Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Sharpin promotes hepatocellular carcinoma progression via transactivation of Versican expression
Oncogenesis 5, e277 (December 2016). doi:10.1038/oncsis.2016.76
Authors: Y Tanaka, K Tateishi, T Nakatsuka, Y Kudo, R Takahashi, K Miyabayashi, K Yamamoto, Y Asaoka, H Ijichi, R Tateishi, J Shibahara, M Fukayama, T Ishizawa, K Hasegawa, N Kokudo & K Koike
ERK-mediated NF-κB activation through ASIC1 in response to acidosis
Oncogenesis 5, e279 (December 2016). doi:10.1038/oncsis.2016.81
Authors: B Chen, J Liu, T-T Ho, X Ding & Y-Y Mo
In vivo functional dissection of a context-dependent role for Hif1α in pancreatic tumorigenesis
Oncogenesis 5, e278 (December 2016). doi:10.1038/oncsis.2016.78
Authors: T Cheng, Z Jian, K Li, S Raulefs, I Regel, S Shen, X Zou, J Ruland, G O Ceyhan, H Friess, C W Michalski, J Kleeff & B Kong
Sharpin promotes hepatocellular carcinoma progression via transactivation of Versican expression
Oncogenesis 5, e277 (December 2016). doi:10.1038/oncsis.2016.76
Authors: Y Tanaka, K Tateishi, T Nakatsuka, Y Kudo, R Takahashi, K Miyabayashi, K Yamamoto, Y Asaoka, H Ijichi, R Tateishi, J Shibahara, M Fukayama, T Ishizawa, K Hasegawa, N Kokudo & K Koike
Background. The analgesic efficacy of continuous transversus abdominis plane (TAP) blocks in comparison with that of single-injection TAP blocks is not clear. This randomized, triple-blind, placebo-controlled trial investigated the benefits of adding continuous TAP blocks to single-injection TAP blocks after a laparotomy.
Methods. Eighty consecutive patients undergoing midline laparotomy for gynaecological cancer were randomized and received bilateral TAP infusions with either ropivacaine 0.1% (n=40, Rop group) or normal saline (n=40, NS group) at 10 ml h–1 per side for 50 h after surgery. After surgery, bilateral oblique subcostal TAP blocks were performed using ropivacaine 0.1%, 50 ml per side, and then catheters were threaded into the bilateral TAPs. Subsequently, continuous TAP infusions and patient-controlled i.v. morphine administration were initiated. The primary outcome was cumulative morphine consumption by 24 h after TAP catheter placement. Secondary outcomes included pain scores, postoperative nausea and vomiting severity, and time to first ambulation and flatus.
Results. The cumulative morphine consumption (median [interquartile range]) 24 h after TAP catheter placement was lower in the Rop group (0.25 [0.11–0.48] mg kg–1) than in the NS group (0.44 [0.24–0.73] mg kg–1; 95% confidence interval difference in medians, –0.30 to – 0.03; P=0.01). No statistically significant differences were observed in the secondary outcomes, except for reduced pain scores in the Rop group obtained during coughing 1 and 24 h after TAP catheter placement.
Conclusions. Addition of continuous TAP blocks to single-injection TAP blocks reduces pain and morphine consumption after a laparotomy for gynaecological cancer.
Clinical trial registration. UMIN Clinical Trials Registry identification number UMIN000013449 (http://ift.tt/1lXJedE).
Background. Decreased plasma fibrinogen concentration shortly after injury is associated with higher blood transfusion needs and mortality. In North America and the UK, cryoprecipitate transfusion is the standard-of-care for fibrinogen supplementation during acute haemorrhage, which often occurs late during trauma resuscitation. Alternatively, fibrinogen concentrate (FC) can be beneficial in trauma resuscitation. However, the feasibility of its early infusion, efficacy and safety remain undetermined. The objective of this trial was to evaluate the feasibility, effect on clinical and laboratory outcomes and complications of early infusion of FC in trauma.
Methods. Fifty hypotensive (systolic arterial pressure ≤100 mm Hg) adult patients requiring blood transfusion were randomly assigned to either 6 g of FC or placebo, between Oct 2014 and Nov 2015 at a tertiary trauma centre. The primary outcome, feasibility, was assessed by the proportion of patients receiving the intervention (FC or placebo) within one h of hospital arrival. Plasma fibrinogen concentration was measured, and 28-day mortality and incidence of thromboembolic events were assessed.
Results. Overall, 96% (43/45) [95% CI 86–99%] of patients received the intervention within one h; 95% and 96% in the FC and placebo groups, respectively (P=1.00). Plasma fibrinogen concentrations remained higher in the FC group up to 12 h after admission with the largest difference at three h (2.9 mg dL –1 vs. 1.8 mg dL –1; P<0.01). The 28-day mortality and thromboembolic complications were similar between groups.
Conclusions. Early infusion of FC is feasible and increases plasma fibrinogen concentration during trauma resuscitation. Larger trials are justified.
Background. The incidence of intraneural injection during trainee anaesthetist ultrasound guided nerve block varies between 16% in experts and up to 35% in trainees. We hypothesized that elastography, an ultrasound-based technology that presents colour images of tissue strain, had the potential to improve trainee diagnosis of intraneural injection during UGRA, when integrated with B-Mode ultrasound onto a single image.
Methods. We recorded 40 median nerve blocks randomly allocated to 0.25 ml, 0.5 ml, 1 ml volumes to five sites, on both arms of two soft embalmed cadavers, using a dedicated B-Mode ultrasound and elastography transducer. We wrote software to fuse elastogram and B-Mode videos, then asked 20 trainee anaesthetists whether injection was intraneural or extraneural when seeing B-Mode videos, adjacent B-Mode and elastogram videos, fusion elastography videos or repeated B-Mode ultrasound videos.
