Advances in drug delivery system for platinum agents based combination therapy

Platinum-based anticancer agents are widely used as first-line drugs in cancer chemotherapy for various solid tumors. However, great side effects and occurrence of resistance remain as the major drawbacks for almost all the platinum drugs developed. To conquer these problems, new strategies should be adopted for platinum drug based chemotherapy. Modern nanotechnology has been widely employed in the delivery of various therapeutics and diagnostic. It provides the possibility of targeted delivery of a certain anticancer drug to the tumor site, which could minimize toxicity and optimize the drug efficacy. Here, in this review, we focused on the recent progress in polymer based drug delivery systems for platinum-based combination therapy.

Immunotherapy for recurrent hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is presented frequently in late stages that are not amenable for curative treatment.Even for patients who can undergo resection for curative treatment of HCC,up to 50%recur.For patients who were not exposed to systemic therapy prior to recurrence,recurrence frequently cannot be subjected to curative therapy or local treatments.Such patients have several options of immunotherapy(IO).This includes programmed cell death protein 1(PD-1)and cytotoxic T-lymphocyte associated protein 4 treatment,combination of PD-1 and vascular endothelial growth factor inhibitor or single agent PD-1 therapy when all other options are deemed inappropriate.There are also investigational therapies in this area that explore either PD-1 and tyrosine kinase inhibitors or a novel agent in addition to PD-1 with vascular endothelial growth factor inhibitors.This minireview explored IO options for patients with recurrent HCC who were not exposed to systemic therapy at the initial diagnosis.We also discussed potential IO options for patients with recurrent HCC who were exposed to first-line therapy with curative intent at diagnosis.

Long-term alpha interferon and lamivudine combination therapy in non-responder patients with anti-HBe-positive chronic hepatitis B:Results of an open,controlled trial

AIM: To investigate the safety and efficacy of long-term combination therapy with alpha interferon and lamivudine in non-responsive patients with anti-HBe-positive chronic hepatitis B.METHODS: 34 patients received combination treatment (1 month lamivudine, 12 month lamivudine+interferon, 6month lamivudine), 24 received lamivudine (12 months),24 received interferon (12 months). Interferon was administered at 6 MU tiw and lamivudine at 100 mg orally once daily. Patients were followed up for 6 months after treatment.RESULTS: At the end of treatment, HBV DNA negativity rates were 88 % with lamivudine+interferon, 99 % with lamivudine and 55 % with interferon, (P=0.004, combination therapy vs. interferon, and P=0.001 lamivudine vs.interferon), and serum transaminase normalization rates were 84 %, 91% and 53 % (P=0.01 combination therapy vs. interferon, and P=0.012 lamivudine vs. interferon). Six months later, HBV DNA negativity rates were 44 % with lamivudine+interferon, 33 % with lamivudine and 25 % with interferon, and serum transaminase normalization rates were 61%, 42 % and 45 %, respectively, without statistical significance. No YMDD variants were observed with lamivudine+interferon (vs. 12 % with lamivudine). The combination therapy appeared to be safe. CONCLUSION: Although viral clearance and transaminase normalization are slower with long-term lamivudine+interferon than that with lamivudine alone, the combination regimen seems to provide more lasting benefits and to protect against the appearance of YMDD variants. Studies with other regimens regarding sequence and duration are needed.

Oligospermia due to partial maturation arrest responds to low dose estrogen-testosterone combination therapy resulting in live-birth: a case report

A man having severe oligospermia, due to partial maturation arrest at spermatid stage, was given low dose estrogen-testosterone combination therapy for three months. His sperm count increased enormously, following which his wife conceived and delivered a healthy baby at term.

Standard triple therapy for Helicobacter pylori infection in China: A meta-analysis

AIM: To assess the efficacy and safety of standard triple therapy compared with other pre-existing and new therapies in China.

Immuno-oncology combinations： raising the tail of the survival curve

There have been exponential gains in immuno-oncology in recent times through the development of immune checkpoint inhibitors. Already approved by the U.S. Food and Drug Administration for advanced melanoma and non-small cell lung cancer,immune checkpoint inhibitors also appears to have significant antitumor activity in multiple other tumor types. An exciting component of immunotherapy is the durability of antitumor responses observed, with some patients achieving disease control for many years. Nevertheless, not all patients benefit, and efforts should thus now focus on improving the efficacy of immunotherapy through the use of combination approaches and predictive biomarkers of response and resistance. There are multiple potential rational combinations using an immunotherapy backbone, including existing treatments such as radiotherapy, chemotherapy or molecularly targeted agents, as well as other immunotherapeutics. The aim of such antitumor strategies will be to raise the tail on the survival curve by increasing the number of long term survivors, while managing any additive or synergistic toxicities that may arise with immunotherapy combinations. Rational trial designs based on a clear understanding of tumor biology and drug pharmacology remain paramount. This article reviews the biology underpinning immuno-oncology, discusses existing and novel immunotherapeutic combinations currently in development, the challenges of predictive biomarkers of response and resistance and the impact of immuno-oncology on early phase clinical trial design.

