A case of strangulated bowel obstruction in which transabdominal ultrasound was useful for preoperative diagnosis.

A 74-year-old man presented to the emergency department with the chief complaint of abdominal pain. A computed tomography scan showed paralytic ileus. An ileostomy tube was placed, but the symptoms of bowel obstruction did not improve. Two days after admission, the patient's renal function deteriorated. Transabdominal ultrasound (TUS) showed linear high-intensity echoes consistent with a fibrotic band and microbubbles suggestive of circulatory disturbance in the dilated intestinal tract. Subsequent contrast-enhanced ultrasound revealed circulatory disturbance of the small bowel wall. Emergency surgery was performed under the diagnosis of strangulated ileus. Intraoperative examination revealed that the terminal ileum was strangulated by a fibrotic band from the retroperitoneum, which was confirmed by TUS. The fibrotic band was resected, the strangulation was released, and ileocecal resection was performed. Postoperatively, intestinal peristalsis was rapidly restored. TUS was able to depict the fibrotic band, which could not be detected by a computed tomography scan, allowing the patient to undergo immediate surgical treatment. We herein report this case of strangulated bowel obstruction in which TUS and contrast-enhanced ultrasound were useful in preoperative assessment of the patient's condition.

Appendiceal mucocele pathologically classified as appendiceal epithelial hyperplasia and preoperatively diagnosed by contrast-enhanced ultrasonography: A case report.

We report a patient with a mucocele with diffuse wall thickening diagnosed by transabdominal ultrasonography and contrast-enhanced ultrasonography. Transabdominal ultrasonography showed diffuse thickening of the entire appendix wall and an anechoic area that appeared to be fluid collected throughout the appendix lumen. However, the "onion skin sign" was not detected. Contrast-enhanced ultrasonography combined with superb microvascular imaging revealed abundant mucosal blood flow and no abnormal vascular network within the mucosa of the appendix wall. We preoperatively diagnosed a mucocele complicated by acute and chronic appendicitis, and ileocecal resection was performed. Macroscopic and microscopic findings of the resected specimens demonstrated that the appendiceal wall was diffusely thickened, with fibrosis and inflammatory cell infiltration, and that the appendiceal root rumen was narrowed with epithelial hyperplasia. No neoplastic changes were observed. The cause of the appendiceal mucocele was likely fibrosis and stenosis at the root of the appendix due to initial acute appendicitis.

[Three Cases of Appendiceal Goblet Cell Adenocarcinoma in Our Institution].

Appendiceal goblet cell adenocarcinoma(AGCA)is a newly designated pathological term adopted in the 5th edition of the WHO classification. It is synonymous with goblet cell carcinoid, which was previously categorized as a part of appendiceal carcinoid. However, since 2018, it has been classified as a subtype of adenocarcinoma. We have experienced 3 cases of this relatively rare tumor, of which 2 were initially diagnosed with acute appendicitis and were diagnosed with AGCA by pathological examination after an emergency appendectomy. Each of them underwent additional ileocolic resection with lymph node dissection as the second surgery. In the 3rd case, an appendiceal tumor was detected during preoperative examinations for an ovarian tumor. Staging laparoscopy revealed comorbid peritoneal dissemination, and only the appendix and right ovary were removed in the consecutive surgery. The ovarian tumor was pathologically diagnosed as a metastasis of AGCA. In this case, the introduction of oxaliplatin-based systemic chemotherapy after surgery achieved a complete response after more than 2 years. Although no recurrence has been observed in all 3 cases to date, AGCA is considered highly malignant compared to conventional appendiceal carcinoids. Therefore, it is crucial to practice multidisciplinary treatments, including sufficient radical surgery based on a precise diagnosis of AGCA, as is performed for advanced colorectal cancer.

[A case of CA19-9-producing esophagogastric junction cancer with ovarian juvenile granulosa cell tumor and rectal cancer].

