Phase I dose escalation and expansion study of golidocitinib, a highly selective JAK1 inhibitor, in relapsed or refractory peripheral T-cell lymphomas.

BACKGROUND: Relapsed or refractory peripheral T-cell lymphomas (r/r PTCLs) are a group of rare and aggressive diseases that lack effective therapies. Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is reported to be associated with PTCLs. Golidocitinib is an oral, potent JAK1 selective inhibitor evaluated in a phase I/II multinational study in patients with r/r PTCLs. PATIENTS AND METHODS: Patients with r/r PTCLs were eligible. The primary objectives were to assess safety and tolerability of golidocitinib and to define its recommended phase II dose (RP2D). The secondary objectives were to evaluate its antitumor activity and pharmacokinetics (PK). RESULTS: A total of 51 patients were enrolled and received golidocitinib treatment at 150 or 250 mg once daily (QD). The median prior lines of therapies were 2 (range: 1-8). Golidocitinib was tolerated at both doses tested, while a higher incidence of serious adverse events and dose modifications at 250 mg were observed. The most common grade ≥3 drug-related treatment-emergent adverse events were neutropenia (27.5%) and thrombocytopenia (11.8%). An objective response rate of 39.2% and a complete response rate of 21.6% were observed. With median follow-up time of 14.7 and 15.9 months, the median duration of response (DoR) and progression-free survival were 8.0 and 3.3 months, respectively. Based on these data, 150 mg QD was defined as the RP2D. Golidocitinib demonstrated a favorable PK profile as an oral agent. Biomarker analysis suggested a potential correlation between JAK/STAT pathway aberrations and clinical activity of golidocitinib. CONCLUSIONS: In this phase I study, golidocitinib demonstrated an acceptable safety profile and encouraging antitumor efficacy in heavily pretreated patients with r/r PTCLs. These results support the initiation of the multinational pivotal study in patients with r/r PTCLs.

The ECHELON-2 Trial: 5-year results of a randomized, phase III study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma.

BACKGROUND: For patients with peripheral T-cell lymphoma (PTCL), outcomes using frontline treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like therapy are typically poor. The ECHELON-2 study demonstrated that brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) exhibited statistically superior progression-free survival (PFS) per independent central review and improvements in overall survival versus CHOP for the frontline treatment of patients with systemic anaplastic large cell lymphoma or other CD30-positive PTCL. PATIENTS AND METHODS: ECHELON-2 is a double-blind, double-dummy, randomized, placebo-controlled, active-comparator phase III study. We present an exploratory update of the ECHELON-2 study, including an analysis of 5-year PFS per investigator in the intent-to-treat analysis group. RESULTS: A total of 452 patients were randomized (1 : 1) to six or eight cycles of A+CHP (N = 226) or CHOP (N = 226). At median follow-up of 47.6 months, 5-year PFS rates were 51.4% [95% confidence interval (CI): 42.8% to 59.4%] with A+CHP versus 43.0% (95% CI: 35.8% to 50.0%) with CHOP (hazard ratio = 0.70; 95% CI: 0.53-0.91), and 5-year overall survival (OS) rates were 70.1% (95% CI: 63.3% to 75.9%) with A+CHP versus 61.0% (95% CI: 54.0% to 67.3%) with CHOP (hazard ratio = 0.72; 95% CI: 0.53-0.99). Both PFS and OS were generally consistent across key subgroups. Peripheral neuropathy was resolved or improved in 72% (84/117) of patients in the A+CHP arm and 78% (97/124) in the CHOP arm. Among patients who relapsed and subsequently received brentuximab vedotin, the objective response rate was 59% with brentuximab vedotin retreatment after A+CHP and 50% with subsequent brentuximab vedotin after CHOP. CONCLUSIONS: In this 5-year update of ECHELON-2, frontline treatment of patients with PTCL with A+CHP continues to provide clinically meaningful improvement in PFS and OS versus CHOP, with a manageable safety profile, including continued resolution or improvement of peripheral neuropathy.

Combination treatment of copanlisib and gemcitabine in relapsed/refractory PTCL (COSMOS): an open-label phase I/II trial.