Azithromycin-containing versus standard triple therapy for Helicobacter pylori eradication:A meta-analysis

AIM： To evaluate whether adding azithromycin to firstline Helicobacter pylori （H pylorl） eradication improved eradication and reduced side effects. METHODS： Eligible articles were identified by searches of electronic databases. We included all randomized trials that compared azithromycin-containing with standard triple-therapy regimens for first-line treatment of H pylori infection. Statistical analysis was performed with Review Manager 5.0.10. Sub-analyses were also performed. RESULTS： We identified 14 randomized trials （1431 patients）. Pooled Hpylori eradication rates were 72.01% （95% CI： 58.09%-85.93%） and 69.78% （95% CI： 66.47%-73.09%） for patients with or without azithromycin by intention-to-treat analysis, and the odds ratio （OR） was 1.17 （95% CI： 0.64-2.14）. The occurrence of side effects differed significantly and was 15.81% （95% CI： 12.50%-19.12%） and 25.20% （95% CI： 21.44%-28.96%） for treatment with or without azithromycin, respectively, and the summary OR was 0.58 （95% CI： 0.41-0.82）. Furthermore, the azithromycin-containing group had a lower occurrence of diarrhea, nausea and taste disturbance. CONCLUSION： Our review suggests that azithromycincontaining triple-therapy regimens could be equally effective in eradication of Hpylori compared with standard first-line triple-therapy regimens.

Low eradication rate of Helicobacterpyloriwith triple 7-14 days and quadriple therapy in Turkey

AIM:The eradication rate of Helicobacter pylori (H pylori) shows variation among countries and regimens of treatment. We aimed to study the eradication rates of different regimens in our region and some factors affecting the rate of eradication. METHODS:One hundred and sixty-four H pylori positive patients (68 males,96 females;mean age:48±12 years) with duodenal or gastric ulcer without a smoking history were included in the study.The patients were divided into three groups according to the treatment regimens.Omeprazole 20mg,clarithromycin 500mg,amoxicillin 1g were given twice daily for 1 week (Group Ⅰ) and 2 weeks (Group Ⅱ). Patients in Group Ⅲ received bismuth subsitrate 300mg, tetracyline 500mg and metronidazole 500mg four times daily in addition to Omeprazole 20mg twice daily.Two biopsies each before and after treatment were obtained from antrum and corpus,and histopathologically evaluated. Eradication was assumed to be successful if no H pylorus was detected from four biopsy specimens taken after treatment.The effects of factors like age,sex,H pylori density on antrum and corpus before treatment,the total H pylori density,and the inflammation scores on the rate of H pylori eradication were evaluated. RESULTS:The overall eradication rate was 42%.The rates in groups Ⅱ and Ⅲ were statistically higher than that in group Ⅰ (P<0.05).The rates of eradication were 24.5%, 40.7% and 61.5% in groups Ⅰ,Ⅱ and Ⅲ,respectively.The eradication rate was negatively related to either corpus H pylori density or total H pylori density (P<0.05).The median age was older in the group in which the eradication failed in comparison to that with successful eradication (55 yr vs 39 yr,P<0.001).No correlation between sex and H pylori eradication was found. CONCLUSION:Our rates of eradication were significantly lower when compared to those reported in literature.We believe that advanced age and high H pylori density are negative predictive factors for the rate of H pylori eradication.

