Impact of previous S-1 treatment on efficacy of liposomal irinotecan plus 5-fluorouracil and leucovorin in patients with metastatic pancreatic cancer.

BACKGROUND/OBJECTIVES: Liposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI + 5-FU/LV) provides survival benefits for metastatic pancreatic adenocarcinoma (mPDAC) refractory to gemcitabine-based treatment, mainly gemcitabine plus nab-paclitaxel (GA), in current practice. Gemcitabine plus S-1 (GS) is another commonly administered first-line regimen before nab-paclitaxel reimbursement; however, the efficacy and safety of nal-IRI + 5-FU/LV for mPDAC after failed GS treatment has not been reported and was therefore explored in this study. METHODS: In total, 177 patients with mPDAC received first-line GS or GA treatment, followed by second-line nal-IRI + 5-FU/LV treatment (identified from a multicenter retrospective cohort in Taiwan from 2018 to 2020); 85 and 92 patients were allocated to the GS and GA groups, respectively. Overall survival (OS), time-to-treatment failure (TTF), and adverse events were compared between the two groups. RESULTS: The baseline characteristics of the two groups were generally similar; however, a higher median age (67 versus 62 years, p < 0.001) and fewer liver metastases (52% versus 78%, p < 0.001) were observed in the GS versus GA group. The median OS was 15.0 and 15.9 months in the GS and GA groups, respectively (p = 0.58). The TTF (3.1 versus 2.8 months, p = 0.36) and OS (7.6 versus 6.7 months, p = 0.83) after nal-IRI treatment were similar between the two groups. More patients in the GS group developed mucositis during nal-IRI treatment (15% versus 4%, p = 0.02). CONCLUSIONS: The efficacy of second-line nal-IRI +5-FU/LV treatment was unaffected by prior S-1 exposure. GS followed by nal-IRI treatment is an alternative treatment sequence for patients with mPDAC.

Efficacy of a four-curvature auxiliary arch at preventing maxillary central incisor linguoclination during orthodontic treatment: a finite element analysis.

BACKGROUND: Correct torque of the incisors is beneficial in the assessment of the effects of orthodontic treatment. However, evaluating this process effectively remains a challenge. Improper anterior teeth torque angle can cause bone fenestrations and exposure of the root surface. METHODS: A three-dimensional finite element model of the maxillary incisor torque controlled by a homemade four-curvature auxiliary arch was established. The four-curvature auxiliary arch placed on the maxillary incisors was divided into four different state groups, among which 2 groups had tooth extraction space retracted traction force set to 1.15 N. Initial displacements and pressure stresses of the periodontal tissue in the maxillary incisors and molars were calculated after torque forces (0.5, 1, 1.5, and 2 N) were applied to the teeth at different stable states. RESULTS: The effect of using the four-curvature auxiliary arch on the incisors was significant but did not affect the position of the molars. Given the absence of tooth extraction space, when the four-curvature auxiliary arch was used in conjunction with absolute anchorage, the recommended force value was < 1.5 N. In the other 3 groups (i.e., molar ligation, molar retraction, and microimplant retraction groups), the recommended force value was < 1 N. The application of a four-curvature auxiliary arch did not influence the molar periodontal and displacement. CONCLUSION: A four-curvature auxiliary arch may treat severely upright anterior teeth and correct cortical fenestrations of the bone and root surface exposure.

TLR3 signaling in macrophages is indispensable for the protective immunity of invariant natural killer T cells against enterovirus 71 infection.