This is a report on a case of CA19-9-producing cancer of esophagogastric junction with rectal cancer and a suspicion of Krukenberg tumor, a metastasized ovarian tumor that would mean an inoperable condition of cancer progression if that were true. This was a case of a woman in her 60s who was diagnosed with double cancers at the esophagogastric junction and rectum with a swollen left ovary. She had a laparoscopic bilateral salpingo-oophorectomy to get a histologic diagnosis, which should affect the subsequent therapeutic strategy because metastasis to the ovary meant an inoperable cancer progression. The resected ovary was diagnosed as juvenile granulosa cell tumor, but not Krukenberg tumor. Thus, subsequent curative surgeries, such as thoracolaparotomy for esophagogastric junction cancer and robot-assisted surgery for rectal cancer, were performed. Immunohistochemical examination revealed that the expression of CA19-9 was strongly observed in the tumor of esophagogastric junction, but not in the tumors of rectum or ovary. Furthermore, serum CA19-9 was drastically decreased after the resection of esophagogastric junction cancer. In aggregate, this esophagogastric junction cancer met the criteria of CA19-9-producing gastric cancer defined by Okinaga et al. So far, 46 cases of CA19-9-producing gastric cancer including this case have been reported in Japanese literature. Interestingly, this case had another characteristic of juvenile granulosa cell tumor, one of borderline malignant sex cord-stromal tumors rarely found in adults.

[Three Cases of Colon Medullary Carcinoma in Our Institution].

Medullary carcinoma of the colorectum is a relatively new histological subtype that was first described in the eighth edition of the Japanese classification of colorectal, appendiceal, and anal carcinoma. In our institution, only 3 cases of medullary carcinoma have been diagnosed since 2013. Case #1 was a 93-year-old woman with type 1 ascending colon cancer; she received a right hemicolectomy. The tumor invaded the subserosal layer, but no lymph nodal metastasis was observed. Case #2 was a 91-year-old woman with obstructive ascending colon cancer. After intracolonic decompression using the transnasal ileus tube, she received a right hemicolectomy. This tumor also extended into the subserosal layer without lymph nodal metastasis. Case #3 was a 65-year-old woman with a family history of cancers; she received a right hemicolectomy for cecal cancer with an aberrant elevation of serum tumor markers such as CEA and CA19-9. The tumor invaded the subserosal layer with regional lymph nodal metastases. Notably, these 3 cases were females who had right-sided tumors and all showed diminished expressions of MLH1 and PMS2 mismatch repair-associated genes, together with epidemiological characteristics of medullary carcinoma. Herein, we report their pathological features along with the corresponding literature review.

Bioelectrical impedance analysis for perioperative water management in adult cardiovascular valve disease surgery.

PURPOSE: Bioelectrical impedance analysis (BIA) has been used recently to measure the body water of patients with acute heart failure. We used BIA in this study to better understand, and possibly identify a predictive marker for, perioperative water behavior in cardiac surgery patients. METHODS: We measured body water and studied its behavior in 44 patients undergoing surgery for cardiac valvular disease at our hospital. Measurements included the levels of extracellular water (ECW), intracellular water (ICW), and total body water, the edema index (EI), and the ratio of ECW to total body water. The first measured EI was defined as the "preoperative EI" and the maximum as the "peak EI". RESULTS: A negative correlation was found between the preoperative EI and the preoperative estimated glomerular filtration rate (eGFR) (R = 0.644, p < 0.001). Positive correlations were found between the peak EI and the ICU stay (R = 0.625, p < 0.001), the peak EI and the ventilation time (R = 0.366, p < 0.01), and the preoperative EI and the ICU stay (R = 0.464, p = 0.026). CONCLUSION: The EI is possibly a predictive marker for perioperative water management in cardiac surgery.

Targeted silencing of SOX2 by an artificial transcription factor showed antitumor effect in lung and esophageal squamous cell carcinoma.

