Nomogram-Based Prognostic Evaluation of Gastric Cancer Patients with Low Counts of Examined Lymph Nodes Outperforms the Predictive Ability of the 7th and 8th Editions of the American Joint Committee on Cancer Staging System.

BACKGROUND: The American Joint Committee on Cancer (AJCC) staging system has limited accuracy in predicting survival of gastric cancer patients with inadequate counts of evaluated lymph nodes (LNs). We therefore aimed to develop a prognostic nomogram suitable for clinical applications in such cases. METHODS: A total of 1511 noncardia gastric cancer patients treated between 1990 and 2010 in the academic surgical center were reviewed to compare the 7th and 8th editions of the AJCC staging system. A nomogram was developed for the prediction of 5-year survival in patients with less than 16 LNs evaluated (n = 546). External validation was performed using datasets derived from the Polish Gastric Cancer Study Group (n = 668) and the SEER database (n = 11,225). RESULTS: The 8th edition of AJCC staging showed better overall discriminatory power compared to the previous version, but no improvement was found for patients with < 16 evaluated LNs. The developed nomogram had better concordance index (0.695) than the former (0.682) or latest (0.680) staging editions, including patients subject to neoadjuvant treatment, and calibration curves showed excellent agreement between the nomogram-predicted and actual survival. High discriminatory power was also demonstrated for both validation cohorts. Subsequently, the nomogram showed the best accuracy for the prediction of 5-year survival through the time-dependent ROC curve analysis in the training and validation cohorts. CONCLUSIONS: A clinically relevant nomogram was built for the prediction of 5-year survival in patients with inadequate numbers of LNs evaluated in surgical specimens. The predictive accuracy of the nomogram was validated in two Western populations.

Pharmacogenomics of selective serotonin reuptake inhibitor treatment for major depressive disorder: genome-wide associations and functional genomics.

A genome-wide association (GWA) study of treatment outcomes (response and remission) of selective serotonin reuptake inhibitors (SSRIs) was conducted using 529 subjects with major depressive disorder. While no SNP associations reached the genome-wide level of significance, 14 SNPs of interest were identified for functional analysis. The rs11144870 SNP in the riboflavin kinase (RFK) gene on chromosome 9 was associated with 8-week treatment response (odds ratio (OR)=0.42, P=1.04 × 10⁻6). The rs915120 SNP in the G protein-coupled receptor kinase 5 (GRK5) gene on chromosome 10 was associated with 8-week remission (OR=0.50, P=1.15 × 10⁻5). Both SNPs were shown to influence transcription by a reporter gene assay and to alter nuclear protein binding using an electrophoretic mobility shift assay. This report represents an example of joining functional genomics with traditional GWA study results derived from a GWA analysis of SSRI treatment outcomes. The goal of this analytical strategy is to provide insights into the potential relevance of biologically plausible observed associations.

Microencapsulated sodium butyrate reduces the frequency of abdominal pain in patients with irritable bowel syndrome.

AIM: Abdominal pain, defaecation disorder and change of bowel habit are the commonest symptoms of irritable bowel syndrome (IBS). The effect of microencapsulated sodium butyrate (MSB) was assessed on the severity of symptoms in patients with IBS. METHOD: Sixty-six patients treated with one of the standard pharmacological therapies for at least 3 months were included in the study. They were randomized to receive MSB as a supplemental treatment to standard therapy or to receiving a placebo. Previous pharmacological therapy was continued throughout the study in both arms. Clinical evaluation was performed at baseline, 4 and 12 weeks. Each assessment was documented by a validated visual analogue score questionnaire measuring the severity of selected clinical symptoms, a closed-end questionnaire measuring the frequency of selected clinical symptoms and a single closed-end question measuring the subjective improvement of symptoms. RESULTS: After 4 weeks there was a significant decrease of pain during defaecation in the MSB group which extended to improvement of urgency and bowel habit at 12 weeks. Reduction of abdominal pain, flatulence and disordered defaecation was not statistically significant. CONCLUSIONS: MSB as a supplemental therapy can reduce the frequency of selected clinical symptoms in patients with IBS, without significant influence on reducing symptom severity.

Using a pharmacogenomic algorithm to guide the treatment of depression.

