Effect of Induction Therapy With Olamkicept vs Placebo on Clinical Response in Patients With Active Ulcerative Colitis: A Randomized Clinical Trial.

Importance: Olamkicept, a soluble gp130-Fc-fusion-protein, selectively inhibits interleukin 6 (IL-6) trans-signaling by binding the soluble IL-6 receptor/IL-6 complex. It has anti-inflammatory activities in inflammatory murine models without immune suppression. Objective: To assess the effect of olamkicept as induction therapy in patients with active ulcerative colitis. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled phase 2 trial of olamkicept in 91 adults with active ulcerative colitis (full Mayo score ≥5, rectal bleeding score ≥1, endoscopy score ≥2) and an inadequate response to conventional therapy. The study was conducted at 22 clinical study sites in East Asia. Patients were recruited beginning in February 2018. Final follow-up occurred in December 2020. Interventions: Eligible patients were randomized 1:1:1 to receive a biweekly intravenous infusion of olamkicept 600 mg (n = 30) or 300 mg (n = 31) or placebo (n = 30) for 12 weeks. Main Outcomes and Measures: The primary end point was clinical response at week 12 (defined as ≥3 and ≥30% decrease from baseline total Mayo score; range, 0-12 [worst] with ≥1 decrease and ≤1 in rectal bleeding [range, 0-3 {worst}]). There were 25 secondary efficacy outcomes, including clinical remission and mucosal healing at week 12. Results: Ninety-one patients (mean age, 41 years; 25 women [27.5%]) were randomized; 79 (86.8%) completed the trial. At week 12, more patients receiving olamkicept 600 mg (17/29 [58.6%]) or 300 mg (13/30 [43.3%]) achieved clinical response than placebo (10/29 [34.5%]), with adjusted difference vs placebo of 26.6% (90% CI, 6.2% to 47.1%; P = .03) for 600 mg and 8.3% (90% CI, -12.6% to 29.1%; P = .52) for 300 mg. Among patients randomized to receive 600 mg olamkicept, 16 of 25 secondary outcomes were statistically significant compared with placebo. Among patients randomized to receive 300 mg, 6 of 25 secondary outcomes were statistically significant compared with placebo. Treatment-related adverse events occurred in 53.3% (16/30) of patients receiving 600 mg olamkicept, 58.1% (18/31) receiving 300 mg olamkicept, and 50% (15/30) receiving placebo. The most common drug-related adverse events were bilirubin presence in the urine, hyperuricemia, and increased aspartate aminotransferase levels, and all were more common in the olamkicept groups compared with placebo. Conclusions and Relevance: Among patients with active ulcerative colitis, biweekly infusion of olamkicept 600 mg, but not 300 mg, resulted in a greater likelihood of clinical response at 12 weeks compared with placebo. Further research is needed for replication and to assess longer-term efficacy and safety. Trial Registration: ClinicalTrials.gov Identifier: NCT03235752.

Cisplatin and Albumin-Based Gold-Cisplatin Nanoparticles Enhance Ablative Radiation Therapy-Induced Antitumor Immunity in Local and Distant Tumor Microenvironment.

PURPOSE: Ablative radiation therapy (RT) is an important strategy to eliminate primary tumor and can potentially induce the abscopal effect. Human serum albumin nanoparticle (NP) was used for controlled release of cisplatin to decrease cisplatin's systemic toxicity, and gold (Au) was added to increase RT-induced immunogenic cell death and potentiate the abscopal antitumor immunity. METHODS AND MATERIALS: The designed albumin-based cisplatin-conjugated AuNPs were administered concurrently with ablative RT. C57BL/6 mice implanted with syngeneic murine Lewis lung carcinoma or murine MB49 tumor models were treated with ablative RT (12 Gy per fraction for 2 fractions, total 24 Gy), cisplatin, or Au-cisplatin NPs. RESULTS: Combining ablative RT with cisplatin or Au-cisplatin NPs both destroyed the primary tumor effectively and elicited immunogenic cell death accompanied by release of danger-associated molecular patterns. This enhanced recruitment of effector tumor-infiltrating immune cells, including natural killer T cells and CD8+ T cells, and elicited an increased percentage of professional antigen-presenting CD11c+ dendritic cells. Transient weight loss, accompanying hepatotoxicity, nephrotoxicity, and hematopoietic suppression, was observed as a systemic adverse event in the cisplatin but not the Au-cisplatin NPs group. Cisplatin and Au-cisplatin NPs both showed equivalent ability to reduce metastatic potential when combined with ablative RT, confirmed by suppressed unirradiated flank tumor growth and decreased metastatic lung tumor burden, which translated to improved survival. Mobilization and abundance of effector tumor-infiltrating immune cells including CD8+ T cells and dendritic cells were observed in the distant lung tumor microenvironment after ablative RT with cisplatin or Au-cisplatin NPs, demonstrating increased antitumor immunotherapeutic activity as an abscopal effect. CONCLUSIONS: Compared with cisplatin, the albumin-based Au-cisplatin NPs exhibited equivalent but no superior antitumor immunotherapeutic activity while reducing systemic adverse events and can be safely administered concurrently with ablative RT. Alternative NP formulations may be designed to further improve anticancer outcomes.

