Gefitinib induction followed by chemoradiotherapy in EGFR-mutant, locally advanced non-small-cell lung cancer: LOGIK0902/OLCSG0905 phase II study.

BACKGROUND: The role of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) induction coupled with standard concurrent chemoradiotherapy (CRT) is unclear in unresectable, stage III, EGFR-mutant non-small-cell lung cancer (NSCLC). Therefore, a phase II trial was conducted to evaluate the efficacy and safety of gefitinib induction followed by CRT in this disease setting. PATIENTS AND METHODS: Patients with unresectable, EGFR-mutant, stage III NSCLC were administered gefitinib monotherapy (250 mg/day) for 8 weeks. Subsequently, patients without disease progression during induction therapy were administered cisplatin and docetaxel (40 mg/m2 each) on days 1, 8, 29, and 36 with concurrent radiotherapy at a total dose of 60 Gy. The primary endpoint was the 2-year overall survival (OS) rate, which was hypothesized to reach 85%, with a threshold of the lower limit of 60%. RESULTS: Twenty patients (median age: 66 years; male/female: 9/11; histology: 20 adenocarcinoma; stage IIIA/IIIB: 9/11; and exon 19/21: 10/10) were enrolled. The 2-year OS rate was 90% (90% confidence interval: 71.4% to 96.8%), indicating that this trial met the primary objective. The overall response rate and 1- and 2-year progression-free survival rates were 85.0%, 58.1%, and 36.9%, respectively. Grade ≥3 adverse events (>10%) included hepatic toxicity during the induction phase and neutropenia and febrile neutropenia in the CRT phase. Radiation pneumonitis grade ≥3 or treatment-related death did not occur. CONCLUSIONS: This is the first prospective study to demonstrate the favorable efficacy and safety of EGFR-TKI induction followed by standard CRT in EGFR-mutant, stage III NSCLC. Further confirmatory studies are needed.

Monitoring of somatic mutations in circulating cell-free DNA by digital PCR and next-generation sequencing during afatinib treatment in patients with lung adenocarcinoma positive for EGFR activating mutations.

Background: Analysis of circulating cell-free DNA (cfDNA) is under intensive investigation for its potential to identify tumor somatic mutations. We have now explored the usefulness of such liquid biopsy testing with both the digital polymerase chain reaction (dPCR) and next-generation sequencing (NGS) during treatment of patients with the epidermal growth factor receptor (EGFR) inhibitor afatinib. Patients and methods: Eligible patients had advanced lung adenocarcinoma with EGFR activating mutations and were treated with afatinib. Plasma samples were collected before and during (4 and 24 weeks) afatinib treatment as well as at disease progression. Tumor and plasma DNA were analyzed by dPCR and NGS. Results: Thirty-five patients were enrolled. The objective response rate and median progression-free survival (PFS) were 77.1% and 13.8 months, respectively. Tumor and plasma DNA were available for 32 patients. dPCR and NGS detected EGFR activating mutations in 81.3% and 71.9% of baseline cfDNA samples, respectively. In 19 patients treated with afatinib for ≥24 weeks, the number of EGFR mutant alleles detected in cfDNA by dPCR declined rapidly and markedly after treatment onset, becoming undetectable or detectable at only a low copy number (<10 copies per milliliter) at 4 weeks. Median PFS was slightly longer for patients with undetectable EGFR mutant alleles in cfDNA at 4 weeks than for those in whom such alleles were detectable (14.3 versus 10.0 months). A total of 45 somatic mutations was identified in baseline tumor DNA, and 30 (66.7%) of these mutations were identified in cfDNA by NGS. Allele frequency for somatic mutations in cfDNA determined by NGS changed concordantly during afatinib treatment with the number of EGFR mutant alleles determined by dPCR. Conclusions: Monitoring of cfDNA by dPCR is informative for prediction of afatinib efficacy, whereas that by NGS is reliable and has the potential to identify mechanisms of treatment resistance.

The impact of obesity on venous insufficiency.

