Highly Active and Durable Rh-Mo-Based Catalyst for the NO-CO-C3H6-O2 Reaction Prepared by Using Hybrid Clustering.

We developed a method for preparing catalysts by using hybrid clustering to form a high density of metal/oxide interfacial active sites. A Rh-Mo hybrid clustering catalyst was prepared by using a hybrid cluster, [(RhCp*)4Mo4O16] (Cp* = η5-C5Me5), as the precursor. The activities of the Rh-Mo catalysts toward the NO-CO-C3H6-O2 reaction depended on the mixing method (hybrid clustering > coimpregnation ≈ pristine Rh). The hybrid clustering catalyst also exhibited high durability against thermal aging at 1273 K in air. The activity and durability were attributed to the formation of a high-density of Rh/MoOx interfacial sites. The NO reduction mechanism on the hybrid clustering catalyst was different from that on typical Rh catalysts, where the key step is the N-O cleavage of adsorbed NO. The reducibility of the Rh/MoOx interfacial sites contributed to the partial oxidation of C3H6 to form acetate species, which reacted with NO+O2 to form N2 via the adsorbed NCO species. The formation of reduced Rh on Rh4Mo4/Al2O3 was not as essential as that on typical Rh catalysts; this explained the improvement in durability.

Impact of chronological age on efficacy and safety of fluoropyrimidine plus bevacizumab in older non-frail patients with metastatic colorectal cancer: a combined analysis of individual data from two phase II studies of patients aged >75 years.

OBJECTIVE: Many clinical trials for older patients with metastatic colorectal cancer have been conducted, and fluoropyrimidine and bevacizumab are standard treatments. However, the relationship between age and the efficacy and safety of this treatment is unclear in older metastatic colorectal cancer patients. METHODS: Individual data from two phase II studies on older (≥75 years), non-frail patients with metastatic colorectal cancer treated with uracil-tegafur/leucovorin or S-1 combined with bevacizumab were collected. Patient characteristics were evaluated with multiple regression analyses for survival outcomes, using the Cox proportional hazard model and linear regression analyses for the worst grade of adverse events. RESULTS: We enrolled 102 patients with a median age of 80 years (range, 75-88 years). Of the 70 patients who died, seven (10%) died of causes unrelated to disease or treatment. The study treatment was discontinued due to adverse events in 19 patients (18.6%), with 63% aged ≥85 years. The adverse event that most commonly resulted in treatment discontinuation was grade 2 fatigue (21%). Chronological age was not associated with progression-free survival (Hazard ratio, 1.03; P = 0.40) or overall survival (Hazard ratio, 1.02; P = 0.65). Age was weakly associated with non-hematologic adverse events (regression coefficient [R], 0.27; P = 0.007), especially fatigue (R, 0.23; P = 0.02) and nausea (R, 0.19; P = 0.06), but not with hematologic (R, 0.05; P = 0.43) or bevacizumab-related (R, -0.06; P = 0.56) adverse events. CONCLUSIONS: The efficacy of fluoropyrimidine plus bevacizumab was age-independent in patients with metastatic colorectal cancer aged ≥75 years, and attention should be paid to non-hematologic adverse events as age increases.

Cancer-related FGFR2 overexpression and gene amplification in Japanese patients with gastric cancer.

OBJECTIVE: Fibroblast growth factor receptor 2 (FGFR2) has been proposed as a novel druggable target in unresectable gastric cancer. FGFR2 alteration has been reported as associated with poor prognosis even in patients with gastric cancer who received systemic chemotherapy. This study aimed to evaluate the frequency of FGFR2 overexpression and gene amplification in clinical specimens from Japanese patients with recurrent or unresectable gastric cancer. METHODS: This observational study enrolled patients who were histologically or cytologically confirmed with unresectable HER2-negative or unknown gastric or gastroesophageal junctional adenocarcinoma treated with at least one previous chemotherapy. FGFR2 overexpression and gene amplification in the specimens were evaluated by immunohistochemical staining and fluorescence in situ hybridization methods, respectively. RESULTS: In a total of 173 eligible cases, FGFR2 immunohistochemistry score was evaluated as 0, 1, 2, 3 and 4 for 20, 80, 35, 28 and 10 cases, respectively. In 151 evaluable cases with FGFR2 immunohistochemistry scores of 1-4, FGFR2 copy number expressed as fluorescence in situ hybridization signals were detected as <4, ≥4 < 10 and ≥10 copies for 123, 16 and 12 cases, respectively. FGFR2 copy number showed an increasing tendency along with higher FGFR2 immunohistochemistry scores in the corresponding specimen. The response rate and time to treatment failure for first line chemotherapy did not have any obvious relationship to FGFR2 immunohistochemistry score and FGFR2 copy number. CONCLUSIONS: Although FGFR2 overexpression and gene amplification were shown in Japanese patients with unresectable gastric cancer, these alterations did not impact the effects of cytotoxic agents as first line chemotherapy.

