Standard or high dose chemoradiotherapy, with or without the protease inhibitor nelfinavir, in patients with locally advanced pancreatic cancer: The phase 1/randomised phase 2 SCALOP-2 trial.

BACKGROUND: The multi-centre two-stage SCALOP-2 trial (ISRCTN50083238) assessed whether dose escalation of consolidative chemoradiotherapy (CRT) or concurrent sensitization using the protease inhibitor nelfinavir improve outcomes in locally advanced pancreatic cancer (LAPC) following four cycles of gemcitabine/nab-paclitaxel. METHODS: In stage 1, the maximum tolerated dose (MTD) of nelfinavir concurrent with standard-dose CRT (50.4 Gy in 28 fractions) was identified from a cohort of 27 patients. In stage 2, 159 patients were enrolled in an open-label randomized controlled comparison of standard versus high dose (60 Gy in 30 fractions) CRT, with or without nelfinavir at MTD. Primary outcomes following dose escalation and nelfinavir use were respectively overall survival (OS) and progression free survival (PFS). Secondary endpoints included health-related quality of life (HRQoL). RESULTS: High dose CRT did not improve OS (16.9 (60 % confidence interval, CI 16.2-17.7) vs. 15.6 (60 %CI 14.3-18.2) months; adjusted hazard ratio, HR 1.13 (60 %CI 0.91-1.40; p = 0.68)). Similarly, median PFS was not improved by nelfinavir (10.0 (60 %CI 9.9-10.2) vs. 11.1 (60 %CI 10.3-12.8) months; adjusted HR 1.71 (60 %CI 1.38-2.12; p = 0.98)). Local progression at 12 months was numerically lower with high-dose CRT than with standard dose CRT (n = 11/46 (23.9 %) vs. n = 15/45 (33.3 %)). Neither nelfinavir nor radiotherapy dose escalation impacted on treatment compliance or grade 3/4 adverse event rate. There were no sustained differences in HRQoL scores between treatment groups over 28 weeks post-treatment. CONCLUSIONS: Dose-escalated CRT may improve local tumour control and is well tolerated when used as consolidative treatment in LAPC but does not impact OS. Nelfinavir use does not improve PFS.

Time From Colorectal Cancer Surgery to Adjuvant Chemotherapy: Post Hoc Analysis of the SCOT Randomized Clinical Trial.

Importance: The timing of adjuvant chemotherapy after surgery for colorectal cancer and its association with long-term outcomes have been investigated in national cohort studies, with no consensus on the optimal time from surgery to adjuvant chemotherapy. Objective: To analyze the association between the timing of adjuvant chemotherapy after surgery for colorectal cancer and disease-free survival. Design, Setting, and Participants: This is a post hoc analysis of the phase 3 SCOT randomized clinical trial, from 244 centers in 6 countries, investigating the noninferiority of 3 vs 6 months of adjuvant chemotherapy. Patients with high-risk stage II or stage III nonmetastatic colorectal cancer who underwent curative-intended surgery were randomized to either 3 or 6 months of adjuvant chemotherapy consisting of fluoropyrimidine and oxaliplatin regimens. Those with complete information on the date of surgery, treatment type, and long-term follow-up were investigated for the primary and secondary end points. Data were analyzed from May 2022 to February 2024. Intervention: In the post hoc analysis, patients were grouped according to the start of adjuvant chemotherapy being less than 6 weeks vs greater than 6 weeks after surgery. Main Outcomes and Measures: The primary end point was disease-free survival. The secondary end points were adverse events in the total treatment period or the first cycle of adjuvant chemotherapy. Results: A total of 5719 patients (2251 [39.4%] female; mean [SD] age, 63.4 [9.3] years) were included in the primary analysis after data curation; among them, 914 were in the early-start group and 4805 were in the late-start group. Median (IQR) follow-up was 72.0 (47.3-88.1) months, with a median (IQR) of 56 (41-66) days from surgery to chemotherapy. Five-year disease-free survival was 78.0% (95% CI, 75.3%-80.8%) in the early-start group and 73.2% (95% CI, 72.0%-74.5%) in the late-start group. In an adjusted Cox regression analysis, the start of adjuvant chemotherapy greater than 6 weeks after surgery was associated with worse disease-free survival (hazard ratio, 1.24; 95% CI, 1.06-1.46; P = .01). In adjusted logistic regression models, there was no association with adverse events in the total treatment period (odds ratio, 0.82; 95% CI, 0.65-1.04; P = .09) or adverse events in the first cycle of treatment (odds ratio, 0.77; 95% CI, 0.56-1.09; P = .13). Conclusions and Relevance: In this international population of patients with high-risk stage II and stage III colorectal cancer, starting adjuvant chemotherapy more than 6 weeks after surgery was associated with worse disease-free survival, with no difference in adverse events between the groups. Trial Registration: isrctn.org Identifier: ISRCTN59757862.

