Clinical Outcomes of Conservative Treatment for Low-Risk Ductal Carcinoma in Situ: A Systematic Review and Pooled Analysis.

AIMS: The current gold standard of treatment for ductal carcinoma in situ (DCIS) is surgical resection with or without adjuvant radiotherapy. However, the increased detection and radical treatment of DCIS did not result in a declined incidence of invasive breast cancers, leading to the debate if DCIS has been overtreated. While ongoing randomised controlled trials on active surveillance of DCIS are still in progress, this systematic review aims to evaluate the best evidence on conservative treatment for DCIS from the literature. MATERIALS AND METHODS: This systematic review was conducted in line with the PRISMA statement. We included all relevant studies published up to June 2022 for analysis. The primary outcomes were overall survival and breast cancer-specific survival (BCSS) of conservative treatment for DCIS. RESULTS: Three studies, with a total of 34 007 women with low-risk DCIS, were included in the analysis. Active and conservative treatments both resulted in excellent 10-year BCSS, with no statistically insignificant difference (98.6% versus 96.0%, 31 478 women). One study comparing 5-year BCSS of active and conservative treatments only in subjects aged over 80 years also reported [AQ1]an insignificant difference (98.2% versus 96.0%, 2529 women). One study measuring 5- and 10-year overall survival between the treatment groups also reported [AQ1]an insignificant difference (5-year: 96.2% versus 92.4%; 10-year: 85.6% versus 86.7%, 31 106 women). CONCLUSION: BCSS between active and conservative treatment for women with low-risk DCIS is both excellent and comparable, suggesting that conservative treatment is a possible alternative without compromising survival.

Emergency attendances and hospitalisations for complications after transrectal ultrasound-guided prostate biopsies: a five-year retrospective multicentre study.

INTRODUCTION: Transrectal ultrasound-guided (TRUS) prostate biopsy is an established procedure for diagnosis of prostate cancer. Complications after TRUS biopsy are not well reported in Hong Kong. This study evaluated the 5-year incidences of TRUS biopsy complications and potential risk factors for those complications. METHODS: This was a retrospective review of biopsies performed from 2013 to 2017 in two local hospitals, using data retrieved from electronic medical records. The primary outcome was the occurrence of complications requiring either emergency attendances or hospitalisations within 30 days after biopsy. Potential risk factors were examined using multiple logistic regression analysis. RESULTS: In total, 1699 men were included (mean age ± standard deviation: 67 ± 7 years; median prostate-specific antigen level: 7.9 µg/L [interquartile range, 5.5-12.6 µg/L]); 4.3% had pre-biopsy bacteriuria. Overall, 5.7% and 3.8% of post-biopsy complications required emergency attendances and hospitalisations, respectively. Gross haematuria and rectal bleeding requiring emergency attendances developed in 2.1% and 0.4% of men; 0.8% and 0.4% required hospitalisations. Furthermore, 1.5% of men developed acute urinary retention requiring hospitalisations; 1.9% and 1.2% had post-biopsy infections requiring emergency attendances and hospitalisations, respectively, and 0.9% had urosepsis requiring hospitalisations. Prostate volume >48 cc was associated with an increased risk of post-biopsy retention (odds ratio 2.75, 95% confidence interval: 1.23-4.17). CONCLUSIONS: The rate of overall complications after TRUS biopsy was low. The most common complications requiring emergency attendances and hospitalisations were gross haematuria and acute urinary retention, respectively. Prostate volume >48 cc increased the risk of post-biopsy urinary retention.

Development of high-throughput and high sensitivity capillary gel electrophoresis platform method for Western, Eastern, and Venezuelan equine encephalitis (WEVEE) virus like particles (VLPs) purity determination and characterization.

