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Background: This multicenter study investigated the predictive value of baseline AFP and on-treatment AFP response for survival in hepatocellular carcinoma (HCC) patients with regorafenib. Materials & methods: A total of 578 patients with HCC treated with regorafenib from 12 institutions in South Korea and Italy were included. Baseline AFP (cutoff, 400 ng/ml) and AFP response (20% reduction from baseline) were analyzed for overall survival (OS) and progression-free survival (PFS). Results: Baseline AFP below 400 ng/ml was a significant factor that was independently associated with longer OS and PFS. AFP response was also a significant factor independently associated with longer OS and PFS. Conclusion: Baseline AFP and AFP response may be used as prognostic factors for survival in HCC treated with regorafenib.

Background/Aims: Despite the increasing need for geriatric assessment prior to chemotherapy, the method for this assessment remains inadequate for older cancer patients. We aimed to propose a simple assessment method to predict the performance of adjuvant chemotherapy in older patients after colon cancer surgery.Methods: This prospective study included patients over 65 years of age who were scheduled for adjuvant chemotherapy after colon cancer surgery. Before initiating chemotherapy, their functional status was assessed on the basis of activities of daily living (ADL)/instrumental activities of daily living (IADL). These parameters were analyzed with clinical characteristics and the patterns of adjuvant chemotherapy. The focus was on the completion rate of adjuvant chemotherapy.Results: A total of 89 patients with a median age of 72 years were analyzed. Among them, 54 (61%) were non-impaired and 35 (39%) were impaired regarding their ADL/IADL classification. Low body mass index and impairment of ADL/IADLs were significantly associated with chemotherapy interruption. Among toxicities, fatigue and hand-foot syndrome were independent prognostic factors for chemotherapy interruption. Impairments of ADL/IADL were significantly associated with fatigue regardless of age. Based on age and ADL/IADL stratification, younger patients (≤ 72 years) and/or those who were ADL/IADL non-impaired were significantly more likely to complete adjuvant chemotherapy than older patients (> 72 years) and ADL/IADL impaired patients (p = 0.038). This was regardless of the chemotherapy regimen.Conclusions: Functional assessment using ADL/IADL is a convenient method to predict chemotherapy toxicity and performance. These results suggested that routine screening for ADL/IADLs could guide appropriate patient selection for the completion of adjuvant chemotherapy and predict expected outcomes.

Purpose: The Hippo pathway is a tumor suppressor in the liver. However, the clinical significance of Hippo pathway inactivation in HCC is not clearly defined. We analyzed genomic data from human and mouse tissues to determine clinical relevance of Hippo pathway inactivation in HCC.Experimental Design: We analyzed gene expression data from Mst1/2−/− and Sav1−/− mice and identified a 610-gene expression signature reflecting Hippo pathway inactivation in the liver [silence of Hippo (SOH) signature]. By integrating gene expression data from mouse models with those from human HCC tissues, we developed a prediction model that could identify HCC patients with an inactivated Hippo pathway and used it to test its significance in HCC patients, via univariate and multivariate Cox analyses.Results: HCC patients (National Cancer Institute cohort, n = 113) with the SOH signature had a significantly poorer prognosis than those without the SOH signature [P < 0.001 for overall survival (OS)]. The significant association of the signature with poor prognosis was further validated in the Korean (n = 100, P = 0.006 for OS) and Fudan University cohorts (n = 242, P = 0.001 for OS). On multivariate analysis, the signature was an independent predictor of recurrence-free survival (HR, 1.6; 95% confidence interval, 1.12–2.28: P = 0.008). We also demonstrated significant concordance between the SOH HCC subtype and the hepatic stem cell HCC subtype that had been identified in a previous study (P < 0.001).Conclusions: Inactivation of the Hippo pathway in HCC is significantly associated with poor prognosis. Clin Cancer Res; 22(5); 1256–64. ©2015 AACR.

Recurrence risk score and its clinical significance.

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Purpose: The Cancer Genome Atlas (TCGA) project recently uncovered four molecular subtypes of gastric cancer: Epstein–Barr virus (EBV), microsatellite instability (MSI), genomically stable (GS), and chromosomal instability (CIN). However, their clinical significances are currently unknown. We aimed to investigate the relationship between subtypes and prognosis of patients with gastric cancer.Experimental Design: Gene expression data from a TCGA cohort (n = 262) were used to develop a subtype prediction model, and the association of each subtype with survival and benefit from adjuvant chemotherapy was tested in 2 other cohorts (n = 267 and 432). An integrated risk assessment model (TCGA risk score) was also developed.Results: EBV subtype was associated with the best prognosis, and GS subtype was associated with the worst prognosis. Patients with MSI and CIN subtypes had poorer overall survival than those with EBV subtype but better overall survival than those with GS subtype (P = 0.004 and 0.03 in two cohorts, respectively). In multivariate Cox regression analyses, TCGA risk score was an independent prognostic factor [HR, 1.5; 95% confidence interval (CI), 1.2–1.9; P = 0.001]. Patients with the CIN subtype experienced the greatest benefit from adjuvant chemotherapy (HR, 0.39; 95% CI, 0.16–0.94; P = 0.03) and those with the GS subtype had the least benefit from adjuvant chemotherapy (HR, 0.83; 95% CI, 0.36–1.89; P = 0.65).Conclusions: Our prediction model successfully stratified patients by survival and adjuvant chemotherapy outcomes. Further development of the prediction model is warranted. Clin Cancer Res; 23(15); 4441–9. ©2017 AACR.