The objective of this study was to evaluate the potential benefit of utilizing a pharmacogenomic testing report to guide the selection and dosing of psychotropic medications in an outpatient psychiatric practice. The non-randomized, open label, prospective cohort study was conducted from September 2009 to July 2010. In the first cohort, depressed patients were treated without the benefit of pharmacogenomic testing (the unguided group). A DNA sample was obtained from patients in the unguided group, but the results were not shared with either the physicians or patients until the end of the 8-week study period. In the second cohort (the guided group), testing results were provided at the beginning of the 8-week treatment period. Depression ratings were collected at baseline and after 2 weeks, 4 weeks and 8 weeks of treatment using the Quick Inventory of Depressive Symptomatology, Clinician Rated (QIDS-C16) and the 17-item Hamilton Rating Scale for Depression (HAM-D17). Clinician and patient satisfaction was also assessed. The reduction in depressive symptoms achieved within the guided treatment group was greater than the reduction of depressive symptoms in the unguided treatment group using either the QIDS-C16 (P=0.002) or HAM-D17 (P=0.04). We concluded that a rapidly available pharmacogenomic interpretive report provided clinical guidance that was associated with improved clinical outcomes for depressed patients treated in an outpatient psychiatric clinic setting.

Catechol O-methyltransferase pharmacogenomics and selective serotonin reuptake inhibitor response.

We applied a systematic pharmacogenetic approach to investigate the role of genetic variation in the gene encoding catechol O-methyltransferase (COMT) in individual variation in selective serotonin reuptake inhibitor (SSRI) response among depressed patients. In all, 23 single-nucleotide polymorphisms (SNPs) in COMT were genotyped using DNA from the Sequenced Treatment Alternatives to Relieve Depression (STAR(*)D) study (N=1914). One SNP, rs13306278, located in the distal promoter region of COMT, showed significant association with remission in White non-Hispanic (WNH) subjects (P=0.038). Electromobility shift assay for rs13306278 showed alternation in the ability of the variant sequence to bind nuclear proteins. A replication study was performed using samples from the Mayo Clinic Pharmacogenetics Research Network Citalopram/Escitalopram Pharmacogenomic study (N=422) that demonstrated a similar trend for association. Our findings suggest that novel genetic markers in the COMT distal promoter may influence SSRI response phenotypes.

Pouchitis may increase the risk of dysplasia after restorative proctocolectomy in patients with ulcerative colitis.

AIM: Dysplasia of the pouch mucosa after restorative proctocolectomy is rare. The aim of this study was to establish whether there is a correlation between pouchitis and dysplasia. METHOD: A group of 276 patients treated for ulcerative colitis by restorative proctocolectomy between 1984 and 2009 was analysed. The presence or absence of pouchitis and dysplasia within the pouch was evaluated. RESULTS: Inflammation was diagnosed in 66 (23.9%) patients, low-grade dysplasia in five (1.8%), high-grade dysplasia in three (1.1%), and cancer in one patient (0.4%). The prevalence of low-grade dysplasia was significantly higher in patients with inflammation than in those without (P < 0.04). High-grade dysplasia was significantly more frequent in pouchitis than in non-inflamed pouches (P < 0.01). Logistic regression analysis suggested that the occurrence of mucosal inflammation increased the risk of low grade dysplasia. CONCLUSION: Patients with chronic pouchitis are at risk of dysplasia and require surveillance of the pouch.

Glycine and a glycine dehydrogenase (GLDC) SNP as citalopram/escitalopram response biomarkers in depression: pharmacometabolomics-informed pharmacogenomics.

Major depressive disorder (MDD) is a common psychiatric disease. Selective serotonin reuptake inhibitors (SSRIs) are an important class of drugs used in the treatment of MDD. However, many patients do not respond adequately to SSRI therapy. We used a pharmacometabolomics-informed pharmacogenomic research strategy to identify citalopram/escitalopram treatment outcome biomarkers. Metabolomic assay of plasma samples from 20 escitalopram remitters and 20 nonremitters showed that glycine was negatively associated with treatment outcome (P = 0.0054). This observation was pursued by genotyping tag single-nucleotide polymorphisms (SNPs) for genes encoding glycine synthesis and degradation enzymes, using 529 DNA samples from SSRI-treated MDD patients. The rs10975641 SNP in the glycine dehydrogenase (GLDC) gene was associated with treatment outcome phenotypes. Genotyping for rs10975641 was carried out in 1,245 MDD patients in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, and its presence was significant (P = 0.02) in DNA taken from these patients. These results highlight a possible role for glycine in SSRI response and illustrate the use of pharmacometabolomics to "inform" pharmacogenomics.

