Co-active receptor tyrosine kinases mitigate the effect of FGFR inhibitors in FGFR1-amplified lung cancers with low FGFR1 protein expression.

Targeted therapies are effective in subsets of lung cancers with EGFR mutations and anaplastic lymphoma kinase (ALK) translocations. Large-scale genomics have recently expanded the lung cancer landscape with FGFR1 amplification found in 10-20% of squamous cell carcinomas (SCCs). However, the response rates have been low for biomarker-directed fibroblast growth factor receptor (FGFR) inhibitor therapy in SCC, which contrasts to the relatively high rates of response seen in EGFR mutant and ALK-translocated lung cancers treated with epidermal growth factor receptor (EGFR) inhibitors and ALK inhibitors, respectively. In order to better understand the low response rates of FGFR1-amplified lung cancers to FGFR inhibitors, relationships between gene copy number, mRNA expression and protein expression of FGFR1 were assessed in cell lines, tumor specimens and data from The Cancer Genome Atlas. The importance of these factors for the sensitivity to FGFR inhibitors was determined by analyzing drug screen data and conducting in vitro and in vivo experiments. We report that there was a discrepancy between FGFR1 amplification level and FGFR1 protein expression in a number of these cell lines, and the cancers with unexpectedly low FGFR1 expression were uniformly resistant to the different FGFR inhibitors. Further interrogation of the receptor tyrosine kinase activity in these discordant cell lines revealed co-activation of HER2 and platelet-derived growth factor receptor-α (PDGFRα) caused by gene amplification or ligand overexpression maintained phosphoinositide 3-kinase (PI3K) and MEK/ERK signaling even in the presence of FGFR inhibitor. Accordingly, co-inhibition of FGFR1 and HER2 or PDGFRα led to enhanced drug responses. In contrast, FGFR1-amplified high FGFR1 protein-expressing lung cancers are sensitive to FGFR inhibitor monotherapy by downregulating ERK signaling. Addition of a PI3K inhibitor to these high FGFR1 protein-expressing cancers further sensitized them to FGFR inhibitor. These data reveal that biomarker-directed trials for FGFR1-amplified SCC require assessment of FGFR1 protein expression and uncover novel therapeutic strategies for FGFR1-amplified SCC with low FGFR1 protein expression.

FHL1 on chromosome X is a single-hit gastrointestinal tumor-suppressor gene and contributes to the formation of an epigenetic field defect.

Tumor-suppressor genes on chromosome X can be inactivated by a single hit, any of the point mutations, chromosomal loss and aberrant DNA methylation. As aberrant DNA methylation can be induced frequently, we here aimed to identify a tumor-suppressor gene on chromosome X inactivated by promoter DNA methylation. Of 69 genes on chromosome X upregulated by treatment of a gastric cancer cell line with a DNA-demethylating agent, 5-aza-2'-deoxycytidine, 11 genes had low or no expression in the cell line and abundant expression in normal gastric mucosae. Among them, FHL1 was frequently methylation-silenced in gastric and colon cancer cell lines, and methylated in primary gastric (21/80) and colon (5/50) cancers. Knockdown of the endogenous FHL1 in two cell lines by two kinds of shRNAs significantly increased cell growth in vitro and sizes of xenografts in nude mice. Expression of exogenous FHL1 in a non-expressing cell line significantly reduced its migration, invasion and growth. Notably, a somatic mutation (G642T; Lys214Asn) was identified in one of 144 colon cancer specimens, and the mutant FHL1 was shown to lack its inhibitory effects on migration, invasion and growth. FHL1 methylation was associated with Helicobacter pylori infection and accumulated in normal-appearing gastric mucosae of gastric cancer patients. These data showed that FHL1 is a methylation-silenced tumor-suppressor gene on chromosome X in gastrointestinal cancers, and that its silencing contributes to the formation of an epigenetic field for cancerization.

Evaluation of beta-blocker therapy in patients with dilated cardiomyopathy--Clinical meaning of iodine 123-metaiodobenzylguanidine myocardial single-photon emission computed tomography.