Enterovirus 71 (EV71) is the most virulent pathogen among enteroviruses that cause hand, foot and mouth disease in children but rarely in adults. The mechanisms that determine the age-dependent susceptibility remain largely unclear. Here, we found that the paucity of invariant natural killer T (iNKT) cells together with immaturity of the immune system was related to the susceptibility of neonatal mice to EV71 infection. iNKT cells were crucial antiviral effector cells to protect young mice from EV71 infection before their adaptive immune systems were fully mature. EV71 infection led to activation of iNKT cells depending on signaling through TLR3 but not other TLRs. Surprisingly, iNKT cell activation during EV71 infection required TLR3 signaling in macrophages, but not in dendritic cells (DCs). Mechanistically, interleukin (IL)-12 and endogenous CD1d-restricted antigens were both required for full activation of iNKT cells. Furthermore, CD1d-deficiency led to dramatically increased viral loads in central nervous system and more severe disease in EV71-infected mice. Altogether, our results suggest that iNKT cells may be involved in controlling EV71 infection in children when their adaptive immune systems are not fully developed, and also imply that iNKT cells might be an intervention target for treating EV71-infected patients.

Targeted nanoparticle delivery overcomes off-target immunostimulatory effects of oligonucleotides and improves therapeutic efficacy in chronic lymphocytic leukemia.

Several RNA-targeted therapeutics, including antisense oligonucleotides (ONs), small interfering RNAs, and miRNAs, constitute immunostimulatory CpG motifs as an integral part of their design. The limited success with free antisense ONs in hematologic malignancies in recent clinical trials has been attributed to the CpG motif-mediated, TLR-induced prosurvival effects and inefficient target modulation in desired cells. In an attempt to diminish their off-target prosurvival and proinflammatory effects and specific delivery, as a proof of principle, in the present study, we developed an Ab-targeted liposomal delivery strategy using a clinically relevant CD20 Ab (rituximab)-conjugated lipopolyplex nanoparticle (RIT-INP)- and Bcl-2-targeted antisense G3139 as archetypical antisense therapeutics. The adverse immunostimulatory responses were abrogated by selective B cell-targeted delivery and early endosomal compartmentalization of G3139-encapsulated RIT-INPs, resulting in reduced NF-κB activation, robust Bcl-2 down-regulation, and enhanced sensitivity to fludarabine-induced cytotoxicity. Furthermore, significant in vivo therapeutic efficacy was noted after RIT-INP-G3139 administration in a disseminated xenograft leukemia model. The results of the present study demonstrate that CD20-targeted delivery overcomes the immunostimulatory properties of CpG-containing ON therapeutics and improves efficient gene silencing and in vivo therapeutic efficacy for B-cell malignancies. The broader implications of similar approaches in overcoming immunostimulatory properties of RNA-directed therapeutics in hematologic malignancies are also discussed.

Application of 3D printed titanium mesh and digital guide plate in the repair of mandibular defects using double-layer folded fibula combined with simultaneous implantation.

Fibula transplantation plays an irreplaceable role in restoring the function and morphology of the defected mandible. However, the complex load-bearing environment of the mandible makes it urgent to accurately reconstruct the mandible, ensure the position of the condyle after surgery, and restore the patient's occlusal function and contour. The intervention of digital design and three-dimensional (3D) printed titanium mesh provides a more efficient method and idea to solve this problem. Digital design guides the accurate positioning, osteotomy, and simultaneous implant placement during surgery, and 3D printed titanium mesh ensures stable condyle position after surgery, restoring good mandibular function. The double-layer folded fibula maintains the vertical height of the mandible and a good facial contour, and simultaneous implant placement can establish a good occlusal relationship. This study conducted a retrospective analysis of five patients with jaw defects who underwent digital fibula reconstruction over the past 3 years. It was found that the surgical protocol combining digital design, 3D printed intraoperative guides, 3D printed titanium mesh, free fibula flap, immediate implant, and occlusal reconstruction to repair jaw defects had more ideal facial appearance and biological function. It will provide a more reliable surgical protocol for clinical management of large mandibular defects.

Effect of previous conventional irinotecan treatment in patients with pancreatic cancer being treated with liposomal irinotecan plus 5-fluorouracil and leucovorin.