Results. Fusion elastography improved the diagnosis of intraneural injection compared with B-Mode ultrasound, Diagnostic Odds Ratio (DOR) (95%CI) 21.7 (14.5 - 33.3) vs DOR 7.4 (5.2 – 10.6), P < 0.001. Compared with extraneural injection, intraneural injection was identified on fusion elastography as a distinct, brighter translucent image, geometric ratio 0.33 (95%CI: 0.16 – 0.49) P < 0.001. Fusion elastography was associated with greater trainee diagnostic confidence, OR (95%CI) 1.89 (1.69 – 2.11), P < 0.001, and an improvement in reliability, Kappa 0.60 (0.55 - 0.66).
Conclusions. Fusion elastography improved the accuracy, reliability and confidence of trainee anaesthetist diagnosis of intraneural injection.
Background. The laparoscopic approach is becoming increasingly frequent for many different surgical procedures. However, the combination of pneumoperitoneum and Trendelenburg positioning associated with this approach may increase the patient's risk for elevated intracranial pressure (ICP). Given that the gold standard for the measurement of ICP is invasive, little is known about the effect of these common procedures on ICP.
Methods. We prospectively studied 40 patients without any history of cerebral disease who were undergoing laparoscopic procedures. Three different methods were used for non-invasive estimation of ICP: ultrasonography of the optic nerve sheath diameter (ONSD); transcranial Doppler-based (TCD) pulsatility index (ICPPI); and a method based on the diastolic component of the TCD cerebral blood flow velocity (ICPFVd). The ONSD and TCD were measured immediately after induction of general anaesthesia, after pneumoperitoneum insufflation, after Trendelenburg positioning, and again at the end of the procedure.
Results. The ONSD, ICPFVd, and ICPPI increased significantly after the combination of pneumoperitoneum insufflation and Trendelenburg positioning. The ICPFVd showed an area under the curve of 0.80 [95% confidence interval (CI) 0.70–0.90] to distinguish the stage associated with the application of pneumoperitoneum and Trendelenburg position; ONSD and ICPPI showed an area under the curve of 0.75 (95% CI 0.65–0.86) and 0.70 (95% CI 0.58–0.81), respectively.
Conclusions. The concomitance of pneumoperitoneum and the Trendelenburg position can increase ICP as estimated with non-invasive methods. In high-risk patients undergoing laparoscopic procedures, non-invasive ICP monitoring through a combination of ONSD ultrasonography and TCD-derived ICPFVd could be a valid option to assess the risk of increased ICP.
Lithium is widely used in medicine and the therapy is often long term. Apart from beneficial effects, its application can cause diverse side effects. The current study was performed with the aim of the evaluation of the effect of lithium and/or selenium administration on magnesium, calcium and silicon levels in rats. The study was performed on rats divided into four groups (six animals each): control—received saline, Li—received Li2CO3 (2.7 mg Li/kg b.w.), Se—received Na2SeO3·H2O (0.5 mg Se/kg b.w.), and Li+Se—received simultaneously Li2CO3 and Na2SeO3·H2O (2.7 and 0.5 mg Se/kg b.w.). The administration was performed in form of water solutions by a stomach tube once a day for 6 weeks. In the organs (liver, kidney, brain, spleen, heart, lung and femoral muscle), the concentrations of magnesium, calcium and silicon were determined. Lithium significantly increased Ca in the kidney, brain and spleen. Coadministration of selenium reversed this effect. No changes of magnesium in organs were observed. Silicon was affected only in spleen—an increase vs. control was observed in all studied groups. The beneficial influence of coadministration of selenium in case of calcium lets us suggest that an issue of its possible use as an adjuvant alleviating side effects in lithium-treated subjects is worth being continued.
Lithium is widely used in medicine and the therapy is often long term. Apart from beneficial effects, its application can cause diverse side effects. The current study was performed with the aim of the evaluation of the effect of lithium and/or selenium administration on magnesium, calcium and silicon levels in rats. The study was performed on rats divided into four groups (six animals each): control—received saline, Li—received Li2CO3 (2.7 mg Li/kg b.w.), Se—received Na2SeO3·H2O (0.5 mg Se/kg b.w.), and Li+Se—received simultaneously Li2CO3 and Na2SeO3·H2O (2.7 and 0.5 mg Se/kg b.w.). The administration was performed in form of water solutions by a stomach tube once a day for 6 weeks. In the organs (liver, kidney, brain, spleen, heart, lung and femoral muscle), the concentrations of magnesium, calcium and silicon were determined. Lithium significantly increased Ca in the kidney, brain and spleen. Coadministration of selenium reversed this effect. No changes of magnesium in organs were observed. Silicon was affected only in spleen—an increase vs. control was observed in all studied groups. The beneficial influence of coadministration of selenium in case of calcium lets us suggest that an issue of its possible use as an adjuvant alleviating side effects in lithium-treated subjects is worth being continued.
Biologicals directed against tumour necrosis factor (TNF) have proven their efficacy in the treatment of spondyloarthritis and rheumatoid arthritis. We present a radiolabelling method for certolizumab pegol (CZP), a commercially available humanized Fab′-fragment directed against TNF. A biodistribution and dosimetry study was conducted.
Tc-S-HYNIC CZP was synthesized. The in vitro TNF neutralizing activity was tested by exposing L929s-cells to various concentrations 99mTc-S-HYNIC CZP and measuring TNF-induced cytotoxicity. For biodistribution and dosimetry, WB images and blood and urine sampling were performed up to 24 h pi. Cumulative activities were estimated using mono-exponential fitting, and organ doses were estimated using OLINDA/EXM. The effective dose was calculated using the International Commission on Radiological Protection 103 recommendations. The uptake of the tracer in the peripheral joints was assessed visually and semiquantitatively.
