A phase II study of amrubicin and carboplatin for previously untreated patients with extensive-disease small cell lung cancer

Background: Amrubicin is active in the treatment of extensive-disease small cell lung cancer (ED-SCLC), and carboplatin is an analogue of cisplatin with less non-hematological toxicity. Purpose: The purpose of this study was to determine the efficacy and toxicity of amrubicin and carboplatin combination chemotherapy for previously untreated patients with ED-SCLC. Patients and methods: Eligibility criteria were chemotherapy-naive ED-SCLC patients, performance status 0-1, age ?75, and adequate hematological, hepatic and renal function. Based on the phase I study, the patients received amrubicin 35 mg/m2 i.v. infusion on days 1, 2, and 3, and carboplatin AUC 5 i.v. infusion on day 1. Four cycles of chemotherapy were repeated every 3 weeks. Results: Thirty-five patients were enrolled, and 34 patients were eligible and assessable for response, toxicity, and survival. Patients\u27 characteristics were as follows: male/female = 26/8; performance status 0/1 = 4/30; median age (range) = 64 (41-75); stage IV = 34. Evaluation of responses was 6 complete response, 21 partial response, and 7 stable disease (response rate 79.4 %, 95 % CI 63.6-88.5 %). Grade 3 and 4 leukopenia, neutropenia, and thrombocytopenia occurred in 59, 82, and 26 %, respectively. There were no treatment-related deaths or pneumonitis. Three patients experienced hypotension as an amrubicin infusion reaction. The median progression-free survival time was 6.5 months. The median overall survival time and 1-, 2-, and 3-year survival rates were 15.6 months, and 63, 28, and 7 %, respectively. Conclusions: Amrubicin and carboplatin were effective and tolerable as chemotherapy for previously untreated patients with ED-SCLC. Further investigation of amrubicin and carboplatin is warranted

Factors related to liability for damages for adverse events occurring in long-term care facilities.

Globally, residents of long-term care facilities (LTCFs) often experience adverse events (AEs) and corresponding lawsuits that result in suffering among the residents, their families, and the facilities. Hence, we conducted a study to clarify the factors related to the facilities' liabilities for damages for the AEs that occur at LTCFs in Japan. We analyzed 1,495 AE reports from LTCFs in one Japanese city. A binomial logistic regression analysis was conducted to identify factors associated with liability for damages. The independent variables were classified as: residents, organizations, and social factors. In total, 14% of AEs resulted in the facility being liable for damages. The predictors of liability for damages were as follows: for the resident factors, the increased need for care had an adjusted odds ratio (AOR) of 2.00 and care levels of 2-3; and AOR of 2.48 and care levels of 4-5. The types of injuries, such as bruises, wounds, and fractures, had AORs of 3.16, 2.62, and 2.50, respectively. Regarding the organization factors, the AE time, such as noon or evening, had an AOR of 1.85. If the AE occurred indoors, the AOR was 2.78, and if it occurred during staff care, the AOR was 2.11. For any follow-ups requiring consultation with a doctor, the AOR was 4.70, and for hospitalization, the AOR was 1.76. Regarding the type of LTCF providing medical care in addition to residential care, the AOR was 4.39. Regarding the social factors, the reports filed before 2017 had an AOR of 0.58. The results of the organization factors suggest that liability tends to arise in situations where the residents and their family expect high quality care. Therefore, it is imperative to strengthen organizational factors in such situations to avoid AEs and the resulting liability for damages

Phase II trial of a non‐platinum triplet for patients with advanced non‐small cell lung carcinoma (NSCLC) overexpressing ERCC1 messenger RNA

Background We prospectively evaluated the efficacy and toxicity of a non‐platinum triplet regimen for patients with advanced non‐small cell lung cancer (NSCLC) expected to be platinum‐resistant. Methods Patients were diagnosed with NSCLC using endobronchial ultrasonography with a guide sheath as a core biopsy. RNA was immediately isolated from unfixed biopsy specimens, and quantitative real‐time reverse transcription‐PCR assays were performed to determine ERCC1 messenger RNA expression. Patients with advanced, untreated NSCLC showing high ERCC1 levels (ΔCt ≧ 6.5) were assigned a non‐platinum triplet regimen of irinotecan and paclitaxel plus bevacizumab. The primary end point was the objective response rate (ORR). Results A total of 141 untreated patients were evaluated and 30 patients were entered into this phase II trial. The ORR was 66.7% (95% confidence interval [CI] 47.2–82.7) and median progression‐free survival (PFS) was 215 days. Grade 4 thrombosis occurred in one patient, but other toxicities were mild and controllable. Fifty‐six patients were treated with platinum‐containing regimens and 24 patients responded (ORR 42.8%, 95% CI 29.7–56.7). Twenty‐nine of these patients had high ERCC1 levels, of which 6 patients responded; 27 patients had low ERCC1 levels, 18 patients responded (P = 0.0053 by Fisher’s exact test). Conclusion The triplet combination might be effective for patients with advanced, untreated NSCLC overexpressing ERCC1. ERCC1 messenger RNA levels may be a predictive factor for response to platinum‐containing regimens