SOX2 is a transcription factor essential for early mammalian development and for the maintenance of stem cells. Recently, SOX2 was identified as a lineage specific oncogene, recurrently amplified and activated in lung and esophageal squamous cell carcinoma (SCC). In this study, we have developed a zinc finger-based artificial transcription factor (ATF) to selectively suppress SOX2 expression in cancer cells and termed the system ATF/SOX2. We engineered the ATF using six zinc finger arrays designed to target a 19 bp site in the SOX2 distal promoter and a KOX transcriptional repressor domain. A recombinant adenoviral vector Ad-ATF/SOX2 that expresses ATF/SOX2 suppressed SOX2 at the mRNA and protein levels in lung and esophageal SCC cells expressing SOX2. In these kinds of cells, Ad-ATF/SOX2 decreased cell proliferation and colony formation more effectively than the recombinant adenoviral vector Ad-shSOX2, which expresses SOX2 short hairpin RNA (shSOX2). Ad-ATF/SOX2 induced the cell cycle inhibitor CDKN1A more strongly than Ad-shSOX2. Importantly, the ATF did not suppress the cell viability of normal human cells. Moreover, Ad-ATF/SOX2 effectively inhibited tumor growth in a lung SCC xenograft mouse model. These results indicate that ATF/SOX2 would lead to the development of an effective molecular-targeted therapy for lung and esophageal SCC.

False-Positive Cases of Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomographic Scans in Metastasis of Esophageal Cancer.

Of 129 esophagectomies at our institute from June 2010 to March 2015, we experienced three preoperative positron emission tomography-computed tomographic (PET/CT) false positives. Bone metastasis was originally suspected in 2 cases, but they were later found to be bone metastasis negative after a preoperative bone biopsy and clinical course observation. The other cases suspected of mediastinal lymph node metastasis were diagnosed as inflammatory lymphadenopathy by a pathological examination of the removed lymph nodes. Conducting a PET/CT is useful when diagnosing esophageal cancer metastasis, but we need to be aware of the possibility of false positives. Therapeutic decisions should be made based on appropriate and accurate diagnoses, with pathological diagnosis actively introduced if necessary.

SOX2 suppresses CDKN1A to sustain growth of lung squamous cell carcinoma.

Since the SOX2 amplification was identified in lung squamous cell carcinoma (lung SCC), SOX2 transcriptional downstream targets have been actively investigated; however, such targets are often cell line specific. Here, in order to identify highly consensus SOX2 downstream genes in lung SCC cells, we used RNA-seq data from 178 lung SCC specimens (containing tumor and tumor-associated cells) and analyzed the correlation between SOX2 and previously-reported SOX2-controlled genes in lung SCC. In addition, we used another RNA-seq dataset from 105 non-small cell lung cancer cell lines (NSCLC; including 4 lung SCC cell lines) and again analyzed the correlation between SOX2 and the reported SOX2-controlled genes in the NSCLC cell lines (no tumor-associated cells). We combined the two analyses and identified genes commonly correlated with SOX2 in both datasets. Among the 99 genes reported as SOX2 downstream and/or correlated genes, we found 4 negatively-correlated (e.g., CDKN1A) and 11 positively-correlated genes with SOX2. We used biological studies to demonstrate that CDKN1A was suppressed by SOX2 in lung SCC cells. G1 cell cycle arrest induced by SOX2 siRNA was rescued by CDKN1A siRNA. These results indicate that the tumorigenic effect of SOX2 in lung SCC cells is mediated in part by suppression of CDKN1A.

Feasibility of oral administration of S-1 as adjuvant chemotherapy in gastric cancer: 4-week S-1 administration followed by 2-week rest vs. 2-week administration followed by 1-week rest.

