Clinically conserved genomic subtypes of gastric adenocarcinoma.

Gastric adenocarcinoma (GAC) is a lethal disease characterized by genomic and clinical heterogeneity. By integrating 8 previously established genomic signatures for GAC subtypes, we identified 6 clinically and molecularly distinct genomic consensus subtypes (CGSs). CGS1 have the poorest prognosis, very high stem cell characteristics, and high IGF1 expression, but low genomic alterations. CGS2 is enriched with canonical epithelial gene expression. CGS3 and CGS4 have high copy number alterations and low immune reactivity. However, CGS3 and CGS4 differ in that CGS3 has high HER2 activation, while CGS4 has high SALL4 and KRAS activation. CGS5 has the high mutation burden and moderately high immune reactivity that are characteristic of microsatellite instable tumors. Most CGS6 tumors are positive for Epstein Barr virus and show extremely high levels of methylation and high immune reactivity. In a systematic analysis of genomic and proteomic data, we estimated the potential response rate of each consensus subtype to standard and experimental treatments such as radiation therapy, targeted therapy, and immunotherapy. Interestingly, CGS3 was significantly associated with a benefit from chemoradiation therapy owing to its high basal level of ferroptosis. In addition, we also identified potential therapeutic targets for each consensus subtype. Thus, the consensus subtypes produced a robust classification and provide for additional characterizations for subtype-based customized interventions.

Consensus subtypes of hepatocellular carcinoma associated with clinical outcomes and genomic phenotypes.

BACKGROUND AND AIMS: Although many studies revealed transcriptomic subtypes of HCC, concordance of the subtypes are not fully examined. We aim to examine a consensus of transcriptomic subtypes and correlate them with clinical outcomes. APPROACH AND RESULTS: By integrating 16 previously established genomic signatures for HCC subtypes, we identified five clinically and molecularly distinct consensus subtypes. STM (STeM) is characterized by high stem cell features, vascular invasion, and poor prognosis. CIN (Chromosomal INstability) has moderate stem cell features, but high genomic instability and low immune activity. IMH (IMmune High) is characterized by high immune activity. BCM (Beta-Catenin with high Male predominance) is characterized by prominent ß-catenin activation, low miRNA expression, hypomethylation, and high sensitivity to sorafenib. DLP (Differentiated and Low Proliferation) is differentiated with high hepatocyte nuclear factor 4A activity. We also developed and validated a robust predictor of consensus subtype with 100 genes and demonstrated that five subtypes were well conserved in patient-derived xenograft models and cell lines. By analyzing serum proteomic data from the same patients, we further identified potential serum biomarkers that can stratify patients into subtypes. CONCLUSIONS: Five HCC subtypes are correlated with genomic phenotypes and clinical outcomes and highly conserved in preclinical models, providing a framework for selecting the most appropriate models for preclinical studies.

Nomogram for predicting the overall survival of underweight patients with colorectal cancer: a clinical study.

BACKGROUND: An underweight individual is defined as one whose Body Mass Index (BMI) is < 18.5 kg/m2. Currently, the prognosis in patients with colorectal cancer (CRC) who are also underweight is unclear. METHODS: Information on South Korean patients who underwent curative resection for CRC without distant metastasis was collected from health insurance registry data between January 2014 and December 2016. We compared the overall survival (OS) of underweight and non-underweight (BMI ≥ 18.5 kg/m2) patients after adjusting for confounders using propensity score matching. A nomogram to predict OS in the underweight group was constructed using the significant risk factors identified in multivariate analysis. The predictive and discriminative capabilities of the nomogram for predicting 3- and 5-year OS in the underweight group were validated and compared with those of the tumor, node, and metastasis (TNM) staging system in the training and validation sets. RESULTS: A total of 23,803 (93.6%) and 1,644 (6.4%) patients were assigned to the non-underweight and underweight groups, respectively. OS was significantly worse in the underweight group than in the non-underweight group for each pathological stage (non-underweight vs. underweight: stage I, 90.1% vs. 77.1%; stage IIA, 85.3% vs. 67.3%; stage IIB/C, 74.9% vs. 52.1%; and stage III, 73.2% vs. 59.4%, P < 0.001). The calibration plots demonstrated that the nomogram exhibited satisfactory consistency with the actual results. The concordance index (C-index) and area under the receiver operating characteristic curve (AUC) of the nomogram exhibited better discriminatory capability than those of the TNM staging system (C-index, nomogram versus TNM staging system: training set, 0.713 versus 0.564, P < 0.001; validation set, 0.691 versus 0.548, P < 0.001; AUC for 3- and 5- year OS, nomogram versus TNM staging system: training set, 0.748 and 0.741 versus 0.610 and 0.601; validation set, 0.715 and 0.753 versus 0.586 and 0.579, respectively). CONCLUSIONS: Underweight patients had worse OS than non-underweight patients for all stages of CRC. Our nomogram can guide prognostic predictions and the treatment plan for underweight patients with CRC.

