Involvement of 27-hydroxycholesterol on the progression of non-small cell lung cancer via the estrogen receptor.

The oxysterol 27-hydroxycholesterol (27HC) promotes the proliferation of breast cancer cells as a selective estrogen receptor modulator (SERM), but it is mostly produced by alveolar macrophages in vivo. The present study evaluated hypothesis that 27HC may also promote the proliferation of lung cancer cells. In the tumor and nontumor regions of lung tissue from 23 patients with non-small cell lung cancer (NSCLC) who underwent lung cancer surgery, we compared the 27HC content and its synthetic and catabolic enzyme expressions (CYP27A1 and CYP7B1), the expressions of the estrogen receptor (ER) gene and its target gene cMYC by using high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS), real-time RT-PCR, and immunohistochemical staining. In addition, we evaluated the effects of 27HC and ß-estradiol (E2) treatments on the proliferation of a cultured lung cancer cell line (H23 cells) expressing ERß. In squamous cell carcinoma and in adenocarcinoma, the 27HC content was significantly higher in the tumor region than in the nontumor region, and in cancer grade III than in the other cancer grades. CYP27A1-positive macrophages were histologically detected in the nontumor regions of both cancer types, whereas the gene and protein expressions of ERß, as well as the CYP7B1 and cMYC genes, were significantly increased in the tumor tissues. In cultured H23 cells, proliferation was significantly increased by 27HC and E2 treatments for 48 h. Similar to breast cancer, the present results supported idea that the 27HC produced from alveolar macrophages promotes the proliferation of lung cancer cells highly expressing ER through the SERM action. Therefore, 27HC should be an important target for cancer therapy of NSCLC.

[Long-term Survival Giant Cell Carcinoma of the Lung with Chest Wall Invasion by Multidisciplinary Therapy:Report of a Case].

Giant cell carcinoma of the lung is a rare tumor with poor prognosis. A 70-year-old male was referred to our hospital because of chest pain and abnormal shadow on the chest X-ray. He had a lung tumor invading the chest wall. The tumor was surgically removed, and since the diagnosis of giant cell carcinoma with p-N2 was obtained pathologically, adjuvant chemotherapy was performed. However, the local recurrence was found at eight months after surgery and was treated with radiotherapy( total 70 Gy/28 Fr). The patient has been well for over 10 years with no clinically evident recurrence after treatment.

Investigation of EGFR mutations in non-small cell lung cancer usually undetectable by PCR methods.

Epidermal growth factor receptor (EGFR) mutations are the most significant genomic drivers of non-small cell lung cancer (NSCLC) and determine the efficacy of EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy. PCR methods are used clinically for the detection of EGFR mutations. The Scorpion Amplification Refractory Mutation System (Scorpion-ARMS) and the cobas® EGFR Mutation Test v2 (cobas v2) are widely used PCR methods. However, those PCR methods only selectively detect the common EGFR mutations. The aim of the present study was to reveal the true frequency of EGFR mutations in NSCLC by investigating EGFR mutations usually undetectable by PCR methods by using direct sequencing. A total of 70 Japanese patients who underwent lung resection for NSCLC between September 2016 and March 2019 were included in the present study. Subsequently, PCR methods and direct sequencing were performed. In total, 29 mutations were detected by cobas v2. In total, 41 patients were identified as EGFR wild-type by cobas v2, among whom direct sequencing detected mutations in 3 patients. Subsequent Scorpion-ARMS was performed in the 3 patients in whom direct sequencing detected mutations. In total, one exon 21 L858R + G863D compound mutation was identified as a L858R single mutation, and two other mutations were undetectable. Moreover, 1 patient who was 'wild-type' on cobas v2 but 'EGFR mutation' on direct sequencing developed recurrence after surgery and responded to EGFR-TKI treatment. In present study, the percentage of undetectable EGFR mutations by cobas v2 was 9.4% in 32 mutations. It was inferred that the cause of the discrepancy in the mutation type (L858R + G863D in exon 21, and L858R in exon 21) between cobas v2 and Scorpion ARMS was due to the different limit of detection between these two PCR methods. In conclusion, the findings of the present study suggested that a selective mutation detection method may decrease the opportunity of patients with NSCLC to receive EGFR-TKI therapy. Thus, the development of a screening test to determine the EGFR status as wild-type or mutant is required for EGFR-TKI therapy.

Digital Breast Tomosynthesis Complements Two-Dimensional Synthetic Mammography for Secondary Examination of Breast Cancer.

