Post-Graphene 2D Materials: Structures, Properties, and Cancer Therapy Applications.

Cancer is one of the most serious diseases challenging human health and life span. Cancer has claimed millions of lives worldwide. Early diagnosis and effective treatment of cancer are very important for the survival of patients. In recent years, 2D nanomaterials have shown great potential in the development of anticancer treatment by combining their inherent physicochemical properties after surface modification. 2D nanomaterials have attracted great interest due to their unique nanosheet structure, large surface area, and extraordinary physicochemical properties. This article reviews the advantages and application status of emerging 2D nanomaterials for targeted tumor synergistic therapy compared with traditional therapeutic strategies. In order to investigate novel potential anticancer strategies, this paper focuses on the surface modification, cargo delivery capability, and unique optical properties of emerging 2D nanomaterials. Finally, the current problems and challenges in cancer treatment are summarized and prospected.

Subtractive Nanopore Engineered MXene Photonic Nanomedicine with Enhanced Capability of Photothermia and Drug Delivery for Synergistic Treatment of Osteosarcoma.

Two-dimensional (2D) nanomaterials as drug carriers and photosensitizers have emerged as a promising antitumor strategy. However, our understanding of 2D antitumor nanomaterials is limited to intrinsic properties or additive modification of different materials. Subtractive structural engineering of 2D nanomaterials for better antitumor efficacy is largely overlooked. Here, subtractively engineered 2D MXenes with uniformly distributed nanopores are synthesized. The nanoporous defects endowed MXene with enhanced surface plasmon resonance effect for better optical absorbance performance and strong exciton-phonon coupling for higher photothermal conversion efficiency. In addition, porous structure improves the binding ability between drug and unsaturated bonds, thus promoting drug-loading capacity and reducing uncontrolled drug release. Furthermore, the porous structure provides adhesion sites for filopodia, thereby promoting the cellular internalization of the drug. Clinically, osteosarcoma is the most common bone malignancy routinely treated with doxorubicin-based chemotherapy. There have been no significant treatment advances in the past decade. As a proof-of-concept, nanoporous MXene loaded with doxorubicin is developed for treating human osteosarcoma cells. The porous MXene platform results in a higher amount of doxorubicin-loading, faster near-infrared (NIR)-controlled doxorubicin release, higher photothermal efficacy under NIR irradiation, and increased cell adhesion and internalization. This facile method pioneers a new paradigm for enhancing 2D material functions and is attractive for tumor treatment.

Emerging 2D pnictogens: a novel multifunctional photonic nanoplatform for cutting-edge precision treatment.

The elements of the pnictogen group, known as the 15th (VA) family in the periodic table, including phosphorus (P), arsenic (As), antimony (Sb) and bismuth (Bi), have been widely used by alchemists to treat various diseases since ancient times and hold a pivotal position in the history of medicine, owing to their diverse pharmacological activities. Recently, with the development of modern nanotechnology, pnictogen group elements appear in a more innovative form, namely two-dimensional (2D) pnictogens (i.e. phosphorene, arsenene, and bismuthene) with a unique layered crystal structure and extraordinary optoelectronic characteristics, which endow them with significant superiority as a novel multifunctional photonic nanoplatform for cutting-edge precision treatment of various diseases. The puckered layer structure with ultralarge surface area make them ideal drug and gene delivery vectors that can avoid degradation and reduce target effects. The anisotropic morphology allows their easier internalization by cells and may improve gene transfection efficiency. Tunable optoelectronic characteristics endow them with excellent phototherapy performance as well as the ability to act as an optical switch to initiate subsequent therapeutic events. This review provides a brief overview of the properties, preparation and surface modifications of 2D pnictogens, and then focuses on its applications in cutting-edge precision treatment as a novel multifunctional photonic nanoplatform, such as phototherapy, photonic medicine, photo-adjuvant immunotherapy and photo-assisted gene therapy. Finally, the challenges and future development trends for 2D pnictogens are provided. With a focus on 2D pnictogen-based multifunctional photonic nanoplatforms, this review may also provide profound insights for the next generation innovative precision therapy.

18[Formula: see text]-Glycyrrhetinic Acid Inhibits TGF-[Formula: see text]-Induced Epithelial-to-Mesenchymal Transition and Metastasis of Hepatocellular Carcinoma by Targeting STAT3.

