CACA Guidelines for Holistic Integrative Management of Breast Cancer.

Purpose: Breast cancer is now the most common malignant tumor worldwide. About one-fourth of female cancer patients all over the world suffer from breast cancer. And about one in six female cancer deaths worldwide is caused by breast cancer. In terms of absolute numbers of cases and deaths, China ranks first in the world. The CACA Guidelines for Holistic Integrative Management of Breast Cancer were edited to help improve the diagnosis and comprehensive treatment in China. Methods: The Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to classify evidence and consensus. Results: The CACA Guidelines for Holistic Integrative Management of Breast Cancer include the epidemiology of breast cancer, breast cancer screening, breast cancer diagnosis, early breast cancer treatment, advanced breast cancer treatment, follow-up, rehabilitation, and traditional Chinese medicine treatment of breast cancer patients. Conclusion: We to standardize the diagnosis and treatment of breast cancer in China through the formulation of the CACA Guidelines.

Efficacy of Moxifloxacin plus Treatment of Physician's Choice in Patients with Metastatic Breast Cancer.

LESSONS LEARNED: Moxifloxacin plus continuation of the previous treatment of physician's choice shows promising efficacy in patients with metastatic breast cancer. The addition of moxifloxacin shows well-tolerated toxicities. BACKGROUND: Recent studies have confirmed bacterial infection as an important contributor in cancer. Elimination of tumor-associated microbes may lead to a reduction in tumors and improved survival. Moxifloxacin is an orally administrated fourth-generation quinolone with broad-spectrum coverage against tumor-associated bacteria. METHODS: In this study, we assessed the efficacy and safety of moxifloxacin in combination with treatment of physician's choice (TPC) in patients with metastatic breast cancer (MBC). In this single-arm, phase II study, we recruited 30 patients with MBC who had a trend toward disease progression (stable disease [SD] with increased tumor size) during TPC before enrollment at Sun Yat-sen University Cancer Center between January 1 and July 30, 2018. Eligible patients were given moxifloxacin once daily at a dose of 400 mg from days 1 to 7 of a 28-day cycle, in addition to continuing to receive the therapy previously selected by their physicians. Tumor response was determined according to RECIST (version 1.1). Progression-free survival (PFS) was calculated using the Kaplan-Meier method. RESULTS: The concomitant use of moxifloxacin and previous TPC yielded a median PFS of 6.6 months (95% confidence interval [CI]: 4.0-9.1) and a 1-year PFS of 25.9% (95% CI: 10.0%-41.9%). Objective responses were achieved in seven (23.3%, 95% CI: 7.3%-39.4%) patients. The clinical benefit rate was 46.7% (95% CI: 27.7%-65.6%). No grade 4 adverse events (AEs) and four grade 3 AEs were observed, none of which were considered to have definite relation to moxifloxacin. CONCLUSION: The combination of moxifloxacin with previous TPC shows promising efficacy and well-tolerated toxicities in patients with MBC.

Efficacy, Safety, and Tolerability of Pertuzumab, Trastuzumab, and Docetaxel for Patients With Early or Locally Advanced ERBB2-Positive Breast Cancer in Asia: The PEONY Phase 3 Randomized Clinical Trial.

Importance: Prospective assessment of treatments known to benefit patients in global clinical trials in specific racial groups is essential. Objective: To compare the efficacy, safety, and tolerability of adding pertuzumab to trastuzumab and docetaxel vs placebo, trastuzumab, and docetaxel in Asian patients with ERBB2-positive early or locally advanced breast cancer. Design, Setting, and Participants: This multicenter, double-blind, placebo-controlled phase 3 trial enrolled 329 women with ERBB2-positive early (T2-3, N0-1, M0) or locally advanced breast cancer (T2-3, N2 or N3, M0; T4, any N, M0) and primary tumor larger than 2 cm from March 14, 2016, to March 13, 2017. Analysis of the primary end point was performed on an intention-to-treat basis. Interventions: Before surgery, patients received 4 cycles of intravenous pertuzumab (840-mg loading dose and 420-mg maintenance doses), trastuzumab (8-mg/kg loading dose and 6-mg/kg maintenance doses), and docetaxel (75 mg/m2) or intravenous placebo, trastuzumab, and docetaxel every 3 weeks. After surgery, patients received 3 cycles of intravenous fluorouracil, epirubicin, and cyclophosphamide followed by 13 cycles of the same intravenous anti-ERBB2 therapy (pertuzumab and trastuzumab or placebo and trastuzumab) for up to 1 year. Main Outcomes and Measures: The primary end point was independent review committee-assessed total pathologic complete response rate. The 2-sided Cochran-Mantel-Haenszel test, stratified by disease category and hormone receptor status, was used to compare rates between treatment groups. Results: In total, 329 female patients were randomized (pertuzumab, 219; and placebo, 110; mean [SD] age, 48.8 [9.5] years). In the intention-to-treat population, total pathologic complete response rates were 39.3% (86 of 219) in the pertuzumab group and 21.8% (24 of 110) in the placebo group (difference, 17.5% [95% CI, 6.9%-28.0%]; P = .001). Of the most common grade 3 or higher adverse events, there was a higher incidence of neutropenia in the pertuzumab group (83 of 218 [38.1%] vs 36 of 110 [32.7%]). Serious adverse events were reported in 10.1% of patients (22 of 218) in the pertuzumab group and 8.2% of patients (9 of 110) in the placebo group. Conclusions and Relevance: Treatment with pertuzumab, trastuzumab, and docetaxel resulted in a statistically significant improvement in the total pathologic complete response rate vs placebo, trastuzumab, and docetaxel for the neoadjuvant treatment of ERBB2-positive early or locally advanced breast cancer in Asian patients. Safety data were in line with the known pertuzumab safety profile and generally comparable between treatment groups. The PEONY trial adds to the totality of data showing the benefit of the pertuzumab regimen. Trial Registration: ClinicalTrials.gov identifier: NCT02586025.