BACKGROUND: Current treatment options for peripheral T-cell lymphomas (PTCLs) in the relapsed/refractory setting are limited and demonstrate modest response rates with rare achievement of complete response (CR). PATIENTS AND METHODS: This phase I/II study (NCT03052933) investigated the safety and efficacy of copanlisib, a phosphatidylinositol 3-kinase-α/-δ inhibitor, in combination with gemcitabine in 28 patients with relapsed/refractory PTCL. Patients received escalating doses of intravenous copanlisib on days 1, 8, and 15, administered concomitantly with fixed-dose gemcitabine (1000 mg/m2 on days 1 and 8) in 28-day cycles. RESULTS: Dose-limiting toxicity was not observed in the dose-escalation phase and 60 mg copanlisib was selected for phase II evaluation. Twenty-five patients were enrolled in phase II of the study. Frequent grade ≥3 adverse events (AEs) included transient hyperglycemia (57%), neutropenia (45%), thrombocytopenia, (37%), and transient hypertension (19%). However, AEs were manageable, and none were fatal. The overall response rate was 72% with a CR rate of 32%. Median duration of response was 8.2 months, progression-free survival was 6.9 months, and median overall survival was not reached. Combination treatment produced a greater CR rate in patients with angioimmunoblastic T-cell lymphoma than those with PTCL-not otherwise specified (55.6% versus 15.4%, respectively, P = 0.074) and progression-free survival was significantly longer (13.0 versus 5.1 months, respectively, P = 0.024). In an exploratory gene mutation analysis of 24 tumor samples, TSC2 mutation was present in 25% of patients and occurred exclusively in responders. CONCLUSION: The combination of copanlisib and gemcitabine is a safe and effective treatment option in relapsed/refractory PTCLs and represents an important new option for therapy in this rare group of patients.

Phthalyl starch nanoparticles as prebiotics enhanced nisin production in Lactococcus lactis through the induction of mild stress in probiotics.

AIM OF THE STUDY: Effect of internalized phthalyl starch nanoparticles (PSNs) on the antimicrobial ability of Lactococcus lactis (LL) KCTC 2013. METHODS AND RESULTS: Phthalyl starch nanoparticles were prepared by self-assembly of phthalyl starch and the amount of the hydrophobic phthalic moieties were characterized by nuclear magnetic resonance: PSN1 (DS: 14·3 mol.%), PSN2 (DS: 17·8 mol.%) and PSN3 (DS: 30·4 mol.%). The sizes of PSN1, PSN2 and PSN3 measured by dynamic light scattering were 364·7, 248·4 and 213·4 nm, respectively, and the surface charges of PSNs measured by electrophoretic light scattering were negative charges and PSNs were spherical in shape according to scanning electron microscope. It was found that when PSNs were treated with LL, the PSNs were internalized into LL through nanoparticle size-, energy- and glucose transporter-dependent mechanisms. The internalization was confirmed by confocal laser scanning microscopy and fluorescence-activated cell sorting. Nisin was isolated and identified by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. Also, more nisin was produced from PSNs-treated LL than untreated- or starch-treated LL. Co-culture assay and agar diffusion test were performed to test the antimicrobial ability. Antimicrobial ability against Gram-negative Escherichia coli k88, Salmonella gallinarum and Gram-positive Listeria monocytogenes of LL treated with PSNs was higher than that of untreated or starch-treated group. Finally, it was found that the expression level of stress response genes dnaK, dnaJ and groES was significantly higher in PSNs-treated groups compared with starch-treated group or LL alone. CONCLUSION: The internalization of PSNs into LL enhanced the production of nisin through mild intracellular stimulation, resulting in enhanced antimicrobial ability. SIGNIFICANCE AND IMPACT OF THE STUDY: This study shows the promising potential of PSNs as new prebiotics for increasing the production of nisin, thus demonstrating a new method for the biological production of such antimicrobial peptides.

Sequential chemotherapy/radiotherapy was comparable with concurrent chemoradiotherapy for stage I/II NK/T-cell lymphoma.

