Nivolumab plus regorafenib in patients with small bowel adenocarcinoma: A case report.

INTRODUCTION: Small bowel adenocarcinomas (SBAs) are rare cancers that have a distinct clinical characteristic and genetic profile. The only potentially curative treatment for localized SBAs is surgery, and treatment options are limited for patients in the advanced stage of disease. PATIENT CONCERNS: A 39-year-old woman presented in October 2015 with a complaint of persistent vomiting for 8 months. DIAGNOSIS: The patient had obstruction caused by a 3 × 2 cm mass at the ascending part of the duodenum and suspected metastasis in the right adnexal region. Postoperative pathology showed a moderately differentiated adenocarcinoma with serosal invasion. The diagnosis was stage IV duodenum adenocarcinoma with right adnexal metastasis. INTERVENTIONS: After the failure of multi-line treatment with chemotherapy and targeted therapy, she was treated with the immune checkpoint inhibitor nivolumab plus regorafenib. OUTCOMES: Disease control lasted for 15 months with markedly improved symptoms. CONCLUSION: To the best of our knowledge, this is the first case of small bowel adenocarcinoma that has been treated with nivolumab combined with regorafenib. This case highlights the potential efficacy of combining nivolumab and regorafenib in the treatment of SBAs.

Phase I dose-escalation and expansion study of PARP inhibitor, fluzoparib (SHR3162), in patients with advanced solid tumors.

OBJECTIVE: Fluzoparib (SHR3162) is a novel, potent poly(ADP-ribose) polymerases (PARP)1, 2 inhibitor that showed anti-tumor activity in xenograft models. We conducted a phase I, first-in-human, dose-escalation and expansion (D-Esc and D-Ex) trial in patients with advanced solid cancer. METHODS: This was a 3+3 phase I D-Esc trial with a 3-level D-Ex at 5 hospitals in China. Eligible patients for D-Esc had advanced solid tumors refractory to standard therapies, and D-Ex enrolled patients with ovarian cancer (OC). Fluzoparib was administered orally once or twice daily (bid) at 11 dose levels from 10 to 400 mg/d. Endpoints included dose-finding, safety, pharmacokinetics, and antitumor activity. RESULTS: Seventy-nine patients were enrolled from March, 2015 to January, 2018 [OC (47, 59.5%); breast cancer (BC) (16, 20.3%); colorectal cancer (8, 10.1%), other tumors (8, 10.1%)]; 48 patients were treated in the D-Esc arm and 31 in the D-Ex arm. The maximum tolerated dose (MTD) was 150 mg bid, with a half-life of 9.14 h. Grade 3/4 adverse events included anemia (7.6%) and neutropenia (5.1%). The objective response rate (ORR) was 30% (3/10) in patients with platinum-sensitive OC and 7.7% (1/13) in patients with BC. Among patients treated with fluzoparib ≥120 mg/d, median progression-free survival (mPFS) was 7.2 [95% confidence interval (95% CI), 1.8-9.3] months in OC, 9.3 (95% CI, 7.2-9.3) months in platinum-sensitive OC, and 3.5 (range, 2.0-28.0) months in BC. In patients with germline BC susceptibility gene mutation (gBRCA Mut) (11/43 OC; 2/16 BC), mPFS was 8.9 months for OC (range, 1.0-23.2; 95% CI, 1.0-16.8) and 14 and 28 months for BC (those two patients both also had somaticBRCA Mut). CONCLUSIONS: The MTD of fluzoparib was 150 mg bid in advanced solid malignancies. Fluzoparib demonstrated single-agent antitumor activity in BC and OC, particularly in BRCA Mut and platinum-sensitive OC.

Anti-PD-1 Antibody SHR-1210 Combined with Apatinib for Advanced Hepatocellular Carcinoma, Gastric, or Esophagogastric Junction Cancer: An Open-label, Dose Escalation and Expansion Study.