Association between chronic venous disease and obesity has recently been studied, with indications that it may worsen in obese patients. The aim of study was to correlate clinical classes of chronic venous disease according to Clinical Etiology Anatomy Pathophysiology (CEAP) classification and body mass index, as well as to compare the severity of chronic venous disease in obese and nonobese patients. This retrospective cross-sectional prevalence study was conducted at the Maringá State University and Belczak Vascular Center along a period of 2 years, consisting of a random sample of 482 patients with complaints compatible with chronic venous disease. Data obtained from patient's files included gender, age, weight and height (for calculating body mass index), and clinical class (C) of chronic venous disease according to CEAP classification. Statistical analysis included Spearman's correlation coefficient, Chi-square test (for comparing frequencies), and Student's t-test (for comparing means). Significant positive correlation between body mass index and clinical classes was established for women (0.43), but not for men (0.07). Obesity (body mass index : ≥ : 30.0) was significantly more frequent in patients with chronic venous disease in clinical classes 3 (p < 0.001) and 4 (p = 0.002) and less frequent in patients with chronic venous disease in clinical class 1 (p < 0.001). This study evidenced significant correlation between body mass index and clinical classes of chronic venous disease in women, but not in men. It also corroborated the negative impact of obesity on the clinical severity of chronic venous disease.

Determination of reduced, protein-unbound, and total concentrations of N-acetyl-L-cysteine and L-cysteine in rat plasma by postcolumn ligand substitution high-performance liquid chromatography.

A high-performance liquid chromatographic assay was developed for the quantitative determination of the sulfur-containing amino acids N-acetyl-L-cysteine (NAC) and L-cysteine (Cys) in rat plasma. The thiols were separated by reverse-phase ion-pair chromatography, and the column eluent was continuously mixed with an iodoplatinate-containing solution. The substitution of sulfur of the thiol compound with iodide was quantitatively determined by measuring changes in the absorption at 500 nm. The low-molecular-weight disulfides and mixed disulfide conjugates of thiols with proteins were entirely reduced to the original reduced compounds by dithiothreitol. By reducing these two types of disulfides separately during sample pretreatment, the reduced, protein-unbound, and total thiol concentrations could also be determined. Validation testing was performed, and no problems were encountered. The limit of detection was approximately 20 pmol of thiol on the column. The present method was used to measure the plasma concentrations of NAC and Cys in the rat after a bolus intravenous administration of NAC, focusing on disulfide formation. The binding of NAC to protein through mixed disulfide formation proceeds in a time-dependent and reversible manner. Moreover, this "stable" covalent binding might limit total drug elimination, while the unbound NAC is rapidly eliminated. Consequently, the analytical method described in this study is very useful for the determination of plasma NAC and Cys, including disulfide conjugates derived from them.

Extradigital glomus tumor causing para-Achilles tendon pain. A case report.

A 48-year-old woman with a 15-year history of a painful nodule in the para-Achilles tendon area was evaluated by clinical examination, magnetic resonance imaging and ultrasonography, then treated by simple surgical excision of the nodule. Pathology revealed a glomus tumor, which is extremely rare in the para-Achilles tendon area. This is the first report of a glomus tumor in this location.

Effects of transforming growth factor-beta1 on the gene expression of decorin, biglycan, and alkaline phosphatase in osteoblast precursor cells and more differentiated osteoblast cells.

In this study, the effects of incubating two clonal rat osteoblastic cell lines at different stages of differentiation, ROB-C26 (C26) and ROB-C20 (C20), with transforming growth factor-beta1 (TGF-beta1) on the gene expression of decorin, biglycan, and alkaline phosphatase were examined. C26 cells are a potential osteoblast precursor cell line that is also capable of differentiating into muscle cells and adipocytes and is differentiated into osteoblasts after treatment with bone morphogenetic protein-2. C20 cells are a more differentiated osteoblastic cell line. Our Northern blot studies demonstrated that after treatment with TGF-beta1 (0, 0.1, 1.0, 5.0, and 10 ng/ml), a dose- and time-dependent decrease in decorin mRNA expression was found in C26 cells. In contrast, the effect of decorin mRNA with TGF-beta1 was not determined in C20 cells, since decorin mRNA expression was extremely low in this cell line even in the absence or presence of TGF-beta1. Although TGF-beta1 treatment resulted in no appreciable effect on biglycan mRNA expression in both cell lines in a dose- and time-dependent manner, it decreased significantly the expression of alkaline phosphatase in both cell lines at the gene and protein level. Reverse transcriptase-polymerase chain reaction analysis revealed the gene expression of decorin, and TGF-beta type I and type II receptors in both cell lines. These results indicate that osteoblasts progenitor cells express both decorin and biglycan mRNAs. In contrast, more differentiated and mature osteoblastic cells express preferentially biglycan mRNA. TGF-beta1 exerts different effects on the expression of decorin and biglycan mRNAs, and is a potent inhibitor of the gene expression of alkaline phosphatase during osteoblast differentiation.