In vitro tests showed blocking of TNF cytotoxicity by the 99mTc-S-HYNIC CZP formulation comparable to the effect obtained with the unlabelled CZP with or without the HYNIC linker. We analysed eight patients with rheumatoid arthritis or spondyloarthritis. The highest mean absorbed organ doses were recorded for kidneys, spleen, and liver: 56 (SD 7), 34 (SD 6), and 33 (SD 7) μGy/MBq. The effective dose was 6.1 (SD 0.9) mSv for a mean injected activity of 690 (SD 35) MBq. The urinary excretion was 15.1% (SD 8.1) of the IA at 22.5 h. Blood analysis yielded a distribution half-life of 1.2 h (SD 1.5) and an elimination half-life of 26.9 h (SD 2.7). Visual analysis of the scans revealed marked tracer accumulation in the clinically affected peripheral joints. In addition, there was a statistically significant higher uptake of the tracer in the swollen joints (median uptake ratio compared to background of 3.3 in rheumatoid arthritis and 2.4 in peripheral spondyloarthritis) compared to clinically negative joints (respectively 1.3 and 1.6).
We present a radiolabelling technique for CZP, a Fab′-fragment directed against TNF and currently used as a therapeutic agent in rheumatology. An effective dose of 6.1 mSv (SD 0.9) was estimated. We confirmed the uptake of this new radiopharmaceutical in clinically affected peripheral joints.
90Y PET/CT post-radioembolization imaging has demonstrated that the distribution of 90Y in a tumor can be non-uniform. Using computational modeling, we predicted the dosimetric impact of post-treatment 90Y PET/CT-guided percutaneous ablation of the portions of a tumor receiving the lowest absorbed dose. A cohort of fourteen patients with non-resectable liver cancer previously treated using 90Y radioembolization were included in this retrospective study. Each patient exhibited potentially under-treated areas of tumor following treatment based on quantitative 90Y PET/CT. 90Y PET/CT was used to guide electrode placement for simulated adjuvant radiofrequency ablation in areas of tumor receiving the lowest dose. The finite element method was used to solve Penne's bioheat transport equation, coupled with the Arrhenius thermal cell-death model to determine 3D thermal ablation zones. Tumor and unablated tumor absorbed-dose metrics (average dose, D50, D70, D90, V100) following ablation were compared, where D70 is the minimum dose to 70% of tumor and V100 is the fractional tumor volume receiving more than 100 Gy.
Compared to radioembolization alone, 90Y radioembolization with adjuvant ablation was associated with predicted increases in all tumor dose metrics evaluated. The mean average absorbed dose increased by 11.2 ± 6.9 Gy. Increases in D50, D70, and D90 were 11.0 ± 6.9 Gy, 13.3 ± 10.9 Gy, and 11.8 ± 10.8 Gy, respectively. The mean increase in V100 was 7.2 ± 4.2%. All changes were statistically significant (P < 0.01). A negative correlation between pre-ablation tumor volume and D50, average dose, and V100 was identified (ρ < − 0.5, P < 0.05) suggesting that adjuvant radiofrequency ablation may be less beneficial to patients with large tumor burdens.
This study has demonstrated that adjuvant 90Y PET/CT-guided radiofrequency ablation may improve tumor absorbed-dose metrics. These data may justify a prospective clinical trial to further evaluate this hybrid approach.
Sorafenib, an oral multikinase inhibitor, has anti-proliferative and anti-angiogenic activities and is therapeutically effective against renal cell carcinoma (RCC). Recently, we have evaluated the tumor responses to sorafenib treatment in a RCC xenograft using [Methyl-3H(N)]-3′-fluoro-3′-deoxythythymidine ([3H]FLT). Contrary to our expectation, the FLT level in the tumor significantly increased after the treatment. In this study, to clarify the reason for the elevated FLT level, dynamic 3′-[18F]fluoro-3′-deoxythymidine ([18F]FLT) positron emission tomography (PET) and kinetic studies were performed in mice bearing a RCC xenograft (A498).
The A498 xenograft was established in nude mice, and the mice were assigned to the control (n = 5) and treatment (n = 5) groups. The mice in the treatment group were orally given sorafenib (20 mg/kg/day p.o.) once daily for 3 days. Twenty-four hours after the treatment, dynamic [18F]FLT PET was performed by small-animal PET. Three-dimensional regions of interest (ROIs) were manually defined for the tumors. A three-compartment model fitting was carried out to estimate four rate constants using the time activity curve (TAC) in the tumor and the blood clearance rate of [18F]FLT.
The dynamic pattern of [18F]FLT levels in the tumor significantly changed after the treatment. The rate constant of [18F]FLT phosphorylation (k3) was significantly higher in the treatment group (0.111 ± 0.027 [1/min]) than in the control group (0.082 ± 0.009 [1/min]). No significant changes were observed in the distribution volume, the ratio of [18F]FLT forward transport (K1) to reverse transport (k2), between the two groups (0.556 ± 0.073 and 0.641 ± 0.052 [mL/g] in the control group).
Our dynamic PET studies indicated that the increase in FLT level may be caused by the phosphorylation of FLT in the tumor after the sorafenib treatment in the mice bearing a RCC xenograft. Dynamic PET studies with kinetic modeling could provide improved understanding of the biochemical processes involved in tumor responses to therapy.
