Determination of a novel photosensitizer sinoporphyrin sodium in human plasma by ultra-performance liquid chromatography-tandem mass spectrometry.

Sinoporphyrin sodium (DVDMS) is a new photosensitizer (PS) and it is used in photodynamic therapy (PDT) against tumor. In this paper, a simple, rapid and specific ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the quantitation of DVDMS in human plasma was developed. The analytes were extracted from plasma samples using liquid-liquid extraction (LLE) after addition of testosterone (internal standard) and chromatographed on an AQUITY UPLC Protein BEH C4 column (50 × 2.1 mm, i.d. 1.7 µm) thermostatted at 40 °C with acetonitrile-water (0.1% formic acid and 0.1 mM K2EDTA) as the gradient mobile phase at flow rate of 0.5 mL/min. The detection was performed on an API 5500 mass spectrometer coupled with electrospray ionization (ESI) source in positive mode. The multiple reactions monitoring (MRM) transitions of m/z 1143.6→563.2 and m/z 289.3→109.1 were used to quantify DVDMS and IS, respectively. The assay was validated over the concentration range of 30-3000 ng/mL. Precision and accuracy are in accordance with the generally accepted criteria for bioanalytical methods. The extraction recovery and the matrix effect were investigated. This method was successfully applied to pharmacokinetic (PK) study of DVDMS in Chinese patients with solid tumor after treated with DVDMS-PDT for the first time.

The Gut Microbiome Is Associated with Clinical Response to Anti-PD-1/PD-L1 Immunotherapy in Gastrointestinal Cancer.

We report on a comprehensive analysis of the gut microbiomes of patients with gastrointestinal (GI) cancer receiving anti-PD-1/PD-L1 treatment. The human gut microbiota has been associated with clinical responses to anti-PD-1/PD-L1 immunotherapy in melanoma, non-small cell lung cancer, and renal cell carcinoma. We aimed to investigate this association in GI cancers. We also identified bacterial taxa with patient stratification potential. We recruited 74 patients with advanced-stage GI cancer receiving anti-PD-1/PD-L1 treatment and collected their fecal samples prior to and during immunotherapy, along with clinical evaluations. Our 16S rRNA taxonomy survey on the fecal samples revealed an elevation of the Prevotella/Bacteroides ratio in patients, with a preferred response to anti-PD-1/PD-L1 treatment, and a particular subgroup of responders harboring a significantly higher abundance of Prevotella, Ruminococcaceae, and Lachnospiraceae The shotgun metagenomes of the same samples showed that patients exhibiting different responses had differential abundance of pathways related to nucleoside and nucleotide biosynthesis, lipid biosynthesis, sugar metabolism, and fermentation to short-chain fatty acids (SCFA). Gut bacteria that were capable of SCFA production, including Eubacterium, Lactobacillus, and Streptococcus, were positively associated with anti-PD-1/PD-L1 response across different GI cancer types. We further demonstrated that the identified bacterial taxa were predictive of patient stratification in both our cohort and melanoma patients from two previously published studies. Our results thus highlight the impact of gut microbiomes on anti-PD-1/PD-L1 outcomes, at least in a subset of patients with GI cancer, and suggest the potential of the microbiome as a marker for immune-checkpoint blockade responses.See articles by Tomita et al., p. 1236, and Hakozaki et al., p. 1243.

Development of an LC-MS/MS method for quantitative analysis of Chlorogenic acid in human plasma and its application to a pharmacokinetic study in Chinese patients with advanced solid tumor.