PDF file - 206K, Figure 6. Modulation of multiple RTKs in KITENIN-overexpressed Caco2 or KITENIN-knockdown HCT116 CRC cells.

Distribution of candidate genes in biological process categories of the Gene Ontology database.

PDF file - 126K, Figure 1. EGF induces synergic AP-1 activation under elevated KITENIN in an EGFR- and EGFR-kinase-independent manner.

Methods

Purpose: This study was aimed at developing and validating a quantitative multigene assay for predicting tumor recurrence after gastric cancer surgery.Experimental Design: Gene expression data were generated from tumor tissues of patients who underwent surgery for gastric cancer (n = 267, training cohort). Genes whose expression was significantly associated with activation of YAP1 (a frequently activated oncogene in gastrointestinal cancer), 5-year recurrence-free survival, and 5-year overall survival were first identified as candidates for prognostic genes (156 genes, P < 0.001). We developed the recurrence risk score (RRS) by using quantitative RT-PCR to identify genes whose expression levels were significantly associated with YAP1 activation and patient survival in the training cohort.Results: We based the RRS assay on 6 genes, IGFBP4, SFRP4, SPOCK1, SULF1, THBS, and GADD45B, whose expression levels were significantly associated with YAP1 activation and prognosis in the training cohort. The RRS assay was further validated in an independent cohort of 317 patients. In multivariate analysis, the RRS was an independent predictor of recurrence [HR, 1.6; 95% confidence interval (CI), 1.02–2.4; P = 0.03]. In patients with stage II disease, the RRS had an HR of 2.9 (95% CI, 1.1–7.9; P = 0.03) and was the only significant independent predictor of recurrence.Conclusions: The RRS assay was a valid predictor of recurrence in the two cohorts of patients with gastric cancer. Independent prospective studies to assess the clinical utility of this assay are warranted. Clin Cancer Res; 22(24); 6228–35. ©2016 AACR.

Figure S1: Significant concordance between silence of Hippo signature and YAP1 expression in human hepatocellular carcinoma (HCC); Figure S2: Venn diagram of gene lists from two different gene expression signatures; Table S1: Genes in the SOH signature; Table S2: Functional categories of genes in the SOH signature; Table S3: Canonical Pathways enriched in the SOH signature; Table S4: Significant association between the SOH subtype and YAP1 protein expression in HCC; Table S5: Univariate and multivariate Cox regression analyses of recurrence-free survival with continuous SOH probability; Table S6: Univariate and multivariate Cox regression analyses of overall survival; Table S7: Univariate and multivariate Cox regression analyses of overall survival with continuous SOH probability; Table S8: Drop in concordance index in multivariable analysis; Table S9: Concordance of silence of Hippo signature with other prognostic HCC gene expression signatures in the NCI cohort; Table S10: Characteristics of HCC patients in the MSH cohort, stratified by SOH signature.

PDF file - 177K, Figure 2. Effects of functional blockade of EGFR via treatment of an anti-EGFR monoclonal antibody on enhanced cell invasion by EGF.

PDF file - 135K, Figure 3. EGF-induced AP-1 synergy under elevated KITENIN conditions does not require activated JNK.

PDF file - 662K, Figure 8. Higher expression levels of KITENIN affect the survival of CRC cells to the anti-proliferative effects of cetuximab.

PDF file - 143K, Figure 5. Dvl2-knockdown does not increase transcription of c-Jun and Dvl2 does not interact with c-Jun.

7 figures and 7 Tables

Purpose: EGF-stimulated signaling via EGF receptor (EGFR) is important in colorectal tumorigenesis and drug targeting. However, anti-EGFR therapy is not effective in a subset of patients with colorectal cancer, suggesting that unidentified EGF-stimulated pathways might play roles in colorectal cancer. Previously, we identified KAI1 C-terminal interacting tetraspanin (KITENIN) as a metastasis-enhancing gene and found it to be highly expressed in sporadic colorectal cancer tissues. We recently found that EGF further increases KITENIN-induced elevated AP-1 activity. Here we attempted to clarify this novel EGF-stimulated molecular pathway and its roles in colorectal cancer.Experimental Design: We analyzed how EGF modulates the downstream signaling pathway of oncogenic KITENIN in colorectal cancer cells. Biological alterations following EGF treatment were identified in KITENIN-overexpressed colorectal cancer cells with or without alteration of EGFR activity.Results: We identified the KITENIN/ErbB4–Dvl2–c-Jun axis as a novel downstream signal of EGF that is switched on under elevated KITENIN conditions in an EGFR-independent manner. This unconventional EGF signal upregulates c-Jun and enhances invasion and anchorage-independent growth of colorectal cancer cells. In addition, tumor tissues from metastatic patients with colorectal cancer who showed initial poor responses to cetuximab/chemotherapy expressed higher levels of KITENIN than did responders to therapy.Conclusions: Our results highlight the role of an EGFR-independent EGF signal in mediating the invasiveness and tumorigenesis of colorectal cancer cells. This unconventional pathway might be related to the limited clinical efficacy of anti-EGFR agents in a subset of patients with colorectal cancer. Clin Cancer Res; 20(15); 4115–28. ©2014 AACR.

