Search

Identification of somatic mutations that contribute to cancer development leads not only to more precise understanding of cancer pathogenesis, but also development of novel molecular targeted therapies. Analyses of cancer genomes using high-throughput sequencing technology are currently conducted as international collaborative research projects, and the results of those analyses are deposited in public databases, allowing everyone in the world to access to these data. To identify a somatic mutation that plays an important role in cancer pathogenesis, we counted the occurrences of each somatic mutation found in the TCGA lung adenocarcinoma dataset and became interested in the CHK2 K373E mutation (c1117A>G), which was present in 31 of 542 patients. The K373E mutation impaired CHK2 autophosphorylation at Thr383 and Ser516. In vitro kinase assay revealed that the K373E mutation markedly attenuates CHK2 kinase activity. Growth curves showed that wild-type CHK2 substantially suppressed cell proliferation, but this effect was lost in the K373E mutant in HCT-15 harboring tetracycline-inducible CHK2. Clonogenic assays revealed that wild-type CHK2 promoted survival after ionizing radiation and this pro-survival function was impaired in K373E CHK2. The results of western blotting and RT-PCR suggested that the p53-independent induction of p21 by CHK2 might underlie these effects. Therefore, we identified a somatic mutation that contributes to cancer pathogenesis, using information in a public database. This kind of attempt is expected to lead to discovering new 'driver' mutations in the future. Citation Format: Masayoshi Higashiguchi, Izumi Nagatomo, Takashi Kijima, Osamu Morimura, Kotaro Miyake, Toshiyuki Minami, Shohei Koyama, Haruhiko Hirata, Kota Iwahori, Takayuki Takimoto, Yoshito Takeda, Hiroshi Kida, Atsushi Kumanogoh. Clarifying the biological significance of the CHK2 K373E somatic mutation discovered in The Cancer Genome Atlas database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3416. doi:10.1158/1538-7445.AM2017-3416

We present a case of adenovirus (ADV) infection in a patient who had undergone nonmyeloablative stem cell transplantation (NST). A 50-year-old man with chronic myelogenous leukemia in the second chronic phase underwent NST from an HLA 2-loci-mismatched sibling. ADV hemorrhagic cystitis developed and progressed to lethal pneumonia. ADV was isolated from urine, bronchoalveolar lavage fluid, and postmortem specimens of kidney and liver. Because there are few reports of lethal pneumonia associated with ADV in Japan, we present the case and discuss the cause of and therapy for the infection.

Perfluoroallyl chloride (PFAC), a fluorine-containing compound, has very severe toxicity, but this toxicity is not well characterised. We report a fatal case of acute chemical lung injury caused by the inhalation of PFAC. A 39-year-old man, working at a chemical factory, inhaled PFAC gas and died 16 days later of acute lung injury with severe pneumothorax. We present his clinical course together with thoracic CT findings, autopsy and analysis of PFAC in blood and urine samples with gas chromatograph-mass spectrometry. Previously, a fatal case of PFAC was reported in 1981 but PFAC was not identified in any of the patient's samples. In our patient, we identified PFAC in both blood and urine samples. Our toxicological analysis may be used as a reference to detect PFAC toxicity in the future. Our study should be helpful for diagnosing lung injury induced by a highly toxic gas, such as PFAC.