Long-term oncologic outcome of D3 lymph node dissection for clinical stage 2/3 right-sided colon cancer.

PURPOSE: To investigate oncologic outcomes including overall survival and disease-free survival depending on the extent of lymphadenectomy (D3 versus D2) by comparing D3 and D2 lymphadenectomy in patients with clinical stage 2/3 right colon cancer. METHODS: Consecutive series of patients who underwent radical resection for right colon cancer at our three hospitals between January 2015 and June 2018 were retrospectively analyzed. Study cohorts were divided into two groups: D3 group and D2 group. Oncologic, pathologic, and perioperative outcomes of the two groups were compared. RESULTS: A total of 295 patients (167 in the D2 group and 128 in the D3 group) were included in this study. Patients' characteristics showed no significant difference between the two groups. The median number of harvested lymph nodes was significantly higher in the D3 group than in the D2 group. The rate of complications was not significantly different between the two groups except for chyle leakage, which was more frequent in the D3 group. Five-year disease-free survival was 90.2% (95% CI: 84.8-95.9%) in the D3 group, which was significantly (p = 0.028) higher than that (80.5%, 95% CI: 74-87.5%) in the D2 group. There was no significant difference in overall survival between the two groups. CONCLUSION: Our results indicate that D3 lymphadenectomy is associated with more favorable 5-year disease-free survival than D2 lymphadenectomy for patients with stage 2/3 right-sided colon cancer. D3 lymphadenectomy might improve oncologic outcomes in consideration of the recurrence rate.

Prognostic significance of high metabolic activity in breast cancer: PET signature in breast cancer.

High metabolic activity, reflected in increased glucose uptake, is one of the hallmarks of many cancers including breast cancer. However, not all cancers avidly take up glucose, suggesting heterogeneity in their metabolic demand. Thus, we aim to generate a genomic signature of glucose hypermetabolism in breast cancer and examine its clinical relevance. To identify genes significantly associated with glucose uptake, gene expression data were analyzed together with the standardized uptake values (SUVmax) of 18F-fluorodeoxy-glucose on positron emission tomography (PET) for 11 breast cancers. The resulting PET signature was evaluated for prognostic significance in four large independent patient cohorts (n = 5417). Potential upstream regulators accountable for the high glucose uptake were identified by gene network analysis. A PET signature of 242 genes was significantly correlated with SUVmax in breast cancer. In all four cohorts, high PET signature was significantly associated with poorer prognosis. The prognostic value of this PET signature was further supported by Cox regression analyses (hazard ratio 1.7, confidential interval 1.48-2.02; P < 0.001). The PET signature was also strongly correlated with previously established prognostic genomic signatures such as PAM50, Oncotype DX, and NKI. Gene network analyses suggested that MYC and TBX2 were the most significant upstream transcription factors in the breast cancers with high glucose uptake. A PET signature reflecting high glucose uptake is a novel independent prognostic factor in breast cancer. MYC and TBX2 are potential regulators of glucose uptake.

Identification of prognostic biomarker in predicting hepatocarcinogenesis from cirrhotic liver using protein and gene signatures.