18[Formula: see text]-glycyrrhetinic acid (GA) is the active ingredient of the traditional Chinese medicinal herb Glycyrrhizae radix et rhizoma. We previously demonstrated that GA inhibited tumor growth in hepatocellular carcinoma (HCC). However, the effect of GA on transforming growth factor-[Formula: see text] (TGF-[Formula: see text]-induced epithelial-mesenchymal transition (EMT) and metastasis were still unclear. In this study, in vitro transwell assays and immunofluorescence (IF) demonstrated that GA inhibited TGF-[Formula: see text]-induced migration, invasion and EMT of HCC cells. However, it had little effect on the inhibition of proliferation by TGF-[Formula: see text]. Moreover, we confirmed that GA suppressed the metastasis of HCC cells in vivousing an ectopic lung metastasis model. Furthermore, we found that GA inhibited TGF-[Formula: see text]-induced EMT mainly by reducing the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which played an essential role in TGF-[Formula: see text]-induced EMT and cell mobility. Mechanistically, GA inhibited the phosphorylation of STAT3 by increasing the expression of Src homology 2 domain-containing protein tyrosine phosphatases 1 and 2 (SHP1 and SHP2). Therefore, we concluded that GA inhibited TGF-[Formula: see text]-induced EMT and metastasis via the SHP1&SHP2/STAT3/Snail pathway. Our data provide an attractive therapeutic target for future multimodal management of HCC.

Detection of an anti-angina therapeutic module in the effective population treated by a multi-target drug Danhong injection: a randomized trial.

It's a challenge for detecting the therapeutic targets of a polypharmacological drug from variations in the responsed networks in the differentiated populations with complex diseases, as stable coronary heart disease. Here, in an adaptive, 31-center, randomized, double-blind trial involving 920 patients with moderate symptomatic stable angina treated by 14-day Danhong injection(DHI), a kind of polypharmacological drug with high quality control, or placebo (0.9% saline), with 76-day following-up, we firstly confirmed that DHI could increase the proportion of patients with clinically significant changes on angina-frequency assessed by Seattle Angina Questionnaire (ΔSAQ-AF ≥ 20) (12.78% at Day 30, 95% confidence interval [CI] 5.86-19.71%, P = 0.0003, 13.82% at Day 60, 95% CI 6.82-20.82%, P = 0.0001 and 8.95% at Day 90, 95% CI 2.06-15.85%, P = 0.01). We also found that there were no significant differences in new-onset major vascular events (P = 0.8502) and serious adverse events (P = 0.9105) between DHI and placebo. After performing the RNA sequencing in 62 selected patients, we developed a systemic modular approach to identify differentially expressed modules (DEMs) of DHI with the Zsummary value less than 0 compared with the control group, calculated by weighted gene co-expression network analysis (WGCNA), and sketched out the basic framework on a modular map with 25 functional modules targeted by DHI. Furthermore, the effective therapeutic module (ETM), defined as the highest correlation value with the phenotype alteration (ΔSAQ-AF, the change in SAQ-AF at Day 30 from baseline) calculated by WGCNA, was identified in the population with the best effect (ΔSAQ-AF ≥ 40), which is related to anticoagulation and regulation of cholesterol metabolism. We assessed the modular flexibility of this ETM using the global topological D value based on Euclidean distance, which is correlated with phenotype alteration (r2: 0.8204, P = 0.019) by linear regression. Our study identified the anti-angina therapeutic module in the effective population treated by the multi-target drug. Modular methods facilitate the discovery of network pharmacological mechanisms and the advancement of precision medicine. (ClinicalTrials.gov identifier: NCT01681316).

Donafenib Versus Sorafenib in First-Line Treatment of Unresectable or Metastatic Hepatocellular Carcinoma: A Randomized, Open-Label, Parallel-Controlled Phase II-III Trial.

