Efficacy of concurrent chemoradiotherapy alone for loco-regionally advanced nasopharyngeal carcinoma: long-term follow-up analysis.

BACKGROUND: To analysis the clinical outcomes of concurrent chemoradiotherapy (CCRT) alone based on 10-year results for loco-regionally advanced nasopharyngeal carcinoma (LANPC), so as to provide evidence for individualized treatment strategy and designing appropriate clinical trial for different risk LANPC patients. METHODS: Consecutive patients with stage III-IVa (AJCC/UICC 8th) were enrolled in this study. All patients received radical intensity-modulated radiotherapy (IMRT) and concurrent cisplatin chemotherapy (CDDP). The hazard ratios (HRs) of death risk in patients with T3N0 was used as baseline, relative HRs were calculated by a Cox proportional hazard model to classify different death risk patients. Survival curves for the time-to-event endpoints were analyzed by the Kaplan-Meier method and compared using the log-rank test. All statistical tests were conducted at a two-sided level of significance of 0.05. RESULTS: A total of 456 eligible patients were included. With 12-year median follow-up, 10-year overall survival (OS) was 76%. 10-year loco-regionally failure-free survival (LR-FFS), distant failure-free survival (D-FFS) and failure-free survival (FFS) were 72%, 73% and 70%, respectively. Based on the relative hazard ratios (HRs) of death risk, LANPC patients were classified into 3 subgroups, low-risk group (T1-2N2 and T3N0-1) contained 244 patients with HR < 2; medium-risk group (T3N2 and T4N0-1) contained 140 patients with HR of 2 - 5; high-risk group (T4N2 and T1-4N3) contained 72 patients with HR > 5. The 10-year OS for patients in low-, medium-, and high-risk group were 86%, 71% and 52%, respectively. Significantly differences of OS rates were found between each of the two groups (low-risk group vs. medium-risk group, P < 0.001; low-risk group vs. high-risk group, P < 0.001; and medium-risk group vs. high-risk group, P = 0.002, respectively). Grade 3-4 late toxicities included deafness/otitis (9%), xerostomia (4%), temporal lobe injury (5%), cranial neuropathy (4%), peripheral neuropathy (2%), soft tissue damage (2%) and trismus (1%). CONCLUSIONS: Our classification criteria demonstrated that significant heterogeneity in death risk among TN substages for LANPC patients. IMRT plus CDDP alone maybe suitable for low-risk LANPC (T1-2N2 or T3N0-1), but not for medium- and high-risk patients. These prognostic groupings provide a practicable anatomic foundation to guide individualized treatment and select optimal targeting in the future clinical trials.

A pH-Activatable Copper-Biomineralized Proenzyme for Synergistic Chemodynamic/Chemo-Immunotherapy against Aggressive Cancers.

Artificial enzymes have demonstrated therapeutic benefits against diverse malignant tumors, yet their antitumor potencies are still severely compromised by non-selective catalysis, low atomic-utilization efficiency, and undesired off-target toxicity. Herein, it is reported that peroxidase-like biomineralized copper (II) carbonate hydroxide nanocrystals inside single albumin nanocages (CuCH-NCs) act as a pH-activatable proenzyme to achieve tumor-selective and synergistic chemodynamic/chemo-immunotherapy against aggressive triple-negative breast cancers (TNBCs). These CuCH-NCs show pH-sensitive Cu2+ release, which spontaneously undergoes glutathione (GSH)-mediated reduction into Cu+ species for catalyzing the evolution of H2 O2 into hydroxyl radicals (·OH) in a single-atom-like manner to cause chemodynamic cell injury, and simultaneously activates non-toxic disulfiram to cytotoxic complex for yielding selective chemotherapeutic damage via blocking cell proliferation and amplifying cell apoptosis. CuCH-NCs exhibit considerable tumor-targeting capacity with deep penetration depth, thus affording preferable efficacy against orthotopic breast tumors through synergistic chemodynamic/chemotherapy, together with good in vivo safety. Moreover, CuCH-NCs arouse distinct immunogenic cell death effect and upregulate PD-L1 expression upon disulfiram combination, and thus synergize with anti-PD-L1 antibody to activate adaptive and innate immunities, together with relieving immunosuppression, finally yielding potent antitumor efficacy against both primary and metastatic TNBCs. These results provide insights into smart and high-performance proenzymes for synergistic therapy against aggressive cancers.

Increased MCL-1 synthesis promotes irradiation-induced nasopharyngeal carcinoma radioresistance via regulation of the ROS/AKT loop.