Real-World Evidence of Effectiveness and Safety of Vedolizumab for Inflammatory Bowel Disease in Taiwan: A Prospective Nationwide Registry (VIOLET) Study.

BACKGROUND: This nationwide prospective registry study investigated the real-world effectiveness, safety, and persistence of vedolizumab (VDZ) in inflammatory bowel disease (IBD) patients in Taiwan. Disease relapse rates after VDZ discontinuation due to reimbursement restriction were assessed. METHODS: Data were collected prospectively (January 2018 to May 2020) from the Taiwan Society of IBD registry. RESULTS: Overall, 274 patients (147 ulcerative colitis [UC] patients, 127 Crohn's disease [CD] patients) were included. Among them, 70.7% with UC and 50.4% with CD were biologic-naïve. At 1 year, 76.0%, 58.0%, 35.0%, and 62.2% of UC patients and 57.1%, 71.4%, 33.3%, and 30.0% of CD patients achieved clinical response, clinical remission, steroid-free remission, and mucosal healing, respectively. All patients underwent hepatitis B and tuberculosis screening before initiating biologics, and prophylaxis was recommended when necessary. One hepatitis B carrier, without antiviral prophylaxis due to economic barriers, had hepatitis B reactivation during steroid tapering and increasing azathioprine dosage, which was controlled with an antiviral agent. No tuberculosis reactivation was noted. At 12 months, non-reimbursement-related treatment persistence rates were 94.0% and 82.5% in UC and CD patients, respectively. Moreover, 75.3% of IBD patients discontinued VDZ due to mandatory drug holiday. Relapse rates after VDZ discontinuation at 6 and 12 months were 36.7% and 64.3% in CD patients and 42.9% and 52.4% in UC patients, respectively. CONCLUSIONS: The findings demonstrated VDZ effectiveness in IBD patients in Taiwan, with high treatment persistence rates and favorable safety profiles. A substantial IBD relapse rate was observed in patients who had mandatory drug holiday.

Anemia in inflammatory bowel disease course is associated with patients' worse outcome.

BACKGROUND: Purpose: Anemia affects the life quality of inflammatory bowel disease (IBD) patients, but no report from Asian about anemia screening and its impact previously. We aimed to explore the prevalence and impact of anemia among the IBD patients in Taiwan. METHODS: A retrospective study was conducted from January 2006 to February 2018 at National Taiwan University Hospital. Clinical characteristics and outcomes were analyzed. RESULTS: A total of 1604 IBD patients were enrolled [494 Crohn's disease (CD) and 1110 ulcerative colitis (UC)]. Overall, 95.3% (471/494) of CD and 87.9% (976/1110) of UC patients underwent anemia screening. Anemia screening rate in IBD patients significantly increased from 62.6% (162/259) in 2006 to 77.2% (838/1086) in 2017. The mean time from IBD diagnosis to anemia screening was 122.4 days in CD patients and even longer in UC patients at 216.2 days. Persistent anemia was found in 47.3% (548/1158) of the screened patients. Risk factors of persistent anemia included low body mass index [odds ratio (OR) = 1.96, p < 0.01], steroid [OR = 2.96, p < 0.01], thiopurine [OR = 2.62, p < 0.01], colectomy [OR = 6.3, p < 0.01], and small bowel resection [OR = 3.21, p < 0.05)] after IBD diagnosis. Compared with those without anemia, anemic IBD patients had higher admission (p < 0.01) and mortality rates (p < 0.01). CONCLUSION: The anemia screening rate was acceptable and increased over time in Taiwan. Since anemia is associated with worse outcomes, earlier survey and treatment of anemia in IBD patients is recommended.