PURPOSE: Donafenib, a novel multikinase inhibitor and a deuterated sorafenib derivative, has shown efficacy in phase Ia and Ib hepatocellular carcinoma (HCC) studies. This study compared the efficacy and safety of donafenib versus sorafenib as first-line therapy for advanced HCC. PATIENTS AND METHODS: This open-label, randomized, parallel-controlled, multicenter phase II-III trial enrolled patients with unresectable or metastatic HCC, a Child-Pugh score ≤ 7, and no prior systemic therapy from 37 sites across China. Patients were randomly assigned (1:1) to receive oral donafenib (0.2 g) or sorafenib (0.4 g) twice daily until intolerable toxicity or disease progression. The primary end point was overall survival (OS), tested for noninferiority and superiority. Efficacy was primarily assessed in the full analysis set (FAS), and safety was assessed in all treated patients. RESULTS: Between March 21, 2016, and April 16, 2018, 668 patients (intention-to-treat) were randomly assigned to donafenib and sorafenib treatment arms; the FAS included 328 and 331 patients, respectively. Median OS was significantly longer with donafenib than sorafenib treatment (FAS; 12.1 v 10.3 months; hazard ratio, 0.831; 95% CI, 0.699 to 0.988; P = .0245); donafenib also exhibited superior OS outcomes versus sorafenib in the intention-to-treat population. The median progression-free survival was 3.7 v 3.6 months (P = .0570). The objective response rate was 4.6% v 2.7% (P = .2448), and the disease control rate was 30.8% v 28.7% (FAS; P = .5532). Drug-related grade ≥ 3 adverse events occurred in significantly fewer patients receiving donafenib than sorafenib (125 [38%] v 165 [50%]; P = .0018). CONCLUSION: Donafenib showed superiority over sorafenib in improving OS and has favorable safety and tolerability in Chinese patients with advanced HCC, showing promise as a potential first-line monotherapy for these patients.

Abscisic acid suppresses the activation of NLRP3 inflammasome and oxidative stress in murine allergic airway inflammation.

Abscisic acid (ABA), a well-known natural phytohormone reportedly exerts anti-inflammatory and anti-oxidative properties in diabetes and colitis. However, the efficacy of ABA against allergic airway inflammation and the underlying mechanism remain unknown. Herein, an OVA-induced murine allergic airway inflammation model was established and treated with ABA in the presence or absence of PPAR-γ antagonist GW9662. The results showed that ABA effectively stunted the development of airway inflammation, and concordantly downregulated OVA-induced activation of NLRP3 inflammasome, suppressed oxidative stress and decreased the expression of mitochondrial fusion/fission markers including Optic Atrophy 1 (OPA1), Mitofusion 2 (Mfn2), dynamin-related protein 1 (DRP1) and Fission 1 (Fis1). Moreover, ABA treatment further increased OVA-induced expression of PPAR-γ, while GW9662 abrogated the inhibitory effect of ABA on allergic airway inflammation as well as on the activation of NLRP3 inflammasome and oxidative stress. Consistently, ABA inhibited the activation of NLRP3 inflammasome, suppressed oxidative stress and mitochondrial fusion/fission in LPS-stimulated Raw264.7 cells via PPAR-γ. Collectively, ABA ameliorates OVA-induced allergic airway inflammation in a PPAR-γ dependent manner, and such effect of ABA may be associated with its inhibitory effect on NLRP3 inflammasome and oxidative stress. Our results suggest the potential of ABA or ABA-rich food in protecting against asthma.

Progress in the therapeutic applications of polymer-decorated black phosphorus and black phosphorus analog nanomaterials in biomedicine.

Wonderful black phosphorus (BP) and some BP analogs (BPAs) have been increasingly studied for their biomedical applications owing to their fascinating properties and biodegradability, but opportunities and challenges have always coexisted in their study. Poor stability upon exposure to the natural environment is the major obstacle hampering their in vivo applications. BP/polymer and BPAs/polymer nanocomposites can not only efficiently prevent their oxidation and aggregation but also exhibit "biological activity" due to synergistic effects. In this review, we briefly describe the synthesis methods and stability strategies of BP/polymer and BPAs/polymer. Then, advances pertaining to their exciting therapeutic applications in various fields are systematically introduced, such as cancer therapy (phototherapy, drug delivery, and synergistic immunotherapy), bone regeneration, and neurogenesis. Some challenges for future clinical trials and possible directions for further study are finally discussed.

Tumor calcification as a prognostic factor in cetuximab plus chemotherapy-treated patients with metastatic colorectal cancer.

