Defining the Standard of the Terminology of the Mechanical Ventilation Data in Japan.

To effectively use data from intensive care unit patient information systems at multiple hospitals, it is necessary to standardize the data into a well-ordered form. However, terms often vary between devices. We designed a mechanical ventilation concept model and applied data to that model using existing tools and expert opinions. The JSICM glossary was revised based on this study.

Reduction in X-ray Retake Rate Using the Token Economy Method.

Excessive retakes of X-ray images increase labor and material costs, as well as result in excess radiation exposure for patients and a long waiting time. In this study, we evaluated the effectiveness of the token economy method as a management method for reducing X-ray retake rate among radiology technicians. The results showed a 2.5% reduction in retake rate, indicating the effectiveness of our method. In addition, we suggest that the token-economy-based approach can be applied to other hospital management problems.

A New Procedure for Reconstructing the Knee Extension Mechanism After Resection of the Knee Joint and Patella: A Case Report.

CASE: We reconstructed the knee extension mechanism using a novel procedure for a 16-year-old adolescent girl with osteosarcoma that invaded her femur, patella, and patellar tendon. The knee joint was replaced with a megaprosthesis, and the extension mechanism was reconstructed using artificial ligaments sandwiched with bone cement forming a patella. At the one-year follow-up, she could walk using a knee orthosis without crutches. CONCLUSIONS: Reconstruction of the knee extension mechanism after patellectomy remains challenging. Our new method achieved an acceptable knee function and is, therefore, useful for patients undergoing excision of the knee joint and extension mechanism.

Survival by Depth of Response and Efficacy by International Metastatic Renal Cell Carcinoma Database Consortium Subgroup with Lenvatinib Plus Pembrolizumab Versus Sunitinib in Advanced Renal Cell Carcinoma: Analysis of the Phase 3 Randomized CLEAR Study.

BACKGROUND: The extent of tumor shrinkage has been deemed a predictor of survival for advanced/metastatic renal cell carcinoma (RCC), a disease with historically poor survival. OBJECTIVE: To perform an exploratory analysis of overall survival (OS) by tumor response by 6 mo, and to assess the efficacy and survival outcomes in specific subgroups. DESIGN, SETTING, AND PARTICIPANTS: CLEAR was an open-label, multicenter, randomized, phase 3 trial of first-line treatment of advanced clear cell RCC. INTERVENTION: Patients were randomized 1:1:1 to lenvatinib 20 mg orally daily with pembrolizumab 200 mg intravenously once every 3 wk, lenvatinib plus everolimus (not included in this analysis), or sunitinib 50 mg orally daily for 4 wk on treatment/2 wk of no treatment. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Landmark analyses were conducted to assess the association of OS with tumor shrinkage and progressive disease status by 6 mo. Progression-free survival, duration of response, and objective response rate (ORR) were analyzed by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk subgroup and by the presence of target kidney lesions. Efficacy was assessed by an independent review committee as per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS AND LIMITATIONS: Landmark analyses by tumor shrinkage showed that patients enrolled to lenvatinib plus pembrolizumab arm with a confirmed complete response or >75% target-lesion reduction by 6 mo had a 24-mo OS probability of ≥91.7%. A landmark analysis by disease progression showed that patients with no progression by 6 mo had lower probabilities of death in both arms. Patients with an IMDC risk classification of intermediate/poor had longer median progression-free survival (22.1 vs 5.9 mo) and a higher ORR (72.4% vs 28.8%) with lenvatinib plus pembrolizumab versus sunitinib. Similarly, results favored lenvatinib plus pembrolizumab in IMDC-favorable patients and those with/without target kidney lesions. Limitations of the study are that results were exploratory and not powered/stratified. CONCLUSIONS: Lenvatinib plus pembrolizumab showed improved efficacy versus sunitinib for patients with advanced RCC; landmark analyses showed that tumor response by 6 mo correlated with longer OS. PATIENT SUMMARY: In this report of the CLEAR trial, we explored the survival of patients with advanced renal cell carcinoma by assessing how well they initially responded to treatment. We also explored how certain groups of patients responded to treatment overall. Patients were assigned to cycles of either lenvatinib 20 mg daily plus pembrolizumab 200 mg every 3 wk or sunitinib 50 mg daily for 4 wk (followed by a 2-wk break). Patients who either had a "complete response" or had their tumors shrunk by >75% within 6 mo after starting treatment with lenvatinib plus pembrolizumab had better survival than those with less tumor reduction by 6 mo. Additionally, patients who had more severe disease (as per the International Metastatic Renal Cell Carcinoma Database Consortium) at the start of study treatment survived for longer without disease progression with lenvatinib plus pembrolizumab than with sunitinib.