BACKGROUND: Recent studies have suggested the suboptimal efficacy of liposomal irinotecan plus 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) in metastatic pancreatic ductal adenocarcinoma (mPDAC) patients previously treated with conventional irinotecan. This study investigated the effect of conventional irinotecan treatment in mPDAC patients receiving nal-IRI+5-FU/LV by analyzing a population-based dataset. METHODS: We reviewed 667 consecutive mPDAC patients treated with nal-IRI+5-FU/LV between August 2018 and November 2020 at Taiwanese medical centers. Eighty-six patients previously treated with conventional irinotecan were matched to 86 patients not treated with conventional irinotecan, following propensity matching for age, sex, performance status, metastatic organ site, pre-treatment carbohydrate antigen 19-9 level, lines of prior chemotherapy treatment, and time from first-line treatment to nal-IRI+5-FU/LV therapy. RESULTS: The median overall survival and time-to-treatment failure were 4.8 and 2.6 vs 4.1 and 2.1 months, respectively, for patients who were and were not previously treated with conventional irinotecan. The tumor response and disease control rates were 5.8% and 32.6% vs 5.8% and 37.2%, respectively, for patients previously treated and not treated with conventional irinotecan. No significant differences were observed in survival times and tumor response rates between the two groups. CONCLUSIONS: Previous conventional irinotecan treatment does not compromise the efficacy of subsequent nal-IRI+5-FU/LV treatment in mPDAC patients.

Phoenixin-20 suppresses lipopolysaccharide-induced inflammation in dental pulp cells.

Pulpal infection is one of the most common causes of dental emergency admission. Tooth pain due to infection caused by gram-negative bacteria is the main manifestation of this sort of dental problem. The GPR173 signaling pathway is a highly conserved G-protein-coupled receptor that mediates neurological and reproductive function. In this study, we found that GPR173 was fairly expressed in isolated human dental pulp cells, and its expression was reduced in response to pro-inflammatory lipopolysaccharide (LPS) treatment. The activation of GPR173 by its ligand Phoenixin-20 reduced LPS-induced cytotoxicity, as revealed by a reduction in the release of LDH. Additionally, Phoenixin-20 suppressed LPS-induced release of pro-inflammatory cytokines and inflammatory mediators, including IL-6, MCP-1, VCAM-1, and ICAM-1, as well as MMP-2 and MMP-9. Mechanistically, we showed the suppressive action of Phoenixin-20 on LPS-induced activation of TLR-4 and Myd88 as well as the activation of the NF-κB pathway. Collectively, our study demonstrates that the GPR173 signaling pathway is an important mediator of LPS-induced inflammation, and the activation of GPR173 by its natural ligand Phoenixin-20 exhibits robust anti-inflammatory effects in dental pulp cells, suggesting that GPR173 is an interesting target molecule in the development of pulp cell-based therapies.

[Evaluation of dental medical quality based on efficacy coefficient model].

PURPOSE: To evaluate the dental quality comprehensively by data model of efficacy coefficient based on the principle of multi-objective programming. METHODS: The correlation index of dental medical quality was selected by Delphi method, while the index weight was determined by the scale of the analytic hierarchy process. Then efficacy coefficient method was used to evaluate the dental quality of Shanghai Stomatological Hospital in a certain period. RESULTS: During the period of 2016-2017, the D value of the efficiency coefficient was 84.92, 83.41, 86.99 and 81.98, respectively, which demonstrated that the overall quality of the hospital was in good condition. CONCLUSIONS: The efficiency coefficient method can objectively reflect the comprehensive level of medical quality, which can provide a strong support for comprehensive evaluation and control of the quality of dental hospital.

Protective effects of SIRT6 against lipopolysaccharide (LPS) are mediated by deacetylation of Ku70.

Progression of pulpitis is facilitated by the immune system's response to bacteria, enhancing the production of inflammatory regulators. Bacterial lipopolysaccharide (LPS) is the major structural component of the outer wall of all Gram-negative bacteria and a potent activator of the immune system. Apoptosis is believed to play an important role in the inflammatory process of pulpitis. SIRT6 is a member of class III of histone deacetylases (HDACs), also called sirtuins (SIRTs). The role of SIRT6 in apoptosis in pulpitis is unknown. In this study, we found that the expression of SIRT6 in human dental pulp cells (hDPCs) was down-regulated by treatment with LPS. MTT and LDH assays revealed that overexpression of SIRT6 in hDPCs attenuated cell death induced by LPS. Consistently, our results demonstrated that SIRT6 was able to protect hDPCs from apoptosis. We found that SIRT6 could interact with Ku70, an important apoptosis regulator, by the immunoprecipitation (IP) experiment. SIRT6 physically binds to Ku70. Overexpression of SIRT6 reduced acetylation of Ku70 and promoted interaction of Ku70 with the proapoptotic protein Bax. These studies underscore an essential role of SIRT6 in the survival of hDPCs in stress situations.