Multidisciplinary Delphi Consensus on Safety of Combining Transarterial Radioembolization with Yttrium-90 Microspheres with Systemic Anticancer Agents for the Treatment of Liver Malignancy.

PURPOSE: To provide guidance, via multidisciplinary consensus statements, on the safety interactions between systemic anticancer agents (such as radiosensitizing chemotherapy, immunotherapy, targeted therapy, and peptide receptor radionuclide therapy) and transarterial radioembolization (TARE) with yttrium-90 (90Y)-labeled microspheres in the treatment of primary and metastatic liver malignancies. MATERIALS AND METHODS: A literature search identified 59 references that informed 26 statements on the safety of 90Y TARE combined with systemic therapies. Modified Delphi method was used to develop consensus on statements through online anonymous surveys of the 12 panel members representing the fields of interventional radiology, medical oncology, surgical oncology, hepatology, and pharmacy, focusing on hepatocellular carcinoma (HCC), metastatic colorectal cancer (mCRC), neuroendocrine tumors, metastatic breast cancer, and intrahepatic cholangiocarcinoma. RESULTS: High-level evidence was limited. Level 1 data in patients with mCRC suggest that some radiosensitizing chemotherapies (eg, oxaliplatin) require temporary dose reduction when used concomitantly with 90Y TARE, and some targeted therapies (eg, vascular endothelial growth factor inhibitors and antiangiogenic tyrosine kinase inhibitors) should be avoided for at least 4 weeks before 90Y TARE. In patients with HCC, the feasibility of 90Y TARE and immunotherapy has been demonstrated with Level 4 evidence. Data are more limited for other primary and secondary liver malignancies, and consensus statements were driven by expert opinion (Level 5). CONCLUSIONS: Given the absence of evidence-based guidelines on the safety of 90Y TARE in combination with systemic anticancer therapy, these consensus statements provide expert guidance on the potential risks when considering specific combinations.

Optimal maintenance strategy following FOLFOX plus anti-EGFR induction therapy in patients with RAS wild type metastatic colorectal cancer: An individual patient data pooled analysis of randomised clinical trials.

BACKGROUND: Anti-EGFR antibodies plus doublet chemotherapy is the standard of care in RAS/BRAF wild-type metastatic colorectal cancer (mCRC). No phase-3 level of evidence is available to guide treatment de-escalation after anti-EGFR-based first-line. Several randomised clinical trials investigated de-intensification strategies with 5-fluorouracil/leucovorin (5-FU/LV) and/or anti-EGFR. METHODS: We performed an individual patient data pooled analysis of Valentino, Panama, MACRO-2, COIN-B trials including RAS wild-type mCRC patients who received first-line therapy with FOLFOX plus panitumumab or cetuximab followed by pre-specified maintenance strategy. Only patients who started maintenance according to the assigned arm were included. Patients were categorised by type of maintenance (i.e. 5-FU/LV, anti-EGFR or 5-FU/LV + anti-EGFR). Progression-free survival (PFS) and overall survival (OS) were calculated from the start of maintenance; toxicity was evaluated for the maintenance treatment period. RESULTS: A total of 518 patients were included in the pooled analysis. Overall, 123, 185 and 210 patients received maintenance with 5-FU/LV, anti-EGFR, 5-FU/LV + anti-EGFR, respectively. Median PFS was 5.6, 6.0 and 9.0 (P = 0.009) and OS was 25.7, 24.0 and 28.0 months (P = 0.134) in 5-FU/LV, anti-EGFR and 5-FU/LV + anti-EGFR arms, respectively. Monotherapy maintenance (either 5-FU/LV or anti-EGFR) was inferior to combination in terms of PFS (hazard ratios [HR] 1.26, P = 0.016) and non-significantly trending also in OS (HR 1.20, P = 0.111). An increase of overall any grade and grade ≥ 3 AEs and selected AEs was reported in combination compared to either 5-FU/LV or anti-EGFR arms. CONCLUSIONS: This pooled analysis including four randomised phase II supports the use of 5-FU/LV plus anti-EGFR as the preferred maintenance regimen. Data provide rational for a more individualised maintenance treatment approach based on tumour and patients features.