Introduction Gefitinib induces severe hepatotoxicity in approximately a quarter of Japanese patients with epidermal growth factor receptor (EGFR) mutation–positive non–small-cell lung cancer (NSCLC). Gefitinib is metabolized by cytochrome P450 (CYP) enzymes—including CYP3A4/5, CYP1A1, and CYP2D6—in the liver. We hypothesized that polymorphisms of the CYP2D6 gene may account for gefitinib-induced hepatotoxicity. Patients and Methods Polymorphisms of the CYP2D6 gene were analyzed in 55 patients with NSCLC who experienced grade ≥ 2 transaminase elevation from gefitinib. The distribution of the CYP2D6 genotype was compared with that of the healthy Japanese population. The correlations between the nonfunctional allele *5 or the reduced-function allele *10 and hepatotoxicity-related clinical factors were also examined. Results The distribution of the CYP2D6 genotype in the study participants was not different from that of the general Japanese population, reported previously. Existence of allele *5 or *10 did not correlate with clinical factors such as onset of hepatotoxicity within 2 months, grade ≥ 3 serum transaminase elevation, and tolerability to dose reduction or rechallenge of gefitinib. However, in 7 patients taking CYP3A4-inhibitory drugs, rechallenge of gefitinib again caused hepatotoxicity in 4 patients with allele *5 or *10 but not in 3 patients with normal alleles ( P = .029). Moreover, switching to erlotinib did not cause hepatotoxicity in any of 17 patients with allele *5 or *10 but did in 3 of 8 patients without these alleles ( P = .024). Conclusion Reduced function of CYP2D6 may partly account for gefitinib-induced hepatotoxicity when CYP3A4 is inhibited. Erlotinib could be safely used in patients with decreased CYP2D6 activity even after they experienced gefitinib-induced hepatotoxicity.

A standard therapy is not established for locally advanced non-small-cell lung cancer(NSCLC)complicated with chronic renal failure, although some cases of the disease have been reported. We report a case of a locally advanced squamous cell carcinoma of the lung, complicated with chronic renal failure. He was successfully treated with weekly docetaxel(DOC)and concurrent thoracic radiotherapy, and no deterioration of renal function was observed. In locally advanced NSCLC complicated with renal dysfunction, treatment with weekly DOC and concurrent thoracic radiotherapy is considered to be a therapeutic option. Since radiation pneumonitis occurred in the present case, the accumulation and precise analysis of applicable cases is an important subject for future consideration.

Renal dysfunction is a characteristic of many patients with cancer; however, a standard therapy has not been established for stage III or IV non-small-cell lung cancer (NSCLC) complicated with chronic renal failure. Docetaxel has a proven significant activity against NSCLC. This agent is predominantly eliminated by hepatobiliary extraction and is safe in patients with renal failure, including dialysis patients. Docetaxel is, thus, a therapeutic option in that patient population. Here, we report acute tubular nephrotoxicity secondary to docetaxel in NSCLC patients, even in patients with normal renal function. Little is known about tubular nephrotoxicity induced by docetaxel; however, oncologists should be aware of its possibility.

We report a 39-year-old man with intravascular large B-cell lymphoma (IVLBCL) who had been treated as a case with pulmonary arterial hypertension (PAH) for one year. After he became worse, diffuse pulmonary (18)F-fluorodeoxyglucose (FDG) uptake in positron emission tomography (PET) suggested the existence of IVLBCL in the lung showing normal CT images. The diagnosis was confirmed with random transbronchial lung biopsy, and he was then successfully treated. Since IVLBCL presenting PAH has been rare and is difficult to diagnose, early application of FDG-PET may provide early recognition of the disorder, leading to a better outcome.

Hyperparathyroidism is a rare cause of pancreatic inflammatory disease, however their causal relationship has been widely accepted. The appropriate therapy is less clear when patients with hyperparathyroidism-associated pancreatitis develop complications such as pseudocysts. We describe a 51-year-old woman with primary hyperparathyroidism who developed pancreatic pseudocysts extending into the mediastinum. After the correction of hyperparathyroidism by removal of a parathyroid adenoma, the pseudocysts were resolved and no additional treatment was necessary. In patients with primary hyperparathyroidism who develop uncomplicated pancreatic pseudocysts, surgical correction of primary hyperparathyroidism may precede the interventional treatment on the pancreas when possible.

