High somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: prospective study.

AIMS: We previously showed that the nab-paclitaxel plus S-1 (NPS) regimen had promising effects against metastatic pancreatic ducal adenocarcinoma (mPDAC), whose efficacy however could not be precisely predicted by routine biomarkers. This prospective study aimed to investigate the values of mutations in circulating tumor DNA (ctDNA) and their dynamic changes in predicting response of mPDAC to NPS chemotherapy. METHODS: Paired tumor tissue and blood samples were prospectively collected from patients with mPDAC receiving first-line NPS chemotherapy, and underwent next-generation sequencing with genomic profiling of 425 genes for ctDNA. High mutation allelic frequency (MAF) was defined as ≥ 30% and ≥ 5% in tumor tissue and blood, respectively. Kappa statistics were used to assess agreement between mutant genes in tumor and ctDNA. Associations of mutations in ctDNA and their dynamic changes with tumor response, overall survival (OS), and progression-free survival (PFS) were assessed using the Kaplan-Meier method, multivariable-adjusted Cox proportional hazards regression, and longitudinal data analysis. RESULTS: 147 blood samples and 43 paired tumor specimens from 43 patients with mPDAC were sequenced. The most common driver genes with high MAF were KRAS (tumor, 35%; ctDNA, 37%) and TP53 (tumor, 37%; ctDNA, 33%). Mutation rates of KRAS and TP53 in ctDNA were significantly higher in patients with liver metastasis, with baseline CA19-9 ≥ 2000 U/mL, and/or without an early CA19-9 response. κ values for the 5 most commonly mutated genes between tumor and ctDNA ranged from 0.48 to 0.76. MAFs of the genes mostly decreased sequentially during subsequent measurements, which significantly correlated with objective response, with an increase indicating cancer progression. High mutations of KRAS and ARID1A in both tumor and ctDNA, and of TP53, CDKN2A, and SMAD4 in ctDNA but not in tumor were significantly associated with shorter survival. When predicting 6-month OS, AUCs for the 5 most commonly mutated genes in ctDNA ranged from 0.59 to 0.84, larger than for genes in tumor (0.56 to 0.71) and for clinicopathologic characteristics (0.51 to 0.68). Repeated measurements of mutations in ctDNA significantly differentiated survival and tumor response. Among the 31 patients with ≥ 2 ctDNA tests, longitudinal analysis of changes in gene MAF showed that ctDNA progression was 60 and 58 days ahead of radiologic and CA19-9 progression for 48% and 42% of the patients, respectively. CONCLUSIONS: High mutations of multiple driving genes in ctDNA and their dynamic changes could effectively predict response of mPDAC to NPS chemotherapy, with promising reliable predictive performance superior to routine clinicopathologic parameters. Inspiringly, longitudinal ctDNA tracking could predict disease progression about 2 months ahead of radiologic or CA19-9 evaluations, with the potential to precisely devise individualized therapeutic strategies for mPDAC.

PD-1 inhibitor combined with albumin paclitaxel and apatinib as second-line treatment for patients with metastatic gastric cancer: a single-center, single-arm, phase II study.

BACKGROUND: Immune checkpoint inhibitors have been approved for first- and third-line treatment of advanced gastric cancer. However, pembrolizumab alone in the second line did not improve overall survival compared to chemotherapy in the KEYNOTE-061 study. In this study, we aimed to explore the efficacy and safety of a three-drug regimen of PD-1 inhibitor combined with albumin paclitaxel and apatinib (a VEGFR inhibitor) for the second-line treatment of patients with metastatic gastric cancer (mGC). METHODS: This was a single-center, single-arm, phase II clinical study. Patients with mGC with stable microsatellite and negative HER-2 expression who failed first-line chemotherapy were enrolled. The enrolled patients were treated with PD-1 inhibitor (selected according to patients' requirements) in combination with albumin paclitaxel (125 mg/m2, intravenously, days 1 and 8, or 250 mg/m2, intravenously, day 1) and apatinib (250 or 500 mg, orally, days 1-21) every 3 weeks. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response, and adverse events (AEs). RESULTS: From July 11, 2019, to October 13, 2022, a total of 43 patients were enrolled, of whom 10 were PD-L1 negative, 11 were PD-L1 positive, and 22 had unknown PD-L1 expression. As of the data cutoff on April 1st, 2023, nine patients had partial response, 29 had stable disease, and five experienced progressive disease, with the ORR of 20.9% and DCR of 88.3%. The median PFS was 6.2 months (95% CI, 3.9-9.3), and the median OS was 10.1 months (95% CI, 7.5-14.1). All patients suffered from alopecia and neurotoxicity. The other main AEs of grade 1 or 2 were bone marrow suppression (N = 21, 48.8%), hand-foot reaction (N = 19, 44.2%), hypertension (N = 18, 41.9%), hypothyroidism (N = 11, 25.6%), gastrointestinal bleeding (N = 3, 7.0%), and liver function damage (N = 5, 11.6%). Two patients reported grade 3-4 immune-related liver damage. CONCLUSION: Second-line PD-1 inhibitor combined with albumin paclitaxel and apatinib showed certain efficacy and safety in patients with mGC. TRIAL REGISTRATION: Clinical trials, NCT04182724. Registered 27 November 2019; retrospectively registered, https://clinicaltrials.gov/study/NCT04182724.

Survival outcome of different treatment sequences in patients with locally advanced and metastatic pancreatic cancer.