Fabrication of psoralen-loaded lipid-polymer hybrid nanoparticles and their reversal effect on drug resistance of cancer cells.

In the present study, a lipid-polymer hybrid drug carrier system was developed to encapsulate psoralen (PSO), a multidrug resistance reversal agent and traditional Chinese medicine. Emphasis was focused the parameters that influence physicochemical characteristics, and then the drug release profile, stability, cytotoxicity and drug resistance reversal effect of the lipid-polymer hybrid nanoparticles (LPNs) were investigated. It was found that various formulation parameters affected NP size, drug loading (DL) and release characteristics. Hydrophilic 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-carboxy(polyethylene glycol)2000 increased the ζ potential and thus the stability of the NPs, but also enlarged their diameter. The amount of PSO influenced their DL and encapsulation efficiency, but did not show any effect on drug release kinetics. Next, the stability of the LPNs in different media and their storage characteristics were assessed. Finally, the cytotoxicity and multidrug resistance reversal effect was studied in the K562 and HepG2 cell lines. The analysis of half maximal inhibitory concentration values demonstrated that combination therapy with doxorubicin (DOX) and PSO-loaded LPNs (P-LPNs) was 14- and 23-fold more effective than a single-dose DOX treatment in resistant K562 and HepG2 cells, respectively, and 2.2- and 2.1-fold more effective than a single-dose combination regimen of DOX and PSO in solution, respectively. These data indicate that the LPNs have superior properties compared with a combination therapy in solution.

Inhibition of Kupffer Cell Autophagy Abrogates Nanoparticle-Induced Liver Injury.

The possible adverse effects of engineered nanomaterials on human health raise increasing concern as our research on nanosafety intensifies. Upon entry into a human body, whether intended for a theranostic purpose or through unintended exposure, nanomaterials tend to accumulate in the liver, leading to hepatic damage. A variety of nanoparticles, including rare earth upconversion nanoparticles (UCNs), have been reported to elicit hepatotoxicity, in most cases through inducing immune response or activating reactive oxygen species. Many of these nanoparticles also induce autophagy, and autophagy inhibition has been shown to decrease UCN-induced liver damage. Herein, using UCNs as a model engineered nanomaterial, this study uncovers a critical role for Kupffer cells in nanomaterial-induced liver toxicity, as depletion of Kupffer cells significantly exacerbates UCN-induced liver injury. Furthermore, UCN-induced prodeath autophagy in Kupffer cells, and inhibition of autophagy with 3-MA, a well-established chemical inhibitor of autophagy, enhances Kupffer cell survival and further abrogates UCN-induced liver toxicity. The results reveal the critical importance of Kupffer cell autophagy for nanoparticle-induced liver damage, and inhibition of autophagy may constitute a novel strategy for abrogating nanomaterial-elicited liver toxicity.

Cationic Polystyrene Resolves Nonalcoholic Steatohepatitis, Obesity, and Metabolic Disorders by Promoting Eubiosis of Gut Microbiota and Decreasing Endotoxemia.