Biologicals directed against tumour necrosis factor (TNF) have proven their efficacy in the treatment of spondyloarthritis and rheumatoid arthritis. We present a radiolabelling method for certolizumab pegol (CZP), a commercially available humanized Fab′-fragment directed against TNF. A biodistribution and dosimetry study was conducted.
Tc-S-HYNIC CZP was synthesized. The in vitro TNF neutralizing activity was tested by exposing L929s-cells to various concentrations 99mTc-S-HYNIC CZP and measuring TNF-induced cytotoxicity. For biodistribution and dosimetry, WB images and blood and urine sampling were performed up to 24 h pi. Cumulative activities were estimated using mono-exponential fitting, and organ doses were estimated using OLINDA/EXM. The effective dose was calculated using the International Commission on Radiological Protection 103 recommendations. The uptake of the tracer in the peripheral joints was assessed visually and semiquantitatively.
In vitro tests showed blocking of TNF cytotoxicity by the 99mTc-S-HYNIC CZP formulation comparable to the effect obtained with the unlabelled CZP with or without the HYNIC linker. We analysed eight patients with rheumatoid arthritis or spondyloarthritis. The highest mean absorbed organ doses were recorded for kidneys, spleen, and liver: 56 (SD 7), 34 (SD 6), and 33 (SD 7) μGy/MBq. The effective dose was 6.1 (SD 0.9) mSv for a mean injected activity of 690 (SD 35) MBq. The urinary excretion was 15.1% (SD 8.1) of the IA at 22.5 h. Blood analysis yielded a distribution half-life of 1.2 h (SD 1.5) and an elimination half-life of 26.9 h (SD 2.7). Visual analysis of the scans revealed marked tracer accumulation in the clinically affected peripheral joints. In addition, there was a statistically significant higher uptake of the tracer in the swollen joints (median uptake ratio compared to background of 3.3 in rheumatoid arthritis and 2.4 in peripheral spondyloarthritis) compared to clinically negative joints (respectively 1.3 and 1.6).
We present a radiolabelling technique for CZP, a Fab′-fragment directed against TNF and currently used as a therapeutic agent in rheumatology. An effective dose of 6.1 mSv (SD 0.9) was estimated. We confirmed the uptake of this new radiopharmaceutical in clinically affected peripheral joints.
90Y PET/CT post-radioembolization imaging has demonstrated that the distribution of 90Y in a tumor can be non-uniform. Using computational modeling, we predicted the dosimetric impact of post-treatment 90Y PET/CT-guided percutaneous ablation of the portions of a tumor receiving the lowest absorbed dose. A cohort of fourteen patients with non-resectable liver cancer previously treated using 90Y radioembolization were included in this retrospective study. Each patient exhibited potentially under-treated areas of tumor following treatment based on quantitative 90Y PET/CT. 90Y PET/CT was used to guide electrode placement for simulated adjuvant radiofrequency ablation in areas of tumor receiving the lowest dose. The finite element method was used to solve Penne's bioheat transport equation, coupled with the Arrhenius thermal cell-death model to determine 3D thermal ablation zones. Tumor and unablated tumor absorbed-dose metrics (average dose, D50, D70, D90, V100) following ablation were compared, where D70 is the minimum dose to 70% of tumor and V100 is the fractional tumor volume receiving more than 100 Gy.
Compared to radioembolization alone, 90Y radioembolization with adjuvant ablation was associated with predicted increases in all tumor dose metrics evaluated. The mean average absorbed dose increased by 11.2 ± 6.9 Gy. Increases in D50, D70, and D90 were 11.0 ± 6.9 Gy, 13.3 ± 10.9 Gy, and 11.8 ± 10.8 Gy, respectively. The mean increase in V100 was 7.2 ± 4.2%. All changes were statistically significant (P < 0.01). A negative correlation between pre-ablation tumor volume and D50, average dose, and V100 was identified (ρ < − 0.5, P < 0.05) suggesting that adjuvant radiofrequency ablation may be less beneficial to patients with large tumor burdens.
This study has demonstrated that adjuvant 90Y PET/CT-guided radiofrequency ablation may improve tumor absorbed-dose metrics. These data may justify a prospective clinical trial to further evaluate this hybrid approach.
Sorafenib, an oral multikinase inhibitor, has anti-proliferative and anti-angiogenic activities and is therapeutically effective against renal cell carcinoma (RCC). Recently, we have evaluated the tumor responses to sorafenib treatment in a RCC xenograft using [Methyl-3H(N)]-3′-fluoro-3′-deoxythythymidine ([3H]FLT). Contrary to our expectation, the FLT level in the tumor significantly increased after the treatment. In this study, to clarify the reason for the elevated FLT level, dynamic 3′-[18F]fluoro-3′-deoxythymidine ([18F]FLT) positron emission tomography (PET) and kinetic studies were performed in mice bearing a RCC xenograft (A498).
The A498 xenograft was established in nude mice, and the mice were assigned to the control (n = 5) and treatment (n = 5) groups. The mice in the treatment group were orally given sorafenib (20 mg/kg/day p.o.) once daily for 3 days. Twenty-four hours after the treatment, dynamic [18F]FLT PET was performed by small-animal PET. Three-dimensional regions of interest (ROIs) were manually defined for the tumors. A three-compartment model fitting was carried out to estimate four rate constants using the time activity curve (TAC) in the tumor and the blood clearance rate of [18F]FLT.
The dynamic pattern of [18F]FLT levels in the tumor significantly changed after the treatment. The rate constant of [18F]FLT phosphorylation (k3) was significantly higher in the treatment group (0.111 ± 0.027 [1/min]) than in the control group (0.082 ± 0.009 [1/min]). No significant changes were observed in the distribution volume, the ratio of [18F]FLT forward transport (K1) to reverse transport (k2), between the two groups (0.556 ± 0.073 and 0.641 ± 0.052 [mL/g] in the control group).