Cisplatin-loaded gold nanoshells mediate chemo-photothermal therapy against primary and distal lung cancers growth.

Lung cancer is the most common cause of cancer mortality worldwide. The advances in surgery, radiotherapy, chemotherapeutic and immunotherapeutic drugs have progressed in the past decades, but the prognosis of lung cancer is still poor. In this study, we developed cisplatin (CDDP)-loaded human serum albumin (HSA)-based gold nanoshells (HCP@GNSs) for synergistic chemo-photothermal therapy (chemo-PTT). The HCP@GNSs not only acted as drug nanocarriers for chemotherapy but also serve as a superior mediator for PTT, which could exhibit a temperature increase upon a near infrared (NIR) laser exposure that was sufficient for photothermal ablation. HCP@GNSs were highly biocompatible and hemocompatible nanocarriers, while the synergistic chemo-PTT resulting from HCP@GNSs plus NIR exposure displayed stronger cytotoxicity effect than HCP@GNSs or PTT alone, especially at a low CDDP concentration. In vivo analysis demonstrated that HCP@GNSs-mediated chemo-PTT increased necrosis in tumors to achieve a high tumor clearance rate with no adverse side effects. Moreover, HCP@GNSs-medicated chemo-PTT induced the recruitment of dendritic cells, B-cells, and natural killer T-cells in distal tumors to inhibit the growth of the tumors. Therefore, the CDDP-loaded HCP@GNSs may be a potential nanomedicine candidate for curative lung cancer treatment in the future.

Retention Time Extended by Nanoparticles Improves the Eradication of Highly Antibiotic-Resistant Helicobacter pylori.

Helicobacter pylori infection usually causes gastrointestinal complications, including gastrointestinal bleeding or perforation, and serious infections may lead to gastric cancer. Amoxicillin is used to treat numerous bacterial infections but is easily decomposed in the gastric acid environment via the hydrolyzation of the ß-lactam ring. In this study, we develop chitosan-based nanoparticles loaded with amoxicillin (CAANs) as an H. pylori eradication platform. The CAANs were biocompatible and could retain the antibiotic activity of amoxicillin against H. pylori growth. The mucoadhesive property of chitosan and alginate enabled the CAANs to adhere to the mucus layers and penetrate through these to release amoxicillin in the space between the layers and the gastric epithelium. The use of this nanoparticle could prolong the retention time and preserve the antibiotic activity of amoxicillin in the stomach and help enhance the eradication rate of H. pylori and reduce treatment time. These CAANs, therefore, show potential for the effective treatment of highly antibiotic-resistant H. pylori infection using amoxicillin.

Characteristics of primary signet ring cell carcinoma of colon and rectum: a case control study.

BACKGROUND: Primary signet ring cell carcinoma of the colon and rectum (PSRCCR) is rare, usually diagnosed at advanced stage with poor outcomes. We aimed to find possible diagnostic clues in order to help diagnosis. METHODS: A retrospective study of PSRCCR patients from 1993 to 2018 was reviewed at a single tertiary center. Colorectal adenocarcinoma patients as control group with 1:4 ratio was also enrolled. RESULTS: 18 patients with PSRCCR were identified. The prevalence rate was 0.16% (18 of 11,515). The mean age was 50.2 years-old in PSRCCR group and 63 years-old in non-SRCC colorectal cancer patients (p < 0.001). Diagnosis tool depends on colonoscopy were much less in PSRCCR group than control group (44.4% vs 93%, p < 0.001). SRCC patients had higher level of CEA (68.3 vs 17.7 ng/mL, p = 0.004) and lower level of Albumin (3.4 vs 4.3 g/dL, p < 0.001). The majority of PSRCCR tumor configuration was ulcerative and infiltrative. More PSRCCR pathology presented as high-grade carcinoma (66.7 vs 1.4%, p < 0.001) and lymphovascular invasion (77.8 vs 44.4%, p = 0.011) than control group. More PSRCCR patients were diagnosed at advanced stage (88.8 vs 40.3%, p = 0.001). Higher mortality was also noticed in PSRCCR group than control group (72.2 vs 20.8%, p < 0.001). CONCLUSION: For young patients with long segment colonic stenosis and ulcerative/ infiltrative mucosa but endoscopic biopsy failed to identify malignant cells, earlier operation or non-colon site biopsy is suggested for diagnosing the PSRCCR.