BACKGROUND: Despite some therapeutic advances, improvement in survival rates of unresectable and/or metastatic pancreatic ductal adenocarcinoma (PDAC) has been minimal over recent decade. We aimed to evaluate the impact of different treatment sequences on clinical outcomes of advanced PDAC at our academic institution. METHODS: In this single institution retrospective analysis, we assessed characteristics and survival rates of unresectable and/or metastatic pancreatic PDAC patients who started a systemic treatment between 01/2015 and 12/2021. Survival analyses were performed by Kaplan-Meier and Cox proportional hazards model. RESULTS: The number of 285 patients received at least two lines of treatment, but only 137 patients were suitable for third-line treatment. Subgroup analysis showed that thirty-seven patients received A line (gemcitabine/nab-paclitaxel or nab-paclitaxel combined therapy to FOLFIRINOX) therapy, 37 patients received B line (nab-paclitaxel combined therapy to gemcitabine combined therapy to FOLFIRINOX) therapy, 21 patients received C line (nab-paclitaxel combined therapy to gemcitabine combined therapy to oxaliplatin or irinotecan combined therapy) therapy. Survival rates for different treatment lines were significantly different and median overall survival (OS) was 14.00, 18.00, and 14.00 months, respectively (p<0.05). CONCLUSION: Our study provides real-world evidence for the effectiveness of different treatment sequences and underscores the treatment sequences on survival outcome when considering the entire management in advanced PDAC.

A real-world analysis of second-line treatment option, gemcitabine plus anlotinib and anti-PD1, in advanced pancreatic cancer.

BACKGROUND: In the second-line treatment of advanced pancreatic cancer (APC), there is only one approved regimen based on the phase III NAPOLI-1 trial. However, for patients progressing after Nab-paclitaxel and Gemcitabine (Nab-P/Gem) or Nab-P combinations, second-line treatment were very limited. METHODS: This is a retrospective single-center analysis of patients. Our aim was to determine the effectiveness and tolerability of a novel regimen, gemcitabine plus Anlotinib and anti-PD1, in APC patients and to compare it with oxaliplatin, irinotecan, leucovorin, and fluorouracil (FOLFIRINOX) in the second-line setting who have failed on the first-line Nab-P combinations. RESULTS: In total, twenty-three patients received Gemcitabine plus Anlotinib and anti-PD1 in the second-line, 28 patients were treated with FOLFORINOX. There was no significant difference in overall survival (OS) or progression free survival (PFS) for either of the two sequences (p > 0.05). Patients who received Gemcitabine plus Anlotinib and anti-PD1 had a median PFS of 4.0 months (95% CI: 1.1-6.9) versus 3.5 months (95% CI 1.8-5.2) in FOLFORINOX group (p = 0.953). The median OS of Gemcitabine plus Anlotinib and anti-PD1 was 9.0 months (95% CI: 4.0-13.7) and 8.0 months (95% CI: 5.5-10.5) in FOLFORINOX group (p = 0.373). Grade ≥3 treatment-emergent adverse events (AEs) occurred for 13% of patients with Gemcitabine plus Anlotinib and anti-PD1 and 40% for FOLFORINOX. CONCLUSION: Our data confirms the effectiveness of Gemcitabine plus Anlotinib and anti-PD1 as a well-tolerated regimen in the second-line treatment of APC and extends available data on its use as a second-line treatment option when compared with FOLFIRINOX.

Outcomes Following Different Thermal Ablation Strategies in Patients with Unresectable Colorectal Liver Metastases.

Background For patients with unresectable colorectal liver metastases (CRLM), clinical guidelines recommend imaging-guided thermal ablation combined with systemic therapy. However, the optimal thermal ablation strategy remains unclear. Purpose To compare long-term outcomes between patients who underwent upfront ablation or delayed ablation for unresectable CRLM. Materials and Methods This retrospective study included patients with unresectable CRLM (three or fewer lesions; diameter, <3 cm) admitted to one of seven hospitals between October 2009 and December 2020. Upfront ablation was performed 2-4 weeks before the start of systemic therapy, and delayed ablation was performed 2-3 months after the start of systemic therapy. Propensity score matching was applied to adjust for differences in baseline variables between groups. Disease-free survival (DFS) was the primary outcome. Overall survival (OS), complications, and adverse events were secondary outcomes. Outcomes were compared between groups by using the log-rank test. Results In total, 255 patients who underwent delayed ablation (mean age, 57 years ± 11 [SD]; 184 men [72%]) and 103 patients who underwent upfront ablation (mean age, 56 years ± 12; 72 men [70%]) were included. After propensity score matching (n = 100 in both groups), the 5-year DFS for patients who underwent upfront ablation was better compared with patients who underwent delayed ablation (36% vs 21%; P = .02). For 5-year OS, no evidence of a difference was observed between ablation strategies (delayed ablation, 59% vs upfront ablation, 64%; P = .49). Additionally, no differences were observed between ablation strategies with respect to the rates of ablative complications (delayed ablation, 6% vs upfront ablation, 5%; P = .76) or drug-related adverse events (delayed and upfront ablation both 9%; P = .99). Conclusion In patients with relatively few (three or fewer) and small (<3 cm) unresectable CRLM, upfront thermal ablation combined with adjuvant systemic therapy led to better DFS compared with delayed ablation. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Georgiades in this issue.

Comparison of efficacy and safety between PD-1 inhibitors and PD-L1 inhibitors plus platinum-etoposide as first-line treatment for extensive-stage small-cell lung cancer: a multicenter, real-world analysis.