Immediate surgery compared with short-course neoadjuvant gemcitabine plus capecitabine, FOLFIRINOX, or chemoradiotherapy in patients with borderline resectable pancreatic cancer (ESPAC5): a four-arm, multicentre, randomised, phase 2 trial.

BACKGROUND: Patients with borderline resectable pancreatic ductal adenocarcinoma have relatively low resection rates and poor survival despite the use of adjuvant chemotherapy. The aim of our study was to establish the feasibility and efficacy of three different types of short-course neoadjuvant therapy compared with immediate surgery. METHODS: ESPAC5 (formerly known as ESPAC-5f) was a multicentre, open label, randomised controlled trial done in 16 pancreatic centres in two countries (UK and Germany). Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, biopsy proven pancreatic ductal adenocarcinoma in the pancreatic head, and were staged as having a borderline resectable tumour by contrast-enhanced CT criteria following central review. Participants were randomly assigned by means of minimisation to one of four groups: immediate surgery; neoadjuvant gemcitabine and capecitabine (gemcitabine 1000 mg/m2 on days 1, 8, and 15, and oral capecitabine 830 mg/m2 twice a day on days 1-21 of a 28-day cycle for two cycles); neoadjuvant FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, folinic acid given according to local practice, and fluorouracil 400 mg/m2 bolus injection on days 1 and 15 followed by 2400 mg/m2 46 h intravenous infusion given on days 1 and 15, repeated every 2 weeks for four cycles); or neoadjuvant capecitabine-based chemoradiation (total dose 50·4 Gy in 28 daily fractions over 5·5 weeks [1·8 Gy per fraction, Monday to Friday] with capecitabine 830 mg/m2 twice daily [Monday to Friday] throughout radiotherapy). Patients underwent restaging contrast-enhanced CT at 4-6 weeks after neoadjuvant therapy and underwent surgical exploration if the tumour was still at least borderline resectable. All patients who had their tumour resected received adjuvant therapy at the oncologist's discretion. Primary endpoints were recruitment rate and resection rate. Analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN, 89500674, and is complete. FINDINGS: Between Sept 3, 2014, and Dec 20, 2018, from 478 patients screened, 90 were randomly assigned to a group (33 to immediate surgery, 20 to gemcitabine plus capecitabine, 20 to FOLFIRINOX, and 17 to capecitabine-based chemoradiation); four patients were excluded from the intention-to-treat analysis (one in the capecitabine-based chemoradiotherapy withdrew consent before starting therapy and three [two in the immediate surgery group and one in the gemcitabine plus capecitabine group] were found to be ineligible after randomisation). 44 (80%) of 55 patients completed neoadjuvant therapy. The recruitment rate was 25·92 patients per year from 16 sites; 21 (68%) of 31 patients in the immediate surgery and 30 (55%) of 55 patients in the combined neoadjuvant therapy groups underwent resection (p=0·33). R0 resection was achieved in three (14%) of 21 patients in the immediate surgery group and seven (23%) of 30 in the neoadjuvant therapy groups combined (p=0·49). Surgical complications were observed in 29 (43%) of 68 patients who underwent surgery; no patients died within 30 days. 46 (84%) of 55 patients receiving neoadjuvant therapy were available for restaging. Six (13%) of 46 had a partial response. Median follow-up time was 12·2 months (95% CI 12·0-12·4). 1-year overall survival was 39% (95% CI 24-61) for immediate surgery, 78% (60-100) for gemcitabine plus capecitabine, 84% (70-100) for FOLFIRINOX, and 60% (37-97) for capecitabine-based chemoradiotherapy (p=0·0028). 1-year disease-free survival from surgery was 33% (95% CI 19-58) for immediate surgery and 59% (46-74) for the combined neoadjuvant therapies (hazard ratio 0·53 [95% CI 0·28-0·98], p=0·016). Three patients reported local disease recurrence (two in the immediate surgery group and one in the FOLFIRINOX group). 78 (91%) patients were included in the safety set and assessed for toxicity events. 19 (24%) of 78 patients reported a grade 3 or worse adverse event (two [7%] of 28 patients in the immediate surgery group and 17 [34%] of 50 patients in the neoadjuvant therapy groups combined), the most common of which were neutropenia, infection, and hyperglycaemia. INTERPRETATION: Recruitment was challenging. There was no significant difference in resection rates between patients who underwent immediate surgery and those who underwent neoadjuvant therapy. Short-course (8 week) neoadjuvant therapy had a significant survival benefit compared with immediate surgery. Neoadjuvant chemotherapy with either gemcitabine plus capecitabine or FOLFIRINOX had the best survival compared with immediate surgery. These findings support the use of short-course neoadjuvant chemotherapy in patients with borderline resectable pancreatic ductal adenocarcinoma. FUNDING: Cancer Research UK.

