Gonadal Influence on the Toxicity of 2-(2′-Hydroxy-3′,5′-di-tert-butylphenyl) benzotriazole in Rats

Previously, we showed that susceptibility of male rats to the toxicity of an ultraviolet absorber, 2-(2′-hydroxy-3′,5′-di-tert-butylphenyl)benzotriazole (HDBB), was nearly 25 times higher than that of females. In the current study, we investigated the role of sex steroids in the mediation of the gender-related difference using castrated rats. Male and female castrated CD(SD) rats were given HDBB by gavage at 0, 0.5, 2.5, or 12.5 mg/kg/day for 28 days. No deaths, clinical signs of toxicity, or changes in body weight or food consumption were found at any doses. Blood biochemical changes suggestive of hepatic damage, such as increased levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase, were detected at 12.5 mg/kg/day in males. Absolute and relative liver weight increased at 0.5 mg/kg/day and above in males and at 12.5 mg/kg/day in females. In the liver, histopathological changes, such as nucleolar enlargement, increased mitosis, hypertrophy in hepatocytes, and/or focal necrosis were observed at 0.5 mg/kg/day and above in males, and at 2.5 mg/kg/day and above in females. These findings indicate that castration markedly reduced the gender-related differences in toxicity of HDBB in rats.     

Immunohistochemical analysis of RTKs expression identified HER3 as a prognostic indicator of gastric cancer

Standard treatment in Japan for the 13th Japanese Gastric Cancer Association stage II/III advanced gastric cancer is postoperative adjuvant S‐1 administration after curative surgery. High expression of receptor type tyrosine kinases (RTKs) has repeatedly represented poor prognosis for cancers. However it has not been demonstrated whether RTKs have prognostic relevance for stage II/III gastric cancer with standard treatment. Tumor tissues were obtained from 167 stage II/III advanced gastric cancer patients who underwent curative surgery and received postoperative S‐1 chemotherapy from 2000 to 2010. Expression of the RTKs including EGFR, HER2, HER3, IGF‐1R, and EphA2 was analyzed using immunohistochemistry (IHC). Analysis using a multivariate proportional hazard model identified the most significant RTKs that represented independent prognostic relevance. When tumor HER3 expression was classified into IHC 1+/2+ (n = 98) and IHC 0 (n = 69), the cumulative 5‐year Relapse Free Survival (5y‐RFS) was 56.5 and 82.9%, respectively (P = 0.0034). Significant prognostic relevance was similarly confirmed for IGF‐1R (P = 0.014), and EGFR (P = 0.030), but not for EphA2 or HER2 expression. Intriguingly, HER3 expression was closely correlated with IGF‐1R (P < 0.0001, R = 0.41), and EphA2 (P < 0.0001, R = 0.34) expression. Multivariate proportional hazard model analysis identified HER3 (IHC 1+/2+) (HR; 1.53, 95% CI, 1.11–2.16, P = 0.0078) as the sole RTK that was a poor prognostic factor independent of stage. Of the 53 patients who recurred, 40 patients (75.5%) were HER3‐positive. Thus, of the RTKs studied, HER3 was the only RTK identified as an independent prognostic indicator of stage II/III advanced gastric cancer with standard treatment.     

Significance of lymph node metastasis in pancreatic neuroendocrine tumor

Purpose

Pancreatic neuroendocrine tumor (PNET) is relatively rare and has a generally better prognosis than does pancreatic cancer. However, as its prognosis in patients with lymph node metastasis (LNM) is unclear, lymph node dissection for PNET is controversial. Our study aimed to clarify the significance of LNM in PNET.

Methods

We retrospectively examined 83 PNET patients who underwent pancreatic resections with lymph node dissection at Kumamoto University Hospital, Saiseikai Kumamoto Hospital, and Kumamoto Regional Medical Center from April 2001 to December 2014. Their clinicopathological parameters were analyzed by the absence or presence of LNM, and with regard to the disease-free survival (DFS) and overall survival (OS). A predictive score of LNM was also made using the age, tumor size, primary tumor location, and tumor function.

Results

Although the 5-year OS was 74.8% for LNM⁺ and 94.6% for LNM^? (P?=?0.002), LNM was not an independent risk factor for the OS in a multivariate analysis. However, tumors larger than 1.8 cm were found to be an independent prognostic factor, and the cut-off value for the predictive score was 1.69.

Conclusions

Although LNM was not an independent prognostic factor, lymph node dissection is recommended for patients whose predictive score is larger than 1.69.