OBJECTIVE: To compare the performance of two-dimensional synthetic mammography (SM) combined with digital breast tomosynthesis (DBT) (SM/DBT) and full-field digital mammography (FFDM) including women with DBT (FFDM/DBT) undergoing secondary examination for breast cancer. MATERIAL AND METHODS: Out of 186 breasts, including 52 with breast cancers; FFDM/DBT and SM/DBT findings were interpreted by four expert clinicians. Radiation doses of FFDM, SM/DBT, and FFDM/DBT were determined. Inter-rater reliabilities were analyzed between readers and between FFDM/DBT and SM/DBT by Cohen's Kappa coefficients. Diagnostic accuracy was compared between SM/DBT and FFDM/DBT by Fisher's exact tests. Two representative cancer cases were examined for differences in the interpretation between FFDM and SM. RESULTS: A higher radiation dose was required in FFDM/DBT than in SM/DBT (median: 1.50 mGy vs. 2.95 mGy). Inter-rater reliabilities were similar between both readers and modalities. Both sensitivity and specificity were equivalent in FFDM/DBT and SM/DBT (p = 0.874-1.00). Compared with FFDM, SM did not clearly show abnormalities with subtle margins in the two representative cancer cases. CONCLUSION: SM/DBT had a similar performance to FFDM/DBT in detecting breast abnormalities but requires less radiation. DBT complements SM to improve accuracy to a level equivalent to that of FFDM. Taken together, SM/DBT may be a good substitute for FFDM/DBT for the secondary examination of breast cancer.

Intrathoracic lipoma in the horizontal fissure of the right lung: a case report.

Lipomas are benign tumors that originate from mesenchymal tissue, such as subcutaneous tissue. Intrathoracic lipomas are rare, and they can occur in the chest wall, mediastinum and bronchi. In the present case, the patient had an intrathoracic lipoma that was located in the horizontal fissure of the right lung. Retrospective review of chest radiographs taken at a previous health checkup confirmed that the tumor was growing. The patient had no symptoms, and computed tomography and magnetic resonance imaging suggested that the tumor was a hamartoma. The tumor was resected by video-assisted thoracic surgery, and was diagnosed by pathological analysis as an intrathoracic lipoma consisting of no atypical fats.

Glomus Tumor in a Segmental Bronchus: A Case Report.

Glomus tumors originate from a neuroarterial structure called the glomus body, and grow mostly in soft tissue. It is rare for glomus tumors to develop in the respiratory system. The patient of the present case had an abnormal shadow in the right lung on chest X-ray, and computed tomography (CT) findings displayed a lung tumor in the right S6. Bronchoscopy was performed for the diagnosis of the lung tumor, and a polypoid bronchial tumor was unexpectedly found to occupy the right B3. The bronchial tumor was diagnosed as a glomus tumor, and the lung tumor was diagnosed as an adenocarcinoma. The bronchial glomus tumor was cauterized by argon plasma coagulation (APC). Three weeks after the cauterization by APC, the right lower lobectomy was performed for the treatment of the lung adenocarcinoma. The patient has remained disease free for 2 years.

Comparison of the amino acid profile between the nontumor and tumor regions in patients with lung cancer.

Energy metabolism in cancer cells is reprogrammed to meet the energy demands for cell proliferation under strict environments. In addition to the specifically activated metabolism of cancer, including the Warburg effect and glutaminolysis, most amino acids (AAs) are utilized for gluconeogenesis. Significant increases in AAs and energy metabolites in the tumor region occur in gastric and colon cancers. However, a different AA-related energy metabolism may exist in lung cancer because of the abundant blood supply to lung tissue. This study compared the profiles of AAs and their related metabolites in energy metabolism, analyzed by an HPLC-MS/MS system, between tissues from nontumor and tumor regions collected from 14 patients with non-small cell lung cancer (NSCLC). In the energic metabolism precursor categories, the glucogenic AAs, which included the pyruvate precursors (Ser, Gly, Thr, Ala, and Trp), the α-ketoglutarate precursors (Glu, Gln, and Pro) and the succinyl-CoA precursors (Val, Ile, and Met) were significantly increased in the tumor region compared to in the nontumor region. However, no significant differences existed between the two regions in the ketogenic AAs (Leu, Lys, and Tyr). These differences were not observed between the subgroups with and without diabetes mellitus in the two regions. The metabolites on the left-hand side of the TCA cycle were significantly higher in the tumor region, but no differences in metabolites in the right-hand side. The mRNA expressions of major AA transporters and cancer proliferation factors were also significantly increased in the tumor region, compared to these in their counterparts. In lung cancer, glucogenic AAs that are actively transported from circulating fluids would be predominantly utilized for gluconeogenesis, with and without diabetes mellitus. The characteristics of the AA-related metabolism would be associated with tissue-specific cell proliferation in patients with NSCLC.