This study aimed to explore the correlation between survival and tumor calcification in patients with metastatic colorectal cancer who received cetuximab combined with chemotherapy. The study was a single-center retrospective analysis that enrolled 111 patients who had received therapy between April 2011 and October 2016. Tumor calcification and treatment efficacy were evaluated independently by radiologists on the basis of computed tomography scans. Clinical characteristics and follow-up data were collected from electronic medical records. Correlations between tumor calcification and clinical characteristics, tumor response rate, and patient survival were analyzed. Among the 111 enrolled patients, 27 had tumor calcification [27/111 (24.3%)]. The median progression-free survival was significantly longer for patients with tumor calcification than for those without calcification (9.3 vs. 6.2 months, P=0.022). Patients with tumor calcification also had a higher objective response rate (55.6 vs. 31%, P=0.021) and better overall survival (21.9 vs. 16.5 months, P=0.084). The correlation between calcification features and prognosis showed that patients with an increasing number of calcifications after treatment had a significantly longer median overall survival (22.9 vs. 9.1 months, P=0.033). Simultaneously, new liver metastases and multiple calcifications also showed a trend toward better overall survival. There were also no significant correlations between clinical characteristics (sex, age, gene mutation, primary tumor location, pathological type, blood test result) and survival (Supplementary Table 1, Supplemental digital content 1, http://links.lww.com/ACD/A280). Tumor calcification is associated with a better treatment outcome and is a potential prognostic marker.

Omnipotent phosphorene: a next-generation, two-dimensional nanoplatform for multidisciplinary biomedical applications.

Phosphorene, also known as single- or few-layer black phosphorus (FLBP), is a new member of the two-dimensional (2D) material family and has attracted significant attention in recent years for applications in optoelectronics, energy storage and biomedicine due to its unique physicochemical properties and excellent biocompatibility. FLBP is regarded as a potential biological imaging agent for cancer diagnosis due to its intrinsic fluorescence (FL) and photoacoustic (PA) properties and negligible cytotoxicity. FLBP-based photothermal and photodynamic therapies have emerged with excellent anti-tumour therapeutic efficacies due to their unique physical properties, such as near-infrared (NIR) optical absorbance, large extinction coefficients, biodegradability and reactive oxygen species (ROS) or heat generation upon light irradiation. Furthermore, FLBP is a promising drug delivery platform because of its high drug-loading capacity due to its puckered layer structure with an ultralarge surface area, and FLBP is size-controllable with facile surface chemical modification. Because of the marked advantages of FLBP nanomaterials in biomedical applications, an overview of the latest progress and paradigms of FLBP-based nanoplatforms for multidisciplinary biomedical applications is presented in this tutorial review.

18ß-Glycyrrhetinic-acid-mediated unfolded protein response induces autophagy and apoptosis in hepatocellular carcinoma.

18ß-Glycyrrhetinic acid (GA) is the active ingredient of the traditional Chinese medicine, Glycyrrhrzae Radix et Rhizoma. Here, we explored the effects of GA on hepatocellular carcinoma (HCC) in vitro and in vivo and the underlying molecular mechanisms. We confirmed that GA suppressed proliferation of various HCC cell lines. Treatment of GA caused G0/G1 arrest, apoptosis and autophagy in HCC cells. GA-induced apoptosis and autophagy were mainly due to the unfolded protein response. We compared the roles of the ATF4/CHOP and IRE1α/XBP1s UPR pathways, which were both induced by GA. The ATF4/CHOP cascade induced autophagy and was indispensable for the induction of apoptosis in GA-treated HCC cells. In contrast, the IRE1α/XBP1s cascade protected HCC cells from apoptosis in vitro and in vivo induced by GA. Despite this, activation of autophagy protected HCC cells from apoptosis induced by GA. We concluded that pharmacological inhibition of autophagy or IRE1α may be of benefit to enhance the antitumor activity of GA.

Cardiotoxicity of 5-fluorouracil and capecitabine in Chinese patients: a prospective study.