Background: In stage I/II natural killer (NK)/T-cell lymphoma, concurrent chemoradiotherapy (CCRT) had previously been shown to result in superior outcome compared with anthracycline-containing regimens, which have since been considered ineffective. The role of CCRT in comparison with approaches employing nonanthracycline-containing chemotherapy (CT) and sequential radiotherapy (RT) in such patients remains to be defined. Patients and methods: Three hundred and three untreated patients (207 men, 96 women; median age: 51, 18-86 years) with stage I/II NK/T-cell lymphoma who had received nonanthracycline-containing regimens were collected from an international consortium and retrospectively analyzed. Treatment included single modality (CT and RT), sequential modalities (CT + RT; RT + CT) and concurrent modalities (CCRT; CCRT + CT). The impact of clinicopathologic parameters and types of treatment on complete response (CR) rate, progression-free-survival (PFS) and overall-survival (OS) was evaluated. Results: For CR, stage (P = 0.027), prognostic index for NK/T-cell lymphoma (PINK) (P = 0.026) and types of initial treatment (P = 0.011) were significant prognostic factors on multivariate analysis. On Cox regression analysis, ECOG performance score (P = 0.021) and PINK-EBV DNA (PINK-E) (P = 0.002) significantly impacted on PFS; whereas ECOG performance score (P = 0.008) and stage (P < 0.001) significantly impacted on OS. For comparing CCRT ± CT and sequential CT + RT, CCRT ± CT patients (n = 190) were similar to sequential CT + RT patients (n = 54) in all evaluated clinicopathologic parameters except two significantly superior features (higher proportion of undetectable circulating EBV DNA on diagnosis and lower PINK-E scores). Despite more favorable pre-treatment characteristics, CCRT ± CT patients had CR rate, PFS and OS comparable with sequential CT + RT patients on multivariate and Cox regression analyses. Conclusions: In stage I/II NK/T-cell lymphomas, when effective chemotherapeutic regimens were used, CCRT and sequential CT + RT gave similar outcome.

Adjuvant everolimus in high-risk diffuse large B-cell lymphoma: final results from the PILLAR-2 randomized phase III trial.

Background: Patients with diffuse large B-cell lymphoma (DLBCL) with an International Prognostic Index (IPI) ≥3 are at higher risk for relapse after a complete response (CR) to first-line rituximab-based chemotherapy (R-chemo). Everolimus has single-agent activity in lymphoma. PILLAR-2 aimed to improve disease-free survival (DFS) with 1 year of adjuvant everolimus. Patients and methods: Patients with high-risk (IPI ≥3) DLBCL and a positron emission tomography/computed tomography-confirmed CR to first-line R-chemo were randomized to 1 year of everolimus 10 mg/day or placebo. The primary end point was DFS; secondary end points were overall survival, lymphoma-specific survival, and safety. Results: Between August 2009 and December 2013, 742 patients were randomized to everolimus (n = 372) or placebo (n = 370). Median follow-up was 50.4 months (range 24.0-76.9). Overall, 47% of patients were ≥65 years, 50% were male, and 42% had an IPI of 4 or 5. 48% and 67% completed everolimus and placebo, respectively. Primary reasons for everolimus discontinuation versus placebo were adverse events (AEs; 30% versus 12%) and relapsed disease (6% versus 13%). Everolimus did not significantly improve DFS compared with placebo (hazard ratio 0.92; 95% CI 0.69-1.22; P = 0.276). Two-year DFS rate was 77.8% (95% CI 72.7-82.1) with everolimus and 77.0% (95% CI 72.1-81.1) with placebo. Common grade 3/4 AEs with everolimus were neutropenia, stomatitis, and decreased CD4 lymphocytes. Conclusions: Adjuvant everolimus did not improve DFS in patients already in PET/CT-confirmed CR. Future approaches should incorporate targeted agents such as everolimus with R-CHOP rather than as adjuvant therapy after CR has been obtained. ClinicalTrials.gov: NCT00790036.

Effect of goal-directed haemodynamic therapy in free flap reconstruction for head and neck cancer.

