Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: The additive or synergistic sustained antitumour effect of immune checkpoint inhibitors in combination with oxaliplatin-based chemotherapy has previously been reported. We investigated the efficacy of nivolumab plus oxaliplatin-based chemotherapy versus placebo plus oxaliplatin-based chemotherapy as first-line therapy for patients with HER2-negative, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer. METHODS: We did a randomised, multicentre, double-blind, placebo-controlled, phase 2-3 trial (ATTRACTION-4) at 130 centres (hospitals, cancer centres, and medical centres) across Japan, South Korea, and Taiwan. We enrolled patients aged 20 years and older with previously untreated (except for neoadjuvant or adjuvant chemotherapy completed ≥180 days before recurrence), HER2-negative, unresectable, advanced or recurrent gastric or gastro-oesophageal junction cancer (regardless of PD-L1 expression), at least one measurable lesion per Response Evaluation Criteria in Solid Tumours guidelines (version 1.1), and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned (1:1) to chemotherapy every 3 weeks (intravenous oxaliplatin 130 mg/m2 on day 1 plus either oral S-1 40 mg/m2 [SOX] or oral capecitabine 1000 mg/m2 [CAPOX], twice daily on days 1-14), in addition to either 360 mg nivolumab intravenously every 3 weeks (nivolumab plus chemotherapy group) or placebo (placebo plus chemotherapy group). Randomisation was done using an interactive web response system with block sizes of four and stratified by intensity of PD-L1 expression, ECOG performance status score, disease status, and geographical region. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoints were centrally assessed progression-free survival and overall survival in the intention-to-treat population, which included all randomly assigned patients. Safety was assessed in all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT02746796. Trial recruitment is complete and follow-up is ongoing. FINDINGS: Between March 23, 2017, and May 10, 2018, 724 patients were randomly assigned to treatment: 362 patients to the nivolumab plus chemotherapy group and 362 to the placebo plus chemotherapy group. At the time of data cutoff on Oct 31, 2018, with a median follow-up of 11·6 months (IQR 8·7-14·1), median progression-free survival at a prespecified interim analysis was 10·45 months (95% CI 8·44-14·75) in the nivolumab plus chemotherapy group and 8·34 months (6·97-9·40) in the placebo plus chemotherapy group (hazard ratio [HR] 0·68; 98·51% CI 0·51-0·90; p=0·0007). At the time of data cutoff on Jan 31, 2020, with a median follow-up of 26·6 months (IQR 24·1-29·0), median overall survival at the final analysis was 17·45 months (95% CI 15·67-20·83) in the nivolumab plus chemotherapy group and 17·15 months (15·18-19·65) in the placebo plus chemotherapy group (HR 0·90; 95% CI 0·75-1·08; p=0·26). The most common treatment-related grade 3-4 adverse events were neutrophil count decreased (71 [20%] of 359 patients in the nivolumab plus chemotherapy group vs 57 [16%] of 358 patients in the placebo plus chemotherapy group) and platelet count decreased (34 [9%] vs 33 [9%]). Treatment-related serious adverse events of any grade were observed in 88 (25%) patients in the nivolumab plus chemotherapy group and in 51 (14%) in the placebo plus chemotherapy group, of which the most common was decreased appetite (18 [5%] vs ten [3%]). Six treatment-related deaths occurred: three in the nivolumab plus chemotherapy group (one each of febrile neutropenia, hepatic failure, and sudden death) and three in the placebo plus chemotherapy group (one each of sepsis, haemolytic anaemia, and interstitial lung disease). INTERPRETATION: Nivolumab combined with oxaliplatin-based chemotherapy significantly improved progression-free survival, but not overall survival, in Asian patients with untreated, HER2-negative, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer, and could potentially be a new first-line treatment option for these patients. FUNDING: Ono Pharmaceutical and Bristol-Myers Squibb.

Hybrid Reaction Systems for the Synthesis of Alkylated Compounds Based upon Cu-Catalyzed Coupling of Radicals and Organometallic Species.

A transition metal catalyzed alkylation with an alkyl halide is one of the most difficult reactions to achieve, because of the difficult oxidative addition of an alkyl-halogen bond to a metal, and the tendency of the resulting alkylmetal intermediate to undergo a ß-hydride elimination reaction to give an olefin. In this review, we discuss hybrid reaction systems involving Cu catalyzed combination of radicals and organometallic species, which enable facile alkylation reactions to construct C-C and C-heteroatom bonds. This paper highlights recent progress in arylation, alkenylation, alkynylation, cyclization, addition and introduction of heteroatoms via these hybrid reaction systems.