PURPOSE: This study assessed the safety and efficacy of SHR-1210 (anti-PD-1 antibody) and apatinib (VEGFR2 inhibitor) as combination therapy in patients with advanced hepatocellular carcinoma (HCC), gastric, or esophagogastric junction cancer (GC/EGJC). PATIENTS AND METHODS: This was an open-label, dose-escalation (phase Ia) and expansion study (phase Ib). In phase Ia, patients (n = 15) received SHR-1210 200 mg every 2 weeks and apatinib 125-500 mg once daily until unacceptable toxicity or disease progression. In phase Ib, patients (n = 28) received apatinib at the phase Ia-identified recommended phase II dose (RP2D) plus SHR-1210. The primary objectives were safety and tolerability and RP2D determination. RESULTS: At data cutoff, 43 patients were enrolled. In phase Ia, four dose-limiting toxicity events were observed (26.7%): one grade 3 lipase elevation (6.7%) in the apatinib 250 mg cohort and three grade 3 pneumonitis events (20%) in the apatinib 500 mg cohort. The maximum tolerated RP2D for apatinib was 250 mg. Of the 33 patients treated with the R2PD combination, 20 (60.6%) experienced a grade ≥3 treatment-related adverse event; adverse events in ≥10% of patients were hypertension (15.2%) and increased aspartate aminotransferase (15.2%). The objective response rate in 39 evaluable patients was 30.8% (95% CI: 17.0%-47.6%). Eight of 16 evaluable HCC patients achieved a partial response (50.0%, 95% CI: 24.7%-75.4%). CONCLUSIONS: SHR-1210 and apatinib combination therapy demonstrated manageable toxicity in patients with HCC and GC/EGJC at recommended single-agent doses of both drugs. The RP2D for apatinib as combination therapy was 250 mg, which showed encouraging clinical activity in patients with advanced HCC.

DNA in serum extracellular vesicles is stable under different storage conditions.

BACKGROUND: Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, can be secreted by most cell types and released in perhaps all biological fluids. EVs contain multiple proteins, specific lipids and several kinds of nucleic acids such as RNAs and DNAs. Studies have found that EVs contain double-stranded DNA and that genetic information has a certain degree of consistency with tumor DNA. Therefore, if genes that exist in exosomes are stable, we may be able to use EVs genetic testing as a new means to monitor gene mutation. METHODS: In this study, EVs were extracted from serum under various storage conditions (4 °C, room temperature and repeated freeze-thaw). We used western blotting to examine the stability of serum EVs. Then, we extracted DNA from EVs and tested the concentration changing under different conditions. We further assessed the stability of EVs DNA s using polymerase chain reaction (PCR) and Sanger sequencing. RESULTS: EVs is stable under the conditions of 4 °C (for 24 h, 72 h, 168 h), room temperature (for 6 h, 12 h, 24 h, 48 h) and repeated freeze-thaw (after one time, three times, five times). Also, serum DNA is mainly present in EVs, especially in exosomes, and that the content and function of DNA in EVs is stable whether in a changing environment or not. We showed that EVs DNA stayed stable for 1 week at 4 °C, 1 day at room temperature and after repeated freeze-thaw cycles (less than three times). However, DNA from serum EVs after 2 days at room temperature or after five repeated freeze-thaw cycles could be used for PCR and sequencing. CONCLUSIONS: Serum EVs and EVs DNA can remain stable under different environments, which is the premise that EVs could serve as a novel means for genetic tumor detection and potential biomarkers for cancer diagnostics and prognostics.

Hair mercury concentrations and associated factors in an electronic waste recycling area, Guiyu, China.