Dual-Functional Polymeric Micelles Co-Loaded with Antineoplastic Drugs and Tyrosine Kinase Inhibitor for Combination Therapy in Colorectal Cancer.

The aim of this research was to evaluate the receptor tyrosine kinase inhibitor Sunitinib combined with SN-38 in polymeric micelles for antitumor efficacy in colorectal cancer. First, SN-38 and Sunitinib co-loaded micelles were developed and characterized. We studied cell viability and cellular uptake in HCT-116 cells. Then, subcutaneous HCT-116 xenograft tumors were used for ex vivo biodistribution, antitumor efficacy, and histochemical analysis studies. Results of cellular uptake and ex vivo biodistribution of SN-38/Sunitinib micelles showed the highest accumulation in tumors compared with other normal organs. In the antitumor effect studies, mice bearing HCT-116 tumors were smallest at day 28 after injection of SN-38/Sunitinib micelles, compared with other experiment groups (p < 0.01). As demonstrated by the results of inhibition on multi-receptors by Sunitinib, we confirmed that SN-38/Sunitinib co-loaded micelles to be a treatment modality that could inhibit VEGF and PDGF receptors and enhance the antitumor effect of SN-38 (p < 0.05). In summary, we consider that this micelle is a potential formulation for the combination of SN-38 and Sunitinib in the treatment of colorectal cancer.

Association of young age and male sex with primary sclerosing cholangitis in Taiwanese patients with inflammatory bowel disease.

BACKGROUND/AIMS: Primary sclerosing cholangitis (PSC) is associated with inflammatory bowel disease (IBD). We aimed to evaluate the prevalence, clinical manifestation, and outcomes of PSC in Taiwanese patients with IBD. METHODS: This retrospective study enrolled patients with IBD admitted from January 1, 1996, to December 31, 2018, to National Taiwan University Hospital. A case-matched analysis was performed comparing patients with IBD with and without PSC according to age, sex, and time of admission, with ratios of 1:4 and 1:2 in the adult and pediatric groups, respectively. RESULTS: In total, 763 patients with IBD were enrolled, 12 of whom were also diagnosed with PSC (1.57%). All these patients had ulcerative colitis (UC). A greater incidence of IBD with PSC was observed in younger patients than in older patients. Male sex was a risk factor for PSC in pediatric patients with IBD (P=0.015); 75% of these patients were diagnosed with PSC along with or after the diagnosis of UC. There was no significant difference in colitis extent and severity between the groups; however, a higher proportion of rectal sparing was observed in patients with PSC (P=0.001). There was no significant difference in cancer development between the groups (P=0.679). CONCLUSIONS: A 1.57% prevalence of PSC was observed in Taiwanese patients with IBD. The majority of patients with IBD and PSC were men and were diagnosed at a younger age. Hence, routine evaluation of biliary enzymes and liver imaging is recommended in young male patients with IBD.

The synergistic effect of chemo-photothermal therapies in SN-38-loaded gold-nanoshell-based colorectal cancer treatment.

Aim: 7-Ethyl-10-hydroxycamptothecin (SN-38)-loaded gold nanoshells nanoparticles (HSP@Au NPs) were developed for combined chemo-photothermal therapy to treat colorectal cancer. Materials & methods: SN-38-loaded nanoparticles (HSP NPs) were prepared by the lyophilization-hydration method, and then developed into gold nanoshells. The nanoparticles were characterized and assessed for photothermal properties, cytotoxicity and hemocompatibility in vitro. In vivo anticancer activity was tested in a tumor mouse model. Results: The HSP@Au NPs (diameter 186.9 nm, zeta potential 33.4 mV) led to significant cytotoxicity in cancer cells exposed to a near-infrared laser. Moreover, the HSP@Au NP-mediated chemo-photothermal therapy displayed significant tumor growth suppression and disappearance (25% of tumor clearance rate) without adverse side effects in vivo. Conclusion: HSP@Au NPs may be promising in the treatment of colorectal cancer in the future.