BACKGROUND & AIMS Atezolizumab plus bevacizumab (Ate/Bev) has demonstrated efficacy and safety in patients with advanced hepatocellular carcinoma (HCC) in the phase III trial. Further evaluation is necessary to investigate the safety and efficacy of Ate/Bev in real settings. METHODS This was a multicentre retrospective analysis. Between May 2020 and February 2021, 138 patients received Ate/Bev as first-line treatment for advanced HCC from 11 institutions. We excluded patients with Child-Pugh B or C and BCLC D stage, and the remaining 121 patients were included in this analysis. RESULTS According to RECIST 1.1, the objective response and disease control rates were 24.0% and 76.0%. The median follow-up duration was 5.9 months (95% confidence interval [CI], 5.4-6.4), the median progression-free survival (PFS) was 6.5 months (95% CI, 4.1-9.0), and median overall survival (OS) was not reached (95% CI, not available). The most frequent grade 3-4 adverse event was aspartate aminotransferase elevation (10.7%). In the multivariate analyses, AFP increase (P = .037), baseline neutrophil-to-lymphocyte ratio (NLR) ≥ 5 (P = .023), and best response to stable disease or progressive disease (P = .019) were significantly associated with worse PFS. Macrovascular invasion (P = .048) and baseline NLR ≥5 (P

Multidetector computed tomographic urography (MDCTU) is not yet sufficient to be used in the clinical staging of upper tract urothelial carcinoma (UTUC). This study aimed to compare the diagnostic accuracy of MDCTU T stage classification and pathologic T staging for UTUC. We retrospectively evaluated 125 patients with UTUC who underwent preoperative MDCTU. A single radiologist classified the MDCTU pattern of the tumors as either low or advanced T stage for localized or locally advanced tumors, respectively. The diagnostic values of MDCTU for locally advanced tumors and the kappa agreement between MDCTU and pathologic T stage were investigated. Among 85 pathologic low T stage (Ta–T2) tumors, 71 low T stage tumors were correctly detected by MDCTU, while 30 out of 40 advanced T stage (T3–T4) tumors were correctly diagnosed by MDCTU. MDCTU led to under-staging in 8% (10/125) tumors and over-staging in 11.2% (14/125) tumors. Therefore, the overall accuracy of MDCTU in the diagnosis of low and advanced T stage tumors was 80.8% (101/125 patients). The sensitivity for advanced T stage tumors was 75% (30/40), the specificity was 83.5% (71/85), and the positive and negative predictive values were 68.1% (30/44) and 87.6% (71/81), respectively. The kappa agreement value between the MDCTU T stage and pathologic T stage was 0.57 (95% confidence interval (CI) 0.42–0.72), which was statistically significant (P = 0.001). MDCTU T stage classification may be relatively accurate for the detection and staging of UTUC correspondence with a pathologic stage.

BackgroundRegulatory T-cells (Treg) are essential in maintaining self tolerance, but they can also suppress anti-tumor immunity in the tumor microenvironment (TME). Treg are recruited into tumors by C-C motif chemokine ligand 17 (CCL17), and 22 (CCL22), which are produced by tumor cells and other cells in the TME. These chemokines serve as a ”homing signal” to Treg by binding to their cognate receptor, C-C chemokine receptor type 4 (CCR4), the predominant chemokine receptor on human Treg.1 2 3 FLX475, is an orally available and selective small-molecule antagonist of CCR4. In preclinical studies it has demonstrated potent inhibition of CCL17- and CCL22-induced CCR4-mediated chemotaxis, an increase in the intratumoral Teff/Treg ratio, and anti-tumor efficacy as a single agent and in combination with checkpoint inhibitors. In a first-in-human healthy volunteer study, the orally-available CCR4 antagonist was well tolerated, with solid safety profile. A receptor occupancy (RO) pharmacodynamic (PD) assay using peripheral blood Treg demonstrated the ability to safely achieve exposure levels predicted to maximally inhibit Treg recruitment into tumors.4 The proposed mechanism of action, pharmacokinetics (PK), PD, and safety profile of FLX475 have enabled the optimized design of an ongoing Phase 2 study to assess the safety, efficacy of FLX475 in combination with pembrolizumab in patients with advanced or metastatic gastric cancer.MethodsThis clinical trial is a Phase 2, open-label study to assess the safety and efficacy of FLX475 in combination with pembrolizumab in patients with advanced or metastatic gastric cancer (NCT04768686). Approximately 90 subjects may be enrolled across 2 cohorts to examine the safety and efficacy when administered 100mg PO QD of FLX475 with 200mg IV Q3W of pembrolizumab. In cohort 1, checkpoint inhibitor naïve Epstein-Barr Virus (EBV)-negative gastric cancer subjects who have progressed on at least 2 prior systemic treatments for advanced or metastatic gastric cancer will be enrolled, and in cohort 2, checkpoint inhibitor naïve EBV-positive gastric cancer subjects who had at least 1 prior systemic treatment for advanced or metastatic gastric cancer will be enrolled. Both EBV negative and positive gastric cancer are predicted to express high levels of CCR4 ligands and enriched in Treg (i.e. ‘charged tumor’). The study is planned initially as a 2-stage design for each cohort, and an interim analysis reviewing efficacy and safety results as well as available PK and PD data for both cohorts will be performed prior to stage 2.AcknowledgementsThanks to the patients, and to their families and caregivers for allowing us to be part of the journey.RAPT Therapeutics, Inc., South San Francisco, CA, USA is providing FLX475 for the study.Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA is providing pembrolizumab for the study.Trial RegistrationNCT04768686ReferencesTalay O, et al. Potent and selective C-C chemokine receptor (CCR4) antagonists potentiate anti-tumor immune responses by inhibiting regulatory T cells (Treg). J Immunother Cancer 2017;5(Suppl 2):P467 (SITC 2017).Curiel, Tyler J, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature medicine 10.9 (2004):942–949.Nakayama et al. Selective induction of Th2-attracting chemokines CCL17 and CCL22 in human B cells by latent membrane protein 1 of Epstein-Barr virus. J Virol 2004 February; 78(4):1665–74.van Marle S, et al. Pharmacokinetics, pharmacodynamics, and safety of FLX475, an orally-available, potent, and selective small-molecule antagonist of CCR4, in healthy volunteers. J Immunother Cancer 2018;6(Suppl 1):P484 (SITC 2018).