BACKGROUND: 5-Fluorouracil (5-FU) and capecitabine-associated cardiotoxicity ranging from asymptomatic electrocardiography (ECG) abnormalities to severe myocardial infarction has been reported in a number of studies, but such cardiotoxicity in Chinese patients with malignant diseases has not been investigated to date. In the present study, we aimed to prospectively evaluate the incidence rates and clinical manifestations of 5-FU- and capecitabine-associated cardiotoxicity in cancer patients recruited from multiple centers in China. METHODS: Among the 527 patients who completed the study, 196 received 5-FU-based chemotherapy and 331 received capecitabine-based chemotherapy as either first-line or adjuvant therapy. Adverse events were reported during the treatment and up to 28 days of follow-up. Outcome measures included ECG, myocardial enzymes, cardiac troponin, brain natriuretic peptide and echocardiography. Univariate analysis and logistic regression were performed for subgroup analysis and identification of significant independent variables that are associated with cardiotoxicity of both agents. RESULTS: In total, 161 of 527 patients (30.6%) experienced cardiotoxicity. The incidence rate of cardiotoxicity was 33.8% (112/331) in the capecitabine group, which was significantly higher than the rate of 25% (49/196) in the 5-FU group (P = 0.0042). 110/527 patients (20.9%) suffered arrhythmia, 105/527 (19.9%) developed ischemic changes, while only 20/527 patients (3.8%) presented heart failure and 6/527 patients (1.1%) had myocardial infarction. Pre-existing cardiac disease, hypertension, capecitabine-based chemotherapy and duration of treatment were identified as significant risk factors associated with cardiotoxicity. The odds ratio were 15.7 (prior history of cardiac disease versus no history), 1.86 (capecitabine versus 5-FU), 1.06 (5-8 versus 1-4 chemotherapy cycles) and 1.58 (hypertension versus no hypertension), respectively. CONCLUSIONS: Cardiotoxicity induced by fluoropyrimidines in the Chinese population may be underestimated in clinical practice. Close monitoring of patients is recommended, especially for those patients at high risk for cardiotoxicity. Possible risk factors are duration of treatment, capecitabine-based chemotherapy, pre-existing cardiac diseases and hypertension. Trial registration This study was initiated on January 22, 2014 and has been retrospectively registered with the registration number ChiCTR1800015434.

Conceptually Novel Black Phosphorus/Cellulose Hydrogels as Promising Photothermal Agents for Effective Cancer Therapy.

Black phosphorus (BP) has recently emerged as an intriguing photothermal agent in photothermal therapy (PTT) against cancer by virtue of its high photothermal efficiency, biocompatibility, and biodegradability. However, naked BP is intrinsically characterized by easy oxidation (or natural degradation) and sedimentation inside the tumor microenvironment, leading to a short-term therapeutic and inhomogeneous photothermal effect. Development of BP-based nanocomposites for PTT against cancer therefore remains challenging. The present work demonstrates that green and injectable composite hydrogels based on cellulose and BP nanosheets (BPNSs) are of great efficiency for PTT against cancer. The resultant cellulose/BPNS-based hydrogel possesses 3D networks with irregular micrometer-sized pores and thin, strong cellulose-formed walls and exhibits an excellent photothermal response, enhanced stability, and good flexibility. Importantly, this hydrogel nanoplatform is totally harmless and biocompatible both in vivo and in vitro. This work may facilitate the development of BP-polymer-based photothermal agents in the form of hydrogels for biomedical-related clinic applications.

Novel concept of the smart NIR-light-controlled drug release of black phosphorus nanostructure for cancer therapy.

A biodegradable drug delivery system (DDS) is one the most promising therapeutic strategies for cancer therapy. Here, we propose a unique concept of light activation of black phosphorus (BP) at hydrogel nanostructures for cancer therapy. A photosensitizer converts light into heat that softens and melts drug-loaded hydrogel-based nanostructures. Drug release rates can be accurately controlled by light intensity, exposure duration, BP concentration, and hydrogel composition. Owing to sufficiently deep penetration of near-infrared (NIR) light through tissues, our BP-based system shows high therapeutic efficacy for treatment of s.c. cancers. Importantly, our drug delivery system is completely harmless and degradable in vivo. Together, our work proposes a unique concept for precision cancer therapy by external light excitation to release cancer drugs. If these findings are successfully translated into the clinic, millions of patients with cancer will benefit from our work.

A phase II trial of concurrent 3D-CRT/IMRT and oxaliplatin, 5-fluorouracil and leucovorin (FOLFOX) in gastric cancer patients with R0 gastrectomy and D2 lymph node dissection.