Safety and Efficacy of Anlotinib, a Multikinase Angiogenesis Inhibitor, in Patients with Refractory Metastatic Soft-Tissue Sarcoma.

Purpose: The prognosis for patients with refractory soft-tissue sarcoma (STS) is dismal. Anlotinib has previously shown antitumor activity on STS in preclinical and phase I studies.Patients and Methods: Patients 18 years and older, progressing after anthracycline-based chemotherapy, naïve from angiogenesis inhibitors, with at least one measurable lesion according to RECIST 1.1, were enrolled. The main subtypes eligible were undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), leiomyosarcoma (LMS), synovial sarcoma (SS), fibrosarcoma (FS), alveolar soft-part sarcoma (ASPS), and clear cell sarcoma (CCS). Participants were treated with anlotinib. The primary endpoint was progression-free rate at 12 weeks (PFR12 weeks).Results: A total of 166 patients were included in the final analysis. Overall, the PFR12 weeks was 68%, and objective response rate was 13% (95% confidence interval, 7.6%-18%). The median progression-free survival (PFS) and overall survival (OS) were 5.6 and 12 months, respectively. The PFR12 weeks, median PFS and OS were: 58%, 4.1 and 11 months for UPS (n = 19); 63%, 5.6 and 13 months for LPS (n = 13); 75%, 11 and 15 months for LMS (n = 26); 75%, 7.7 and 12 months for SS (n = 47); 81%, 5.6 and 12 months for FS (n = 18); 77%, 21 and not reached for ASPS (n = 13); 54%, 11 and 16 months for CCS (n = 7); and 44%, 2.8 and 8.8 months for other sarcoma (n = 23), respectively. The most common clinically significant grade 3 or higher adverse events were hypertension (4.8%), triglyceride elevation (3.6%), and pneumothorax (2.4%). No treatment-related death occurred.Conclusions: Anlotinib showed antitumor activity in several STS entities. The toxicity was manageable. Clin Cancer Res; 24(21); 5233-8. ©2018 AACR.

Diazoxide, a K(ATP) channel opener, prevents ischemia-reperfusion injury in rodent pancreatic islets.

Diazoxide (DZ) is a pharmacological opener of ATP-sensitive K(+) channels that has been used for mimicking ischemic preconditioning and shows protection against ischemic damage. Here we investigated whether diazoxide supplementation to University of Wisconsin (UW) solution has cellular protection during islet isolation and improves in vivo islet transplant outcomes in a rodent ischemia model. C57/B6 mice pancreata were flushed with UW or UW + DZ solution and cold preserved for 6 or 10 h prior to islet isolation. Islet yield, in vitro and in vivo function, mitochondrial morphology, and apoptosis were evaluated. Significantly higher islet yields were observed in the UW + DZ group than in the UW group (237.5 ± 25.6 vs. 108.7 ± 49.3, p < 0.01). The islets from the UW + DZ group displayed a significantly higher glucose-induced insulin secretion (0.97 ng/ml ± 0.15 vs. 0.758 ng/ml ± 0.21, p = 0.009) and insulin content (60.96 ng/islet ± 13.94 vs. 42.09 ng/islet ± 8.15, p = 0.002). The DZ-treated islets had well-preserved mitochondrial morphology with superior responses of mitochondrial potentials, and calcium influx responded to glucose. A higher number of living cells and less late apoptotic cells were observed in the UW + DZ group (p < 0.05). Additionally, the islets from the UW + DZ group had a significantly higher cure rate and improved glucose tolerance. This study is the first to report mitoprotective effects of DZ for pancreas preservation and islet isolation. In the future, it will be necessary to further understand the underlying mechanism for the mitoprotection and to test this promising approach for pancreas preservation and the islet isolation process in nonhuman primates and ultimately humans.

Cyclin G2 suppresses estrogen-mediated osteogenesis through inhibition of Wnt/ß-catenin signaling.