Fibroblast growth factor receptor 4 (FGFR4) is known to induce cancer cell proliferation, invasion, and antiapoptosis through activation of RAS/RAF/ERK and PI3K/AKT pathways, which are also known as major molecular bases of colon cancer carcinogenesis related with epidermal growth factor receptor (EGFR) signaling. However, the interaction between FGFR4 and EGFR signaling in regard to colon cancer progression is unclear. Here, we investigated a potential cross‐talk between FGFR4 and EGFR, and the effect of anti‐EGFR therapy in colon cancer treatment. To explore the biological roles of FGFR4 in cancer progression, RNA sequencing was carried out using FGFR4 transfected colon cell lines. Gene ontology data showed the upregulation of genes related to EGFR signaling, and we identified that FGFR4 overexpression secretes EGFR ligands such as amphiregulin (AREG) with consequent activation of EGFR and ErbB3. This result was also shown in in vivo study and the cooperative interaction between EGFR and FGFR4 promoted tumor growth. In addition, FGFR4 overexpression reduced cetuximab‐induced cytotoxicity and the combination of FGFR4 inhibitor (BLU9931) and cetuximab showed profound antitumor effect compared to cetuximab alone. Clinically, we found the positive correlation between FGFR4 and AREG expression in tumor tissue, but not in normal tissue, from colon cancer patients and these expressions were significantly correlated with poor overall survival in patients treated with cetuximab. Therefore, our results provide the novel mechanism of FGFR4 in connection with EGFR activation and the combination of FGFR4 inhibitor and cetuximab could be a promising therapeutic option to achieve the optimal response to anti‐EGFR therapy in colon cancer., Our study has characterized the cross‐talk between fibroblast growth factor receptor 4 (FGFR4) and epidermal growth factor receptor (EGFR)/ErbB3 signaling by the contribution of EGFR ligands secreted from FGFR4. These findings provide experimental evidence for combined treatment with FGFR4 inhibitor and anti‐EGFR therapy in colon cancer.

BACKGROUND & AIMS Regorafenib demonstrated a clinical benefit for patients with unresectable hepatocellular carcinoma (uHCC) in the phase III RESORCE trial. Considering the heterogeneity of uHCC and discrepancies in its characteristics between prospective trials and daily practice, real-life evidence is necessary. METHODS This multicentre, retrospective analysis was performed by the Korean Cancer Study Group. In total, 440 patients who received regorafenib between January 2017 and November 2019 were identified in nine tertiary referral hospitals in Korea. RESULTS All patients received prior sorafenib, and the median time-to-progression (TTP) on sorafenib was 3.9 months (range, 0.2-71.6). Regorafenib was used as the second, third and fourth to seventh lines of therapy in 305 (69.3%), 115 (26.1%) and 20 (4.5%) patients respectively. According to the RECIST v1.1, the overall response rate was 7.7% (n = 34), and the median progression-free survival (PFS) and overall survival (OS) were 3.2 (95% CI, 2.8-3.5) and 12.1 (95% CI, 9.7-14.5) months respectively. Immune checkpoint inhibitors (ICIs) were given in 115 patients (26.1%) prior to regorafenib. There were no differences in PFS and OS with regorafenib according to the prior use of ICIs (PFS, P = .61; OS, P = .63). The occurrence of hand-foot skin reaction (HFSR) was associated with a better OS (P < .001). CONCLUSIONS The real-life clinical outcomes of regorafenib for patients who progressed on prior systemic therapy including ICIs were consistent with the phase III trial results. HFSR was significantly associated with better OS with regorafenib.

Early [stage I and II (T2N0M0)] laryngeal cancer types are currently recommended to be treated with a single modality, consisting of definitive radiation therapy or larynx-preserving surgery. Although the treatment outcomes of stage I are good, the frequency of successful outcomes decreases with T2N0M0. Therefore, the present study investigated the treatment outcomes of different treatment methods in T2N0M0 laryngeal cancer. In total, 83 patients with previously untreated T2N0M0 laryngeal squamous cell carcinoma were enrolled. Patients were grouped by treatment method: Radiation therapy (RT; 27 patients); chemoradiotherapy (CRT; 46 patients) with cisplatin base; and surgery-based therapy (SBT; ten patients). The recurrence rates of the RT, CRT and SBT groups were 44.4, 19.6 and 50%, respectively. Moreover, the local control rates of the RT, CRT and SBT groups were 55.6, 87.0 and 80%, respectively. The CRT group had a significantly lower recurrence rate and higher local control rate compared with the RT group (P