INTRODUCTION: Cirrhosis primes the liver for hepatocellular carcinoma (HCC) development. However, biomarkers that predict HCC in cirrhosis patients are lacking. Thus, we aimed to identify a biomarker directly from protein analysis and relate it with transcriptomic data to validate in larger cohorts. MATERIAL AND METHOD: Forty-six patients who underwent hepatectomy for HCC that arose from cirrhotic liver were enrolled. Reverse-phase protein array and microarray data of these patients were analyzed. Clinical validation was performed in two independent cohorts and functional validation using cell and tissue microarray (TMA). RESULTS: Systematic analysis performed after selecting 20 proteins from 201 proteins with AUROC >70 effectively categorized patients into high (n = 20) or low (n = 26) risk HCC groups. Proteome-derived late recurrence (PDLR)-gene signature comprising 298 genes that significantly differed between high and low risk groups predicted HCC well in a cohort of 216 cirrhosis patients and also de novo HCC recurrence in a cohort of 259 patients who underwent hepatectomy. Among 20 proteins that were selected for analysis, caveolin-1 (CAV1) was the most dominant protein that categorized the patients into high and low risk groups (P < .001). In a multivariate analysis, compared with other clinical variables, the PDLR-gene signature remained as a significant predictor of HCC (HR 1.904, P = .01). In vitro experiments revealed that compared with mock-transduced immortalized liver cells, CAV1-transduced cells showed significantly increased proliferation (P < .001) and colony formation in soft agar (P < .033). TMA with immunohistochemistry showed that tissues with CAV1 expression were more likely to develop HCC than tissues without CAV1 expression (P = .047). CONCLUSION: CAV1 expression predicts HCC development, making it a potential biomarker and target for preventive therapy.

The Effect of Time Synchronization Error in LAN-Based Digital Substation.

In this paper, the effect of time synchronization error on protection algorithms are studied for the usage of the LAN-based collaborative protection. In order to derive the effect of time synchronization, this paper proposes a substation model which is constructed with IEEE 1588 Precision Time Protocol (PTP) supported intelligent electronic devices. The proposed model is used as an example of a target platform to study the effect of time synchronization error with two typical substation protection algorithms, i.e., current differential-based substation protection and distance protection algorithms. From the analyzed and the simulated results, it was well observed that time synchronization error is a significant error-causing factor for both protection algorithms, resulting in erroneous detection of faults and erroneous estimation of fault distances, respectively. The results of research performed in this paper are expected to provide a good guide for constructing the future LAN-based digital power substation with precise time synchronization.

Improved Time-Synchronization Algorithm Based on Direct Compensation of Disturbance Effects.

In this paper, an improved time-synchronization algorithm is proposed. The improvement of time synchronizing performance was achieved by introducing a stochastic model-based direct compensation of the disturbance effects appearing in the IEEE 1588 Precision Time Protocol (PTP)-based time synchronization system. A dynamic model of PTP clock system was obtained by reflecting the three major sources of disturbances, i.e., clock frequency drift, clock rate offset, and network noise. With the application of the dynamic model of the PTP clock system, the effects of the disturbances can be effectively eliminated in the PTP time synchronization control loop. Computer simulations are performed to verify the performance of the proposed time synchronization algorithm by applying the various types of disturbances, including network noise and clock drift. The simulation results are compared with those of other representative time synchronization algorithms, i.e., IEEE 1588 PTP algorithm and Kalman-filter-based algorithm. It is shown that the proposed algorithm improves time synchronizing performance up to 84% with respect to that of the Kalman-filter-based synchronization algorithm when simulated with colored noise type disturbances. The proposed time synchronization algorithm is expected to contribute for the realization of future Ethernet-based industry-plant monitoring and control including IEC 61850-based digital substation.

Iron chelator-induced apoptosis via the ER stress pathway in gastric cancer cells.

Many reports have shown the anticancer effects of iron deficient on cancer cells, but the effects of iron-chelators on gastric cancer have not been clearly elucidated. Recently, we reported that iron chelators induced an antiproliferative effect in human malignant lymphoma and myeloid leukemia cells. In the present study, we investigated the antitumor activity of these two iron-chelating agents, deferoxamine (DFO) and deferasirox (DFX), with gastric cancer cell lines, and their apoptosis-inducing effects as the potential mechanism. We found that iron chelators displayed significant antiproliferative activity in human gastric cancer cell lines, which may be attributed to their induction of G1 phase arrest and apoptosis. We also found that iron chelators induced reactive oxygen species (ROS) production, resulting in the activation of both c-Jun N-terminal kinase (JNK) and endoplasmic reticulum (ER) stress apoptotic pathways in gastric cancer cells. Taken together, our data suggest that iron chelators induced apoptosis in gastric cancer, involving ROS formation ER stress and JNK activation.

BMP-2 induces motility and invasiveness by promoting colon cancer stemness through STAT3 activation.