In 2006, the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) demonstrated that S-1 is an effective adjuvant therapy for gastric cancer. Following that study, S-1 has been used as the standard adjuvant therapy for gastric cancer in Japan. However, the 1-year completion rate was only 65.8% in the ACTS-GC study and feasibility remains a critical issue. We conducted a study to evaluate the feasibility of 2 weekly administration regimens of S-1 as adjuvant chemotherapy in gastric cancer. The criteria for eligibility included histologically proven stage II (excluding T1), IIIA or IIIB gastric cancer with D2 lymph-node dissection. The patients were randomly assigned to either arm A (S-1 administration for 4 weeks followed by 2 weeks of rest) or arm B (S-1 administration for 2 weeks followed by 1 week of rest). In each arm, treatment was continued for 12 months unless recurrence or severe adverse events were observed. The primary endpoint was feasibility (protocol treatment completion rate). The secondary endpoints were safety, relapse-free survival and overall survival. A total of 47 patients were assigned to arms A or B between May, 2008 and February, 2010. During the first interim analysis, the protocol treatment completion rates in arms A and B were 83 and 100%, respectively at 6 months and 49 and 89%, respectively, at 12 months (P=0.0046). Therefore, S-1 administration for 2 weeks followed by 1 week rest was more feasible as adjuvant chemotherapy in gastric cancer. Grade 3 adverse events in arm A included fatigue (8.0%), anorexia (8.0%), nausea (4.0%), vomiting (4.0%) and hand-foot syndrome (4.0%), whereas none were observed in arm B. There were no reported grade 4 adverse events in either arm. In conclusion, the 2-week S-1 administration followed by 1-week rest regimen appears to be a more feasible oral administration regimen for S-1 as adjuvant chemotherapy in gastric cancer.

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.

Inhibition of the growth factor MDK/midkine by a novel small molecule compound to treat non-small cell lung cancer.

Midkine (MDK) is a heparin-binding growth factor that is highly expressed in many malignant tumors, including lung cancers. MDK activates the PI3K pathway and induces anti-apoptotic activity, in turn enhancing the survival of tumors. Therefore, the inhibition of MDK is considered a potential strategy for cancer therapy. In the present study, we demonstrate a novel small molecule compound (iMDK) that targets MDK. iMDK inhibited the cell growth of MDK-positive H441 lung adenocarcinoma cells that harbor an oncogenic KRAS mutation and H520 squamous cell lung cancer cells, both of which are types of untreatable lung cancer. However, iMDK did not reduce the cell viability of MDK-negative A549 lung adenocarcinoma cells or normal human lung fibroblast (NHLF) cells indicating its specificity. iMDK suppressed the endogenous expression of MDK but not that of other growth factors such as PTN or VEGF. iMDK suppressed the growth of H441 cells by inhibiting the PI3K pathway and inducing apoptosis. Systemic administration of iMDK significantly inhibited tumor growth in a xenograft mouse model in vivo. Inhibition of MDK with iMDK provides a potential therapeutic approach for the treatment of lung cancers that are driven by MDK.

Antiproliferative effect of a novel mTOR inhibitor temsirolimus contributes to the prolonged survival of orthotopic esophageal cancer-bearing mice.

Esophageal squamous cell carcinoma (ESCC) remains one of the most aggressive cancers with poor prognosis regardless of a several reports that indicate a better therapeutic efficacy using some new chemotherapeutic agents. Recent drug development has contributed to an improved specificity to suppress mTOR activity by which many types of malignancies can be explosively progressed. Temsirolimus (CCI-779, TricelTM) is one of recently synthesized analogs of rapamycin and has provided better outcomes for patients with renal cell carcinoma. In this study, we experimentally evaluated an efficacy of targeting mTOR by temsirolimus for ESCC treatment, with an assessment of its survival advantage using an advanced ESCC animal model. First, we confirmed that the expression of phosphorylated mTOR was increased in 46 of 58 clinical ESCC tumor tissues (79.3%) and appeared to get strengthened with tumor progression. All of ESCC cell lines used in this study revealed an increase of mTOR phosphorylation, accompanied with the upregulation of hypoxia inducible factor-I α (HIF-1α), one of the critical effectors regulated by mTOR. Temsirolimus treatment apparently suppressed the activation of mTOR and its downstream effectors, resulting in the reduced ability of ESCC cell proliferation. Finally, the weekly administration of temsirolimus significantly diminished the size of subcutaneous tumors (vehicle, 3261.6 ± 722.0; temsirolimus, 599.2 ± 122.9; p = 0.007) in nude mice and effectively prolonged orthotopic esophageal cancer-bearing mice (median survival periods: control, 31 d; temsirolimus, 43 d; p = 0.0024). These data suggests that targeting mTOR by temsirolimus may become a therapeutic alternative for esophageal cancer, with a contribution to a better outcome.