Enhanced G1 arrest and apoptosis via MDM4/MDM2 double knockdown and MEK inhibition in wild-type TP53 colon and gastric cancer cells with aberrant KRAS signaling.

Murine double minute homolog 2 (MDM2) is an oncoprotein that induces p53 degradation via ubiquitin-ligase activity. MDM4 cooperates with MDM2-mediated p53 degradation, directly inhibiting p53 transcription by binding to its transactivation domain. Our previous study reported that the simultaneous inhibition of MDM2 and MDM4 using nutlin-3 (an inhibitor of the MDM2-p53 interaction) and chimeric small interfering RNA with DNA-substituted seed arms (named chiMDM2 and chiMDM4) more potently activated p53 than the MDM2 or MDM4 inhibitor alone and synergistically augmented antitumor effects in various types of cancer cells with the wild-type (wt) TP53. Recently, the synergism of MDM2 and mitogen-activated protein kinase kinase (MEK) inhibitors has been demonstrated in wt TP53 colorectal and non-small cell lung cancer cells harboring mutant-type (mt) KRAS. The current study examined whether chiMDM4 augmented the synergistic antitumor effects of MDM2 and MEK inhibition using chiMDM2 or nutlin-3 and trametinib, respectively. ChiMDM2 and trametinib used in combination demonstrated a synergistic antitumor activity in HCT116 and LoVo colon cancer cells, and SNU-1 gastric cancer cells harboring wt TP53 and mt KRAS. Furthermore, chiMDM4 synergistically enhanced this combinational effect. Similar results were observed when nutlin-3 was used instead of chiMDM2. MDM4/MDM2 double knockdown combined with trametinib treatment enhanced G1 arrest and apoptosis induction. This was associated with the accumulation of p53, suppression of phosphorylated-extracellular signal-regulated kinase 2, inhibition of retinoblastoma phosphorylation, suppression of E2F1-activated proteins, and potent activation of pro-apoptotic proteins, such as Fas and p53 upregulated modulator of apoptosis. The results inidcated that the triple inhibition of MDM4, MDM2 and MEK exerted a potent antitumor effect in wt TP53 colon and gastric cancer cells with mt KRAS. Simultaneous activation of p53 and inhibition of aberrant KRAS signaling may be a rational treatment strategy for gastrointestinal tumors.

MDM4 as a Prognostic Factor for Patients With Gastric Cancer With Low Expression of p53.

BACKGROUND/AIM: The oncoproteins murine double minute (MDM) 2 and MDM4 inactivate tumor-suppressor protein p53. Their mutual relationship with the prognosis of gastric cancer (GC) remains unknown. PATIENTS AND METHODS: Expression of MDM2, MDM4, and p53 in tumors of 241 patients with GC were evaluated immunohistochemically. Effects of overexpression of MDM4 on tumor-growth properties and sensitivity to cytotoxic drugs were investigated using NUGC4 human GC cell line. RESULTS: High expression of p53 was associated with poor overall survival in the whole population. Among 173 patients with low expression of p53 (implying nonmutation), high expression of MDM4 was an independent factor of poor prognosis in both stage I-III and IV, but of MDM2 was not. MDM4-transduced NUGC4 cells formed twice as many colonies and had a higher 50% inhibitory concentration for 5-fluorouracil and oxaliplatin than did the control cells. CONCLUSION: MDM4 expression is a factor conferring poor prognosis in patients with GC with low expression of p53 and may confer drug resistance.

