A preliminary report of head-to-head comparison of 18-gene-based clinical-genomic model and oncotype DX 21-gene assay for predicting recurrence of early-stage breast cancer.

BACKGROUND: The information of Oncotype DX applied in Asian breast cancer patients is limited. A recurrence index for distant recurrence (RI-DR) has been developed for early-stage breast cancer (EBC) from tumor samples in Chinese patients. In this study, we compared the prognostic performance of the Oncotype DX (ODx) recurrence score (RS) with the RI-DR for any recurrence risk type. MATERIALS AND METHODS: One hundred thirty-eight (138) patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative EBC who were previously tested with ODx were included for testing with the RI-DR. The cutoff score to partition the low- and high-risk patients was 26 for RS and 36 for RI-DR. The primary endpoint was recurrence-free survival (RFS). RESULTS: The concordance between the RI-DR and RS was 83% in N0 patients and 81% in node-positive patients when the RS score cutoff was set at 26. With a median follow-up interval of 36.8 months, the 4-year RFS for the high- and low-risk groups categorized by the RS were 61.9% and 95.0%, respectively (hazard ratio: 10.6, 95.0% confidence interval [CI]: 1.8-62.9). The 4-year RFS in the high- and low-risk groups categorized by the RI-DR were 72.6% and 98.5%, respectively (hazard ratio: 18.9, 95% CI: 1.8-138.8). CONCLUSION: This paper illustrated the performance of RI-DR and ODx RS in breast cancer women in Taiwan. There was high concordance between the RI-DR and RS. The RI-DR is not inferior to the RS in predicting RFS in EBC patients. This study will fill the gap between the current and best practice in Chinese patients.

Stoma Bridge Types and Their Impact on Patient Outcomes: A Retrospective Analysis and Prospective Global Survey of Surgical Practice.

PURPOSE: The purpose of this study was to describe the effect of rigid or flexible stoma bridges used for loop ostomy diversions on peristomal skin integrity. Additional aims were to describe surgeon practices related to stoma bridges, and determine the availability of an ostomy nurse specialist. DESIGN: Retrospective chart review and cross-sectional survey. SAMPLE AND SETTING: The sample used to address the first aim (effect of stoma bridges) comprised 93 adult patients cared for at Morristown Medical Center, Atlantic Health System, Morristown, New Jersey, an acute care facility. Data provided by 355 colorectal surgeons from 30 countries were used to describe surgeon practice in this area and determine the availability of an ostomy nurse specialist. Respondents were invited from an international roster of colorectal surgeons obtained with permission from the American Society of Colon and Rectal Surgeons (ASCRS). METHODS: In order to accomplish the initial aim, we retrospectively reviewed medical records of patients who underwent ostomy surgery from 2008 to 2015 and met inclusion criteria. In order to meet our additional aims, analyzed data were obtained from a survey of colorectal surgeons that queried practices related to stoma bridges, and availability of an ostomy nurse specialist. RESULTS: Patients managed with a rigid bridge were significantly more likely to experience leakage beneath the pouching system faceplate than were patients managed by a flexible bridge (42% vs 11%, P < .001). Slightly less than one quarter of patients who developed leakage (n = 22, 24%) experienced pressure and moisture-related peristomal skin complications. Peristomal wounds, inflammation, and infection were significantly higher when a rigid bridge was used (χ test, P < .003). The surgeon's survey (N = 355) showed variability in the use of bridges. Ninety-three percent of all surgeons indicated an ostomy nurse specialist was part of their health care team. CONCLUSIONS: Rigid ostomy bridges were associated with a higher likelihood of leakage from underneath the faceplate of the pouching system and impaired peristomal skin integrity. Analysis of colorectal surgeon responses to a survey indicated no clear consensus related to bridge use in patients undergoing loop ostomies.

Lamb survival, glutathione redox state and immune function of neonates and lambs from periparturient Merino ewes supplemented with rumen-protected methionine.