[Corrigendum] Resveratrol inhibits the invasion and metastasis of colon cancer through reversal of epithelial­mesenchymal transition via the AKT/GSK­3ß/Snail signaling pathway.

Subsequently to the publication of the above article, an interested reader drew to the authors' attention that the Nc­control and si­AKT1­control data panels featured in Fig. 4A for the SW480 Transwell assay experiments on p. 2788 appeared to contain overlapping data, such that the data, which were intended to show the results from experiments performed under different experimental conditions, may have been derived from the same original source. Furthermore, in Fig. 5 on p. 2789, there appeared to be some overlapping data comparing the AKT1 western blotting data with the p­AKT1 data, and the same data also appeared in Fig. 4D for the p­AKT1 data presented there. The authors have re­examined their original data, and have realized that these figures were assembled incorrectly; essentially, the si­AKT1­control data panel was selected incorrectly for Fig. 4A, and the authors were able to retrieve the original data for the western blots presented in Fig. 5. The corrected versions of Figs. 4 and 5 are shown on the next page. The authors confirm that these errors did not have any major impact on the conclusions reported in their paper, and are grateful to the Editor of Molecular Medicine Reports for allowing them this opportunity to publish a Corrigendum. Furthermore, the authors apologize to the readership for any inconvenience caused. [Molecular Medicine Reports 20: 2783­2795, 2019; DOI: 10.3892/mmr.2019.10528].

Is antibody-drug conjugate a rising star for clinical treatment of solid tumors? A systematic review and meta-analysis.

Antibody-drug conjugates (ADCs) show significant advantages in cancer treatment due to their high selectivity and anti-tumor activity, but the efficacy and safety of the treatment of solid tumors are unknown. We searched research databases, major conference proceedings and trial registries for randomized controlled trials (RCTs). Then, we selected qualified studies and extracted dates. Studies were assessed for quality, and a meta-analysis was conducted to quantify effects of ADCs on overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and adverse events (AEs). The within-study heterogeneity was evaluated by subgroup and sensitivity analysis. Eleven RCTs with 4353 participants were included. ADCs had better PFS (HR: 0.69, 95 % CI: 0.56-0.82) and OS (HR: 0.76, 95 % CI: 0.61-0.92). ADCs resulted in lower risk of febrile neutropenia in blood system. Conversely, ADC therapy had not a prepotent on ORR (RR: 1.36, 95 % CI: 0.71-2.60).

Erratum: Jiedu Sangen Decoction Reverses Epithelial-to-mesenchymal Transition and Inhibits Invasion and Metastasis of Colon Cancer via AKT/GSK-3ß Signaling Pathway: Erratum.

[This corrects the article DOI: 10.7150/jca.32873.].

Transcription factor POU4F2 promotes colorectal cancer cell migration and invasion through hedgehog-mediated epithelial-mesenchymal transition.

