Efficacy,Pharmacokinetics, and Biodistribution of Thermosensitive Chitosan/β-Glycerophosphate Hydrogel Loaded with Docetaxel

Docetaxel (DTX) is a widely used anticancer drug for various solid tumors. However, its poor solubility in water and lack of specification are two limitations for clinical use. The aim of the study was to develop a thermosensitive chitosan/β-glycerophosphate (C/GP) hydrogel loaded with DTX for intratumoral delivery. The in vitro release profiles, in vivo antitumor efficacy, pharmacokinetics, and biodistribution of DTX-loaded C/GP hydrogel (DTX-C/GP) were evaluated. The results of in vitro release study demonstrated that DTX-C/GP had the property of controlled delivery for a reasonable time span of 3 weeks and the release period was substantially affected by initial DTX strength. The antitumor efficacy of DTX-C/GP was observed at 20 mg/kg in H22 tumor-bearing mice. It was found that the tumor volume was definitely minimized by intratumoral injection of DTX-C/GP. Compared with saline group, the tumor inhibition rate of blank gel, intravenous DTX solution, intratumoral DTX solution, and DTX-C/GP was 2.3%, 29.8%, 41.9%, and 58.1%, respectively. Further, the in vivo pharmacokinetic characteristics of DTX-C/GP correlated well with the in vitro release. DTX-C/GP significantly prolonged the DTX retention and maintained a high DTX concentration in tumor. The amount of DTX distributed to the normal tissues was minimized so that the toxicity was effectively reduced. In conclusion, DTX-C/GP demonstrated controlled release and significant efficacy and exhibited potential for further clinical development.     

Efficacy of Influenza Vaccination and Tamiflu? Treatment – Comparative Studies with Eurasian Swine Influenza Viruses in Pigs

Recent epidemiological developments demonstrated that gene segments of swine influenza A viruses can account for antigenic changes as well as reduced drug susceptibility of pandemic influenza A viruses. This raises questions about the efficacy of preventive measures against swine influenza A viruses. Here, the protective effect of vaccination was compared with that of prophylactic Tamiflu® treatment against two Eurasian swine influenza A viruses. 11-week-old pigs were infected by aerosol nebulisation with high doses of influenza virus A/swine/Potsdam/15/1981 (H1N1/1981, heterologous challenge to H1N1 vaccine strain) and A/swine/Bakum/1832/2000 (H1N2/2000, homologous challenge to H1N2 vaccine strain) in two independent trials. In each trial (i) 10 pigs were vaccinated twice with a trivalent vaccine (RESPIPORC® FLU3; 28 and 7 days before infection), (ii) another 10 pigs received 150 mg/day of Tamiflu® for 5 days starting 12 h before infection, and (iii) 12 virus-infected pigs were left unvaccinated and untreated and served as controls. Both viruses replicated efficiently in porcine respiratory organs causing influenza with fever, dyspnoea, and pneumonia. Tamiflu® treatment as well as vaccination prevented clinical signs and significantly reduced virus shedding. Whereas after homologous challenge with H1N2/2000 no infectious virus in lung and hardly any lung inflammation were detected, the virus titre was not and the lung pathology was only partially reduced in H1N1/1981, heterologous challenged pigs. Tamiflu® application did not affect these study parameters.In conclusion, all tested preventive measures provided protection against disease. Vaccination additionally prevented virus replication and histopathological changes in the lung of homologous challenged pigs.     

Concurrent Treatment with Anti-DLL4 Enhances Antitumor and Proapoptotic Efficacy of a γ-Secretase Inhibitor in Gastric Cancer