     

Review of testicular toxicity of dinitrophenolic compounds, 2-sec-butyl-4,6-dinitrophenol, 4,6-dinitro-o-cresol and 2,4-dinitrophenol

The present review paper summarizes the data available in the literature concerning dinitrophenolic compounds and evaluates male reproductive toxicity in experimental animals. Gavage and feeding doses of 2-sec-butyl-4,6-dinitrophenol (dinoseb; CAS No. 88-85-7) manifested testicular toxicity, and 4,6-dinitro-o-cresol (DNOC; CAS No. 534-52-1) showed similar but weaker testicular toxicity in laboratory animals. Consecutive doses of dinoseb and DNOC by gavage seemed to induce spermatotoxicity by disturbing spermiogenesis or the maturation process of sperm in the epididymis, and the most probable target cells of spermatotoxicity were thought to be testicular spermatids in rats. Prolonged exposure to dinoseb and DNOC in the diet also induced testicular toxicity in rats. However, the feeding dose of dinoseb irreversibly affected the early stage of spermatogenesis and produced infertility in rats. On the other hand, 2,4-dinitrophenol (DNP; CAS No. 51-28-5) did not show testicular toxicity in laboratory animals according to available literature. Further studies in laboratory animals with nitrophenolic compounds are required for clarification of their testicular toxicity and for risk assessment in humans.     

Reproductive and developmental toxicity screening test of tetrahydrofurfuryl alcohol in rats

Twelve male and female rats per group were given tetrahydrofurfuryl alcohol (THFA) by gavage at 0, 15, 50, 150 or 500 mg/kg/day. Males were dosed for 47 days, beginning 14 days before mating, and females were dosed for 42–52 days beginning 14 days before mating to day 4 of lactation throughout the mating and gestation period. Changes in locomotor activity, inhibition of body weight gain, and/or histopathological changes in the thymus, spleen, testes and/or epididymides were observed in males and females at 150 mg/kg and above. No effects of THFA were found on the copulation index, fertility index, or the number of corpora lutea and implantations in pregnant females. At 500 mg/kg, no pregnant females delivered any pups. At 150 mg/kg, gestation length was prolonged, and the total number of pups born and the number of live pups on postnatal days 0 and 4 was markedly decreased. No effects of THFA were found on the sex ratio and body weight of live pups, or the incidence of pups with malformations or variations. Based on these findings, the NOAELs for parental and reproductive/developmental toxicity of THFA were concluded to be 50 mg/kg/day in rats.     

Which questionnaires should we use to evaluate quality of life in patients with chronic graft-vs-host disease?

AimTo investigate the ability of two standard quality of life (QOL) questionnaires – The Short Form (36-item) Health Survey (SF-36) and The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ C30) to evaluate QOL in patients with chronic graft-vs-host disease (cGVHD) graded according to National Institutes of Health (NIH) consensus criteria.MethodsIn this cross-sectional study, QOL was assessed in patients who underwent allogeneic stem cell transplantation (allo-SCT) at the University Hospital Centre Zagreb and were alive and in complete remission for more than one year after allo-SCT.ResultsThe study included 58 patients, 38 patients with cGVHD and 20 controls, patients without cGVHD. Patients with cGVHD scored according to the NIH criteria had significantly lower scores of global health status and lower QOL on all SF-36 subscales and most of QLQ C30 functional subscales (P < 0.050 for all comparisons). Furthermore, patients with active cGVHD had significantly lower QOL scores than patients with inactive cGVHD, and this difference was most evident in physical functioning subscale of SF-36 (P = 0.0007) and social functioning subscale of QLQ C30 (P = 0.009).ConclusioncGVHD scored according to the NIH criteria is correlated with patient-reported QOL, particularly in the physical domains as detected by SF-36. QLQ C30 questionnaire adds more information on social functioning and should be used as a valuable tool in the evaluation of social domains in cGVHD patients.Although it is potentially lifesaving for a variety of hematological malignant and non-malignant disorders, allogeneic stem cell transplantation (allo-SCT) carries a significant risk of acute and late post-transplant complications. Improvements in transplantation techniques and supportive care have resulted in a reduction of early transplant-related mortality (1,2). However, the burden of late complications remains high, and two thirds of long-term allo-SCT survivors experience at least one chronic health condition (3). These complications occur due to treatment exposures before and during allo-SCT, cause substantial mortality, and severely impair patients’ functional status and quality of life (QOL). This is why today the aim of the treatment is not just to cure the primary hematological disease, but to facilitate the recovery of the physical and emotional functioning and improve QOL and social reintegration in family and work environment.Health-related QOL is now considered to be one of the relevant treatment outcomes because it provides a broader understanding of the patient’s status beyond simple disease-free survival. It is a multi-dimensional construct comprised of several related domains including physical, emotional, social, and role functioning, as well as a person''s overall evaluation of his or her well-being and ability to function (4,5). Better understanding of QOL in long-term survivors is necessary to provide adapted pre-transplant counseling and recommendations for post-transplant follow-up.With a cumulative incidence of 40%-70% and significant mortality, chronic GVHD (cGVHD) represents the most important late complication following allo-SCT (6,7). Moreover, it seems that the incidence of cGVHD in the recent years has been increasing, probably due to the fact that much older patients undergo allo-SCT, as well as due to the increased use of peripheral blood stem cell grafts and matched unrelated donors, all known risk factors for cGVHD (8). In a series of publications originating from 2005 National Institutes of Health (NIH) Consensus Conference, investigators proposed means to standardize diagnosis, scoring, histopathology, biomarkers, response assessment, and research in cGVHD (9-14). These criteria were developed to advance clinical trials and consequently improve the management of cGVHD and long-term survivorship after allo-SCT.As one of the important treatment outcomes, QOL is increasingly being subjected to the same degree of rigorous study as other significant allo-SCT outcomes. Most of the studies so far have reported a negative, significant association between cGVHD and QOL after allo-SCT (15-20). However, some of the studies have found no association (21-25), and this relationship still needs to be elucidated. The awareness of the relationship between QOL and cGVHD is necessary to further facilitate the prevention and treatment of cGVHD.The aim of this study was to examine the effect of cGVHD on QOL in our cohort of long-term allo-SCT survivors with the use of two standard QOL questionnaires; The Short Form (36-item) Health Survey (SF-36) and The EORTC Quality of Life Questionnaire (QLQ C30). Furthermore, we assessed QOL according to cGVHD severity and activity defined by the NIH consensus criteria.     