Antiproliferative effect of the HSP90 inhibitor NVP-AUY922 is determined by the expression of PTEN in esophageal cancer.

Heat shock protein 90 (HSP90), a molecular chaperone, has provoked great interest as a promising molecular target for cancer treatment, due to its involvement in regulating the conformation, stability and functions of key oncogenic proteins. At present, a variety of chemical compounds targeting HSP90 have been developed and have shown convincing anti-neoplastic activity in various preclinical tumor models. The aim of our study was to evaluate the antitumor effects of a novel HSP90 inhibitor, NVP-AUY922, in esophageal squamous cancer cells (ESCC). Four ESCC cell lines (TE-1, TE-4, TE-8, TE-10) were examined. NVP-AUY922 potently inhibited the proliferation of ESCC, particularly in PTEN-null TE-4 cells with a 2-3 times lower IC50 than the other three cell lines. Western blot analysis showed that PTEN-null TE-4 cells exhibited higher AKT and ERK activity, which contribute to cell proliferation and survival. NVP-AUY922 significantly suppressed the activity of AKT and ERK in TE-4 but not in PTEN-proficient TE-10 cells. Genetic modification experiments demonstrated that the sensitivity to NVP-AUY922 was decreased by exogenous transduction of PTEN in TE-4 and increased by silencing PTEN expression in intact PTEN-expressing TE-10, suggesting that the expression of PTEN may be associated with cell sensitivity in HSP90 inhibition. Furthermore, the enhanced activity of AKT in PTEN-silenced TE-10 was more easily suppressed by NVP-AUY922. Collectively, NVP-AUY922 exhibits a strong antiproliferative effect, revealing its potential as a novel therapeutic alternative to current ESCC treatment. The effect may be improved further by impeding PTEN expression.

Novel HSP90 inhibitor NVP-AUY922 enhances the anti-tumor effect of temsirolimus against oral squamous cell carcinoma.

BACKGROUND AND AIM: Heat shock protein 90 (HSP90) and mammalian target of rapamycin (mTOR) are involved in the molecular pathogenesis of advanced oral squamous cell carcinoma. HSP90 inhibitors are capable of effectively interfering with multiple signaling pathways, including the mTOR signaling pathway. However, the combined effects of HSP90 and mTOR inhibitors on oral squamous cell carcinoma are still unknown. In this study, we investigated the dual treatment of the novel HSP90 inhibitor NVP-AUY922 and temsirolimus against oral squamous cell carcinoma. MATERIALS AND METHODS: The effect of the combination of NVP-AUY922 and temsirolimus on oral squamous cell carcinoma in vitro and in vivo was determined by MTS assay and mouse xenograft models. The effect of the combination on angiogenesis was determined by tube formation assay and angioreactor. RESULTS: The combination treatment of NVP-AUY922 and temsirolimus significantly inhibited the proliferation of SAS oral squamous cell carcinoma cells in vitro and suppressed the growth of oral squamous cell carcinoma xenografts in vivo. We have clearly shown that the combination treatment of NVP-AUY922 and temsirolimus inhibited vascular formation both in vitro and in vivo. Moreover, the combination treatment of NVP-AUY922 and temsirolimus prolonged the survival rate in mice xenografted with oral squamous cell carcinoma. CONCLUSIONS: Here, we showed the activity of a combination of mTOR and HSP90 inhibitors for the treatment of advanced oral squamous carcinoma.