Releasing severe adhesions around the eminence and the synovial portion of the TMJ: a clinical study of combined treatment using hydraulic lavage, arthroscopic surgery and rehabilitative therapy.

This paper evaluates the effects of treatment with a pumping technique and arthroscopic lysis and lavage, followed by rehabilitative training, on condylar head mobility of the temporomandibular joint (TMJ). We studied 32 TMJs in 19 patients suffering from chronic closed lock with severe adhesion. The results were compared between cases with adhesions concentrated in two areas: mostly in the posterior and/or the anterior synovial portion of the upper TMJ compartment (11 joints) and mostly around the eminence (21 joints). The results showed a statistically significant improvement in condylar head movement for both groups between the initial and final stages of treatment. However, the results also suggested that patients with adhesion concentrated around the eminence are less likely to recover condylar head mobility to the same extent as those in the other group.

Comparison of immunopharmacological actions of 8 kinds of kampo-hozais clinically used in atopic dermatitis on delayed-type hypersensitivity in mice.

We studied here the effects of 8 kinds of kampo-hozais clinically used to treat atopic dermatitis (Shofu-san, Toki-inshi, Unsei-in, Oren-gedoku-to, Ji-zuso-ippo, Jumi-haidoku-to, Juzen-taiho-to, Hochu-ekki-to) on delayed-type hypersensitivity (DTH), using three types of murine models such as picryl chloride (PC)-induced (contact hypersensitivity), sheep red blood cell (SRBC)-induced (Jones-Mote's reaction) and tuberculin-induced DTH response, in order to clarify and to compare the immunopharmacological action of kampo-hozais. Most of the kampo-hozais investigated here suppressed PC-induced contact hypersensitivity, especially at the inductive phase. Comparing the efficacies of these kampo-hozais on the three types of DTH responses in mice, they were generally divided into 4 groups. Shofu-san significantly reduced PC-induced and tuberculin-induced DTH responses but not a SRBC-induced DTH response. On the other hand, Toki-inshi reduced contact hypersensitivity, tuberculin type DTH response and Jones-Mote's reaction. Ji-zuso-ippo and Juzen-taiho-to suppressed mainly Jones-Mote's reaction, and Unsei-in, Oren-gedoku-to and Jumi-haidoku-to intensively suppressed contact hypersensitivity. We thought that these findings could help us understand how to use these kampo-hozais properly.

Worsening of pre-existing TMJ dysfunction following sagittal split osteotomy: a study of three cases.

When patients seeking treatment for malocclusion also suffer from temporomandibular joint (TMJ) disorders, it is hard to predict the result of simultaneous treatment of both conditions, or to plan for its different goals, because of unpredictable changes in the relationship between the disk, the fossa and the condylar head. Prediction is harder in cases of presurgical TMJ hypomobility, especially those with adhesion in the upper TMJ compartment. Authors differ widely on the likely effect of orthognathic surgery on TMJ disorders. This paper reports three cases in which TMJ disorders worsened after treatment of malocclusion by sagittal split osteotomy. It examines how presurgical diagnosis of TMJ disorders could assist treatment planning in such cases. The results suggest that microbleeding in the upper TMJ compartment during orthognathic surgery, as well as long-term postoperative intermaxillary fixation, carries a risk of creating worse adhesion that adversely affects the outcome for patients. Therefore, preoperative diagnosis of disk position and pathological conditions in the upper TMJ compartment, as well as careful choice of method and term of postoperative fixation, are essential in planning the treatment of malocclusion with sagittal split osteotomy.