BACKGROUND: Patients with heart failure show signs of cardiac sympathetic dysfunction such as elevation of blood norepinephrine (NE) level, as a result of reduction in the number of sympathetic nerves, decrease in myocardial NE content, accelerated NE turnover or spillover of NE, and NE reuptake disorder at sympathetic nerve endings. In dilated cardiomyopathy (DCM), iodine 123-metaiodobenzylguanidine (MIBG) used clinically as a tracer for imaging of the sympathetic function was found to be useful in evaluation of severity and prognosis. METHODS AND RESULTS: A total of 143 (123)I-MIBG myocardial single-photon emission computed tomography (SPECT) images were taken at successive intervals on 58 patients with DCM (mean age 54 +/- 11 years), as well as before and after therapy to determine the severity of DCM and the therapeutic effect of beta-blocker. Patients were divided into group A (n = 20), in which left ventricular ejection fraction (LVEF) improved by 10% or more within 6 months after the administration of beta-blocker, and group B (n = 20), in which there was less than a 10% change in LVEF. After (123)I-MIBG myocardial SPECT was taken, the washout rate for the entire left ventricle was calculated from early and delayed images. The estimations of extent score and severity score were based on the polar map prepared from short axial images taken from 17 healthy volunteers (mean age 35 +/- 5 years). There was a significant correlation between LVEF and (123)I-MIBG findings (extent score, severity score, and washout rate) obtained before and after beta-blocker therapy. After beta-blocker therapy, LVEF and (123)I-MIBG findings significantly improved in group A. On the other hand, no change occurred in (123)I-MIBG findings in group B. There was no significant difference in LVEF between group A (32.1% +/- 8.0%) and group B (29.5% +/- 7.2%). Also, there was no significant difference in the washout rate between group A (54.4% +/- 10.9%) and group B (52.9% +/- 7.2%). Comparison of (123)I-MIBG images before beta-blocker therapy of group A and group B revealed that the extent score (26.5 +/- 16.0 vs 44.5 +/- 21.1, respectively; P <.01) and the severity score (24.9 +/- 21.9 vs 58.2 +/- 35.2, respectively; P <.01) on the basis of the early (123)I-MIBG image was significantly lower for group A. CONCLUSIONS: From the above findings, patients with DCM in which (123)I-MIBG uptake is high on early images were expected to show improvement in cardiac function by beta-blocker therapy. Findings also suggested that (123)I-MIBG was useful for examining the severity of DCM, determining the applicability of beta-blocker therapy, estimating the maintenance dosage of beta-blocker, and evaluating prognosis.

Are superficial bullae with broad bases suitable for ablation?

Superficial bullae with broad bases are not suitable for resection, because the residual lung is too deformed to re-expand adequately when we resect them. Therefore, we believe superficial bullae with broad bases are suitable for ablation. It is not clear, however, whether ablated superficial bullae with broad bases remain contracted after treatment or not. We examined the morphologic changes of ablated superficial bullae with broad bases on chest computed tomographs. Ten patients with superficial bullae with broad bases that could be identified on computed tomograph underwent ablation using an electrocoagulator. These bullae were examined by chest computed tomograph preoperatively and again one, three and 12 months after surgery. There were no intra-operative complications. Postoperatively, the only complication was prolonged air leak (more than 7 days) in 1 (10%) patient. Pneumothorax after the operation presented in 1 (10%) patient. Morphologically, a disappearance of air space associated with bulla-wall thickness was observed in 9 (90%) of the 10 heat-ablated lesions and air space decreased in 1 (10%) lesion. Heat ablation proved to be effective in patients with SBBs. Lesions remained contracted for at least one year after the operation.

[The role of surgery for chronic empyema of the advanced ages].

Chronic empyema, a sequelae of pulmonary tuberculosis, is now a only tuberculosis-related disease which was remained to be treated surgically. The candidates who have basically poor respiratory function are now attained advanced age. Over a 15 years period (1980-95), 22 patients 70 years of age or older underwent surgical intervention for chronic empyema at our hospital. There were 17 men and 5 women, ranging from 70 to 80 years of age (median age 75.0). They were 15.3% of all 145 surgically treated patients during same period. The empyema continued latent from 25 to 58 years (average 39.8 years). On admission they complained of productive cough (9), fever (9), hemosputam (5) and mass on the chest wall. Their Hugh-Johnes classification for dyspnea was I.: 4, II.: 6, III.: 11, IV.: 1 respectively. Their %VC ranged from 31.5 to 79.0 (average 54.8). In fifteen patients, tubercle bacilli (5), aspergillus (3) and other bacteria (9) were discovered in the empyema space. Surgical procedures consisted of 1 pneumonectomy (4.5%), 12 decortication or curettage of empyema wall (54.5%), 4 extraperiosteal air plombage (18%) and 5 other procedures (muscle or omental plombage, thoracoplasty, fenestration and others) (22.7%). There were no operative death and no lethal postoperative complication. In contrast, lethal postoperative complications such as GVIID, MOF and gastrointestinal bleeding occurred in the younger group. There were 2 cases of late respiratory failure in 70 years or older and 6 cases in younger group. Seventy-four years man who, preoperative %VC 33.0, underwent pneumonectomy died of asphyxia 6 month postoperatively. Another 74 years man who, preoperative %VC 76.1, developed respiratory failure after relapse of pulmonary tuberculosis. Four patients of younger group who developed late respiratory failure had all received thoracoplasty as a second operation. Other 2 patients, preoperative %VC 33.0 and 27.4 respectively, had undergone pneumonectomy. The risk of lethal postoperative complication or late respiratory failure were dependent mainly on preoperative respiratory function or surgical procedure selected rather than the age of patients.