BACKGROUND: Immunotherapy in combination with platinum-etoposide (EP) chemotherapy has been approved as a first-line treatment for extensive-stage small cell lung cancer (ES-SCLC). However, real-world (RW) data regarding the use of immune checkpoint inhibitors (ICIs) in ES-SCLC are lacking. We aimed to assess the differences between programmed death protein 1 (PD-1) inhibitors and programmed death ligand 1 (PD-L1) inhibitors, both in conjunction with EP chemotherapy, as first-line treatment for ES SCLC. METHODS: We conducted a real-world, multicenter, retrospective cohort, controlled study to compare the prognosis, efficacy, and safety of PD-1 and PD-L1 inhibitors in ES-SCLC patients when used along with chemotherapy. Each patient received up to six cycles of etoposide, carboplatin, or cisplatin combined with ICI drugs, including PD-1 and PD-L1 inhibitors. The primary endpoints were investigator-assessed progression-free survival (PFS) and overall survival (OS). The secondary endpoints were the investigator-assessed objective response rate (ORR) and disease control rate (DCR) according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). RESULTS: Between January 2017 and December 2021, 194 patients with ES-SCLC from three clinical centers in a PLA general hospital were included in our study, including 93 patients in the PD-1 group and 101 patients in the PD-L1 group. At the time of data cutoff, progression-free survival in the PD-1 group (median PFS, 6.8 months; 95% CI, 5.3-8.1) was similar to that in the PD-L1 group (median PFS, 6.4 months; 95% CI, 5.5-7.5); the stratified hazard ratio for PFS was 1.12 (95% CI, 0.83-1.53; P = 0.452). The median OS was similar in the PD-1 and PD-L1 groups (15.8 m vs. 17.7 m, P = 0.566); the hazard ratio was 0.90 (95% CI, 0.62-1.30, P = 0.566). The two groups had comparable investigator-assessed confirmed objective response rates (ORR) (76.3% vs. 76.2%). Adverse effect (AE)-related discontinuation occurred in 4 (4.3%) patients in the PD-1 group and 2 (2.0%) patients in the PD-L1 group. Deaths due to AEs of any cause occurred in 2 (2.2%) patients in the PD-1 inhibitor group and 1 (1.0%) patient in the PD-L1 inhibitor group. CONCLUSIONS: Our research revealed that there were no significant differences in efficacy or prognosis between PD-1 inhibitor + EP chemotherapy and PD-L1 inhibitor + EP chemotherapy. The two groups seemed to have comparable safety profiles, but the number of discontinuation or death events was too small to draw a firm conclusion.

Up-Front Versus Delayed Thermal Ablation for Colorectal Liver Oligometastases: A Multicenter Retrospective Study Using Propensity Score Matching.

BACKGROUND. Thermal ablation combined with systemic therapy is an accepted treatment of colorectal liver oligometastases (CLOM). Consensus is lacking regarding the optimal timing of thermal ablation relative to systemic therapy. OBJECTIVE. The purpose of our study was to compare delayed and up-front thermal ablation in terms of efficacy and safety in the treatment of patients with CLOM. METHODS. This retrospective multicenter study included 440 patients (316 men, 124 women; mean age, 57.1 ± 11.1 [SD] years) with CLOM from nine hospitals between October 2009 and December 2020. Patients underwent delayed (n = 322) or up-front (n = 118) thermal ablation in combination with systemic therapy. Analyses included all patients using crude data, all patients using inverse probability treatment weighting (IPTW), and a subset of patients using propensity score matching (PSM) at a 1:1 ratio to balance baseline variables (108 matched patients for each group [i.e., delayed ablation and up-front ablation]). Patients were classified as having a low or high tumor burden score (TBS) on the basis of the number and size of the liver metastases. The primary outcome was progression-free survival (PFS); secondary outcomes included overall survival (OS), complications from ablation, and adverse events (AEs) from systemic therapy. Survival analysis used the Kaplan-Meier method. RESULTS. The median follow-up was 2.9 years. The 5-year PFS was 17.1% for delayed ablation versus 33.6% for up-front ablation in all patients and 17.9% versus 34.7% after PSM. Delayed ablation was associated with worse PFS in the crude analysis (HR = 0.62), IPTW analysis (HR = 0.66), and PSM analysis (HR = 0.62) (all p < .05). No analysis showed a significant difference in OS between delayed and up-front ablation. Crude, IPTW, and PSM analyses showed better PFS for up-front compared with delayed ablation in patients with a low TBS (HR = 0.62-0.67; all p < .05); none of these analyses showed significant difference in PFS in patients with a high TBS. Delayed ablation and up-front ablation groups showed no difference in frequency of grade III or IV ablation complications (4.7% vs 6.8%, p = .38) or grade III or IV systemic therapy AEs (12.4% vs 10.2%, p = .53). CONCLUSION. In patients with CLOM, up-front ablation achieved better PFS compared with delayed ablation, although only among patients with a low TBS. CLINICAL IMPACT. These findings could help optimize clinical implementation of thermal ablation in patients who are not candidates for surgical resection.

MBD3 promotes hepatocellular carcinoma progression and metastasis through negative regulation of tumour suppressor TFPI2.

BACKGROUND: The mechanism of recurrence and metastasis of hepatocellular carcinoma (HCC) is complex and challenging. Methyl-CpG binding domain protein 3 (MBD3) is a key epigenetic regulator involved in the progression and metastasis of several cancers, but its role in HCC remains unknown. METHODS: MBD3 expression in HCC was detected by immunohistochemistry and its association with clinicopathological features and patient's survival was analysed. The effects of MBD3 on hepatoma cells growth and metastasis were investigated, and the mechanism was explored. RESULTS: MBD3 is significantly highly expressed in HCC, associated with the advanced tumour stage and poor prognosis in HCC patients. MBD3 promotes the growth, angiogenesis and metastasis of HCC cells by inhibiting the tumour suppressor tissue factor pathway inhibitor 2 (TFPI2). Mechanistically, MBD3 can inhibit the TFPI2 transcription via the Nucleosome Remodeling and Deacetylase (NuRD) complex-mediated deacetylation, thus reactivating the activity of matrix metalloproteinases (MMPs) and PI3K/AKT signaling pathway, leading to the progression and metastasis of HCC CONCLUSIONS: Our results unravel the novel regulatory function of MBD3 in the progression and metastasis of HCC and identify MBD3 as an independent unfavourable prognostic factor for HCC patients, suggesting its potential as a promising therapeutic target as well.

Nab-paclitaxel plus S-1 with or without PD-1 inhibitor in pancreatic ductal adenocarcinoma with only hepatic metastases: a retrospective cohort study.

