Taishi Harada

Background: Bone is one of the frequent cancer metastatic lesion, and bone metastasis develop poor patient prognosis because of cancer pain, pathological fracture, and spinal cord compression. For lung cancer patients with bone metastasis and high bone metabolic marker, it is suggested that suppressing the marker by zoledoronic acid improve patient prognosis.

As the incidence of lung cancer in the elderly is increasing worldwide, there exists a need to develop a clinically effective, less toxic therapy for this patient population. Although erlotinib has shown proven effectiveness against non-small cell lung cancer (NSCLC), few studies have prospectively investigated its application to elderly patients. Patients aged ≥75 years with advanced or recurrent NSCLC including wild-type EGFR who had previously received one or two chemotherapy regimens were enrolled in this trial. Erlotinib was initially administered at a dose of 150 mg/day orally until disease progression or unacceptable toxicities occurred. The primary endpoint was the objective response rate. Forty patients were enrolled between May 2009 and January 2014. An objective response was observed in 8 patients (20%, 95%CI=9.1-35.7%), and the disease control rate reached 62.5% (95%CI=45.8-77.3%). After a median follow-up period of 12.2 months (range=1.4-47.2 months), the median progression-free survival period was 5.0 months (95%CI=2.3-7.6 months), and the median survival period was 12.2 months (95%CI=6.1-24.7 months). Major toxicities were skin disorders, fatigue, and anorexia. Most adverse events were grade 2 or less, but 13 patients (32.5%) required a dose reduction. Two patients developed interstitial lung disease, that was nevertheless reversible, and there were no treatment-related deaths. Although the percentage of patients requiring dose reduction seemed relatively higher than that in previous studies, erlotinib is a potentially useful therapeutic option for unselected elderly patients with previously treated advanced or recurrent NSCLC, as has been also shown for younger patients.

Here, we report a case of lung adenocarcinoma resistant to crizotinib harboring KRAS mutation and the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene. Our case suggests that KRAS mutation in addition to EML4-ALK fusion gene may cause the resistance to crizotinib. J Med Cases. 2014;5(12):631-633 doi: http://dx.doi.org/10.14740/jmc1985w

A 65-year-old woman was referred to our hospital for investigation of increased opacity in the right lower lung field of the chest X-ray. Chest CT demonstrated a large tumor in the right thoracic cavity. A preoperative needle biopsy was performed. The microscopic appearance revealed many spindle cells. An immunohistochemical study was positive for CD34 and vimentin. Solitary fibrous tumor of the pleura was strongly suspected and the operation was performed. The tumor arose from the visceral pleura and was pedunculated. The resected specimen was positive for CD34 and vimentin. The tumor was diagnosed as solitary fibrous tumor of the pleura. Although this case was diagnosed 11 years after detection, the tumor was completely resected. Solitary fibrous tumors are usually cured with complete resection, but long-term clinical follow up is needed because of the possibility of recurrence and metastasis.

Nuclear factor kappaB (NFkappaB) is a transcription factor which is importantly implicated in cancer cell growth. In a previous report, we confirmed that lung cancer cell growth was suppressed significantly by the blockade of NFkappaB function. In this study the combination effect of chemotherapy and inhibition of NFkappaB on the human lung cancer cell line, NCI-H460, in vitro and in vivo was investigated. In the in vitro experiment, 50% of cell growth inhibitory concentrations (IC50) of chemotherapy agents were determined alone or when combined with adenovirus mediated IkappaBalpha gene transfer. Annexin-V/PI stain and caspase 3 activity measurement were used to detect the apoptosis caused by treatment. In the in vivo experiment, the tumor growth suppressive effect of combination treatment was evaluated for tumor-bearing mice. NFkappaB, p53 and VEGF expression in the tumors were also analyzed immunohistologically. Several chemotherapy agents, including paclitaxel, showed lower IC50s when combined with AdIkappaBalpha infection in vitro. Apoptosis through activation of the caspase 3 pathway was enhanced by the combination treatment. For established NCI-H460 tumors, combined treatment significantly inhibited tumor growth. Immunohistochemical staining showed increased expression of p65 after paclitaxel treatment, while paclitaxel in combination with AdIkappaBalpha intratumoral injection eliminated this expression accompanied by the slightly reduced expression of VEGF, with stable p53 status. A combination of chemotherapy and IkappaBalpha could inhibit tumor growth effectively by blocking the expression of NFkappaB and inducing apoptosis. Moreover, it might allow reduction of the dose of chemotherapy agents and provide benefit for clinical application.