Phase II study of S-1 on alternate days plus bevacizumab in patients aged ≥ 75 years with metastatic colorectal cancer (J-SAVER).

BACKGROUND: Alternate-day administration of S-1 is thought to reduce toxicities. This phase II study evaluated S-1 on alternate days combined with bevacizumab as first-line treatment for elderly patients with metastatic colorectal cancer. PATIENTS AND METHODS: Eligible patients had histologically proven colorectal adenocarcinoma, measurable metastatic lesions, age ≥ 75 years, Eastern Cooperative Oncology Group performance status ≤ 1, no previous chemotherapy, and refused oxaliplatin- or irinotecan-containing regimens. Patients received 40 mg, 50 mg, or 60 mg (body surface area ≤ 1.25 m2, > 1.25 to ≤ 1.50 m2, or > 1.50 m2, respectively) of S-1 twice orally on Sunday, Monday, Wednesday, and Friday every week. Bevacizumab (7.5 mg/kg) was administered every 3 weeks. The primary endpoint was progression-free survival. RESULTS: Of 54 enrolled patients, 50 patients were evaluated for efficacy and 53 for safety. The median age was 79 years (range 75-88 years). The median progression-free survival was 8.1 months (95% confidence interval (CI) 6.7-9.5 months). The median overall survival was 23.1 months (95% CI 17.4-28.8 months). The response rate was 44% (95% CI 30.2-57.8%), and the disease control rate was 88% (95% CI 79.0-97.0%). Grade 3 or higher hematologic, non-hematologic, and bevacizumab-related adverse events occurred in 9%, 11%, and 25% of patients, respectively. The most common grade 3 and 4 treatment-related adverse events were hypertension (11%), nausea (6%), fatigue (6%), anemia (6%), and proteinuria (6%). Only 6 patients discontinued treatment due to adverse events. CONCLUSION: S-1 on alternate days combined with bevacizumab showed better tolerability and comparable survival compared with the results of similar studies.

Augmented antitumor activity of 5-fluorouracil by double knockdown of MDM4 and MDM2 in colon and gastric cancer cells.

Inactivation of the TP53 tumor suppressor gene is essential during cancer development and progression. Mutations of TP53 are often missense and occur in various human cancers. In some fraction of wild-type (wt) TP53 tumors, p53 is inactivated by upregulated murine double minute homolog 2 (MDM2) and MDM4. We previously reported that simultaneous knockdown of MDM4 and MDM2 using synthetic DNA-modified siRNAs revived p53 activity and synergistically inhibited in vitro cell growth in cancer cells with wt TP53 and high MDM4 expression (wtTP53/highMDM4). In the present study, MDM4/MDM2 double knockdown with the siRNAs enhanced 5-fluorouracil (5-FU)-induced p53 activation, arrested the cell cycle at G1 phase, and potentiated the antitumor effect of 5-FU in wtTP53/highMDM4 human colon (HCT116 and LoVo) and gastric (SNU-1 and NUGC-4) cancer cells. Exposure to 5-FU alone induced MDM2 as well as p21 and PUMA by p53 activation. As p53-MDM2 forms a negative feedback loop, enhancement of the antitumor effect of 5-FU by MDM4/MDM2 double knockdown could be attributed to blocking of the feedback mechanism in addition to direct suppression of these p53 antagonists. Intratumor injection of the MDM4/MDM2 siRNAs suppressed in vivo tumor growth and boosted the antitumor effect of 5-FU in an athymic mouse xenograft model using HCT116 cells. These results suggest that a combination of MDM4/MDM2 knockdown and conventional cytotoxic drugs could be a promising treatment strategy for wtTP53/highMDM4 gastrointestinal cancers.

Newly developed endoscopic detachable snare ligation therapy for colonic diverticular hemorrhage: a multicenter phase II trial (with videos).

