PAI-1 mediates acquired resistance to MET-targeted therapy in non-small cell lung cancer.

Mechanisms underlying primary and acquired resistance to MET tyrosine kinase inhibitors (TKIs) in managing non-small cell lung cancer remain unclear. In this study, we investigated the possible mechanisms acquired for crizotinib in MET-amplified lung carcinoma cell lines. Two MET-amplified lung cancer cell lines, EBC-1 and H1993, were established for acquired resistance to MET-TKI crizotinib and were functionally elucidated. Genomic and transcriptomic data were used to assess the factors contributing to the resistance mechanism, and the alterations hypothesized to confer resistance were validated. Multiple mechanisms underlie acquired resistance to crizotinib in MET-amplified lung cancer cell lines. In EBC-1-derived resistant cells, the overexpression of SERPINE1, the gene encoding plasminogen activator inhibitor-1 (PAI-1), mediated the drug resistance mechanism. Crizotinib resistance was addressed by combination therapy with a PAI-1 inhibitor and PAI-1 knockdown. Another mechanism of resistance in different subline cells of EBC-1 was evaluated as epithelial-to-mesenchymal transition with the upregulation of antiapoptotic proteins. In H1993-derived resistant cells, MEK inhibitors could be a potential therapeutic strategy for overcoming resistance with downstream mitogen-activated protein kinase pathway activation. In this study, we revealed the different mechanisms of acquired resistance to the MET inhibitor crizotinib with potential therapeutic application in patients with MET-amplified lung carcinoma.

Periostin secreted by cancer-associated fibroblasts promotes cancer progression and drug resistance in non-small cell lung cancer.

Cancer-associated fibroblasts (CAFs) are important components in the tumor microenvironment, and we sought to identify effective therapeutic targets in CAFs for non-small cell lung cancer (NSCLC). In this study, we established fibroblast cell lines from the cancerous and non-cancerous parts of surgical lung specimens from patients with NSCLC and evaluated the differences in behaviors towards NSCLC cells. RNA sequencing analysis was performed to investigate the differentially expressed genes between normal fibroblasts (NFs) and CAFs, and we identified that the expression of periostin (POSTN), which is known to be overexpressed in various solid tumors and promote cancer progression, was significantly higher in CAFs than in NFs. POSTN increased cell proliferation via NSCLC cells' ERK pathway activation and induced epithelial-mesenchymal transition (EMT), which improved migration in vitro. In addition, POSTN knockdown in CAFs suppressed these effects, and in vivo experiments demonstrated that the POSTN knockdown improved the sensitivity of EGFR-mutant NSCLC cells for osimertinib treatment. Collectively, our results showed that CAF-derived POSTN is involved in tumor growth, migration, EMT induction, and drug resistance in NSCLC. Targeting CAF-secreted POSTN could be a potential therapeutic strategy for NSCLC. KEY MESSAGES: • POSTN is significantly upregulated in CAFs compared to normal fibroblasts in NCSLC. • POSTN increases cell proliferation via activation of the NSCLC cells' ERK pathway. • POSTN induces EMT in NSCLC cells and improves the migration ability. • POSTN knockdown improves the sensitivity for osimertinib in EGFR-mutant NSCLC cells.

Extra-gastrointestinal stromal tumor arising in the lesser omentum with a platelet-derived growth factor receptor alpha (PDGFRA) mutation: a case report and literature review.

BACKGROUND: Gastrointestinal stromal tumors (GIST) arising from sites other than the gastrointestinal (GI) tract, termed extra-gastrointestinal stromal tumors (EGIST), are rare. Among EGIST, those with platelet-derived growth factor receptor alpha (PDGFRA) mutations are even rarer, with only a few cases reported. About 80% of GIST has KIT mutations, and 10% of GIST have PDGFRA mutations, which commonly affect the TK2 domain (exon 18). Among the exon 18 mutations, the D842V substitution is limited to gastric GIST. In EGIST, the degree of KIT and PDGFRA mutations varies on where the location of the tumor is, and it is suggested that omental EGIST is similar to gastric GIST. Adjuvant imatinib therapy is recommended for high-risk GIST; however, it is known that imatinib is less effective against GIST with a PDGFRA D842V mutation. CASE PRESENTATION: A 75-year-old man was referred to our hospital with an extrinsic tumor of the lesser curvature of the gastric body. Intraoperative findings showed a tumor located outside of the lesser omentum with no connection between the tumor and the gastric wall. The tumor was subsequently resected. Pathological examination indicated a GIST arising in the lesser omentum measuring 70 mm in its longer dimension. Because the tumor had a PDGFRA mutation (D842V substitution), imatinib was suspected to lack efficacy to the tumor. Thus, although the tumor was considered clinically to have a high risk of recurrence, adjuvant imatinib therapy was not indicated. The patient has been free of recurrence for 29 months since the surgery. CONCLUSION: We described a case of EGIST with a PDGFRA mutation arising in the lesser omentum. And we reviewed 57 cases of omental EGIST and showed that the clinicopathological characteristics and mutation status in omental EGIST were very similar to gastric GIST. In particular, PDGFAR D842V mutation rate in omental EGIST seemed as high as that in gastric GIST. These results suggested that omental EGIST is strongly related to gastric GIST, so the behavior of omental EGIST might be akin to gastric GIST. However, further studies are required to determine the prognosis and the necessity of adjuvant therapy for EGIST with a PDGFRA mutation.