Estrogen plays an important role in the maintenance of bone formation, and deficiency in the production of estrogen is directly linked to postmenopausal osteoporosis. To date, the underlying mechanisms of estrogen-mediated osteogenic differentiation are not well understood. In this study, a pluripotent mesenchymal precursor cell line C2C12 was used to induce osteogenic differentiation and subjected to detection of gene expressions or to manipulation of cyclin G2 expressions. C57BL/6 mice were used to generate bilateral ovariectomized and sham-operated mice for analysis of bone mineral density and protein expression. We identified cyclin G2, an unconventional member of cyclin, is involved in osteoblast differentiation regulated by estrogen in vivo and in vitro. In addition, the data showed that ectopic expression of cyclin G2 suppressed expression of osteoblast transcription factor Runx2 and osteogenic differentiation marker genes, as well as ALP activity and in vitro extracellular matrix mineralization. Mechanistically, Wnt/ß-catenin signaling pathway is essential for cyclin G2 to inhibit osteogenic differentiation. To the best of our knowledge, the current study presents the first evidence that cyclin G2 serves as a negative regulator of both osteogenesis and Wnt/ß-catenin signaling. Most importantly, the basal and 17ß-estradiol-induced osteogenic differentiation was restored by overexpression of cyclin G2. These results taken together suggest that cyclin G2 may function as an endogenous suppressor of estrogen-induced osteogenic differentiation through inhibition of Wnt/ß-catenin signaling.

Classical CMF regimen as adjuvant chemotherapy for triple-negative breast cancer may be more effective compared with anthracycline or taxane-based regimens.

Patients suffering from triple-negative breast cancer (TNBC) have poor prognosis mainly because no standard treatment is currently available. Our objectives were to explore the prognostic factors for first relapse of patients with TNBC. A cohort of 687 patients with TNBC, diagnosed and treated between January 1995 and December 2008 at Sun Yat-sen University Cancer Center, were retrospectively analyzed. Cox proportional hazards models were fitted to explore factors that predict relapse development. Survival rate was computed using the Kaplan-Meier product limit method. The median age of the 687 patients was 46 (range 16-76 years), and 64.8% of the patients were pre-menopausal. The median follow-up time was 56 months (range 14-156 months), in which 194 patients had recurrence, and 115 died. The median recurrence-free time was 25 months (range 4-143 months), with 118 (60.8%) of the cases first relapsing at a single site. The three- and five-year disease-free survival rates were 79.7 and 72.6%, respectively. Primary tumor size at diagnosis, lymph node status, and type of regimen used in the (neo)adjuvant chemotherapy were considered independent predictors of first relapse. CMF-containing adjuvant chemotherapy significantly decreased recurrence compared with the anthracycline- or taxane-based regimens (RR = 0.66, 95%; CI 0.45-0.96; P = 0.030). The median time from first relapse to death was 26 months (range 2-121 months). The two- and five-year survival rates were 60.6 and 36.6%, respectively. Liver metastasis at first recurrence and progression-free survival over 12 months after first-line therapy were two important factors that affected survival rate after recurrence. The median relapse time of TNBC was about 2 years after diagnosis. CMF regimens for TNBC patients may be more effective than anthracycline- or taxane-based regimens. Liver metastasis at first recurrence signifies unfavorable prognosis.

Human pancreatic islet isolation: Part II: purification and culture of human islets.

Management of Type 1 diabetes is burdensome, both to the individual and society, costing over 100 billion dollars annually. Despite the widespread use of glucose monitoring and new insulin formulations, many individuals still develop devastating secondary complications. Pancreatic islet transplantation can restore near normal glucose control in diabetic patients, without the risk of serious hypoglycemic episodes that are associated with intensive insulin therapy. Providing sufficient islet mass is important for successful islet transplantation. However, donor characteristics, organ procurement and preservation affect the isolation outcome. At University of Illinois at Chicago (UIC) we developed a successful isolation protocol with an improved purification gradient. The program started in January 2004 and more than 300 isolations were performed up to November 2008. The pancreata were sent in cold preservation solutions (UW, University of Wisconsin or HTK, Histidine-Tryptophan Ketoglutarate) to the Cell Isolation Laboratory at UIC for islet isolation. Pancreatic islets were isolated using the UIC method, which is a modified version of the method originally described by Ricordi et al. As described in Part I: Digestion and Collection of Pancreatic Tissue, human pancreas was trimmed, cannulated, perfused, and digested. After collection and at least 30 minutes of incubation in UW solution, the tissue was loaded in the cell separator (COBE 2991, Cobe, Lakewood, CO) for purification. Following purification, islet yield (expressed as islet equivalents, IEQ), tissue volume, and purity was determined according to standard methods. Isolated islets were cultured in CMRL-1066 media (Mediatech, Herndon, VA), supplemented with 1.5% human albumin, 0.1% insulin-transferrin-selenium (ITS), 1 ml of Ciprofloxacin, 5 ml o f 1M HEPES, and 14.5 ml of 7.5% Sodium Bicarbonate in T175 flasks at 37 degrees C overnight culture before islets were transplanted or used for research.