Wool growth in Merino sheep demands a high level of sulphur amino acids, competing with body growth and the immune system, which may play a role in increasing the risk of lamb mortality. The hypothesis that dietary supplementation of methionine (Met) to Merino ewes during the late stages of pregnancy will improve foetal growth and alter immune competency of ewes and lambs was tested in a total of 120 grazing, pregnant Merino ewes. Sixty ewes were group-supplemented with 6.3 g/d rumen-protected Met (Met-Plus) per sheep from day 111 of pregnancy until day 7 after lambing, and the other 60 animals were used as a non-supplemented Control. Lambs from Met-supplemented ewes tended to be 10% heavier than Control lambs (p = 0.10), which did not affected the survival rate at weaning significantly. The supplemented ewes had slightly higher concentrations of total glutathione (GSH) in plasma at lambing (p < 0.06), but there were no differences between 1 and 3 months post-lambing in GSH, glutathione disulphide (GSSG) and the GSSG:GSH ratio. The GSSG:GSH ratio in the blood of ewes was elevated at lambing (p < 0.05), hinting that ewes were undergoing increased oxidative stress. The Met supplementation elevated the total IgG concentration (p < 0.05) in lambs aged 4 and 6 weeks, but did not change the IgG concentrations in colostrum and in plasma of 1-week-old lambs, and white blood cell counts and leukocyte types. The trend towards higher lamb birth weights in the Met-supplemented group requires further investigation as this may influence survival at birth and weaning.

Correlation of ER, PR, and HER2 at the protein and mRNA levels in Asian patients with operable breast cancer.

Breast cancer is the most common cancer and the leading cause of cancer-related deaths in women. The estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are the important biomarkers in the prognosis of breast cancer, and their expression is used to categorize breast cancer into subtypes. We aimed to analyze the concordance among ER, PR, and HER2 expression levels and breast cancer subtyping results obtained by immunohistochemistry (IHC, for protein) and reverse transcriptase-polymerase chain reaction (RT-PCR, for mRNA) and to assess the recurrence-free survival (RFS) of the different subtypes as determined by the two methods. We compared biomarker expression by IHC and RT-PCR in 397 operable breast cancer patients and categorized all patients into luminal, HER2, and triple-negative (TN) subtypes. The concordance of biomarker expression between the two methods was 81.6% (κ = 0.4075) for ER, 87.2% (κ = 0.5647) for PR, and 79.1% (κ = 0.2767) for HER2. The κ-statistic was 0.3624 for the resulting luminal, HER2, and TN subtypes. The probability of 5-year RFS was 0.78 for the luminal subtype versus 0.77 for HER2 and 0.51 for TN, when determined by IHC (P=0.007); and 0.80, 0.71, and 0.61, respectively, when determined by the RT-PCR method (P=0.008). Based on the current evidence, subtyping by RT-PCR performs similar to conventional IHC with regard to the 5-year prognosis. The PCR method may thus provide a complementary means of subtyping when IHC results are ambiguous.

A Clinicogenetic Prognostic Classifier for Prediction of Recurrence and Survival in Asian Breast Cancer Patients.

BACKGROUND: Several prognostic factors affect the recurrence of breast cancer in patients who undergo mastectomy. Assays of the expression profiles of multiple genes increase the probability of overexpression of certain genes and thus can potentially characterize the risk of metastasis. METHODS: We propose a 20-gene classifier for predicting patients with high/low risk of recurrence within 5 years. Gene expression levels from a quantitative PCR assay were used to screen 473 luminal breast cancer patients treated at Taiwan Hospital (positive for estrogen and progesterone receptors, negative for human epidermal growth factor receptor 2). Gene expression scores, along with clinical information (age, tumor stage, and nodal stage), were evaluated for risk prediction. The classifier could correctly predict patients with and without relapse (logistic regression, P<0.05). RESULTS: A Cox proportional hazards regression analysis showed that the 20-gene panel was prognostic with hazard ratios of 5.63 (95% confidence interval 2.77-11.5, univariate) and 5.56 (2.62-11.8, multivariate) for the "genetic" model, and of 8.02 (3.52-18.3, univariate) and 19.8 (5.96-65.87, multivariate) for the "clinicogenetic" model during a 5-year follow-up. CONCLUSIONS: The proposed 20-gene classifier can successfully separate the patients into two risk groups, and the two risk group had significantly different relapse rate and prognosis. This 20-gene classifier can provide better estimation of prognosis, which can help physicians to make better personalized treatment plans.

