Direct progression of capsular invasive carcinomas from subcapsular focal hyperplasias induced by hypothyroidism-mediated tumor promotion in a rat two-stage thyroid carcinogenesis model

Purpose

Some goitrogens promote thyroid carcinogenesis in rats in an initiation-promotion model; this model frequently produces carcinomas that invade fibrously thickened capsules, termed capsular invasive carcinomas (CICs). The present study tested a hypothesis that CICs originate from parenchymal proliferative lesions located beneath the capsule.

Methods

Cell proliferation activity, cell-cycle kinetics and cellular invasion were immunohistochemically examined in subcapsular proliferative lesions in male F344 rats treated with an anti-thyroid agent, propylthiouracil or sulfadimethoxine, during the tumor-promotion phase after initiation with N-bis(2-hydroxypropyl)nitrosamine.

Results

Focal follicular cell hyperplasias (FFCHs) were the most commonly observed parenchymal proliferative lesions. Subcapsular FFCHs located near CICs showed more Ki-67⁺ cells in the capsular side than the contrary parenchymal center side. Most of these FFCHs located near CICs showed accumulated immunoreactivity for cyclin A, cyclin D, cyclin E and cyclin-dependent kinase-2, whereas most subcapsular FFCHs located elsewhere did not show such accumulated expression of cell-cycle molecules. Subcapsular FFCHs immunoreactive at the capsular front for tenascin-C, a tumor invasion marker of extracellular matrix protein, showed high proliferation activity.

Conclusions

Subcapsular FFCH-forming cells can potentially spread directly into the fibrously thickened capsule to form CICs by accelerating cell-cycle activity.     

Predictors of response of patients with solid tumors to granulocyte colony-stimulating factor

Background Granulocyte colony-stimulating factor administration is an important component of supportive therapy in chemotherapy-induced leukopenia. Although patient response to granulocyte colony-stimulating factor administration is known to vary, the factors responsible for poor response have not been identified. Objective To identify the predictors of the responses of patients with solid tumors to granulocyte colony-stimulating factor. Setting A 600-bed university hospital offering secondary and tertiary care in Japan. Methods This retrospective cohort study examined the response of 181 patients with solid tumors who were administered prophylactic granulocyte colony-stimulating factor for the first time after they developed severe grade 3/4 leukopenia (white blood cell count <2,000 × 10^?9/L) because of adjuvant or neoadjuvant chemotherapy. The granulocyte colony-stimulating factor response was defined as the length of the leukocyte recovery period, which was assessed as the period within which the normal white blood cell count (white blood cell count >3,000 × 10^?9/L) is reached after the first dosage of granulocyte colony-stimulating factor. After classification of the patients as either poor or normal granulocyte colony-stimulating factor responders according to the confidence interval of the recovery period, their characteristics were compared. Main outcome measure The time for recovery to normal white blood cell count was 2–7 days (90 % confidence interval), and the cutoff value for differentiating poor responders (n = 14) from normal responders (n = 167) was 8 days. Univariate analysis identified previous radiotherapy, number of chemotherapy courses, high granulocyte colony-stimulating factor dosage, and hypoalbuminemia to be significantly associated with granulocyte colony-stimulating factor response. Multivariate analysis identified undergoing four or more chemotherapy courses (odds ratio = 5.09; 95 % confidence interval, 1.14–22.71) and heart failure (odds ratio = 5.96; 95 % confidence interval, 1.09–32.57) to be significantly associated with poor granulocyte colony-stimulating factor response. Conclusions Undergoing four or more chemotherapy courses and heart failure are independent risk factors for poor response to granulocyte colony-stimulating factor. These findings may help prevent the complications of leukopenia during chemotherapy and highlight the need to develop better strategies for preventing and treating infectious disease in patients undergoing granulocyte colony-stimulating factor administration.     

Open stent-grafting using the Matsui-Kitamura stent for a distal arch aneurysm; an idea for insertion of stent graft and organ protection

For the improvement in the clinical results of open stent-grafting, the development of a device system and prevention of spinal cord injury are important. For that reasons, we devised 2 methods for the open stent-grafting with the Matsui-Kitamura (MK) stent. First, the applicator using transesophagial echo transducer cover made insertion of the stent-graft system easy and safe. Next, to prevent ischemic spinal injury and protect major abdominal organ, blood return to lower body was established from femoral artery with occluding the stent graft by balloon. However, these procedures might need to examine whether it really contributes to the improvement in the clinical results.     

