Decrease of pro-angiogenic monocytes predicts clinical response to anti-angiogenic treatment in patients with metastatic renal cell carcinoma

The modulation of subpopulations of pro-angiogenic monocytes (VEGFR-1+ CD14 and Tie2+ CD14) was analyzed in an ancillary study from the prospective PazopanIb versus Sunitinib patient preferenCE Study (PISCES) (NCT01064310), where metastatic renal cell carcinoma (mRCC) patients were treated with two anti-angiogenic drugs, either sunitinib or pazopanib. Blood samples from 86 patients were collected prospectively at baseline (T1), and at 10 weeks (T2) and 20 weeks (T3) after starting anti-angiogenic therapy. Various subpopulations of myeloid cells (monocytes, VEGFR-1+ CD14 and Tie2+ CD14 cells) decreased during treatment. When patients were divided into two subgroups with a decrease (defined as a >20% reduction from baseline value) (group 1) or not (group 2) at T3 for VEGFR-1+ CD14 cells, group 1 patients presented a median PFS and OS of 24 months and 37 months, respectively, compared with a median PFS of 9 months (p = 0.032) and a median OS of 16 months (p = 0.033) in group 2 patients. The reduction in Tie2+ CD14 at T3 predicted a benefit in OS at 18 months after therapy (p = 0.04). In conclusion, in this prospective clinical trial, a significant decrease in subpopulations of pro-angiogenic monocytes was associated with clinical response to anti-angiogenic drugs in patients with mRCC

Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE).

BACKGROUND: Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting. PATIENTS AND METHODS: In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8\u2009mg/kg loading dose, then 6\u2009mg/kg every 3\u2009weeks (q3w)] and pertuzumab (840\u2009mg loading dose, then 420\u2009mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS). RESULTS: Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54\u2009years; 29% had received prior trastuzumab. Median treatment duration was 16\u2009months for pertuzumab and trastuzumab and 4\u2009months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9-22.7] months overall (19.6, 23.0 and 18.1\u2009months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%-82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%). CONCLUSIONS: Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile. CLINICALTRIALS.GOV: NCT01572038

Final results from the PERUSE study of first-line pertuzumab plus trastuzumab plus a taxane for HER2-positive locally recurrent or metastatic breast cancer, with a multivariable approach to guide prognostication

Background: The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. Patients and methods: Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. Results: Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade 653 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). Conclusions: Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design

Evaluation of feasibility, efficiency and safety of a pure NOTES gastrojejunal bypass with gastric outlet obstruction, in an in vivo porcine model

Introduction: Natural orifice transluminal endoscopic surgery (NOTES) gastrojejunal anastomosis (GJA) is a less invasive surgery for bariatric procedures and gastric outlet obstruction. The aim of this study was to evaluate the feasibility, efficacy, and safety of a pure NOTES gastrojejunal bypass using an in vivo porcine model. Material and methods: A prospective study was performed on nine swine. A double-channel scope was used. The intervention steps were: (i) gastric incision; (ii) peritoneal access; (iii) jejunal loop selection and mobilization into the stomach; (iv) stoma creation within the gastric wall and incision; (v) anastomosis suture and pylorus closure using a T-tag prototype. The animals were assessed clinically for 3 weeks including the weight gain. The patency of the GJA was assessed at necropsy and a histological analysis was performed. Results: We successfully performed all the procedures with a mean (standard deviation [SD]) operative time of 108 (26) minutes. We used a mean of 5.55 (1.30) stitches. There were no intraprocedural adverse events. Five animals survived up till euthanasia at 3 weeks (65 %). These showed a significant difference in weight curves of a loss of 3.2 kg compared with gain of 5.2 kg in a control group. Four pigs died from anastomotic dehiscence complicated by peritonitis. Conclusion: Gastrojejunal bypass with a pure NOTES approach is feasible. This procedure is effective, resulting in a patent anastomosis and a significant weight loss. However, the anastomotic dehiscence is a major concern because of its mortality rate, and further studies including improvement of the suturing device and the technique are needed

Efficacy of endoscopic gastrojejunal bypass in obese Yucatan pigs: a comparative animal study

Abstract Background Natural orifice transluminal endoscopy surgery (NOTES) gastrojejunal anastomosis (GJA) with duodenal exclusion (DE) could be used as a less invasive alternative to surgical gastric bypass. The aim of this study was to compare the efficacy and safety of both methods for bariatric purpose. Methods This was a prospective, experimental and comparative study on 27 obese living pigs, comparing 4 groups: GJA alone (group 1, G1), GJA + DE (group 2, G2), surgical gastric bypass (group 3, G3), control group (group 4, G4). GJA was endoscopically performed, using NOTES technic and LAMS, while DE was performed surgically for limb length selection. Animals were followed for 3 months. Primary outcome included technical success and weight change, while secondary endpoints included the rate of perioperative mortality and morbidity, histological anastomosis analysis and biological analysis. Results Technical success was 100% in each intervention group. No death related to endoscopic procedures occurred in the endoscopic groups, while early mortality (< 1 month) was 57,1% in the surgical group, all due to anastomotic dehiscence. At 3 months, compared to baseline, mean weight change was + 3,1% in G1 (p = 0,46); -14,9% in G2 (p = 0,17); +5,6% in G3 (p = 0,38) and + 25% in G4 (p = 0,029). Histopathological analysis of endoscopic GJA showed complete fusion of different layers without leak or abscess. Conclusions Endoscopic GJA with DE provides the efficacy of bypass on weight control in an animal model. Next steps consist of the development of devices to perform exclusively endoscopically limb length selection and DE

Molecular markers of cartilage breakdown and synovitis at baseline as predictors of structural progression of hip osteoarthritis. The ECHODIAH* Cohort

OBJECTIVE: To determine whether systemic markers of bone, cartilage, and synovium can predict structural progression of osteoarthritis (OA). METHODS: Patients with painful hip OA were treated with diacerein or placebo in a multicentre, prospective, double blind, 3 year follow up trial. The following information was collected at entry: demographics, characteristics of hip OA, and 10 markers: N‐propeptides of collagen types I and III, cartilage oligomeric matrix protein, YKL‐40, hyaluronan (sHA), matrix metalloproteinases‐1 and ‐3, C reactive protein, C‐terminal crosslinking telopeptides of collagen types I and II (uCTX‐II). Radiographs were obtained at entry and every year. Structural progression was defined as a joint space decrease ⩾0.5 mm or requirement for total hip replacement. Grouped survival analysis was performed with time to structural progression as dependent variable, and clinical data, radiographic findings, treatment groups (diacerein versus placebo), and markers as explanatory measures. RESULTS: In the 333 patients in whom all markers were measured, high functional impairment, a joint space width <2 mm, and lateral migration of the femoral head at baseline increased the risk of progression, but diacerein had a protective effect (relative risk = 0.75; 95% confidence interval (CI) 0.54 to 0.96). In addition, patients in whom uCTX‐II and sHA were in the upper tertile had a relative risk of progression of 3.73 (95% CI 2.48 to 5.61) compared with patients with markers in the two lower tertiles. CONCLUSION: In this large cohort, combined measurements of uCTX‐II and sHA were a new predictor of the structural progression of hip OA