[Chest wall reconstruction for lung cancer patient].

To prevent flail chest after chest wall resection, chest wall reconstruction was performed to 74 primary lung cancer patients during the period between 1975 and 1994, out of 1,435 resected lung cancer patients, while in 29 cases, chest wall resection were performed without reconstruction. Numbers of ribs resected were from 1 to 5, mean 2.7, median 3. Chest wall reconstructions were performed in 66.7% of the patients for 2 ribs resected cases, 83.8% for 3 ribs cases, and 90.9% for more than 4 ribs cases. For chest wall reconstruction double layered Marlex mesh was used since 1982, while Dacron or Teflon felt was used until 1984. There was no flail chest, wound infection or operative death in the patients with chest wall resection and reconstruction. Survival curve of the p-T 3 N 0, 1 M 0 received chest wall reconstruction was compatible to the stage II cases out of 1,435 resected lung cancer patients (47.1% and 43.0% at 5 years). There is no need to perform chest wall reconstruction in cases like 1st to 3rd rib resection, or whose chest wall defect is covered with scapula. If the chest wall defect is lower than that and also lateral or anterior, chest wall reconstruction is indicated, even if resected ribs are less than 3. We should not hesitate to remove chest wall in order to get complete resection of the tumor, if tumor invasion is suspected surgically. Because we can reconstruct the chest wall with satisfactorily low risk of complications.

[Clinical meaning of 123I-MIBG myocardial SPeCT in patients with dilated cardiomyopathy].

MIBG-myocardial SPECT was performed on patients with dilated cardiomyopathy (DCM) undergoing treatment with beta blocker (Nipradilol). The findings of MIBG-myocardial SPECT were compared with the changes in cardiac function obtained by echocardiograms. The patients enrolled in the study were seven males who has been diagnosed as definitely suffering from DCM according to diagnostic guidelines provided by the Ministry of Health and Welfare. The patients were aged 57.5 +/- 10.2 years. Following intravenous administration of 111 MBq (3 mCi) of MIBG, myocardial SPECT was taken 20 minutes, and 4 hours later. The washout rate of the left ventricular wall was higher in the unchanged group (40.7 +/- 1.2%) than in the improved group (30.3 +/- 6.1%). Both the early and delayed images showed higher extent and severity scores for the unchanged group than for the improved group. A correlation of LVEF with the washout rates was demonstrated (r = -0.819, p < 0.05). A correlation was also observed between the variations in LVEF before and after beta blocker therapy with the washout rates (r = -0.969, p < 0.01), MIBG-myocardial SPECT suggested possibility of the evaluation of severity and prognosis in the patients with DCM.

Carcinosarcoma of the lung. Report of a case and review of the literature.

We describe a case of carcinosarcoma of the lung in a 60-year-old female who was admitted with complaints of productive cough and an abnormal shadow in the chest X-ray. Sputum cytology showed both squamous cell carcinoma and adenocarcinoma cells. Malignant nonepithelial cells were identified in the needle biopsy specimen. Right middle and lower lobectomy was performed to reveal a carcinosarcoma by microscopic and immunohistochemical examination. This case was histologically unusual because it presented multiple carcinomatous elements (squamous cell carcinoma and adenocarcinoma). It was classified as peripheral type according to the clinical classification, showing an extremely poor prognosis. The histogenesis and clinical features of this rare tumor are discussed.

[The role of surgery in the treatment of chronic empyema].

For the last ten years we had 56 patients operated for the empyema which occupied almost all the thoracic cavity. We evaluated their postoperative pulmonary functions and their sequelae. The pathological features of the resected lung and empyema wall were also examined. Surgical procedures consisted of 25 extraperiostal air plombage, 14 pleuropneumonectomy, 8 decortication, and 9 other procedures (lobectomy, muscle-flap, omental flap, and others). Preoperative %VC of patients with extraperiostal air plombage, those with pleuropneumonectomy, those with decortications and those with other procedures were 59.6 +/- 12.6, 46.4 +/- 11.1, 63.0 +/- 10.1, and 53.8 +/- 11.7 respectively. Of 11 patients who developed severe respiratory impairments (%VC less than 40 and/or FEV 1/VC predicted less than 30) post operatively, 4 had extraperiostal air plombage, 4 had pleuropneumonectomy, and 3 had other procedures. In general, degree of respiratory impairment was more severe in patients who underwent multiple surgical procedures. Of 18 patients who survived 5 years or more, %VC was under 50% in 9, and of those nine patients five had 30% decrease in VC compared to the preoperative values and there were 2 patients with extraperiostal air plombage in whom extreme shrinkage and deformity of hemithorax were observed though they had neither additional surgeries nor recurrences. Hemangioma was often seen on the walls of empyema and in some they became so large as to cause mediastinal shift. There were patients with round atelectasis, which, we thought, could have caused abscess or inflammatory granuloma.