Overall survival and objective response in advanced unresectable hepatocellular carcinoma: A subanalysis of the REFLECT study.

BACKGROUND & AIMS: Validated surrogate endpoints for overall survival (OS) are important for expediting the clinical study and drug-development processes. Herein, we aimed to validate objective response as an independent predictor of OS in individuals with unresectable hepatocellular carcinoma (HCC) receiving systemic anti-angiogenic therapy. METHODS: We investigated the association between objective response (investigator-assessed mRECIST, independent radiologic review [IRR] mRECIST and RECIST v1.1) and OS in REFLECT, a phase III study of lenvatinib vs. sorafenib. We conducted landmark analyses (Simon-Makuch) of OS by objective response at 2, 4, and 6 months after randomization. RESULTS: Median OS was 21.6 months (95% CI 18.6-24.5) for responders (investigator-assessed mRECIST) vs. 11.9 months (95% CI 10.7-12.8) for non-responders (hazard ratio [HR] 0.61; 95% CI 0.49-0.76; p <0.001). Objective response by IRR per mRECIST and RECIST v1.1 supported the association with OS (HR 0.61; 95% CI 0.51-0.72; p <0.001 and HR 0.50; 95% CI 0.39-0.65; p <0.001, respectively). OS was significantly prolonged for responders vs. non-responders (investigator-assessed mRECIST) at the 2-month (HR 0.61; 95% CI 0.49-0.76; p <0.001), 4-month (HR 0.63; 95% CI 0.51-0.80; p <0.001), and 6-month (HR 0.68; 95% CI 0.54-0.86; p <0.001) landmarks. Results were similar when assessed by IRR, with both mRECIST and RECIST v1.1. An exploratory multivariate Cox regression analysis identified objective response by investigator-assessed mRECIST (HR 0.55; 95% CI 0.44-0.68; p <0.0001) and IRR-assessed RECIST v1.1 (HR 0.49; 95% CI, 0.38-0.64; p <0.0001) as independent predictors of OS in individuals with unresectable HCC. CONCLUSIONS: Objective response was an independent predictor of OS in individuals with unresectable HCC in REFLECT; additional studies are needed to confirm surrogacy. Participants achieving a complete or partial response by mRECIST or RECIST v1.1 had significantly longer survival vs. those with stable/progressive/non-evaluable disease. GOV NUMBER: NCT01761266. IMPACT AND IMPLICATIONS: This analysis of data taken from a completed clinical trial (REFLECT) looked for any link between objective response and overall survival time in individuals with unresectable HCC receiving anti-angiogenic treatments. Significantly longer median overall survival was found for responders (21.6 months) vs. non-responders (11.9 months). Overall survival was also significantly longer for responders vs. non-responders (based on objective response status at 2, 4, and 6 months) in the landmark analysis. Our results indicate that objective response is an independent predictor of overall survival in this setting, confirming its validity as a rapid marker of efficacy that can be applied in phase II trials; however, further validation is required to determine is validity for other systemic treatments (e.g. immunotherapies), or as a surrogate of overall survival.

Large Reduction in Postoperative Posterior Tibial Slope Risks Anterior Collapse of the Tibial Component in Fixed-Bearing Unicompartmental Knee Arthroplasty.