PURPOSE: The evidence regarding programmed cell death 1 (PD-1) inhibitors on pancreatic ductal adenocarcinoma (PDAC) with metastases remains controversial. This study aimed to assess the efficacy and safety of Nab-paclitaxel plus S1 (NPS) with or without Sintilimab, a PD-1 inhibitor, in patients with PDAC with only hepatic metastases (mPDAC). METHODS: Untreated mPDAC patients who received NPS with (the combination group) or without Sintilimab (the NPS group) were retrospectively studied. Surgery was considered when the pancreatic tumor became resectable or borderline resectable on radiological examinations, and with complete metabolic response of liver metastases. RESULTS: Between October 2017 and February 2020, 32 patients were in the combination group and 34 patients in the NPS group. Successful salvage resection was achieved in 17 (25.8%) patients after tumor-downstaging (combination 12 vs. NPS 5, P = 0.03). The median overall survival (OS) was 16.8 months in the combination group and 10.0 months in the NPS group (P = 0.002). Remarkable OS benefit was observed in patients with decline in CA19-9 of ≥ 50% (16.0 vs. 6.5, P = 0.003), reduction in 18F-fluorodeoxyglucose uptake of primary tumor of ≥ 50% (16.5 vs. 10.0, P < 0. 001) and after salvage resection (20.1 vs. 11.0, P < 0. 001). No significant difference in Grade 3 or higher adverse events were seen between the two groups (40.6% vs. 32.4%, P = 0.49). CONCLUSIONS: Despite the inherent biases of this retrospective study, the addition of Sintilimab significantly improved salvage resection rates and OS compared with the NPS regimen and had a favorable safety profile in treatment naïve mPDAC patients.

Knockdown of circBFAR inhibits proliferation and glycolysis in gastric cancer by sponging miR-513a-3p/hexokinase 2 axis.

The relationship between circular RNAs (circRNAs) and many types of cancer has been of great interest. A novel circRNA, circBFAR, has been identified, but the functions of circBFAR and its underlying mechanism in gastric cancer (GC) have not been reported. This study was designed to investigate the role of circBFAR in GC and its downstream miRNA targets. Quantitative real-time polymerase reaction was used to detect the expression of circBFAR and miRNAs. Cell counting kit-8 and EdU were used to detect the proliferation of GC cells. Measurement of the extracellular acidification rate, oxygen consumption rate and lactate acid production were performed to assess the glycolysis levels. The results showed that circBFAR exhibited higher expression in GC tissues and cell lines. circBFAR was proven to promote GC proliferation by targeting the miR-513a-3p/hexokinase 2 (HK2) axis. Inhibition of circBFAR also led to a significant decrease in the glycolysis levels. In this study, we found a circBFAR/miR-513a-3p/HK2 axis in GC and revealed the relationship between circBFAR and glycolysis for the first time. circBFAR may serve as a novel target of GC individualized therapy.

Vascular endothelial growth factor (VEGF) targeting therapy for persistent, recurrent, or metastatic cervical cancer.

