Features and prognostic impact of distant metastasis in patients with stage IV lung adenocarcinoma harboring EGFR mutations: importance of bone metastasis

Mutated epidermal growth factor receptor (EGFR) and signaling pathways were associated with multiple brain and intra-pulmonary metastases, oncogenic progression and metastasis. However, features of metastasis to other organs and the independent prognostic influence of metastatic lesions were not elucidated in patients with lung cancer harboring EGFR mutations. Between January 2007 and April 2012, we treated 277 patients diagnosed with stage IV lung adenocarcinoma. Studied were 246 patients with available tumor EGFR mutation data who also underwent radiographic evaluation of lung, abdominal, brain, and bone metastases. The EGFR mutated group (N = 98) had significantly more metastatic lesions in the brain and bone than the wild-type group (N = 148): brain, 3 (1–93) versus 2 (1–32) median (range), P = 0.023; bone, 3 (1–43) versus 2 (1–27), P = 0.035, respectively. In addition, EGFR mutations were significantly more frequent in patients with multiple than non-multiple lung metastases (24/40 vs. 12/42, P = 0.004). Multivariate analysis showed that bone metastasis was a significant independent negative predictive factor of overall survival (OS) in patients with mutated [hazard ratio (HR) 2.04; 95 % confidence interval (CI) 1.17–3.64; P = 0.011] and wild-type EGFR (HR 2.09; 95 % CI 1.37–3.20; P < 0.001). In conclusion, patients with mutated EGFR had more lung, brain, and bone metastases, and bone metastasis was an independent negative predictor of OS.     

Prenatal molecular diagnosis of X‐linked hydrocephalus via a silent C924T mutation in the L1CAM gene

We present a case of a patient whose L1CAM gene in X‐chromosome has a C924T transition. Her first son's ventriculomegaly was prenatally detected. A mature infant was born, his head circumference was large, and thumbs were bilaterally adducted. X‐linked hydrocephalus (XLH) was suspected. The DNA examination revealed that both her and boy's LICAM gene had a C924T transition. She became pregnant 5 years later and amniocentesis was performed. The results of cytogenetic analysis revealed that the fetus was female. She continued her pregnancy and delivered a healthy girl. She again became pregnant 3 years later. The chromosomal analysis revealed that the fetus was male. Fetal DNA analysis determined that the fetus had the inherited mutation. She chose to terminate the pregnancy. A C924T mutation can be disease causing for XLH, and the detection of this mutation would aid in genetic counseling for the prenatal diagnosis of XLH.     

A minimally invasive abdominal and left thoracic approach as a palliative treatment for adenocarcinoma of the esophagogastric junction with severe stenosis: A case report

We report a novel technique for combined laparoscopy and thoracoscopy for far‐advanced adenocarcinoma of the esophagogastric junction (AEG). A 56‐year‐old man presented with far‐advanced AEG, and an esophagogastroduodenoscopy revealed a type 2 lesion that encircled the esophagogastric junction. CT revealed stenosis of the esophagogastric junction, suspected invasion into the left side of the diaphragm, and lymph node metastases in the abdomen. We diagnosed Siewert type II AEG (cT4aN1M0, cStage IIIA) according to the Japanese Classification of Gastric Carcinoma, version 14. Laparoscopic and thoracoscopic proximal gastrectomy and lower esophagectomy with double‐tract reconstruction were performed as a palliative resection via a minimally invasive abdominal and left thoracic approach. However, localized peritoneal dissemination was detected. The patient was discharged with no postoperative morbidity. Hence, a minimally invasive abdominal and left thoracic approach provides good visualization, and it is safe for lower esophageal transection and intrathoracic anastomosis in the treatment of locally advanced AEG invading the surrounding tissues.     

Infrequent alterations of the p16INK4A gene in liver cancer

We examined the genomic status of the p16^INK4A (inhibitor of cyclin-dependent kinase 4 A) and cyclin-dependent kinase 4 (CDK4) genes in 62 human hepatocellular carcinomas (HCCs), 5 cholangiocellular carcinomas and 6 cell lines derived from human liver cancers. Although no samples showed the homozygous deletion of the p16^INK4A gene, we detected intragenic mutations of the p16^INK4A gene in 3 HCCs and one HCC cell line, which led to an amino-acid substitution or a frameshift. In 2 HCC samples with mis-sense mutations of the p16^INK4A gene, loss of heterozygosity on 9p22 was also detected, suggesting that the loss of function of p16 was induced during hepatocarcinogenesis. On the other hand, amplification or rearrangement of the CDK4 gene was not detected in any samples examined in this study. These results indicated that the mutations or deletions of the p16^INK4A gene are not frequent, but may play a role in a sub-set of human HCC. © 1996 Wiley-Liss, Inc.     

A practical method for the aziridination of α,β-unsaturated carbonyl compounds with a simple carbamate utilizing sodium hypochlorite pentahydrate

The efficient formation of tert-butyl N-chloro-N-sodio-carbamate by the reaction of simple tert-butyl carbamate with sodium hypochlorite pentahydrate (NaOCl·5H₂O) would be a practical and green method for the aziridination of α,β-unsaturated carbonyl compounds. The process described herein is transition-metal free, all of the materials are commercially available, the byproducts (NaCl and H₂O) are environmentally benign and the reaction is stereoselective. The resulting aziridines are potential precursors of amino acids.

The efficient formation of tert-butyl N-chloro-N-sodio-carbamate by the reaction of simple tert-butyl carbamate with sodium hypochlorite pentahydrate would be a practical and green method for the aziridination of α,β-unsaturated carbonyl compounds.     

Novel Compounds Identified by Structure-Based Prion Disease Drug Discovery Using In Silico Screening Delay the Progression of an Illness in Prion-Infected Mice

The accumulation of abnormal prion protein (PrP^Sc) produced by the structure conversion of PrP (PrP^C) in the brain induces prion disease. Although the conversion process of the protein is still not fully elucidated, it has been known that the intramolecular chemical bridging in the most fragile pocket of PrP, known as the “hot spot,” stabilizes the structure of PrP^C and inhibits the conversion process. Using our original structure-based drug discovery algorithm, we identified the low molecular weight compounds that predicted binding to the hot spot. NPR-130 and NPR-162 strongly bound to recombinant PrP in vitro, and fragment molecular orbital (FMO) analysis indicated that the high affinity of those candidates to the PrP is largely dependent on nonpolar interactions, such as van der Waals interactions. Those NPRs showed not only significant reduction of the PrP^Sc levels but also remarkable decrease of the number of aggresomes in persistently prion-infected cells. Intriguingly, treatment with those candidate compounds significantly prolonged the survival period of prion-infected mice and suppressed prion disease-specific pathological damage, such as vacuole degeneration, PrP^Sc accumulation, microgliosis, and astrogliosis in the brain, suggesting their possible clinical use. Our results indicate that in silico drug discovery using NUDE/DEGIMA may be widely useful to identify candidate compounds that effectively stabilize the protein.Electronic supplementary materialThe online version of this article (10.1007/s13311-020-00903-9) contains supplementary material, which is available to authorized users.