In this paper, we describe development of a high-throughput, highly sensitive method based on Lab Chip CGE-SDS platform for purity determination and characterization of virus-like particle (VLP) vaccines. A capillary gel electrophoresis approach requiring about 41 s per sample for analysis and demonstrating sensitivity to protein initial concentrations as low as 20 µg/mL, this method has been used previously to evaluate monoclonal antibodies, but this application for lot release assay of VLPs using this platform is unique. The method was qualified and shown to be accurate for the quantitation of VLP purity. Assay repeatability was confirmed to be less than 2% relative standard deviation of the mean (% RSD) with interday precision less than 2% RSD. The assay can evaluate purified VLPs in a concentration range of 20-249 µg/mL for VEE and 20-250 µg/mL for EEE and WEE VLPs.

Whole-Organism Cellular Pathology: A Systems Approach to Phenomics.

Phenotype is defined as the state of an organism resulting from interactions between genes, environment, disease, molecular mechanisms, and chance. The purpose of the emerging field of phenomics is to systematically determine and measure phenotypes across biology for the sake of understanding. Phenotypes can affect more than one cell type and life stage, so ideal phenotyping would include the state of every cell type within the context of both tissue architecture and the whole organism at each life stage. In medicine, high-resolution anatomic assessment of phenotype is obtained from histology. Histology's interpretative power, codified by Virchow as cellular pathology, is derived from its ability to discern diagnostic and characteristic cellular changes in diseased tissues. Cellular pathology is observed in every major human disease and relies on the ability of histology to detect cellular change in any cell type due to unbiased pan-cellular staining, even in optically opaque tissues. Our laboratory has shown that histology is far more sensitive than stereomicroscopy for detecting phenotypes in zebrafish mutants. Those studies have also shown that more complete sampling, greater consistency in sample orientation, and the inclusion of phenotypes extending over longer length scales would provide greater coverage of common phenotypes. We are developing technical approaches to achieve an ideal detection of cellular pathology using an improved form of X-ray microtomography that retains the strengths and addresses the weaknesses of histology as a screening tool. We are using zebrafish as a vertebrate model based on the overlaps between zebrafish and mammalian tissue architecture, and a body size small enough to allow whole-organism, volumetric imaging at cellular resolution. Automation of whole-organism phenotyping would greatly increase the value of phenomics. Potential societal benefits would include reduction in the cost of drug development, a reduction in the incidence of unexpected severe drug and environmental toxicity, and more rapid elucidation of the contributions of genes and the environment to phenotypes, including the validation of candidate disease alleles identified in population and personal genetics.

Initial results of selective renal parenchymal clamping with an adjustable kidney clamp in nephron-sparing surgery: an easy way to minimise renal ischaemia.

INTRODUCTION: A renal parenchymal clamp has been used at our centre since March 2012. It is used in position over the kidney to achieve optimal vascular control of a tumour while minimising parenchymal ischaemia. This study aimed to report the feasibility, surgical outcome, and oncological control of a kidney clamp in partial nephrectomy. METHODS: This study was conducted at a teaching hospital in Hong Kong. Partial nephrectomies performed from January 2009 to March 2015 were reviewed. The tumour characteristics and surgical outcomes of kidney clamp were studied and compared with traditional hilar clamping. RESULTS: A total of 92 patients were identified during the study period. Kidney clamps were used in 20 patients and hilar clamping in 72, with a mean follow-up of 27 and 37 months, respectively. For patients in whom a kidney clamp was applied, all tumours were exophytic to a different extent and the majority (90%) were located at the polar region. The PADUA (preoperative aspects and dimensions used for an anatomical) classification nephrometry score was also lower than those in whom hilar clamping was used (7.07 vs 8.34; P=0.002). The clamp was used in open, laparoscopic, and robot-assisted surgery. Operating time was shorter (207 ± 72 mins vs 306 ± 80 mins; P<0.001) and estimated blood loss was lower (205 ± 191 mL vs 331 ± 275 mL; P=0.045) with kidney clamp. No acute kidney injury occurred. Postoperative renal function was comparable between the two groups. CONCLUSIONS: Partial nephrectomy using parenchymal clamping is safe and feasible in selected cases. The postoperative renal function and oncological control were satisfactory.