BACKGROUND: Cervical cancer ranks as the fourth leading cause of death from cancer in women. Historically, women with metastatic or recurrent cervical cancer have had limited treatment options. New anti-angiogenesis therapies, such as vascular endothelial growth factor (VEGF) targeting agents, offer an alternative strategy to conventional chemotherapy; they act by inhibiting the growth of new blood vessels, thereby restricting tumour growth by blocking the blood supply. OBJECTIVES: To assess the benefits and harms of VEGF targeting agents in the management of persistent, recurrent, or metastatic cervical cancer. SEARCH METHODS: We performed searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, online registers of clinical trials, and abstracts of scientific meetings up until 27 May 2020. SELECTION CRITERIA: We examined randomised controlled trials (RCTs) that evaluated the use of VEGF targeting agents alone or in combination with conventional chemotherapy or other VEGF targeting agents. DATA COLLECTION AND ANALYSIS: Three review authors independently screened the results of search strategies, extracted data, assessed risk of bias, and analysed data according to the standard methods expected by Cochrane. The certainty of evidence was assessed via the GRADE approach. MAIN RESULTS: A total of 1634 records were identified. From these, we identified four studies with a total of 808 participants for inclusion. We also identified two studies that were awaiting classification and nine ongoing studies. Bevacizumab plus chemotherapy versus chemotherapy Treatment with bevacizumab plus chemotherapy may result in lower risk of death compared to chemotherapy alone (hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.62 to 0.95; 1 study, 452 participants; low-certainty evidence). However, there are probably more specific adverse events when compared to chemotherapy alone, including gastrointestinal perforations or fistulae (risk ratio (RR) 18.00, 95% CI 2.42 to 133.67; 1 study, 440 participants; moderate-certainty evidence); serious thromboembolic events (RR 4.5, 95% CI 1.55 to 13.08; 1 study, 440 participants; moderate-certainty evidence); and hypertension (RR 13.75, 95% CI 5.07 to 37.29; 1 study, 440 participants; moderate-certainty evidence). There may also be a higher incidence of serious haemorrhage (RR 5.00, 95% CI 1.11 to 22.56; 1 study, 440 participants; low-certainty evidence). In addition, the incidence of serious adverse events is probably higher (RR 1.44, 95% CI 1.16 to 1.79; 1 study, 439 participants; moderate-certainty evidence). The incremental cost-effectiveness ratio was USD 295,164 per quality-adjusted life-year (1 study, 452 participants; low-certainty evidence). Cediranib plus chemotherapy versus chemotherapy Treatment with cediranib plus chemotherapy may or may not result in similar risk of death when compared to chemotherapy alone (HR 0.94, 95% CI 0.53 to 1.65; 1 study, 69 participants; low-certainty evidence). We found very uncertain results for the incidences of specific adverse events, including gastrointestinal perforations or fistulae (RR 3.27, 95% CI 0.14 to 77.57; 1 study, 67 participants; very low-certainty evidence); serious haemorrhage (RR 5.45, 95% CI 0.27 to 109.49; 1 study, 67 participants; very low-certainty evidence); serious thromboembolic events (RR 3.41, 95% CI 0.14 to 80.59; 1 study, 60 participants; very low-certainty evidence); and serious hypertension (RR 0.36, 95% CI 0.02 to 8.62; 1 study, 67 participants; very low-certainty evidence). In addition, there may or may not be a similar incidence of serious adverse events compared to chemotherapy alone (RR 1.15, 95% CI 0.75 to 1.78; 1 study, 67 participants; low-certainty evidence). Apatinib plus chemotherapy or chemotherapy/brachytherapy versus chemotherapy or chemotherapy/brachytherapy Treatment with apatinib plus chemotherapy or chemotherapy/brachytherapy may or may not result in similar risk of death compared to chemotherapy alone or chemotherapy/brachytherapy alone (HR 0.90, 95% CI 0.51 to 1.60; 1 study, 52 participants; low-certainty evidence). However, hypertension events may occur at a higher incidence as compared to chemotherapy alone or chemotherapy/brachytherapy alone (RR 5.14, 95% CI 1.28 to 20.73; 1 study, 52 participants; low-certainty evidence). Pazopanib plus lapatinib versus lapatinib Treatment with pazopanib plus lapatinib may result in higher risk of death compared to lapatinib alone (HR 2.71, 95% CI 1.16 to 6.31; 1 study, 117 participants; low-certainty evidence). We found very uncertain results for the incidences of specific adverse events, including gastrointestinal perforations or fistulae (RR 2.00, 95% CI 0.19 to 21.59; 1 study, 152 participants; very low-certainty evidence); haemorrhage (RR 2.00, 95% CI 0.72 to 5.58; 1 study, 152 participants; very low-certainty evidence); and thromboembolic events (RR 3.00, 95% CI 0.12 to 72.50; 1 study, 152 participants; very low-certainty evidence). In addition, the incidence of hypertension events is probably higher (RR 12.00, 95% CI 2.94 to 49.01; 1 study, 152 participants; moderate-certainty evidence). There may or may not be a similar incidence of serious adverse events as compared to lapatinib alone (RR 1.45, 95% CI 0.94 to 2.26; 1 study, 152 participants; low-certainty evidence). Pazopanib versus lapatinib Treatment with pazopanib may or may not result in similar risk of death as compared to lapatinib (HR 0.96, 95% CI 0.67 to 1.38; 1 study, 152 participants; low-certainty evidence). We found very uncertain results for the incidences of specific adverse events, including gastrointestinal perforations or fistulae (RR 1.03, 95% CI 0.07 to 16.12; 1 study, 150 participants; very low-certainty evidence); haemorrhage (RR 1.03, 95% CI 0.31 to 3.40; 1 study, 150 participants; very low-certainty evidence); and thromboembolic events (RR 3.08, 95% CI 0.13 to 74.42; 1 study, 150 participants; very low-certainty evidence). In addition, the incidence of hypertension events is probably higher (RR 11.81, 95% CI 2.89 to 48.33; 1 study, 150 participants; moderate-certainty evidence). The risk of serious adverse events may or may not be similar as compared to lapatinib (RR 1.31, 95% CI 0.83 to 2.07; 1 study, 150 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: We found low-certainty evidence in favour of the use of bevacizumab plus chemotherapy. However, bevacizumab probably increases specific adverse events (gastrointestinal perforations or fistulae, thromboembolic events, hypertension) and serious adverse events. We found low-certainty evidence that does not support the use of cediranib plus chemotherapy, apatinib plus chemotherapy, apatinib plus chemotherapy/brachytherapy, or pazopanib monotherapy. We found low-certainty evidence suggesting that pazopanib plus lapatinib worsens outcomes. The VEGF inhibitors apatinib and pazopanib may increase the probability of hypertension events.

Efficacy and safety of chemotherapy combined with bevacizumab in Chinese patients with metastatic colorectal cancer: A prospective, multicenter, observational, non-interventional phase IV trial.

OBJECTIVE: Bevacizumab has an important and evolving role in improving outcomes in patients with metastatic colorectal cancer (mCRC) worldwide and was approved in China in 2010. However, there are limited real-world data on the efficacy and safety of chemotherapy regimens combined with bevacizumab in Chinese patients with mCRC. This observational, phase IV trial study aimed to obtain more experience on the efficacy and safety of bevacizumab combined with chemotherapy in Chinese mCRC patients. METHODS: Between September 2013 and November 2016, patients with histologically confirmed mCRC were enrolled in a prospective, multicenter, observational, non-interventional phase IV trial at 26 centers across China. Eligible patients received different chemotherapeutic regimens combined with bevacizumab. The efficacy and safety data in the intention-to-treat study population were analyzed. RESULTS: A total of 611 patients were included in the efficacy analysis. The median overall survival and median progression-free survival was 18.00 and 10.05 months, respectively. The objective response rate was 21.00% and disease control rate was 89.40%. In subgroup analyses, the survival differences were observed according to metastatic status, duration of treatment and elevation in blood pressure. A total of 613 patients were evaluable for safety assessments. And 569 (92.82%) patients reported at least one adverse event (AE), and 151 (24.63%) experienced grade 3 or higher AEs. The incidence of bevacizumab-associated AEs of special interest was reported in 31 (5.06%) patients with hypertension (n=12), abscesses and fistulae (n=7), bleeding (n=6), proteinuria (n=3), gastrointestinal perforation (n=2) and venous thrombotic events (n=1). CONCLUSIONS: This observational phase IV trial broadens our experience and knowledge of bevacizumab in the Chinese population and provides a good indication of its overall efficacy and safety. Bevacizumab in combination with chemotherapy offers clinical benefits to Chinese patients with mCRC and has an acceptable and manageable safety profile.