Gefitinib has a modest activity in previously treated patients with advanced non-small cell lung cancer (NSCLC). However, the efficacy and safety of gefitinib monotherapy in untreated advanced NSCLC is not known. We retrospectively reviewed the records of 12 patients of NSCLC who were unfit or refused cytotoxic chemotherapy, and were treated with a single-agent gefitinib as first-line therapy in our hospital. The patients were 6 males and 6 females. The median age was 76.5 years (range 34-82). The histological types were adenocarcinoma in all patients. Clinical stage was IIB in one patient, IIIB in four, and IV in seven. Five were elderly patients and four were patients with ECOG PS (performance status) 3. Five had partial response (PR), and two had stable disease (SD). The response rate was 41%. The median time to progression (TTP) was 126 days. Grade 1 diarrhea was observed in three patients, grade 1 or 2 eruption paronychia was in eight, and grade 1 or 2 liver dysfunction was in two. No grade 3 or 4 toxicities occurred. Gefitinib monotherapy may provide an opportunity for untreated NSCLC, particularly unsuitable patients with standard chemotherapy. Prospective studies of gefitinib monotherapy as first-line treatment are warranted.

A 61-year-old man consulted our hospital because of bloody sputum. Cells of Class V (adenocarcinoma) were found on sputum cytologic examination. Chest computed tomography (CT) showed reticular shadows but no obvious mass was detected. Positron emission tomography with 18-fluorodeoxyglucose (FDG-PET) revealed FDG uptake in both lower lung fields and more increased FDG uptake in a small area of the left lung field. Repeated chest CT, bronchial brushing, bronchial washing, and lung-imaging fluorescence endoscopy were performed, however, resulting in no detection of the primary site of lung cancer. Six months after initial consultation, chest CT showed an enlargement of the shadow in left S6 corresponding to the area of the more increased FDG uptake in PET. On the other hand, the shadow in right S10 did not change in size. Bronchial brushing of the left S6 was performed again, and class IV cells (adenocarcinoma) were found. After left lower lobectomy, diagnoses of well differentiated adenocarcinoma and usual interstitial pneumonia (UIP) were established histologically. There has been no report demonstrating the efficacy of FDG-PET for diagnosis of lung cancer with idiopathic pulmonary fibrosis (IPF).However, combination of lung cancer should be considered if PET shows spots of high FDG uptake in the lung fields of IPF.

A 68-year-old man was admitted to our hospital for cough and dyspnea. Laboratory data showed positive human T-lymphotropic virus type 1 (HTLV-1) antibody and elevated level of soluble interleukin-2 receptor (4225 U/ml). Thoracic computed tomography showed emphysema, reticular shadow, ground-glass attenuation, and subpleural consolidation (Figure 1). Bronchofiberscopy was carried out and cytologic examination of bronchoalveolar lavage fluid revealed atypical lymphocytes. These cells showed positive reaction for CD2, CD3, CD4, CD5, and CD25 and negative for CD8 in flow cytometry. Specimens of transbronchial lung biopsy showed massive infiltration of malignant lymphocytes, which were

Lubrication of gear tooth is necessary for cooling as well as reducing friction losses. It is, however, difficult for rather high speed gear because both rotation of the gear itself and associated aero motion interferes the lubrication. In Addition lubrication consumes excess energy due to such kind of churning. To realize efficient lubrication it is worthy to feed lubricant from both ends of tooth in axial direction by the aid of sucking action of tooth spaces just after meshing. This probably make possible that the oil can reach the tooth surface as earlier as possible. Authors investigated the action of air due to pumping action of a spur gear pair by means of both pressure measurement and the hot wire anemometry at the bottom of tooth space to get fundamental data to asses the feasibility of the proposed way. It has been revealed that the behavior is mostly governed by geometric characteristics around the mesh area rather than operational speed, i.e., temporal response of the pressure and flow velocity is proportional to the speed of gear. It has been also found that pressure variation precedes the flow velocity. Sucking phenomena begins when the backlash space passes through the pitch point whereas the pressure is readily negative due to the mass inertia effect of air getting out of the tooth space.