Implications of overweight in gastric cancer: A multicenter study in a Western patient population.

AIMS: The purpose of this study was to evaluate the effects of overweight on surgical and long-term outcomes in a Western population of patients with gastric cancer (GC). METHODS: An electronic database of all patients with resectable GC treated between 1986 and 1998 at seven university surgical centres cooperating in the Polish Gastric Cancer Study Group was reviewed. Overweight was defined as a body mass index (BMI) of 25 kg/m(2) or higher. RESULTS: Four hundred and ninety-two of 1992 (25%) patients were overweight. Postoperatively, higher BMI was associated with higher rates of cardiopulmonary complications (16% vs 12%, P = 0.001) and intra-abdominal abscess (6.9% vs 2.9%, P < 0.001). However, other complications and mortality rates were unaffected. The median disease-specific survival of overweight patients was significantly higher (36.7 months, 95% confidence interval (CI) 29.0-44.4) than those with BMI<25 kg/m(2) (25.7 months, 95%CI 23.2-28.1; P = 0.003). These differences were due to the lower frequencies of patients with T3 and T4 tumours, metastatic lymph nodes, distant metastases, and non-curative resections. A Cox proportional hazards model identified age, depth of infiltration, lymph node metastases, distant metastases, and residual tumour category as the independent prognostic factors. CONCLUSIONS: Overweight is not the independent prognostic factor for long-term survival in a Western-type population of GC.

Adjuvant chemotherapy with etoposide, adriamycin and cisplatin compared with surgery alone in the treatment of gastric cancer: a phase III randomized, multicenter, clinical trial.

OBJECTIVE: The aim of this study was to evaluate the efficacy of adjuvant chemotherapy with etoposide, Adriamycin and cisplatin (EAP) after potentially curative resections for gastric cancer. METHODS: After surgery, patients were randomly assigned to the EAP or control arm. Chemotherapy included 3 courses, administered every 28 days. Each cycle consisted of doxorubicin (20 mg/m(2)) on days 1 and 7, cisplatin (40 mg/m(2)) on days 2 and 8, and etoposide (120 mg/m(2)) on days 4, 5, and 6. RESULTS: Of 309 eligible patients, 141 were allocated to chemotherapy and 154 to the supportive care group. Four (2.8%) treatment-related deaths were recorded, including 3 due to septic complications of myelosuppression and 1 due to cardiocirculatory failure. Grade 3 or 4 toxicities were found in 17 (22%) patients. According to the intention-to-treat analysis, the median survival was 41.3 months (95% confidence interval, 24.5-58.2) and 35.9 months (95% confidence interval, 25.5-46.3) in the chemotherapy and control group, respectively (p = 0.398). Subgroup analysis revealed survival benefit from chemotherapy in patients with tumors infiltrating the serosa and in those with 7-15 metastatic lymph nodes. CONCLUSION: Three cycles of EAP regimen postoperatively offer no survival advantage in gastric cancer patients.

SLC6A4 variation and citalopram response.

The influence of genetic variations in SLC6A4 (serotonin transporter gene) on citalopram treatment of depression using the Sequenced Treatment to Relieve Depression (STAR*D) sample was assessed. Of primary interest were three previously studied polymorphisms: 1) the VNTR variation of the second intron, 2) the indel promoter polymorphism (5HTTLPR or SERT), and 3) a single nucleotide polymorphism (SNP) rs25531. Additionally, SLC6A4 was resequenced to identify new SNPs for exploratory analyses. DNA from 1914 subjects in the STAR*D study were genotyped for the intron 2 VNTR region, the indel promoter polymorphism, and rs25531. Associations of these variants with remission of depressive symptoms were evaluated following citalopram treatment. In white non-Hispanic subjects, variations in the intron 2 VNTR (point-wise P = 0.041) and the indel promoter polymorphism (point-wise P = 0.039) were associated with remission following treatment with citalopram. The haplotype composed of the three candidate loci was also associated with remission, with a global p-value of 0.040 and a maximum statistic simulation p-value of 0.0031 for the S-a-12 haplotype, under a dominant model. One SNP identified through re-sequencing the SLC6A4 gene, Intron7-83-TC, showed point-wise evidence of association, which did not remain significant after correction for the number of SNPs evaluated in this exploratory analysis. No associations between these SLC6A4 variations and remission were found in the white Hispanic or black subjects. These findings suggest that multiple variations in the SLC6A4 gene are associated with remission in white non-Hispanic depressed adults treated with citalopram. The mechanism of action of these variants remains to be determined.