As a POU homeodomain transcription factor, POU4F2 has been implicated in regulating tumorigenic processes in various cancers. However, the role of POU4F2 in colorectal cancer (CRC) remains unclear. Here, we revealed that POU4F2 functions as a tumor promotor in CRC. Bioinformatics analysis in specimens from CRC patients and expression analysis in CRC cell lines showed that POU4F2 was upregulated at the mRNA and protein levels in CRC. Depletion of POU4F2 suppressed the metastatic phenotypes of CRC cells, including cell migration, invasion, and the expression of epithelial-mesenchymal transition (EMT) markers. Moreover, depletion of POU4F2 decreased the number of lung metastatic nodes in nude mice. Mechanistically, POU4F2 positively regulated the Hedgehog signaling pathway, as inferred from the downregulation of the expression of sonic Hedgehog homolog, patched 1, Smoothened, and GLI family zinc finger 1 in vitro and vivo following silencing of POU4F2. Furthermore, the SMO agonist SAG reversed the effects of POU4F2 knockdown in CRC. Functionally, POU4F2 contributed to the Hedgehog signaling-regulated activation of the EMT process and promotion of CRC cell migration and invasion. Collectively, these findings elucidated the role of POU4F2 as a tumor promotor in CRC through the regulation of Hedgehog signaling-mediated EMT and suggested that POU4F2 suppression might be a promising therapeutic target in inhibiting CRC metastasis.

A population-based study: how to identify high-risk T1 gastric cancer patients?

In T1 gastric cancer (GC), lymph nodes metastasis (LNM) is considered as a significant prognostic predictor and closely associated with following therapeutic approaches as well as distant metastasis (DM). This study aimed to not only seek risk factors of LNM and DM but also unpack the prognosis in T1 GC patients. We performed a retrospective study enrolling 5547 patients in T1 GC from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate logistic regression models were produced to recognize independent risk factors of LNM and DM. Cox regression analyses were performed to identify important prognostic factors of overall survival (OS). Cancer-specific cumulative incidence was plotted by cumulative incidence function. Three nomograms of LNM, DM and OS were established and validated by receiver operating characteristic (ROC) and calibration curves to evaluate discrimination and accuracy. Decision curve analysis (DCA), clinical impact curves (CIC) and subgroups based on risk scores were constructed to measure nomograms clinical utility. The area under the curve (AUC) of LNM nomogram and DM nomogram were 0.735 and 0.896, respectively. OS nomogram was constructed and the corresponding C-index was 0.797. In conclusion, our user-friendly nomograms, which aimed to predict LNM, DM and OS in T1 gastric cancer patients, have shown high efficiency of discrimination and accuracy. These useful and visual tools may have advantageous clinical utility to identify high-risk T1 gastric patients and help clinicians to draw up an individual therapeutic strategy.

Resveratrol and Its Analogs: Potent Agents to Reverse Epithelial-to-Mesenchymal Transition in Tumors.

Epithelial-to-mesenchymal transition (EMT), a complicated program through which polarized epithelial cells acquire motile mesothelial traits, is regulated by tumor microenvironment. EMT is involved in tumor progression, invasion and metastasis via reconstructing the cytoskeleton and degrading the tumor basement membrane. Accumulating evidence shows that resveratrol, as a non-flavonoid polyphenol, can reverse EMT and inhibit invasion and migration of human tumors via diverse mechanisms and signaling pathways. In the present review, we will summarize the detailed mechanisms and pathways by which resveratrol and its analogs (e.g. Triacetyl resveratrol, 3,5,4'-Trimethoxystilbene) might regulate the EMT process in cancer cells to better understand their potential as novel anti-tumor agents. Resveratrol can also reverse chemoresistance via EMT inhibition and improvement of the antiproliferative effects of conventional treatments. Therefore, resveratrol and its analogs have the potential to become novel adjunctive agents to inhibit cancer metastasis, which might be partly related to their blocking of the EMT process.

Causes of Death After Colorectal Cancer Diagnosis: A Population-Based Study.

Background: Non-cancer causes of death in patients with colorectal cancer (CRC) have not received much attention until now. The purpose of the current study is to investigate the non-cancer causes of death in patients with CRC at different periods of latency. Methods: Eligible patients with CRC were included from the Surveillance, Epidemiology, and End Results (SEER) database, and standardized mortality ratios (SMRs) were calculated using the SEER*Stat software 8.3.8. Results: A total of 475,771 patients with CRC were included, of whom 230,841 patients died during the follow-up period. Within 5 years, CRC was the leading cause of death. Over time, non-cancer causes of death account for an increasing proportion. When followed up for more than 10 years, non-cancer deaths accounted for 71.9% of all deaths worldwide. Cardiovascular diseases were the most common causes of non-cancer deaths, accounting for 15.4% of the total mortality. Patients had a significantly higher risk of death from septicemia within the first year after diagnosis compared with the general population (SMR, 3.39; 95% CI, 3.11-3.69). Within 5-10 years after CRC diagnosis, patients had a significantly higher risk of death from diabetes mellitus (SMR, 1.27; 95% CI, 1.19-1.36). During the course of more than 10 years, patients with CRC had a significantly higher risk of death from atherosclerosis (SMR 1.47; 95% CI, 1.11-1.9). Conclusions: Although CRC has always been the leading cause of death in patients with CRC, non-cancer causes of death should not be ignored. For patients with cancer, we should not only focus on anti-tumor therapies but also pay attention to the occurrence of other risks to prevent and manage them in advance.