BACKGROUND AND AIMS: We previously reported preliminary safety results for a new method, endoscopic detachable snare ligation (EDSL), for diverticular hemorrhage. This method does not need endoscope removal to attach a ligation device after detection of the bleeding site. The aim of the present study was to evaluate the efficacy and safety of EDSL in a larger patient population. METHODS: This prospective study was conducted in 12 institutions. Patients suspected of having diverticular hemorrhage without serious systemic disease were enrolled. The primary endpoint was early (within 30 days) recurrent bleeding rate in patients treated with EDSL. The secondary endpoints were overall early recurrent bleeding rate in patients with definite diverticular bleeding and adverse events in patients treated with EDSL. RESULTS: From June 2015 to March 2017, bleeding diverticula were detected in 123 of 205 enrolled patients (60%), of whom 101 (82%) were treated with EDSL. Most patients (20/22) in whom EDSL was not successful were treated with clipping. The early recurrent bleeding rate was 7.9% (95% confidence interval, 2.6%-13.2%; 8/101) in patients who could be treated with EDSL. The median total endoscopic and EDSL procedure time was 40 minutes (interquartile range, 15-71) and 4 minutes (interquartile range, 1-7), respectively. Two mild adverse events, colonic diverticulitis and temporary abdominal pain, were observed. CONCLUSION: EDSL was confirmed to be useful and safe for treatment of colonic diverticular hemorrhage. (Clinical trial registration number: UMIN 000001858.).

Hepatocellular adenoma in a woman who was undergoing testosterone treatment for gender identity disorder.

A 32-year-old Japanese woman was admitted to our hospital for the diagnosis and treatment of multiple liver tumors. She had been receiving 125 mg testosterone enanthate every 2 weeks following female-to-male gender identity disorder (GID) diagnosis at 20 years of age. Ultrasonography, computed tomography, and magnetic resonance imaging showed 11 hepatic nodular tumors with a maximum diameter of 28 mm. Liver tumors with hepatocellular adenoma (HCA) were diagnosed with needle biopsy. Segmentectomy of the left lateral lobe including two lesions, subsegmentectomy of S6 including two lesions, enucleation of each tumor in S5 and S7, and open surgical radiofrequency ablation for each tumor in S4 and S7 were performed. Immunohistochemical specimens showed that the tumor cells were diffusely and strongly positive for glutamine synthetase and that the nuclei were ectopically positive for ß-catenin. Thus, the tumors were diagnosed as ß-catenin-activated HCA (b-HCA). Transcatheter arterial chemoembolization plus subsequent radiofrequency ablation was performed for the 3 residual lesions in S4 and S8. Although testosterone enanthate was being continued for GID, no recurrence was observed until at least 22 months after the intensive treatments. HCA development in such patients receiving testosterone should be closely monitored using image inspection.

Gastric Adenocarcinoma with Dual Differentiation toward Neuroendocrine and α-Fetoprotein-Producing Features: Report of 2 Cases.

Some gastric carcinomas show composite features of neuroendocrine carcinoma (NEC) and α-fetoprotein (AFP)-producing carcinoma, which are very rare; only a few cases have been reported to date. We reviewed an additional 2 such cases of gastric carcinoma, which were both advanced aggressive tumors showing regional lymph node metastasis and distant metastasis. Both cases were accompanied by ordinary adenocarcinoma forms, implying that they had preceded the NEC and AFP-producing carcinoma components. A distinctive feature was the finding suggestive of dual differentiation of tumor cells to neuroendocrine and AFP-producing phenotypes, which was identified even in the metastatic tumor in the regional lymph node. Because both tumors predominantly showed poorly differentiated forms, the final pathologic diagnosis must rely on the immunohistochemistry. Pathologists should always keep in mind the existence of such tumors for the correct diagnosis of some gastric carcinomas with specific phenotypes, especially in pathologic diagnosis on biopsy.

C-Arm Cone Beam Computed Tomography Guidance for Radiofrequency Ablation in Hepatocellular Carcinoma.