Early intervention using high-precision radiotherapy preserved visual function for five consecutive patients with optic nerve sheath meningioma

Background

There has been a paradigm shift in the treatment for optic nerve sheath meningioma (ONSM) from surgery to fractionated stereotactic radiotherapy (FSRT) in other countries. However, FSRT has seldom been performed in Japan. The purpose of this retrospective study is to reconfirm the effectiveness of early intervention with precision radiotherapy for ONSM reported in our previous study.

Methods

Five consecutive patients with ONSM were retrospectively analyzed. All patients underwent intensity-modulated radiotherapy (IMRT) or FSRT. They received the early interventions between 1.5 and 7 months after deterioration of the disease. The median dose was 52.8 Gy (range 46.0–59.4 Gy) and the median number of fractions was 25 (range 22–33).

Results

All patients experienced reestablishment of vision at the median follow-up time of 36 months (range 18–54 months). Four of them noted early improvement of visual deficits during the treatment course (range 2–4 weeks) and the remaining patient improved 3 weeks after completion of IMRT. The median tumor reduction was 53% (range 39–75%). One patient with diabetes mellitus developed retinal bleeding as a result of radiation retinopathy 16 months after IMRT, although the doses were acceptable. The remaining 4 patients have no late toxicity at the follow-up time of 31–54 months.

Conclusions

A paradigm shift is necessary from surgery to early intervention using precision radiotherapy for the treatment of ONSM in Japan.

     

Cell cycle regulation of chromatin binding and nuclear localization of human Cdc7-ASK kinase complex

BACKGROUND: During the course of DNA replication, regulation of cellular localization and chromatin binding of involved factors plays critical roles. Cdc7 kinase is required for DNA replication and its kinase activity is cell cycle-regulated by its activation subunit Dbf4/ASK. In mammals, it is not known at which time point during the cell cycle Cdc7 and Dbf4/ASK proteins are imported into nuclei and loaded on to chromatin. RESULTS: We have constructed a series of truncation and deletion derivatives of ASK and expressed them as fusion proteins with GFP in mammalian cells. Both Dbf4-motif-M and -C conserved in Dbf4/ASK protein family are required for huCdc7 kinase activation. Two stretches of amino acid sequences, NLS1 (P346KKKRIK) and NLS2 (K201RVGSGAQKTRTGRLKK), are important for ASK nuclear localization. In stable transformants expressing GFP-fused full-length ASK under the tetracycline inducible promoter, GFP-ASK protein accumulates in nuclei at the telophase, but its binding to chromatin does not reach a maximum until late G1, whereas huCdc7 is imported into nuclei and binds to chromatin at early G1. An important substrate of Cdc7-ASK at the G1/S transition is likely to be MCM. Indeed, over-expression of both huCdc7 and ASK results in the elevated phosphorylation of endogenous MCM2 protein, as manifested by appearance of the mobility-shifted form on SDS-PAGE, but does not cause any significant effects on cell cycle progression. CONCLUSIONS: Nuclear localization and chromatin binding of endogenous huCdc7 and GFP-ASK expressed during the post-mitotic phase are independently regulated. Although GFP-ASK is presumably imported into nuclei through its two nuclear localization signals at telophase, it may require additional signals for chromatin binding, the level of which increases at late G1 phase.     

Neurogenic stunned myocardium associated with status epileptics and postictal catecholamine surge

A 75-year-old woman developed left ventricular apical ballooning, shortly after recovering from status epileptics. Plasma noradrenaline and adrenaline levels were 2.05 ng/ml and 0.48 ng/ml, respectively. Endomyocardial biopsy disclosed patchy areas of interstitial myocardial fibrosis, atrophy and vacuolization of cardiac myocytes, and some disappearance of myocyte nuclei. Follow-up echocardiography showed that the left ventricular apical ballooning was restored to normal within 25 days. These findings are compatible with neurogenic stunned myocardium. It is important to recognize that patients suffering from intractable seizures may harbor a risk of postictal catecholamine surge and catecholamine-induced myocardial dysfunction.     

