Osimertinib in poor performance status patients with T790M-positive advanced non-small-cell lung cancer after progression of first- and second-generation EGFR-TKI treatments (NEJ032B)

Background

Osimertinib is effective in patients with T790M mutation-positive advanced non-small-cell lung cancer (NSCLC) resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, its effectiveness and safety in patients with poor performance status (PS) are unknown.

Methods

Enrolled patients showed disease progression after treatment with gefitinib, erlotinib, or afatinib; T790M mutation; stage IIIB, IV, or recurrent disease; and PS of 2–4. Osimertinib was orally administered at a dose of 80 mg/day. The primary endpoint of this phase II study (registration, jRCTs061180018) was response rate and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate, and safety.

Results

Thirty-three patients were enrolled, of which 69.7% and 24.2% had PS of 2 and 3, respectively. One patient was excluded due to protocol violation; in the remaining 32 patients, the response rate was 53.1%; disease control rate was 75.0%; PFS was 5.1 months; and OS was 10.0 months. The most frequent adverse event of grade 3 or higher severity was lymphopenia (12.1%). Interstitial lung disease (ILD) was observed at all grades and at grades 3–5 in 15.2% (5/33) and 6.1% (2/33) of patients, respectively. Treatment-related death due to ILD occurred in one patient. Patients negative for activating EGFR mutations after osimertinib administration had longer median PFS than those positive for these mutations.

Conclusion

Osimertinib was sufficiently effective in EGFR-TKI-resistant, poor PS patients with T790M mutation-positive advanced NSCLC. Plasma EGFR mutation clearance after TKI treatment could predict the response to EGFR-TKIs.

     

Birt‐Hogg‐Dubé syndrome‐associated renal cell carcinoma: Histopathological features and diagnostic conundrum

Birt‐Hogg‐Dubé (BHD) syndrome is associated with the development of hereditary renal cell carcinoma (RCC) and is caused by a germline mutation in the folliculin gene. Most cases of BHD syndrome‐associated RCC (BHD‐RCC) are less aggressive than sporadic clear cell RCC and multifocal. Therefore, it is critical to distinguish BHD‐RCC from its sporadic counterparts to identify and monitor affected families and to preserve renal function for as long as possible. The World Health Organization/International Society of Urological Pathology consensus classification defined distinct entities for certain hereditary RCC; however, BHD‐RCC was not included in this classification. Although the clinical features and molecular mechanisms of BHD‐RCC have been investigated intensively over the last two decades, pathologists and urologists occasionally face difficulties in the diagnosis of BHD‐RCC that require genetic testing. Affected patients usually have miscellaneous benign disorders that often precede renal carcinogenesis. In the present review, we summarize the current understanding of the histopathological features of BHD‐RCC based on our epidemiological studies of Japanese families and a literature review. Pathological diagnostic clues and differential diagnosis of BHD‐RCC from other hereditary RCC are also briefly discussed.     

Characterization of inter-tissue and inter-strain variability of TCE glutathione conjugation metabolites DCVG,DCVC, and NAcDCVC in the mouse

Trichloroethylene (TCE) is a ubiquitous environmental toxicant that is a liver and kidney carcinogen. Conjugation of TCE with glutathione (GSH) leads to formation of nepthrotoxic and mutagenic metabolites postulated to be critical for kidney cancerdevelopment; however, relatively little is known regarding their tissue levels as previous analytical methods for their detection lacked sensitivity. Here, an LC-MS/MS-based method for simultaneous detection of S-(1,2-dichlorovinyl)-glutathione (DCVG), S-(1,2-dichlorovinyl)-L-cysteine (DCVC), and N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine (NAcDCVC) in multiple mouse tissues was developed. This analytical method is rapid, sensitive (limits of detection (LOD) 3–30 fmol across metabolites and tissues), and robust to quantify all three metabolites in liver, kidneys, and serum. The method was used to characterize inter-tissue and inter-strain variability in formation of conjugative metabolites of TCE. Single oral dose of TCE (24, 240 or 800 mg/kg) was administered to male mice from 20 inbred strains of Collaborative Cross. Inter-strain variability in the levels of DCVG, DCVC, and NAcDCVC (GSD = 1.6–2.9) was observed. Whereas NAcDCVC was distributed equally among analyzed tissues, highest levels of DCVG were detected in liver and DCVC in kidneys. Evidence indicated that inter-strain variability in conjugative metabolite formation of TCE might affect susceptibility to adverse health effects and that this method might aid in filling data gaps in human health assessment of TCE.     

Genetic study on ossification of posterior longitudinal ligament

Family studies and blood grouping tests were conducted in an attempt to elucidate the etiology and genetic mechanism of ossification of posterior longitudinal ligament of the spine (OPLL). Analysis of the collected date revealed the following results: Testing of inheritance pattern Fitness of OPLL to the hypotheses of simple recessive inheritance, simple dominant inheritance and multifactorial inheritance was tested, but fitness to any one of these hypotheses was statistically denied. Analyses of OPLL and genetic markers A comparative study was made between the OPLL patients and healthy donors residing in Tokyo on the phenotype frequency of the blood groups (eight systems), serum groups (six systems) and red cell enzyme groups (three systems). A significant association of OPLL with MN blood groups, Hp types and PGM1 types was observed. Examination of the correlation after combining MN and Hp showed the coefficient of contingency to be C = 0.6739 and that after the multiple combination of MN, Hp and PGM1 revealed the coefficient of contingency to be C = 0.8923, indicating a remarkably high correlation.     