A nodal diagnosis by computed tomography is unreliable for patients who need additional gastrectomy after endoscopic submucosal dissection.

PURPOSE: T1 gastric cancer is treated by endoscopic submucosal dissection (ESD) or surgery, considering the risk of lymph node metastasis. Additional gastrectomy is necessary when the pathological specimens after ESD show some risk of lymph node metastasis. Preoperative computed tomography (CT) after ESD sometimes reveals enlarged lymph nodes, which should prompt surgeons to select D2 over D1/D1+. However, whether or not CT after ESD is reliable remains unclear. METHODS: Patients who underwent radical gastrectomy for clinical T1 between April 2015 and June 2019 were enrolled. The patients were classified into those who underwent CT after ESD (group A) and those who underwent CT before primary surgery or ESD (group B). The accuracy of the nodal diagnosis was compared between groups. RESULTS: A total of 650 patients (group A; 81, group B; 569) were examined. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value (group A vs. group B) were 77.8% vs. 84.2%, 0.0% vs. 15.9%, 84.0% vs. 95.7%, 0.0% vs. 38.2%, and 91.3% vs. 87.1%, respectively. The false-positive rate was 100% in group A and 61.8% in group B (p = 0.011). CONCLUSIONS: A nodal diagnosis by CT is unreliable for patients who need additional gastrectomy after ESD.

Clinicopathological features and surgical outcomes of intraductal tubulopapillary neoplasm of the pancreas: a systematic review.

BACKGROUND AND AIMS: Intraductal tubulopapillary neoplasms (ITPNs) of the pancreas are rare. The purpose of this study was to collate and analyze published data on ITPNs of the pancreas to determine the clinicopathological features of the tumors and the surgical outcomes of patients. PATIENTS AND METHODS: We searched MEDLINE and Igakuchuo-Zasshi for the period of 1980 to 2015 for case reports on surgical resection for ITPN of the pancreas. We evaluated the clinicopathological data associated with pancreatic ITPNs, the prognosis for each patient, and surgical outcomes described in the case reports. RESULTS: We obtained clinicopathological data for 58 patients (33 men and 25 women) with a mean age of 61 years (range, 35-84 years) who had undergone surgical resection for ITPN of the pancreas, including one patient from our clinic. Although ITPNs of the pancreas have different clinicopathological features to intraductal papillary mucinous neoplasms, the treatment strategy for patients with ITPNs is the same as for patients with other cystic neoplasms of the pancreas. The immunohistochemical features of ITPNs included testing positive for cytokeratin 7 and/or cytokeratin 19 and negative for trypsin, MUC2, MUC5AC, and fascin. The overall 1-, 3-, and 5-year survival rates after surgery for the 37 cases with available data were 97.3, 80.7, and 80.7 %, respectively. CONCLUSION: Surgical treatment is the only curative management option for patients with ITPN of the pancreas. To determine the best management strategy for this tumor and improve accuracy of prognosis for patients, we will continue to collect and analyze epidemiological and pathological data.

Completion pancreatectomy for recurrent pancreatic cancer in the remnant pancreas: report of six cases and a review of the literature.

PURPOSE: There are no accepted surgical strategies for the treatment of pancreatic cancer recurrence in the remnant pancreas after initial resection. We retrospectively analyzed our experiences with patients undergoing completion pancreatectomy for recurrent pancreatic cancer in the remnant pancreas. METHODS: Six patients with recurrent pancreatic cancer in the remnant pancreas underwent completion pancreatectomy between March 2005 and December 2012. Operative, postoperative, and pathological data and long-term outcomes for these six patients were analyzed retrospectively. RESULTS: There was no operative morbidity or mortality associated with completion pancreatectomy. The median survival times were 49.0 and 27.5 months after initial resection and second pancreatectomy, respectively. However, all six patients died during follow-up. Five patients had recurrent pancreatic cancer at the time of death. One patient had no recurrence but had poor blood sugar control and eventually died after repeated bouts of cholangitis. CONCLUSIONS: Completion pancreatectomy is a safe and effective option in select patients with local pancreatic cancer recurrence in the remnant pancreas after initial pancreatectomy. It is essential to select patients who have a good performance status and can tolerate major surgery and the resultant apancreatic state.