Gene expression profiling in prognosis of distant recurrence in HR-positive and HER2-negative breast cancer patients.

There had been several studies using gene-expression profiling in predicting distant recurrence in breast cancer. In this study, we developed an 18-gene classifier (18-GC) to predict distant recurrence of breast cancer and compared it with the 21-gene panel (Oncotype DX®, ODx) in performance. Included were 224 breast cancer patients with positive hormonal receptor (HR+) and negative human epidermal growth factor receptor 2 (HER2-). We compared the demographic, clinical, and survival information of the patients, and further compared the prediction of recurrence risk obtained by using the 18-GC with that by ODx. To have the best combined sensitivity and specificity, receiver operating characteristics (ROC) curve analysis was performed to determine the cutoff values for several breakpoint scores. For the new 18-GC, a breakpoint score of 21 was adopted to produce a combined highest sensitivity (95%) and specificity (39%) in detecting distant recurrence. At this breakpoint score, 164 of the 224 patients were classified by the 18-GC in the same risk level as by ODx, giving a concordance rate of 73%. Along with patient age and tumor stage, this 18-GC was found to be an independent significant prognostic factor of distant metastasis of breast cancer. We have thus created a new gene panel assay for prediction of distant recurrence in HR+ and HER2- breast cancer patients. With a high concordance rate with ODx, this new assay may serve as a good tool for individual breast cancer patients to make an informed decision on whether adjuvant chemotherapy should be performed post-surgery.

The path of a click stimulus from ear canal to umbo.

The tympanic membrane (TM) has a key role in transmitting sounds to the inner ear, but a concise description of how the TM performs this function remains elusive. This paper probes TM operation by applying a free field click stimulus to the gerbil ear and exploring the consequent motions of the TM and umbo. Motions of the TM were measured both on radial tracks starting close to the umbo and on a grid distal and adjacent to the umbo. The experimental results confirmed the high fidelity of sound transmission from the ear canal to the umbo. A delay of 5-15 µs was seen in the onset of TM motion between points just adjacent to the umbo and mid-radial points. The TM responded with a ringing motion, with different locations possessing different primary ringing frequencies. A simple analytic model from the literature, treating the TM as a string, was used to explore the experimental results. The click-based experiments and analysis led to the following description of TM operation: A transient sound pressure on the TM causes a transient initial TM motion that is maximal âˆ¼ at the TM's radial midpoints. Mechanical forces generated by this initial prominent TM distortion then pull the umbo inward, leading to a delayed umbo response. The initial TM deformation also gives rise to prolonged mechanical ringing on the TM that does not result in significant umbo motion, likely due to destructive interference from the range of ringing frequencies. Thus, the umbo's response is a high-fidelity representation of the transient stimulus. Because any sound can be considered as a consecutive series of clicks, this description is applicable to any sound stimulus.

Experience of General Surgery Residents in the Creation of Small Bowel and Colon Anastomoses.