Effect of pulmonary blood flow on lung water and pulmonary hemodynamics in the canine lung lobe.

The isolated left middle lobes of canine lungs were perfused in situ, by stepwise elevation of the blood flow. The weight gain of the lung lobe per initial bloodless dry lung weight (delta w g/min.IdQ1) showed a significant (p less than 0.001) correlation with the blood flow per body weight (F, ml/min.kg) with a regression line of delta w = 8.3 X 10-4F2.3. The pulmonary venous pressure (Pv) correlated significantly (p less than 0.001) with the pulmonary artery pressure (Pa), i.e. Pa = 11.2 + 1.3 Pv, with a constant left atrial pressure (Pla). The total pulmonary vascular resistance [TPVR = (Pa - Pla)/F] and the small pulmonary artery resistance [SR = (Pa-Pv)/F] decreased by steps with a constant pulmonary venous resistance (VR = TPVR-SR), and VR/TPVR increased by steps as the flow was increased. By incremental blood flow through the restricted lung tissue, we conclude that fluid filtration into the interstitium was flow-dependent, the pulmonary capillaries and precapillaries provided a large capacity for blood flow and the resistance to the flow was directed to the postcapillary site.

Statistical survey of tracheobronchoplasty in Japan.

In a survey of 142 hospitals in Japan, 1562 operations involving tracheobronchoplasty, 565 involving tracheoplasty, and 992 involving bronchoplasty were found to have been done from 1954 to 1984. The number of operations showed a steep increase from 1965 and reached more than 200 a year by 1984. This increase comes from larger numbers of bronchoplasty procedures being performed for lung cancer (58.8% in toto) and of tracheoplasty procedures for thyroid cancer (9.7% in toto). Fifty-seven operative modes could be classified, in which bronchial anastomosis was most frequent (62.1%), followed in order by tracheal anastomosis (18.0%), and tracheobronchial anastomosis (5.9%). Complications, encountered in 16.9% in toto, resulted in death in 22.3%, with fistula bleeding in all and anastomotic stricture in 47.7%. Anastomotic stricture alone had a higher mortality rate than anastomotic stricture combined with recurrent palsy (p less than 0.01). The tracheal anastomosis mode had a higher complication rate than that of the bronchial anastomosis mode (p less than 0.01). Among the 57 modes, the complication rates were lower than those of each stem mode in the following: suture of the tracheal wall (p less than 0.05), tracheal patch grafting (p less than 0.01), sleeve resection of the right main bronchus (p less than 0.02), and sleeve lobectomy of the right lower lobe (p less than 0.001). Complication rates were higher than those of each stem mode in these procedures: prosthetic replacement of the trachea (p less than 0.001), sleeve resection of the right main bronchus (p less than 0.05), and the montage-type carinal reconstruction (p less than 0.05) modes. The tracheal anastomosis mode was classified into two categories, standard and extensive. The latter showed complication rates higher than the former (p less than 0.01), tracheoplasty (p less than 0.0025), and the tracheal anastomosis stem mode (p less than 0.0025). Complication rates have decreased with time, being 21.8% with the tracheal anastomosis mode and 10.8% with the bronchial anastomosis mode in the past 9 years.

[Prognostic values of the doubling time of serum carcinoembryonic antigen and calcitonin levels in medullary thyroid carcinoma].

Fifteen patients operated on for medullary thyroid carcinoma with elevated postoperative serum calcitonin (CT) levels underwent serial measurements of serum CT and carcinoembryonic antigen (CEA) levels. Both CT and CEA levels showed an exponential increase in 12 patients and a slight decrease in three. CEA levels manifested less fluctuation than CT levels. The doubling time of these tumor marker levels calculated from the regression line in each patient showed a strong correlation with three-year survival, recurrence within five years, and the time interval between surgery and recurrence of the tumor, allowing quantitative prediction of the prognosis. However, the doubling time of CEA was longer than that of CT in most patients.

Tracheobronchoplasty for lung cancer.

Forty-seven patients were pathologically studied in order to identify the kind of local tumoral spread occurring in lung cancer with particular reference to direct infiltration, intra and peribronchial metastasis and multicentricity. The potential absolute and relative criteria for bronchoplasty for lung cancer are discussed. Eighty-three patients were treated over a five-year period with bronchoplasty for malignancy. Survival data show that bronchoplasty can cure some patients with an absolute indication and save lobar function or improve surgical radicality in patients with relative indications.