Epidemiology, Treatment Patterns and Survival in Canadian Patients With Chronic Hepatitis B-Related Hepatocellular Carcinoma.

Chronic hepatitis B (CHB) is the leading cause of hepatocellular carcinoma (HCC) globally. We described and evaluated the outcomes of patients with CHB-HCC in Canada. In this retrospective cross-sectional cohort study, data were analysed from CHB mono-infected subjects seen between 1 January 2012 and 31 December 2022, and entered the Canadian Hepatitis B Network Registry. Descriptive analysis and chi-squared modelling were used to compare cohorts, followed by multivariable survival analysis regarding survival post-diagnosis. Statistical analyses were completed in R version 2.2. Of the 6711 patients with CHB who met inclusion criteria, 232 (3.5%) developed HCC. Compared with the CHB cohort, the majority of CHB-HCC cohort were male, SEA and HBeAg negative and born in endemic area (80% vs. 56%, 73% vs. 55%, 84% vs. 54%, 64% vs. 40% and all p < 0001). Overall, median HBV DNA level was log 2.54 (IQR: 0-4.04). Advanced liver disease, defined as minimum Fibrosis stage F3, was seen in 9.4% of overall cohort, but 92% of HCC cohort. At diagnosis, median tumour size was 2.5 cm (IQR: 1.7-4.0) and mean tumour number was 1.33 (SD: 1.33), with 81% of patients BCLC 0-A. Fifty-three per cent of patients were diagnosed with HCC as part of surveillance protocols. The survival rate after HCC diagnosis was 78.7%, during the median follow-up of 52.9 months (IQR: 17-90). In multivariable analysis, survival was significantly correlated with diagnosis through the screening programme. In this large cohort of patients with CHB-HCC, the majority of patients were detected with early-stage HCC and received treatment with curative intent, resulting in strong survival rates.

Brain metastases in Asian HER2-positive breast cancer patients: anti-HER2 treatments and their impact on survival.

BACKGROUND: In Asia, large-scale studies on anti-HER2 treatment in HER2-positive breast cancer patients with brain metastases are limited. We studied the treatment patterns of these patients in Asia to evaluate the impact of anti-HER2 treatment on the time to occurrence of brain metastases (TTBM) and survival after brain metastasis (BM). METHODS: A retrospective study of HER2-positive breast cancer patients diagnosed with BM between January 2006 and December 2008 in six Asian countries was conducted. Demographics, tumour characteristics, treatment details, and events dates were collected from medical records. RESULTS: Data from 280 patients were analysed. Before BM, 63% received anti-HER2 treatment. These patients had significantly longer TTBM than those without anti-HER2 treatment (median 33 vs 19 months; P<0.002). After BM, 93% received radiotherapy, 57% received chemotherapy, and 41% received anti-HER2 treatment (trastuzumab and/or lapatinib). Use of both anti-HER2 agents, primarily sequentially, after BM demonstrated the longest survival after BM and was associated with a significant survival benefit over no anti-HER2 treatment (median 26 vs 6 months; hazard ratio 0.37; 95% CI 0.19-0.72). CONCLUSION: Anti-HER2 treatment before BM was associated with longer TTBM. Anti-HER2 treatment after BM was associated with a survival benefit, especially when both trastuzumab and lapatinib were utilised.

Long-term (37 years) clinical outcome of older women with early operable primary breast cancer managed in a dedicated clinic.

BACKGROUND: A dedicated clinic for older women with early primary breast cancer, established in 1973, has recently evolved into a combined surgical/oncology facility. This study aimed to compare the clinical outcome across these periods. METHODS: From 1973 to 2010, 1758 women were managed. Analysis was carried out based on retrospective review and continued update of patient records. RESULTS: In the recent decade, 56.3% had surgery, followed by primary endocrine therapy (PET; 41.1%) and primary radiotherapy (1.5%). Before 1999, 42.8%, 55.6% and 1% of patients had surgery, PET and primary radiotherapy, respectively. The use of adjuvant endocrine therapy and radiotherapy has increased from 33.6% to 54.9% and 5.8% to 34.6%, respectively. A significant improvement was seen in the annual rates of local (2.2% versus 0.5%, P < 0.001), regional (1.8% versus 0.4%, P < 0.001) and distant (2.9% versus 1.9%, P = 0.002) recurrences. Similarly, the 5-year breast cancer-specific and overall survival rates showed improvement [81% versus 91% (P < 0.001) and 56% versus 71% (P < 0.001), respectively]. CONCLUSIONS: In the recent decade, while surgery became the predominant treatment, a significant proportion of patients had non-operative therapies, selection of which was based on multidisciplinary assessment in the clinic. This management approach appears to produce excellent clinical outcome, which is significantly better than that in earlier period.