BACKGROUND: In free flap reconstruction for head and neck cancer, achieving a haemodynamic target using excessive fluid infusion is associated with decreased flap survival rates and extended hospital stays. We hypothesized that goal-directed haemodynamic therapy would improve flap survival rates and shorten hospitalization periods. METHODS: Patients scheduled for free flap reconstruction were randomly assigned to a goal-directed haemodynamic therapy group (n = 31) or a conventional haemodynamic therapy control group (n = 31). The control group received extra bolus fluid and ephedrine or norepinephrine to maintain a mean arterial pressure ≥ 65 mmHg. The goal-directed haemodynamic therapy group received a colloid solution as the extra bolus fluid to maintain a stroke volume variation < 12%; dobutamine, ephedrine, or norepinephrine was administered to maintain a cardiac index ≥ 2.5 l/min/m2 and mean arterial pressure ≥ 65 mmHg. Enhanced recovery after surgery protocols were not used except for fluid therapy. An otolaryngologist blinded to group assignments assessed flap outcomes and classified them as 'survival,' 'at risk' or 'failure.' RESULTS: The hospitalization period was not significantly different between the groups. The goal-directed haemodynamic therapy group had significantly shorter intensive care unit stays and a higher flap survival rate. The crystalloid volume was significantly lower in goal-directed haemodynamic therapy group. Reoperation rates, post-operative complications, and laboratory data including inflammatory markers were similar between the groups. CONCLUSION: Compared to conventional haemodynamic therapy, goal-directed haemodynamic therapy does not reduce hospitalization periods; it may, however, reduce the length of intensive care unit stays and increase flap survival rates. Further studies including multi-centre trials with larger sample sizes are warranted.

Correction to: Advanced Robotic Therapy Integrated Centers (ARTIC): an international collaboration facilitating the application of rehabilitation technologies.

The original article [1] contains a small mistake concerning the ARTIC Team members mentioned in the Acknowledgements. The team member, Rocco Salvatore Calabrò had their name presented incorrectly. This has now been corrected in the original article.

Beyond first-line non-anthracycline-based chemotherapy for extranodal NK/T-cell lymphoma: clinical outcome and current perspectives on salvage therapy for patients after first relapse and progression of disease.

BACKGROUND: Current standard treatment, including non-anthracycline-based chemotherapy and optimal combining of radiotherapy, has dramatically improved outcomes of patients with extranodal natural killer/T-cell lymphoma (ENKTL) during the last decade. This study was conducted to investigate the clinical outcome of ENKTL patients with relapsed or progressive disease after initial current standard therapy. PATIENTS AND METHODS: We retrospectively reviewed patients diagnosed with ENKTL at six centers in four countries (China, France, Singapore, and South Korea) from 1997 to 2015 and analyzed 179 patients who had relapsed or progressed after initial current standard therapy. RESULTS: After a median follow-up of 58.6 months (range 27.9-89.2), the median second progression-free survival (PFS) was 4.1 months [95% confidence interval (CI) 3.04-5.16] and overall survival (OS) was 6.4 months (95% CI 4.36-8.51). Multivariate Cox-regression analysis revealed that elevated lactate dehydrogenase, multiple extranodal sites (≥2), and presence of B symptoms were associated with inferior OS (P < 0.05). OS and PFS were significantly different according to both prognostic index of natural killer lymphoma (PINK) and PINK-E (Epstein-Barr virus) models. Salvage chemotherapy with l-asparaginase (l-Asp)-based regimens showed a significantly better clinical benefit to response rate and PFS, although it did not lead to OS improvement. First use of l-Asp in the salvage setting and l-Asp rechallenge at least 6 months after initial treatment were the best candidates for salvage l-Asp containing chemotherapy. CONCLUSIONS: Most patients with relapsed or refractory ENKTL had poor prognosis with short survival. Further studies are warranted to determine the optimal treatment of patients with relapsed or refractory ENKTL.

Epstein-Barr virus reactivation in extranodal natural killer/T-cell lymphoma patients: a previously unrecognized serious adverse event in a pilot study with romidepsin.