Bone morphogenetic proteins (BMPs) have been involved in metastatic progression and tumorigenesis of many cancer types. However, it remains unclear how BMP-2 contributes to the initiation and development of these cancers. Here, we investigated the role of BMP-2 in colon cancer stem cell (CSC) development from colon cancer cells. We also determined the effects of BMP-2 on CSC development and epithelial-mesenchymal transition (EMT) in human colon cancer cell lines HCT-116 and SW620. We found that BMP-2 enhanced sphere formation of colon cancer cells without serum. Also, BMP-2-induced spheres displayed up-regulation of stemness markers (CD133+ and EpCAM+) and increased drug resistance, hallmarks of CSCs. Importantly, expression of EMT activators p-Smad1/5 and Snail and N-cadherin was increased in the spheres' cells, indicating that BMP-2 signaling might result in CSC self-renewal and EMT. Furthermore, siRNA-mediated knockdown of signal transducer and activator of transcription 3 (STAT3) in HCT-116 cells reversed BMP-2-induced EMT and stem cell formation. Taken together, our results suggest that the BMP-2 induced STAT3-mediated induction of colon cancer cell metastasis requires an EMT and/or changes in CSC markers.

Transanal Minimally Invasive Surgery (TAMIS) for Rectal Lesions: A Systematic Review.

BACKGROUND/AIMS: Transanal minimally invasive surgery (TAMIS) has received attention as an alternative to transanal endoscopic microsurgery for rectal lesions. We review the effectiveness and safety of TAMIS for the treatment of rectal lesions. METHODOLOGY: The MEDLINE, Web of Science, and Cochrane Library databases were searched using predefined inclusion criteria. The primary outcomes were positive margin rate, recurrence rate, conversion rate, range of applications, and complication rates. To derive pooled estimates of proportions with 95% Confidence Interval (CI) for the outcomes, a random effect model was used. RESULTS: Twelve studies including 155 patients were identified. The weighted mean size of rectal lesions was 3.3 cm (range 0.2-10 cm) and the weighted mean distance from the anal verge was 7.4 cm (range 0-20 cm). Six studies enrolled only the patients with low and mid rectal lesions mainly to avoid peritoneal entrance during excision. CONCLUSIONS: Based on the evidence from this limited number of studies, TAMIS appears to be an effective and safe treatment for rec tal lesions. However, the clinical outcome of TAMIS according to the location of the rectal lesions needs to be clarified. Comparison with other established surgical treatments are also mandatory.

Effective utilization of polypectomy in endoscopic salvage treatment of rectal neuroendocrine tumors: a retrospective cohort study.

Purpose: Current guidelines recommend endoscopic resection for rectal neuroendocrine tumors (RNETs) under 10 mm. Incomplete resections necessitate salvage procedures, highlighting the need for complete R0 resection. This study evaluates the efficacy and safety of wide hot snare polypectomy (WHSP) compared to endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR) for the salvage treatment of small RNETs. Methods: This retrospective study was conducted at Korea University Guro Hospital from January 2018 to December 2022. It compared the outcomes of salvage resections for RNETs ≤10 mm using 2 approaches: ESD and EMR vs. WHSP. Demographics, tumor characteristics, and clinical outcomes were compared. Efficacy was evaluated by the histological complete resection rate and procedure time, while safety was assessed by the incidence of complications. Results: Out of 135 patients undergoing salvage resection for RNET, 14 who underwent transanal excision were excluded. Of the remaining 121, 99 underwent EMR or ESD, and 22 underwent WHSP. Baseline characteristics were similar between the 2 groups. The WHSP group demonstrated a significantly higher R0 resection rate (72.7% vs. 49.5%, P = 0.010) and a shorter median procedure time (3.5 minutes vs. 8.3 minutes). No complications were reported in the WHSP group. Conclusion: WHSP is a rapid, straightforward, safe, and effective approach for the salvage treatment of RNETs less than 10 mm in diameter, particularly in patients without additional risk factors.

Optimal withdrawal time in initial surveillance colonoscopy after colorectal cancer surgery: comparison between anterior/low anterior resection and right hemicolectomy.