Long-term clinical outcome of oestrogen receptor-positive operable primary breast cancer in older women: a large series from a single centre.

INTRODUCTION: A Cochrane review of seven randomised trials (N=1571) comparing surgery and primary endocrine therapy (PET) (oestrogen receptor (ER) unselected) shows no difference in overall survival (OS). We report outcome of a large series with ER-positive (ER+) early invasive primary breast cancer. METHODS: Between 1973 and 2009, 1065 older (≥ 70 years) women (median age 78 years (70-99)) had either surgery (N=449) or PET (N=616) as initial treatment. RESULTS: At 49-month median follow-up (longest 230 months), the 5-year breast cancer-specific survival (BCSS) and OS were 90 and 62%, respectively. Majority (74.2%) died from causes other than breast cancer. The rates (per annum) of local/regional recurrence (<1%) (following surgery), contralateral tumour (<1%) and metastases (<3%) were low. For patients on PET, 97.9% achieved clinical benefit (CB) at 6 months, with median time to progression of 49 months (longest 132 months) and significantly longer BCSS when compared with those who progressed (P<0.001). All patients with strongly ER+ (H-score >250) tumours achieved CB and had better BCSS (P<0.01). Patients with tumours having an H-score >250 were found to have equivalent BCSS regardless of treatment (surgery or PET; P=0.175), whereas for those with H-score ≤ 250, surgery produced better outcome (P<0.001). CONCLUSION: Older women with ER+ breast cancer appear to have excellent long-term outcome regardless of initial treatment. Majority also die from non-breast cancer causes. Although surgery remains the treatment of choice, patients with ER-rich (H-score >250) tumours tend to do equally well when treated by PET. This should be taken into account when therapies are considered.

Chemoradiotherapy for rectal cancer: an updated analysis of factors affecting pathological response.

AIMS: With the aim of improving locoregional control, the use of preoperative chemoradiotherapy (CRT) for rectal cancer has increased. A pathological complete response (pCR) is often used as a surrogate marker for the efficacy of different CRT schedules. By analysing factors affecting pCR, this analysis aims to guide the development of future trials. MATERIALS AND METHODS: Searches of Medline, EMBASE and the electronic American Society of Clinical Oncology abstract databases were carried out to identify prospective phase II and phase III trials using preoperative CRT to treat rectal cancer. Trials were eligible for inclusion if they defined: the CRT drugs, the radiation dose and the pCR rate. Phase I patients were excluded from the analysis. A multivariate analysis examined the effect of the above variables on the pCR rate and in addition the use of neoadjuvant chemotherapy, the type of publication (peer reviewed vs abstract), the year of publication and whether the cancers were stated to be inoperable, fixed or threatening the circumferential resection margin were included. The method of analysis used was weighted linear modelling of the pCR rate. RESULTS: Sixty-four phase II and seven phase III trials were identified including a total of 4732 patients. Statistically significant factors associated with pCR were the use of two drugs, the method of fluoropyrimidine administration (with continuous intravenous 5-fluorouracil being the most effective) and a higher radiotherapy dose. Although the use of two drugs was associated with a higher rate of pCR, no single schedule seemed to be more effective. None of the other factors analysed significantly influenced pCR. CONCLUSIONS: A higher rate of pCR is seen in studies using two drugs, infusional 5-fluorouracil and a radiotherapy dose of 45 Gy and above.

Use of imatinib mesylate in gastrointestinal stromal tumours: Pan-Birmingham Cancer Network experience.