Unique muscularity in cyclists' thigh and trunk: A cross‐sectional and longitudinal study

This study examined the influence of regular training in competitive cycling on individual muscle volume of the thigh and psoas major cross‐sectionally and longitudinally. T1‐weighted magnetic resonance (MR) images of the trunk and right thigh were obtained from eight experienced varsity male cyclists (experience: > 4 years) and 10 untrained men (experiment 1), and from 12 (10 males, two females) varsity cyclists before and after competitive cycling training for 6 months (experiment 2). From the MR images, the volumes of each of the quadriceps femoris and hamstrings, total adductors, gracilis, sartorius, and psoas major were determined. The volumes of the monoarticular thigh muscles, semitendinosus, and psoas major muscles were significantly greater in the experienced cyclists than in the untrained men (experiment 1), and increased significantly after the competitive training for 6 months (experiment 2). In contrast, the volumes of the other biarticular thigh muscles were similar among the experienced cyclists and untrained men (experiment 1), and did not change by competitive cycling training (experiment 2). The results indicate that competitive cycling training induces muscle‐specific hypertrophy of the synergistic muscles, especially between the monoarticular and biarticular muscles, leading to quantitative profiles of the musculature in experienced cyclists.     

Formulation of nimodipine nanocrystals for oral administration

The aim of this paper is to optimize nimodipine (NMD) nanocrystals (NCs) for oral administration. The effects of independent process variables (microprecipitation temperature, shearing speed, shearing time, homogenization pressure and number of cycles) on the particle size have been studied. Experiments were conducted to optimize the formulation composition. A single factor exploration was used to screen the primary stabilizers. Then, the selected polymers/surfactants were further optimized using an L9 (3⁴) orthogonal design. The optimal formulation was composed of NMD (0.7 %, w/v), F127 (0.4 %, w/v), HPMC-E5 (0.1 %, w/v), and sodium deoxycholate (0.05 %, w/v) and was rod-shaped as shown by SEM observations, and it had a particle size of 833.3 ± 20.6 nm, determined by laser diffraction. These aqueous NCs were physically stable for 15 days. To further improve the stability, the NCs were freeze-dried. The powder obtained exhibited acceptable flowability and was physically stable for at least 24 months. Additionally, the NMD NCs displayed much higher dissolution profiles than the bulk drug. The pharmacokinetic results showed that the relative bioavailability was 397 % in comparison with Nimotop^®, suggesting that NCs are an efficient strategy for improving the oral bioavailability of poorly water-soluble drugs.     

Extranodal rosai-dorfman disease presenting as incidental bone tumor: a case report

We report a case of primary extranodal Rosai-Dorfman disease presenting as a painless lesion in the left ilium of a 71-year-old African-American man.