Association of Parity and Infant Feeding Method with Breast Density on Mammography.

BACKGROUND: Mammography (MMG) is widely used for the screening and diagnosis of breast cancer. High breast density on MMG prevents breast cancer detection. In the present study, we analyzed the effects of parity and infant feeding method on mammographic breast density. MATERIALS AND METHODS: Ninety women diagnosed as having breast cancer were analyzed. Using the results of medical questionnaires, subjects were grouped according to their parity and infant feeding method, into either nulliparity or parity, and formula-feeding or breastfeeding. Each group consisted of 30 consecutive women from 45 to 49 years. Nulliparous group was unaffected by either parity or breastfeeding, formula-feeding group was affected by parity but not breastfeeding, and breastfeeding group was affected by both parity and breastfeeding. Mammographic breast density was evaluated on the contralateral and cancer-free breast, and was classified into ≥ 50% dense as high breast density and < 50% dense according to the Boyd quantitative scale. The association of parity and infant feeding method with breast density on MMG was analyzed using the Fisher's exact test. RESULTS: Regarding parity, high breast densities were observed in 40% and 17% of nulliparous and parous breasts, respectively. Nulliparous breasts had significantly higher density than parous breasts (p  =  0.010). Regarding infant feeding method, 17% of breasts in both the formula-feeding and breastfeeding groups had high densities. Infant feeding method was not associated with mammographic breast density (p  =  1.0). CONCLUSION: Nulliparity is associated with higher breast density, and parity, regardless of infant feeding method, induces atrophic changes of breast tissue.

Frequency and significance of epidermal growth factor receptor mutations detected by PCR methods in patients with non-small cell lung cancer.

Epidermal growth factor receptor (EGFR) is the most important driver gene of non-small cell lung cancer (NSCLC) as EGFR mutations determine the efficacy of EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy. In the present study, the comprehensive ability of widely used polymerase chain reaction (PCR) methods to detect EGFR mutations was determined. Among the 35 EGFR mutations detected via the direct sequencing of 73 patients with NSCLC, 11 types were identified in exons 18, 19 and 21. Among the 11 mutation types, all exon 18 and 21 mutations were identified by 2 widely used PCR methods, namely, Scorpion-Amplification Refractory Mutation System and cobas v2. However, among the 9 different exon 19 deletions, 3 types were not identified by the 2 methods. In addition, 25 samples with EGFR mutations were analyzed by the 2 methods, including a sample from a patient with an unidentified exon 19 deletion, the T751_I759 deletion and insertion S; this patient had long-term disease control as a result of EGFR-TKI therapy. The 2 methods could not detect this unidentified deletion, whereas sizing capillary electrophoresis for the comprehensive detection of exon 19 deletions detected this deletion. It is generally thought that patients with exon 19 mutations have higher response rates to EGFR-TKI therapy than patients with exon 21 mutations. The present study confirmed the EGFR mutation status by comparing the mutations with the Catalog Of Somatic Mutations In Cancer, which is the world's largest and most comprehensive resource for analyzing the effects of somatic mutations in human cancers. The predicted frequency of EGFR mutations identified by the 2 methods was 85%. The frequency of mutations detectable by the 2 methods was less for exon 19 than exon 21. Therefore, the results of the present study suggest that decreasing false-negative detection of exon 19 deletions is crucial for the clinical testing of EGFR mutations.

Head-down tilt position successfully prevent severe brain air embolism.

Air embolisms are rare life-threatening complications that develop under various conditions, including surgery. During segmentectomy for thoracic surgery, air is blown into the selected bronchus for segment margin detection. This may result in the formation of an air embolus. Herein, we report a case of successful recovery from sudden intraoperative cardiac arrest due to an air embolism in a patient undergoing left superior division segmentectomy via open thoracotomy. Intraoperatively, the patient was positioned head-down. Upon blowing air into the bronchus, the patient suddenly developed cardiac arrest. Open-chest cardiac massage and low-temperature therapy were commenced and the patient recovered. The head-down position prevents the air embolus from reaching the brain and thus prevents severe brain damage, whereas continuous open-chest massage and low temperature prevents severe body damage from anticipated cardiac air embolism. Thus, operation in the head-down position is useful in preventing severe brain damage from brain air embolisms.