AIMS: Imatinib mesylate, a selective tyrosine kinase receptor inhibitor of KIT and PDGFRalpha, is currently licensed for the treatment of unresectable or metastatic gastrointestinal stromal tumours (GISTs), which are KIT positive. Partial response rates in 65% of patients and stable disease in 20% of patients are typically seen. The aim of this study was to assess the effectiveness and toxicity of an unselected cohort of patients treated with imatinib mesylate and to compare these results with published data. MATERIALS AND METHODS: A retrospective audit of the use of imatinib mesylate in GISTs within the Pan-Birmingham Cancer Network was carried out. In total, 39 patients were identified, the first commenced imatinib mesylate in September 2001. RESULTS: The most common primary tumour sites were small intestine (19 [49%]) and stomach (12 [31%]). Initial curative resection was carried out in 21 (54%), palliative resection in three (8%) and 15 (38%) were unresectable. Of those who had curative resection, the median time to recurrence was 13 months (range 2-276). Common sites of metastases were liver (19 [49%]) and peritoneum (12 [31%]). At 24 months 70% remained on imatinib. A partial response was reported in 23 (59%), stable disease in seven (18%) and disease progression in four (10%). Five patients (13%) have yet to be reassessed at 3 months. Imatinib was well tolerated with minor side-effects; peri-orbital oedema (nine [23%]), skin rash (four [10%]), minor gastrointestinal bleed (one [3%]). No significant toxicity was documented in 18 (46%). CONCLUSIONS: The response rates achieved in this unselected cohort of patients are consistent with published data. The duration of tumour control is good, with most patients responding to imatinib mesylate for more than 2 years. Side-effects are mild and acceptable.

Synergistic action of recombinant alpha-amylase and glucoamylase on the hydrolysis of starch granules.

Barley alpha-amylase 1 mutant (AMY) and Lentinula edodes glucoamylase (GLA) were cloned and expressed in Saccharomyces cerevisiae. The purified recombinant AMY hydrolyzed corn and wheat starch granules, respectively, at rates 1.7 and 2.5 times that of GLA under the same reaction conditions. AMY and GLA synergistically enhanced the rate of hydrolysis by approximately 3x for corn and wheat starch granules, compared to the sum of the individual activities. The exo-endo synergism did not change by varying the ratio of the two enzymes when the total concentration was kept constant. A yield of 4% conversion was obtained after 25 min 37 degrees C incubation (1 unit total enzyme, 15 mg raw starch granules, pH 5.3). The temperature stability of the enzyme mixtures was < or =50 degrees C, but the initial rate of hydrolysis continued to increase with higher temperatures. Ca(++) enhanced the stability of the free enzymes at 50 degrees C incubation. Inhibition was observed with the addition of 10 mM Fe(++) or Cu(++), while Mg(++ )and EDTA had lesser effect.

Downregulation of renal tubular Wnt/ß-catenin signaling by Dickkopf-3 induces tubular cell death in proteinuric nephropathy.

Studies on the role of Wnt/ß-catenin signaling in different forms of kidney disease have yielded discrepant results. Here, we report the biphasic change of renal ß-catenin expression in mice with overload proteinuria in which ß-catenin was upregulated at the early stage (4 weeks after disease induction) but abrogated at the late phase (8 weeks). Acute albuminuria was observed at 1 week after bovine serum albumin injection, followed by partial remission at 4 weeks that coincided with overexpression of renal tubular ß-catenin. Interestingly, a rebound in albuminuria at 8 weeks was accompanied by downregulated tubular ß-catenin expression and heightened tubular apoptosis. In addition, there was an inverse relationship between Dickkopf-3 (Dkk-3) and renal tubular ß-catenin expression at these time points. In vitro, a similar trend in ß-catenin expression was observed in human kidney-2 (HK-2) cells with acute (upregulation) and prolonged (downregulation) exposure to albumin. Induction of a proapoptotic phenotype by albumin was significantly enhanced by silencing ß-catenin in HK-2 cells. Finally, Dkk-3 expression and secretion was increased after prolonged exposure to albumin, leading to the suppression of intracellular ß-catenin signaling pathway. The effect of Dkk-3 on ß-catenin signaling was confirmed by incubation with exogenous Dkk-3 in HK-2 cells. Taken together, these data suggest that downregulation of tubular ß-catenin signaling induced by Dkk-3 has a detrimental role in chronic proteinuria, partially through the increase in apoptosis.