Worldwide, nasopharyngeal carcinoma (NPC) is a rare head and neck cancer; however, it is a common malignancy in southern China. Radiotherapy is the most important treatment strategy for NPC. However, although radiotherapy is a strong tool to kill cancer cells, paradoxically it also promotes aggressive phenotypes. Therefore, we mimicked the treatment process in NPC cells in vitro. Upon exposure to radiation, a subpopulation of NPC cells gradually developed resistance to radiation and displayed cancer stem-cell characteristics. Radiation-induced stemness largely depends on the accumulation of the antiapoptotic myeloid cell leukemia 1 (MCL-1) protein. Upregulated MCL-1 levels were caused by increased stability and more importantly, enhanced protein synthesis. We showed that repeated ionizing radiation resulted in persistently enhanced reactive oxygen species (ROS) production at a higher basal level, further promoting protein kinase B (AKT) signaling activation. Intracellular ROS and AKT activation form a positive feedback loop in the process of MCL-1 protein synthesis, which in turn induces stemness and radioresistance. AKT/MCL-1 axis inhibition attenuated radiation-induced resistance, providing a potential target to reverse radiation therapy-induced radioresistance.

Potential effect of EGCG on the anti-tumor efficacy of metformin in melanoma cells.

Metformin, a first-line drug for type 2 diabetes mellitus, has been recognized as a potential anti-tumor agent in recent years. Epigallocatechin-3-gallate (EGCG), as the dominant catechin in green tea, is another promising adjuvant agent for tumor prevention. In the present work, the potential effect of EGCG on the anti-tumor efficacy of metformin in a mouse melanoma cell line (B16F10) was investigated. Results indicated that EGCG and metformin exhibited a synergistic effect on cell viability, migration, and proliferation, as well as signal transducer and activator of transcription 3/nuclear factor-κB (STAT3/NF-κB) pathway signaling and the production of inflammation cytokines. Meanwhile, the combination showed an antagonistic effect on cell apoptosis and oxidative stress levels. The combination of EGCG and metformin also differentially affected the nucleus (synergism) and cytoplasm (antagonism) of B16F10 cells. Our findings provide new insight into the potential effects of EGCG on the anti-tumor efficacy of metformin in melanoma cells.

Aerobic denitrification performance and nitrate removal pathway analysis of a novel fungus Fusarium solani RADF-77.

Increasing nitrogenous contaminants have caused immense challenges to the environment and human health. As compared to physical and chemical methods, biological denitrification is considered to be an effective solution due to its environmental friendliness, high efficiency, and low cost. In the present work, a novel fungal strain identified as Fusarium solani (RADF-77) was isolated from cellulose material-supported denitrification reactor; this strain is capable of removing nitrogen under aerobic conditions. The average NO3--N removal rate for RADF-77 were 4.43 mg/(L·h) and 4.50 mg/(L·d), when using glucose and tea residue as carbon source, respectively. The nitrogen balance revealed that 53.66% of N vanished via gaseous products. Transcriptional results revealed that respiratory and assimilative nitrate reductases may work together for nitrate removal. Our results indicate that RADF-77 could be used as a potential means of enhancing nitrate-removal performance, as well as recycling tea residue, which is the main byproduct of the manufacture of tea extracts.

Towards a better knot: Using mechanics methods to evaluate three knot-tying techniques in laparo-endoscopic single-site surgery.

INTRODUCTION: Knot tying is difficult but important for laparo-endoscopic single-site surgery (LESS). There are several techniques for LESS knot-tying. However, objective assessment of these skills has not yet been established. The aim of this study was to assess three different knot-tying techniques in LESS using mechanical methods. MATERIALS AND METHODS: The subject tied 24 knots, eight knots with each of the three techniques in an inanimate box laparoscopic trainer while the movements of their instruments were evaluated using a LESS mechanical evaluation platform. The operations were assessed on the basis of the time, average load of the dominant hand. Then, forces caused the knots to rupture were measured using a material testing system and used to compare the knots's strength. RESULTS: The intracorporeal one-hand knot-tying technique presented significantly better time and average load scores than the extracorporeal knot-tying technique (P < 0.01), and the intracorporeal side winding technique was more time and average load consuming in comparison to other techniques during the performance of knot-tying (P < 0.01). The intracorporeal one-handed knot-tying knots can tolerate better distraction forces compared with the intracorporeal side winding knot-tying knots and the extracorporeal knot-tying knots (P < 0.05). CONCLUSIONS: The intracorporeal one-hand knot-tying technique and knots showed better results than the intracorporeal "side winding" technique and the extracorporeal knot-tying technique in terms of the time, average load taken and the force caused the knot to rupture.