Our dynamic PET studies indicated that the increase in FLT level may be caused by the phosphorylation of FLT in the tumor after the sorafenib treatment in the mice bearing a RCC xenograft. Dynamic PET studies with kinetic modeling could provide improved understanding of the biochemical processes involved in tumor responses to therapy.
SAG (Sensitive to Apoptosis Gene), also known as RBX2, ROC2 or RNF7, is a RING component of CRL (Cullin-RING ligase), required for its activity. Our recent study showed that SAG/RBX2 co-operated with Kras to promote lung tumorigenesis, but antagonized Kras to inhibit skin tumorigenesis, suggesting a tissue/context dependent function of Sag. However, it is totally unknown whether and how Sag would play in prostate tumorigenesis, triggered by Pten loss.
Sag and Pten double conditional knockout mice were generated and prostate specific deletion of Sag and Pten was achieved by PB4-Cre, and their effect on prostate tumorigenesis was evaluated by H&E staining. The methods of immunohistochemistry (IHC) staining and Western blotting were utilized to examine expression of various proteins in prostate cancer tissues or cell lines. The effect of SAG knockdown in proliferation, survival and migration was evaluated in two prostate cancer cell lines. The poly-ubiquitylation of PHLPP1 and DEPTOR was evaluated by both in vivo and in vitro ubiquitylation assays.
SAG is overexpressed progressively from early-to-late stage of human prostate cancer with the highest expression seen in metastatic lesion. Sag deletion inhibits prostate tumorigenesis triggered by Pten loss in a mouse model as a result of suppressed proliferation. SAG knockdown in human prostate cancer cells inhibits a) proliferation in monolayer and soft agar, b) clonogenic survival, and c) migration. SAG is an E3 ligase that promotes ubiquitylation and degradation of PHLPP1 and DEPTOR, leading to activation of the PI3K/AKT/mTOR axis, whereas SAG knockdown caused their accumulation. Importantly, growth suppression triggered by SAG knockdown was partially rescued by simultaneous knockdown of PHLPP1 or DEPTOR, suggesting their causal role. Accumulation of Phlpp1 and Deptor with corresponding inactivation of Akt/mTOR was also detected in Sag-null prostate cancer tissues.
Sag is an oncogenic cooperator of Pten-loss for prostate tumorigenesis. Targeting SAG E3 ligase may, therefore, have therapeutic value for the treatment of prostate cancer associated with Pten loss.
SAG (Sensitive to Apoptosis Gene), also known as RBX2, ROC2 or RNF7, is a RING component of CRL (Cullin-RING ligase), required for its activity. Our recent study showed that SAG/RBX2 co-operated with Kras to promote lung tumorigenesis, but antagonized Kras to inhibit skin tumorigenesis, suggesting a tissue/context dependent function of Sag. However, it is totally unknown whether and how Sag would play in prostate tumorigenesis, triggered by Pten loss.
Sag and Pten double conditional knockout mice were generated and prostate specific deletion of Sag and Pten was achieved by PB4-Cre, and their effect on prostate tumorigenesis was evaluated by H&E staining. The methods of immunohistochemistry (IHC) staining and Western blotting were utilized to examine expression of various proteins in prostate cancer tissues or cell lines. The effect of SAG knockdown in proliferation, survival and migration was evaluated in two prostate cancer cell lines. The poly-ubiquitylation of PHLPP1 and DEPTOR was evaluated by both in vivo and in vitro ubiquitylation assays.
SAG is overexpressed progressively from early-to-late stage of human prostate cancer with the highest expression seen in metastatic lesion. Sag deletion inhibits prostate tumorigenesis triggered by Pten loss in a mouse model as a result of suppressed proliferation. SAG knockdown in human prostate cancer cells inhibits a) proliferation in monolayer and soft agar, b) clonogenic survival, and c) migration. SAG is an E3 ligase that promotes ubiquitylation and degradation of PHLPP1 and DEPTOR, leading to activation of the PI3K/AKT/mTOR axis, whereas SAG knockdown caused their accumulation. Importantly, growth suppression triggered by SAG knockdown was partially rescued by simultaneous knockdown of PHLPP1 or DEPTOR, suggesting their causal role. Accumulation of Phlpp1 and Deptor with corresponding inactivation of Akt/mTOR was also detected in Sag-null prostate cancer tissues.
Sag is an oncogenic cooperator of Pten-loss for prostate tumorigenesis. Targeting SAG E3 ligase may, therefore, have therapeutic value for the treatment of prostate cancer associated with Pten loss.
The main purpose of this study was to evaluate the effectiveness of the education system using social media. Eight educational video clips were developed instructing the viewer on cancer-related issues such as prevention, treatment, and survivorship. Each video was made with participation of medical professors and posted on a YouTube channel. A mobile phone application was produced containing a scheduler function, introduction of a community cancer center program, and cancer information. A medical blog was established to provide stationary materials such as images and articles. Descriptive analysis was done by Google analytics. From May of 2014 to June of 2016, 15,247 total views were recorded on the YouTube channel, and the average view duration was about 3 min. The most popular video was about chemotherapy treatment; 5409 (36%) people watched this video, and 3615 (23.5%) people viewed a video on balanced dietary habits. As well as South Korea, 1,113 (7%) views were confirmed in the United States and 175 (1%) in Japan. The equipment used to watch the contents were mobile phones (59%), laptops (33%), and tablets (6%). Five hundred people installed the smartphone application from March of 2015 to July of 2016. Three hundred eighty-three medical contents were posted on the blog since March of 2015. Cancer education is necessary to address the education needs of patients with cancer and their caregivers. Education based on social media could be an effective method that reaches beyond geographical boundaries.