BACKGROUND: Romidepsin, a histone deacetylase (HDAC) inhibitor, has been approved for the treatment of relapsed and refractory peripheral T-cell lymphoma. However, the efficacy and safety of romidepsin has never been studied in patients with relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma (ENKTL). PATIENTS AND METHODS: We conducted an open-label, prospective pilot study to evaluate the efficacy and feasibility of romidepsin in the treatment of patients with ENKTL. The treatment was intravenous infusion of romidepsin (14 mg/m(2)) for 4 h on days 1, 8, and 15 of a 28-day cycle, and was repeated until disease progression or the occurrence of unacceptable toxicity. RESULTS: A total of five patients enrolled on to this pilot study. However, three patients developed fever and elevated liver enzyme and bilirubin levels immediately after their first administration of romidepsin. We suspected that these events were associated with Epstein-Barr virus (EBV) reactivation because of the rapidly elevated EBV DNA titers in blood from these patients. An in vitro study with the ENKTL cell line SNK-6 cells also showed that HDAC inhibitors including romidepsin increased the copy number of EBV DNA in a dose-dependent manner. These findings suggested that romidepsin-induced histone acetylation reversed the repressed state of the genes required for EBV reactivation and that romidepsin treatment may have caused EBV reactivation in EBV-infected tumor cells in ENKTL patients. Therefore, we discontinued the enrollment of patients into this pilot study. CONCLUSIONS: Our study suggests that the use of romidepsin may cause severe EBV reactivation in patients with ENKTL.

A phase II study of everolimus (RAD001), an mTOR inhibitor plus CHOP for newly diagnosed peripheral T-cell lymphomas.

BACKGROUND: Everolimus, an oral mTOR inhibitor, has single-agent activity against relapsed lymphomas. Thus, we carried out a phase II study of everolimus in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) as a first-line treatment for patients with peripheral T-cell lymphoma (PTCL) based on our phase I study results. PATIENTS AND METHODS: Participants (n = 30) received CHOP with 5 mg everolimus per day from day 1 to 14 every 21 days for a total of six cycles. The primary end point was the overall response rate (ORR), which included complete response (CR) and partial response (PR) to this regimen. Immunohistochemistry was used to evaluate the expression of phosphatase and tensin homology (PTEN) and phosphorylated S6 kinase (pS6K) as a response. RESULTS: The objective response rate was 90% with CR (n = 17) and PR (n = 10). The CR rate was different among subtypes; angioimmunoblastic T-cell lymphoma (AITL, n = 3) had a CR whereas PTCL-not-otherwise specified and ALK-negative anaplastic large-cell lymphoma (ALCL) patients showed 63% (12/19) and 29% (2/7) of CR rate, respectively. This difference in CR rate among subtypes was associated with PTEN loss because PTEN loss was not seen in AITL but 33% of ALCL patients. The most common toxicity was hematological, with 80% of patients experiencing at least one event of grade 3/4 neutropenia, and 60% of patients had grade 3/4 thrombocytopenia. CONCLUSION: The everolimus plus CHOP was effective for PTCL patients, and its efficacy might be related with the preservation of PTEN.

Subjective apnoea symptoms are associated with daytime sleepiness in patients with moderate and severe obstructive sleep apnoea: a retrospective study.

OBJECTIVES: Most previous studies have failed to show a relation between daytime sleepiness and apnoea severity in patients with obstructive sleep apnoea (OSA). We determined the relation between daytime sleepiness and subjective and objective apnoea severity in newly diagnosed patients with moderate-to-severe OSA. DESIGN: Retrospective cross-sectional study. SETTING: Tertiary referral centre. PARTICIPANTS: A total of 559 adults with newly diagnosed moderate and severe OSA. MAIN OUTCOME MEASURES: Daytime sleepiness was evaluated using the Epworth Sleepiness Scale (ESS). Subjective and objective apnoea severities were assessed using the Sleep Breathing Scale (SBS) and polysomnography respectively. Sleep quality and depressive symptoms were evaluated using Medical Outcomes Study-Sleep Scale and Beck Depression Inventory (BDI) respectively. RESULTS: The mean ESS score was 9.8 (SD 5.0). ESS score was correlated with SBS score (P < 0.001), apnoea-hypopnoea index (AHI) (P = 0.027), minimal oxygen saturation (MinSaO2 ) (P = 0.021), body mass index (BMI) (P = 0.007) and BDI score (P < 0.001). Linear regression analysis showed that higher SBS (P = 0.005) and BDI scores (P < 0.001) were associated with higher ESS score after controlling for gender, BMI and AHI. Apnoea-hypopnoea index, MinSaO2 and BMI were not independently related to ESS score. CONCLUSIONS: Daytime sleepiness was related to subjective OSA symptoms but not objective apnoea severity measured by polysomnography in patients with moderate-to-severe OSA. These findings suggest the usefulness of the subjective apnoea severity as an indicator of OSA disease severity.

