[Resection of Chest Wall Metastasis from Rectal Mucinous Carcinoma-A Case Report].

An 81-year-old woman with rectal mucinous carcinoma underwent a laparoscopic low anterior resection in February 2019, followed by chemotherapy using XELOX plus Bev. The adjuvant chemotherapy was discontinued due to interstitial pneumonia. During a follow-up consultation 2 years later, chest computed tomography(CT)imaging revealed a nodule in her right lung(S9). Based on a radiological diagnosis of metastasis and considering her history of rectal cancer, a partial resection of the right lung was executed. One year after the pulmonary resection, a growing nodule in her right lateral chest wall was detected. A metastatic chest wall tumor was suspected, and a right chest wall tumor resection at the 5th and 6th ribs was performed. A rectal mucinous carcinoma metastasis was diagnosed using histopathological examination. The postoperative course was good, and she was discharged from hospital on the 10th day. To conclude, there are few reported cases of rectal cancer chest wall metastasis, and a further accumulation of similar cases is necessary for the development of treatment options.

A case report of a collision tumor composed of pancreatic ductal adenocarcinoma and peri-pancreatic mucosa-associated lymphoid tissue lymphoma.

BACKGROUND: Collision tumors are composed of two distinct tumor components. Collision tumors composed of pancreatic ductal adenocarcinoma and malignant lymphoma occurring in the pancreas have not been previously described in the scientific literature. In this case report, we describe a unique patient with a collision tumor composed of pancreatic ductal adenocarcinoma and peri-pancreatic mucosa-associated lymphoid tissue (MALT) lymphoma occurring in the pancreas. CASE PRESENTATION: An 82-year-old woman presented to our hospital complaining of dizziness. Computed tomography (CT) and magnetic resonance imaging (MRI) showed a large lymphoid lesion spreading from the peri-pancreatic tissue heading to the hepatic hilar plate, involving the hepatoduodenal ligament and the entire duodenum, also showing a hard tumor in the pancreas head. We performed echo-guided needle biopsies for each tumor and diagnosed a collision tumor composed of pancreatic ductal adenocarcinoma and low-grade B cell lymphoma. The patient underwent pancreaticoduodenectomy. The resected specimen showed an elastic hard tumor, 90 × 75 mm in size, located in the pancreatic head, and a whitish-yellow hard tumor involving the lower bile duct, 31 mm in size, located in the center of the pancreatic head. Pathological and immunohistochemical examination proved that pancreatic ductal adenocarcinoma and MALT lymphoma originating from the peri-pancreatic head collided in the pancreatic head. CONCLUSIONS: To best of our knowledge, this is the first report of a surgically resected collision tumor of pancreatic ductal adenocarcinoma and MALT lymphoma originating from the peri-pancreatic head. A needle biopsy is useful when inconsistent findings are observed on diagnostic CT and MRI of tumor lesions since there is the possibility of a collision tumor.

TAE226, a Bis-Anilino Pyrimidine Compound, Inhibits the EGFR-Mutant Kinase Including T790M Mutant to Show Anti-Tumor Effect on EGFR-Mutant Non-Small Cell Lung Cancer Cells.

TAE226, a bis-anilino pyrimidine compound, has been developed as an inhibitor of focal adhesion kinase (FAK) and insulin-like growth factor-I receptor (IGF-IR). In this study, we investigated the effect of TAE226 on non-small-cell lung cancer (NSCLC), especially focusing on the EGFR mutational status. TAE226 was more effective against cells with mutant EGFR, including the T790M mutant, than against cells with wild-type one. TAE226 preferentially inhibited phospho-EGFR and its downstream signaling mediators in the cells with mutant EGFR than in those with wild-type one. Phosphorylation of FAK and IGF-IR was not inhibited at the concentration at which the proliferation of EGFR-mutant cells was inhibited. Results of the in vitro binding assay indicated significant differences in the affinity for TAE226 between the wild-type and L858R (or delE746_A750) mutant, and the reduced affinity of ATP to the L858R (or delE746_A750) mutant resulted in good responsiveness of the L858R (or delE746_A750) mutant cells to TAE226. Of interest, the L858R/T790M or delE746_A750/T790M mutant enhanced the binding affinity for TAE226 compared with the L858R or delE746_A750 mutant, resulting in the effectiveness of TAE226 against T790M mutant cells despite the T790M mutation restoring the ATP affinity for the mutant EGFR close to that for the wild-type. TAE226 also showed higher affinity of about 15-fold for the L858R/T790M mutant than for the wild-type one by kinetic interaction analysis. The anti-tumor effect against EGFR-mutant tumors including T790M mutation was confirmed in mouse models without any significant toxicity. In summary, we showed that TAE226 inhibited the activation of mutant EGFR and exhibited anti-proliferative activity against NSCLCs carrying EGFR mutations, including T790M mutation.