Background: Although the posterior tibial slope (PTS) of the tibial component in unicompartmental knee arthroplasty is recommended to be between 3° and 7°, variations in preoperative PTS are wide. The purpose of this study was to evaluate the influence of the changes in preoperative and postoperative PTS on clinical outcomes. Methods: One-hundred and eighty-two knees that underwent medial fixed-bearing unicompartmental knee arthroplasty were evaluated retrospectively. The mean follow-up period was 36.4 ± 13.2 months (range, 24 to 63 months). Preoperative and postoperative PTS were measured on lateral radiographs. Knees were classified in the large reduction group if the postoperative PTS was reduced by more than 5° compared with the preoperative value and in the small reduction group if not. Knee flexion angle and 2011 Knee Society Knee Scoring System were evaluated at the last follow-up of at least 2 years. Results: Thirty-three knees were classified in the large reduction group, and 149 knees were classified in the small reduction group. The preoperative and postoperative PTS of large and small reduction groups were 10.9 ± 2.2, 3.6 ± 2.4 degrees and 7.7 ± 2.7, 7.1 ± 2.4 degrees, respectively. Flexion angle and 2011 Knee Society Knee Scoring System were not significantly different between the groups. However, the incidence of anterior collapse of the tibial component in the large group was significantly higher than that in the other group (P < .001). Conclusions: Large reduction in the postoperative PTS may be associated with anterior tibial collapse, and therefore this study shows one potential benefit for matching native slope.

Impact of bodyweight-based starting doses on the safety and efficacy of lenvatinib in primarily Japanese patients with hepatocellular carcinoma.

AIM: The phase III REFLECT study utilized bodyweight-based lenvatinib dosing in patients with unresectable hepatocellular carcinoma, based on results of the phase II Study 202. This post hoc analysis compared efficacy and safety in patients with lower and higher bodyweights. METHODS: This comparison included patients from Study 202 (Japanese, n = 43; Korean, n = 3) and Japanese patients from REFLECT (n = 81) who received lenvatinib. In Study 202, all patients received a starting dose of lenvatinib 12 mg/day; in REFLECT, patients received starting doses based on bodyweight (patients <60 kg, 8 mg/day; ≥60 kg, 12 mg/day). Safety and efficacy were assessed in both studies according to bodyweight. RESULTS: In Study 202, treatment-related, treatment-emergent adverse events (TEAEs) led to dose reductions in 80.8% and 55.0% of patients in the lower and higher bodyweight groups, respectively. In REFLECT, treatment-related TEAEs led to dose reductions in 52.5% and 70.7% of patients in the 8 and 12 mg groups, respectively. In Study 202, median overall survival (OS) was 16.2 months (95% confidence interval [CI], 9.8-25.1) and 21.3 months (95% CI, 10.1-not estimable) in the lower and higher bodyweight groups, respectively. In REFLECT, median OS was 15.8 months (95% CI, 10.4-27.6) and 18.2 months (95% CI, 11.3-26.9) in the 8 and 12 mg groups, respectively. CONCLUSIONS: Comparison between patients in Study 202 and REFLECT demonstrates efficacy was maintained with improved safety in patients with lower bodyweights who received lenvatinib 8 mg/day in REFLECT versus patients who received lenvatinib 12 mg/day in Study 202.

Proliferative flexor tenosynovitis in the index finger of a 10-year-old baseball player gloved hand: A case report.

Flexor tenosynovitis is rare in young children. This case report describes that of a 10-year-old boy with diffuse swelling of the left index finger, pain when catching a ball, and progressive inability for full flexing of the finger 2 months after starting baseball play. Magnetic resonance imaging showed a defined lesion with iso-signal intensity to muscle on T1-weighted imaging, and with high signal intensity to muscle on T2-weighted imaging. It was enhanced in T1-weighted fat suppression imaging with gadolinium enhancement. Surgical excision relieved the symptom. Histopathological findings mainly indicated proliferation of synoviocytes and plasma cell and lymphocyte infiltration. We speculated that the physical impact of the ball on the left index finger of his gloved hand during catching activated some immunological mechanism and thereby caused nonspecific tenosynovitis in this young baseball player. Awareness of this pathophysiology might raise confidence in proper diagnosis for assessing the swelling of fingers in young baseball players.