Extra-pulmonary neuroendocrine carcinoma is a rare and aggressive cancer. Although several biological and histological markers have been suggested as prognostic factors for this cancer, the prognostic importance of systemic inflammatory markers, including the neutrophil-lymphocyte ratio and platelet-lymphocyte ratio, is unclear. This study aimed to evaluate the association between systemic inflammatory markers and the prognosis of extra-pulmonary neuroendocrine carcinoma. We retrospectively analyzed the clinical data of 85 patients with unresectable or metastatic extra-pulmonary neuroendocrine carcinoma who received platinum-based chemotherapy as first-line chemotherapy from August 2007 to November 2019. We used time-dependent receiver operating characteristic curve analysis to determine the cut-off values. The cut-off values for the neutrophil-lymphocyte ratio and platelet-lymphocyte ratio were 3.0 and 158.5, respectively. There was no significant difference in the Eastern Cooperative Oncology Group performance status score, Ki-67 index, or response to chemotherapy between groups. The high neutrophil-lymphocyte ratio group showed significantly worse overall survival (high vs. low, median 11.1 vs. 21.0 months, log-rank p=0.004) and shorter median progression-free survival, but the latter was not statistically significant. The high platelet-lymphocyte ratio group also showed significantly worse progression-free survival and overall survival than the low platelet-lymphocyte ratio group (high vs. low: median 5.6 vs. 9.8 months, log-rank p=0.047 and median 13.8 vs. 21.0 months, log-rank p=0.013, respectively). In multivariable analysis, a high neutrophil-lymphocyte ratio was an independent prognostic factor for overall survival. The neutrophil-lymphocyte ratio is a potent and readily available prognostic factor for extra-pulmonary neuroendocrine carcinoma.

Intravesical immunotherapy or chemotherapy for non-muscle invasive bladder cancer is a well established treatment for preventing or delaying tumour recurrence following tumour resection. However, up to 70% of patients may fail and new intravesical agents with improved effectiveness are needed. Gemcitabine is a relatively new anticancer drug that has shown activity against bladder cancer. OBJECTIVES: To evaluate the effectiveness and toxicity of intravesical gemcitabine in preventing tumour recurrence and progression in non-muscle invasive bladder cancer (NMIBC). SEARCH METHODS: A search strategy was developed for MEDLINE to identify randomised trials of intravesical gemcitabine for the treatment of non-muscle invasive bladder cancer. The searches were from 1947 to May 2011. Other databases searched included EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials, LILACS, SCOPUS, BNI, Biomed Central, Web of Science and BIOSIS. Handsearching of meeting proceedings, international guidelines and trial registries was also carried out. SELECTION CRITERIA: The titles and abstracts of the combined electronic and handsearching were manually screened by three authors independently to determine if they met the inclusion criteria for this review. Studies were selected if they were randomised, controlled trials or quasi-randomised clinical trials that included intravesical gemcitabine in at least one arm of a comparative study. DATA COLLECTION AND ANALYSIS: Data extraction was carried out by three reviewers. The information retrieved included the author's details, the study design, the characteristics of the recruited patients, details of the interventions and data relating to the primary, and secondary outcome measures. MAIN RESULTS: Six relevant randomised trials were identified with the number of patients randomised in each trial varying from 30 to 341 (total 704). All trials compared gemcitabine to active controls and varied in the reporting of outcomes. One study compared a single post-operative instillation of intravesical gemcitabine with a saline placebo in 341 patients and found no significant difference in the rates of tumour recurrence (28% versus 39%, respectively) or recurrence-free survival (HR (hazard ratio) 0.95, 95% CI 0.64 to1.39, P = 0.77). The rate of progression to invasive disease was greater with gemcitabine (2.4% versus 0.8%). A further trial compared gemcitabine with intravesical mitomycin C and demonstrated that the rates of recurrence (28% versus 39%) and progression (11% versus 18%) were lower with gemcitabine but did not reach statistical significance. The global incidence of adverse events was significantly less with gemcitabine (38.8% versus 72.2%, P = 0.02).Three trials compared gemcitabine with intravesical BCG but a meta-analysis was not possible due to clinical heterogeneity. In untreated patients at intermediate risk of recurrence (primary Ta-T1 no CIS) one trial showed that gemcitabine and BCG were similar with respective recurrence rates of 25% and 30% (P = 0.92) and overall progression equal (P = 1.0). Dysuria (12.5% versus 45%, P < 0.05) and frequency (10% versus 45%, P < 0.001) were significantly less with gemcitabine. In a second trial of high risk patients the recurrence rate was significantly greater with gemcitabine compared to BCG (53.1% and 28.1%, P = 0.04) and the time to recurrence significantly shorter with gemcitabine (25.5 versus 39.4 months, P = 0.042). Finally in a third trial of high risk patients who had failed previous intravesical BCG therapy, gemcitabine was associated with significantly fewer recurrences (52.5% versus 87.5%, P = 0.002) and a longer time to recurrence (3.9 versus 3.1 months, P = 0.9) compared to BCG. Progression rates were similar in both groups (33% versus 37.5%, P = 0.12) with no significant differences in grade 2 or 3 toxicities.The final trial was a marker lesion study which reported greater response rates when intravesical gemcitabine (2 g) was given as three bi-weekly doses (36%) or six weekly doses (40%) compared to a single dose (9%). AUTHORS' CONCLUSIONS: A single dose immediately following surgery is ineffective based on one study. Gemcitabine may be more active than mitomycin C with a lower toxicity profile. Compared to intravesical BCG therapy, gemcitabine had similar effects in intermediate risk patients, less effective in high risk patient and superior in BCG refractory patients. However, each randomised trial identified represents a different clinical setting in NMIBC and therefore the evidence base is limited. Consequently these data should be interpreted with caution until further corroborative evidence becomes available. The aim of intravesical therapy in NMIBC is to prevent tumour recurrence and progression and to avoid the morbidity associated with cystectomy. Intravesical gemcitabine is a promising drug that may add to the urologist's options in achieving this goal.