A Chinese Retrospective Multicenter Study of First-Line Chemotherapy for Advanced Pancreatic Cancer.

BACKGROUND Pancreatic cancer (PC) is a common digestive system tumor. For patients with advanced pancreatic cancer (APC), chemotherapy is still the predominant treatment. However, no large-scale clinical studies have been done of it as first-line therapy for APC. The goal of the present study was to assess real-world outcomes with chemotherapy in that setting. MATERIAL AND METHODS We retrospectively analyzed data from 322 patients with APC who were treated with chemotherapy at 4 hospitals in different cities in China. The first-line regimens used were AS (nab-paclitaxel and S-1), AG (nab-paclitaxel and gemcitabine), and FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin). RESULTS Of the patients, 232 received AS, 79 received AG, and 11 received FOLFIRINOX. The median number of chemotherapy cycles was 5. The median overall survival (mOS) was 9 months and the median progression-free survival (mPFS) was 5 months. The AS, AG, and FOLFIRINOX regimens were associated with mOS rates of 9 months, 9 months, and 10 months, respectively. The mPFS rates for the AS, AG, and FOLFIRINOX regimens were 5, 4, and 5 months, respectively. The differences between the PFS rates for the regimens were statistically significant. The overall response rate (ORR) and overall disease control rate (DCR) for chemotherapy were 38% and 81.8%, respectively. The ORRs for the AS, AG, and FOLFIRINOX regimens were 46.9%, 18.7%, and 0%, respectively. The DCRs for the AS, AG and FOLFIRINOX regimens were 87.2%, 69.3%, and 63.6%, respectively. The differences between the ORRs and DCRs for the regimens were statistically significant. The incidences of grade 3/4 adverse events (AEs) associated with the AS, AG, and FOLFIRINOX regimens were 29.9%, 25%, and 36.4%, respectively. CONCLUSIONS The AS regimen was associated with a higher ORR and DCR than the other 2 regimens, with a lower rate of AEs.

Follicular helper T cells promote the effector functions of CD8+ T cells via the provision of IL-21, which is downregulated due to PD-1/PD-L1-mediated suppression in colorectal cancer.

Recent studies have demonstrated that higher expression of follicular helper T cell (Tfh)-associated genes is associated with better prognosis in breast cancer and colorectal cancer (CRC), but the underlying mechanisms remain unclear. In this study, we compared the function of Tfh cells in non-cancer (NC) controls and in CRC patients between stages II and IV. Data showed that the level of CD4+CXCR5+ Tfh cells were significantly upregulated in stage II CRC patients but was progressively reduced in stage III and stage IV patients. The frequency of PD-1+ cells in CD4+CXCR5+ Tfh cells, on the other hand, was progressively increased from NC patients to CRC patients with increasing severity. Interestingly, the CD4+CXCR5+PD-1- Tfh cells, but not the CD4+CXCR5+PD-1+ Tfh cells, promoted the CD107a expression and IFN-γ expression by CD8+ T cells. This CD8+ T cell-promoting capacity was dependent on the expression of IL-21, as this capacity was significantly impaired by IL-21 neutralization. Tfh cells from CRC patients with advanced stages presented gradual reduction in the capacity to stimulate CD8+ T cells and the capacity to produce IL-21. In addition, treatment with autologous PD-L1-expressing tumor cells further suppressed the IL-21 expression by PD-1+ Tfh cells. Together, these data demonstrated that Tfh cells potently enhanced the effector functions of CD8+ T cells in an IL-21-dependent pathway; however, this role of Tfh cells was limited in CRC patients due to PD-1/PD-L1-mediated suppression.

Timing of chemotherapy-induced neutropenia predicts prognosis in metastatic colon cancer patients: a retrospective study in mFOLFOX6 -treated patients.

BACKGROUND: The occurrence of Chemotherapy-induced neutropenia (CIN) was reported to be a predictor of better survival in several cancers. The objective of our study is to evaluate the relationship between the timing of CIN and prognosis. METHODS: Between June 2012 and August 2014, 290 patients with confirmed metastatic colon cancer received at least one cycle of mFOLFOX6 as first-line chemotherapy were eligible for assessment as all patients group. Of the 232 received at least six cycles of mFOLFOX6 and survived 150 days after treatment were considered as landmark group. Timing of CIN was categorized into absence, early-onset and late-onset CIN groups. The end of cycle 3 was the cutoff to differentiate early-onset or late-onset. The correlation between timing of CIN with survival was analyzed by Kaplan-Meier method and Cox proportional hazards model. RESULTS: In all patients group, the median survival of patients without neutropenia, early-onset and late-onset neutropenia were 6.7, 20.7 and 12.8 months (P < 0.001). The patients with early-onset and late-onset CIN had better prognosis than CIN absence by multivariate analysis. Findings were much the same for landmark group. CONCLUSIONS: In conclusion, timing of CIN is an independent predictor of prognosis in metastatic colon cancer patients received mFOLFOX6, whereas an early-onset of CIN predicts longer survival.

Efficacy and safety of weekly nab-paclitaxel plus gemcitabine in Chinese patients with metastatic adenocarcinoma of the pancreas: a phase II study.