A pandemic of metabolic diseases, consisting of type 2 diabetes, nonalcoholic fatty liver disease, and obesity, has imposed critical challenges for societies worldwide, prompting investigation of underlying mechanisms and exploration of low-cost and effective treatment. In this report, we demonstrate that metabolic disorders in mice generated by feeding with a high-fat diet without dietary vitamin D can be prevented by oral administration of polycationic amine resin. Oral administration of cholestyramine, but not the control uncharged polystyrene, was able to sequester negatively charged bacterial endotoxin in the gut, leading to 1) reduced plasma endotoxin levels, 2) resolved systemic inflammation and hepatic steatohepatitis, and 3) improved insulin sensitivity. Gut dysbiosis, characterized as an increase of the phylum Firmicutes and a decrease of Bacteroidetes and Akkermansia muciniphila, was fully corrected by cholestyramine, indicating that the negatively charged components in the gut are critical for the dysbiosis. Furthermore, fecal bacteria transplant, derived from cholestyramine-treated animals, was sufficient to antagonize the metabolic disorders of the recipient mice. These results indicate that the negatively charged components produced by dysbiosis are critical for biogenesis of metabolic disorders and also show a potential application of cationic polystyrene to treat metabolic disorders through promoting gut eubiosis.

[Stress distribution in abutment teeth and related tissues under different design of connector: three-dimensional finite element analysis].

PURPOSE: To compare the stress distribution in abutment teeth and related tissues under the same material and different loading between improved major connector design and traditional major connector design. METHODS: One 55-year-old male patient with unilateral maxillary first molar and second molar missing was chosen. The stress distribution in abutment teeth and related tissues were evaluated with spiral CT scanning, Mimics, Geomagic Studio software, a study model was built and finite element analysis was performed using ANSYS software. RESULTS: With the improved major connector design, the stress of abutment decreased significantly, the stress of periodontal decreased, the stress of edentulous mucosa increased significantly and became more balanced, the trend of stimulated absorption of alveolar bone decreased. CONCLUSIONS: For patients with distal free defect of dentition, the design of improved major connector has the effect of stress interruption, can protect the abutment better, detract the stress of the denture and has an good protective effect on the edentulous mucosa and alveolar bone.

Cardenolides from Calotropis gigantea as potent inhibitors of hypoxia-inducible factor-1 transcriptional activity.

ETHNOPHARMACOLOGICAL RELEVANCE: Calotropis gigantea (L.) Dryand (Apocynaceae) is a medicinal plant native to southern China, India and Southeast Asia. It has been traditionally used for the treatment of several diseases including cancers in these countries. AIM OF THE STUDY: This study aimed to isolate bioactive cardenolides from C. gigantea, to screen their hypoxia-inducible factor (HIF-) 1 inhibitory activity, and to analyze the structure-activity relationship (SAR). MATERIALS AND METHODS: Isolation and purification of cardenolides from the latex and the fruits of C. gigantea were performed by using a series of separation techniques. Their structures were fully characterized by elucidating their NMR and HRMS data. The HIF-1 inhibitory activities of cardenolides were evaluated by using a T47D cell-based dual-luciferase reporter assay. The potent cardenolides were selected to further evaluate their dose-response manner. Cytotoxic effects of selected cardenolides were also examined against breast cancer cell line (MCF-7) and normal mammary epithelial cell line (MCF-10A) by MTT assay. RESULTS: Among twenty isolated cardenolides, compounds 1, 3, 4, 6-8, 14 and 17 exhibited stronger HIF-1 inhibitory activities than that of digoxin, a well-known HIF-1 inhibitor (P<0.001). These eight cardenolides inhibited HIF-1 transcriptional activity in a dose-dependent manner with IC50 values in nanomolar potency (21.8-64.9nM). An analysis of SAR revealed the great contributions of a ß-configuration of the substituents at positions of C-2' and C-3', an aldehydic moiety on C-19, and the dioxane moiety between the aglycone and sugar parts of cardenolides to the HIF-1 inhibitory activity. In contrast, a hydroxyl group at any positions of C-15, C-16 and C-4' of cardenolides showed negative effects on suppressing HIF-1 transcriptional activity. In addition, these eight cardenolides also exhibited potent cytotoxic effects against human breast cancer cell MCF-7 (IC50 values ranged from 30.5 to 68.8nM), but less toxic effects to human normal mammary epithelial cell MCF-10A (IC50 values >20µM). CONCLUSIONS: This is the first report of a comprehensive study of SAR on cardenolides from C. gigantea as HIF-1 inhibitors. Eight cardenolides (1, 3, 4, 6-8, 14 and 17) showed both potent HIF-1 inhibitory activity and strong cytotoxic effect against MCF-7 cancer cells in nanomolar level. The findings of these cardenolides provided important insights into the development of these potent HIF-1 inhibitors as anticancer drug.