Purpose: This study aimed to investigate the optimal withdrawal time (WT) for initial surveillance colonoscopy after curative resection for colorectal cancer (CRC) by comparing anterior/low anterior resection (AR/LAR) and right hemicolectomy (RHC) groups. Methods: This retrospective study analyzed 1,212 patients who underwent initial surveillance colonoscopy after CRC resection between 2015 and 2022. The patients were divided into the AR/LAR (n = 846) and RHC (n = 366) groups. The optimal WT was determined using receiver operating characteristic curve analysis and validated using logistic regression models. The adenoma and advanced neoplasia detection rates (ADR/ANDR) were evaluated based on the optimal WT. Results: The optimal WT was 7 and 6 minutes in the AR/LAR and RHC groups, respectively. In multivariate analysis, WT ≥7 and ≥6 minutes in the AR/LAR (odds ratio [OR], 2.38; 95% confidence interval [CI], 1.75-3.24; P < 0.001) and RHC (OR, 2.64; 95% CI, 1.59-4.39; P = 0.001) groups, respectively, were significant factors for adenoma detection. In the AR/LAR group, ADR was 41.5% for WT ≥7 minutes compared to 21.9% for WT <7 minutes (P < 0.001). In the RHC group, ADR for WT ≥6 minutes was 33.9% compared to 15.8% for WT <6 minutes (P < 0.001). The ANDR also significantly improved with longer WTs in both groups. Conclusion: This study suggests that a minimum WT of 7 and 6 minutes for AR/LAR and RHC patients, respectively, during the initial surveillance colonoscopy after CRC resection is optimal for maintaining a satisfactory ADR and ANDR. These findings highlight the importance of tailoring colonoscopic procedures according to the type of surgical resection.

Cannabidiol enhances Atezolizumab efficacy by upregulating PD-L1 expression via the cGAS-STING pathway in triple-negative breast cancer cells.

The treatment of patients with triple negative breast cancer (TNBC) relies on cytotoxic therapy. Currently, atezolizumab and chemotherapy can be combined in patients with TNBC. However, this approach is not effective for all patients with low reactivity to atezolizumab. As there is a lack of alternative treatment options, new anti-cancer drugs are urgently needed to enhance atezolizumab reactivity against TNBC. Recent strategies have focused on regulating the expression of programmed death-ligand 1 (PD-L1) or enhancing immune response activation by combining anti-cancer drugs with immune checkpoint inhibitors (ICIs). Cannabidiol (CBD), a cannabinoid component derived from the cannabis plant, has been reported to have anti-cancer therapeutic potential because of its capacity to induce apoptotic cell death in tumor cells while avoiding cytotoxicity in normal cells. Previous studies have demonstrated the effects of CBD on apoptosis in various cancer cell types. However, the potential role of CBD as an immune modulator in the regulation of PD-L1 expression and anti-cancer immune responses remains to be explored. In this study, we found that CBD stimulated PD-L1 expression in TNBC cells, which significantly induced the CBD-mediated cGAS-STING pathway activation. Taken together, we demonstrated that the combination of CBD and anti-PD-L1 antibody enhances the anti-cancer immune response in vitro and in vivo experiments. Our findings identified the mechanism of PD-L1 regulation by CBD in TNBC cells and suggested that CBD could be a potential candidate for the development of new combinatorial strategies with ICIs in TNBC patients.

A machine learning-based approach for predicting renal function recovery in general ward patients with acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is a significant challenge in healthcare. While there are considerable researches dedicated to AKI patients, a crucial factor in their renal function recovery, is often overlooked. Thus, our study aims to address this issue through the development of a machine learning model to predict restoration of kidney function in patients with AKI. METHODS: Our study encompassed data from 350,345 cases, derived from three hospitals. AKI was classified in accordance with the Kidney Disease: Improving Global Outcomes. Criteria for recovery were established as either a 33% decrease in serum creatinine levels at AKI onset, which was initially employed for the diagnosis of AKI. We employed various machine learning models, selecting 43 pertinent features for analysis. RESULTS: Our analysis contained 7,041 and 2,929 patients' data from internal cohort and external cohort respectively. The Categorical Boosting Model demonstrated significant predictive accuracy, as evidenced by an internal area under the receiver operating characteristic (AUROC) of 0.7860, and an external AUROC score of 0.7316, thereby confirming its robustness in predictive performance. SHapley Additive exPlanations (SHAP) values were employed to explain key factors impacting recovery of renal function in AKI patients. CONCLUSION: This study presented a machine learning approach for predicting renal function recovery in patients with AKI. The model performance was assessed across distinct hospital settings, which revealed its efficacy. Although the model exhibited favorable outcomes, the necessity for further enhancements and the incorporation of more diverse datasets is imperative for its application in real- world.

Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial.