The Notch signaling pathway has been identified as a therapeutic target for cancers. γ-Secretase inhibitors (GSIs) have been progressively recognized as potential anticancer drugs. The present study aimed to investigate the effects of anti-delta like legend 4 (anti-DLL4) treatment on the anticancer efficacy of GSIs in gastric cancer. SGC-7901-GFP human gastric cancer cells were tested for DLL4 expression by rosette formation test and immunofluorescence, and then were treated with anti-DLL4 antibody N-[N-(3,5-difluorophenacetyl)-L-ananyl]-S-phenylglycine t-butyl ester (DAPT, a type of GSI), or a combination of anti-DLL4 antibody and DAPT. The effects of in vitro treatments on cell apoptosis, cell cycle, and cell invasion were analyzed. For in vivo study, an orthotopic mouse model of gastric cancer was established with green fluorescence expressing SGC-7901. Ultrasound targeted microbubble destruction was used to treat tumor-bearing mice with anti-DLL4 antibody conjugated microbubbles, DAPT, and a combination of the two. Real-time fluorescence imaging was performed to assess tumor cell inhibition in each group. Following in vivo treatments, apoptosis of tumor cells and the expression of apoptosis-related genes BAX, Bcl-2, and P53 were detected by TUNEL and immunohistochemical staining. In vivo combined treatment of anti-DLL4 and DAPT led to a higher rate of cell apoptosis and greater inhibition of cell invasion than that observed with DAPT treatment alone. DAPT and anti-DLL4 combination therapy resulted in decreased cell distribution at G1 phase and increased cell distribution at S phase, compared to the untreated control group (P < .01). In vivo combined therapy with anti-DLL4 and DAPT significantly increased tumor growth inhibition and tumor cell apoptosis when compared to DAPT therapy alone (P < .05). In addition, combined treatment significantly increased expression of BAX and P53 and reduced Bcl-2 expression (P < .05). Conversely, treatment with DAPT alone only increased expression of BAX and P53 (P < .05), suggesting that the reduction of Bcl-2 expression may play an important role in the synergetic antitumor and proapoptosis effects of the combined treatment. Concurrent treatment with anti-DLL4 enhances the antitumor and proapoptotic efficacy of the γ-secretase inhibitor in gastric cancer both in vitro and in vivo.     

A Randomized Multicenter Study of Optimal Circadian Time of Vinorelbine Combined with Chronomodulated 5‐Fluorouracil in Pretreated Metastatic Breast Cancer Patients: EORTC Trial 05971

Studies in animals synchronized with an alternation of 12 h of light and 12 h of darkness have showed that hematological and systemic toxicities could be reduced if vinorelbine were administered 19 or 23 hours after light onset (HALO), corresponding to 17:00 and 21:00 h in diurnally active humans. This trial aimed to define the least toxic time of vinorelbine administration in metastatic breast cancer patients. Initially, the study treatment consisted of three courses of vinorelbine of 30 mg/m²/d on D1 and D6 and chronomodulated 5‐fluorouracil of 850 mg/m² from D2 to D5 every 21 days. Ninety metastatic breast cancer patients were randomized to receive vinorelbine at one of the eight possible dosing times. Further to the recommendations of the Independent Data Monitoring Committee, the vinorelbine dose was reduced to 25 mg/m²/d midway through the study. The primary objective of the study was detection of the least toxic time based on the incidence of grade 3–4 (G3–4) neutropenia. To show a significant result, the 90% confidence interval width of the least toxic time had to be<6 h. The least toxic time detection based on the incidence of other toxicities was also analyzed. The time of least drug toxic was estimated using a logistic regression model assuming that the logit transformation of the toxicity rate follows a sinusoidal distribution over 24 h. The bootstrap technique was used to obtain the 90% confidence interval. The least toxic time of G3–4 neutropenia was observed at 21:00 h with a non‐significant 90% CI. Secondary endpoint analyses indicated the least toxic time could differ when based on other toxicity parameters (e.g., a significant least toxic time of 17:00 h was observed for G3–4 leucopenia), in agreement with animal data. The least toxic time of 10:30 h was estimated for any G3–4 gastrointestinal toxicity. This results of this study do not allow us to recommend an optimal time for vinorelbine administration. It has highlighted, however, the inherent methodological difficulties in the conduct of such a trial in the human setting. It indicates that future optimal time‐finding trials should have tolerability and/or activity as the primary endpoint in place of a particular toxicity. The randomized optimal time‐finding design may be used to identify the best time of chemotherapy administration. (Author correspondence: bcoudert@dijon.fnclcc.fr)     

The Changes of Lipid Metabolism in Advanced Renal Cell Carcinoma Patients Treated with Everolimus: A New Pharmacodynamic Marker?

Background

Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved for the treatment of metastatic renal cell carcinoma (mRCC). We aimed to assess the association between the baseline values and treatmentrelated modifications of total serum cholesterol (C), triglycerides (T), body mass index (BMI), fasting blood glucose level (FBG) and blood pressure (BP) levels and the outcome of patients treated with everolimus for mRCC.