A simple and specific, rapid resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for determination of chlorogenic acid in human plasma using neochlorogenic acid as the internal standard. Plasma samples were precipitated with methanol and separated on a Zorbax C18 column (50 × 2.1 mm, i.d. 1.8 µm) at a flow rate of 0.4 mL/min using a gradient mobile phase of methanol-water containing 0.1% formic acid (v/v). The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring in negative ESI mode. The method was fully validated over the concentration range of 10-2000 ng/mL. The indicators of inter- and intra-day precision (RSD%) were all within 10.7%, and the accuracy (RE%) was ranged from -3.0% to 10.6%. Moreover, we evaluated this bioanalytical method by re-analysis of incurred samples as an additional measure of assay reproducibility. This method was successfully applied to pharmacokinetic study of CGA in Chinese subjects with advanced solid tumor after intramuscular injection administration of Chlorogenic acid for injection (CAFI).

MRI in predicting the response of gastrointestinal stromal tumor to targeted therapy: a patient-based multi-parameter study.

BACKGROUND: To investigate the performance of quantitative indicators of MRI in early prediction of the response of gastrointestinal stromal tumor (GIST) to targeted therapy in a patient-based study. METHODS: MRI examinations were performed on 62 patients with GIST using 1.5 T scanners before and at two and 12 weeks after treatment with targeted agents. The longest diameter (LD) and contrast-to-noise ratio (CNR) of the tumors were measured by T2-weighted imaging (T2WI), and the apparent diffusion coefficient (ADC) was determined using diffusion-weighted imaging (DWI). The pre-therapy and early percentage changes (%Δ) of the three parameters were compared with regard to their abilities to differentiate responder and non- responder patients, using ROC curves. RESULTS: There were 42 patients in responder and 20 in non-responder group. After two weeks of therapy, the percentage changes in the ADC and LD were significantly different between the two groups (ADC: responder 30% vs. non- responder 1%, Z = - 4.819, P < 0.001; LD: responder - 7% vs. non- responder - 2%, Z = - 3.238, P = 0.001), but not in T2WI-CNR (responder - 3% vs. non-responder 9%, Z = - 0.663, P = 0.508). The AUCs on ROC for %ΔLD, %ΔT2WI-CNR and %ΔADC after two weeks of therapy were 0.756, 0.552 and 0.881, respectively, for response differentiation. When %ΔADC ≥15% was used to predict responder, the PPV was 93.3%. CONCLUSIONS: The percentage change of the ADC after two weeks of therapy outperformed T2WI-CNR and longest diameter in predicting the early response of GIST to targeted therapy.

Sulfatinib, a novel kinase inhibitor, in patients with advanced solid tumors: results from a phase I study.

Sulfatinib is a small molecule kinase inhibitor that targets tumor angiogenesis and immune modulation. This phase I study (NCT02133157) investigated the safety, pharmacokinetic characteristics, and preliminary anti-tumor activity of sulfatinib in patients with advanced solid tumors. The study included a dose-escalation phase (50-350 mg/day, 28-day cycle) with a Fibonacci (3+3) design, and a tumor-specific expansion phase investigating the tumor response to treatment. Two sulfatinib formulations were assessed: formulation 1 (5, 25, and 50 mg capsules) and formulation 2 (50 and 200 mg capsules). Seventy-seven Chinese patients received oral sulfatinib; the maximum tolerated dose was not reached. Dose-limiting toxicities included abnormal hepatic function and coagulation tests, and upper gastrointestinal hemorrhage. The most common treatment-related adverse events were proteinuria, hypertension and diarrhea. Among 34 patients receiving sulfatinib formulation 2, one patient with hepatocellular carcinoma and eight with neuroendocrine tumors exhibited a partial response; 15 had stable disease. The objective response rate was 26.5% (9/34) and the disease control rate was 70.6% (24/34). Pharmacokinetic, safety, and efficacy data supported continuous oral administration of sulfatinib at 300 mg as the recommended phase II dose. Sulfatinib exhibited an acceptable safety profile and encouraging antitumor activity in patients with advanced solid tumors, particularly neuroendocrine tumors.

Weight loss correlates with macrophage inhibitory cytokine-1 expression and might influence outcome in patients with advanced esophageal squamous cell carcinoma.