Chylothorax in POEMS syndrome.

Chylothorax results from various causes, such as malignancy, trauma, or infection. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) is a multisystemic syndrome that is associated with plasma cell disorder. Pleural effusion is a common manifestation of POEMS syndrome, but the association of POEMS syndrome with chylothorax has not been reported. We report on a 61-year-old female patient who initially presented with dyspnea and bilateral leg edema. Importantly, the patient had normal renal function. Her chest X-ray and computed tomographic imaging showed bilateral pleural effusion, and her chest drainage revealed chylothorax. Detailed examination failed to reveal the definitive cause of the chylothorax. She received several treatments for chylothorax, namely, a low-fat diet or fasting, total parenteral nutrition, a somatostatin analog (octreotide), thoracic duct ligation by video-assisted thoracic surgery, and pleurodesis. However, further examination revealed endocrinopathy, monoclonal plasma cell disorder, peripheral neuropathy, and elevation of the serum level of vascular endothelial growth factor. The patient's condition was consequently diagnosed as POEMS syndrome. Eventually, her chylothorax was controlled by pleurodesis, and she was transferred to another hospital for stem cell transplantation. Herein, we report on the apparent first case of POEMS syndrome with chylothorax. In some cases of idiopathic chylothorax, the underlying primary disease may be latent, such as in the present patient. POEMS syndrome is rare, but this syndrome should be included in the differential diagnosis of chylothorax with unexplained etiology.

Ribosomal synthesis of peptides with C-terminal lactams, thiolactones, and alkylamides.

All change at the C terminus: We have established a novel methodology for the ribosomal synthesis of peptides featuring C-terminal cyclization and various modifications, including macrocyclization, by making use of genetic code reprogramming. The C-terminal amide modification of linear and cyclic peptides should enhance their physiological stabilities, and open up the possibility of developing new drug-like peptides. The C terminus of a peptide expressed by the translation apparatus generally ends in a carboxylate group. On the other hand, the C termini of some naturally occurring peptides have amide moieties instead of carboxylates, which are believed to give better biostability. Here, we describe a new strategy for the ribosomal synthesis of peptides featuring C-terminal lactam, thiolactone, and alkylamide units. The method was based on the concept of genetic code reprogramming involving the flexizymes (flexible tRNA acylation ribozymes) and the PURE (peptide synthesis using recombinant elements) system, in which vacant codons are reassigned to nonproteinogenic amino acids; this enabled us to convert the C termini of peptides into the above functionalities. We have also applied this method to the synthesis of a macrocyclic peptide closed by an amide bond formed between a lysine side chain and the peptide C terminus. This method thus offers us new opportunities to express various peptides with C-terminal modifications as well as macrocyclic peptides using the translation apparatus, and potentially to accelerate the discovery of peptidic drugs designed for various therapeutic targets.

EGFR and HER2 genomic gain in recurrent non-small cell lung cancer after surgery: impact on outcome to treatment with gefitinib and association with EGFR and KRAS mutations in a Japanese cohort.

BACKGROUND: Sensitivity to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and frequency of activation mutations in EGFR is lower in Caucasian than Asian non small-cell lung cancer (NSCLC) patients. Increased EGFR gene copy numbers evaluated by fluorescence in situ hybridization (FISH) has been reported as predictor of clinical benefit from EGFR-TKIs in Caucasian NSCLC patients. This study was carried out to verify whether EGFR FISH had similar performance in Japanese patients. METHODS: A cohort of 44 Japanese patients with recurrent NSCLC after surgery was treated with gefitinib 250 mg daily. The cohort included 48% females and 52% never-smokers; 73% had prior chemotherapy and 57% had stage III-IV at the time of surgery. Adenocarcinoma was the most common histology (86%). FISH was performed using the EGFR/Chromosome Enumeration Probe 7 and PathVysion DNA probes (Abbott Molecular). Specimens were classified as FISH positive when showing gene amplification or high polysomy (> or = 4 copies of the gene in > or = 40% of tumor cells). Tumor response to gefitinib was assessed by RECIST for 33 patients with measurable diseases. RESULTS: Twenty-nine tumors (66%) were EGFR FISH+ and 23 (53%) were HER2 FISH+. Overall response rate was 52%, representing 65% of EGFR FISH+ patients and 29% of EGFR FISH- patients (p = 0.0777). Survival was not impacted by the EGFR FISH (p = 0.9395) or the HER2 FISH (p = 0.0671) status. EGFR FISH+ was significantly associated with HER2 FISH+ (p = 0.015) and presence of EGFR mutation (p = 0.0060). EGFR mutation significantly correlated with response (p < 0.0001) and survival after gefitinib (p = 0.0204). EGFR and HER2 FISH status were not associated with KRAS mutation. CONCLUSION: Frequency of EGFR FISH+ status was higher and its predictive power for TKI sensitivity was lower in this Japanese cohort than in Western NSCLC cohorts. These findings support differences in the mechanisms of EGFR pathway activation in NSCLC between Asian and Caucasian populations. Confirmation of these results in larger cohorts is warranted.