Methods

177 patients were included in this retrospective analysis. Time to progression (TTP), clinical benefit (CB) and overall survival (OS) were evaluated.

Results

Basal BMI was significantly higher in patients who experienced a CB (p=0,0145). C,T and C+T raises were significantly associated with baseline BMI (p=0.0412, 0.0283 and 0.0001). Median TTP was significantly longer in patients with T raise compared to patients without T (10 vs 6, p=0.030), C (8 vs 5, p=0.042) and C+T raise (10.9 vs 5.0, p=0.003). At the multivariate analysis, only C+T increase was associated with improved TTP (p=0.005). T raise (21.0 vs 14.0, p=0.002) and C+T increase (21.0 vs 14.0, p=0.006) were correlated with improved OS but were not significant at multivariate analysis.

Conclusion

C+T raise is an early predictor for everolimus efficacy for patients with mRCC.     

Is There Any Role of Arsenic Toxicity in HPV Related Oral Squamous Cell Carcinoma?

Biological Trace Element Research - Arsenic is a potent human carcinogen affecting the rate of cancer deaths worldwide. In India, West Bengal is the worst affected state by arsenic. To our best...     

Lower Healthcare Costs Associated with the Use of a Single-Pill ARV Regimen in the UK, 2004–2008

Aim

Investigate the cost and effects of a single-pill versus two- or three pill first-line antiretroviral combinations in reducing viral load, increasing CD4 counts, and first-line failure rate associated with respective regimens at 6 and 12 months.

Methods

Patients on first-line TDF+3TC+EFV, TDF+FTC+EFV, Truvada®+EFV or Atripla® between 1996–2008 were identified and viral load and CD4 counts measured at baseline, six and twelve months respectively. Factors that independently predicted treatment failure at six and twelve months were derived using multivariate Cox''s proportional hazard regression analyses. Use and cost of hospital services were calculated at six and twelve months respectively.

Results

All regimens reduced viral load to below the limit of detection and CD4 counts increased to similar levels at six and twelve months for all treatment regimens. No statistically significant differences were observed for rate of treatment failure at six and twelve months. People on Atripla® generated lower healthcare costs for non-AIDS patients at £5,340 (£5,254 to £5,426) per patient-semester and £9,821 (£9,719 to £9,924) per patient-year that was £1,344 (95%CI £1,222 to £1,465) less per patient-semester and £1,954 (95%CI £1,801 to £2,107) less per patient-year compared with Truvada®+EFV; healthcare costs for AIDS patients were similar across all regimens.

Conclusion

The single pill regimen is as effective as the two- and three-pill regimens of the same drugs, but if started as first-line induction therapy there would be a 20% savings on healthcare costs at six and 17% of costs at twelve months compared with Truvada®+EFV, that generated the next lowest costs.     

Decreased plasma DEK Oncogene Levels Correlate with p16-Negative Disease and Advanced Tumor Stage in a Case–Control Study of Patients with Head and Neck Squamous Cell Carcinoma

Head and neck cancer (HNC) remains the sixth most common malignancy worldwide and survival upon recurrence and/or metastasis remains poor. HNSCC has traditionally been associated with alcohol and nicotine use, but more recently the Human Papilloma Virus (HPV) has emerged as a favorable prognostic risk factor for oropharyngeal HNSCC. However, further stratification with additional biomarkers to predict patient outcome continues to be essential. One candidate biomarker is the DEK oncogenic protein, which was previously detected in the urine of patients with bladder cancer and is known to be secreted by immune cells such as macrophages. Here, we investigated if DEK could be detected in human plasma and if DEK levels correlated with clinical and pathological variables of HNSCC. Plasma was separated from the peripheral blood of newly diagnosed, untreated HNSCC patients or age-matched normal healthy controls and analyzed for DEK protein using ELISA. Plasma concentrations of DEK protein were lower in p16-negative tumors compared to both normal controls and patients with p16-positive tumors. Patients with lower plasma concentrations of DEK were also more likely to have late stage tumors and a lower white blood cell count. Contrary to previously published work demonstrating a poor prognosis with high intratumoral DEK levels, we show for the first time that decreased concentrations of DEK in patient plasma correlates with poor prognostic factors, including HPV-negative status as determined by negative p16 expression and advanced tumor stage.     