EBV-positive diffuse large B-cell lymphoma in young adults: is this a distinct disease entity?

BACKGROUND: Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) of the elderly is defined only in adults older than 50 years. However, EBV-positive DLBCL can affect younger patients. We investigated the prevalence, clinical characteristics and survival outcomes of EBV-positive DLBCL in young adults. PATIENTS AND METHODS: We analyzed patients with de novo DLBCL who were registered in the Samsung Medical Center (SMC) retrospective lymphoma cohort and prospective SMC Lymphoma Cohort Study I (ClinicalTrials.gov: NCT00822731). RESULTS: A total of 571 cases were included in the analysis. The prevalence of EBV positivity was 6.7% (13/195) and 9.3% (35/376) in the young group (≤50 years) and in the elderly group (>50 years), respectively. EBV status was closely associated with unique unfavorable clinical characteristics [older age, more advanced stage, two or more sites of extranodal involvement, higher International Prognostic Index (IPI), and age-adjusted IPI risk] only in the elderly group. Poor prognostic impact of EBV positivity on overall survival was observed only in the elderly group [hazard ratio (HR) 2.86; 95% confidence interval (CI) 1.83-4.47; P < 0.001], but not in the young group (HR 1.17; 95% CI 0.35-3.89; P = 0.801). CONCLUSION: A substantial proportion of EBV-positive DLBCL of the elderly can occur in young adults. EBV positivity of DLBCL in young adults was not associated with unfavorable clinical characteristics or worse outcomes. We suggest that EBV-positive DLBCL should not be confined only in the elderly and 'EBV-positive DLBCL in young adults' needs to be considered as a clinically distinct disease entity. ClinicalTrials.gov: NCT02060435.

Incidence of infection according to intravenous immunoglobulin use in autologous hematopoietic stem cell transplant recipients with multiple myeloma.

BACKGROUND: Although intravenous immunoglobulin (IVIG) is not routinely recommended, many centers still use IVIG during the post-hematopoietic stem cell transplant (HSCT) period. METHOD: A total of 162 multiple myeloma (MM) patients who underwent autologous (auto-) HSCT between January 2008 and June 2013 were retrospectively reviewed. Primary objective was determination of the impact of IVIG on post-transplant infection, and secondary objectives included identification of overall incidence of infection, type of infection, and risk factors for infection after auto-HSCT in MM patients. RESULTS: After auto-HSCT, 53 of 162 patients (32.7%) experienced 104 infectious events. Upper respiratory infection was most common (n = 31, 29.8%) and pneumonia (n = 27, 26.0%) and herpes zoster (n = 15, 14.4%) came next. Among the identifiable organisms causing respiratory infection, influenza virus (n = 10) and Pneumococcus (n = 9) were predominant. Incidence of infection was not statistically different according to IVIG use (34.8% in IVIG (-) vs. 31.3% in IVIG (+), P = 0.631). Incidence of infection requiring hospitalization and multiple episodes of infection showed no difference between the groups (P = 0.147, P = 0.156). In a Cox proportional hazard model, none of the factors including age, gender, type of disease, stage, tandem (vs. single) transplantation,and IVIG was prognostic for infectious event after auto-HSCT (P = 0.955, hazard ratio 0.980 with 95% confidence interval 0.481-1.997 for IVIG). CONCLUSION: In auto-HSCT recipients with MM, incidence of post-transplant infection was not different according to prophylactic IVIG use.

Deep neuromuscular block improves the surgical conditions for laryngeal microsurgery.