Effects of Laser Annealing Parameters on Optical and Electrical Properties of ITO/Metallic Glass Alloy Bi-layer Films.

AgAlMg (AAM) films with three different atomic percentage compositions are prepared, namely, Ag12Al62Mg26 (denoted as A1AM), Ag22Al46Mg32 (denoted as A2AM), and Ag36Al25Mg39 (denoted as A3AM). In addition, the AAM films are deposited with four different thicknesses, i.e., 3, 6, 9, and 12 nm. The indium-tin oxide thickness is assigned a constant value of 30 nm in every case. The results show that the optical transmittance of the AAM/IAAM films improves (i.e., increases) with a reducing AAM film thickness, while the electrical resistivity improves (i.e., reduces) with an increasing film thickness. It is shown that the IA2AM film with an AMM thickness of 9 nm yields the optimal compromise between the optical transmittance and the electrical resistivity. The as-deposited IAAM films are found to have optical transmittance and electric resistivity values of 65 % and 90 Ω/□, respectively. The IA2AM films are annealed using a near-infrared laser at different pulse energies with a wavelength of 1064 nm and repetition rates ranging from 100 ~ 400 kHz. For both films, the optical and electrical properties are enhanced as the pulse energy increases to a certain critical value due to a transition from an amorphous microstructure to a crystalline structure. Given a repetition rate of 400 kHz and a pulse energy of 1.03 µJ, the optical transmittance and sheet resistance of the IAAM film are found to be 80 % and 15 Ω/□, respectively. The corresponding value of the Haacke figure of merit changed from 0.15 × 10(-3) to 7.16 × 10(-3) Ω(-1) due to the optimal laser annealing conditions.

Laparoscopic liver resection: lessons learnt after 100 cases.

OBJECTIVE: To share our institutional experience in laparoscopic liver resection and our learning curve after the first 100 cases of laparoscopic liver resection. DESIGN: Case series with internal comparison. SETTING: A regional hospital in Hong Kong. PATIENTS: Our institution started performing laparoscopic liver resection since 2006. All patients who underwent laparoscopic liver resections from March 2006 to October 2012 were identified in a prospectively collected database. The demographic data and operative outcomes of these patients were extracted, and results of the early (from March 2006 to May 2010) and late (from June 2010 to October 2012) study periods were compared. RESULTS: Between March 2006 and October 2012, 100 laparoscopic liver resections were performed for 98 patients in the Department of Surgery, Kwong Wah Hospital, Hong Kong. They were 69 (70%) males and 29 (30%) females, and the median age was 65 years. The final histological diagnoses were as follows: hepatocellular carcinoma (n=72), colorectal liver metastases (n=14), intrahepatic cholangiocarcinoma (n=4), and benign disease (n=10). There were more anatomical resections, major hepatectomies as well as resections of more anatomically challenging right-sided and posterosuperior lesions in the late versus the early period; however, operative outcomes remained comparable in both periods. CONCLUSION: Laparoscopic hepatectomies are feasible with growing experience. Bearing in mind the diversity in the level of operative techniques with various types of laparoscopic liver resections, more experience is needed to overcome the learning curve.

Controlled experiments measuring personal exposure to PM2.5 in close proximity to cigarette smoking.

Few measurements of exposure to secondhand smoke (SHS) in close proximity to a smoker are available. Recent health studies have demonstrated an association between acute (<2 h) exposures to high concentrations of SHS and increased risk of cardiovascular and respiratory disease. We performed 15 experiments inside naturally ventilated homes and 16 in outdoor locations, each with 2-4 non-smokers sitting near a cigarette smoker. The smoker's and non-smokers' real-time exposures to PM2.5 from SHS were measured by using TSI SidePak monitors to sample their breathing zones. In 87% of the residential indoor experiments, the smoker received the highest average exposure to SHS, with PM2.5 concentrations ranging from 50-630 µg/m(3) . During the active smoking period, individual non-smokers sitting within approximately 1 m of a smoker had average SHS exposures ranging from negligible up to >160 µg/m(3) of PM2.5 . The average incremental exposure of the non-smokers was higher indoors (42 µg/m(3) , n = 35) than outdoors (29 µg/m(3) , n = 47), but the overall indoor and outdoor frequency distributions were similar. The 10-s PM2.5 averages during the smoking periods showed great variability, with multiple high concentrations of short duration (microplumes) both indoors and outdoors.