Copper-Catalyzed Amination of Congested and Functionalized α-Bromocarboxamides with either Amines or Ammonia at Room Temperature.

There are several reports on the synthesis of alkylamines, but most of the reported methods are not suitable for the synthesis of hindered amines. In this research, we found that a copper catalyst is effective for the formation of congested C-N bonds at room temperature. Control experiments revealed that a copper amide is a key intermediate. Moreover, when a chiral amine was used, a quaternary carbon stereogenic center was created with good selectivity.

Association of lubricin concentration in synovial fluid and clinical status of osteoarthritic knee.

OBJECTIVES: Although lubricin plays a role in controlling inflammation and pain as well as being a mechanical lubricant, clinical relevance of lubricin concentration in synovial fluid (SF) is unknown. The purpose was to determine whether lubricin concentration in SF is associated with the clinical status of the knee. METHODS: SF was obtained from 61 knee joints from patients who underwent any knee surgery with several stages of knee osteoarthritis. Lubricin/PRG4 concentration in SF was measured by enzyme-linked immunosorbent assay (ELISA). Clinical evaluations of the knee by the Kellgren and Lawrence (K-L) system, Knee Society Score (KSS), and the range of knee motion, and assessment of joint laxity were performed. Association of lubricin concentration in SF and these clinical factors was statistically analyzed. RESULTS: There was no significant correlation between lubricin concentration in SF and age, sex, K-L grade, or KSS. However, lubricin concentration was significantly correlated with anteroposterior laxity (R = 0.50, p < 0.001), full flexion angle (R = 0.39, p < 0.01), and range of knee motion (R = 0.38, p < 0.01), but not full extension angle, varus laxity, or valgus laxity. CONCLUSIONS: Lubricin concentration was correlated with joint flexibility, but not with clinical symptoms, including pain at that time.

Preoperative varus laxity correlates with overcorrection in medial opening wedge high tibial osteotomy.

PURPOSE: Medial opening wedge high tibial osteotomy (HTO) is a realignment of the lower limb. Despite accurate preoperative planning and careful surgical techniques, many HTOs result in alignment correction errors. These alignment correction errors may be due to soft tissue laxity around the knee such as varus or valgus laxity. The purpose of this study was to examine the relationship of varus and valgus laxity of the knee and alignment correction errors, and to have a formula to predict the subsequent degree of these correction errors. MATERIALS AND METHODS: Fifty knees from 41 patients undergoing opening wedge HTO for knee osteoarthritis were involved. Standing full-length anteroposterior radiographs of the lower limb and the tibia, and varus and valgus stress radiographs of the knee were used to evaluate alignment and joint laxity. Parameters were global correction (the change in the hip-knee-ankle angle), bony correction (the change in the medial proximal tibial angle), and soft tissue correction (global correction - bony correction). RESULTS: The average of global correction, bony correction, and soft tissue correction were 12.8° ± 4.3°, 9.4° ± 3.2°, and 3.4° ± 2.5°, respectively. Preoperative varus laxity was moderately correlated with soft tissue correction (R = 0.58), and in which the slope of the line in the scatter plot represented 0.59, implying that soft tissue correction increases by 0.59° for every 1° of preoperative varus laxity. CONCLUSIONS: Preoperative varus laxity is correlated with soft tissue correction, suggesting that more accurate alignment correction could be achieved by surgical planning taking into account preoperative varus laxity as a factor of soft tissue correction.

Effect of Wedge Insertion Angle on Posterior Tibial Slope in Medial Opening Wedge High Tibial Osteotomy.