BACKGROUND: This phase II bridging study assessed the safety and efficacy of nab-paclitaxel/gemcitabine (Metastatic Pancreatic Adenocarcinoma Clinical Trial [MPACT] regimen) in Chinese patients with metastatic pancreatic cancer (MPC). METHODS: This 3-part sequential study evaluated nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 on days 1, 8, and 15 every 4 weeks. Part 1 evaluated safety. Part 2 evaluated efficacy using Simon's optimal 2-stage design: if >2 responses were observed in Stage 1 (n = 28), 54 additional patients would be enrolled in Stage 2. If >9 responses were observed, the study was complete. Otherwise, nab-paclitaxel/gemcitabine would be compared with gemcitabine alone in Part 3. The primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response (DOR), overall survival (OS), and safety. RESULTS: Eighty-three patients were treated. The prespecified primary endpoint was met: the independently assessed ORR in Stages 1 + 2 was 35% (95% CI, 24.8-46.2); therefore, Part 3 was not initiated. The median DOR was 8.9 months (95% CI, 6.01-8.94). The median OS and progression-free survival were 9.2 (95% CI, 7.6-11.1) and 5.5 (95% CI, 5.29-7.16) months, respectively. The 12-month OS rate was 30%. In an updated analysis, the median OS was 9.3 months and the 12-month OS rate was 32%. Longer OS was observed in patients with baseline neutrophil-to-lymphocyte ratio ≤ 5 vs > 5. The most common grade ≥ 3 adverse events were leukopenia (35%), neutropenia (34%), anemia (15%), thrombocytopenia (10%), and fatigue (13%). Grade 3 peripheral neuropathy occurred in 7% of patients (no grade 4 reported). CONCLUSIONS: The MPACT regimen of nab-paclitaxel/gemcitabine is efficacious in Chinese patients with MPC. No new safety signals were observed. TRIAL REGISTRATION: NCT02135822 , May 8, 2014.

Thrombopoietin receptor agonists for prevention and treatment of chemotherapy-induced thrombocytopenia in patients with solid tumours.

BACKGROUND: Chemotherapy-induced thrombocytopenia (CIT) is defined as a peripheral platelet count less than 100×109/L, with or without bleeding in cancer patients receiving myelosuppressive chemotherapy. CIT is a significant medical problem during chemotherapy, and it carries the risk of sub-optimal overall survival and bleeding. Alternative interventions to platelet transfusion are limited. Different stages of preclinical and clinical studies have examined the thrombopoietin receptor agonists (TPO-RAs) for CIT in patients with solid tumours. OBJECTIVES: To assess the effects of TPO-RAs to prevent and treat CIT in patients with solid tumours:(1) to prevent CIT in patients without thrombocytopenia before chemotherapy, (2) to prevent recurrence of CIT, and (3) to treat CIT in patients with thrombocytopenia during chemotherapy. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, to 28 September 2017), MEDLINE (from 1950 to 28 September 2017), as well as online registers of ongoing trials (Clinical Trials, Chinese Clinical Trial Register, Australian New Zealand Clinical Trial Registry, WHO ICTRP Search Portal, International Standard Randomised Controlled Trial Number registry, GlaxoSmithKline Clinical Study Register, and Amgen Clinical Trials) and conference proceedings (American Society of Hematology, American Society of Clinical Oncology, European Hematology Association, European Society of Medical Oncology, and Conference Proceedings Citation Index-Science, from 2002 up to September 2017) for studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing TPO-RAs alone, or in combination with other drugs, to placebo, no treatment, other drugs, or another TPO-RAs for CIT in patients with solid tumours. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the results of the search strategies, extracted data, assessed risk of bias, and analysed data according to standard methodological methods expected by Cochrane. MAIN RESULTS: We identified six trials eligible for inclusion, of which two are ongoing, and one awaiting classification study. The three included trials were conducted at many different sites in Europe, America, and Asia. All of the three studies recruited adult and elder participants (no children were included) with solid tumours, and compared TPO-RAs with placebo. No studies compared TPO-RAs alone, or in combination with other drugs, to no treatment, or other drugs, or another TPO-RAs.We judged the overall risk of bias as high as we found a high risk for detection bias. We assessed the risk of bias arising from inadequate blinding of outcome assessors as high for number and severity of bleeding episodes (one of the primary outcomes).To prevent CIT: We included two trials (206 participants) comparing TPO-RAs (eltrombopag, multiple-dose oral administration with chemotherapy) with placebo. The use of TPO-RAs may make little or no difference to the all-cause mortality at 33 weeks of follow-up (RR 1.35, 95% CI 0.53 to 3.45; one trial, 26 participants; low quality of evidence). There is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one bleeding episode of any severity (RR 0.62, 95% CI 0.22 to 1.78; two trials, 206 participants; very low quality of evidence). There is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one severe/life-threatening bleeding episode (RR 0.36, 95% CI 0.06 to 2.06; two trials, 206 participants; very low quality of evidence). No studies were found that looked at overall survival (one of the primary outcomes), the number of treatment cycles with at least one bleeding episode, the number of days on which bleeding occurred, the amount of bleeding, or quality of life.To prevent recurrence of CIT: We included one trial (62 participants) comparing TPO-RAs (romiplostim, single-dose subcutaneous administration with chemotherapy) with placebo. There is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one bleeding episode of any severity (RR 2.80, 95% CI 0.17 to 47.53; one trial, 62 participants; very low quality of evidence). There is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one severe/life-threatening bleeding episode (no severe/life-threatening bleeding episodes; one trial, 62 participants; very low quality of evidence). No studies were found that looked at overall survival (one of the primary outcomes), the number of treatment cycles with at least one bleeding episode, the number of days on which bleeding occurred, the amount of bleeding, or quality of life. We found one ongoing study (expected recruitment 74 participants), it is planned to give TPO-RAs (romiplostim, subcutaneous administration with chemotherapy) to participants, but to date this trial has not reported any outcomes.To treat CIT: We found one ongoing study (expected recruitment 83 participants), which is planned to give TPO-RAs (eltrombopag, seven days orally) to participants when their platelet counts are less than 75×109/L during chemotherapy. This trial was originally planned to complete in March 2017, however, the completion date has passed and no results are reported.The one awaiting classification study included patients without thrombocytopenia before chemotherapy (to prevent CIT), patients with thrombocytopenia during chemotherapy (to prevent recurrence of CIT), and other patients during chemotherapy (uncertain whether CIT had happened). There was no evidence for a difference in the number of patients with at least one bleeding episode of any severity (RR 0.27, 95% CI 0.07 to 1.02; one trial, 75 participants). There was no evidence for a difference in the number of patients with at least one severe/life-threatening bleeding episode (RR 0.44, 95% CI 0.03 to 6.77; one trial, 75 participants). This study did not address overall survival or quality of life. AUTHORS' CONCLUSIONS: No certain conclusions can be drawn due to the lack of strong evidence in the review. The available weak evidence did not support the use of TPO-RAs for preventing CIT or preventing recurrence of CIT in patients with solid tumours. There was no evidence to support the use of TPO-RAs for treating CIT in patients with solid tumours.