Biocompatibility of supercritical CO2-treated titanium implants in a rat model.

Supercritical phase CO2 is a promising method for sterilizing implantable devices and tissue grafts. The goal of this study is to evaluate the biocompatibility of titanium implants sterilized by supercritical phase CO2 in a rat subcutaneous implantation model. At 5 weeks post implantation titanium implants sterilized by supercritical phase CO2 produce a soft tissue reaction that is comparable to other methods of sterilization (steam autoclave, ultraviolet light radiation, ethylene oxide gas, and radio-frequency glow-discharge), as indicated by the thickness and density of the foreign body capsule, although there were some differences on the capillary density. Overall the soft tissue response to the implants was similar among all methods of sterilization, indicating supercritical phase CO2 treatment did not compromise the biocompatibility of the titanium implant.

Effects of sterilization on implant mechanical property and biocompatibility.

This article concisely reviews the effects of sterilization on the mechanical properties and surface chemistries of implantable biomaterials. This article also summarizes the biological effects of the sterilization-related changes in the implant. Because there are so many different types of implant materials currently in use (including metals, polymers, and diverse biological materials), the response of tissue to these different materials varies dramatically. This review further discusses the effects of sterilization on in vivo and in vitro tissue response specifically to implantable metals and polyethylene, with the possibility of future biocompatibility testing of the implants sterilized with supercritical phase carbon dioxide sterilization.

Asphalt volcanism and chemosynthetic life in the Campeche Knolls, Gulf of Mexico.

In the Campeche Knolls, in the southern Gulf of Mexico, lava-like flows of solidified asphalt cover more than 1 square kilometer of the rim of a dissected salt dome at a depth of 3000 meters below sea level. Chemosynthetic tubeworms and bivalves colonize the sea floor near the asphalt, which chilled and contracted after discharge. The site also includes oil seeps, gas hydrate deposits, locally anoxic sediments, and slabs of authigenic carbonate. Asphalt volcanism creates a habitat for chemosynthetic life that may be widespread at great depth in the Gulf of Mexico.

Nanoindentation properties of compression-moulded ultra-high molecular weight polyethylene.

This paper investigates the elastic modulus and hardness of untreated and treated compression-moulded ultra-high molecular weight polyethylene (UHMWPE) tibial inserts of a total knee replacement (TKR) prosthesis. Investigations were carried out at a nanoscale using a Nanoindenter at penetration depths of 100,250 and 500 nm. The nanomechanical properties of surface and subsurface layers of the compression-moulded tibial inserts were studied using the untreated UHMWPE. The nanomechanical properties of intermediate and core layers of the compression-moulded tibial insert were studied using the cryoultrasectioned and etched UHMWPE treated samples. The cryoultrasectioning temperature (-150 degrees C) of the samples was below the glass transition temperature, Tg (-122 +/- 2 degrees C ), of UHMWPE. The measurement of the mechanical response of crystalline regions within the nanostructure of UHMWPE was accomplished by removing the amorphous regions using a time-varying permanganic-etching technique. The percentage crystallinity of UHMWPE was measured using differential scanning calorimetry (DSC) and the Tg of UHMWPE was determined by dynamic mechanical analysis (DMA). Atomic force microscopy (AFM) was used to assess the effect of surface preparation on the samples average surface roughness, Ra. In this study, it was demonstrated that the untreated UHMWPE samples had a significantly lower (p < 0.0001) elastic modulus and hardness relative to treated UHMWPE cryoultrasectioned and etched samples at all penetration depths. No significant difference (p > 0.05) in elastic modulus and hardness between the cryoultrasectioned and etched samples was observed. These results suggest that the surface nanomechanical response of an UHMWPE insert in a total joint replacement (TJR) prosthesis is significantly lower compared with the bulk of the material. Additionally, it was concluded that the nanomechanical response of material with higher percentage crystallinity (67 per cent) was predominantly determined by the crystalline regions within the semi-crystalline UHMWPE nanostructure.

