interestingly, transient transfection of miR-182 into cultured uveal melanoma cells led to a significant decrease in cell growth, migration, and invasiveness. Cells transfected with miR-182 demonstrated cell cycle G1 arrest and increased apoptotic activity. Using bioinformatics, we identified three potential targets of miR-182, namely MITF, BCL2 and cyclin D2. miR-182 was shown to have activity on mRNA expression by targeting the 3′ untranslated region of MITF, BCL2 and cyclin D2. Subsequent Western blot analysis confirmed the downregulation of MITF, BCL2 and cyclin D2 protein expression. The expression of oncogene c-Met and its downstream Akt and ERK1/2 pathways was also downregulated by miR-182. Concordant with the findings that miR-182 was decreased in uveal melanoma tissue samples, overexpression of miR-182 also suppressed the in vivo growth of uveal melanoma cells. Our results demonstrated that miR-182, a p53 dependent miRNA, suppressed the expression of MITF, BCL2, cyclin D2 and functioned as a potent tumor suppressor in uveal melanoma cells.

Cystic fibrosis (CF) is the most common life-limiting recessive genetic disease among Caucasians caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) with over 95% male patients infertile. However, whether CFTR mutations could affect spermatogenesis and result in azoospermia remains an open question. Here we report compromised spermatogenesis, with significantly reduced testicular weight and sperm count, and decreased cAMP-responsive element binding protein (CREB) expression in the testes of CFTR knockout mice. The involvement of CFTR in HCO(3) (-) transport and the expression of the HCO(3) (-) sensor, soluble adenylyl cyclase (sAC), are demonstrated for the first time in the primary culture of rat Sertoli cells. Inhibition of CFTR or depletion of HCO(3) (-) could reduce FSH-stimulated, sAC-dependent cAMP production and phosphorylation of CREB, the key transcription factor in spermatogenesis. Decreased CFTR and CREB expression are also observed in human testes with azoospermia. The present study reveals a previously undefined role of CFTR and sAC in regulating the cAMP-CREB signaling pathway in Sertoli cells, defect of which may result in impaired spermatogenesis and azoospermia. Altered CFTR-sAC-cAMP-CREB functional loop may also underline the pathogenesis of various CF-related diseases.

Purpose MicroRNAs (miRNAs) can contribute to tumorigenesis by acting as either oncogenes or tumor suppressor genes. The authors' previous studies on miR-34a showed that miRNA can influence the growth of uveal melanoma cells. In this study, they investigated the role of miR-137 in the pathogenesis of uveal melanoma. Methods Real-time RT-PCR was used to screen the expression levels of miR-137 in uveal melanocytes and uveal melanoma cell lines. Cell proliferation was examined by MTS assay and cell cycle was analyzed by flow cytometry. The target genes of miR-137 were predicted by bioinformatics and confirmed using a luciferase reporter assay. The expression of MITF, CDK6, and cell cycle regulatory proteins was determined by Western blot analysis. The ability to increase miR-137 expression by epigenetic drugs was tested using real-time RT-PCR. Results miR-137 expression was lower in uveal melanoma cell lines than in uveal melanocytes. Ectopic transfection of miR-137 into uveal melanoma cells induced G1 cell cycle arrest, leading to a significant decrease in cell growth. Overexpression of miR-137 downregulated MITF, a transcription factor with oncogenic activity. Moreover, the introduction of miR-137 downregulated the oncogenic tyrosine kinase protein receptor c-Met and cell cycle-related proteins, including CDK6. One avenue to increase the expression levels of miR-137 was through treatment with a DNA hypomethylating agent, 5-aza-2'-deoxycytidine, and a histone deacetylase inhibitor, trichostatin A. Conclusions The results showed that miR-137 can act as a tumor suppressor in uveal melanoma cell proliferation through downregulation of the targets MITF and CDK6. miR-137 may be epigenetically silenced during uveal melanoma tumorigenesis.

Neuroendocrine tumors (NETs) of the gastrointestinal tract have a propensity for hepatic metastases. Surgical resection for hepatic metastases remains the gold standard for long-term survival, but many patients present with multifocal tumors, precluding surgery with increasing use of chemoembolization. However, there are few studies examining long-term survival factors. We reviewed our 15-year experience with chemoembolization in 123 patients with unresectable NET liver metastases, whose prognosis was evaluated upon baseline clinical factors. There were 64 males (53%) and 59 females (47%). Average age at presentation was 56 years (range: 14.3-85.5 years). Abdominal pain (44%) was the most common presenting symptom, followed by diarrhea (30%) and weight lost (22%). Patients underwent an average 7.3 cycles of chemoembolization (range 1-32 cycles). Responses: 62% of patients had PR; 24% had stable disease and 14% had tumor progression. Overall 3-, 5- and 10-year survivals were 59, 36 and 20% of patients with a mean follow-up of 3.2 years (range 2 weeks-18.3 years) and mean survival of 3.3 years. Univariate analysis showed that age greater than 60 years had worse outcome (P0.01), as did baseline serum albumin of ≤ 3.5 g/dL and prothrombin time13 s. Location of the primary tumor (P = 0.68), gender (P = 0.4) and serum NET peptide levels did not influence survival. However, multivariate analysis showed that a low baseline serum albumin level was an independent factor for prognosis (P = 0.003). Chemoembolization for unresectable NETs metastatic to liver is useful for tumor size reduction, symptom palliation and can be associated with prolonged survival.