OBJECTIVE: Toxic heavy metals are released to the environment constantly from unregulated electronic waste (e-waste) recycling in Guiyu, China, and thus may contribute to the elevation of mercury (Hg) and other heavy metals levels in human hair. We aimed to investigate concentrations of mercury in hair from Guiyu and potential risk factors and compared them with those from a control area where no e-waste processing occurs. METHODS: A total of 285 human hair samples were collected from three villages (including Beilin, Xianma, and Huamei) of Guiyu (n=205) and the control area, Jinping district of Shantou city (n=80). All the volunteers were administered a questionnaire regarding socio-demographic characteristics and other possible factors contributed to hair mercury concentration. Hair mercury concentration was analyzed by hydride generation atomic fluorescence spectrometry (AFS). RESULTS: Our results suggested that hair mercury concentrations in volunteers of Guiyu (median, 0.99; range, 0.18-3.98µg/g) were significantly higher than those of Jinping (median, 0.59; range, 0.12-1.63µg/g). We also observed a higher over-limit ratio (>1µg/g according to USEPA) in Guiyu than in Jinping (48.29% vs. 11.25%, P<0.001). Logistic regression model showed that the variables of living house also served as an e-waste workshop, work related to e-waste, family income, time of residence in Guiyu, the distance between home and waste incineration, and fish intake were associated with hair mercury concentration. After multiple stepwise regression analysis, in the Guiyu samples, hair mercury concentration was found positively associated with the time residence in Guiyu (ß=0.299, P<0.001), and frequency of shellfish intake (ß=0.184, P=0.016); and negatively associated with the distance between home and waste incineration (ß=-0.190, P=0.015) and whether house also served as e-waste workshop (ß=-0.278, P=0.001). CONCLUSIONS: This study investigated human mercury exposure and suggested elevated hair mercury concentrations in an e-waste recycling area, Guiyu, China. Living in Guiyu for a long time and work related to e-waste may primarily contribute to the high hair mercury concentrations.

In vitro and in vivo evaluation of chitosan/ß-glycerol phosphate composite membrane for guided bone regeneration.

Chitosan and ß-glycerol phosphate (CS/ß-GP) composite, with a thermosensitive sol-gel transition behavior, has been tested as one of the viable materials for barrier membrane fabrication. These studies have provided us with a new concept for a guided bone regeneration (GBR) membrane design. The composition, porous structure of the membrane, and the neutral mild preparation procedures make the CS/ß-GP membrane a potentially active guide for bone regeneration. In this study, the CS/ß-GP composite membrane, with different concentrations of ß-GP, was studied to assess their potential utility in GBR application. The initial attachment of the ST2 stromal cell line to the CS/ß-GP composite membrane was better than their attachment to the pure CS membrane. The proliferation and osteoblastic differentiation of the cells were much higher on the CS/ß-GP composite membrane as compared to the pure CS membrane (p < 0.05). A mild inflammatory response was observed around the implanted CS/ß-GP composite membrane without any foreign body reaction that continued up to 4 weeks of postsurgery. This primary study indicated that the in vitro and in vivo bioactivities of the CS/ß-GP composite membrane fulfilled the requirements for GBR technique.

Superior osteogenic capacity of different mesenchymal stem cells for bone tissue engineering.

OBJECTIVE: We evaluated the effect of human bone marrow stromal cells (hBMSCs), human adipose tissue-derived mesenchymal stem cells (hAD-MSCs), and umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in bone tissue engineering and identified a reliable cell source. STUDY DESIGN: Alkaline phosphatase (ALP) activity and quantitative polymerase chain reaction were used to evaluate osteogenic in vitro, X-ray and histologic analysis in vivo. RESULTS: hBMSCs exhibited strongest ALP staining, followed by hAD-MSCs and hUC-MSCs. At 7 days, hUC-MSCs and hAD-MSCs had higher expression of collagen type I and Runt-related transcription factor 2 than hBMSCs, and hUC-MSCs showed higher osteopontin expression. Bone structure was observed in the hUC-MSC group. Defects showed good healing in the hBMSC and hAD-MSC groups. Enhanced green fluorescent protein and osteopontin were detected in newly formed bone at 8 weeks. CONCLUSIONS: Our results suggested that hUC-MSCs and hAD-MSCs could be used for bone tissue engineering effectively; hUC-MSCs could serve as a new alternative cell source.