Guided current-induced skyrmion motion in 1D potential well.

Magnetic skyrmions are particle-like magnetization configurations which can be found in materials with broken inversion symmetry. Their topological nature allows them to circumvent around random pinning sites or impurities as they move within the magnetic layer, which makes them interesting as information carriers in memory devices. However, when the skyrmion is driven by a current, a Magnus force is generated which leads to the skyrmion moving away from the direction of the conduction electron flow. The deflection poses a serious problem to the realization of skyrmion-based devices, as it leads to skyrmion annihilation at the film edges. Here, we show that it is possible to guide the movement of the skyrmion and prevent it from annihilating by surrounding and compressing the skyrmion with strong local potential barriers. The compressed skyrmion receives higher contribution from the spin transfer torque, which results in the significant increase of the skyrmion speed.

HLA-DR typing: a comparison between nylon wool adherence and T cell rosetting in the isolation of B cells.

A comparison was made between two different methods of B cell isolation, nylon wool adherence versus SRBC rosetting in terms of the technical ease of B cell purification and the reproducibility of DR phenotyping. It was found that B cells isolated by either method from 30 randomly selected donors gave equivalent results in the determination of DR phenotypes. Due to its simplicity and reliability, nylon wool adherence may be preferred over the SRBC rosette method for the routine phenotyping of B cells.

Technetium-99m-human fibrinogen.

Exogenous fibrinogen has been successfully labeled with 99mTc using a modified electrolytic method. The exact labeling mechanism has not been determined. Experimental data suggest that the labeling process of 99mTc-fibrinogen is quite similar to that of 99mTc-human serum albumin as reported earlier by Benjamin. Technetium-99m-fibrinogen is stable in human plasma or in 1% buffered human serum albumin. A binding efficiency of 76% has been achieved with approximately 25% clottable protein. The entire labeling procedure requires less than 1 hr of preparation time. This short labeling time in a closed system may allow development of a practical method for labeling autologous fibrinogen, thus eliminating the risk of hepatitis transmission.

In vitro assessment of Tc-99m labeled bovine thrombin and streptokinase-activated human plasmin: concise communication.

Bovine thrombin and streptokinase-activated human plasmin have been labeled with Tc-99m using stannous reduction of pertechnetate under physiological conditions (pH 7.4). The binding efficiency of radiotechnetium to these enzymes is greater than 94%, with less than 5% of reduced but unbound Tc-99m (Sn) complex as assayed by ascending paper radiochromatography using ITLC silica gel plate. Free or unbound pertechnetate is less than 1%. In vitro enzymatic analyses of the Tc-99m-labeled enzymes demonstrate no evidence of protein denaturation or significant loss of enzymatic activity after labeling. Both labeled enzymes are biochemically active in vitro with their respective substrates.

Imaging endocarditis with Tc-99m-labeled antibody--an experimental study: concise communication.

The sensitivity and specificity of Tc-99m-labeled antibacterial antibody (Tc-99m Ab) for detecting bacterial endocarditis were evaluated in an experimental model. Rabbit-produced antistaphylococcal antibody was extracted using Rivanol and chemically labeled with Tc-99m. This Tc-99m Ab was injected intravenously in New Zealand rabbits 24 hr after producing Staphylococcus aureus endocarditis of the aortic valve. Imaging and tissue analyses were performed on the following day. All 11 animals developed S. aureus aortic-valve vegetations and showed increased uptake of Tc-99m Ab at the aortic valve, 118 times higher than at the uninfected tricuspid valve. Although high hepatic radioactivity and anatomic uncertainties interfered with in vivo delineation of these lesions, images of the excised hearts showed all affected valves. Two rabbits inoculated with Escherichia coli did not develop endocarditis and had little uptake of Tc-99m Ab, while six rabbits with enterococcal endocarditis had no uptake of the Tc-99m Ab in their vegetations. The findings suggest potential value of Tc-99m Ab on the rapid diagnosis of endocarditis.