Kinesin Family member 4A: A Potential Predictor for Progression of Human Oral Cancer

<div><p>Background</p><p>Kinesin family member 4A (KIF4A), a microtubule-based motor protein, was implicated in regulation of chromosomal structure and kinetochore microtubule dynamics. Considering the functions of KIF4A, we assumed that KIF4A is involved in progression of oral squamous cell carcinomas (OSCCs) via activation of the spindle assembly checkpoint (SAC). However, little is known about the relevance of KIF4A in the behavior of OSCC. We investigated the KIF4A expression status and its functional mechanisms in OSCC.</p> <p>Methods</p><p>The KIF4A expression levels in seven OSCC-derived cells were analyzed by quantitative reverse transcriptase-polymerase chain reaction and immunoblotting analyses. Using a KIF4A knockdown model, we assessed the expression of (SAC)-related molecules (BUB1, MAD2, CDC20, and cyclin B1), cell-cycle, and cellular proliferation. In addition to <i>in</i><i>vitro</i> data, the clinical correlation between the KIF4A expression levels in primary OSCCs (n = 106 patients) and the clinicopathologic status by immunohistochemistry (IHC) also were evaluated. </p> <p>Results</p><p>KIF4A mRNA and protein were up-regulated significantly (<i>P</i> < 0.05) in seven OSCC-derived cells compared with human normal oral keratinocytes. In the KIF4A knockdown cells, SAC activation was observed via increased BUB1 expression on the kinetochores, appropriate kinetochore localization of MAD2, down-regulation of CDC20, up-regulation of cyclin B1, and cell-cycle arrested at G2/M phase. The results showed that cellular proliferation of KIF4A knockdown cells decreased significantly (<i>P</i> < 0.05) compared with control cells. IHC showed that KIF4A expression in primary OSCCs was significantly (<i>P</i> < 0.05) greater than in the normal oral counterparts and that KIF4A-positive OSCCs were correlated closely (<i>P</i> < 0.05) with tumoral size. </p> <p>Conclusions</p><p>Our results proposed for the first time that KIF4A controls cellular proliferation via SAC activation. Therefore, KIF4A might be a key regulator for tumoral progression in OSCCs.</p> </div

Expression of KIF4A in shKIF4A cells.

<p>(<b>A</b>) qRT-PCR shows that KIF4A mRNA expression in the shKIF4A cells (HSC-3-and Ca9-22-derived transfectants; 2 clones each) is significantly lower than in the shMock cells (<i>P</i> < 0.05, Mann-Whitney U test). (<b>B</b>) Immunoblotting analysis shows that the KIF4A protein levels in shKIF4A-transfected cells (HSC-3- and Ca9-22-derived transfectants; 2 clones each) also have decreased markedly compared with that in the shMock cells (<i>P</i> < 0.05, Mann-Whitney U test).</p

Localization of BUB1 and MAD2 during the prometaphase in shMock and shKIF4A cells.

<p>Localization of BUB1 and MAD2 to the kinetochores is compared in shKIF4A and shMock cells by immunofluorescence. (<b>A</b>) BUB1 on kinetochores increased in shKIF4A cells compared with that in the shMock cells (green, KIF4A; red, BUB1; blue, DNA). (<b>B</b>) Appropriate localization of MAD2 is seen in shKIF4A cells, whereas kinetochore localization is not seen in the shMock cells (green, KIF4A; red, MAD2; blue, DNA).</p

Reduced cellular growth in shKIF4A cells.

<p>To determine the effect of shKIF4A on cellular proliferation, shKIF4A and shMock cells were seeded in six-well plates at a density of 1×10⁴ viable cells/well. Both transfectants were counted on seven consecutive days. The cellular growth of shKIF4A-transfected cells (HSC-3- and Cas9-22-derived transfectants; 2 clones each) were significantly inhibited compared with shMock cells after 7 days (168 hours). The results were expressed as the means ± SEM of values from three assays. The asterisks indicate significant differences between the shKIF4A and shMock cells (<i>P</i> < 0.05, Mann-Whitney U test).</p

Evaluation of KIF4A expression in OSCC-derived cellular lines.

<p>(<b>A</b>) Quantification of KIF4A mRNA expression in OSCC-derived cellular lines by qRT-PCR analysis. Significant up-regulation of KIF4A mRNA is seen in seven OSCC-derived cellular lines compared with the HNOKs (<i>P</i> < 0.05, Mann-Whitney U test). Data are expressed as the means ± SEM of triplicate results. (<b>B</b>) Immunoblotting analysis of KIF4A protein in the OSCC-derived cellular lines and HNOKs. KIF4A protein expression is up-regulated in the OSCC-derived cellular lines compared with that in the HNOKs. Densitometric KIF4A protein data are normalized to GAPDH protein levels. The values are expressed as a percentage of the HNOKs (<i>P</i> < 0.05, Mann-Whitney U test).</p