OBJECTIVE: To assess the usefulness of C-arm cone beam computed tomography (CBCT) combined with ultrasound for the treatment of hepatocellular carcinoma (HCC) by radiofrequency ablation (RFA). METHODS: Patients underwent RFA following transcatheter arterial chemoembolization (TACE) or RFA alone under ultrasound or CBCT guidance combined with ultrasound-based techniques. They were divided into 2 groups based on the use (C group) and nonuse (NC group) of CBCT guidance. The technical success of RFA and local tumor progression after the first RFA session were evaluated by dynamic contrast-enhanced imaging methods. Between-group differences were assessed retrospectively. RESULTS: We enrolled 198 patients with 260 HCC nodules. The complete ablation rates were 63.0 and 89.4% in the NC and C groups, respectively. In log-rank testing, local tumor progression occurred significantly more often in the NC group when RFA was used without TACE, in males when des-gamma-carboxy prothrombin was ≥29 mAU/mL, and when the diameter of a nodule was ≥18 mm. On Cox proportional-hazards regression analysis, the NC group, RFA alone without TACE, and male gender were significant independent variables. CONCLUSION: TACE followed by RFA under CBCT and ultrasound guidance improves the reliability of ablation of target HCC nodules, reduces the need for additional treatment sessions, and prevents local tumor progression.

Correlations of survival with progression-free survival, response rate, and disease control rate in advanced biliary tract cancer: a meta-analysis of randomised trials of first-line chemotherapy.

BACKGROUND: The need to promote novel drug development for advanced biliary tract cancer (ABTC) has emphasised the importance of determining whether various efficacy end points can act as surrogates for overall survival (OS). METHODS: We conducted a literature search of randomised trials of first-line chemotherapy for ABTC and investigated correlations between efficacy end points and OS using weighted linear regression analysis. The ratios of the median OS, median progression-free survival (PFS), response rate, and disease control rate in each trial were used to summarise treatment effects. The surrogate threshold effect (STE), which was the minimum treatment effect on PFS required to predict a non-zero treatment effect on OS, was calculated. RESULTS: Seventeen randomised trials with 36 treatment arms were identified, and a sample size of 2148 patients with 19 paired arms was analysed. The strongest correlation between all evaluated efficacy end points was observed between median OS and median PFS ratios (r(2)=0.66). In trials with gemcitabine-containing therapies and targeted agents, the r(2)-values were 0.78. The STE was estimated at 0.83 for all trials and 0.81 for trials with gemcitabine-containing therapies, and was not calculated for trials with targeted agents. CONCLUSIONS: The median PFS ratio correlated well with the median OS ratio, and may be useful for planning a clinical trial for novel drug development.

Successful Treatment with Modified FOLFOX6 and Panitumumab in a Cecal Cancer Patient Undergoing Hemodialysis.

Combination chemotherapy of mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin) plus panitumumab, a fully human monoclonal antibody against epidermal growth factor receptor (EGFR), is one of the standard treatments for metastatic colorectal cancer (mCRC) without KRAS mutation. A few reports suggested no need of dose adjustment of cetuximab, a similar chimeric anti-EGFR antibody, in patients with renal impairment. However, panitumumab combined with cytotoxic drugs for hemodialysis patients has not been reported. We herein report a case of a hemodialysis mCRC patient successfully treated with mFOLFOX6 and panitumumab combination therapy.

Phase I study of gemcitabine, cisplatin, and S-1 combination therapy for patients with untreated advanced biliary tract cancer.

BACKGROUND: To develop a triplet regimen containing gemcitabine, cisplatin, and S-1 (GPS), we assessed the recommended dose for patients with untreated advanced biliary tract cancer in this phase I study. METHODS: Dose-limiting toxicities (DLTs) were evaluated for the following two dose levels: gemcitabine (1000 mg/m(2) for level 1 and 1200 mg/m(2) for level 2 on day 1), cisplatin (30 mg/m(2) fixed dose on day 1), and S-1 (40-60 mg/day fixed dose twice a day for 7 days), every 2 weeks until progression. DLTs for each level were evaluated in six or more patients during the first two cycles. RESULTS: A total of 18 patients were enrolled and 16 patients were evaluated. DLTs at level 1 were observed in two of 10 patients. At level 2, a DLT was observed in one of six patients. The main grade 3 or 4 treatment-related adverse events were neutropenia and leukopenia, and a few non-hematological toxicities were observed. Among 14 patients with measurable lesions, the best response rate was 50%. CONCLUSIONS: GPS with a relative dose intensity corresponding to 90% of the standard gemcitabine plus cisplatin regimen could be administered safely, and showed preliminary antitumor activity. Survival benefits will be studied subsequently.