Towards the Holy Grail: What can we do for truly scarless surgery?

The work of Muhe and Mouret in the late 1980s, paved the way for mainstream laparoscopic procedures and it rapidly became the mainstream method for many intra-abdominal procedures. Natural orifice transluminal surgery (NOTES) and Laparo-endoscopic single-site surgery (LESS) are very exciting new modalities in the field of minimally invasive surgery which work for further reducing the scars of standard laparoscopy and towards scarless surgery. However, according to objective assessment of the literatures, there is no clearly demonstrated benefit of NOTES (LESS), even cosmesis is poorly supported and had mixed results in the available data. NOTES (LESS) is far from the truly scarless surgery. Towards the Holy Grail, we have developed several techniques of creating nonvisible scar and named them as "Scar-hidden Endoscopic Surgery". With the rapid development of science and technology, we believe that minimally invasive surgery over the next 2 decades will continue to bring remarkable change and realize truly scarless surgery even we may not be able to imagine what lies ahead.

Distant metastasis risk and patterns of nasopharyngeal carcinoma in the era of IMRT: long-term results and benefits of chemotherapy.

PURPOSE: To report the distant metastasis (DM) risk and patterns for nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT) and to analyze the benefits of chemotherapy based on DM risk. MATERIALS AND METHODS: 576 NPC patients were analyzed. The DM rates were calculated using the Kaplan-Meier method, and the log-rank test was used to compare differences. The patients were divided into different risk subclassifications according to DM hazard ratios. RESULTS: 91 patients developed DM after treatment, with bone as the most common metastatic sites. 82.4% of DMs occurred within 3 years of treatment. Patients were classified as low-risk, intermediate-risk and high-risk, and the corresponding 5-year DM rates were 5.1%, 13.1% and 32.4%, respectively (P < 0.001). Chemotherapy failed to decrease the DM rate in the low-risk subclassification, but decreased the DM risk in the intermediate-risk subclassification (P = 0.025). In the high-risk subclassification, the DM rate was 31.9% though chemotherapy was used, which was significantly higher than that of other two subclassifications. CONCLUSIONS: DM is the dominant treatment failure in NPC treated by IMRT, with similar occurrence times and distributions to those that occurred in the era of conventional radiotherapy. Further studies on treatment optimization are needed in high-risk patients.

Risk factors and prediction-score model for distant metastasis in nasopharyngeal carcinoma treated with intensity-modulated radiotherapy.

The objective of this study is to identify the risk factors and construct a prediction-score model for distant metastasis (DM) in nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiotherapy (IMRT). A total of 520 nonmetastatic NPC patients were analysed retrospectively. The independent risk factors for DM were tested by multivariate Cox regression analysis. The prediction-score model was established according to the regression coefficient. The median follow-up was 88.4 months. The 5-year DM rate was 15.1%. N2-3, primary tumour volume of nasopharynx (GTVnx) >24.56 cm(3), haemoglobin change after treatment (ΔHGB) >25.8 g/L, albumin-globulin ratio (AGR) ≤1.34, pretreatment neutrophil-lymphocyte ratio (NLR) >2.81 and pretreatment serum lactate dehydrogenase (LDH) >245 U/L were significantly adverse independent predictive factors for DM. Three subgroups were defined based on the prediction-score model: low risk (0-2), intermediate risk (3-4) and high risk (5-8). The 5-year DM rates were 4.6, 21.8 and 50.8%, respectively (P < 0.001). The areas under the curve for DM in the prediction-score model and the UICC/AJCC staging system seventh edition were 0.748 and 0.627, respectively (P < 0.001). The scoring model is useful in evaluating the risk of DM in IMRT-treated NPC patients and guiding future therapeutic trials. Further prospective study is needed.

Development of a measurement system for laparoendoscopic single-site surgery: reliability and repeatability of digital image correlation for measurement of surface deformations in SILS port.

OBJECTIVE: Analysis of mechanical measurements in laparoendoscopic single-site surgery (LESS) is important for instrument design and surgical simulators. The aim of this study was to develop a measuring system for different instruments and manipulations in LESS using a single-incision laparoscopic surgery (SILS) port. METHODS: The loads on the SILS port were applied and recorded by the universal material testing machine by the following method. The handle of the forceps inserted in the SILS port was connected with the machine by a fishing wire and pulled at a constant rate. The surface deformations (displacements and strains) of the SILS port were recorded with digital image correlation (DIC) simultaneously. The correlation between deformation measurements and loads were analyzed. This experiment was repeated 8 times. RESULTS: Strong correlations existed between deformation measurements calculated by DIC and objective criteria "loads" applied and recorded by the universal material testing machine (r>0.98). The correlation coefficients were statistically significant (P<.001). A high repeatability of the results appeared in all repetitions of the experiment. CONCLUSIONS: A DIC measurement system has been developed for LESS, and comprehensive mechanical parameters of a SILS port can be obtained precisely by using this system. It is reliable and repeatable for evaluation of instruments and manipulations in LESS.