BACKGROUND: To evaluate the safety and efficacy of a concurrent three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) plus oxaliplatin, 5-fluorouracil and leucovorin (FOLFOX) regimen in completely resected gastric cancer patients with D2 lymph node dissection. MATERIALS AND METHODS: Patients with stage IB-IIIC gastric cancer (per the AJCC, 7th edition) who had undergone R0 and D2 gastrectomy were recruited. Two cycles of FOLFOX with concurrent 3D-CRT or IMRT (50.4 Gy/28f) were administered. One and an additional five cycles of FOLFOX were delivered before and after concurrent chemoradiotherapy, respectively. Primary endpoints were relapse-free survival (RFS) and overall survival (OS), with adverse events as secondary endpoints. RESULTS: From 2008 to 2011, 110 patients were evaluable. The 1-, 2- and 3-year RFS and OS were 86.2, 72.2, 67.8 and 94.7, 87.2, 77.6%, respectively. On multivariate analysis, stage (≤ IIIA vs. >IIIA) was a statistically significant factor affecting both RFS and OS. Additionally, the T-category (≤ T4a vs. = T4b) was a statistically significant factor affecting only the RFS. The most commonly observed grade 3 or 4 adverse events were nausea and vomiting, decreased appetite, leukopenia/neutropenia and fatigue, each of which occurred in 14.5, 11.8, 9.1 and 6.4% patients, respectively. CONCLUSIONS: Adjuvant 3D-CRT/IMRT to a dose of 50.4 Gy/28f with concurrent FOLFOX is safe and effective in patients following radical gastrectomy with D2 lymph node dissection.

Phase I study of postoperative radiotherapy concurrent with S-1 in patients with gastric cancer.

Postoperative chemoradiotherapy (CRT) with concurrent 5-fluorouracil is the standard care for gastric cancer patients after curative surgery. The previous studies revealed that the subgroup of patients with high recurrence risk would benefit most from adjuvant CRT. S-1, a novel oral fluorouracil, has showed very effective in metastatic gastric cancer and became the standard option for gastric cancer with D2 dissection. The safety and dosage of S-1 combined with postoperative radiotherapy have not yet been evaluated. This study is to determine the maximum tolerate dose (MTD) and dose-limiting toxicity (DLT) of S-1 given concurrently with postoperative high-dose radiotherapy in gastric cancer. Patients with more advanced stage (pT4 and/or pN+) after R0 resection were recruited. Eligible patients received one cycle standard SOX (S-1 plus oxaliplatin) chemotherapy, then S-1 monotherapy with concurrent radiotherapy for 6 weeks, followed by additional three cycles of SOX. During the concurrent CRT, S-1 was administered on every radiotherapy treatment day according to a predefined dose-escalation schedule. Radiotherapy (3D-RT or IMRT) was given to a total dose of 50.4 Gy in 28 fractions. DLT was defined as grade 3 or 4 hematologic and non-hematologic toxicity. From March 2011 to October 2012, 21 patients were enrolled at five dose levels: 40 (n = 3), 50 (n = 3), 60 (n = 6), 70 (n = 6) and 80 mg/m(2)/day (n = 3). D2-dissection was performed in 18 patients (85.7 %) and 15 patients (71.4 %) had stage III disease. The most common dose-related toxicity was anorexia, nausea and vomiting, fatigue and leucopenia. DLT was occurred in one patient at 60 mg/m(2)/day (grade 3 fatigue), one patient at 70 mg/m(2)/day (grade 3 vomiting and anorexia), two patients at 80 mg/m(2)/day (one with grade 3 vomiting and anorexia; another with grade 3 febrile leucopenia). Four patients did not complete CRT as planned. Overall, this phase I study demonstrated that postoperative CRT with daily S-1 was feasible in gastric cancer and the MTD of S-1 concurrent with radiotherapy was 70 mg/m(2)/day. This S-1-based postoperative CRT will be investigated in a multicenter phase III study in West China.

Low-dose capecitabine adjuvant chemotherapy in elderly stage II/III colorectal cancer patients (LC-ACEC): study protocol for a randomized controlled trial.

BACKGROUND: Over half of the patients were diagnosed with colorectal cancer after 70 years of age. The choice of the most suitable chemotherapy strategy is the major challenge for elderly patients. Previous trials indicated that elderly patients with stage II/III colorectal cancer obtained no significant benefits from oxaliplatin-based adjuvant chemotherapy. Therefore, single-agent oral capecitabine is regarded as an effective alternative with retained efficacy and improved flexibility. However, the optimal dose of capecitabine for elderly patients remains controversial. Recent studies have adopted a low-dose strategy (1,000 mg/m(2)) for elderly patients, but the long-term efficacy of this strategy has not been identified so far. Thus, we designed this trial to investigate non-inferiority of the lower-dose strategy of capecitabine compared with the approved-dose strategy for adjuvant chemotherapy of elderly patients with stage II/III colorectal cancer. METHODS: LC-ACEC (Low-dose Capecitabine Adjuvant Chemotherapy for Elderly Patients With Stage II/III Colorectal Cancer) is a prospective, randomized, open-label, non-inferiority phase III clinical trial including 926 eligible patients. Patients will be randomly assigned to receive a capecitabine adjuvant chemotherapy strategy of lower dose (1,000 mg/m(2) twice daily on days 1 to 14 of every 21 days) or approved dose (1,250 mg/m(2) twice daily on days 1 to 14 of every 21 days). The primary outcome is 3-year disease-free survival. Secondary outcomes include 3-year overall survival, toxic and side effects during treatment, completion rate, and quality of life. DISCUSSION: This is the first randomized trial to evaluate the efficacy and safety of a low-dose strategy of capecitabine in adjuvant chemotherapy of elderly patients with stage II/III colorectal cancer, and the results are believed to provide new evidence on the treatment of elderly patients with colorectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02316535 (Dec. 12, 2014).