Azithromycin in a triple therapy for H.pylori eradication in active duodenal ulcer

AIM:To assess and compare the efficacy and safety of two triple regimes:A)metronidazole,amoxicillin and omeprazole, which is still widely used in Russia,and B)azithromycin, amoxicillin and omeprazole in healing active duodenal ulcer and H.pylori eradication. METHODS:100 patients with active duodenal ulcer were included in the open,multicentre,randomized study with comparative groups.Patients were randomly assigned to one of the following one-week triple regimes:A) metronidazole 500 mg bid,amoxicillin I g bid and omeprazole 20 mg bid(OAM,n=50)and B)azithromycin 1 god for the first 3 days(total dose 3 g),amoxicillin 1 g bid and omeprazole 20 mg bid(OAA,n=50).Omeprazole 20 mg od was given after the eradication course as a monotherapy for three weeks.The control endoscopy was performed 8 weeks after the entry.H.pyloriinfection was determined in the entry of the study and four weeks after the cessation of treatment by means of histology and CLO-test. RESULTS:97 patients completed the study according to the protocol(1 patient of the OAM group did not come to the control endoscopy,2 patients of the OAA group stopped the treatment because of mild allergic urticaria).Duodenal ulcers were healed in 48 patients of the OAM group(96 %, C190.5-100 %)and in 46 patients of the OAA group(92 %, CI 89.5-94.5 %)(p=ns).H.pyloHinfection was eradicated in 15 out of 50 patients with OAM(30 %,CI 17-43 %)and in 36 out of 50 patients treated with OAA(72 %;CI 59-85 %) (P<0.001)-ITT analysis.CONCLUSION: The triple therapy with omeprazole, amoxicillin and metronidazole failed to eradicate H.pylori'vc\ the majority of patients, which is an essential argument to withdraw this regimen out of the national recommendations. Macrolide with amoxicillin are preferable to achieve higher eradication rates. Azithromycin (1 g od for the first 3 days) can be considered as a successful component of the triple PPI-based regimen.

The Antagonistic Action of Heat-Clearing and Detoxifying Chinese Drugs on Endotoxins

In the recent decade, interest in treatment and prevention of many critical, severe and acute diseases caused by bacterial endotoxins has been aroused along with the advance of the knowledge on the nature of the endotoxin and the conditions involved. In abroad, attention has been mainly payed to raising antisera and monocolonal antibodies against the endotoxin and the induced mediators. However, the allergic reactions and the cost are still the problems. Till now, there is no drug that can antagonize endotoxin with high effectiveness and low toxicity. Clinical treatments are still confined in inhibiting or killing the pathogen, and correcting the internal environmental disturbance. Being less toxic and rich in resources with low cost and less side-effects, screening of effective Chinese drugs for antagonizing endotoxin is of important and practical significance. Endotoxin belongs to the category of toxic evils, or more precisely, the heat toxin in TCM. Therefore the application of heat-clearing and detoxifying Chinese drugs to antagonizing endotoxins is consistent with the theory of TCM. Some achievements in this field are reported as follows.

A DNA Nano-train Carrying a Predefined Drug Combination for Cancer Therapy

Herein,we reported a tumor cell-targeting aptamer-nano-train to deliver paclitaxel(PTX)and combretastatin A4(CA4)at a predefined ratio to cancer cells based on DNA nanotechnology.Such a drug-carrying aptamer-nano-train(aptamer-NT-PTX/CA4)was prepared via self-assembly of two DNA hairpins,which were conjugated with PTX and CA4,respectively,induced by aptamer trigger.Our research revealed that the aptamer-NT-PTX/CA4 could specifically recognize CD71-positive cancer cells,but not CD71-negative healthy normal cells,and achieve synergistic therapeutic effect on cancer cells.The aptamer-nano-train-based strategy is simple and efficient,and provides a new platform for drug combination cancer therapy.

Type 2 diabetes mellitus affects eradication rate of Helicobacter pylori

AIM: To study the eradication rate of Helicobacter pylori (Hp) in a group of type 2 diabetes and compared it with an age and sex matched non-diabetic group.METHODS: 40 diabetic patients (21 females, 19 males;56±7 years) and 40 non-diabetic dyspeptic patients (20females, 20 males; 54±9 years) were evaluated. Diabetic patients with dyspeptic complaints were referred for upper gastrointestinal endoscopies; 2 corpus and 2 antral gastric biopsy specimens were performed on each patient. Patients with positive Hp results on histopathological examination comprised the study group. Non-diabetic dyspeptic patients seen at the Gastroenterology Outpatient Clinic and with the same biopsy and treatment protocol formed the control group.A triple therapy with amoxycillin (1 g b.i.d), clarithromycin (500 mg b.i.d) and omeprazole (20 mg b.i.d.) was given to both groups for 10 days. Cure was defined as the absence of Hp infection assessed by corpus and antrum biopsies in control upper gastrointestinal endoscopies performed 6weeks after completing the antimicrobial therapy.RESULTS: The eradication rate was 50 % in the diabetic group versus 85 % in the non-diabetic control group (P＜0.001).CONCLUSION: Type 2 diabetic patients showed a significantly lower eradication rate than controls which may be due to changes in microvasculature of the stomach and to frequent antibiotic usage because of recurrent bacterial infections with the development of resistant strains.