Association of Survival and Immune-Related Adverse Events With Anti-PD-1/PD-L1 and Anti-CTLA-4 Inhibitors, Alone or Their Combination for the Treatment of Cancer: A Systematic Review and Meta-Analysis of 13 Clinical Trials.

BACKGROUND: Cancer, with sustained high mortality, is a worldwide threat to public health. Despite the survival benefit over conventional therapies shown in immune checkpoint inhibitor (ICI), only a minority of patients benefit from single ICI. But combination therapy holds the promise of achieving better efficacy over monotherapy. We performed a systematic review and meta-analysis to assess the efficacy and safety of ICI-based combination therapy for cancer. METHODS: A search was conducted to retrieve relevant studies in electronic databases and major conferences. Two investigators independently performed data extraction, making a systematic data extraction, assembly, analysis and interpretation to compare the overall survival (OS), progression-free survival (PFS), overall response rate (ORR), all and high grade immune related adverse events (IRAEs) between combination therapy and monotherapy. Therefore, only the studies satisfying the criteria were included. Finally, we performed subgroup, sensitivity, and publication bias analysis to examine the heterogeneity and bias of resources. RESULTS: A total of 2,532 patients from thirteen studies were enrolled. Compared to ICI alone, combination therapy, with a high risk and high grade IRAEs for the majority of all, offers a better survival benefit (OS: HR: 0.86, 95% CI: 0.76 to 0.98; PFS: HR: 0.79, 95% CI: 0.69 to 0.90) and objective response (ORR: RR: 1.91, 95% CI: 1.40 to 2.60). CONCLUSIONS: ICI-based combination therapy was confirmed as the optimum treatment for cancer, especially when using specific dosage and regimen to treat certain tumor types with no absolute demand for the detection of PD-L1 expression. Meanwhile, attention should also be paid on potential toxicity, especially the IRAEs.

Efficacy and Safety of Acupuncture-Moxibustion Therapy on Chemotherapy-Induced Leukopenia: A Systematic Review and Meta-Analysis.

BACKGROUND: Acupuncture-moxibustion therapy (AMT), as an integral part of complementary and alternative medicine, has been used for centuries in treatment of numerous diseases. Nevertheless, there is no available supportive evidence on the efficacy and safety of acupuncture-moxibustion therapy in patients with chemotherapy-induced leukopenia (CIL). The purpose of this study is to evaluate the efficacy and safety of acupuncture-moxibustion therapy in treating chemotherapy-induced leukopenia. METHODS: Relevant studies were searched in nine databases up to September 19, 2020. Two reviewers independently screened the studies for eligibility, extracted data, and assessed the methodological quality of selected studies. Meta-analysis of the pooled mean difference (MD) and risk ratio (RR) with their respective 95% confidence intervals (CI) were calculated. RESULTS: 17 studies (1206 patients) were included, and the overall quality of the included studies was moderate. In comparison with medical therapy, AMT has a better clinical efficacy for CIL (RR, 1.24; 95% CI, 1.17-1.32; P < 0.00001) and presents advantages in increasing leukocyte count (MD, 1.10; 95% CI, 0.67-1.53; P < 0.00001). Also, the statistical results show that AMT performs better in improving the CIL patients' Karnofsky performance score (MD, 5.92; 95% CI, 3.03-8.81; P < 0.00001). CONCLUSION: This systematic review and meta-analysis provides updated evidence that AMT is a safe and effective alternative for the patients who suffered from CIL.

Risk factors and predictors of lymph nodes metastasis and distant metastasis in newly diagnosed T1 colorectal cancer.