Evaluating the need for and effect of percutaneous transluminal angioplasty on arteriovenous fistulas by using total recirculation rate per dialysis session ("clearance gap").

The functioning of an arteriovenous fistula (AVF) used for vascular access during hemodialysis has been assessed mainly by dilution methods. Although these techniques indicate the immediate recirculation rate, the results obtained may not correlate with Kt/V. In contrast, the clearance gap (CL-Gap) method provides the total recirculation rate per dialysis session and correlates well with Kt/V. We assessed the correlation between Kt/V and CL-Gap as well as the change in radial artery (RA) blood flow speed in the fistula before percutaneous transluminal angioplasty (PTA) in 45 patients undergoing continuous hemodialysis. The dialysis dose during the determination of CL-Gap was 1.2 to 1.4 Kt/V. Patients with a 10% elevation or more than a 10% relative increase in CL-Gap underwent PTA (n = 45), and the values obtained for Kt/V and CL-Gap before PTA were compared with those obtained immediately afterward. The mean RA blood flow speed improved significantly (from 52.9 to 97.5cm/sec) after PTA, as did Kt/V (1.07 to 1.30) and CL-Gap (14.1% to -0.2%). A significant correlation between these differences was apparent (r = -0.436 and p = 0.003). These findings suggest that calculating CL-Gap may be useful for determining when PTA is required and for assessing the effectiveness of PTA, toward obtaining better dialysis.

Jejunal interposition reconstruction with a stomach preserving esophagectomy improves postoperative weight loss and reflux symptoms for esophageal cancer patients.

BACKGROUND: Conventional reconstruction after an esophagectomy uses a gastric tube, which commonly causes several postoperative complaints such as gastric acid reflux in long-term survival cases. Intestinal interposition between the remnant esophagus and the stomach is an option to reduce complaints, and in this study, the advantages of jejunal interposition reconstruction with a stomach preserving esophagectomy (SPE) were assessed. MATERIALS AND METHODS: Eleven cases of jejunal interposition with an SPE and 16 cases with gastric tube reconstruction as a control were subject to a comparison of operation time, amount of bleeding, postoperative quality of life, and endoscopic findings. RESULTS: The SPE group had a longer operation time (SPE: 560 ± 121 min, control 414 ± 83 min, P = 0.038), whereas there was no significant difference in blood loss. Postoperative weight loss was significantly recovered in the SPE group (SPE versus control = 94.0 ± 5.4% versus 87.5 ± 4.7% at 3 mo, P = 0.017; 97.2 ± 7.5% versus 85.0 ± 5.2% at 6 mo, P = 0.010), and there was a significant decrease in the occurrence of reflux symptoms such as heartburn, odynophagia, and cough when jejunal interposition with an SPE was done. Furthermore, reflux esophagitis and Barrett's epithelium were found in six out of 12 cases (50%) of the control group by postoperative endoscopy, while no cases in the SPE group had either condition (P < 0.01). CONCLUSIONS: This reconstruction method is a promising option to improve postoperative quality of life, mainly due to the long-term elimination of reflux esophagitis, which assists in the recovery of postoperative weight loss.

Esophageal cancer exhibits resistance to a novel IGF-1R inhibitor NVP-AEW541 with maintained RAS-MAPK activity.