Prosthetic restorations with osseointegrated implants after bone grafts to correct large jaw defects caused by extraction of multi-impacted teeth: a case report.

A case is reported of a 21-year-old Japanese man examined for unerupted molar teeth on the left side of both jaws. Intraoral examination revealed edentulous regions from the second premolar to the molar, with moderate atrophy of the upper alveolar ridge. A panoramic X-ray revealed eight impacted teeth. The impacted mandibular teeth were extracted through decortication and bone replacement. The impacted maxillary teeth were extracted following reflection of a mucoperiosteal flap. The large defects caused by the extractions in both jaws were filled with autogenous cancellous marrow and bone chips. Eleven months later, in the first stage of the Branemark implant procedure, fixtures were placed in the edentulous regions of both jaws, with simultaneous additional corticocancellous block onlay bone grafting in the maxilla to correct slight resorption. After another seven months, second-stage abutment surgery was performed. Occlusion was then restored through a prosthetic procedure. Next, orthodontic treatment was commenced, using the implant supported teeth as an anchor. Despite the slight resorption in the maxilla, implantation was successful and occlusion was restored in the previously edentulous regions. This suggests that application of a simultaneous corticocancellous block onlay bone graft is a valuable basis for implant procedures in the maxilla.

Regulation mechanism of the catalytic activity of bovine adrenal cytochrome P-450(11)beta.

In our previous paper (Ikushiro et al. (1992) J. Biol. Chem. 267, 1464), two catalytic states were proposed for bovine adrenocortical P-450(11)beta at 37 degrees C: one in liposome membranes and the other in liposome membranes containing P-450scc. Similar reaction characteristics were observed at 5 degrees C and all the experiments in this study were performed at 5 degrees C. P-450(11)beta-proteoliposomes had relatively low 11 beta-hydroxylase activity and could catalyze aldosterone formation from 11-deoxycorticosterone. Relatively high 11 beta-hydroxylase activity was observed in P450(11)beta-proteoliposomes containing P-450scc and in Tween-20 solubilized P-450(11)beta, in which no aldosterone formation could be detected. Optical titration indicated binding of corticosterone to P-450(11)beta to be much weaker in the Tween-20 solubilized state than in proteoliposomes. Corticosterone competitively inhibited 11 beta-hydroxylation reaction of P-450(11)beta-proteoliposomes, but neither in P-450(11)beta-proteoliposomes containing P-450scc nor in the Tween-20 solubilized system. The binding of corticosterone to P-450(11)beta was concluded quite weak in proteoliposomes in the presence of P-450scc and in the Tween-20 solubilized state. Aldosterone formation thus was not possible in these systems. Inability of the bovine adrenocortical zonae fasciculata and reticularis to produce aldosterone may be due to the weak binding of corticosterone to P-450(11)beta in these zones.

[A case of sweat gland carcinoma arising in a mature cystic teratoma of the ovary].

A case of sweat gland carcinoma arising in a mature cystic teratoma in a 63-year-old woman is reported. The patient was admitted with the complaint of a lower abdominal pain. Under the diagnosis of a mature cystic teratoma of the right ovary, the tumor was removed. Histologically, adenocarcinoma was found in the wall of the mature cystic teratoma. A part of the tumor showed a differentiation of the secretory portion and duct of the sweat gland. Histochemically, sialic acid containing mucoprotein was defected. Electron microscopically, the tumor cells were found to have secretory granules and intracytoplasmic canaliculi. Therefore, the tumor was diagnosed as a sweat gland carcinoma arising from a mature cystic teratoma.

Amoxapine-induced tardive dyskinesia.

A case report of amoxapine-induced tardive dyskinesia following discontinuation of amoxapine therapy is reported. During 68 weeks of therapy, the patient received a maximum of amoxapine 400 mg/d. Six months after amoxapine discontinuation, the patient continued to have symptoms of tardive dyskinesia. These symptoms correlate with the dopamine receptor-blocking property of amoxapine and its metabolites. We propose that amoxapine therapy be monitored for the long-term as well as the short-term adverse effects of dopamine receptor-blockade.