BACKGROUND: Lymph nodes metastasis (LNM) and distant metastasis (DM) are important prognostic factors in colorectal cancer (CRC) and determine the following treatment approaches. We aimed to find clinicopathological factors associated with LNM and DM, and analyze the prognosis of CRC patients with T1 stage. METHODS: A total of 17 516 eligible patients with T1 CRC were retrospectively enrolled in the study based on the Surveillance, Epidemiology, and End Results (SEER) database during 2004-2016. Logistic regression analysis was performed to identify risk factors for LNM and DM. Unadjusted and adjusted Cox proportional hazard models were used to identify prognostic factors for overall survival. We performed the cumulative incidence function (CIF) to further determine the prognostic role of LNM and DM in colorectal cancer-specific death (CCSD). LNM, DM, and OS nomogram were constructed based on these models and evaluated by the C-index and calibration plots for discrimination and accuracy, respectively. The clinical utility of the nomograms was measured by decision curve analyses (DCAs) and subgroups with different risk scores. RESULTS: Tumor grade, mucinous adenocarcinoma, and age accounted for the first three largest proportion among the LNM nomogram scores (all, P < .001), whereas N stage, carcinoembryonic antigen (CEA), and tumor size occupied the largest percentage in DM nomogram (all, P < .001). OS nomogram was formulated to visually to predict 3-, 5-, and 10- year overall survivals for patients with T1 CRC. The calibration curves showed an effectively predictive accuracy of prediction nomograms, of which the C-index were 0.666, 0.874, and 0.760 for good discrimination, respectively. DCAs and risk subgroups revealed the clinical effectiveness of these nomograms. CONCLUSIONS: Novel population-based nomograms for T1 CRC patients could objectively and accurately predict the risk of LNM and DM, as well as OS for different stages. These predictive tools may help clinicians to make individual clinical decisions, before clinical management.

Clinical efficacy and safety of anti-PD-1/PD-L1 inhibitors for the treatment of advanced or metastatic cancer: a systematic review and meta-analysis.

Anti-PD-1/PD-L1 inhibitors provide a survival advantage over conventional therapies for treatment of advanced or metastatic cancer. However, the factors determining which patients benefit the most from anti-PD-1/PD-L1 inhibitors are unknown, making treatment-related decisions difficult. We performed a systematic review and meta-analysis of acquired data to assess the efficacy and toxicity of anti-PD-1/PD-L1 inhibitors in advanced and metastatic cancer. A thorough search strategy was applied to identify randomised controlled trials (RCTs) in Pubmed, Embase, Cochrane, and major conferences. Studies meeting predefined selection criteria were selected, and two independent investigators performed data extraction; overall survival (OS), progression-free survival (PFS), and overall response rate were compared between anti-PD-1/PD-L1 inhibitors and control therapies. We calculated the pooled response rate and 95% CIs of all-grade and high-grade (≥3) adverse effects and evaluated the within-study heterogeneity using subgroup, sensitivity, and meta-regression analyses. In final, we included eligible 35 RCTs (21047 patients). The main estimated hazard ratios (HRs) for OS and PFS were 0.76 (0.71-0.82) and 0.81 (0.73-0.89) in a random-effects model. The anti-PD-1/PD-L1 inhibitor group had a significantly high risk for all-grade immune-related adverse events. Anti-PD-1/PD-L1 inhibitors were identified as a preferable treatment option for advanced or metastatic cancer patients who are male, aged < 65 years, current or former smokers, had no CNS or liver metastasis, had not EGFR mutation, and had high PD-L1 expression.

To be or not to be: whether anti-angiogenic agent combined with immune checkpoint inhibitoris necessary in the treatment of advanced or metastatic renal cell carcinoma.