Randomized multicenter phase III study of a modified docetaxel and cisplatin plus fluorouracil regimen compared with cisplatin and fluorouracil as first-line therapy for advanced or locally recurrent gastric cancer.

BACKGROUND: The V325 study showed that docetaxel, cisplatin, and fluorouracil (DCF) prolonged overall survival (OS) of patients with advanced gastric cancer, but with a high incidence of dose-limiting toxicities. We investigated the efficacy and safety of a modified DCF (mDCF) regimen for Chinese patients with advanced gastric cancer. METHODS: Untreated advanced gastric cancer patients randomly received docetaxel and cisplatin at 60 mg/m(2) (day 1) followed by fluorouracil at 600 mg/m(2)/day (days 1-5; mDCF regimen) or cisplatin at 75 mg/m(2) (day 1) followed by fluorouracil at 600 mg/m(2)/day (days 1-5; CF) every 3 weeks. The primary end point was progression-free survival (PFS). The secondary end points were OS, overall response rate (ORR), time-to-treatment failure (TTF), and safety. RESULTS: In total, 243 patients were randomized to treatment (mDCF regimen 121; CF 122). Compared with CF, the mDCF regimen significantly improved PFS and OS: the median PFS was 7.2 and 4.9 months, respectively [hazard ratio (HR) 0.58, log-rank P = 0.0008], and the median OS was 10.2 and 8.5 months, respectively (HR = 0.71, P = 0.0319). Additionally, the mDCF regimen improved the parameters used as secondary objectives: the ORR was 48.7% with the mDCF regimen versus 33.9% with CF (P = 0.0244); the median TTF was 3.4 months with the mDCF regimen and 2.4 months with CF (HR = 0.67, P = 0.0027). Grade 3 and grade 4 treatment-related adverse events occurred in 77.3 % of patients who received the mDCF regimen versus 46.1% of patients who received CF (P < 0.001). CONCLUSIONS: The mDCF regimen, compared with CF, significantly prolonged PFS and OS and enhanced ORR of Chinese patients with advanced gastric cancer. The mDCF regimen achieved efficacy comparable to that of DCF but with fewer toxicities, which is appropriate for the Chinese population.

Combined microwave ablation and systemic chemotherapy for liver metastases from oesophageal cancer: Preliminary results and literature review.

PURPOSE: Oesophageal cancer is a highly aggressive disease with about 50% of patients presenting with advanced or metastatic disease at initial diagnosis. In this study we assessed combined microwave ablation (MWA) and systemic chemotherapy in the treatment of liver metastases arising from oesophageal squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Between February 2009 and June 2014, OSCC patients who underwent percutaneous MWA + concurrent systemic chemotherapy and systemic chemotherapy alone for liver metastases were enrolled in this study. Overall survival (OS) and progression-free survival (PFS) were recorded and compared between groups. RESULTS: In total 15 patients with 25 liver metastases who underwent ultrasound-guided percutaneous MWA and chemotherapy were enrolled in this study. Technical success was achieved in 96% (24/25) of metastatic liver tumours. No major or minor complications associated with MWA procedures were observed. The median OS and PFS from initial MWA were 13 months and 4 months. The 1-, 2-, 3-, 4-year OS rates after MWA were 53.3%, 26.7%, 13.3%, and 13.3%, respectively. The 1- and 2-year PFS rates after MWA were 26.7% and 13.3%. The OS and PFS of the MWA + systemic chemotherapy group were superior than those of patients who received systemic chemotherapy alone (P = 0.011 and 0.030, respectively). CONCLUSIONS: Combined MWA with systemic chemotherapy is a feasible, safe and effective treatment for liver metastases from OSCC.

Adenosine Triphosphate (ATP) Inhibits Voltage-Sensitive Potassium Currents in Isolated Hensen's Cells and Nifedipine Protects Against Noise-Induced Hearing Loss in Guinea Pigs.

BACKGROUND There is increasing evidence that adenosine triphosphate (ATP), a well-known neurotransmitter and neuromodulator in the central nervous system, plays an important role as an extracellular chemical messenger in the cochlea. MATERIAL AND METHODS Using a whole-cell recording technique, we studied the effects of ATP on isolated Hensen's cells, which are supporting cells in the cochlea, to determine if they are involved in the transduction of ions with hair cells. RESULTS ATP (0.1-10 µM) reduced the potassium current (IK+) in the majority of the recorded Hensen's cells (21 out of 25 cells). An inward current was also induced by high concentrations of ATP (100 µM to 10 mM), which was reversibly blocked by 100 µM suramin (a purinergic antagonist) and blocked by nifedipine (an L-type calcium channel blocker). After the cochleas were perfused with artificial perilymph solutions containing nifedipine and exposed to noise, the amplitude increase in the compound action potential (CAP) threshold and the reduction in cochlear microphonics was lower than when they were exposed to noise alone. CONCLUSIONS Our results suggest that ATP can block IK+ channels at a low concentration and induce an inward Ca2+ current at high concentrations, which is reversed by purinergic receptors. Nifedipine may have a partially protective effect on noise-induced hearing loss (NIHL).