[Adjuvant chemotherapy for resectable non-small cell lung cancer (NSCLC)].

A randomized clinical trial of adjuvant chemotherapy has been evaluated for non-small cell lung cancer (NSCLC) patients, because the prognosis of early NSCLC does not enough after surgery (stage I: 70-80%, stage II: 50% in overall 5-years survival). Japanese guide line for lung cancer treatment (2005 edition) recommends adjuvant chemotherapy after complete resection for pathological stage IB, II and IIIA. Previous studies have suggested that uracil-tegafur has benefit for stage IB NSCLC patients, and platinum-based adjuvant chemotherapy has benefit for stage IB, II and IIIA NSCLC patients. In 2007 ASCO Annual Meeting, Harpole D talked about molecular prognostic profiles in early resected NSCLC. The goal of this study design is to validate a molecular-based tumor model that identifies those patients at low risk for cancer recurrence who will not benefit from adjuvant chemotherapy. The remaining patients will be randomly assigned to observation (the present standard of care) or adjuvant chemotherapy to determine the efficacy of adjuvant in this population. Biomarker for response of chemotherapy will be available to know who has benefit from adjuvant chemotherapy. When each patient has appropriate adjuvant chemotherapy, the prognosis is improved by that.

Omental transposition for lymphedema after a breast cancer resection: report of a case.

Lymphedema of the arm and hand is one of the major complications after a breast cancer resection. Conservative treatment for the treatment of lymphedema, such as compression garments and centripetal massage, is very important for these cases. However, if the lymphedema is difficult to control with conservative treatment and the patient's quality of life (QOL) is compromised due to swelling of the arms, surgical treatment should be considered. We used omental transposition to improve the status of lymphedema in the present patient whose left arm and hand had been swollen for 5 years, which thus prevented her from being able to lift her arm. After the operation, she was able to lift her left arm herself and perform tasks with her left hand, thereby obtaining a better QOL than before the operation regarding her left arm movement.

Four cases of chylous fistula after breast cancer resection.

Chylous fistulas in cases treated surgically for breast cancer only, are rare. We encountered four chylous fistula cases after breast cancer operations out of a total of 851 cases, all of which involved the left breast. Chylous fistulas were confirmed by axillary white fluid and were unrelated to obesity, surgical method or the area of axillary lymph node dissection. All four cases of chylous fistulas were successfully treated conservatively, with no special dietary control and no surgical treatment.

Spondyloepimetaphyseal dysplasia with joint laxity leptodactylic form: clinical course and phenotypic variations in four patients.

We describe a 5-year-old boy and a 33-year-old woman with spondyloepimetaphyseal dysplasia with joint laxity leptodactylic form (spondyloepimetaphyseal dysplasia with multiple dislocations) (MIM 6003546), and two 12-year-old girls with the disorder who were previously reported as examples of a variant of sponatrime dysplasia. Their clinical manifestations included midface hypoplasia, micromelic short stature, and generalized joint laxity that caused multiple joint problems, including thoracolumbar scoliosis, hip subluxation, progressive genu valgum with knee and patellar subluxation, elbow subluxation, and malalignment of the wrist. Laryngotracheomalacia was present in two individuals, and myopathy was noted in one. The radiological findings in the four individuals included mild platyspondyly most conspicuous in infancy, narrow interpediculate distances of the lumbar spine evident in infancy, retarded epiphyseal ossification that evolved to epiphyseal dysplasia and later to degenerative joint disease, metaphyseal irregularities and striations present in early childhood, and leptodactylic appearance (slender short tubular bones) of the hand.