The main purpose of this study was to evaluate the effectiveness of the education system using social media. Eight educational video clips were developed instructing the viewer on cancer-related issues such as prevention, treatment, and survivorship. Each video was made with participation of medical professors and posted on a YouTube channel. A mobile phone application was produced containing a scheduler function, introduction of a community cancer center program, and cancer information. A medical blog was established to provide stationary materials such as images and articles. Descriptive analysis was done by Google analytics. From May of 2014 to June of 2016, 15,247 total views were recorded on the YouTube channel, and the average view duration was about 3 min. The most popular video was about chemotherapy treatment; 5409 (36%) people watched this video, and 3615 (23.5%) people viewed a video on balanced dietary habits. As well as South Korea, 1,113 (7%) views were confirmed in the United States and 175 (1%) in Japan. The equipment used to watch the contents were mobile phones (59%), laptops (33%), and tablets (6%). Five hundred people installed the smartphone application from March of 2015 to July of 2016. Three hundred eighty-three medical contents were posted on the blog since March of 2015. Cancer education is necessary to address the education needs of patients with cancer and their caregivers. Education based on social media could be an effective method that reaches beyond geographical boundaries.
To evaluate Telephone-Delivered Cognitive Behavioural Therapy (T-CBT) compared to CBT face to face treatment as usual (TAU-CBT), in cancer patients with high psychological needs, in terms of mental health and coping.
A prospective randomised equivalence trial with Patient Reported Outcome (PRO's), measured pre- and post-therapy including; Hospital Anxiety and Depression Scale (HADS), Mental Adjustment to Cancer Scale: Helpless/Hopeless subscale only (MAC H/H), Checklist of Cancer Concerns (CLCC) and the Cancer Coping Questionnaire (CCQ). A study-specific Service Evaluation Questionnaire (SEQ) was included.
Assessment of change scores, in n = 118 randomised patients referred for psychological care, indicate significant improvements (p < 0.01 or greater) for both therapy groups pre-post therapy in HADS anxiety, depression and total scores and cancer concerns (CLCC). Overall, for the groups combined, there is a significant shift towards reduction of CCQ stress (p = 0.028) and worry (p = 0.003) post-therapy when compared to baseline levels. Median number of therapy sessions was four. For cancer coping (CCQ) and for Mental Adjustment to Cancer (MAC) there were significant change scores only for Positive Focus and Helpless/hopeless scores respectively, in the TAU-CBT group. Although equivalence was not observed, the data demonstrate that T-CBT was non-inferior to TAU-CBT.
Delivery of CBT to patients with clinician identified high need, can be offered according to patient choice without loss of mental health benefit. Both TAU-CBT and T-CBT are effective at reducing mental health problems on the specific outcome measures.
To evaluate Telephone-Delivered Cognitive Behavioural Therapy (T-CBT) compared to CBT face to face treatment as usual (TAU-CBT), in cancer patients with high psychological needs, in terms of mental health and coping.
A prospective randomised equivalence trial with Patient Reported Outcome (PRO's), measured pre- and post-therapy including; Hospital Anxiety and Depression Scale (HADS), Mental Adjustment to Cancer Scale: Helpless/Hopeless subscale only (MAC H/H), Checklist of Cancer Concerns (CLCC) and the Cancer Coping Questionnaire (CCQ). A study-specific Service Evaluation Questionnaire (SEQ) was included.
Assessment of change scores, in n = 118 randomised patients referred for psychological care, indicate significant improvements (p < 0.01 or greater) for both therapy groups pre-post therapy in HADS anxiety, depression and total scores and cancer concerns (CLCC). Overall, for the groups combined, there is a significant shift towards reduction of CCQ stress (p = 0.028) and worry (p = 0.003) post-therapy when compared to baseline levels. Median number of therapy sessions was four. For cancer coping (CCQ) and for Mental Adjustment to Cancer (MAC) there were significant change scores only for Positive Focus and Helpless/hopeless scores respectively, in the TAU-CBT group. Although equivalence was not observed, the data demonstrate that T-CBT was non-inferior to TAU-CBT.
Delivery of CBT to patients with clinician identified high need, can be offered according to patient choice without loss of mental health benefit. Both TAU-CBT and T-CBT are effective at reducing mental health problems on the specific outcome measures.
Large social networks have been associated with better overall survival, though not consistently with breast cancer (BC)–specific outcomes. This study evaluated associations of postdiagnosis social networks and BC outcomes in a large cohort.
Women from the After Breast Cancer Pooling Project (n = 9267) provided data on social networks within approximately 2 years of their diagnosis. A social network index was derived from information about the presence of a spouse/partner, religious ties, community ties, friendship ties, and numbers of living first-degree relatives. Cox models were used to evaluate associations, and a meta-analysis was used to determine whether effect estimates differed by cohort. Stratification by demographic, social, tumor, and treatment factors was performed.
There were 1448 recurrences and 1521 deaths (990 due to BC). Associations were similar in 3 of 4 cohorts. After covariate adjustments, socially isolated women (small networks) had higher risks of recurrence (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.15-1.77), BC-specific mortality (HR, 1.64; 95% CI, 1.33-2.03), and total mortality (HR, 1.69; 95% CI, 1.43-1.99) than socially integrated women; associations were stronger in those with stage I/II cancer. In the fourth cohort, there were no significant associations with BC-specific outcomes. A lack of a spouse/partner (P = .02) and community ties (P = .04) predicted higher BC-specific mortality in older white women but not in other women. However, a lack of relatives (P = .02) and friendship ties (P = .01) predicted higher BC-specific mortality in nonwhite women only.