Identifying and quantifying secondhand smoke in source and receptor rooms: logistic regression and chemical mass balance approaches.

Identifying and quantifying secondhand tobacco smoke (SHS) that drifts between multiunit homes is critical to assessing exposure. Twenty-three different gaseous and particulate measurements were taken during controlled emissions from smoked cigarettes and six other common indoor source types in 60 single-room and 13 two-room experiments. We used measurements from the 60 single-room experiments for (i) the fitting of logistic regression models to predict the likelihood of SHS and (ii) the creation of source profiles for chemical mass balance (CMB) analysis to estimate source apportionment. We then applied these regression models and source profiles to the independent data set of 13 two-room experiments. Several logistic regression models correctly predicted the presence of cigarette smoke more than 80% of the time in both source and receptor rooms, with one model correct in 100% of applicable cases. CMB analysis of the source room provided significant PM2.5 concentration estimates of all true sources in 9 of 13 experiments and was half-correct (i.e., included an erroneous source or missed a true source) in the remaining four. In the receptor room, CMB provided significant estimates of all true sources in 9 of 13 experiments and was half-correct in another two.

Increased risk of pulmonary tuberculosis in patients with previous non-tuberculous mycobacterial disease.

OBJECTIVE: To investigate whether or not there is an increased risk of pulmonary tuberculosis (PTB) after non-tuberculous mycobacterial (NTM) disease. DESIGN: A retrospective cohort study of 212 NTM patients and 4240 control cases. RESULTS: Patients with previous NTM disease had a significantly higher incidence of PTB than controls (incidence rate ratio [IRR] 14.74, 95%CI 8.71-24.94, P < 0.0001). Cox's proportional hazards analysis yielded an adjusted hazards ratio (aHR) of 10.15 (95%CI 5.67-18.17, P < 0.05) for NTM-associated PTB. The majority of the PTB cases (17/23, 73.9%) were diagnosed within 6 months after the diagnosis of NTM disease. Older age (≥65 years, aHR 4.45, 95%CI 1.94-10.22, P < 0.05), male sex (aHR 1.75, 95%CI 1.01-3.13, P < 0.05), human immunodeficiency virus (HIV) infection (aHR 12.49, 95%CI 3.20-48.79, P < 0.05) and chronic obstructive pulmonary disease (aHR 4.46, 95%CI 2.19-9.10, P < 0.05) were independent risk factors for developing PTB after NTM disease. The cumulative incidence of PTB in patients with previous NTM disease was significantly higher than in controls (P < 0.0001, Kaplan-Meier analysis). However, there was no significant difference in the survival rates in the two cohorts. CONCLUSION: Increased PTB prevalence after NTM disease was demonstrated. HIV infection was the greatest independent risk factor for subsequent development of PTB.

Plasma glucose-lowering action of allantoin is induced by activation of imidazoline I-2 receptors in streptozotocin-induced diabetic rats.