Expression of Na(+)/K(+)-ATPase alpha subunit isoforms in rat salivary glands: occurrence of sense and antisense RNAs of the alpha3 isoform in the sublingual gland

We examined the expression of Na(+)/K(+)-ATPase alpha-subunit isoforms in rat salivary glands by RT-PCR. Isoform alpha1 was expressed strongly in all three major salivary glands. The alpha2 isoform was expressed in both submandibular gland (SMG) and sublingual gland (SLG) but faintly in the parotid gland (PG). The alpha3 was detected only in the SLG, and the alpha3 mRNA in the SLG was 1/8 of its level in the brain. Na(+)/K(+)-ATPase alpha3 isoform in the SLG, was localized predominantly on the basolateral plasma membranes in serous cells by immunohistochemical method. We also found the presence of natural antisense RNA of the alpha3 isoform in rat SLG: the 1st-strand cDNA prepared with gene-specific forward primers targeted to the CDS region and to the promoter region of the alpha3 gene in place of oligo(dT) or gene-specific reverse primers produced reasonable PCR products corresponding to the alpha3 cDNA sequence by the subsequent PCR reaction. Synthesis of the 1st-strand cDNA with the gene-specific forward primers was prevented by RNase digestion of the total RNA preparation, indicating that the PCR products in the RT-PCR system were not due to the contaminated genomic DNA, if any. The alpha3 protein level in rat SLG increased with aging, and levels of both alpha3 mRNA (sense RNA) and alpha3 antisense RNA were higher in SLGs of aged rats than in those of young rats, respectively.     

Morphometric analysis of digital radiographic bone images for trabecular bone structure

A morphometric analysis system of digital radiographic images was constructed for the clinical evaluation of bone trabecular structural change. This system consisted of computed radiography, a mathematical morphological filter, skeletal morphometric measurements, star volume analysis, and node-strut analysis. The computed radiographic data were morphologically processed, and the trabecular structure was extracted as binary skeletal images. Analyses were made with regard to the skeletal number, separation, perimeter, complexity, continuity, and connectivity. A trial study of this system was used to evaluate the therapeutic efficacy of vitamin K₂ in the osteoporotic patients. The system enabled the quantitative evaluation of bone trabecular structural change. Significant differences were observed in the parameters of the skeletal perimeter, skeletal number, and skeletal connectivity in the femur, and improvements in the trabecular structure were indicated. In the lumbar vertebra, significant differences were observed in nearly the same parameters as the femur, although the trabecular structure had deteriorated. These results suggest that the system for bone morphometric analysis of digital radiographic images is useful for the evaluation of structural change in bone trabeculation. Source of support This work was performed at Kanagawa Dental College, Research Center of Advanced Technology for Craniomandibular Function and was supported by a grant-in-aid for Bioventure Research from the Japanese Ministry of Education, Culture, Sports, Science, and Technology.     

Pre-operative drilling simulation method for dental implant treatment

The position, depth and direction of implant placement are often planned based on evaluation of radiographs and study casts. Insertion planned in such a manner may not be adequate for precise and safe surgery in some cases due to inadequate working clearance in the oral cavity. In order to obtain high initial stability and ensure osseointegration at the implant-bone interface, careful and precise drilling must be performed at the implant placement site. Therefore, we propose the necessity of evaluating the operability of implant treatment-devices prior to surgery. The amount of handling space needed during implant placement surgery was determined. The results showed that for implants with a length of 7-18 mm, a vertical distance of as much as 50-60 mm was required, depending on the implant platform. These results suggest the necessity of pre-operative drilling simulation in each individual. Handling space was measured with angled heads and probes fabricated on a trial basis for pre-surgical drilling simulation in the oral cavity. We believe that these instruments may be clinically useful in estimating the amount of handling space required prior to surgery and ensuring precise implant placement. Evaluation of the intra-oral environment for handling of treatment devices should be included in the pre-surgical intra-oral evaluation of dental implant cases to avoid changes in treatment planning due to intra-oral interference during the course of surgery.     

Effects of wearing complete dentures on swallowing in the elderly

The purpose of this study was to evaluate effects of wearing complete dentures on swallowing in the elderly. Sixteen nondysphagic edentulous volunteers (mean age: 75.0 yrs) were studied in terms of surface electromyography of the anterior belly of digastrics and masseter muscles, tongue pressure toward the hard palate, and the laryngeal movement. The subjects swallowed 2 ml water under four conditions, with upper and lower dentures, without lower denture, without upper denture, and without upper and lower dentures. Dipper-type of swallowing was prescribed. A repeated-measures ANOVA was used for statistical analysis. Total swallowing duration and the latent period until laryngeal elevation were significantly prolonged without upper or lower denture, and without both dentures (p < 0.05). They were significantly shorter without lower denture than those without upper denture, and without both dentures (p < 0.05). Duration of the preparatory stage was significantly prolonged without upper denture, and without both dentures comparing with the others (p < 0.05). Duration of the oral stage was significantly prolonged without upper denture, and without both dentures comparing with the duration with both dentures (p < 0.05). There were no changes in the pharyngeal stage with or without dentures. The prolongation of total swallowing duration was due to the prolongation of the preparatory and oral stages. The prolongation of swallowing would affect the oral-pharyngeal coordination of swallowing, and exacerbate the depression of swallowing functions with aging. These results suggested that wearing complete dentures contributes to maintain physiological procedure of swallowing in the elderly.