Token Economy-Based Hospital Bed Allocation to Mitigate Information Asymmetry: Proof-of-Concept Study Through Simulation Implementation.

BACKGROUND: Hospital bed management is an important resource allocation task in hospital management, but currently, it is a challenging task. However, acquiring an optimal solution is also difficult because intraorganizational information asymmetry exists. Signaling, as defined in the fields of economics, can be used to mitigate this problem. OBJECTIVE: We aimed to develop an assignment process that is based on a token economy as signaling intermediary. METHODS: We implemented a game-like simulation, representing token economy-based bed assignments, in which 3 players act as ward managers of 3 inpatient wards (1 each). As a preliminary evaluation, we recruited 9 nurse managers to play and then participate in a survey about qualitative perceptions for current and proposed methods (7-point Likert scale). We also asked them about preferred rewards for collected tokens. In addition, we quantitatively recorded participant pricing behavior. RESULTS: Participants scored the token economy-method positively in staff satisfaction (3.89 points vs 2.67 points) and patient safety (4.38 points vs 3.50 points) compared to the current method, but they scored the proposed method negatively for managerial rivalry, staff employee development, and benefit for patients. The majority of participants (7 out of 9) listed human resources as the preferred reward for tokens. There were slight associations between workload information and pricing. CONCLUSIONS: Survey results indicate that the proposed method can improve staff satisfaction and patient safety by increasing the decision-making autonomy of staff but may also increase managerial rivalry, as expected from existing criticism for decentralized decision-making. Participant behavior indicated that token-based pricing can act as a signaling intermediary. Given responses related to rewards, a token system that is designed to incorporate human resource allocation is a promising method. Based on aforementioned discussion, we concluded that a token economy-based bed allocation system has the potential to be an optimal method by mitigating information asymmetry.

Impact of Carbon Ion Radiotherapy on Inoperable Bone Sarcoma.

Management of patients with bone sarcoma who are unsuitable for surgery is challenging. We aimed to analyze the clinical outcomes among such patients who were treated with carbon ion radiotherapy (C-ion RT). We reviewed the medical records of the patients treated with C-ion RT between April 2011 and February 2019 and analyzed the data of 53 patients. Toxicities were classified using the National Cancer Institute's Common Terminology Criteria for Adverse Events (Version 4.0). The median follow-up duration for all patients was 36.9 months. Histologically, 32 patients had chordoma, 9 had chondrosarcoma, 8 had osteosarcoma, 3 had undifferentiated pleomorphic sarcoma, and 1 had sclerosing epithelioid fibrosarcoma. The estimated 3-year overall survival (OS), local control (LC), and progression-free survival (PFS) rates were 79.7%, 88.6%, and 68.9%, respectively. No patients developed grade 3 or higher acute toxicities. Three patients developed both grade 3 radiation dermatitis and osteomyelitis, one developed both grade 3 radiation dermatitis and soft tissue infection, and one developed rectum-sacrum-cutaneous fistula. C-ion RT showed favorable clinical outcomes in terms of OS, LC, and PFS and low rates of toxicity in bone sarcoma patients. These results suggest a potential role for C-ion RT in the management of this population.

Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma.