In a large pooled cohort, larger social networks were associated with better BC-specific and overall survival. Clinicians should assess social network information as a marker of prognosis because critical supports may differ with sociodemographic factors. Cancer 2016. © 2016 American Cancer Society.
Large social networks have been associated with better overall survival, though not consistently with breast cancer (BC)–specific outcomes. This study evaluated associations of postdiagnosis social networks and BC outcomes in a large cohort.
Women from the After Breast Cancer Pooling Project (n = 9267) provided data on social networks within approximately 2 years of their diagnosis. A social network index was derived from information about the presence of a spouse/partner, religious ties, community ties, friendship ties, and numbers of living first-degree relatives. Cox models were used to evaluate associations, and a meta-analysis was used to determine whether effect estimates differed by cohort. Stratification by demographic, social, tumor, and treatment factors was performed.
There were 1448 recurrences and 1521 deaths (990 due to BC). Associations were similar in 3 of 4 cohorts. After covariate adjustments, socially isolated women (small networks) had higher risks of recurrence (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.15-1.77), BC-specific mortality (HR, 1.64; 95% CI, 1.33-2.03), and total mortality (HR, 1.69; 95% CI, 1.43-1.99) than socially integrated women; associations were stronger in those with stage I/II cancer. In the fourth cohort, there were no significant associations with BC-specific outcomes. A lack of a spouse/partner (P = .02) and community ties (P = .04) predicted higher BC-specific mortality in older white women but not in other women. However, a lack of relatives (P = .02) and friendship ties (P = .01) predicted higher BC-specific mortality in nonwhite women only.
In a large pooled cohort, larger social networks were associated with better BC-specific and overall survival. Clinicians should assess social network information as a marker of prognosis because critical supports may differ with sociodemographic factors. Cancer 2016. © 2016 American Cancer Society.
Sara Socorro Faria, Paulo César Fernandes Jr, Marcelo José Barbosa Silva, Vladmir C Lima, Wagner Fontes, Ruffo Freitas-Junior, Agda Karina Eterovic and Patrice Forget
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Sara Socorro Faria, Paulo César Fernandes Jr, Marcelo José Barbosa Silva, Vladmir C Lima, Wagner Fontes, Ruffo Freitas-Junior, Agda Karina Eterovic and Patrice Forget
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This case report described the endodontic treatment and decompression of an extensive lesion in the anterior region of the mandible, detected during clinical and radiographic examination, in a patient with a complaint of slight tenderness to palpation in the area of mandibular right lateral incisor and canine. These teeth had been accessed without proper clinical evaluation, and their pulp tissues were exposed. The periodontal tissues were healthy, with no signs of inflammation or fistula. On radiographic examination, a radiolucent lesion with well-defined borders was seen extending from the distal root of mandibular left second premolar to the mesial root of mandibular right second premolar. Central and lateral mandibular left incisors were unresponsive to thermal pulp testing and exhibited coronal discoloration, consistent with a diagnosis of pulp necrosis. Due to persistent discharge from the root canal system during endodontic procedures despite application of intracanal medicament (calcium hydroxide paste), the decision was made to biopsy and decompress the lesion and conclude endodontic treatment. Histopathologic examination revealed a periapical granuloma. After endodontic treatment of the involved teeth, at 4-year clinical and radiographic follow-up, the affected region was almost completely repaired.
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Central venous access is an important aspect of neonatal intensive care management. Malpositioned central catheters have been reported to induce cardiac tachyarrhythmia in adult populations and there are case reports within the neonatal population. We present a case of a preterm neonate with a preexisting umbilical venous catheter (UVC), who then developed a supraventricular tachycardia (SVT). This was initially treated with intravenous adenosine with transient reversion. Catheter migration was subsequently detected, with the UVC tip located within the heart. Upon withdrawal of the UVC and a final dose of adenosine, the arrhythmia permanently resolved. Our literature review confirms that tachyarrhythmia is a rare but recognised neonatal complication of malpositioned central venous catheters. We recommend the immediate investigation of central catheter position when managing neonatal tachyarrhythmia, as catheter repositioning is an essential aspect of management.
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Sinus pneumatization is a complex variable process that begins in early life and continues for many years. We present a case of a 6-year-old boy with progressive headaches and neurologic symptoms suggestive of intracranial pathology. The presence of enhancing tissue within the sphenoid sinus created a diagnostic dilemma which leads to a transsphenoidal biopsy. Knowledge of imaging characteristics associated with incomplete pneumatization can help differentiate it from more ominous skull base pathology and prevent unnecessary testing. We describe four-year imaging follow-up in a patient with incomplete pneumatization of the sphenoid sinus presenting as an enhancing mass lesion with subsequent follow-up imaging demonstrating gradual regression and increased aeration of the sphenoid sinus.
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Video-recording of emerging minimally invasive surgical procedures is likely to become an integral component of patient record-keeping in the future for prostate cancer treatment. No prior work has shown the impact of videotaping of laparoscopic prostatectomy on patient outcomes. Our aim was to determine correlation between independent peer review of videotaping quality scores of extraperitoneal laparoscopic prostatectomy (ELRP) with complications, re-admissions, functional, and early oncological outcomes.