BACKGROUND: Adequate neuromuscular block is required throughout laryngeal microsurgery. We hypothesized that the surgical conditions would improve under a deeper level of rocuronium-induced neuromuscular block. METHODS: Seventy-two patients undergoing laryngeal microsurgery were randomly allocated to either the 'post-tetanic counts 1-2' (PTC1-2) group or the 'train-of-four counts 1-2' (TOFcount1-2) group according to the level of neuromuscular block used. Two different doses of rocuronium (1.2 or 0.5 mg kg(-1)) were used after anaesthetic induction, and two respective targets of neuromuscular block (post-tetanic counts ≤2 or train-of-four count of 1 or 2) were used. Surgical conditions were assessed by the surgeon using a five-point rating scale (extremely poor/poor/acceptable/good/optimal), and clinically acceptable surgical conditions were defined as those which were rated acceptable, good, or optimal. The occurrence of vocal cord movement and postoperative adverse events was assessed. RESULTS: The surgical conditions were significantly different between the PTC1-2 and TOFcount1-2 groups (extremely poor/poor/acceptable/good/optimal: 0/2/1/7/26 and 3/10/2/14/7, respectively, P<0.001). The incidence of clinically acceptable surgical conditions was significantly higher in the PTC1-2 group than in the TOFcount1-2 group (94 vs 64%, P=0.003). The percentage of patients who exhibited vocal cord movement was significantly lower in the PTC1-2 group than in the TOFcount1-2 group (3 vs 39%, P<0.001). The incidence of postoperative adverse events was not significantly different except for the less frequent occurrence of mouth dryness in the PTC1-2 group (P=0.035). CONCLUSIONS: Deep neuromuscular block (post-tetanic count of 1-2) surgical conditions in patients undergoing laryngeal microsurgery improves. CLINICAL TRIAL REGISTRATION: NCT01980069.

The impact of activated p-AKT expression on clinical outcomes in diffuse large B-cell lymphoma: a clinicopathological study of 262 cases.

BACKGROUND: Oncogenic phosphatidylinositol-3-kinase/serine-threonine kinase (PI3K/AKT) pathway plays a critical role in cell proliferation and growth. Phosphorylated AKT (p-AKT) has been reported to be abnormally overexpressed and to have poor prognostic impact in solid tumors. PATIENTS AND METHODS: To define the clinical implications of p-AKT expression in diffuse large B-cell lymphoma (DLBCL), we calculated arbitrary units (AUs) by multiplying the intensity and the proportion of p-AKT expression and investigated the impact of p-AKT expression on clinical outcomes. We assessed 262 patients with DLBCL. Based on a cutoff value of the upper limit of the third quartile of AUs, 56 patients were classified as high p-AKT and the remaining 206 patients were classified as low p-AKT. RESULTS: The high p-AKT group was closely associated with more advanced stage (stage III-IV, P = 0.02), two or more extranodal involvement (P = 0.03), lactic dehydrogenase elevation (P = 0.03), higher International Prognostic Index risk groups (high intermediate/high, P = 0.02), and the presence of B-symptoms (P = 0.01). The high p-AKT group showed substantially worse overall survival (OS) (median OS, 115.0 months versus not reached, P = 0.004) and progression-free survival (PFS) (median PFS, 25.5 versus 105.8 months, P = 0.019) compared with the low p-AKT group. Multivariate analysis revealed that high p-AKT expression retained its significant poor prognostic impact for OS (hazard ratio 1.7; 95% confidence interval, 1.0-2.7; P = 0.031). The subgroup with high p-AKT expression and concurrent Epstein-Barr virus positivity showed worst prognosis with the median OS and PFS of 15.2 and 7.4 months. CONCLUSION: DLBCL patients with high p-AKT expression showed distinct clinical features and followed a more rapidly deteriorating clinical course with worse OS and PFS. Thus, a more effective treatment option should be developed for this subset of DLBCL patients, and targeting PI3K/AKT pathway may be a promising therapeutic strategy.

Incidence and risk factors of poor mobilization in adult autologous peripheral blood stem cell transplantation: a single-centre experience.