BACKGROUND Immunotherapy has revolutionized the clinical outcomes of intractable cancer patients. Little is known about the intestinal nonpathogenic bacterial composition of hepatocellular carcinoma (HCC) patients treated by immunotherapy. AIM To determine whether there is a correlation between gut bacterial composition and prognosis in HCC patients. METHODS From September 2019 to March 2020, we prospectively collected fecal samples and examined the gut microbiome of 8 advanced HCC patients treated with nivolumab as a second- or third-line systemic treatment. Fecal samples were collected before the start of immunotherapy. Fecal samples of patients with progression during treatment were collected at the time of progression, and fecal samples of patients who showed good response to nivolumab were collected after 5-7 mo as follow-up. Metagenomic data from 16S ribosomal RNA sequencing were analyzed using CLC Genomics Workbench. Microbiome data were analyzed according to therapeutic response. RESULTS All 8 patients were male, of which 6 had underlying chronic hepatitis B. A higher Shannon index was found in the responders than in the non-responders after nivolumab therapy (P = 0.036). The unweighted beta diversity analysis also showed that the overall bacterial community structure and phylogenetic diversity were clearly distinguished according to therapeutic response. There was no significant difference in the diversity or composition of the patient gut microbiome according to the immunotherapy used. Several taxa specific to therapeutic response were designated as follows: Dialister pneumosintes, Escherichia coli, Lactobacillus reteri, Streptococcus mutans, Enterococcus faecium, Streptococcus gordonii, Veillonella atypica, Granulicatella sp., and Trchuris trichiura for the non-responders; Citrobacter freundii, Azospirillum sp. and Enterococcus durans for the responders. Of note, a skewed Firmicutes/Bacteroidetes ratio and a low Prevotella/Bacteroides ratio can serve as predictive markers of non-response, whereas the presence of Akkermansia species predicts a good response. CONCLUSION The current presumptive study suggests a potential role for the gut microbiome as a prognostic marker for the response to nivolumab in treatment of HCC patients.

2621 Background: The IIP, defined by enriched intratumoral tumor-infiltrating lymphocytes (TIL), is a potential tumor-agnostic biomarker of responsiveness to ICI therapy. Here, we validate the IIP, as assessed by Lunit SCOPE IO, an AI-powered spatial TIL analyzer that runs on routine H&E-stained whole-slide images (WSI), for clinical outcome prediction in a large, multi-center international cohort of ICI-treated patients, demonstrating its utility as a practical biomarker to guide ICI treatment planning. Methods: Lunit SCOPE IO was developed using 17,849 H&E WSI of multiple cancer types, annotated by 104 board-certified pathologists (13.5 x 109 µm2 area and 6.2 x 106 TIL). IIP+ tumors were defined as those with ≥ 20% of all 1 mm2 tumor tiles in a WSI classified as having a high intratumoral TIL density. We evaluated the correlation between IIP and ICI treatment outcomes (overall response rate (ORR) and progression-free survival (PFS), assessed by RECIST v1.1) in a real-world dataset of 1,806 patients ( > 16 primary tumor types) retrospectively collected from Stanford University Medical Center, Samsung Medical Center, Chonnam National University Hospital, Seoul National University Bundang Hospital, and Northwestern University. IIP status was sub-analyzed by PD-L1 22C3 tumor proportion score (TPS, n = 798), microsatellite status, and tumor mutational burden (TMB, n = 130). Results: The IIP+ phenotype (35.2%, 636 of 1,806) was highly enriched in nasopharyngeal carcinoma (68.0%), melanoma (56.3%), renal cell carcinoma (52.9%), and non-small cell lung cancer (NSCLC, 33.7%). The IIP+ proportion by PD-L1 TPS ( < 1% / ≥ 1%) was 21.6% and 40.7%, respectively. While 33.3% of microsatellite unstable (MSI-H) or TMB-high (≥ 10/Mb) tumors were IIP+, a substantial proportion (26.1%) of microsatellite stable (MSS), TMB-low tumors were IIP+. The ORR in IIP+ patients was significantly higher (26.0% vs. 15.8% in IIP-, p < 0.001). Median PFS for IIP+ was 5.3 months (95% CI 4.6-6.9 m), significantly longer than that for IIP- (3.1 m, 95% CI 2.8-3.6 m), with a hazard ratio (HR) of 0.68 (95% CI 0.61-0.76, p < 0.001). The association held after excluding NSCLC patients (n = 909) (HR 0.69, 95% CI 0.59-0.81, p < 0.001). On subgroup analysis, IIP+ correlated significantly with prolonged PFS, regardless of ICI regimen (mono / combo therapy) or PD-L1 TPS ( < 1% / ≥ 1%). Of note, IIP+ was predictive of favorable PFS only in the MSS, TMB-low group (n = 88, HR 0.56, 95% CI 0.33-0.96), but not in the MSI-H or TMB-high groups. Conclusions: The IIP, as evaluated by Lunit SCOPE IO, may represent a practical, clinically-actionable biomarker predictive of favorable ICI treatment outcomes across diverse cancer patient populations, including those with PD-L1 negative, MSS/TMB-low tumors, in whom predictive biomarkers are urgently needed.