Interaction of green tea polyphenol epigallocatechin-3-gallate with sunitinib: potential risk of diminished sunitinib bioavailability.

Sunitinib, a novel oral multi-targeted tyrosine kinase inhibitor for patients with metastatic renal cell carcinoma (mRCC) and advanced gastrointestinal stromal tumor, has a good prospect for clinical application and is being investigated for the potential therapy of other tumors. We observed the phenomenon that drinking tea interfered with symptom control in an mRCC patient treated with sunitinib and speculated that green tea or its components might interact with sunitinib. This study was performed to investigate whether epigallocatechin-3-gallate (EGCG), the major constituent of green tea, interacted with sunitinib. The interaction between EGCG and sunitinib was examined in vitro and in vivo. (1)H nuclear magnetic resonance ((1)H-NMR) spectroscopy and mass spectrometry (MS) were used to analyze the interaction between these two molecules and whether a new compound was formed. Solutions of sunitinib and EGCG were intragastrically administered to rats to investigate whether the plasma concentrations of sunitinib were affected by EGCG. In this study, we noticed that a precipitate was formed when the solutions of sunitinib and EGCG were mixed under both neutral and acidic conditions. (1)H-NMR spectra indicated an interaction between EGCG and sunitinib, but no new compound was observed by MS. Sticky semisolid contents were found in the stomachs of sunitinib and EGCG co-administrated mice. The AUC(0-∞) and C (max) of plasma sunitinib were markedly reduced by co-administration of EGCG to rats. Our study firstly showed that EGCG interacted with sunitinib and reduced the bioavailability of sunitinib. This finding has significant practical implications for tea-drinking habit during sunitinib administration.

Postoperative chemoradiotherapy in gastric cancer: a phase I study of radiotherapy with dose escalation of oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX regimen).

Concurrent chemoradiotherapy begins to be more and more widely accepted as a standard adjuvant treatment in gastric cancer. And oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) also reveals to be a very effective regimen in gastric cancer. But the safety and the dosages of FOLFOX combining with radiotherapy are still unknown. This study was to determine the maximum-tolerated dose and the dose-limiting toxicity of FOLFOX with higher-dose concurrent radiotherapy (RT) as adjuvant treatment in patients with gastric cancer. Patients with Stage II/III gastric cancer after surgery were recruited. They received one cycle of induction chemotherapy (standard FOLFOX4). Then, they received 50.4 Gy in 1.8-Gy fractions in combination with two cycles of concurrent FOLFOX, and oxaliplatin among this regimen was administered with escalating doses. Dose-limiting toxicity including grade 3 or grade 4 hematologic and nonhematologic toxicities was investigated. Fifteen patients were enrolled at the following dose levels: oxaliplatin 55 mg/m(2) (3 patients), 65 mg/m(2) (6 patients), and 75 mg/m(2) (6 patients). Dose-limiting toxicity was observed in 1 patient at 65 mg/m(2) (grade 4 leukopenia) and in 3 patients at 75 mg/m(2) (1 patient had grade 4 leukopenia, 1 had grade 3 thrombocytopenia, and 1 had grade 3 stomatitis). Combination chemotherapy FOLFOX with oxaliplatin 65 mg/m(2), d 1; leucovorin 200 mg/m(2), 2 h, d1-2; 5-fluorouracil 400 mg/m(2), iv, d 1-2 and 600 mg/m(2) civ, 22 h, d 1-2 given concurrently with RT (50.4 Gy) can be recommended as a safer and preferable regimen for the adjuvant treatment of patients with gastric cancer.