Collagen induces cytokine production by synovial fluid mononuclear cells in rheumatoid arthritis.

Synovial fluid (SF) mononuclear cells (MNC) from 13 patients with rheumatoid arthritis (RA) and 12 patients with other arthritic diseases (OD) including osteoarthritis (OA), gout and spondyloarthritis (SA) were cultured in the presence of collagen types I and II or lipopolysaccharide (LPS) for 24 h. Interleukin-1 (IL-1), IL-6 and tumor necrosis factor-alpha (TNF-alpha) in the SF and culture supernatants were assayed using ELISA. The results showed that one-half of the RA patients with high SF monocyte count had high SF IL-6 levels that coincided with the high spontaneous release of IL-6 by SF MNC. In the other RA patients with lower SF monocyte count, type II collagen induced significantly higher IL-1 beta than the medium control levels by SF MNC (P < 0.01) or that of the other diseases (P < 0.01). Similarly, type II collagen-induced IL-6 and TNF-alpha production rose significantly (P < 0.01) from SF MNC of RA but less from OD (P < 0.05). In addition, type I collagen could also induce IL-1, IL-6 and TNF-alpha in these samples from RA and OD patients but was less potent than type II collagen. Our results indicate that collagen-induced cytokines may be important in the pathogenesis of the disease.

Polypoidal choroidal vasculopathy and neovascularized age-related macular degeneration.

OBJECTIVE: To determine the nature and frequency of polypoidal choroidal vasculopathy (PCV) in a series of patients suspected of having neovascularized age-related macular degeneration (AMD). METHODS: A prospective analysis of 167 consecutive, newly diagnosed patients aged 55 years or older with presumed neovascularized AMD was performed. All patients were examined with fundus biomicroscopy as well as fluorescein and indocyanine green angiography. RESULTS: Choroidal neovascularization secondary to AMD was diagnosed in 154 (92.2%) of 167 patients; 13 (7.8%) patients had PCV. The patients affected by PCV were younger than those with AMD (P = .01). Peripapillary choroidal neovascularization was seen in 3 (1.9%) of 154 patients with AMD and 3 (23.1%) of 13 patients with PCV (P = .006). Significant drusen were present in 63 (70%) of 90 fellow eyes with unilateral AMD compared with only 1 (16.7%) of 6 eyes with PCV (P = .02). Only 5 patients with AMD (3.2%) were nonwhite compared with 3 patients with PCV (23.1%) (P = .02). CONCLUSIONS: A measurable number of elderly patients with findings suggestive of neovascularized AMD and serosanguineous macular manifestations will instead have PCV. Polypoidal choroidal vasculopathy can occur in any sex or race, but is more commonly seen in the peripapillary area, without associated drusen, and in nonwhite patients. It is important to differentiate AMD from PCV because there are significant differences in the demographic risk profile, natural course, visual prognosis, and management of these patients.

Cloning and characterization of two cellulase genes from Lentinula edodes.

Lentinula edodes has traditionally been grown on fallen logs. It produces a wide array of enzymes to digest the lignocellulolytic substrate for nutrients. Thus, this organism represents a rich source of potentially potent lignocellulolytic enzymes that can be harnessed for conversion of biomass to simple sugars. These sugars can then be used as feedstock for ethanol production or other chemical syntheses. We have cloned two cellulase genes from L. edodes grown on a wood substrate without the use of genomic or cDNA libraries by using a PCR-based strategy employing degenerate primers directed at the cellulose-binding domain. cel7A encoded a 516-amino acid protein that belonged to glycosyl hydrolase family 7 and had sequence similarities to cbhI genes from other fungi. cel6B encoded a 444-amino acid protein that belonged to glycosyl hydrolase family 6 and had sequence similarities to cbhII genes from other fungi. We demonstrated that cel7A and cel6B transcript levels were positively correlated to L. edodes growth in the presence of crystalline cellulose.

Rapid detection of acute appendicitis with Tc-99m-labeled intact polyvalent human immune globulin.