Acquired resistance to EGFR inhibitors is associated with a manifestation of stem cell-like properties in cancer cells.

Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitor (TKI) is a critical problem in the treatment of lung cancer. Although several mechanisms have been shown to be responsible for acquired resistance, all mechanisms have not been uncovered. In this study, we investigated the molecular and cellular profiles of the acquired resistant cells to EGFR-TKI in EGFR-mutant lung cancers. Four EGFR-mutant cell lines were exposed to gefitinib by stepwise escalation and high-concentration exposure methods, and resistant sublines to gefitinib were established. The molecular profiles and cellular phenotypes of these resistant sublines were characterized. Although previously reported, alterations including secondary EGFR T790M mutation, MET amplification, and appearance of epithelial-to-mesenchymal transition (EMT) features were observed, these 2 drug-exposure methods revealed different resistance mechanisms. The resistant cells with EMT features exhibited downregulation of miRNA-200c by DNA methylation. Furthermore, the HCC827-derived subline characterized by the high-concentration exposure method exhibited not only EMT features but also stem cell-like properties, including aldehyde dehydrogenase isoform 1 (ALDH1A1) overexpression, increase of side-population, and self-renewal capability. Resistant sublines with stem cell-like properties were resistant to conventional chemotherapeutic agents but equally sensitive to histone deacetylase and proteasome inhibitors, compared with their parental cells. ALDH1A1 was upregulated in clinical samples with acquired resistance to gefitinib. In conclusion, our study indicates that the manner of EGFR-TKI exposure influences the mechanism of acquired resistance and the appearance of stem cell-like property with EGFR-TKI treatment.

The anti-proliferative effect of heat shock protein 90 inhibitor, 17-DMAG, on non-small-cell lung cancers being resistant to EGFR tyrosine kinase inhibitor.

Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, is frequently observed after initiation of TKIs therapy. Non-small-cell lung cancers (NSCLC) with activating EGFR mutations were reported to be sensitive to heat shock protein 90 (Hsp90) inhibitors regardless of the secondary TKI-resistant T790M mutation. We established EGFR-TKI resistant clones for PC-9 cell lines, harboring EGFR exon 19 deletions, with or without the secondary T790M mutation. We examined the anti-proliferative effect of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), an orally active Hsp90 inhibitor, on the growth of NSCLC cell lines in vitro and in vivo. In MTS assay, the IC(50) values of 17-DMAG for 13 EGFR-mutant cell lines including eight EGFR-TKI resistant cell lines ranged from 0.04 to 0.16 µM while those for seven EGFR-wild type cell lines ranged from 1.6 to 27.4 µM. Western blot analysis revealed that phospho-EGFR, phospho-Akt, phospho-MAPK, cdk4, and cyclin D1 were more readily depleted by 17-DMAG treatment in EGFR-mutant cell lines than in EGFR-wild type cell lines. Cleaved PARP expression confirmed apoptosis in response to 17-DMAG treatment in EGFR-mutant cell lines but not in EGFR-wild type cell lines. In mice xenograft models, 17-DMAG significantly reduced the growth of EGFR-mutant lines irrespective of T790M mutation. These results suggested that 17-DMAG is a potential novel therapeutic agent for NSCLC patients with EGFR mutations with or without EGFR-TKI resistance.