Allantoin, an active principle of yam, is documented to lower plasma glucose in diabetic rats. However, action mechanisms of allantoin remain obscure. It has been indicated that metformin shows ability to activate imidazoline I-2 receptors (I-2R) to lower blood sugar. Allantoin has also a chemical structure similar to metformin; both belong to guanidinium derivative. Thus, it is of special interest to know the effect of allantoin on I-2R. In the present study, the marked plasma glucose-lowering action of allantoin in streptozotocin-induced type-1 like diabetic rats was blocked by specific I-2R antagonist, BU224, in a dose-dependent manner. Also, the increase of ß-endorphin release by allantoin was blocked by BU224 in the same manner. Otherwise, amiloride at the dose sufficient to block I-2AR abolished the allantoin-induced ß-endorphin release and inhibited the blood glucose-lowering action of allantoin markedly but not completely. The direct effect of allantoin on glucose uptake in isolated skeletal muscle was also blocked by BU224. Also, the phosphorylation of AMPK in isolated skeletal muscle was raised by allantoin in a concentration-dependent manner. More-over, insulin sensitivity in diabetic rats was markedly increased by allantoin and this action was also blocked by BU224. These results suggest that allantoin has an ability to activate imidazoline I-2R while I-2AR is linked to the increase of ß-endorphin release and I-2BR is related to other actions including the influence in skeletal muscle for lowering of blood glucose in type-1 like diabetic rats. Thus, allantoin can be developed to treat diabetic disorders in the future.

Activation of imidazoline I-2B receptor by metformin to increase glucose uptake in skeletal muscle.

Metformin (dimethylbiguanide) belongs to guanidinium-derivative and is widely used for treatment of diabetic disorders in clinic. Metformin lowers blood glucose in diabetic animals through increase of glucose uptake into skeletal muscle. Recent evidence indicates that activation of imidazoline I2B receptor (I2BR) by guanidinium-derivatives also increased glucose uptake; however, the effect of metformin on I2BR is still unknown. The blood glucose levels were determined by a glucose kit. The ability of glucose uptake into isolated skeletal muscle or cultured C2C12 cells was determined using 2-[14C]-deoxyglucose as tracer. The expressions of 5' AMP-activated protein kinase (AMPK) and glucose transporter 4 (GLUT-4) were identified by Western blotting analysis. The metformin-induced blood glucose-lowering action was dose-dependently blocked by BU224, a specific I2R antagonist, in Wistar rats. Also, similar reversion by BU224 was observed in isolated skeletal muscle regarding the metformin-induced glucose uptake. Moreover, AMPK phosphorylation by metformin was concentration-dependently reduced by BU224 in isolated skeletal muscle. In addition, signals for metformin increased glucose uptake were identified via I2R/PI3K/PKC/AMPK dependent pathway in C2C12 cells. Thus, we suggest that metformin can activate I2BR to increase glucose uptake and I2BR will be a new target for diabetic therapy.

Decrease of blood lipids induced by Shan-Zha (fruit of Crataegus pinnatifida) is mainly related to an increase of PPARα in liver of mice fed high-fat diet.

Hyperlipidemia is an important risk factor for cardiovascular diseases. Agents for the treatment of hyperlipidemia are well-developed in the clinic while PPARα is a target for lipid-lowering agents. Shan-Zha (Crataegus pinnatifida) is a traditional Chinese medicine used to increase digestion. Also, Shan-Zha fruit extract showed merit to improve obesity and hyperlipidemia in hamsters; however, the mechanism remained obscure. In the present study, hypertriglycemia and hypercholesterolemia were induced by high fat diet in C57BL/6 J male mice. Then, they were orally administered with Shan-Zha fruit extract at an effective dose of 250 mg/kg for 7 days. The liver was removed to estimate the expressions of PPARα and ß-oxidation-related enzyme. Oral intake of Shan-Zha extract significantly improved hyperlipidemia in high fat diet-fed mice with an increase of PPARα expression in liver. Also, expression of PPARα-regulated ß-oxidation-related enzymes was raised in liver by Shan-Zha extract. However, adipose tissue and others were not modified by this treatment of Shan-Zha fruit extract. Thus, Shan-Zha can increase the expression of PPARα to facilitate ß-oxidation-related enzymes in liver for lipid degradation and blood lipid decrement. Also, this is the first report showing Shan-Zha fruit extract can influence liver to lower hyperlipidemia prior to the action in adipose tissue.

Pharmacological activation of peroxisome proliferator-activated receptor δ improves insulin resistance and hepatic steatosis in high fat diet-induced diabetic mice.