Immune therapies in pancreatic ductal adenocarcinoma: Where are we now?

Pancreatic ductal adenocarcinoma(PDAC)is one of the deadliest cancers,mostly due to its resistance to treatment.Of these,checkpoint inhibitors(CPI)are inefficient when used as monotherapy,except in the case of a rare subset of tumors harboring microsatellite instability(<2%).This inefficacy mainly resides in the low immunogenicity and non-inflamed phenotype of PDAC.The abundant stroma generates a hypoxic microenvironment and drives the recruitment of immunosuppressive cells through cancerassociated-fibroblast activation and transforming growth factorβsecretion.Several strategies have recently been developed to overcome this immunosuppressive microenvironment.Combination therapies involving CPI aim at increasing tumor immunogenicity and promoting the recruitment and activation of effector T cells.Ongoing studies are therefore exploring the association of CPI with vaccines,oncolytic viruses,MEK inhibitors,cytokine inhibitors,and hypoxia-and stroma-targeting agents.Adoptive T-cell transfer is also under investigation.Moreover,translational studies on tumor tissue and blood,prior to and during treatment may lead to the identification of biomarkers with predictive value for both clinical outcome and response to immunotherapy.

Initial steroid-free immunosuppression after liver transplantation in recipients with hepatitis c virus related cirrhosis

AIM:Steroids can increase hepatitis C virus(HCV) replication.After liver transplantation(LTx),steroids are commonly used for immunosuppression and acute rejection is usually treated by high steroid dosages.Steroids can worsen the outcome of recurrent HCV infection.Therefore, we evaluated the outcome of HCV infected liver recipients receiving initial steroid-free immunosuppression. METHODS:Thirty patients undergoing LTx received initial steroid-free immunosuppression.Indication for LTx included 7 patients with HCV related cirrhosis.Initial immunosuppression consisted of tacrolimus 2×0.05mg/kg.d po and mycophenolate mofetil(MMF)2×15mg/kg.d po.The tacrolimus dosage was adjusted to trough levels in the target range of 10-15μg/L during the first 3 mo and 5-10μg/L thereafter.Manifestations of acute rejection were verified histologically. RESULTS:Patient and graft survival of 30 patients receiving initial steroid-free immunosuppression was 86% and 83% at 1 and 2 years.Acute rejection occurred in 8/30 patients, including 1 HCV infected recipient.All HCV-infected patients had HCV genotype Ⅱ(lb).HCV seropositivity occurred within the first 4 mo after LTx.The virus load was not remarkably increased during the first year after LTx.Histologically,grafts had no severe recurrent hepatitis. CONCLUSION:From our experience,initial steroid-free immunosuppression does not increase the risk of acute rejection in HCV infected liver recipients.Furthermore,none of the HCV infected patients developed serious chronic liver diseases.It suggests that it may be beneficial to avoid steroids in this particular group of patients after LTx.

CLINICAL STUDY ON 118 CASES OF ULCERATIVE COLITIS TREATED BY INTEGRATION OF TRADITIONAL CHINESE AND WESTERN MEDICINE

118 cases of ulcerative colitis were treated by integration of traditional Chinese and Western medicine. Another 86 cases of ulcerative colitis were treated by simple western drugs as controls. The therapeutic effects for both groups were observed and compared after two therapeutic courses of 40 consecutive days. As a result, 39 cases were cured, 60 cases improved and 19 cases failed, with a total effective rate of 84% in the treatment group; in the control group, 15 cases were cured, 37 cases improved and 34 cases failed, with a total effective rate of 60.5%. Statistically, the difference was very significant (P

SEN virus does not affect treatment response in hepatitis C virus coinfected patients but SEN virus response depends on SEN virus DNA concentration

AIM: To clarify the effect of SEN virus (SENV) infection on a combination therapy including interferon alfa (IFN-α) or pegylated-IFN with ribavirin in patients with chronic hepatitis and the effect of a combination therapy on SENV.METHODS: SENV DNA was determined by polymerase chain reaction in serum samples from 95 patients with chronic hepatitis C. Quantitative analysis was done for SENV H DNA.RESULTS: Twenty-one (22%) of 95 patients were positive for SENV DNA. There was no difference in clinical and biochemical parameters between patients with HCV infection alone and coinfected patients. The sustained response rate for HCV clearance after combination therapy did not differ between patients with SENV (52%) and without SENV(50%, n.s.). SENV DNA was undetectable in 76% of the initially SENV positive patients at the end of follow-up. SENV H response to combination therapy was significantly correlated with SENV DNA level (P=-0.05).CONCLUSION: SENV infection had no influence on the HCV sustained response rate to the combination therapy.Response rate of SENV to the combination therapy depends on SENV DNA level.