Local excision of rectal carcinoma not-exceeding the muscularis layer.

AIM: The aim of the study was to compare the results of treatment by local excision of two different clinical stages of the rectal cancer. MATERIAL AND METHODS: Fifty-eight patients with early rectal carcinoma were operated on during the last 26 years using different methods of local excision. The carcinomas were initially assessed as not-exceeding the muscularis layer of the rectal wall. The tumours, localized up to 12 cm from the anal margin, were removed by means of "parachute" excision (47 patients). In 6 patients, carcinoma localized in the central part of rectum, was excised by means of the Localio method. Transanal endoscopic microsurgery was applied in 5 cases of carcinoma localized on the depth of 5-20 cm from the anal margin. RESULTS: After local excision the patients were divided into two groups: I, tumours of low degree of malignancy, not exceeding submucosal layer (26 patients); II, tumours of low or median degree of malignancy with infiltration of muscularis layer (32 patients). There was a significant difference in cancer relapses between groups I and II. One patient in group I and 9 in group II developed local recurrences (P < 0.05) and 5 patients in group II had neoplastic dissemination (15.6%). CONCLUSIONS: Best results were obtained in patients with carcinoma not exceeding submucosal membrane. In cases of rectal muscular layer infiltrations, the risk of carcinoma relapses was markedly higher. The use of transanal endoscopic microsurgery has permitted removal of tumours from the upper rectum.

Initial closed operation of the CELSS Test Facility Engineering Development Unit.

As part of the NASA Advanced Life Support Flight Program, a Controlled Ecological Life Support System (CELSS) Test Facility Engineering Development Unit has been constructed and is undergoing initial operational testing at NASA Ames Research Center. The Engineering Development Unit (EDU) is a tightly closed, stringently controlled, ground-based testbed which provides a broad range of environmental conditions under which a variety of CELSS higher plant crops can be grown. Although the EDU was developed primarily to provide near-term engineering data and a realistic determination of the subsystem and system requirements necessary for the fabrication of a comparable flight unit, the EDU has also provided a means to evaluate plant crop productivity and physiology under controlled conditions. This paper describes the initial closed operational testing of the EDU, with emphasis on the hardware performance capabilities. Measured performance data during a 28-day closed operation period are compared with the specified functional requirements, and an example of inferring crop growth parameters from the test data is presented. Plans for future science and technology testing are also discussed.

Effects of the sample preparation temperature on the nanostructure of compression moulded ultrahigh molecular weight polyethylene.

In this study, the effects of the sample sectioning temperature on the surface nanostructure and mechanical response of compression moulded ultrahigh molecular weight polyethylene (UHMWPE) at a nanometer scale (nanomechanical properties) have been characterized. The primary focus of this work was to determine if the sample sectioning temperature significantly changed the nanostructure of UHMWPE, while the secondary focus was to characterize the effect on the mechanical response due to the changes in the sectioned surface nanostructure. The goals of this study were: (a) to investigate the potential possibility of creating surface artefacts by the sample preparation technique by sectioning at different temperatures relative to the published range of glass transition temperatures, Tg, for PE (-12, -80 and -25 degrees C); (b) to determine the possibility of molecular orientation induced by plastic deformation of the UHMWPE sample during the process of sample preparation; (c) to measure the relative difference in nanomechanical properties owing to evolution of different nanostructures as a function of sample sectioning temperature. Field emission scanning electron microscopy (FESEM), atomic force microscopy (AFM) and nanoindentation were used to demonstrate that the sectioning temperature caused a change in nanostructure of the compression moulded UHMWPE sectioned surface, explaining the change in mechanical response to indentation at a nanoscale. In this study, it was demonstrated that significant plastic deformation occurs when a shear stress is applied between the glass or diamond blade and the UHMWPE during sample preparation under ambient conditions at a temperature of 22 degrees C. These results also suggest that an optimum sample sectioning temperature should definitely be below the measured Tg of the polymer.