Usefulness of cumulative smoking dose for identifying the EGFR mutation and patients with non-small-cell lung cancer for gefitinib treatment.

We examined the diagnostic accuracy of the cumulative smoking dose for identifying the epidermal growth factor receptor (EGFR) exon 19 deletion and L858R mutation among Japanese patients with non-small-cell lung cancer (NSCLC). EGFR mutations in exon 19 and exon 21 were determined in 1001 NSCLC patients. A receiver-operating characteristic (ROC) curve methodology was applied to estimate the diagnostic accuracy. EGFR mutations were detected in 314 patients (31.4%). A cumulative smoking dose of less than 13 pack-years (PY) was the optimal cut-off point for predicting a positive EGFR mutation status, producing a balance between the sensitivity (73.5%) and the specificity (77%). The area under the ROC curve was 0.77, indicating that the smoking dose had a moderate diagnostic accuracy. The median survival time or the median progression-free survival time of patients who had smoked less than 13 pack-years (PY) were 18.6 and 6.3 months, respectively, while those of patients with equal to or more than 13 PY were 9.6 and 2.4 months, respectively. The overall survival (OS) and progression-free survival (PFS) rates were significantly different between the two groups (OS: hazard ratio [HR] = 0.64, 95% confidence interval [CI] = 0.51-0.80, P = 0.0001) (PFS: HR = 0.58, 95% CI = 0.47-0.71, P < 0.0001). Our study indicated that the smoking dose predicted EGFR mutations with a moderate diagnostic accuracy. Thus, patients who have smoked less than 13 PY might be candidates for gefitinib treatment when EGFR mutation status cannot be determined.

MET gene amplification or EGFR mutation activate MET in lung cancers untreated with EGFR tyrosine kinase inhibitors.

We analyzed MET protein and copy number in NSCLC with or without EGFR mutations untreated with EGFR tyrosine kinase inhibitors (TKIs). MET copy number was examined in 28 NSCLC and 4 human bronchial epithelial cell lines (HBEC) and 100 primary tumors using quantitative real-time PCR. Positive results were confirmed by array comparative genomic hybridization and fluorescence in-situ hybridization. Total and phospho-MET protein expression was determined in 24 NSCLC and 2 HBEC cell lines using Western blot. EGFR mutations were examined for exon 19 deletions, T790M, and L858R. Knockdown of EGFR with siRNA was performed to examine the relation between EGFR and MET activation. High-level MET amplification was observed in 3 of 28 NSCLC cell lines and in 2 of 100 primary lung tumors that had not been treated with EGFR-TKIs. MET protein was highly expressed and phosphorylated in all the 3 cell lines with high MET amplification. In contrast, 6 NSCLC cell lines showed phospho-MET among 21 NSCLC cell lines without MET amplification (p = 0.042). Furthermore, those 6 cell lines harboring phospho-MET expression without MET amplification were all EGFR mutant (p = 0.0039). siRNA-mediated knockdown of EGFR abolished phospho-MET expression in examined 3 EGFR mutant cell lines of which MET gene copy number was not amplified. By contrast, phospho-MET expression in 2 cell lines with amplified MET gene was not down-regulated by knockdown of EGFR. Our results indicated that MET amplification was present in untreated NSCLC and EGFR mutation or MET amplification activated MET protein in NSCLC.

DNA methylation in small lung adenocarcinoma with bronchioloalveolar carcinoma components.

We examined the methylation status in 100 specimens of lung adenocarcinomas measuring 2cm or less and with bronchioloalveolar carcinoma (BAC) components (Noguchi types A-C) and then compared the methylation status between noninvasive tumors (Noguchi type A or B) and invasive tumors (Noguchi type C). Methylation-specific PCR was used to determine the methylation statuses of p16(INK4a), RASSF1A, CDH13, RARbeta, and Cyclin D2. The methylation index that was regarded as representing the degree of methylation was calculated. We also determined the mutational statuses of EGFR exons 19 and 21 using a PCR-based method. A multivariate analysis showed that the aberrant methylation of p16(INK4a), RASSF1A, and CDH13 was significantly more frequent in invasive tumors than in noninvasive tumors [p16(INK4a), 36.5% versus (vs.) 8.3%, P=0.0023; RASSF1A, 46.2% vs. 14.6%, P=0.0012; CDH13, 42.3% vs. 10.4%, P=0.0006]. The methylation index was significantly higher in invasive tumors than in noninvasive tumors (P=0.004). The methylation of p16(INK4a) was significantly more frequent in EGFR wild-type tumors than in EGFR mutant tumors (P=0.021). Our results indicate the involvement of epigenetic alterations in the progression of adenocarcinoma with BAC components.