BACKGROUND: Medial opening wedge high tibial osteotomy (HTO) is a well-established surgery for medial compartment knee osteoarthritis (OA) wherein the lower extremity is realigned to shift the load distribution from the medial compartment of the knee to the lateral compartment. However, this surgery is known to affect the posterior tibial slope angle (PTSA), which could lead to abnormal knee kinematics and instability, and eventually to knee OA. Although PTSA control is as important as coronal realignment, few appropriate measurements for this parameter have been reported. The placement of a wedge spacer might have an effect on PTSA. PURPOSE: To elucidate the relationship between the PTSA and the direction of insertion of a wedge spacer. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: This study assessed 43 knees from 34 patients who underwent medial opening wedge HTO for knee OA. Pre- and postoperative lateral radiographs of the knee as well as postoperative computed tomography scans were performed to evaluate the relationship among PTSA, wedge insertion angle (WIA), and opening gap ratio (distance of the anterior opening gap/distance of the posterior opening gap at the osteotomy site). RESULTS: The PTSA significantly increased from 9.0° ± 2.8° preoperatively to 13.2° ± 4.1° postoperatively (P < .001), resulting in a mean ΔPTSA of 4.7° ± 4.5°. The mean opening gap ratio was 0.86 ± 0.11, and the mean WIA was 25.9° ± 8.4°. The WIA and opening gap ratio were both highly correlated with ΔPTSA (r = 0.71 and 0.72, respectively), implying that a smaller WIA or smaller gap ratio leads to less increase in posterior slope. CONCLUSION: The direction of wedge insertion is highly correlated with PTSA increase, which suggests that the PTSA can be controlled for by adjusting the direction of wedge insertion during surgery. CLINICAL RELEVANCE: Study results suggest that it is possible to adjust the PTSA by controlling the WIA during surgery. Proper attention to WIA can avoid an iatrogenic increase in posterior tibial slope.

Human mannose-binding lectin 2 is directly regulated by peroxisome proliferator-activated receptors via a peroxisome proliferator responsive element.

Human mannose-binding lectin (MBL) is encoded by the MBL2 gene and is a key player in innate immunity. However, the mechanism of the transcriptional regulation of MBL2 is largely unknown. The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that play an important role in a number of biological responses, including lipid homeostasis, immune function and adipogenesis. In this study, we showed that PPARα and PPARγ up-regulate the expression of human MBL2. Using a luciferase assay, electrophoretic mobility-shift assay and chromatin immunoprecipitation assay, we demonstrated that PPARs regulate the expression of human MBL2 via the peroxisome proliferator responsive element (PPRE). On the other hand, MBL2 mRNA expression was not affected by the PPARα ligand both in vivo in rat liver and in vitro in rat H4IIE hepatoma cells. Thus, there is a species difference in regulation of MBL2 gene expression by PPARs between humans and rodents. We also show that the species differences in response to PPAR could be due in part to sequence-specific differences in the PPRE in the promoter region of MBL2. These results indicate that human, but not rat, MBL2 expression is regulated by PPARs via a PPRE.

Regulation of the human SLC25A20 expression by peroxisome proliferator-activated receptor alpha in human hepatoblastoma cells.

Solute carrier family 25, member 20 (SLC25A20) is a key molecule that transfers acylcarnitine esters in exchange for free carnitine across the mitochondrial membrane in the mitochondrial beta-oxidation. The peroxisome proliferator-activated receptor alpha (PPARalpha) is a ligand-activated transcription factor that plays an important role in the regulation of beta-oxidation. We previously established tetracycline-regulated human cell line that can be induced to express PPARalpha and found that PPARalpha induces the SLC25A20 expression. In this study, we analyzed the promoter region of the human slc25a20 gene and showed that PPARalpha regulates the expression of human SLC25A20 via the peroxisome proliferator responsive element.

Reconsideration of drug release from temperature-sensitive liposomes.

The liposomal phase transition temperature was monitored in unstirred suspensions using a differential scanning calorimeter. The main and pre-transition temperatures under conditions of stirring were measured by the change in 90 degrees light scattering using a fluorescence spectrophotometer. Both methods show the same main transition temperature either with or without stirring. Temperature sensitive liposomes were made of DPPC (dipalmitoylphosphatidylcholine), DMPC (dimylisitoylphosphatidylcholine) or DSPC (distearoylphosphatidylcholine). The calcein release profile from the liposomes depends on the stirring time of the liposome suspension at the main transition temperature. For 1 h incubation, the leakage profile with and without stirring is similar. It had been hypothesized that temperature sensitive liposomes released drug at the main-transition temperature. However, calcein leakage from liposomes is observed also at the pre-transition temperature. Thus, a liposomal encapsulated drug will likely leak from DPPC liposomes at body temperature (37 degrees C), even if the liposomes were designed to have a higher main transition temperature.