PURPOSE: The immunomodulatory effect of lenvatinib (a multikinase inhibitor) on tumor microenvironments may contribute to antitumor activity when combined with programmed death receptor-1 (PD-1) signaling inhibitors in hepatocellular carcinoma (HCC). We report results from a phase Ib study of lenvatinib plus pembrolizumab (an anti-PD-1 antibody) in unresectable HCC (uHCC). PATIENTS AND METHODS: In this open-label multicenter study, patients with uHCC received lenvatinib (bodyweight ≥ 60 kg, 12 mg; < 60 kg, 8 mg) orally daily and pembrolizumab 200 mg intravenously on day 1 of a 21-day cycle. The study included a dose-limiting toxicity (DLT) phase and an expansion phase (first-line patients). Primary objectives were safety/tolerability (DLT phase), and objective response rate (ORR) and duration of response (DOR) by modified RECIST (mRECIST) and RECIST version 1.1 (v1.1) per independent imaging review (IIR; expansion phase). RESULTS: A total of 104 patients were enrolled. No DLTs were reported (n = 6) in the DLT phase; 100 patients (expansion phase; included n = 2 from DLT phase) had received no prior systemic therapy and had Barcelona Clinic Liver Cancer stage B (n = 29) or C disease (n = 71). At data cutoff, 37% of patients remained on treatment. Median duration of follow-up was 10.6 months (95% CI, 9.2 to 11.5 months). Confirmed ORRs by IIR were 46.0% (95% CI, 36.0% to 56.3%) per mRECIST and 36.0% (95% CI, 26.6% to 46.2%) per RECIST v1.1. Median DORs by IIR were 8.6 months (95% CI, 6.9 months to not estimable [NE]) per mRECIST and 12.6 months (95% CI, 6.9 months to NE) per RECIST v1.1. Median progression-free survival by IIR was 9.3 months per mRECIST and 8.6 months per RECIST v1.1. Median overall survival was 22 months. Grade ≥ 3 treatment-related adverse events occurred in 67% (grade 5, 3%) of patients. No new safety signals were identified. CONCLUSION: Lenvatinib plus pembrolizumab has promising antitumor activity in uHCC. Toxicities were manageable, with no unexpected safety signals.

Healing Status of Meniscal Ramp Lesion Affects Anterior Knee Stability After ACL Reconstruction.

BACKGROUND: Although the biomechanical importance of the ramp lesion in the anterior cruciate ligament (ACL)-deficient knee has been demonstrated, there is no clear consensus on the appropriate treatment for ramp lesions during ACL reconstruction. PURPOSE: To compare the postoperative outcomes for ramp lesions between patients treated with all-inside repair through the posteromedial portal and those whose ramp lesions were left in situ without repair during ACL reconstruction. We also determined whether ramp lesion healing status affected postoperative knee stability. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 57 patients who underwent anatomic double-bundle ACL reconstruction between August 2011 and December 2017 had attendant ramp lesions. Of these, 25 ramp lesions that were considered stable were left in situ without repair (Nonrepaired group), and 25 ramp lesions, including 21 stable and 4 unstable lesions, were treated using all-inside repair through the posteromedial portal (Repaired group). We evaluated the side-to-side difference (SSD) in anterior tibial translation on stress radiographs and rotational stability by using the pivot-shift test 2 years after surgery, and healing status of the ramp lesions was evaluated on 3.0-T magnetic resonance imaging (MRI) scans 1 year after surgery. RESULTS: The mean SSDs in anterior translation were 2.4 ± 1.6 mm for the Nonrepaired group and 1.9 ± 1.6 mm for the Repaired group, with no significant differences. The positive ratios on the pivot-shift test were not significantly different between groups. Healing rates of ramp lesions on MRI scans showed a significant difference between the Nonrepaired group (60%) and the Repaired group (100%) (P = .001). The mean SSDs for knees in which the ramp lesion had healed as shown on MRI scans and those in which it had not healed were 1.9 ± 1.6 mm and 3.2 ± 1.1 mm, respectively, which was a significant difference (P = .02). CONCLUSION: Healing rates of ramp lesions were significantly better in the Repaired group than in the Nonrepaired group, although postoperative knee stability was not significantly different between groups. Anterior laxity in the knees in which the ramp lesion was unhealed was significantly greater compared with the knees in which the ramp lesion healed. All-inside repair through the posteromedial portal was a reliable surgical procedure to heal ramp lesions.

High absolute lymphocyte counts are associated with longer overall survival in patients with metastatic breast cancer treated with eribulin-but not with treatment of physician's choice-in the EMBRACE study.

