Investigation of optimal schedule of concurrent radiotherapy with S-1 for oral squamous cell carcinoma

In the present study, we examined the appropriate schedule of S-1 medication in the combination with radiation by investigating the safety, the clinical efficacy, and antitumor effects on tumors in nude mice. In the patients with oral squamous cell carcinoma (OSCC), S-1 was given orally according to a 4-week application followed by 2-week rest regimen (4-week regimen), or a 2-week application followed by a 1-week rest regimen (2-week regimen). Radiation was given (2 Gy/day; 5 days/week) for a total of 60 Gy. In nude mouse models, human oral cancer cell lines were used as subcutaneous xenografts in nude mice. The mice were treated by S-1 (10 mg/kg) and radiation (1 Gy) with a 4-week regimen or a 2-week regimen. Apoptotic cells were detected by TUNEL method. In the patients with OSCC, the response rate with the 4-week regimen was 100% and the response rate with the 2-week regimen was 92.3%. However, a high frequency of adverse effect was found in the 4-week regimen when compared to the 2-week regimen. Grade 3 toxicity of leukopenia, neutropenia and stomatitis were seen in 3 cases, grade 3 toxicity of anorexia and nausea were seen in 2 cases, and grade 3 toxicity of decrease of hemoglobin level, heartburn/dyspepsia and increase of bilirubin level were seen in a case of the 4-week regimen. On the other hand, grade 3 toxicity of stomatitis, anorexia, nausea, heartburn/dyspepsia and increase of bilirubin level were seen in a case of the 2-week regimen. In nude mouse models, the 2-week regimen was more effective than the 4-week regimen. In addition, significant increase in the percentage of apoptotic cells was observed in the tumors treated with the 4-week regimen when compared with the tumors treated with the 2-week regimen. No loss of body weight was observed in mice treated with the 2-week regimen during the experimental period. These results suggested that the 2-week regimen might reduce adverse effects, and enhance therapeutic effects compared to the 4-week regimen. Briefly, this 2-week regimen may be a useful concurrent chemo-radiotherapy improving the quality of life (QOL) of patients with OSCC.     

An antisense oligonucleotide to HSP47 inhibits paraquat-induced pulmonary fibrosis in rats

The most common cause of death from poisoning by the widely used, but highly toxic herbicide paraquat is respiratory failure from pulmonary fibrosis, which develops through pathological overproduction of extracellular matrix proteins such as the collagens. Heat shock protein (HSP47) is a collagen-specific molecular chaperone that assists in the posttranslational modifications of procollagens during collagen biosynthesis. We investigated whether treatment with an HSP47-antisense oligonucleotide would inhibit paraquat-induced pulmonary fibrosis in Wistar rats. Rats randomized into three groups (control, paraquat, and paraquat+antisense). Paraquat (20 mg/kg/day) (n=16) or a saline control (n=10) was administered to groups of Wistar rats. Intratracheal administration of the antisense oligonucleotide (100 nmol/kg in saline) was performed after the initial paraquat treatment (n=16). Treatment with paraquat alone induced pulmonary fibrosis in the entire group, while treatment with the antisense oligonucleotide alone did not produce any substantial change in lung histology. Administration of antisense oligonucleotides produced a substantial reduction in paraquat-induced pulmonary fibrosis. An immunoblot analysis confirmed that the HSP47-antisense oligonucleotide inhibited HSP47 production. These findings indicate that the HSP47-antisense oligonucleotide inhibited paraquat-induced pulmonary fibrosis and pneumopathy in rats.     

N-terminus of Etanercept is Proteolytically Processed by Dipeptidyl Peptidase-4

Pharmaceutical Research - Biologics are structurally heterogeneous and can undergo biotransformation in the body. Etanercept (ETN) is a fusion protein composed of a soluble tumor necrosis factor...     

Reversible altered consciousness with brain atrophy caused by valproic acid

A 5-year-old female developed alteration of consciousness during 3 days of long-term treatment with valproic acid for localization-related epilepsy. Computed tomography revealed cerebral atrophy, and electroencephalography presented slow background activity. Consciousness cleared only 12 hours after valproic acid was discontinued, and normal electroencephalography results were evident 1 week later. Cerebral atrophy was nonexistent 2 months later. This rapidly developing but reversible alteration of consciousness in parallel with brain atrophy is recognized as a rare idiosyncratic adverse effect of valproic acid.     

Cortical myoclonus in children

Cortical myoclonus is a distinct clinical condition that can be defined electrophysiologically, and occurs in both children and adults. It is well known that patients sometimes exhibit stimulus-sensitive jerks and giant somatosensory-evoked potentials (SEPs). In contrast, imaging abnormalities are less prominent in many patients. Reports focusing on cortical myoclonus, except for epilepsia partialis continua, in childhood have been limited in Japan. One reason for this could be that Japanese pediatric neurologists are not familiar with the backaveraging technique. We describe the clinical and physiological features of cortical myoclonus in ten children. Routine EEG, EEG backaveraging, SEP measurement, CT/MRI (computed tomography/magnetic resonance imaging), and TMS (transcranial magnetic stimulation) were performed. All patients exhibited clear evidence of cortical myoclonus. In six patients, backaveraging was necessary since spikes were absent on routine EEG. A cortical source of the myoclonus was further supported by a TMS study performed on four patients. The etiologies of the myoclonus were diverse, cerebrovascular disease being the most common (three patients). Stimulus-sensitive or action-induced jerks were observed in three patients. Cortical SEPs were enlarged in one patient, and reduced or absent in six. Lesions were found on CT/MRI in nine patients, in five of whom the margin of the lesion was within, or adjacent to, the sensorimotor cortex. Complete destruction of the sensorimotor cortex was not observed. It was suggested that cortical neurons in the vicinity of a lesion, rather than in the lesion itself, play a role in the generation of focal myoclonus.     

An autopsy case of ornithine transcarbamylase deficiency

We present an autopsy case of ornithine transcarbamylase (OTC) deficiency with grumose degeneration in the dentate nucleus of the cerebellum. The patient had intractable neonatal convulsions and hyperammonemia from the 3rd day after birth. Diagnosis of OTC deficiency was made based on null activity of the enzyme and four-base deletions in exon 9 of the OTC gene. Death was due to sepsis as well as disseminated intravascular coagulation at 1 year and 2 months of age. Neuropathology showed multiple cystic changes and ulegyria in the bilateral frontal and parietal lobes. Multiple cysts were associated with the region, which was infiltrated with macrophages surrounded by astroglia showing palisading pattern. Ferrugination was marked in the thalamus and severe neuronal loss with astrogliotic change in the CA1-2 area of the hippocampus. Grumose degeneration was noted in the dentate nucleus of the cerebellum. This is the first report of grumose degeneration in OTC deficiency.     

Alterations of immune functions in barrier disrupted skin by UVB irradiation

BACKGROUND: While immunologic events elicited by acute barrier disruption or UVB irradiation have been studied in detail, the biological sequel of multiple insults to the skin is not well understood. OBJECTIVE: Since the skin would receive a variety of simultaneous stimuli in daily life, we tested the effects of sequential treatments with barrier disruption and UVB exposure on skin immunity. METHODS: Earlobes of BALB/c mice received tape-stripping and subsequently low-dose UVB exposure. Control mice were treated with either tape-stripping or UVB. The expression of surface markers and cytokine production in Langerhans cells and keratinocytes and the elicitation response of contact hypersensitivity were compared. RESULTS: By flow cytometry, tape-stripping augmented the expression of MHC class II, CD54, CD80, CD86 and CD40 on Langerhans cells, whereas UVB decreased the expression of some of these molecules. Combination of tape-stripping and UVB induced largely intermediate levels between these two. Upon stimulation with L cells expressing CD40L, Langerhans cells from tape-stripped and UVB-irradiated earlobes strongly transcribed mRNA for interleukin-1beta compared to each treatment. In keratinocytes, tape-stripping or UVB slightly upregulated tumor necrosis factor-alpha and interleukin-1alpha production at both mRNA and protein levels, whereas these two treatments synergistically increased the production of these cytokines. The in vitro hapten-presenting ability of Langerhans cells to trinitrophenyl-immune lymph node T cells ranked first in tape-stripping, second in tape-stripping plus UVB and third in UVB, and so did the intensity of elicitation responses in contact hypersensitivity to a hapten, picryl chloride. CONCLUSION: It is suggested that barrier disruption and UVB antagonize with each other in contact hypersensitivity as a reflection of their effects on Langerhans cell antigen-presenting function, but they synergize in cytokine production by both Langerhans cells and keratinocytes.     

Bucillamine-induced toxic epidermal necrolysis and fixed drug eruption

We report two cases of bucillamine-induced bullous reactions with keratinocyte necrosis. The first patient, a 27-year-old woman, developed toxic epidermal necrolysis (TEN) over her whole body after taking bucillamine 300 mg/day for seven days. The second patient, a 63-year-old woman, developed several bullous erythemas on the mucous membranes and legs after taking bucillamine for more than two years. The fixed drug eruptions were diagnosed based on a provocation test in addition to clinical and histopathologic findings. These cases highlight the importance of considering fixed drug eruption as well as TEN in the differential diagnosis of bucillamine-induced bullous drug eruption.