Dihydro-ß-agarofuran sesquiterpene polyesters isolated from the stems of Tripterygium regelii.

Twelve new dihydro-ß-agarofuran polyesters, triptregelines A-J (1-3 and 5-11) and triptregelols A, B (4, 12), together with five known ones (13-17) were isolated from the stems of Tripterygium regelii. The structures were determined on the basis of extensive analysis of spectroscopic data (1D, 2D NMR, and UV etc.) and HRMS data. Cytotoxic effects of these compounds were evaluated against a pair of cancer cell lines, A549 and taxol-resistant A549T. Triptofordin B (14) showed cytotoxicity against both A549 and A549T cells with IC50 value of 21.2 and 10.8µM, respectively. In addition, triptregeline B (2), triptregeline C (3), triptregeline H (9) and 1α, 6ß, 15-triacetoxy-8α-benzoyloxy-4ß-hydroxy-9α-(3-nicotinoyloxy)-dihydro-ß-agarofuran (17) exhibited weak cytotoxic effects on taxol-resistant A549T with IC50 values ranged from 29.4 to 54.4µM. The cytotoxic effect of triptofordin B (14) was much less than taxol with IC50 value of 0.08µM on A549 cancer cell.

2'-Epi-uscharin from the latex of Calotropis gigantea with HIF-1 inhibitory activity.

Two stereoisomeric cardenolides, uscharin (1) and a new compound, 2'-epi-uscharin (2), were isolated from the latex of Calotropis gigantea (Asclepiadaceae). Their structures were fully elucidated based on their spectroscopic data, X-ray crystallographic data and chemical evidences. Both epimers (1 and 2) exhibited strong inhibitory effects on HIF-1 activity with different magnitudes. Compound 1 showed much more potent activity than 2 and digoxin, a well-known HIF-1 inhibitor. Discrepancy in potencies between 1 and 2 revealed the contribution of a ß-configuration of 2' hydroxyl moiety for HIF-1 inhibitory activity. This is a first report of the activity of HIF-1 inhibition of thiazoline ring-containing cardenolides.

In vitro anti-influenza virus activities of a new lignan glycoside from the latex of Calotropis gigantea.

A new lignan glycoside, (+)-pinoresinol 4-O-[6″-O-vanilloyl]-ß-D-glucopyranoside (1) and two known phenolic compounds, 6'-O-vanilloyltachioside (2) and 6'-O-vanilloylisotachioside (3) were isolated from the latex of Calotropis gigantea (Asclepiadaceae). The structure of the new compound was elucidated by using spectroscopic and chemical methods. Three isolates (1-3) and one authentic compound, (+)-pinoresinol 4-O-ß-D-glucopyranoside, were screened for A/PR/8/34 (H1N1) inhibitory activity by cytopathic effect (CPE) inhibition assay on MDCK cells. Compound 1 showed inhibitory activity against A/PR/8/34 (H1N1). In sharp contrast, the other three compounds (2, 3 and (+)-pinoresinol 4-O-ß-D-glucopyranoside) did not show such activity. An analysis of structure-activity relationship between 1 and (+)-pinoresinol 4-O-ß-D-glucopyranoside revealed that the presence of a vanilloyl group in the sugar moiety of 1 is crucial for its anti-influenza virus activity. Compound 1 was further evaluated for in vitro inhibitory activities against a panel of human and avian influenza viruses by CPE inhibition assay. It showed inhibitory effect against human influenza viruses in both subtypes A and B (IC50 values around 13.4-39.8 µM with SI values of 3.7-11.4), while had no effect on avian influenza viruses. Its antiviral activity against human influenza viruses subtype A was further confirmed by plaque reduction assay. The time course assay indicated that 1 exerts its antiviral activity at the early stage of viral replication. A mechanistic study showed that 1 efficiently inhibited influenza virus-induced activation of NF-κB pathway in a dose-dependent manner, but had no effect on virus-induced activation of Raf/MEK/ERK pathway. Further studies demonstrated that nuclear translocation of transcription factor NF-κB induced by influenza virus was significantly blocked by 1, meanwhile, nuclear export of viral ribonucleoproteins was also effectively inhibited. These findings suggest that this new lignan glycoside from Calotropis gigantea, may have therapeutic potential in influenza virus infection through inhibition of NF-κB pathway and viral ribonucleoproteins nuclear export.