Preclinical evaluation of PEGylated liposomal doxorubicin as an effective radiosensitizer in chemoradiotherapy for lung cancer.

PURPOSE: Development of a safe and effective systemic chemotherapeutic agent for concurrent administration with definitive thoracic radiotherapy remains a major goal of lung cancer management. The synergistic effect of PEGylated liposomal doxorubicin and irradiation was evaluated in lung cancer cell lines both in vitro and in vivo. METHODS: In vitro radiosensitization of A549 and LLC cell lines was evaluated by colony formation assay, γH2AX fluorescent staining and western blot assay, and annexin V staining. A radiosensitization study with healthy human lung-derived cell line BEAS-2B was performed for comparative purposes. In vivo radiosensitization was evaluated by tumor ectopic growth, cell survival, pharmacokinetics, and biodistribution analyses. Cleaved caspase­3, the marker for apoptosis, was assessed immunohistochemically in A549 xenograft tumors. RESULTS: Treatment with PEGylated liposomal doxorubicin decreased A549 and LLC cell proliferation in a dose-dependent manner. In vitro studies revealed comparable radiosensitizer advantages of PEGylated liposomal doxorubicin and free doxorubicin, showing equivalent DNA double-strand breaks according to γH2AX fluorescent staining and western blot assays, similar numbers of apoptotic cells in the annexin­V staining assay, and moderately decreased clonogenic survival. In vivo studies demonstrated markedly slow ectopic tumor growth with prolonged survival following treatment with PEGylated liposomal doxorubicin plus irradiation in both A549 and LLC mouse models, suggesting that PEGylated liposomal doxorubicin is more effective as a radiosensitizer than free doxorubicin in vivo. Pharmacokinetics evaluation showed a longer half-life of approximately 40 h for PEGylated liposomal doxorubicin, confirming that the liposomal carrier achieved controlled release. Biodistribution evaluation of PEGylated liposomal doxorubicin confirmed high accumulation of doxorubicin in tumors, indicating the promising drug delivery attributes of PEGylated liposomal doxorubicin. Although free doxorubicin caused histopathologic myocarditis with the cardiac muscle fibers showing varying degrees of damage, PEGylated liposomal doxorubicin caused no such effects. The immunohistochemical expression of cleaved caspase-3-positive cells was greatest expressed in the irradiation and PEGylated liposomal doxorubicin combined treatment group, indicating prolonged tumoricidal effects. CONCLUSIONS: Our study provides preclinical in vitro and in vivo evidence of the effectiveness of PEGylated liposomal doxorubicin as a radiosensitizer, supporting its potential clinical development as a component of chemoradiotherapy.

Evaluation of antitumor immunity by a combination treatment of high-dose irradiation, anti-PDL1, and anti-angiogenic therapy in murine lung tumors.

C57BL/6 mice implanted in the flank with murine Lewis lung carcinoma cells were randomized into control, anti-angiogenic, anti-PD-L1, radiotherapy (RT), RT + anti-angiogenic, RT + anti-PD-L1, and RT + anti-PD-L1 + anti-angiogenic therapy groups. Immune response and immunophenotyping were determined by flow cytometry. Vasculature analysis after RT and anti-angiogenic therapy was assessed by quantified power Doppler sonography. Antitumor response, survival, and rechallenged tumor growth were evaluated. RT increased PD-L1 expression on CD8+ T, CD4+ T, dendritic, myeloid-derived suppressor cells (MDSCs), and tumor cells and increased PD-1 expression on CD8+ and CD4+ T cells. Anti-angiogenic therapy insignificantly decreased the RT-induced PD-1 expression on CD8+ and CD4+ T cells, implying a weak reversal of the immune-suppressive environment. Transient vessel collapse was observed within days after RT, and blood flow recovered at 1 week after RT. RT + anti-PD-L1 suppressed the tumor growth, improved survival, and prolonged immune memory capable of protecting against tumor recurrence, evidenced by local accumulation of CD8+ T cells and reduction in MDSCs in microenvironment. Similar and more prominent effects were observed when anti-VEGF was added to RT + anti-PDL1 therapies, implying an additive, rather than synergistic, antitumor immunity. Phenotypic analyses revealed that anti-cancer treatments increased the proportion of effector memory T cells in TILs and splenocytes, and RT, alone or in combination with other treatments, further increased the proportion of central memory T cells in splenocytes. These results provide evidence on operating the immunosuppressive tumor environment and offer insights into the design of the new combination treatment.