The mechanisms regarding hepatic steatosis related to hepatic insulin resistance have been well documented. However, the agents for treatment of hepatic steatosis and insulin resistance remain poorly developed. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that are responsible for the regulation of glucose and/or lipid metabolism. There are 3 distinct isoforms of PPARs family: PPARα, PPARγ, and PPARδ. Both PPARα and PPARγ agonists are widely used in clinic for the treatment of hyperlipidemia and hyperglycemia. However, the therapeutic efficacy of PPARδ agonists for diabetic disorders remains obscure. In the present study, we used L-165041 as PPARδ agonist to treat the high fat diet (HFD) fed mice. Administration of L-165041 improved the hepatic steatosis and increased the insulin sensitivity in HFD-mice. In addition to the histological identification of hepatic steatosis, the improvement of insulin sensitivity was characterized by the enhanced insulin signals and the increase of hepatic glycogen content. This is the first report showing that pharmacological activation of PPARδ improves insulin resistance in diet-induced diabetic mice. Thus, we suggest that pharmacological activation of PPARδ may be a new strategy for the treatment of diabetic patients with hepatic steatosis.

Current drug discovery strategies for treatment of hepatitis C virus infection.

OBJECTIVES: Hepatitis C virus (HCV) infection represents a major worldwide-health problem. The current standard of care is combination therapy with pegylated interferon and ribavirin, which achieves a successful response in only approximately 40% of genotype I patients. KEY FINDINGS: The biology of HCV infection has been under intensive research and important progress has been made in understanding the replication cycle of the virus. Several therapeutic targets have been under investigation, such as NS3 protease, NS4A replicase and NS5B polymerase. New potential targets, such as NS2 protease, as well as CD-81 and claudin-1 entry co-receptors, have also been identified. SUMMARY: Clinical evaluations of drug candidates targeting NS3 protease, NS4A cofactor, and NS5B polymerase have demonstrated the potential of developing small molecules that interfere with the replication of the virus. Additional issues, including genotype coverage, resistant mutations, and combination therapy represent major challenges for future drug discovery efforts.

Multimedia manuscript: laparoscopic resection of hepatocellular carcinoma at segment 7: the posterior approach to anatomic resection.

BACKGROUND: Open anatomical liver resections remain one of the most effective treatments of hepatocellular carcinoma (HCC) and results in better recurrence-free and overall survival compared to nonanatomical resections [1]. On the other hand, laparoscopic hepatectomies for HCC have recently emerged with the benefits of reduced blood loss, shorter hospital stay, and less severe wound pain [2, 3]. Classically, liver lesions considered suitable for laparoscopic resection were those small tumors (<4 cm) located over the anterior and left lateral segments [3]. However, we would like to expand the current indications and here we present our techniques of laparoscopic anatomical resection for a HCC that was located at right posteriosuperior segment 7. METHODS: Our patient was a 60-year-old gentleman who had Child's A hepatitis B cirrhosis and was on entecavir. During a follow-up CT scan, a 2.6-cm segment 7 lesion with early arterial enhancement and contrast washout was noted and was subsequently confirmed with arteriogram. α-Fetoprotein was 3 ng/ml (normal < 20 ng/ml). The video demonstrates a posterior approach to laparoscopic resection of segment 7. RESULTS: Operative time was 510 min. Blood loss was 800 ml and no perioperative transfusion was required. Postoperative recovery was uneventful and only simple oral analgesics were required for pain control. He was discharged on postoperative day 6. Histology showed a moderately differentiated hepatocellular carcinoma and all resection margins were clear. Subsequent follow-up CT scan 6 months after the operation showed no evidence of recurrence and α-fetoprotein level was normal. CONCLUSIONS: Laparoscopic hepatectomy for HCC over the right posterior segment of the liver is feasible in selected patients with favorable results in terms of wound size, postoperative recovery, and hospital stay. Maximal liver conservation was achieved in performing oncologic anatomical resection of segment 7 instead of a posterior sectionectomy. On the other hand, a posterior approach was recommended because it allowed early intrahepatic control of pedicles and identification of the right hepatic vein to guide parenchymal transection along the intersegmental plane.