BACKGROUND: Eribulin, a nontaxane synthetic inhibitor of microtubule dynamics, is widely used to manage locally advanced or metastatic breast cancer (MBC). Eribulin has demonstrated immunomodulatory activity on the tumour microenvironment. Baseline neutrophil-to-lymphocyte ratio (NLR), a marker of immune status, may predict progression-free survival in eribulin treatment. This post hoc analysis assessed predictors for overall survival (OS). METHODS: The phase 3 open-label study (EMBRACE) of eribulin versus treatment of physician's choice (TPC) in patients with MBC provided source data. Baseline absolute lymphocyte counts (ALCs) and NLR were evaluable in 751 and 713 patients, respectively. RESULTS: Eribulin prolonged OS versus TPC in patients with baseline ALC ≥ 1500/µl (hazard ratio [HR] 0.586; 95% confidence interval [CI] 0.437-0.784; P < 0.001). There was no significant difference by treatment for ALC < 1500/µl (HR 1.002; 95% CI 0.800-1.253; P = 0.989). Univariate and multivariate analyses were performed and identified baseline ALC as a potential predictor of OS in eribulin-treated patients. Interaction analysis of OS supported 1500/µl as a potentially differential cutoff value. NLR at a cutoff value of 3 was associated with prolonged OS (eribulin group). However, similar results were also observed in the TPC group, without apparent interaction effect, suggesting that NLR may be a general prognostic marker rather than a specific predictor of OS for eribulin. DISCUSSION: This hypothesis-generating study speculates that baseline ALC may be an independent predictor for longer OS in eribulin-treated MBC patients and could be clinically impactful because it can be evaluated without the need for additional invasive procedures. TRIAL REGISTRATION: www.ClinicalTrials.gov code: NCT00388726.

Preoperative hand-grip strength can be a predictor of stair ascent and descent ability after total knee arthroplasty in female patients.

BACKGROUND: Hand-grip strength was reported to be important predictor of functional limitation and disability related to low muscle strength in old people. The purpose of this study was to determine whether preoperative hand-grip strength predicts stair ascent and descent ability after total knee arthroplasty (TKA). METHODS: A total of 83 female patients (mean age 75.6 ± 7.2 years) who underwent unilateral TKA were included in this study. We measured body mass index, range of motion of both knees, bilateral quadriceps strength and hand-grip strength before and one year after TKA. One year after TKA, we had the subjects ascend and descend some stairs and recorded the gait pattern (step-to-step or step-over-step) and pain in both knees using a numerical rating scale. We divided the subjects into two groups according to gait pattern. These factors were compared between groups. Receiver Operating Characteristics (ROC) analysis was performed to estimate the preoperative hand-grip strength cut off point for the stair gait pattern. RESULTS: Pre- and postoperative mean hand-grip strengths were 20.1 ± 5.0 kg and 20.7 ± 5.4 kg, respectively, and there was a strong positive correlation between them (r = 0.82, P < 0.001). Quadriceps strength of both limbs significantly improved after TKA (P < 0.001). After TKA, all patients were able to perform both stair ascent and descent. The gait patterns of 27 patients were step-to-step, and 56 patients were step-over-step. Preoperative and postoperative quadriceps strength of both limbs and preoperative and postoperative hand-grip strength were significantly different between the groups. According to the ROC curve, the optimal cut off values of preoperative hand-grip strength for which female patients could ascend and descend the stairs by step-over-step after TKA was set at 19 kg. CONCLUSION: Preoperative hand-grip strength can be used in preoperative screening for stair ascent and descent ability after TKA.

REFLECT-a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset.