The Synergistic Effect of Hyperthermia and Chemotherapy in Magnetite Nanomedicine-Based Lung Cancer Treatment.

BACKGROUND: Lung cancer is the leading cause of cancer patient death in the world. There are many treatment options for lung cancer, including surgery, radiation therapy, chemotherapy, targeted therapy, and combined therapy. Despite significant progress has been made in the diagnosis and treatment of lung cancer during the past few decades, the prognosis is still unsatisfactory. PURPOSE: To resolve the problem of chemotherapy failure, we developed a magnetite-based nanomedicine for chemotherapy acting synergistically with loco-regional hyperthermia. METHODS: The targeting carrier consisted of a complex of superparamagnetic iron oxide (SPIO) and poly(sodium styrene sulfonate) (PSS) at the core and a layer-by-layer shell with cisplatin (CDDP), together with methotrexate - human serum albumin conjugate (MTX-HSA conjugate) for lung cancer-specific targeting, referred to hereafter as SPIO@PSS/CDDP/HSA-MTX nanoparticles (NPs). RESULTS: SPIO@PSS/CDDP/HSA-MTX NPs had good biocompatibility and stability in physiological solutions. Furthermore, SPIO@PSS/CDDP/HSA-MTX NPs exhibited a higher temperature increase rate than SPIO nanoparticles under irradiation by a radiofrequency (RF) generator. Therefore, SPIO@PSS/CDDP/HSA-MTX NPs could be used as a hyperthermia inducer under RF exposure after nanoparticles preferentially targeted and then accumulated at tumor sites. In addition, SPIO@PSS/CDDP/HSA-MTX NPs were developed to be used during combined chemotherapy and hyperthermia therapy, exhibiting a synergistic anticancer effect better than the effect of monotherapy. CONCLUSION: Both in vitro and in vivo results suggest that the designed SPIO@PSS/CDDP/HSA-MTX NPs are a powerful candidate nanoplatform for future antitumor treatment strategies.

Residence Time-Extended Nanoparticles by Magnetic Field Improve the Eradication Efficiency of Helicobacter pylori.

Helicobacter pylori infection is one of the leading causes of several gastroduodenal diseases, such as gastritis, peptic ulcer, and gastric cancer. In fact, H. pylori eradication provides a preventive effect against the incidence of gastric cancer. Amoxicillin is a commonly used antibiotic for H. pylori eradication. However, due to its easy degradation by gastric acid, it is necessary to administer it in a large dosage and to combine it with other antibiotics. This complexity and the strong side effects of H. pylori eradication therapy often lead to treatment failure. In this study, the chitosan/poly (acrylic acid) particles co-loaded with superparamagnetic iron oxide nanoparticles and amoxicillin (SPIO/AMO@PAA/CHI) are used as drug nano-carriers for H. pylori eradication therapy. In vitro and in vivo results show that the designed SPIO/AMO@PAA/CHI nanoparticles are biocompatible and could retain the biofilm inhibition and the bactericidal effect of amoxicillin against H. pylori. Moreover, the mucoadhesive property of chitosan allows SPIO/AMO@PAA/CHI nanoparticles to adhere to the gastric mucus layer and rapidly pass through the mucus layer after exposure to a magnetic field. When PAA is added, it competes with amoxicillin for chitosan, so that amoxicillin is quickly and continuously released between the mucus layer and the gastric epithelium and directly acts on H. pylori. Consequently, the use of this nano-carrier can extend the drug residence time in the stomach, reducing the drug dose and treatment period of H. pylori eradication therapy.

Magnetic nanomedicine for CD133-expressing cancer therapy using locoregional hyperthermia combined with chemotherapy.