BACKGROUND/AIMS: Combination immunotherapy, exemplified by atezolizumab plus bevacizumab, has become the standard of care for inoperable hepatocellular carcinoma (HCC). However, the lack of predictive biomarkers and limited understanding of response mechanisms remain a challenge. METHODS: Using data from the IMbrave150plus cohort, we applied an immune signature score (ISS) predictor to stratify HCC patients treated with atezolizumab plus bevacizumab or with sorafenib alone into potential high and low response groups. By applying multiple statistical approaches including a Bayesian covariate prediction algorithm, we refined the signature to 10 key genes (ISS10) for clinical use while maintaining similar predictive power to the full model. We further validated ISS10 in an independent HCC cohort treated with nivolumab plus ipilimumab. RESULTS: The study identified a significant association between the ISS and treatment response. Among patients classified as high responders, those treated with the atezolizumab plus bevacizumab combination exhibited improved overall and progression-free survival as well as better objective response rate compared to those treated with sorafenib. We also observed a significant correlation between ISS10 and response to nivolumab plus ipilimumab treatment. Analysis of immune cell subpopulations revealed distinct characteristics associated with ISS subtypes. In particular, the ISS10 high subtype displayed a more favorable immune environment with higher proportions of antitumor macrophages and activated T-cells, potentially explaining its better response. CONCLUSION: Our study suggests that ISS and ISS10 are promising predictive biomarkers for enhanced therapeutic outcomes in HCC patients undergoing combination immunotherapy. These markers are crucial for refining patient stratification and personalized treatment approaches to advance the effectiveness of standard-of-care regimens.

Phase 1/1b study of lonafarnib and temozolomide in patients with recurrent or temozolomide refractory glioblastoma.

BACKGROUND: Lonafarnib is an oral selective farnesyltransferase inhibitor, a class of drugs which have shown activity in preclinical glioma models. Temozolomide (TMZ) is an alkylating agent that is the first-line chemotherapy for glioblastoma. METHODS: The current study combined the cytotoxic agent TMZ with the cytostatic agent lonafarnib for patients with recurrent glioblastoma to establish a maximum tolerated dose (MTD) of the combination and its preliminary efficacy. Three dose cohorts of lonafarnib were studied in the phase 1 component of the trial (100 mg twice daily [bid], 150 mg bid, and 200 bid) with dose-dense schedule of TMZ (150 mg/m² daily) administered in an alternating weekly schedule. After establishing the MTD of lonafarnib, a subsequent expansion phase 1b was undertaken to evaluate efficacy, primarily measured by 6-month progression-free survival (PFS-6). RESULTS: Fifteen patients were enrolled into the phase 1 component and 20 patients into the phase 1b component. The MTD of lonafarnib in combination with TMZ was 200 mg bid. Among the patients enrolled into the study, 34 were eligible for 6-month progression evaluation and 35 patients were evaluable for time-to-progression analysis. The PFS-6 rate was 38% (95% confidence interval [CI] = 22%, 56%) and the median PFS was 3.9 months (95% CI = 2.5, 8.4). The median disease-specific survival was 13.7 months (95% CI = 8.9, 22.1). Hematologic toxicities, particularly lymphopenia, were the most common grade 3 and 4 adverse events. There were no treatment-related deaths. CONCLUSIONS: These results demonstrate that TMZ can be safely combined with a farnesyltransferase inhibitor and that this regimen is active, although the current study cannot determine the relative contributions of the 2 agents or the contribution of the novel administration schedule.

Multicenter study of prognostic factors in paraaortic lymph node dissection for metastatic colorectal cancer.

Purpose: The role of paraaortic lymph node dissection (PALND) in colorectal cancer (CRC) has been less evaluated than surgical treatments for other distant metastases. We evaluated surgical outcomes after PALND and identified prognostic factors. Methods: The medical records of patients who underwent PALND for paraaortic lymph node metastasis (PALNM) were reviewed retrospectively. All patients were categorized into the M1a group (isolated PALNM, n = 27), and the M1bc group (distant metastases other than PALNM, n = 26). Three severity factors (PALNM-SF: number of harvested paraaortic lymph nodes [hLN], ≥14; number of metastatic paraaortic lymph nodes [mLN], ≥5; and lymph nodes ratio [mLN/hLN], ≥0.5) were defined to determine their effects on survival. Results: The 5-year overall survival (OS) of the M1a and M1bc groups were 61.1% and 6.4%, respectively (P = 0.0013). The 5-year disease-free survival (DFS) of the M1a group was 47.4%, and the 3-year DFS of the M1bc group was 9.1% (P < 0.001). Patients with 2 or more PALNM-SFs showed worse OS than those with 1 PALNM-SF (P = 0.017). In multivariate analysis, M1bc (non-isolated PALNM) was the only significant factor for survival. In the M1a group, patients with 2 or more PALNM-SFs showed significantly worse survival than those with a single PALNM-SF. In multivariate analysis, 2 or more PALNM-SF was a significant factor for survival. Conclusion: PALND for CRC provided favorable outcomes in the survival of an isolated PALNM, although this was uncertain for non-isolated PALNMs. The PALNM-SFs helped assess the prognosis after PALND.