Determining an effective predictor of clinical drug resistance in small cell lung cancer (SCLC) is considered to be important. In this study, the relationship between the expression of P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) and MRP2, which are the members of ATP-binding cassette superfamily transporter, and of the p53 tumor suppressor gene and the response to chemotherapy were analysed. The expression of P-gp, MRP1, MRP2, and p53 was determined by an immunohistochemical analysis of transbronchial biopsy (TBB) specimens from 61 SCLC patients. The relationship of such expression was also investigated regarding chemotherapy and clinicopathological factors. The response rate in the MRP2-negative group was significantly higher than that in the MRP2-positive group (88% versus 50%). The P-gp-negative group responded significantly better to chemotherapy than the P-gp-positive group, with a response rate of 81% versus 39%. No relationship could be found between the response to chemotherapy and immunostaining for MRP1 or p53. In 37 patients treated with platinum-based chemotherapy, the response rate of patients in the MRP2-negative group was significantly higher than that in the positive group (92% versus 50%). In a multiple logistic regression analysis, MRP2 as well as P-gp were shown to be statistically significant predictors of chemotherapy resistance. These results suggest that immunostaining of MRP2 for TBB specimens may help to predict clinical resistance to platinum agents. This is the first report which indicates that the immunohistochemical expression of MRP2 is positively related to a clinical resistance to platinum.

A 73-year-old man complaining of bloody sputum was admitted to our hospital in August 2000. His giant left lower lung field bulla had been removed in 1997, at which time atelectasis in left S10 was pointed out. Production of bloody sputum was stopped by the emergency bronchial artery embolization, and Nocardia species was found in the sputum. Because of both spontaneous disappearance of Nocardia species and no evidence of Nocardia infection, he was followed carefully by chest radiography every few months. Consolidation appeared in the left lower lung field and right upper lung field in 2005. Nocardia asteroides was frequently obtained from his sputa and lavage fluid under bronchoscopy. Therefore, we diagnosed pulmonary nocardiosis. Oral cotrimoxazole (Trimetoprim 15 mg/kg) was started, the dosage was halved because of adverse effects. Six months of treatment with cotrimoxazole resulted in improvement of the Nocardiosis.

Bleomycin is a radiomimetic antitumor agent with unique genotoxic properties. 1-nitropyrene is an environmental mutagen and carcinogen that undergoes both oxidative and reductive metabolism. In the present study, hepatocellular carcinomas were induced in male A/J mice by the intraperitoneal injection of bleomycin (120 mg/kg) followed by the intraperitoneal administration of 1-nitropyrene (total dose: 1,575 mg/kg). In order to understand the mechanism by which these two compounds induce hepatocellular carcinomas, the incidence and spectrum of mutations in the K-ras proto-oncogene in these hepatocellular carcinomas were analyzed. The hepatocellular carcinomas were induced by the administration of bleomycin and 1-nitropyrene were evaluated for point mutations in exon 1 and exon 2 of the K-ras gene by the polymerase chain reaction and a sequencing analysis. No mutation was found in the hotspots regions of the K-ras gene codon 12, 13, or 61. However, the codon 64 of the K-ras gene mutation was identified in 10 of 10 (100%) hepatocellular carcinomas. All mutations showed the same pattern, which was TAC-CAC transition. Codon 64 of the K-ras gene mutation may thus play an important role in the induction of hepatocellular carcinomas by bleomycin in the existence of 1-nitropyrene. As far as we know, this is the first report of a codon 64 mutation in the K-ras gene in a chemically induced tumor.

The aim of the study is to search the efficient way for the prevention of nosocomial tuberculosis (TB) infection in a university teaching hospital. Through a questionnaire, informations on the degree of interest in TB, on the way how they try to learn about TB infection, and on basic knowledge of TB epidemiology were obtained. The study subjects were most employees including physicians, nursing staffs, medical technicians, pharmacists, clerks as well as medical and dental students, who were younger than 40 years. The study was done from 1999 through 2001, and a total of 2,159 questionnaires in which age, sex and occupational category were completely described were analyzed. Out of total participants, 61.8% participants showed interest in TB, however, only 3.0% had actually attended lecture meeting or collected materials on TB infection. Out of 619 nursing staffs, 431 (69.6%) felt anxiety for TB infection and the disease, and it was significantly higher than the other occupational groups. Of 2,159 participants, 1,472 (68.2%) participants desired to have health examination for TB. On the other hand, less than 50% participants including physicians answered correctly to questions about basic knowledge of TB epidemiology. Through the present study, it was suggested that employees and students in a university hospital do not voluntarily learn about TB, or do not have enough knowledge on TB in spite of their anxiety or interest, but that they are well prepared to obtain essential informations on the prevention of TB infection. Thus, it would be worthwhile to establish a system of education and health examination for the prevention of nosocomial TB infection. On the other hand, the degree of interest in and anxiety about TB in clerical employees was relatively low. Since they have some risk of TB infection through a service at window, the strengthening of health education on TB for them would be necessary.