Aim: Cells with CD133 overexpression, a theoretical cancer stem cells (CSCs) marker, have been shown to induce colorectal cancer (CRC) initiation and relapse. Therefore, the detection and treatment of CSCs are the most important factors in overcoming CRC. Materials & methods: Herein, we developed a magnetite-based nanomedicine (superparamagnetic iron oxide@poly(sodium styrene sulfonate)/irinotecan/human serum albumin-anti-CD133 nanoparticle) using loco-regional hyperthermia combined with chemotherapy for CRC- and CSC-specific targeting treatment. Results: The designed nanoparticles were highly biocompatible and exhibited a higher temperature increase rate under radiofrequency generator irradiation. The nanoparticles could be used as a T2-weighted magnetic resonance imaging contrast media, and also applied during hyperthermia and chemotherapy to display a synergistic anticancer effect. Conclusion: Therefore, the superparamagnetic iron oxide@poly(sodium styrene sulfonate)/irinotecan/human serum albumin-anti-CD133 nanoparticles are a powerful candidate for future antitumor strategies.

Platinum(II) Drug-Loaded Gold Nanoshells for Chemo-Photothermal Therapy in Colorectal Cancer.

In the present study, we utilize a poly[2-(N,N-dimethylamino)ethyl methacrylate]-poly(ε-caprolactone) (PDMA-PCL) micellar template-based gold nanoshell as a nanocarrier of a platinum-based chemotherapeutic drug, dichloro(1,2-diaminocyclohexane)platinum(II) (DACHPt). The gold nanoshells not only function as a drug delivery platform but also provide a remarkable photothermal effect, resulting in synergistically combined chemo-photothermal therapy. With the positively charged outstretched hydrophilic PDMA segments, chloroauric anions are attracted to the PDMA-PCL micellar surface and reduced to gold atoms in situ, forming small seeds that nucleate the subsequent growth of gold nanoshells. The DACHPt-loaded gold nanoshells possess strong absorption in the near-infrared (NIR) region and outstanding photothermal conversion effect; thus, they can promote a temperature increase that is sufficient to ablate tumor cells under NIR laser irradiation at a moderate power density (1 W/cm2). Furthermore, by exploiting the synergistic effects of platinum-based chemotherapy and photothermal therapy, the DACHPt-loaded gold nanoshells exhibited a profound inhibition of tumor growth compared to chemotherapy or photothermal therapy alone. Therefore, the platinum(II)-loaded gold nanoshells that we proposed herein may be a potential alternative for efficient curative therapy for colorectal cancer.

Epidemiological trend in inflammatory bowel disease in Taiwan from 2001 to 2015: a nationwide populationbased study.

BACKGROUND/AIMS: Incidences of inflammatory bowel diseases (IBDs), ulcerative colitis (UC), and Crohn's disease (CD), have been increasing in Asia. In this study, we report the relevant clinical characteristics and determined the epidemiological trend of IBD in Taiwan from 2001 to 2015. METHODS: A retrospective study was conducted to analyze data recorded from January 2001 through December 2015 in the registered database compiled by the National Health Insurance and provided by the Ministry of Health and Welfare, Taiwan. RESULTS: A total of 3,806 patients with catastrophic IBD illness were registered from 2001 to 2015 in Taiwan (CD, 919; UC, 2,887). The crude incidence of CD increased from 0.17/100,000 in 2001 to 0.47/100,000 in 2015, whereas that of UC increased from 0.54/100,000 in 2001 to 0.95/100,000 in 2015. The prevalence of CD increased from 0.6/100,000 in 2001 to 3.9/100,000 in 2015, whereas that of UC increased from 2.1/100,000 in 2001 to 12.8/100,000 in 2015. The male-to-female ratio in the study sample was 2.19 for CD and 1.62 for UC. The median age of those registered with CD was lower than that of those registered for UC: 38.86 and 44.86 years, respectively. A significantly greater increase in CD incidence rate was identified among 20 to 39-year-old compared with other age groups. CONCLUSIONS: Using Taiwan's nationwide insurance database, we determined that the number of patients with CD increased more rapidly during the study period than the number of patients with UC, especially among age 20 to 39-year-old, resulting in a decreased UC-to-CD ratio.

Dual-triggered drug-release vehicles for synergistic cancer therapy.