Large Variations in Risk of Hepatocellular Carcinoma and Mortality in Treatment Na?ve Hepatitis B Patients: Systematic Review with Meta-Analyses

Background

The complications to chronic hepatitis B (HBV) include incidence of hepatocellular carcinoma (HCC) and mortality. The risk of these complications may vary in different patient groups.

Aim

To estimate the incidence and predictors of HCC and in untreated HBV patients.

Methods

Systematic review with random effects meta-analyses of randomized controlled trials and observational studies. Results are expressed as annual incidence (events per 100 person-years) with 95% confidence intervals. Subgroup and sensitivity analyses of patient and study characteristics were performed to identify common risk factors.

Results

We included 68 trials and studies with a total of 27,584 patients (264,919 person-years). In total, 1,285 of 26,687 (5%) patients developed HCC and 730 of 12,511 (6%) patients died. The annual incidence was 0.88 (95% CI, 0.76–0.99) for HCC and 1.26 (95% CI, 1.01–1.51) for mortality. Patients with cirrhosis had a higher risk of HCC (incidence 3.16; 95% CI, 2.58–3.74) than patients without cirrhosis (0.10; 95% CI, 0.02–0.18). The risk of dying was also higher for patients with than patients without cirrhosis (4.89; 95% CI, 3.16–6.63; and 0.11; 95% CI, 0.09–0.14). The risk of developing HCC increased with HCV coinfection, older age and inflammatory activity. The country of origin did not clearly predict HCC or mortality estimates.

Conclusions

Cirrhosis was the strongest predictor of HCC incidence and mortality. Patients with HBV cirrhosis have a 31-fold increased risk of HCC and a 44-fold increased mortality compared to non-cirrhotic patients. The low incidence rates should be taken into account when considering HCC screening in non-cirrhotic patients.

Trial Registration

Prospero CRD42013004764     

Efficacy of Fluensulfone in a Tomato–Cucumber Double Cropping System

Vegetable crops in the southeastern United States are commonly grown on plastic mulch with two crop cycles produced on a single mulch application. Field trials were conducted in 2013 and 2014 in two locations to evaluate the efficacy of fluensulfone for controlling Meloidogyne spp. when applied through drip irrigation to cucumber in a tomato–cucumber double-cropping system. In the spring tomato crop, 1,3-dichloropropene (1,3-D), fluensulfone, and a resistant cultivar significantly decreased root galling by 91%, 73%, and 97%, respectively, compared to the untreated control. Tomato plots from the spring were divided into split plots for the fall where the main plots were the spring treatment and the subplots were cucumber either treated with fluensulfone (3.0 kg a.i./ha. via drip irrigation) or left untreated. The fall application of fluensulfone improved cucumber vigor and reduced gall ratings compared to untreated subplots. Fluensulfone reduced damage from root-knot nematodes when applied to the first crop as well as provided additional protection to the second crop when it was applied through a drip system.     

Efficacy of pain control with topical lidocaine–epinephrine–tetracaine during laceration repair with tissue adhesive in children: a randomized controlled trial

Background:

Some children feel pain during wound closures using tissue adhesives. We sought to determine whether a topically applied analgesic solution of lidocaine–epinephrine–tetracaine would decrease pain during tissue adhesive repair.

Methods:

We conducted a randomized, placebo-controlled, blinded trial involving 221 children between the ages of 3 months and 17 years. Patients were enrolled between March 2011 and January 2012 when presenting to a tertiary-care pediatric emergency department with lacerations requiring closure with tissue adhesive. Patients received either lidocaine–epinephrine–tetracaine or placebo before undergoing wound closure. Our primary outcome was the pain rating of adhesive application according to the colour Visual Analogue Scale and the Faces Pain Scale — Revised. Our secondary outcomes were physician ratings of difficulty of wound closure and wound hemostasis, in addition to their prediction as to which treatment the patient had received.