BACKGROUND: A phase 3, multinational, randomized, non-inferiority trial (REFLECT) compared the efficacy and safety of lenvatinib (LEN) and sorafenib (SOR) in patients with unresectable hepatocellular carcinoma (uHCC). LEN had an effect on overall survival (OS) compared to SOR, statistically confirmed by non-inferiority [OS: median = 13.6 months vs. 12.3 months; hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.79-1.06], and demonstrated statistically significant improvements in progression-free survival (PFS) and the objective response rate (ORR) in the overall population. The results of a subset analysis that evaluated the efficacy and safety of LEN and SOR in the Japanese population are reported. METHODS: The intent-to-treat population enrolled in Japan was analyzed. RESULTS: Of 954 patients in the overall population, 168 Japanese patients were assigned to the LEN arm (N = 81) or the SOR arm (N = 87). Median OS was 17.6 months for LEN vs. 17.8 months for SOR (HR 0.90; 95% CI 0.62-1.29). LEN showed statistically significant improvements over SOR in PFS (7.2 months vs. 4.6 months) and ORR (29.6% vs. 6.9%). The relative dose intensity of LEN and SOR in the Japanese population was lower than in the overall population. Frequently observed, related adverse events included palmar-plantar erythrodysaesthesia syndrome (PPES), hypertension, decreased appetite, and proteinuria in the LEN arm, and PPES, hypertension, diarrhea, and alopecia in the SOR arm. CONCLUSIONS: The efficacy and safety of LEN in the Japanese population were similar to those in the overall population of REFLECT. With manageable adverse events, LEN is a new treatment option for Japanese patients with uHCC. TRIAL REGISTRATION ID: ClinicalTrials.gov. No. NCT01761266.

Impact of Q141K on the Transport of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors by ABCG2.

The ATP-binding cassette transporter ABCG2 is expressed in various organs, such as the small intestine, liver, and kidney, and influences the pharmacokinetics of drugs that are its substrates. ABCG2 is also expressed by cancer cells and mediates resistance to anticancer agents by promoting the efflux of these drugs. In the present study, we investigated the interactions between epidermal growth factor receptor tyrosine kinase inhibitors and ABCG2 by MTT assay, intracellular drug accumulation assay, and FACS. This study showed that four epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) (gefitinib, erlotinib, lapatinib, and afatinib) were transported from tumor cells as substrates of ABCG2. Q141K is a common single-nucleotide polymorphism of ABCG2 in Asians. We demonstrated that the extracellular efflux of gefitinib, erlotinib, and lapatinib was reduced by Q141K, whereas afatinib transport was not affected. In addition, all four EGFR TKIs inhibited the transport of other substrates by both wild-type and variant ABCG2 at 0.1 µM concentrations. Accordingly, epidermal growth factor receptor tyrosine kinase inhibitors may induce interactions with other drugs that are substrates of ABCG2, and single-nucleotide polymorphisms of ABCG2 may influence both the pharmacokinetics and efficacy of these anticancer agents.

AK106-001616, a Potent and Selective Inhibitor of Cytosolic Phospholipase A2: In Vivo Efficacy for Inflammation, Neuropathic Pain, and Pulmonary Fibrosis.

3-[3-Amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)-phenyl]-propionic acid (AK106-001616) is a novel, potent, and selective inhibitor of the cytosolic phospholipase A2 (cPLA2) enzyme. Unlike traditional nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors, AK106-001616 reduced prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) production by stimulated cells. The suppression of PGE2 and LTB4 production was also confirmed using an air pouch model in rats administered a single oral dose of AK106-001616. AK106-001616 alleviated paw swelling in a rat adjuvant-induced arthritis (AIA) model. The maximum effect of the inhibitory effect of AK106-001616 was comparable with that of naproxen on paw swelling in a rat AIA model. Meanwhile, the inhibitory effect of AK106-001616 was more effective than that of naproxen in the mouse collagen antibody-induced arthritis model with leukotrienes contributing to the pathogenesis. AK106-001616 dose dependently reversed the decrease in paw withdrawal threshold not only in rat carrageenan-induced hyperalgesia, but also in a rat neuropathic pain model induced by sciatic nerve chronic constriction injury (CCI). However, naproxen and celecoxib did not reverse the decrease in the paw withdrawal threshold in the CCI model. Furthermore, AK106-001616 reduced the disease score of bleomycin-induced lung fibrosis in rats. In addition, AK106-001616 did not enhance aspirin-induced gastric damage in fasted rats, increase blood pressure, or increase the thromboxane A2/ prostaglandin I2 ratio that is thought to be an underlying mechanism of thrombotic cardiovascular events increased by selective cyclooxygenase-2 inhibitors. Taken together, these data demonstrate that oral AK106-001616 may provide valuable effects for wide indications without attendant gastrointestinal and cardiovascular risks.

Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial.

INTRODUCTION: The objective of this study was to evaluate the efficacy and safety of eribulin monotherapy, relative to vinorelbine, in Chinese women with locally recurrent/metastatic breast cancer (MBC). METHODS: This phase III open-label, randomised, parallel-group, multicentre clinical trial enrolled patients with locally recurrent or MBC who had had 2-5 prior chemotherapy regimens, including an anthracycline and taxane) from September 26, 2013, to May 19, 2015. Women were randomised 1:1 to receive eribulin (1.4 mg/m2, intravenously, on day 1 and day 8) or vinorelbine (25 mg/m2, intravenously, on day 1, day 8 and day 15) every 21 days. The primary end-point was progression-free survival (PFS). Secondary end-points included objective response rate (ORR), duration of response and overall survival (OS). RESULTS: Five hundred thirty women were randomised to receive eribulin (n = 264) or vinorelbine (n = 266). Improvement in PFS was observed with eribulin compared with vinorelbine (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.65-0.98, P = 0.036); median PFS was 2.8 months in both treatment arms. The median OS was 13.4 months with eribulin and 12.5 months with vinorelbine (HR: 1.03, 95% CI: 0.80-1.31, P = 0.838). The ORR was 30.7% (95% CI: 25.2%-36.6%) with eribulin and 16.9% (95% CI: 12.6%-22.0%) with vinorelbine (P < 0.001). Treatment-emergent adverse events leading to treatment discontinuation were less frequent with eribulin (7.2%) than with vinorelbine (14.0%). CONCLUSIONS: Eribulin achieved statistically significantly superior PFS (and response rate) compared with vinorelbine in previously treated women with locally recurrent or MBC. Eribulin appeared to be better tolerated than vinorelbine, with no new safety signals observed. TRIAL REGISTRATION: National Institutes of Health ClinicalTrials.gov registry, NCT02225470. Registered 05 August 2014- Retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT02225470?term=NCT02225470&rank=1.

Younger patients with high varus malalignment of the contralateral knee may be candidates for simultaneous bilateral total knee arthroplasty.

PURPOSE: Bilateral total knee arthroplasty (TKA) is being performed more frequently. However, a consensus on whether simultaneous or staged procedures should be performed is not available. This study reviewed the clinical course of contralateral knees in patients who underwent unilateral TKA (UTKA) to determine which patients are candidates for simultaneous bilateral TKA (BTKA). METHODS: One hundred eighty-six patients with osteoarthritis who underwent UTKA at a single hospital between 2006 and 2009 (follow-up mean, 10.1 years) were retrospectively investigated. Age, sex, obesity, contralateral knee pain, Hospital for Special Surgery score, femorotibial angle (FTA), and Kellgren-Lawrence grades at the time of initial surgery were used to evaluate the risk for requiring contralateral TKA. Survival analysis and receiver-operating characteristic (ROC) analysis were performed. RESULTS: Ninety-one patients (48.9%) underwent contralateral TKA. The FTA of the contralateral knee (CFTA) was an independent related factor (hazard ratio, 1.15; p < 0.001), and the CFTA cut-off value for the next surgery was 183° (area under the curve, 0.85; sensitivity, 80.7%; specificity, 76.2%). The 10-year Kaplan-Meier survival rates for the CFTA < 183° group and the CFTA ≥ 183° group were 79.1% and 27.0%, respectively. In the CFTA ≥ 183° group, age was the predictor of future TKA, and elderly patients tended to not require a second procedure. The age cut-off value for the next surgery was 76 years. CONCLUSIONS: Varus deformities in the contralateral knee predicted additional contralateral TKA. Patients with CFTA ≥ 183° and aged 75 years or younger are considered reasonable candidates for simultaneous BTKA. LEVEL OF EVIDENCE: III.