BACKGROUND: Weight loss during chemotherapy has not been exclusively investigated. Macrophage inhibitory cytokine-1 (MIC-1) might play a role in its etiology. Here, we investigated the prognostic value of weight loss before chemotherapy and its relationship with MIC-1 concentration and its occurrence during chemotherapy in patients with advanced esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: We analyzed 157 inoperable locally advanced or metastatic ESCC patients receiving first-line chemotherapy. Serum MIC-1 concentrations were assessed before chemotherapy. Patients were assigned into two groups according to their weight loss before or during chemotherapy: >5% weight loss group and≤5% weight loss group. RESULTS: Patients with weight loss>5% before chemotherapy had shorter progression-free survival period (5.8 months vs. 8.7 months; p=0.027) and overall survival (10.8 months vs. 20.0 months; p=0.010). Patients with weight loss>5% during chemotherapy tended to have shorter progression-free survival (6.0 months vs. 8.1 months; p=0.062) and overall survival (8.6 months vs. 18.0 months; p=0.022), and if weight loss was reversed during chemotherapy, survival rates improved. Furthermore, serum MIC-1 concentration was closely related to weight loss before chemotherapy (p=0.001) CONCLUSIONS: Weight loss both before and during chemotherapy predicted poor outcome in advanced ESCC patients, and MIC-1 might be involved in the development of weight loss in such patients.

Retrospective analysis of adjuvant chemotherapy for curatively resected gastric cancer.

AIM: To determine the efficacy of adjuvant chemotherapy for gastric cancer in clinical practice, a retrospective analysis was conducted in a high-volume Chinese cancer center. METHODS: Between November 1995 and June 2007, a total of 423 gastric or esophagogastric adenocarcinoma patients who did (Arm A, n = 300) or did not (Arm S, n = 123) receive radical gastrectomy followed by postoperative chemotherapy were enrolled in this retrospective analysis. In Arm A, monotherapy(fluoropyrimidines, n = 25), doublet (platinum/fluoropyrimidines, n = 164), or triplet regimens [docetaxel/cisplatin/5FU (DCF), or modified DCF, epirubicin/cisplatin/5FU (ECF) or modified ECF, etoposide/cisplatin/FU, n = 111] were administered. Disease-free survival (DFS) and overall survival (OS) were compared between the two arms. A subgroup analysis was carried out in Arm A. A multivariate analysis of prognostic factors was conducted. RESULTS: Stage I, II and III cancers accounted for 9.7%, 35.7% and 54.6% of the cases, respectively, according to the American Joint Committee on Cancer (AJCC) staging system, 7(th) edition. Only 178 (42.1%) patients had more than 15 lymph nodes harvested. Hazard ratio estimates for Arm A compared with Arm S were 0.47 (P < 0.001) for OS and 0.59 (P < 0.001) for DFS. The 5-year OS rate was 52% in Arm A vs 36% in Arm S (P = 0.01); the adverse events in Arm A were mild and easily controlled. Ultimately, 73 patients (26.5%) who received doublet or triplet regimens switched to monotherapy with fluoropyrimidines. The OS and DFS did not differ between monotherapy and the combination regimens, however, both were statistically improved in the subgroup of patients who were switched to monotherapy with fluoropyrimidines after doublet or triplet regimens as well as patients who received ≥ 8 cycles of chemotherapy. CONCLUSION: In clinical practice, platinum/fluoropyrimidines with adequate treatment duration is recommended for stage II/III gastric cancer patients according to the 7(th) edition of the AJCC staging system after curative gastrectomy even with limited lymphadenectomy.

[Efficacy of albumin-bound paclitaxel in advanced gastric cancer patients].

OBJECTIVE: To evaluate the safety and efficacy of albumin-bound paclitaxel in patients with advanced gastric cancer (AGC). METHODS: The patients with histopathologic or cytopathologic diagnosed advanced gastric cancer (AGC), