Radioresponse of Thymomas Verified with Histologic Response

Patterns of radiologic response of 10 thymomas treated by preoperative radiotherapy (RT) (18-20 Gy/2 weeks) were determined in conjunction with histologic response. Changes in tumor volume were evaluated with CT scans obtained 5 to 36 days before and 14 to 24 days after the initiation of RT and before surgery. The extent of tumor volume reduction (TR) varied widely (40-78%), while the mean daily volume decrement expressed as a percentage of the pre-RT tumor volume correlated significantly with the pre-RT tumor volume. Histologically, the tumors, all of which were resected 17 to 33 days after RT initiation, generally consisted of predominant fibrous tissues, rare necrotic foci, and few epithelial cells. The TR did not correlate with pre-RT tumor volume, observation period, histologic subtype, or quantity of remaining epithelial cells. The TR of thymomas does not predict RT impact on tumor cells but does reflect the quantity of inherent tumor stroma.     

Prediction of carboplatin clearance calculated by patient characteristics or 24-hour creatinine clearance: a comparison of the performance of three formulae

Purpose: Carboplatin doses can be individualized using the formula of Calvert et al. (Calvert formula) dose (mg) = area under the plasma concentration versus time curve (AUC) · [glomerular filtration rate (GFR) + 25]. Creatinine clearance (Ccr), either measured by the 24-h method or calculated by the formula of Cockcroft and Gault [Cockcroft-Gault (CG) formula], is often substituted for the GFR. The CG formula is based on patient weight, age and sex, and the serum creatinine (Cr) concentration. Another method for predicting carboplatin clearance (CL) using patient characteristics has also been proposed by Chatelut et al. (Chatelut formula). This study was undertaken to evaluate the performance of the three formulae in predicting standard- and low-dose carboplatin pharmacokinetics. Methods: A total of 52 patients with advanced lung cancer were enrolled in this pharmacokinetic study; 37 received standard-dose carboplatin and 25 received low-dose carboplatin. The Cr concentration was measured using an enzymatic assay. The three formulae were used to predict carboplatin CL. The median absolute percent error (MAPE) for each formula was evaluated by comparing the calculated and observed CL. For comparison of AUCs, free platinum plasma concentrations were measured at intervals up to 24 h after carboplatin administration. AUCs were determined and compared with predicted values. Results: In the standard-dose carboplatin group, the MAPEs for the prediction of carboplatin CL from the 24-h Calvert, CG-Calvert and Chatelut formulae were 13%, 12% and 23%, respectively. In the low-dose carboplatin group, the corresponding MAPEs were 27%, 18% and 44%, respectively. Observed standard-dose carboplatin AUCs after aiming for target AUCs of 5 and 6 mg · min/ml using the Calvert formula based upon the 24-h Ccr were 5.3 ± 0.8 and 5.9 ± 0.8, respectively, indicating a small and acceptable bias compared with that predicted from the dosing formula. Conclusions: The pharmacokinetics of standard-dose carboplatin were accurately predicted by the Calvert formula based upon either 24-h or CG-calculated Ccr, but not by the Chatelut formula. Either CG-calculated or 24-h Ccr can be substituted for the GFR in the Calvert formula for the determination of individual doses. The poor predictability of the Chatelut formula found in this study might be the result of a differences in either the Cr assay or the patient population. Therefore, formulae which attempt to estimate GFR are not necessarily valid if either the Cr assay or the patient population is changed. Received: 23 July 1997 / Accepted: 16 December 1997     

Sequence Analysis of Genes Encoding Rodent Homologues of the Human Tumor-rejection Antigen SART-1

Human SART-1 ( hSART-1 ) gene encodes a 125 kD protein with a leucine-zipper motif expressed in the nucleus of all proliferating cells, and a 43 kD protein expressed in the cytosol of most epithelial cancers. In this study, two rodent genes ( rSART-1 and mSART-1 ) homologous to hSART-1 were cloned from cDNA libraries of murine brain and a rat tumor cell line, respectively. mSART-1 and rSART-1 were highly homologous to hSART-1 with 86% and 84% identity at the nucleotide level, and 95% and 91% at the protein level, respectively. The leucine zipper domain and two basic amino acid portions that bind DNA, as well as peptide sequences recognized by human cyto-toxic T lymphocytes (CTLs), were all conserved in these rodent genes. Nuclear protein homologous to the 125 kD hSART-1₈₀₀ protein, but not to the 43 kD cytosol SART-1₂₅₉ protein, was detectable with specific antibody in the nuclear fractions of rodent tumor cell lines, and normal rodent fetal liver and testis. These rodent genes should be a novel tool for studies on the biological roles of the SART-1 gene, and also in the construction of animal models of specific immuno-therapy using SART-1 gene products.     

Mutational Analysis of Androgen Receptor (AR) Gene in 46,XY Patients with Ambiguous Genitalia and Normal Testosterone Secretion: Endocrinological Characteristics of Three Patients with AR Gene Mutations

The prevalence of abnormalities in androgen receptor gene (AR) among patients with ambiguous genitalia is unknown. Moreover, endocrinological data from prepubertal patients with AR mutation are very limited. Thus, the aim of this study was to examine the prevalence of abnormalities in AR among patients with both ambiguous genitalia, which was defined as a combination of two or more genital abnormalities (i.e. hypospadias, microphallus (penile length < 25 mm), hypoplastic scrotum, bifid scrotum, undescended testis) in this study, and normal to elevated T levels. We also compared the endocrinological data of prepubertal patients with AR mutation and ambiguous genitalia with that of those without the AR mutation. We screened 26 Japanese prepubertal 46,XY patients (five from three families were included) with both ambiguous genitalia and normal to elevated T levels. Mutations in AR were found in three (two of the three were related). Among the 23 patients without mutation in AR, the steroid 5-alpha-reductase 2 gene (SRD5A2) was also examined in eight patients with elevated T/dehydrotestosterone ratio after the hCG (>10) or with undervirilized family members. No mutation in SRD5A2 was found. Characteristics of the three patients with mutation in AR were compared with the 23 patients without mutation. In two patients, basal T levels (0.3, 0.2 ng/ml) and peak T levels after the hCG tests (8.3, 8.5 ng/ml) tended to be higher, and the peak LH/ peak FSH ratios after the GnRH tests (4.6, 4.0) were higher than in patients without mutation, at the ages of 1 yr and 9 mo and 3 yr and 8 mo, respectively. In conclusion, an abnormality in either AR or SRD5A2 was not common among patients with ambiguous genitalia and normal testosterone secretion. Elevated peak LH/peak FSH ratio (≥4) after the GnRH test in addition to detectable basal T levels and elevated peak T levels after the hCG test may infer AR abnormality in prepubertal patients with ambiguous genitalia at the age of one and over, although further study is needed, because our data were limited.     

Fetal alcohol spectrum disorders (FASD) among Japanese children of alcoholic mothers]

OBJECTIVE: This study was carried out to examine fetal alcohol spectrum disorders (FASD) among Japanese children of alcoholic mothers. This is the first report concerning FASD in Japan. METHODS: The subjects were 30 alcoholic women who were inpatients in the Kurihama Alcoholism Center and had given birth to children. They were subjected to a semi-structured interview by the author. Sixty healthy women who had not drunk during pregnancy were used as a control group, and they also underwent semi-structured interviews. The alcoholic women were divided into two groups, 13 who drunk during pregnancies and 17 who did not drink. Twenty children experienced of prenatal alcohol exposure and 40 children did not. The three groups; i.e., 13 alcoholic mothers who had drunk during pregnancy and their 20 children (ALD group), 17 alcoholic mothers who had not drunk during pregnancy and their 40 children (ALND group) and 60 non-alcoholic control mothers and their 80 children (Control group), were compared concerning the mothers' drinking problems and abnormal deliveries, children's birth weights, congenital abnormalities, abnormalities of the central nervous system and psychological problems. RESULTS: The mean age of onset of problem drinking of the mothers in the ALD group was significantly lower than that in the mothers of the ALND group, and some of the mothers in the ALD group showed alcohol dependence before their pregnancies. The mean birth weights of the children of the ALD group, ALND group and Control group were 2816 g, 3128 g and 3142 g, respectively and the differences were significant. The children of the ALD group had significantly more abnormal birth episodes, developmental retardation and psychiatric symptoms than those in the other two groups. Among 20 children in the ALD group, FASD was suspected in 6 children (10% of the children of alcoholic mothers). Six children had low birth weights, abnormal birth episodes, mental retardation and psychiatric symptoms. CONCLUSION: One third of the Japanese children of alcoholic mothers had experiences of prenatal alcohol exposure and 10% of them had suspected FASD abnormalities.     

Gastric adenosquamous carcinoma producing granulocyte-colony stimulating factor

We report a case of adenosquamous carcinoma of the stomach that produced granulocyte-colony stimulating factor (G-CSF). The patient, who had an admission diagnosis of advanced gastric cancer, had marked leukocytosis without evidence of infection. After leukemia and metastatic leukemoid reaction were excluded by bone marrow examination, a G-CSF-producing cancer was suspected as the cause of the abnormally elevated serum G-CSF level. The resected stomach tumor was histologically diagnosed as adenosquamous carcinoma; positive expression of G-CSF by tumor cells was shown with immunohistochemical detection, which confirmed the preoperative diagnosis. Recurrent disease in the liver and lymph nodes, accompanied by leukocytosis and re-elevation of serum G-CSF, developed just 3 months after the curative gastrectomy and adjuvant chemotherapy. All of the recurrent disease was resected, restoring normal levels of serum G-CSF. The patient survived for almost 2 years after the initial surgery with extensive chemotherapy, including weekly treatment with paclitaxel, before finally succumbing to liver failure secondary to extensive liver metastasis.     

Highly sensitive detection of melanoma at an early stage based on the increased serum secreted protein acidic and rich in cysteine and glypican-3 levels.