We conducted a single-institution prospective cohort study comparing videotaping quality scores with the outcomes of ELRP in men with localized prostate cancer. Videotaping of surgical procedures were scored by two experienced laparoscopic surgeons using a validated scoring method. Validated record-linkage methodology and self-reported questionnaires were used to assess surgical complications, re-admissions, functional, and oncological outcomes based on a common identifier called as community health index (CHI) number. Pearson correlation coefficients were calculated between the different covariates with statistical significance considered at P < 0.05. Multivariate analyses assessed oncological outcomes (positive surgical margins/biochemical recurrence), post-operative complications, and re-admission into hospital following initial hospital discharge with quality of surgical procedure.
200 men were recruited into the study. 51 (25.5%) participants had post-operative complications. Record-linkage methodology identified 18 (9%) participants had re-admissions within 90 days of the procedure. 13 (6.5%) of these men required percutaneous drainage with hospital stay following re-admissions ranged between 3 and 12 days. 10 (5.0%) participants had intra/peri-operative complications. 23 (11.5%) men reported to primary care physicians for various indications. Higher quality surgical technique videotaped scores (assessed by independent peer review) had a significant correlation with early continence recovery at 3 months post-procedure, (P = 0.013), but lost statistical significance with overall continence at 1 year. No statistical correlation was observed between videotaped scores and oncological outcomes (positive surgical margins/biochemical recurrence), post-operative complications, and readmission into hospital.
Quality of surgical procedure assessed by independent third party videotaping score predicted early resumption of continence following extraperitoenal laparoscopic radical prostatectomy, however, it did not predict complications, oncological or functional outcome as assessed using patient reported outcomes at 12 months. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.
One of the surgical treatment options for lymphedema is vascularized lymph node transfer (VLNT). We present our experience with latissimus dorsi (LD) flap based VLNT for lymphedema treatment.
We reviewed 14 consecutive patients treated with pedicled or free LD VLNT between 2014 and 2016 for recalcitrant upper or lower extremity lymphedema. Seven patients underwent lymphovenous bypass in addition to LD VLNT. Limb volume and quality of life scores using the Lymphedema Life Impact Scale (LLIS) were analyzed for quantitative and qualitative assessment.
Mean duration of lymphedema was 69 months (range 24–124 months). Follow-up ranged from 3 to 12 months (mean 6.7 month). Major complications included one free flap loss and one reoperation for thrombosis. Mean preoperative volume differential between normal and affected limb was 35% (range 3–87%). Volume differential reduction was 48%, 28%, and 46% at 3, 6, and 12 months, respectively. The LLIS score improved from mean of 46.8 before surgery to a mean of 38.6 at 12 month, demonstrating improvement in quality of life.
The LD VLNT provides a viable option for treatment of UE and LE lymphedema in selected patients. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.
Video-recording of emerging minimally invasive surgical procedures is likely to become an integral component of patient record-keeping in the future for prostate cancer treatment. No prior work has shown the impact of videotaping of laparoscopic prostatectomy on patient outcomes. Our aim was to determine correlation between independent peer review of videotaping quality scores of extraperitoneal laparoscopic prostatectomy (ELRP) with complications, re-admissions, functional, and early oncological outcomes.
We conducted a single-institution prospective cohort study comparing videotaping quality scores with the outcomes of ELRP in men with localized prostate cancer. Videotaping of surgical procedures were scored by two experienced laparoscopic surgeons using a validated scoring method. Validated record-linkage methodology and self-reported questionnaires were used to assess surgical complications, re-admissions, functional, and oncological outcomes based on a common identifier called as community health index (CHI) number. Pearson correlation coefficients were calculated between the different covariates with statistical significance considered at P < 0.05. Multivariate analyses assessed oncological outcomes (positive surgical margins/biochemical recurrence), post-operative complications, and re-admission into hospital following initial hospital discharge with quality of surgical procedure.
200 men were recruited into the study. 51 (25.5%) participants had post-operative complications. Record-linkage methodology identified 18 (9%) participants had re-admissions within 90 days of the procedure. 13 (6.5%) of these men required percutaneous drainage with hospital stay following re-admissions ranged between 3 and 12 days. 10 (5.0%) participants had intra/peri-operative complications. 23 (11.5%) men reported to primary care physicians for various indications. Higher quality surgical technique videotaped scores (assessed by independent peer review) had a significant correlation with early continence recovery at 3 months post-procedure, (P = 0.013), but lost statistical significance with overall continence at 1 year. No statistical correlation was observed between videotaped scores and oncological outcomes (positive surgical margins/biochemical recurrence), post-operative complications, and readmission into hospital.
Quality of surgical procedure assessed by independent third party videotaping score predicted early resumption of continence following extraperitoenal laparoscopic radical prostatectomy, however, it did not predict complications, oncological or functional outcome as assessed using patient reported outcomes at 12 months. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.
One of the surgical treatment options for lymphedema is vascularized lymph node transfer (VLNT). We present our experience with latissimus dorsi (LD) flap based VLNT for lymphedema treatment.
We reviewed 14 consecutive patients treated with pedicled or free LD VLNT between 2014 and 2016 for recalcitrant upper or lower extremity lymphedema. Seven patients underwent lymphovenous bypass in addition to LD VLNT. Limb volume and quality of life scores using the Lymphedema Life Impact Scale (LLIS) were analyzed for quantitative and qualitative assessment.
Mean duration of lymphedema was 69 months (range 24–124 months). Follow-up ranged from 3 to 12 months (mean 6.7 month). Major complications included one free flap loss and one reoperation for thrombosis. Mean preoperative volume differential between normal and affected limb was 35% (range 3–87%). Volume differential reduction was 48%, 28%, and 46% at 3, 6, and 12 months, respectively. The LLIS score improved from mean of 46.8 before surgery to a mean of 38.6 at 12 month, demonstrating improvement in quality of life.
The LD VLNT provides a viable option for treatment of UE and LE lymphedema in selected patients. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.