In vivo use of the CYP inhibitor 1‐aminobenzotriazole to increase long‐term exposure in mice

1‐Aminobenzotriazole (ABT) is a well‐known in vivo nonspecific inhibitor of cytochrome P450 (CYP) enzymes. An effective dosing regimen of ABT for a multiple‐administration study is needed to conduct pharmacological studies for proof‐of‐concept, although it has been established for single‐administration study, to characterize the pharmacokinetics of drug candidates. This study demonstrated a suitable dosing vehicle of ABT for continuous administration and increased exposure to antipyrine, which is a nonspecific probe of CYP, using ABT for a long period in mice. The dosing vehicle of ABT was 0.5% (w/v) hydroxypropyl methylcellulose and 0.5% (v/v) Tween 80 in N,N‐dimethylacetamide/20% hydroxypropyl‐β‐cyclodextrin aqueous solution (2:8, v/v) based on the duration of apparent solubility. After implantation of an ALZET osmotic pump with ABT, the plasma concentrations of ABT were maintained at more than 4.1 μg/ml over 336 h. Compared with the vehicle group, the CL_tot of antipyrine with ABT decreased to approximately one‐fourth, and the BA of antipyrine with ABT increased up to 3‐fold. In addition, the enhancement of exposure of antipyrine by ABT was maintained over the 336 h. The body weight, food consumption and hematological parameters of mice did not change with ABT administration for 16 days. These findings demonstrated that pretreatment of ABT can increase long‐term exposure using continuous administration with the ALZET osmotic pump in mice with no overt toxicity. It is concluded that the in vivo use of 1‐aminobenzotriazole can be applied to pharmacological studies for proof‐of‐concept, thus contributing to the selection of drug candidates at an early drug discovery stage. Copyright © 2016 John Wiley & Sons, Ltd.     

Effect of prostatic biopsy on free-to-total prostate-specific antigen ratio in patients with prostate cancer

BACKGROUND: We determined the effect of prostatic biopsy on the changes in total and free prostate-specific antigen (PSA) and free-to-total PSA ratio (F/T ratio) and examined if there are differences in these parameters between patients with benign and malignant histologic findings. METHODS: The concentration of total and free PSA and the F/T ratio were determined in 35 men before and 1 h after prostatic biopsy. The level of PSA was measured with a chemiluminescent enzyme assay. Of 35 patients, nine were diagnosed as having prostate cancer. RESULTS: In patients whose biopsy revealed cancer, the F/T ratio was lower than those without cancer, although there were no differences in total and free PSA value before prostatic biopsy. One hour after prostatic biopsy, there was an increase in the level of total and free PSA and the F/T ratio in all men. The increase in the F/T ratio was greater in patients whose biopsies revealed no prostate cancer. In patients with stage B cancer, these parameters increased more than those with stage C/D cancer. CONCLUSION: Prostatic biopsy causes a dramatic increase in total and free PSA. The F/T ratio also increased after biopsy. The PSA response to prostatic biopsy might be different in patients with and without prostatic malignancy. The response might also be different according to stage of prostate cancer.     

Effect of the active adult learning/patient oriented clerkship on affective reaction of students ∼ from the results of student survey

We have previously reported the efficacy of the Patient Oriented Clerkship (POC) in the clinical clerkship in Showa University Hospitals, by a trial with old four-year pharmacy program students. In the unique clerkship, each student has a patient in charge, and follows his/her clinical conditions throughout the rotation. The aim of the POC is that having the students learn spontaneously (Active Learning) and actively (Adult Learning) promoted by student's commitment and responsibility by communicating with patients and health professionals in a team. As the POC requires students both Active Learning and Adult Learning, we define the POC as Active Adult Learning (AAL). Having a patient in charge for each student gives them many opportunities to participate in the medical team and foster their problem solving skills. Our previous study eventually showed positive results of the POC in the one-month short clerkship in the four-year program. On the other hand, the effect of the unique hospital clerkship in the new six-year program is not known. We conducted a student survey to clarify the learning effect in the new six-year education system which was revised and 2.5 month clinical clerkship was scheduled according to the model core clerkship curriculum. This report is the first report to show a challenge of the AAL/POC clerkship in the new six-year pharmacy education program.