Twenty-eight Cases of Diabetic Foot Ulcer and Gangrene Treated with the Chinese Herbal Medicine Combined with Injection of Ahylsantinfarctase

Since 1995, the Chinese herbal medicine for supplementing qi and activating blood circulation combined with injection of ahylsantinfarctase into the femoral artery has been used in 28 cases of diabetes complicated with gangrene and ulcer of the foot, with quite good therapeutic effects as reported in the following.……

Long-term Effect of TCM Decoctions in Treatment of Nephrotic Syndrome

Fifty-seven cases of nephrotic syndrome were treated with TCM decoctions as accessory treatment for prednisone and cyclophosphamide, and the effects were observed in a follow-up period of 5-15 years. The long-term complete remission rate of 68.4% and recurrence rate of 26.3% in the treatment group were respectively higher and lower than those in the control group (P

Response of TT virus to IFN plus ribavirin treatment in patients with chronic hepatitis C

AIM:TT virus (TTV) is a newly described DNA virus related to postransfusion hepatitis that produces persistent viremia in the absence of clinical manifestations.PEG-IFN plus ribavirin have been useful in the treatment of chronic hepatitis C infection.This study investigated the responses of TT virus (TTV) and hepatitis C virus (HCV) to PEG-IFN plus ribavirin therapy. METHODS:Fifteen patients infected with HCV were treated with PEG-IFN(0.5 μg/body weight/week) and ribavirin (1000 mg-1 200 mg/daily) for 48 weeks,Blood samples were drawn at the beginning and the end of the therapy.Serum TTV DNA and HCV RNA were quantified by real time PCR. RESULTS:At the beginning of treatment,TTV infection was detected in 10/15 (66.6%) of HCV-infected patients.Loss of serum TTV DNA at the end of therapy occurred in 6/10 (60%) patients.Out of these 6 patients,4 (67%) became positive for TTV DNA after 6 months of therapy.Regarding HCV viremia,11/15 (73%) patients were negative for serum HCV RNA after 48 weeks of therapy,7/11 (64%) of these cases also became negative for TTV DNA following the combined treatment.In the 3/4 (75%) patients who were positive for HCV RNA at the end of therapy,TTV DNA was detected as well.Sustained HCV response at 6 months after treatment was 53% (8/15). CONCLUSION:No TTV sustained response can be achieved in any patient after PEG-IFN plus ribavirin administration.

Combination Therapies for Advanced Biliary Tract Cancer

Biliary tract cancers(BTCs)are a group of malignant neoplasms that have recently increased in incidence and have a poor prognosis.Surgery is the only curative therapy.However,most patients are only indicated for palliative therapy because of advanced-stage disease at diagnosis and rapid progression.The current first-line treatment for advanced BTC is gemcitabine and cisplatin chemotherapy.Nonetheless,many patients develop resistance to this regimen.Over the years,few chemotherapy regimens have managed to improve the overall survival of patients.Accordingly,novel therapies such as targeted therapy have been introduced to treat this patient population.Extensive research on tumorigenesis and the genetic profiling of BTC have revealed the heterogenicity and potential target pathways,such as EGFR,VEGF,MEK/ERK,PI3K and mTOR.Moreover,mutational analysis has documented the presence of IDH1,FGFR2,HER2,PRKACA,PRKACB,BRAF,and KRAS gene aberrations.The emergence of immunotherapy in recent years has expanded the treatment landscape for this group of malignancies.Cancer vaccines,adoptive cell transfer,and immune checkpoint inhibitors have been extensively investigated in trials of BTC.Therefore,patient stratification and a combination of various therapies have become a reasonable and important clinical strategy to improve patient outcomes.This review elaborates the literature on combined treatment strategies for advanced BTC from the past few years and ongoing clinical trials to provide new inspiration for the treatment of advanced BTC.