[A retrospective analysis of cetuximab or panitumumab monotherapy for KRAS wild-type metastatic colorectal cancer in clinical practice].

We performed a retrospective study on the use of cetuximab or panitumumab alone in patients with KRAS wild-type metastatic colorectal cancer between November 2008 and February 2012. Twenty-two patients were analyzed and classified as PS 0/1 (good PS group)and PS 2/3/4 (poor PS group)with 11 patients in each group. The response rate, disease control rate, median progression-free survival, and median overall survival were 9%, 73%, 5.1 months (95%confidence interval[CI]: 1.5-8.7), and 16 months (95% CI: 8.8-24), respectively, in the good PS group, and the corresponding values in the poor PS group were 0%, 18%, 0.7 months (95% CI: 0.3-1.0), and 1.5 months (95% CI: 0.7-2.4). Grade 3 or 4 adverse events were skin toxicities (2 patients with grade 3 toxicities), panitumumab-related interstitial lung disease (1 patient with grade 4 toxicity), and cetuximab infusion-related reaction (1 patient with grade 4 toxicity). No treatment-related deaths were observed. In conclusion, the efficacy and safety of cetuximab or panitumumab monotherapy in patients with a good PS in our study were similar to those reported in previous clinical trials, whereas patients with a poor PS showed poorer outcomes.

Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation.

Up-regulated sirtuin 1 (SIRT1), an NAD+-dependent class III histone deacetylase, deacetylates p53 and inhibits its transcriptional activity, leading to cell survival. SIRT1 overexpression has been reported to predict poor survival in some malignancies, including gastric cancer. However, the antitumor effect of SIRT1 inhibition remains elusive in gastric cancer. Here, we investigated the antitumor mechanisms of a sirtuin inhibitor, tenovin-6, in seven human gastric cancer cell lines (four cell lines with wild-type TP53, two with mutant-type TP53, and one with null TP53). Interestingly, tenovin-6 induced apoptosis in all cell lines, not only those with wild-type TP53, but also mutant-type and null versions, accompanied by up-regulation of death receptor 5 (DR5). In the KatoIII cell line (TP53-null), DR5 silencing markedly attenuated tenovin-6-induced apoptosis, suggesting that the pivotal mechanism behind its antitumor effects is based on activation of the death receptor signal pathway. Although endoplasmic reticulum stress caused by sirtuin inhibitors was reported to induce DR5 up-regulation in other cancer cell lines, we could not find marked activation of its related molecules, such as ATF6, PERK, and CHOP, in gastric cancer cells treated with tenovin-6. Tenovin-6 in combination with docetaxel or SN-38 exerted a slight to moderate synergistic cytotoxicity against gastric cancer cells. In conclusion, tenovin-6 has potent antitumor activity against human gastric cancer cells via DR5 up-regulation. Our results should be helpful for the future clinical development of sirtuin inhibitors.

Effectiveness of an endoscopic biopsy procedure using EUS-FNA and EMR-C for diagnosing adenocarcinoma arising from ectopic pancreas: two case reports and a literature review.

Adenocarcinomas arising from the ectopic pancreas in the gastrointestinal wall are rarely described in the literature. In addition, obtaining an accurate preoperative diagnosis is difficult in most cases because these adenocarcinomas occur primarily in the submucosal layer and form submucosal tumors. Endoscopic ultrasonography-guided fine-needle aspiration and endoscopic mucosal resection with a transparent plastic cap-fitted panendoscope followed by a biopsy are useful for histological typing and making the differential diagnosis of adenocarcinoma, gastrointestinal stromal tumor, malignant lymphoma or other. These procedures represent the first step toward diagnosing ectopic pancreatic adenocarcinoma. We herein report two such cases with a review of the pertinent literature.

Risk factors for submucosal and lymphovascular invasion in gastric cancer looking indicative for endoscopic submucosal dissection.