Non-BAC component but not epidermal growth factor receptor gene mutation is associated with poor outcomes in small adenocarcinoma of the lung.

OBJECTIVE: The purpose of this study was to identify risk factors for poor clinical outcome after surgical resection of small lung adenocarcinoma. MATERIALS AND METHODS: Clinical records of 127 patients who had pathologic stage IA lung adenocarcinoma 20 mm or less and who had undergone a lobectomy with mediastinal lymph node dissection were reviewed. The percentage of non-bronchioloalveolar carcinoma (non-BAC) components quantified objectively, and epidermal growth factor receptor gene (EGFR) mutation determined by polymerase chain reaction-based assay were retrospectively linked with clinical data. RESULTS: Based on the percentage of non-BAC component, 127 patients were classified as follows: 26 in group I, BAC, 46 in group II mixed subtype with >or= 50% BAC, 18 in group III, mixed subtype with under 50% BAC, and 37 in group IV, mixed subtype with all non-BAC components or a pure pattern of one of the non-BAC components. Groups I and II were considered to be a "low non-BAC component type" and groups III and IV were considered to be a "high non-BAC component type." EGFR mutations in exon19 and exon21 were observed in 64 patients (50.4%). In terms of recurrence, the high non-BAC component type was the only independent factor for recurrence (p = 0.029). Regarding survival, the high age (p = 0.028) and high non-BAC component type (p = 0.046) were independent risk factors for poor overall survival. They were also independent risk factors for poor disease-free survival (p = 0.025 and p = 0.027, respectively). CONCLUSION: The high non-BAC component but not EGFR mutation status, is an independent risk factor for both recurrence and poor prognosis in patients with stage IA lung adenocarcinoma

[Two cases of advanced low rectal cancer, preoperative chemo-radiation therapy leading to complete histological response].

We report two cases of advanced low rectal cancer, with preoperative chemo-radiation therapy leading to a complete histological response. Case 1 was a 74-year-old male who was diagnosed as advanced low rectal cancer. Preoperative chemo-radiation (a total of 45 Gy radiation+oral 5'-DFUR 800 mg/day for 3 weeks) was performed. Then, 30 days after chemo-radiation, we conducted a low anterior resection with lymph node dissection. Histological examination revealed no residual cancer cells in the resected specimen. Case 2 was a 35-year-old male who was diagnosed as advanced low rectal cancer. Preoperative chemo-radiation (a total of 45 Gy radiation+5-FU 500 mg/day+CDDP 10 mg/day for 3 weeks) was performed. 28 days after chemo-radiation, we conducted an abdominoperineal resection with lymph node dissection and a partial resection of the liver. Histological examination revealed well-differentiated adenocarcinoma in the resected liver tissue, but a rectal tumor was replaced by scar tissue with no viable cells.

[Improved quality of life in a patient with carcinomatous meningitis from invasive lobular carcinoma treated with intrathecal MTX and Ara-C in combination with systemic docetaxel].

Carcinomatous meningitis from breast cancer is rare and has a poor prognosis with a life expectancy of approximately 80 days. We performed intrathecal MTX and Ara-C in combination with systemic docetaxel treatments in the patient, a 44-year-old woman with carcinomatous meningitis from invasive lobular carcinoma previously treated with anthracycline and paclitaxel. Although the patient died 128 days after the onset, intrathecal chemotherapy in combination with systemic docetaxel reduced the number of malignant cells and induced degeneration of the cells in CSF, resulting in improved quality of life.