Sensitivity and Resistance of MET Exon 14 Mutations in Lung Cancer to Eight MET Tyrosine Kinase Inhibitors In Vitro.

BACKGROUND: MNNG HOS transforming gene (MET) exon 14 mutations in lung cancer, including exon 14 skipping and point mutations, have been attracting the attention of thoracic oncologists as new therapeutic targets. Tumors with these mutations almost always acquire resistance, which also occurs in other oncogene-addicted lung cancers. However, the resistance mechanisms and treatment strategies are not fully understood. METHODS: We generated Ba/F3 cells expressing MET exon 14 mutations by retroviral gene transfer. The sensitivities of these cells to eight MET-tyrosine kinase inhibitors (TKIs) were determined using a colorimetric assay. In addition, using N-ethyl-N-nitrosourea mutagenesis, we generated resistant clones, searched for secondary MET mutations, and then examined the sensitivities of these resistant cells to different TKIs. RESULTS: Ba/F3 cells transfected with MET mutations grew in the absence of interleukin-3, indicating their oncogenic activity. These cells were sensitive to all MET-TKIs except tivantinib. We identified a variety of secondary mutations. D1228 and Y1230 were common sites for resistance mutations for type I TKIs, which bind the active form of MET, whereas L1195 and F1200 were common sites for type II TKIs, which bind the inactive form. In general, resistance mutations against type I were sensitive to type II, and vice versa. CONCLUSIONS: MET-TKIs inhibited the growth of cells with MET exon 14 mutations. We also identified mutation sites specific for TKI types as resistance mechanisms and complementary activities between type I and type II inhibitors against those mutations. These finding should provide relevant clinical implication for treating patients with lung cancer harboring MET exon 14 mutations.

Video-Assisted Thoracoscopic Surgery after Preoperative CT-Guided Lipiodol Marking of Small or Impalpable Pulmonary Nodules.

PURPOSE: Small pulmonary lesions that include ground-glass attenuation have been increasingly discovered because of progressive imaging diagnostic technologies. Despite the detection of such small lesions, sometimes it is quite difficult to localize them because of their size or considerable depth from the visceral pleura. In the present study, we examined the usefulness of computed tomography-guided lipiodol marking for thoracoscopic resection of impalpable pulmonary nodules. METHODS: Fifty-six patients with an undiagnosed peripheral lesion(s) of the lung who had undergone preoperative computed tomography-guided lipiodol marking followed by video-assisted thoracoscopic surgery were studied. RESULTS: All of the nodules were successfully marked by computed tomography-guided lipiodol marking, and all except for one case were localized by means of intraoperative fluoroscopy as clear spots. With regard to complications, pneumothorax occurred in 21 patients (37.5%), and only one patient required transient drainage. Although hemorrhaging in the lung parenchyma and hemosputum occurred in nine patients (16.1%) and one patient (1.8%), respectively, no patients were in serious condition. No intra- or postoperative mortality or morbidity was observed. CONCLUSION: Preoperative computed tomography-guided lipiodol marking of small or impalpable pulmonary nodules is a safe and useful procedure for thoracoscopic resection of the lung.

Anastomotic stenosis of the descending colon caused by barium granuloma formation following barium peritonitis: report of a case.

Anastomotic stricture reportedly often recurs following barium peritonitis, regardless of whether the anastomotic diameter is initially sufficient. However, the causes of repetitive stricture have not been clarified. We report a case that suggests the pathophysiology of recurrent anastomotic strictures following barium peritonitis. The patient was a 39-year-old Japanese man with idiopathic perforation of the descending colon after undergoing an upper gastrointestinal barium contrast study. After emergency peritoneal lavage and diverting colostomy, created using the perforated region, the patient recovered uneventfully and 3 months later, the colostomy was closed and the perforated colon was resected. However, 7 months after colostomy closure, abdominal distention gradually developed, and colonoscopy revealed an anastomotic stricture. The patient was referred to our hospital where he underwent resection of the anastomotic stricture. The surgical specimen exhibited barium granulomas not only in the subserosa of the entire specimen, but also in the submucosa and lamina propria localized in the anastomotic site. These findings suggest that barium was embedded in the submucosa and lamina propria with manipulation of the stapled anastomosis and that the barium trapped in the anastomotic site caused persistent inflammation, resulting in an anastomotic stricture.

[A retrospective study of UFT and oral leucovorin combination adjuvant chemotherapy for patients over 76 years old with stage III colon cancer].

OBJECTIVE: To perform a retrospective analysis of UFT and oral leucovorin combination adjuvant chemotherapy for Stage III colon cancer patients over 76 years old, in order to evaluate both treatment efficacy and toxicity. SUBJECTS: Between 2002 and 2011, 333 Stage III colon cancer patients had surgery performed in our institute, and we studied 25 of them on our chemotherapy regimen. RESULTS: Patients'median age was 78 years old, with 12 men and 13 women. Of all the patients, 19 had Stage IIIa and 6 had Stage IIIb. The 3-year disease-free survival rates for Stage III and Stage IIIa patients were 65. 1% and 83. 1%, respectively, and the 3-year overall survival rate for Stage III was 79. 9%. With regard to toxicity, liver function disorder was observed in 8% of the patients, being the adverse event that occurred the most, but there was no Grade 3 or 4 toxicity. CONCLUSION: UFT and oral leucovorin combination adjuvant chemotherapy for Stage III colon cancer patients over 76 years showed a good response, especially for Stage III a.

[A retrospective study of UFT and oral leucovorin plus PSK combination adjuvant chemotherapy in patients with stage III colon cancer].

OBJECTIVE: To perform a retrospective analysis of UFT and oral leucovorin plus PSK combination adjuvant chemotherapy for stage III colon cancer in order to evaluate both treatment efficacy and toxicity. SUBJECTS: Between 2003 and 2009, 273 stage III colon cancer patients underwent surgery in our institute, and we studied 156 of them. RESULTS: Patients' median age was 72 years old; 87 men and 69 women. Of all patients, 119 had stage IIIa and 37 had stage IIIb. The 3-year disease, free survival rates for stage III, stage IIIa and stage IIIb patients were 73. 9%and 80. 6%and 51. 4%, respectively, and the 3-year overall survival rates for stage III was 97. 6%. With regard to toxicity, liver function disorder was observed in 9. 6%of the patients as the most frequent adverse event, but there was no grade 3 or 4 toxicity. CONCLUSION: UFT and oral leucovorin plus PSK combination adjuvant chemotherapy for stage III colon cancer showed a good response especially for stage III a.