BACKGROUND: Submucosal and lymphovascular (SM/LV) invasions of early gastric cancer (EGC) are difficult to diagnose accurately prior to endoscopic submucosal dissection (ESD), and are occasionally found in resected specimens, requiring additional gastrectomy and lymph node dissection. We performed a retrospective study to determine the risk factors for SM/LV invasions. METHODS: We analyzed clinicopathological data (age, sex, cancer location, gross morphology, multifocality, tumor size, histological differentiation, depth of invasion, and the presence or absence of lymphovascular invasion) in patients receiving ESD between 2007 and 2012 and presenting with EGC of 2.0 cm or smaller in size, a differentiated-type adenocarcinoma, and without ulceration. RESULTS: Of 208 lesions consecutively resected by ESD, 143 lesions in 132 patients were included in this study. Submucosal and lymphovascular invasions were detected in 16 lesions. Multivariate analysis revealed three independent risk factors for SM/LV invasions: dominant histology of moderately-differentiated or papillary adenocarcinoma, gross type of 0-IIa + IIc or IIc + IIa, and tumor size of ≥1.5 cm. Lesions exhibiting more than two of these three risk factors were associated with having a 47 % increased incidence of SM/LV invasion (odds ratio 15; 95 % confidence interval 4.6-49.0; P < 0.0001). CONCLUSIONS: Moderately-differentiated or papillary adenocarcinoma, 0-IIa + IIc or IIc + IIa, and a tumor size of ≥1.5 cm were identified as independent risk factors for SM/LV invasion among EGCs which appeared to be an endoscopically good indication for ESD. Careful surveillances including endoscopic ultrasonography or enhanced computed tomography might be needed for high risk patients before ESD.

MDM4 expression as an indicator of TP53 reactivation by combined targeting of MDM2 and MDM4 in cancer cells without TP53 mutation.

MDM2 and MDM4, a structurally related MDM2 homolog, negatively regulates expression and functions of TP53 tumor suppressor gene. To explore the precise expression patterns and function of MDM2 and MDM4 in wild-type (wt) TP53 cancer cells, we analyzed 11 various cancer cell lines with wt TP53. All cell lines exhibited deregulated expression of MDM2 and MDM4, and were divided into two distinct types; the one expressing high levels of MDM4 and another expressing low levels of MDM4. The low MDM4 type expressed higher MDM2 levels than the high MDM4 type. In cells with high MDM4 expression, knockdown of MDM4 or MDM2 reactivated TP53, and simultaneous knockdown of MDM2 and MDM4 synergistically reactivated TP53. In contrast, in cells with low MDM4 expression, knockdown of only MDM2 reactivated TP53. These results suggest that both MDM2 and MDM4 are closely involved in TP53 inactivation in cancer cells with high MDM4 expression, whereas only MDM2, and not MDM4, is a regulator of TP53 in cells with low MDM4 expression. MDM4 expression in wt TP53-tumors is a potential indicator for TP53 reactivation cancer therapy by simultaneous targeting of MDM4 and MDM2. Specific knockdown of MDM2 and MDM4 might be applicable for TP53 restoration therapy.

Predicting skin toxicity according to EGFR polymorphisms in patients with colorectal cancer receiving antibody against EGFR.

BACKGROUND/AIM: Monoclonal antibodies against epidermal growth factor receptor (EGFR) can extend progression-free survival (PFS) and overall survival (OS) in patients with unresectable colorectal cancer; however, skin toxicity often interferes with therapy continuation. PATIENTS AND METHODS: We analyzed the polymorphisms in EGFR and IgG fragment C receptor (FCGR) genes and determined their associations with clinical outcomes including PFS, OS, and skin toxicity. Five polymorphisms in EGFR and FCGR genes in 32 patients with unresectable colorectal cancer who were treated with antibodies against EGFR were examined. RESULTS: Patients carrying the C/C genotype of the EGFR D994D polymorphism displayed significantly less skin toxicity than those with other genotypes, although no significant differences in PFS and OS were noted and no significant interactions were detected for other gene polymorphisms. CONCLUSION: These results suggest that the EGFR D994D polymorphism is a useful biomarker for predicting the severity of skin toxicity in patients receiving antibody against EGFR.