A novel RIP1-mediated canonical WNT signaling pathway that promotes colorectal cancer metastasis via ß -catenin stabilization-induced EMT.

RIP1 (receptor-interacting protein kinase 1) is an important component of TNF-α signaling that contributes to various pathological effects. Here, we revealed new potential roles of RIP1 in controlling WNT/ß-catenin canonical signaling to enhance metastasis of colorectal cancer (CRC). First, we showed that WNT3A treatment sequentially increased the expression of RIP1 and ß-catenin. Immunohistochemical analyses of human CRC tissue arrays consisting of normal, primary, and metastatic cancers indicated that elevated RIP1 expression might be related to ß-catenin expression, carcinogenesis, and metastasis. Intravenous injection of RIP1 over-expressed CRC cells into mice has demonstrated that RIP1 may promote metastasis. Immunoprecipitation (IP) results indicated that WNT3A treatment induces direct binding between RIP1 and ß-catenin, and that this stabilizes the ß-catenin protein in a manner that depends on the regulation of RIP1 ubiquitination via downregulation of the E3 ligase, cIAP1/2. Elimination of cIAP1/2 expression and inhibition of its ubiquitinase activity enhance WNT3A-induced RIP1 and ß-catenin protein expression and binding, which stimulates endothelial-mesenchymal transition (EMT) induction to enhance the migration and invasion of CRC cells in vitro. The results of the in vitro binding assay and IP of exogenous RIP1-containing CRC cells additionally verified the direct binding of RIP1 and ß-catenin. RIP1 expression can destroy the ß-catenin-ß-TrCP complex. Taken together, these results suggest a novel EMT-enhancing role of RIP1 in the WNT pathway and suggest a new canonical WNT3A-RIP1-ß-catenin pathway that contributes to CRC malignancy by promoting EMT.

Phase 2 trial of irinotecan and thalidomide in adults with recurrent anaplastic glioma.

BACKGROUND: Therapeutic options for patients with anaplastic gliomas (AGs) are limited despite better insights into glioma biology. The authors previously reported improved outcome in patients with recurrent glioblastoma treated with thalidomide and irinotecan compared with historical controls. Here, results of the AG arm of the study are reported, using this drug combination. METHODS: Adults with recurrent AG previously treated with radiation therapy, with Karnofsky performance score ≥70, adequate organ function and not on enzyme-inducing anticonvulsants were enrolled. Treatment was in 6-week cycles with irinotecan at 125 mg/m(2) weekly for 4 weeks followed by 2 weeks off, and thalidomide at 100 mg daily increased to 400 mg/day as tolerated. The primary endpoint was progression-free survival rate at 6 months (PFS-6), and the secondary endpoints were overall survival (OS) and response rate (RR). RESULTS: In 39 eligible patients, PFS-6 for the intent-to-treat population was 36% (95% confidence interval [CI] = 21%, 53%), median PFS was 13 weeks (95% CI = 6%, 28%) and RR was 10%(95% CI = 3%, 24%). Radiological findings included 2 complete and 2 partial responses and 17 stable disease. Median OS from study registration was 62 weeks, (95% CI = 51, 144). Treatment-related toxicities (grade 3 or higher) included neutropenia, diarrhea, nausea, and fatigue; 6 patients experienced venous thromboembolism. Four deaths were attributable to treatment-related toxicities: 1 from pulmonary embolism, 2 from colitis, and 1 from urosepsis. CONCLUSIONS: The combination of thalidomide and irinotecan did not achieve sufficient efficacy to warrant further investigation against AG, although a subset of patients experienced prolonged PFS/OS. A trial of the more potent thalidomide analogue, lenalidomide, in combination with irinotecan against AG is currently ongoing.