Although it's widely known that targeted therapy against angiogenesis and immunotherapy agents showed survival benefit over chemoradiotherapy in advanced or metastatic renal cell carcinoma, some patients still cannot receive a satisfied prognosis. We performed a systematic review and meta-analysis to explore the efficacy and safety of anti-angiogenic agents combined with immune checkpoint inhibitors. We conducted a search for randomized controlled trials in Pubmed, Embase, Cochrane, and major conference. Enrolled eligible studies and extracted data were completed by two investigators to compare OS, PFS, and ORR both in PD-L1 and ITT subset. Then, we calculated the pooled RR and 95% CI of all-grade and high-grade adverse effects to study its safety. Besides, we assessed the heterogeneity through subgroup and sensitivity analysis. A total of three RCTs covering 2662 patients were enrolled. In PFS analysis, the estimated HR for ITT subset was 0.74 with 95% CI of 0.65 to 0.84 and for PD-L1 subset was 0.65 with 95% CI of 0.56 to 0.76. And in OS analysis, the result was 0.74 with 95% CI of 0.53 to 1.03 in ITT subset and 0.74 with 95% CI of 0.56 to 0.96 in PD-L1 subset. As for ORR analysis, combination therapy showed advantage rather than monotherapy in ITT subset (RR 1.54; 95% CI 1.11 to 2.14), but conversely in PD-L1 positive subset (RR 1.64; 95% CI 0.94 to 2.84). Additionally, combination therapy failed to show obvious safety in most immune-related adverse events, whatever in all-grade or high grade.

Identification of biomarkers in colon cancer based on bioinformatic analysis.

BACKGROUND: Colon cancer is one of the most common cancers in the world. Targeting biomarkers is helpful for the diagnosis and treatment of colon cancer. This study aimed to identify biomarkers in colon cancer, in addition to those that have already been reported, using microarray datasets and bioinformatics analysis. METHODS: We downloaded two mRNA microarray datasets (GSE44076 and GSE47074) for colon cancer from the Gene Expression Omnibus (GEO) database and the most recent colon cancer data (COAD) from The Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) between colon cancer and adjacent normal tissues were determined based on these three datasets. Additionally, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and protein-protein interaction (PPI) network analysis. The hub genes in the PPI network were then selected and analysed. RESULTS: We identified 150 DEGs and the GO enrichment analysis revealed that these DEGs were enriched in functions related to accelerating the cell cycle, promoting tumour cell accumulation, promoting cell division, positively regulating cell division, and negatively regulating apoptosis. The KEGG pathway analysis indicated that the DEGs were also involved in the cell cycle pathway. In the PPI network, 34 hub genes were found to be enriched in cell division. Prognostic analysis of the 34 hub genes revealed that eight genes (CCNB1, CHEK1, DEPDC1, ECT2, GINS2, HMMR, KIF14, and KIF18A) were associated with the prognosis of colon cancer. And our qRT-PCR results confirmed that DEPDC1, ECT2, GINS2, HMMR and KIF18A were highly expressed in colon cancer cells. CONCLUSIONS: The genes DEPDC1, ECT2, GINS2, HMMR, and KIF18A could serve as novel diagnostic biomarkers of colon cancer.

Quality of life in the FOXFIRE, SIRFLOX and FOXFIRE-global randomised trials of selective internal radiotherapy for metastatic colorectal cancer.

Selective internal radiotherapy (SIRT) is a liver-directed treatment involving the injection of yttrium-90 microspheres into the blood supply of liver tumours. There are very few studies assessing health-related quality of life (HRQOL) in patients treated with SIRT. Patients with liver metastases from colorectal cancer (CRC) were randomised in the FOXFIRE (FFr; ISRCTN83867919), SIRFLOX (SF; NCT00724503) and FOXFIRE-Global (FFrG; NCT01721954) trials of first-line oxaliplatin-fluorouracil (FOLFOX) chemotherapy combined with SIRT versus FOLFOX alone. HRQOL was assessed using the three-level EQ-5D, European Organisation for Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) and EORTC Colorectal Liver Metastases cancer module (EORTC QLQ-LMC21) at baseline, ≤3 months, 6 months, 12 months and annually thereafter from randomisation, and at disease progression. Analyses were conducted on an intention-to-treat basis. In total, 554 patients were randomised to SIRT + FOLFOX and 549 patients to FOLFOX alone. HRQOL was statistically significant lower in SIRT + FOLFOX patients ≤3 months after SIRT administration in all three instruments, particularly global health, physical and role functioning and symptoms of fatigue, nausea/vomiting and appetite loss. By accepted thresholds, these differences were deemed not clinically important. Differences between SIRT + FOLFOX and FOLFOX alone over the 2-year follow up and at disease progression were also not clinically important. Although there is some decrease in HRQOL for up to 3 months following SIRT, the addition of SIRT to FOLFOX chemotherapy does not change HRQOL to a clinically important degree in metastatic CRC patients.