Changing trends of surgical treatment of hilar bile duct cancer: Clinical and experimental perspectives

Dendritic cells (DCs) pulsed with unfractionated tumor cell lysates or defined tumor peptides provide potent vaccines which elicit strong antitumor immunity. In this study, we generated DCs from the 2-h adherent progenitor cells obtained from the peripheral blood of melanoma patients. These DCs were able to capture biotinylated melanoma tumor cell lysates. We examined the efficacy of immunogens composed of DCs loaded either with the melanoma peptide gp100 [amino acids 280–288 (DC/gp100)] or with lysates from melanoma tumor cells (DC/lysates) in inducing cytotoxic T-cells from autologous PBLs of HLA-A2 melanoma patients. After four to five weekly stimulations of bulk PBLs with DC/gp100 or DC/lysates, the cultures were enriched with CD3 + T-cells and exhibited one of three phenotypic and functional patterns: (1) Predominant expression of CD8 + and MHC class I-restricted CTLs which displayed strong lytic activity against melanoma cells and T2 cells loaded with the gp100 peptide, (2) mixed CD4 + /CD8 + phenotype and weak lytic activity, or (3) nonlytic and predominantly CD4 + cultures. Interestingly, T-cell cultures from each patient exhibited similar phenotypes and lytic activities whether the stimulant was DC/gp100 or DC/cell lysates. Our study demonstrates that DCs pulsed with soluble melanoma peptides or cell lysates are capable of inducing CD8 + CTLs from autologous PBLs of some, but not all, melanoma patients. The function and phenotype of the generated T-cell cultures are governed by DCs since both antigens (the gp100 peptide and melanoma lysates), when presented by a given DC preparation, induced similar T-cell cultures. In summary, it may be difficult to predict the nature of the cellular responses elicited by DC/tumor antigen vaccines from patient to patient.

Jejunal diverticula are quite rare. Furthermore, small bowel diverticular disease resulting in enteroliths can lead to complications necessitating surgical intervention. In this manuscript, we report two presentations of jejunal diverticulum with complications from enteroliths followed by a review of the literature. The first case was that of a 79-year-old male who presented with abdominal pain and was found, on computed tomography (CT) scan, to have evidence of intestinal perforation. A laparotomy showed that he had perforated jejunal diverticulitis. The second case was that of an 89-year-old female who presented with recurrent episodes of bowel obstruction. A laparotomy showed that she had an enterolith impacted in her jejunum in the presence of significant diverticular disease. Although a rare entity, familiarity with jejunal diverticular disease, its complications, and its management, should be part of every surgeon’s base of knowledge when considering abdominal pathology.

PURPOSE: MicroRNAs (miRNAs) are endogenously expressed, noncoding, small RNAs that inhibit protein translation through binding to target mRNAs. Recent studies have demonstrated that miRNAs can regulate tumor cell proliferation and migration. MicroRNA-34a (miR-34a), a potential key effector of the p53 tumor-suppressor gene, was studied as a potential tumor suppressor in uveal melanoma. METHODS: Northern blot analysis was performed to detect the expression level of miR-34a in uveal melanoma cells and melanocytes. Subsequently, melanoma cell proliferation and migration were examined by MTS cell proliferation and transwell migration assays, respectively. The target of miR-34a was predicted by bioinformatics and confirmed using a luciferase assay. In addition, expression of c-Met and cell cycle-related proteins was determined by Western blotting and immunofluorescence after the introduction of miR-34a. RESULTS: miR-34a is actively expressed in melanocytes but not in uveal melanoma cells based on Northern blot analysis. Transfection of miR-34a into uveal melanoma cells led to a significant decrease in cell growth and migration. After identification of two putative miR-34a binding sites within the 3' UTR of the human c-Met mRNA, miR-34a was shown to suppress luciferase activity using HEK293 cells with a luciferase reporter construct containing the binding sites. miR-34a was confirmed to downregulate the expression of c-Met protein by Western blotting and immunofluorescence. Furthermore, the introduction of miR-34a downregulated phosphorylated Akt and cell cycle-related proteins. CONCLUSIONS: These results demonstrate that miR-34a acts as a tumor suppressor in uveal melanoma cell proliferation and migration through the downregulation of c-Met .

The epithelial-to-mesenchymal transition (EMT), a process involving the breakdown of cell–cell junctions and loss of epithelial polarity, is closely related to cancer development and metastatic progression. While the cystic fibrosis transmembrane conductance regulator (CFTR), a Cl− and HCO3− conducting anion channel expressed in a wide variety of epithelial cells, has been implicated in the regulation of epithelial polarity, the exact role of CFTR in the pathogenesis of cancer and its possible involvement in EMT process have not been elucidated. Here we report that interfering with CFTR function either by its specific inhibitor or lentiviral miRNA-mediated knockdown mimics TGF-β1-induced EMT and enhances cell migration and invasion in MCF-7. Ectopic overexpression of CFTR in a highly metastatic MDA-231 breast cancer cell line downregulates EMT markers and suppresses cell invasion and migration in vitro, as well as metastasis in vivo. The EMT-suppressing effect of CFTR is found to be associated with its ability to inhibit NFκB targeting urokinase-type plasminogen activator (uPA), known to be involved in the regulation of EMT. More importantly, CFTR expression is found significantly downregulated in primary human breast cancer samples, and is closely associated with poor prognosis in different cohorts of breast cancer patients. Taken together, the present study has demonstrated a previously undefined role of CFTR as an EMT suppressor and its potential as a prognostic indicator in breast cancer.