BACKGROUND AND OBJECTIVES: Collection of sufficient CD34+ cells for autologous peripheral blood stem cell (PBSC) transplantation is frequently failed in patients with lymphoma or multiple myeloma (MM). We investigated the incidence and the predictive factors for poor mobilization. MATERIALS AND METHODS: A total of 205 adult patients (101 lymphoma and 104 MM) were retrospectively included for identifying the incidence of mobilization failure and the predictive factors for poor mobilization in conventional G-CSF-based mobilization regimen. Another 17 patients who used plerixafor for mobilization were included. RESULTS: Overall, 14·1% of patients (21·8% of patients with lymphoma, 6·7% of patients with MM) were poor mobilizers. Univariate analysis and multivariate analysis revealed an interval from G-CSF administration to PBSC collection exceeding 10 days and peripheral blood mononuclear cells count on the first day of collection were predictive factors for poor mobilization in lymphoma, but not in MM. Among plerixafor-treated patient group, 9 of 11 poor mobilizers who received second-cycle plerixafor mobilization were able to collect higher number of CD34+ cells than that of CD34+ cells during the G-CSF-based first mobilization. All patients who had received initial plerixafor mobilization reached 2·0 × 10(6) CD34+ cells/kg during the four leukaphereses. CONCLUSION: In conventional G-CSF-based mobilization, early PBSC collection after G-CSF administration might enhance CD34+ cell yield. A combination of a new mobilizing agent, plerixafor, would be helpful to harvest sufficient number of CD34+ cells for successful transplantation outcome while reducing the effort of collection procedures in poor mobilizers.

The role of SDF-1 and CXCR4 on odontoblastic differentiation in human dental pulp cells.

AIM: To examine the role of stromal cell-derived factor 1 (SDF-1) signalling during odontogenic differentiation in human dental pulp cells (HDPCs). METHODOLOGY: Human dental pulp cells were treated with differentiation medium, recombinant human SDF-1, neutralizing antibody for SDF-1 or CXCR4, pertussis toxin (PTX) and AMD3100. The expression of SDF-1 and its receptor chemokine receptor type 4 (CXCR4) was measured by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. Odontoblastic differentiation was determined using alkaline phosphatase (ALP) activity assay, mineralized nodule formation and marker mRNAs by RT-PCR. RESULTS: Marked upregulation of SDF-1 and CXCR4 mRNA and protein was observed in cells grown 7 days in osteogenic induction medium. The addition of recombinant human SDF-1 to HDPCs significantly (P < 0.05) increased ALP activity, mineralized nodule formation and odontoblast marker mRNAs in a dose-dependent manner. Blocking SDF-1 signalling using antibodies against SDF-1 or CXCR4, or the G-protein-coupled receptor inhibitor PTX, and CXCR4 inhibitor AMD3100, strongly suppressed induction of odontogenic differentiation in HDPCs. CONCLUSIONS: Odontoblastic differentiation was stimulated by SDF-1 activation and repressed by SDF-1/CXCR4 inhibition. Thus, SDF-1/CXCR4 signalling may be a new therapeutic target and strategy to promote repair and regeneration in endodontics.

Integrating reverse electrodialysis with constant current operating capacitive deionization.

The presence of a salinity gradient between saline water streams may result in the production of electricity via either reverse electrodialysis (RED) or forward osmosis. While the former system generates electricity because of the ionic current, the latter process produces electricity due to the osmotic pressure. In this study, RED is coupled with capacitive deionization (CDI) so that highly pure water, fresh water and electricity could be generated simultaneously. A CDI cell is operated at constant current, and it generated ultrapure water and two streams (a lower salinity stream of approximately 17.4 mol NaCl per m(3) and a high salinity stream of approximately 512.8 mol NaCl per m(3)) to be fed to the RED stack from a 15,000 ppm CDI feed concentration. The performed simulation reveals that, the total power generated from the RED using infinitely divided electrodes is 0.57 W/m(2) electrode area. The use of RED in a CDI plant introduces a new approach to minimize CDI brine concentration, which would otherwise have a negative impact on the environment if it were disposed directly without prior treatment.