Safety and efficacy of pegylated liposomal doxorubicin-based adjuvant chemotherapy in patients with stage I-III triple-negative breast cancer.

BACKGROUND/AIM: Pegylated liposomal doxorubicin (PLD) has been proven to be an effective antitumor drug for metastatic breast cancer, with less toxicity than conventional anthracycline. Our objective was to evaluate the efficacy and safety of PLD-based adjuvant chemotherapy compared to conventional chemotherapy for patients with stages I-III Triple-negative breast cancer (TNBC). PATIENTS AND METHODS: A total of 162 patients, histologically proven to have TNBC at stages I-III between 2003 and 2010, were enrolled to evaluate the impact of PLD- and non-PLD-based adjuvant chemotherapy by using the end-pint of overall survival (OS) and relapse-free survival (RFS). RESULTS: Forty-nine (30.2%) patients received PLD-based adjuvant chemotherapy and 113 (69.8%) a non-PLD regimen, including 84 (52%) patients receiving non-PLD anthracycline. The Kaplan-Meier calculation indicated no differences in RFS and OS between the PLD and non-PLD groups. Multivariate analysis adjusted for tumor size and lymph node status also revealed similar RFS (HR=0.86, 95% CI=0.43-1.73, p=0.678) and OS (HR=0.86, 95% CI=0.41-1.79, p=0.692) for PLD-based chemotherapy compared with non-PLD-based. Patients receiving PLD-based chemotherapy had a relatively lower incidence of grade 3-4 neutropenia (25% vs. 41.6%, respectively; p=0.054) and significantly higher incidence of hand-foot syndrome (16.3% vs. 4.4%, respectively; p=0.010). CONCLUSION: PLD-based adjuvant chemotherapy was as effective as conventional chemotherapy for patients with TNBC. PLD is an alternative for patients with TNBC when conventional anthracycline is inappropriate.

Pegylated liposomal doxorubicin-based combination chemotherapy as salvage treatment in patients with advanced hepatocellular carcinoma.

OBJECTIVES: Effective chemotherapy with the least toxicity is important for patients with inoperable or advanced hepatocellular carcinoma. Single use of pegylated liposomal doxorubicin has been reported to be safe and effective with varying treatment response. The authors evaluate its activity in combination with capecitabine or gemcitabine as salvage therapy in these patients. METHODS: At first, intravenous administration of 30 mg/m2 pegylated liposomal doxorubicin for 60 minutes on day 1, with oral capecitabine 1500 mg twice daily from day 1 to day 14 every 4 weeks (trial A) was conducted. Following unfavorable results, a second trial (trial B) was performed to subsequent patients with the same pegylated liposomal doxorubicin schedule, but in combination with 1000 mg/m2 gemcitabine over 30 minutes on day 1 and day 8, followed by a 2-week rest. RESULTS: Both trials showed no objective response, with 2 patients with stable disease in each trial. In trial A, the disease control rate of all evaluative patients (complete response + partial response + stable disease) and progression-free survival of 2 responders were 20%, 164 days and 240 days versus 22%, 75 days and 73 days in trial B. The median overall survival for all patients in trials A and B were 161 days and 84 days respectively. Generally, toxicities were well managed without toxic death. CONCLUSION: Pegylated liposomal doxorubicin-based combination chemotherapy with capecitabine or gemcitabine was not effective as salvage therapy in advanced hepatocellular carcinoma. Further effective systemic chemotherapy for patients with advanced hepatocellular carcinoma is warranted.