Adjuvant chemotherapy for gastric cancer, particularly stage III, improves survival after curative D2 gastrectomy. We investigated the clinical value of the lymph-node ratio (LNR; number of metastatic lymph nodes/number of lymph nodes examined) for selecting the appropriate adjuvant chemotherapy regimen in patients with D2-resected stage II/III gastric cancer.We reviewed the data of 819 patients who underwent curative D2 gastrectomy followed by adjuvant chemotherapy. Of them, 353 patients received platinum-based chemotherapy and 466 received TS-1. The patients were categorized into three groups according to their LNR (LNR 1, 0-0.1; LNR 2, 0.1-0.25; and LNR 3, 0.25), and their disease-free survival (DFS) was evaluated.The DFS curves of the patients were well separated according to stage and LNR. In multivariate analyses, an LNR 0.1 was strongly associated with the 3-year DFS (hazard ratio 2.402, 95% confidence interval 1.607-3.590, P 0.001). Platinum-based chemotherapy improved the 3-year DFS compared to TS-1 in patients with LNR 3 group in stage III gastric cancer (platinum vs. TS-1, median DFS 26.87 vs. 16.27 months, P = 0.028). An LNR 0.1 was associated with benefiting from platinum-based adjuvant chemotherapy in stage III gastric cancer patients with lymphovascular invasion (platinum vs. TS-1, median DFS 47.57 vs. 21.77 months, P = 0.011).The LNR can be used to select the appropriate adjuvant chemotherapy regimen for patients with D2-resected gastric cancer, particularly in stage III.

To evaluate the clinical efficacy and safety of tumor enucleation (TE) compared with partial nephrectomy (PN) for T1 renal cell carcinoma.According to protocol, we searched multiple data sources for published and unpublished randomized controlled trials and nonrandomized studies (NRSs) in any language. We performed systematic review and meta-analysis according to the Cochrane Handbook for Systematic Reviews of Interventions and rated the certainty of the evidence (CoE) using the GRADE framework.We are uncertain about the effects of TE on perioperative (mean difference [MD] 3.38, 95% CI 1.52 to 5.23; I²=68%; 4 NRSs; 942 participants; very low CoE) and long-term (MD 2.31, 95% CI -1.40 to 6.01; I²=57%; 4 NRSs; 542 participants; very low CoE) residual renal function. TE may result in little to no difference in short-term residual renal function (MD 1.04, 95% CI 0.25 to 1.83; I²=0%; 2 NRSs; 256 participants; low CoE). We are uncertain about the effects of TE on cancer-specific mortality (risk ratio [RR] 0.90, 95% CI: 0.11 to 7.28; I²=0%; 2 NRSs; 551 participants; very low CoE) and major adverse events (RR 0.48, 95% CI: 0.30 to 0.79; I²=0%; 10 NRS; 2,360 participants; very low CoE).While TE appears to have similar effects on short term postoperative residual renal function, there were uncertainties on mortality and major adverse events. However, we need rigorous RCTs to elucidate the effects of TE as the evidence stems mostly from NRSs.

Background The clinical features and therapeutic strategies for gastric cancer with positive peritoneal washing cytology but without visible gross peritoneal metastasis have not been defined. The aim of this study was to evaluate the effect and clinical prognostic value of postoperative chemotherapy in gastric cancer patients with positive peritoneal washing cytology without gross peritoneal metastasis who underwent radical D2 gastrectomy in terms of disease-free survival (DFS) and overall survival (OS). Materials and Methods Intraoperative peritoneal washing cytology was performed in 285 patients who underwent radical D2 gastrectomy between April 2004 and May 2016. Of them, 88 patients with positive cytology but without gross peritoneal metastasis were included in the study. In total, 64 patients received postoperative chemotherapy, whereas 24 patients underwent surgery only. Results Most gastric cancer patients with positive cytology without gross peritoneal metastasis demonstrated pT4 and/or pN3 disease. Postoperative chemotherapy improved DFS and OS compared to surgery only in gastric cancer patients with positive cytology without gross peritoneal metastasis (median DFS 11.63 vs. 6.98 months, p p p p

Background Extrapulmonary neuroendocrine carcinoma (EP-NEC) is an aggressive type of cancer with poor prognosis. Although several biological and histological markers are prognostic factors in NEC, the correlation between prognosis and systemic inflammation markers, such as the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR), is unclear. This study evaluated the association between NLR or PLR and median overall survival (OS) or progression-free survival (PFS) in EP-NEC. Methods We retrospectively analyzed the clinical data from patients with unresectable or metastatic EP-NECs who received platinum-based chemotherapy at Chonnam National University Hwasun Hospital from August 2007 to March 2019. The cut-off values for NLR and PLR were 3 and 160, respectively. Results In total, 38 patients were analyzed. Both NLR and PLR at diagnosis had no significant associations with the response to initial chemotherapy. However, in the high-PLR group, median overall survival (OS) and progression-free survival (PFS) were poorer than those in the low-PLR group (high vs. low: 10.6 vs. 17.1 months, log-rank p = 0.007 and 4.1 vs. 9.3 months, log-rank p = 0.032, respectively). However, the high-NLR group had insignificantly poorer median OS and PFS than the low-NLR group. In the multivariate analysis, high PLR and LDH were independent prognostic factors for median OS and PFS. Conclusions High PLR was associated with shorter survival of EP-NEC patients receiving platinum-based chemotherapy. Therefore, PLR may be an independent prognostic factor in EP-NEC.