PURPOSE: There are no available tumor markers detecting primary melanoma at an early stage. The identification of such serum markers would be of significant benefit for an early diagnosis of melanoma. We recently identified glypican-3 (GPC3) as a novel tumor marker but could diagnose only 40% of melanomas. Thereby, we focused out attention on secreted protein acidic and rich in cysteine (SPARC) overexpressed in melanoma as another candidate for tumor marker. EXPERIMENTAL DESIGN: Secreted SPARC protein was quantified using ELISA in the sera from 109 melanoma patients, five patients with large congenital melanocytic nevus, 61 age-matched healthy donors, and 13 disease-free patients after undergoing a surgical removal. We also quantified GPC3 and 5-S-cysteinyldopa in the same serum samples and compared these markers for their diagnostic value. RESULTS: The serum SPARC concentrations in melanoma patients were greater than those in healthy donors (P = 0.001). When we fixed a cutoff value at the mean concentration plus 2 SD of the healthy donors, the serum SPARC was found to have increased in the sera of 36 of the 109 (33%) melanoma patients, whereas there were three (4.9%) false-positive cases of 61 healthy donors. Surprisingly, 19 of 36 patients showing increased SPARC levels were in stages 0 to II. The serum SPARC level decreased under the cutoff level in 10 of 13 patients after surgical removal. Using SPARC and GPC3 in combination thus enabled us to diagnose 47 of 75 (66.2%) melanoma patients at an early stage (0-II). CONCLUSIONS: SPARC or its combination with GPC3 is thus considered a potentially useful tumor marker, especially for melanoma at an early stage.     

Pharmacodynamic evaluation of meropenem,cefepime, or aztreonam combined with a novel β-lactamase inhibitor,nacubactam, against carbapenem-resistant and/or carbapenemase-producing Klebsiella pneumoniae and Escherichia coli using a murine thigh-infection model

BackgroundCarbapenem-resistant Enterobacterales (CRE) and carbapenemase-producing Enterobacterales (CPE) are difficult to treat and are a serious public health threat. Nacubactam (NAC) is a novel non-β-lactam diazabicyclooctane β-lactamase inhibitor with in vitro activity against some Enterobacterales expressing classes of β-lactamases.MethodsThe antimicrobial efficacy of meropenem (MEM), cefepime (FEP), and aztreonam (ATM), each in combination with NAC, were assessed in vitro and in vivo against Klebsiella pneumoniae and Escherichia coli. Ten isolates, including CRE and/or CPE with β-lactamase genes, were used in this study. The relationship between phenotype and in vivo efficacy was assessed in a murine neutropenic thigh-infection model. Efficacy was determined by the change in bacterial quantity.ResultsThe results of the in vitro study showed the minimum inhibitory concentrations of the combination of NAC with either MEM, FEP, or ATM in a 1:1 ratio were 2 to >128-fold lower than those of MEM, FEP, or ATM alone against CRE+ isolates. In addition, combinations of β-lactams and NAC administered in the murine thigh-infection model showed greater efficacy against CRE+/CPE+, CRE+/CPE-, and CRE-/CPE+ isolates harboring various β-lactamase genes (IMP-1, IMP-6, KPC, DHA-1, or OXA-48) compared with MEM, FEP, ATM, and NAC alone.ConclusionMEM, FEP, or ATM in combination with NAC showed potent in vivo antimicrobial activity in a murine thigh-infection model caused by K. pneumoniae and E. coli, including CRE and/or CPE isolates. These findings indicate that these combinations of β-lactams and NAC are potential candidates for the treatment of CRE and/or CPE infections.     

Staphylococcal enterotoxin B is involved in aggravation and recurrence of murine experimental autoimmune uveoretinitis via Vβ8CD4 T cells

Endogenous uveitis is a common cause of visual disability and blindness. The etiology of uveitis remains largely unknown but reasonable etiologic factors include infections. Superantigens are regarded as one of the leading causes of infectious etiology in autoimmune disease. However, the role of superantigens in uveitis remains unclear. In the present study, we investigated the effect of Staphylococcal enterotoxin B (SEB), a member of the superantigens, using an experimental model of autoimmune uveoretinitis (EAU). C57BL/6 mice were immunized with human interphotoreceptor retinoid binding protein (IRBP) peptide, and the severity of EAU disease was scored. Vehicle (PBS) alone or SEB dissolved in PBS was administered by intravenous injection on post-immunization day 10 or on post-immunization day 24. In addition, a systemic immune response study was performed to address the effects of SEB on systemic immunity. EAU was aggravated significantly by the injection of SEB at post-immunization day 10. Furthermore, relapse was induced by the injection of SEB at day 24. On the other hand, SEB injection without IRBP peptide immunization elicited no inflammatory changes in the uvea or retina. Furthermore, SEB enhanced not only the IRBP-specific T-cell proliferative responses but also IFN-γ and IL-17 production. Moreover, the intraocular expression levels of these cytokines was also enhanced by SEB injection. Both anti-CD4 and -Vβ8 Ab administration suppressed disease aggravation and the enhancement of IRBP-specific T-cell responses caused by SEB. These results suggest that SEB is involved significantly in the aggravation or recurrence of endogenous uveitis through activation of autoreactive uveitogenic T cells.