Results:

Children who received the analgesic before wound closure reported less pain (median 0.5, interquartile range [IQR] 0.25–1.50) than those who received placebo (median 1.00, IQR 0.38–2.50) as rated using the colour Visual Analogue Scale (p = 0.01) and Faces Pain Scale – Revised (median 0.00, IQR 0.00–2.00, for analgesic v. median 2.00, IQR 0.00–4.00, for placebo, p < 0.01). Patients who received the analgesic were significantly more likely to report having or to appear to have a pain-free procedure (relative risk [RR] of pain 0.54, 95% confidence interval [CI] 0.37–0.80). Complete hemostasis of the wound was also more common among patients who received lidocaine–epinephrine–tetracaine than among those who received placebo (78.2% v. 59.3%, p = 0.008).

Interpretation:

Treating minor lacerations with lidocaine–epinephrine–tetracaine before wound closure with tissue adhesive reduced ratings of pain and increased the proportion of pain-free repairs among children aged 3 months to 17 years. This low-risk intervention may benefit children with lacerations requiring tissue adhesives instead of sutures. Trial registration: ClinicalTrials.gov, no. PR 6138378804.Minor laceration repair with tissue adhesive, or “skin glue,” is common in pediatrics. Although less painful than cutaneous sutures,¹ tissue adhesives polymerize through an exothermic reaction that may cause a burning, painful sensation. Pain is dependent on the specific formulation of the adhesive used and the method of application. One study of different tissue adhesives reported 23.8%–40.5% of participants feeling a “burning sensation”,² whereas another study reported “pain” in 17.6%–44.1% of children.³ The amounts of adhesive applied, method of application and individual patient characteristics can also influence the feeling of pain.^3,4 Because tissue adhesives polymerize on contact with moisture,^4,5 poor wound hemostasis has the potential to cause premature setting of the adhesive, leading to less efficient and more painful repairs.⁶Preventing procedural pain is a high priority in pediatric care.⁷ Inadequate analgesia for pediatric procedures may result in more complicated procedures, increased pain sensitivity with future procedures⁸ and increased fear and anxiety of medical experiences persisting into adulthood.⁹ A practical method to prevent pain during laceration repairs with tissue adhesive would have a substantial benefit for children.A topically applied analgesic solution containing lidocaine–epinephrine–tetracaine with vasoconstrictive properties provides safe and effective pain control during wound repair using sutures.¹⁰ A survey of pediatric emergency fellowship directors in the United States reported that 76% of respondents use this solution or a similar solution when suturing 3-cm chin lacerations in toddlers.¹¹ However, in a hospital chart review, this solution was used in less than half of tissue adhesive repairs, the remainder receiving either local injection of anesthetic or no pain control.¹² Reluctance to use lidocaine–epinephrine–tetracaine with tissue adhesive may be due to the perception that it is not worth the minimum 20-minute wait required for the analgesic to take effect¹³ or to a lack of awareness that tissue adhesives can cause pain.We sought to investigate whether preapplying lidocaine–epinephrine–tetracaine would decrease pain in children during minor laceration repair using tissue adhesive.     

Streptozocin-Based Chemotherapy in Patients with Advanced Neuroendocrine Neoplasms – Predictive and Prognostic Markers for Treatment Stratification

Background and Aim

Chemotherapy with streptozocin (STZ) in combination with 5-FU or doxorubicin (Dox) represents a standard of care for patients with metastatic pancreatic neuroendocrine neoplasms (pNEN). However, predictive markers for patient selection are still missing. The aim of this study was a retrospective evaluation of the clinicopathological characteristics of pNEN patients receiving STZ-based chemotherapies and to identify predictive and prognostic markers.

Patients and Methods

We retrospectively analyzed 77 patients treated at our center between 1995 and 2013. The median overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier and Cox regression methods, respectively. Uni- and multivariate analyses were performed.

Results

The median PFS (mPFS) in patients receiving STZ/5-FU/Dox was 16 months with a median OS (mOS) of 28 months. Objective response rate (ORR) and disease control rate (DCR) were 34% and 72%, respectively. Biochemical response and positive octreotide scintigraphy predicted objective response. Univariate analysis revealed Ki-67 > 10% and the absence of biochemical or objective response by imaging as independent risk factors for shorter PFS. Additionally, performance status (PS) and resection of the primary tumor were observed to influence mOS. Treatment was well tolerated with less than 10% grade 3 and 4 toxicities.

Conclusions

STZ-based chemotherapy is an effective and well-tolerated treatment option in patients with well differentiated neuroendocrine neoplasms. Positive octreotide scintigraphy and biochemical response predict objective response.