Cancer is a complex and tenacious disease. Drug-delivery systems in combination with multimodal therapy strategies are very promising candidates for cancer theranostic applications. In this study, a new drug-delivery vehicle that combine human serum albumin (HSA)- and poly(sodium 4-styrenesulfonate) (PSS)-coated gold nanorod nanoparticles(GNR/PSS/HSA NPs) was developed for synergistic cancer therapy. Doxorubicin (DOX) was loaded onto GNR/PSS/HSA NPs, by electrostatic and hydrophobic forces, to create multimodal DOX@GNR/PSS/HSA NPs. DOX@GNR/PSS/HSA NPs were found to be highly biocompatible and stable in physiological solutions. Furthermore, GNR/PSS/HSA NPs with or without DOX were designed to exhibit strong absorbance in the near-infrared region and high photothermal conversion efficiency. Therefore, bimodal DOX release from DOX@GNR/PSS/HSA NPs could be triggered by an acidic pH and by near-infrared irradiation after NPs preferentially accumulated at tumor sites, leading to a significant chemotherapeutic effect. Moreover, DOX@GNR/PSS/HSA NPs were designed to be applied during chemo- and photo-thermal combination therapy and exhibited a synergistic anticancer effect that was superior to the effect of monotherapy, from both in vitro and in vivo results. These results suggest that DOX@GNR/PSS/HSA NPs are a strong candidate for a nanoplatform for future antitumor therapeutic strategies.

Anti-angiogenic treatment (Bevacizumab) improves the responsiveness of photodynamic therapy in colorectal cancer.

Photodynamic therapy (PDT) is a treatment utilizing the combined action of photosensitizers and light for the treatment of various cancers. The mechanisms for tumor destruction after PDT include direct tumor cell kill by singlet oxygen species (OS), indirect cell kill via vascular damage, and an elicited immune response. However, it has been reported that many cellular activators, including vascular endothelial growth factor (VEGF), are produced by tumor cells after PDT. In this study, we demonstrate that meta-tetra(hydroxyphenyl) chlorin (mTHPC)-based photodynamic therapy combined with bevacizumab (Avastin™), an anti-VEGF neutralizing monoclonal antibody that blocks the binding of VEGF to its receptor, can enhance the effectiveness of each treatment modality. We evaluated the efficacy of bevacizumab-based anti-angiogenesis in combination with PDT as well as the resulting VEGF levels and microvessel density (MVD) in a mouse model of human colon cancer. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) were performed to assess VEGF concentrations and microvessel density in the various treatment groups, and confocal imaging and high performance liquid chromatography (HPLC) analyses were used to measure the distribution and concentration of mTHPC in tumors. Our results demonstrate that combination of PDT followed by bevacizumab significantly elicits a greater tumor response whereas bevacizumab treatment prior to PDT led to a reduced tumor response. Immunostaining and ELISA analyses revealed a lower expression of VEGF in tumors treated with combination therapy of PDT followed by bevacizumab. However, bevacizumab treatment decreased the accumulation of mTHPC in tumors 24 h after administration, which complemented the results of decreased anti-tumor efficacy of bevacizumab followed by PDT.

Near-Infrared Fluorescent Dye-Decorated Nanocages to Form Grenade-like Nanoparticles with Dual Control Release for Photothermal Theranostics and Chemotherapy.

Recently, nanoparticles (NPs) have been widely investigated for delivery of anticancer drugs. Here, a dual control drug-release modality was developed that uses naturally occurring protein apoferritin loaded with doxorubicin (DOX) and ADS-780 near-infrared (NIR) fluorescent dye-decorated NPs (ADNIR NPs). ADNIR NPs act as a grenade to detonate the targeted tumor site following laser irradiation (photothermal therapy, PTT) and explode into cluster warheads (apoferritin-loaded DOX nanocages, AF-DOX NCs) that further destroy the tumor cells (chemotherapy). Light was shown to disrupt the grenade-like structure of NPs to release AF-DOX NCs as well as DOX from NCs in low-pH intercellular environments. In vitro and in vivo studies showed that the structure of AF-DOX NCs was disassembled to release DOX, which then killed the cancer cells in organelles with acidic environments. In vivo studies showed that the ADNIR NP-decorated with NIR dye facilitated tracking of the accumulated NPs at the tumor site using an IVIS imaging system. Overall, targeted ADNIR NPs with dual-release mechanisms were developed for use in photothermal theranostic and chemotherapy. This modality has high potential for application in cancer treatment and clinical translation for drug delivery and imaging.