BACKGROUND: With the introduction of stapling devices (SDs), the proportion of hand-sewn (HS) intestinal anastomoses (IAs) has declined. As more IAs are constructed with SDs, there are fewer opportunities for general surgery residents (GSRs) to acquire the skills for HS techniques during their training. STUDY DESIGN: Data for this study were extracted from an existing database of all IAs performed at the Department of Surgery of the Morristown Medical Center since 2003. For the purposes of this study, a 5.5-year timeframe was used between July 2006 and 2011, which contained 1659 IA operations on adult patients with resident involvement. GSRs of the 5-year general surgery residency program were grouped by postgraduate year (PGY) for further analysis. RESULTS: The number of all IAs created by each resident during the 5-year training was 67.2 on average. Most of these operations were done in the last 2 years of the training: 45.1% of all IAs in PGY5 and 37.3% of all IAs in PGY4. Of all, 1659 IAs performed in the study period, 711 (42.9% of total) were done laparoscopically and 948 (57.1% of all IAs) were done as open operations. Laparoscopic operations had a proportionally higher rate of SD use when compared to open cases (90.9% vs 82.4%). On average, each resident constructed 9.4 HS IAs (13.98% of all IAs) and 57.8 SD IAs (86.02% of total). Out of all anastomoses, ostomy reversals (30.7%) had the highest percentage of HS suturing followed by right colectomies (27.5%), ileal pouch-anal anastomoses and total colectomies and proctocolectomies (23.3%), small bowel resection (17.0%), and left colectomies (5.5%). Regardless of the location of the operation, stapled and sutured anastomoses had similar outcomes measured by the rate of anastomotic leaks. Residents used significantly more SDs in the creation of anastomoses than HS suturing in the PGY3, PGY4, and PGY5 years. We also documented that attending surgeons who are older more often used HS suturing than their younger colleagues when creating IAs. CONCLUSIONS: The experiences of GSRs in IA operations are heavily weighted toward the use of SDs. There are select cases, however, when HS suturing can have an advantage over stapler use in anastomosis creation. Therefore, we believe that GSRs should continue learning, perfecting, and using the both techniques.

Nematicidal activity of two monoterpenoids and SER-2 tyramine receptor of Caenorhabditis elegans.

In vitro cultures of two nematodes (Caenorhabditis elegans and Ascaris suum) were established to study the nematicidal activity of three monoterpenoids (thymol, carvacrol and p-cymene). Toxicity of thymol and carvacrol was found for the two nematodes tested. The study was then aimed to address whether nematode tyramine receptor (TyrR) could interact with the two compounds by using HEK293 mammalian cells transfected with a C. elegans TyrR (ser-2) sequence, in hope of developing a high-throughput cell-based platform for future screening of new antihelminthic compounds. SER-2 expression and functionality in the transfected cells was first confirmed by green fluorescent protein tagging, competitive receptor binding, intracellular cyclic AMP, and intracellular calcium [Ca(2+)](i) mobilization assays. Thymol and carvacrol were then tested and demonstrated to interact with TyrR in desensitizing SER-2 for tyramine activation in [Ca(2+)](i) mobilization assay, and in translocating SER-2 from membrane to cytoplasm in receptor internalization assay. Receptor internalization activity of thymol and carvacrol was significantly blocked in cells expressing mutant SER-2 with the S210A/S214A double mutations, thus confirming specificity of the interactions. In summary, the current study showed that the nematicidal activity of thymol and carvacrol might be mediated through TyrR as the two compounds could trigger the signaling cascade downstream from the receptor in cells expressing wild-type but not a mutant SER-2. The TyrR-expressing cell system may prove to be a good screening platform for developing new antihelmintic compounds that may overcome parasite drug resistance, especially when such chemicals are used in combination with commercial drugs.

Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue.

Obesity elicits an immune response characterized by myeloid cell recruitment to key metabolic organs, including adipose tissue. However, the response of immune cells to nonpathologic metabolic stimuli has been less well studied, and the factors that regulate the metabolic-dependent accumulation of immune cells are incompletely understood. Here we characterized the response of adipose tissue macrophages (ATMs) to weight loss and fasting in mice and identified a role for lipolysis in ATM recruitment and accumulation. We found that the immune response to weight loss was dynamic; caloric restriction of high-fat diet-fed mice led to an initial increase in ATM recruitment, whereas ATM content decreased following an extended period of weight loss. The peak in ATM number coincided with the peak in the circulating concentrations of FFA and adipose tissue lipolysis, suggesting that lipolysis drives ATM accumulation. Indeed, fasting or pharmacologically induced lipolysis rapidly increased ATM accumulation, adipose tissue chemoattractant activity, and lipid uptake by ATMs. Conversely, dietary and genetic manipulations that reduced lipolysis decreased ATM accumulation. Depletion of macrophages in adipose tissue cultures increased expression of adipose triglyceride lipase and genes regulated by FFA, and increased lipolysis. These data suggest that local lipid fluxes are central regulators of ATM recruitment and that once recruited, ATMs form lipid-laden macrophages that can buffer local increases in lipid concentration.