AIM: To assess the effects of a novel type 1 insulin-like growth factor receptor (IGF-1R) inhibitor, NVP-AEW541, on cell proliferation and signal transduction of esophageal cancer. MATERIALS AND METHODS: Cell proliferation assay and western blot were conducted to assess the antitumor effects of NVP-AEW541. Genetic modification of RAS by expression vector was applied for overexpression of mutant RAS. RESULTS: More than 2 µmol/l of NVP-AEW541 was required to effectively inhibit the proliferation of esophageal cancer. NVP-AEW541 potently blocked the activation of IGF-1R and protein kinase B (PKB, also known as AKT), but not of mitogen-activated protein kinase kinase (MEK) and extracellular-signal-regulated kinases (ERK). Active RAS was not reduced by NVP-AEW541 in esophageal cancer cells TE-1, suggesting that insensitivity of esophageal cancer to NVP-AEW541 is due to the maintained RAS-MAPK activity, which did not arise from RAS mutation. Moreover, the transduction of mutant RAS reduced the sensitivity of TE-1 cells to NVP-AEW541. CONCLUSION: Stimulation of RAS-MAPK pathway is associated with resistance to NVP-AEW541 in esophageal cancer. Combining NVP-AEW541 with inhibitors/antibodies against RAS-MAPK signaling molecules might be more effective for use against esophageal cancer.

Anti-tumor effect of a novel FAK inhibitor TAE226 against human oral squamous cell carcinoma.

OBJECTIVES: Focal adhesion kinase (FAK) overexpression is frequently found in invasive and metastatic cancers, but its role in oral squamous cell carcinoma is not yet well understood. In order to seek therapies targeting oral squamous cell carcinoma, we developed the novel FAK Tyr(397) inhibitor TAE226 and investigated its anti-tumor effects and mechanisms. MATERIALS AND METHODS: Expression of phosphorylated FAK Tyr(397) was examined by immunohistochemical and immunoblot analysis. The effect of TAE226 on in vitro and in vivo studies were confirmed by proliferation, cell cycle, apoptosis and angiogenesis analysis. RESULTS: We found that phosphorylated FAK was highly expressed in human tongue oral squamous cell carcinoma in patients. Importantly, TAE226 greatly suppressed the proliferation, migration and invasion of human oral squamous cell carcinoma SAS cells with an apparent structural change of actin fiber and a loss of cell adhesion. In addition, TAE226 inhibited the expression of phospho-FAK Tyr(397) and phospho AKT Ser(473), resulting in caspase-mediated apoptosis. Furthermore, oral administration of TAE226 in mice suppressed the growth and angiogenesis of oral squamous cell carcinoma xenografts in vivo. CONCLUSIONS: Our results provide compelling evidence that FAK is critically involved in oral squamous cell carcinoma and that the FAK inhibitor TAE226 can potentially be effectively used for the treatment of oral squamous cell carcinoma.

Oral administration of FAK inhibitor TAE226 inhibits the progression of peritoneal dissemination of colorectal cancer.

Peritoneal dissemination is one of the most terrible types of colorectal cancer progression. Focal adhesion kinase (FAK) plays a crucial role in the biological processes of cancer, such as cell attachment, migration, proliferation and survival, all of which are essential for the progression of peritoneal dissemination. Since we and other groups have reported that the inhibition of FAK activity exhibited a potent anticancer effect in several cancer models, we hypothesized that TAE226, a novel ATP-competitive tyrosine kinase inhibitor designed to target FAK, can prevent the occurrence and progression of peritoneal dissemination. In vitro, TAE226 greatly inhibited the proliferation and migration of HCT116 colon cancer cells, while their adhesion on the matrix surface was minimally inhibited when FAK activity and expression was suppressed by TAE226 and siRNA. In vivo, when HCT116 cells were intraperitoneally inoculated in mice, the cells could attach to the peritoneum and begin to grow within 24 h regardless of the pretreatment of cells with TAE226 or FAK-siRNA, suggesting that FAK is not essential, at least for the initial integrin-matrix contact. Interestingly, the treatment of mice before and after inoculation significantly suppressed cell attachment to the peritoneum. Furthermore, oral administration of TAE226 greatly reduced the size of disseminated tumors and prolonged survival in tumor-bearing mice. Taken together, a possible strategy for inhibiting peritoneal dissemination by targeting FAK with TAE226 appears to be applicable through anti-proliferative and anti-invasion/anti-migration mechanisms.