INTRODUCTION Regorafenib is an approved agent in patients with advanced hepatocellular carcinoma (HCC) who progressed on sorafenib, but little is known about its clinical outcomes in Child-Pugh B patients. We aimed to investigate the safety and effectiveness of regorafenib in Child-Pugh B HCC patients. METHODS This multicentre retrospective study included 59 patients with Child-Pugh B HCC who received regorafenib. Comparative analyses were performed with an independent cohort of Child-Pugh class A patients from the same registry (n = 440). RESULTS The median age was 58 years (range, 19-83). All patients had progression on prior sorafenib. Regorafenib was given as 2nd line, and 3rd-4th line systemic therapy in 37 (62.7%) and 22 (37.3%) patients respectively. Compared to Child-Pugh A cohort, grade 3-4 AEs were more common in the Child-Pugh B cohort (27.1% vs 14.1%, P = .017). The median progression-free survival (PFS) and overall survival (OS) were 1.8 and 4.6 months, respectively, and these were significantly poorer than the Child-Pugh A cohort (P = .008 and P < .001 respectively). Child-Pugh B patients with albumin-bilirubin (ALBI) grade 3 had a significantly higher frequency of increased bilirubin (P = .01 for any grade and P = .01 for grade 3-4) and showed significantly poorer OS (P = .021), compared to those with ALBI grade 1 or 2. CONCLUSION Regorafenib's poor clinical outcomes and increased frequency of severe adverse events lead us to discourage its use in the Child-Pugh B population. In particular, regorafenib should not be used in Child-Pugh B patients with ALBI grade 3.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effects of perioperative systemic chemotherapy or immunotherapy (or both) for UTUC.

p73 is a member of the p53 family of transcription factors and, like p53, plays a role as a tumor suppressor. p73 is involved in development, proliferation, apoptosis and metastasis. However, the precise molecular mechanisms underlying its function in inhibiting metastasis remain largely unknown. Here, we show that induction of TAp73 decreased invasion and migration activity of colorectal cancer cells, whereas knockdown of TAp73 led to increased invasion and migration activity. KAI1 was identified as a transcriptional target of TAp73 and its expression is indispensable for TAp73-mediated inhibition of cell invasion and migration. Furthermore, induction of TAp73 in colorectal cancer cells elevated KAI1 expression and decreased the frequency of hepatic metastasis in vivo. Whereas, the decreased invasion and migration activities caused by TAp73 induction were abrogated by knockdown of KAI1. Interestingly, TAp73 and KAI1 are overexpressed in primary colorectal cancers and a significant correlation between TAp73 and KAI1 expression was detected, but their expressions were significantly down-regulated in metastatic cancers. Taken together, our results support a novel role for TAp73 in controlling colorectal cancer cell invasion, migration and metastasis by regulating transcription of KAI1.

Purpose Induction chemotherapy (ICT) with docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by concurrent chemoradiotherapy (CCRT) has the advantages of organ preservation and systemic control in head and neck cancer (HNC). Early prediction of CCRT efficacy may help identify patients who will benefit more from surgery than from CCRT. We investigated the role of interim 18-fluoro-2-deoxy-glucose positron emission tomography computed tomography (FDG PET-CT) after ICT to predict the efficacy of CCRT and clinical outcomes. Methods Tumor responses were retrospectively reviewed after CCRT based on the Response Evaluation Criteria in Solid Tumors. FDG PET-CT imaging was performed before and after three cycles of TPF. We examined the associations between the metabolic response (percentage decrease in the maximum standardized uptake value [SUVmax] and total metabolic tumor volume [MTV]) after ICT and complete response (CR) to CCRT, progression-free survival (PFS), and overall survival (OS). Results We studied 43 HNC patients with a median follow-up of 32.7 months. Lymph node (LN) SUVmax and total MTV decreases from baseline after ICT were greater in patients with a CR to CCRT than in non-CR patients (LN SUVmax, 88.8% vs. 62.5%, respectively; total MTV, 99.7% vs. 89.9%, respectively). Decreases in total MTV ≥ 78% and LN SUVmax ≥73% after ICT predicted CR to CCRT and longer OS and PFS. Conclusions Using interim FDG PET-CT to measure SUVmax and total MTV after three cycles of ICT may be a useful technique for identifying HNC patients who will benefit from CCRT and predicting survival outcomes. Electronic supplementary material The online version of this article (10.1007/s00259-017-3836-8) contains supplementary material, which is available to authorized users.

Purpose: The Cancer Genome Atlas (TCGA) project recently uncovered four molecular subtypes of gastric cancer: Epstein–Barr virus (EBV), microsatellite instability (MSI), genomically stable (GS), and chromosomal instability (CIN). However, their clinical significances are currently unknown. We aimed to investigate the relationship between subtypes and prognosis of patients with gastric cancer. Experimental Design: Gene expression data from a TCGA cohort (n = 262) were used to develop a subtype prediction model, and the association of each subtype with survival and benefit from adjuvant chemotherapy was tested in 2 other cohorts (n = 267 and 432). An integrated risk assessment model (TCGA risk score) was also developed. Results: EBV subtype was associated with the best prognosis, and GS subtype was associated with the worst prognosis. Patients with MSI and CIN subtypes had poorer overall survival than those with EBV subtype but better overall survival than those with GS subtype (P = 0.004 and 0.03 in two cohorts, respectively). In multivariate Cox regression analyses, TCGA risk score was an independent prognostic factor [HR, 1.5; 95% confidence interval (CI), 1.2–1.9; P = 0.001]. Patients with the CIN subtype experienced the greatest benefit from adjuvant chemotherapy (HR, 0.39; 95% CI, 0.16–0.94; P = 0.03) and those with the GS subtype had the least benefit from adjuvant chemotherapy (HR, 0.83; 95% CI, 0.36–1.89; P = 0.65). Conclusions: Our prediction model successfully stratified patients by survival and adjuvant chemotherapy outcomes. Further development of the prediction model is warranted. Clin Cancer Res; 23(15); 4441–9. ©2017 AACR.