Mechanical evaluation of articulating instruments and cross-handed manipulation in laparoendoscopic single-site surgery.

BACKGROUND: Laparoendoscopic single-site surgery (LESS) is limited by loss of triangulation and internal instruments conflict. To overcome these difficulties, some concepts have been introduced, namely, articulating instruments and cross-handed manipulation, which causes the right hand to control the left instrument tip and vice versa. The aim of this study was to compare task performance with different approaches based on a mechanical evaluation platform. METHODS: A LESS mechanical evaluation platform was set up to investigate the performance of 2 tasks (suture pass-through rings and clip-cut) with 3 different settings: uncrossed manipulation with straight instruments (group A, the control group), uncrossed manipulation with articulating instruments (group B), and cross-handed manipulation with articulating instruments (group C). The operation time and average load required for accomplishment of the standard tasks were measured. RESULTS: Group A presented significantly better time scores than group B, and group C consumed the longest time to accomplish the 2 tasks (P < .05). Comparing of average load required to perform the suture pass-through rings task, it differed significantly between dominant and nondominant hand in all groups (P < .01) and was less in group A and group B than group C in dominant hand (P < .01), while it was almost the same in all groups in the nondominant hand. In terms of average load requirement to accomplish clip-cut task, it was almost equal not only between group A and B but also between dominant and nondominant hand while the increase reached statistical significance when comparing group C with other groups (P < .05). CONCLUSIONS: Compared with conventional devices and maneuvering techniques, articulating instruments and cross-handed manipulation are associated with longer operation time and higher workload. Instruments with better maneuverability should be developed in the future for LESS.

Towards scarless surgery: a novel laparoscopic cholecystectomy by using 2-mm needle-shape instruments without trocar.

OBJECTIVE: We introduce a new laparoscopic cholecystectomy by using 2-mm needle-shape instruments and compare it with single-incision laparoscopic cholecystectomy. PATIENTS AND METHODS: From January 2011 to June 2011, 60 patients who satisfied the inclusion and exclusion criteria were prospectively selected and randomized to receive either a scar-hidden novel laparoscopic cholecystectomy (NLC group) (n=30) or a single-incision laparoscopic cholecystectomy (SILC group) (n=30). Their operation time, pain score, and satisfaction score were contrasted. RESULTS: All operations were successful. Two patients were converted to conventional three-port laparoscopic cholecystectomy in the SILC group. No postoperative complications occurred in both groups. The operation time was significantly lower in the NLC group (14.17±3.51 minutes in the NLC group versus 24.67±4.12 minutes in the SILC group, P<.01). As to the satisfaction score, the NLC group was superior to the SILC group (4.53±0.57 in the NLC group versus 4.07±0.52 in the SILC group P<.01). There was also a lower postoperative pain score in the NLC group, although the results did not reach statistical significance. CONCLUSIONS: The new scar-hidden laparoscopic cholecystectomy is a safe and feasible technique. Compared with single-incision laparoscopic cholecystectomy, it has a lower operation time and less difficulty but a higher satisfaction score. It demonstrates a new approach for minimal invasive surgery.

Covert laparoscopic cholecystectomy:a new minimally invasive technique.

To further improve our developed transumbilical endoscopic surgery (TUES), we developed a completely covert laparoscopic cholecystectomy (LC). Twelve cases of LC were recruited for this new approach. First, a 10-mm trocar was placed above the umbilicus for inserting the laparoscope. Two 5-mm trocars were then placed near the right and left ends of the superior margin of the suprapubic hair. After the 5-mm 30° laparoscope was shifted to the left suprapubic trocar, the harmonic scalper, electric hook, and grasper were inserted either through the 10-mm umbilical trocar or through the right suprapubic trocar. All gallbladders were successfully removed without intraoperative complications. The mean operating time was 28.5 ± 5.7 min (range 20-45 min). All patients felt well after surgery and did not need postoperative analgesia. They resumed free oral intake 6h after the procedure. All patients were satisfied with the appearance of the incisions, which were completely hidden in the umbilicus and suprapubic hair. The approach we developed has overcome both external instrument interference around the umbilicus and the loss of triangulation in the operative field. It is relatively simpler than a typical TUES and offers better cosmetic results.