BACKGROUND: Acute appendicitis remains problematic for emergency clinicians. A rapid and definitive test is needed for detecting acute appendicitis before surgical intervention. The purpose of this clinical trial was to determine the efficacy of Tc-99m-labeled intact polyvalent human immune globulin (Tc-99m IgG) in the evaluation of acute appendicitis. STUDY DESIGN: Thirty-five patients with clinically suspected acute appendicitis were evaluated with Tc-99m IgG. After the intravenous injection of 25 mCi (92.5 MBq) of Tc-99m IgG, anterior flow, single photon emission computerized tomography (SPECT) and planar delayed images of the abdomen were obtained. Any abnormal focal uptake of Tc-99m IgG in the right lower quadrant was considered to be a positive scan. RESULTS: Twenty-one patients with a positive Tc-99m IgG scan underwent laparotomy and were found to have acute appendicitis. Of the 14 patients who had negative scans, 7 underwent surgery. In this series, Tc-99m IgG study yielded 21 true-positive, 12 true-negative, and 2 false-negative results with a sensitivity, specificity, and accuracy of 91%, 100%, and 94%, respectively. The positive and negative predictive values were 100% and 86%, respectively. There were no false-positive results. CONCLUSIONS: Tc-99m IgG scintigraphy can provide the clinicians a simple, rapid, and definitive test for the diagnosis of acute appendicitis.

Harvesting a lamellar graft from a corneoscleral button: a new technique.

PURPOSE: To describe a new technique for harvesting a lamellar graft from a corneoscleral button in the absence of an artificial anterior chamber. METHODS: Two layers of sterile fine-weave fabric were wrapped tightly around a glass orbital implant. The corneoscleral button was sutured firmly at its scleral rim onto the fabric. The lamellar graft then was dissected in the regular fashion. RESULTS: The lamellar graft was successfully obtained. During the dissection, the donor cornea and its supporting fabric-covered glass ball were easily handled, and there was minimal risk of perforation of the posterior lamella of the donor cornea. CONCLUSION: This simple technique allows a lamellar graft to be easily obtained from a corneoscleral button without specialized and expensive equipment.

Technetium-99m IgG immunodetection of acute appendicitis in rats.

The efficacy of Tc-99m-labeled intact polyvalent human immune globulin (IgG) for the early localization and detection of acute appendicitis was evaluated by an animal model. Acute appendicitis was surgically produced in adult Sprague-Dawley white rats by ligating a 3-cm segment of the caecum and inoculating with E. coli. After 4-5 days, nuclear scintigraphy was performed following intravenous injection of 5 mCi of Tc-99m IgG via the tail vein. Appendiceal and colonic infections were clearly visualized by Tc-99m IgG scans within 30 min postinjection and confirmed by autopsy and tissue distribution data. With the exception of the liver, the kidneys, and the urinary bladder, abdominal tissue background activity was minimal. These findings suggest that Tc-99m-labeled intact IgG may have potential clinical application in the early detection and diagnosis of acute appendicitis in emergency medicine.

Detection of acute infection/inflammation with Tc-99m labeled intact polyvalent human IgG.

Intact polyvalent human immune globulin (IgG) labeled with Tc-99m by a mild chemical method was investigated with animals infected with either S. aureus or E. coli in the thigh muscle. Focal infection was clearly visualized by Tc-99m IgG scintigraphy within 1 h postinjection. Tc-99m IgG appeared to be concentrated in the liver, spleen, kidneys and urinary bladder. It cleared rapidly via the kidneys resulting minimal of tissue background activity and high infection-to-normal organ ratios. At 24 h postinjection, the ratios of infectious lesion to blood, normal muscle and bone averaged 10:1, 23:1, and 24:1 for S. aureus infection vs 4:1, 9:1 and 9:1 for E. coli infection, respectively. Tc-99m labeled IgG also concentrated in terpentine-induced aseptic inflammatory lesion with a target-to-blood ratio of 4:1, bone 6:1 and normal muscle about 10:1. These findings suggest potential value of Tc-99m IgG as an imaging agent for the early detection of focal infection and inflammation.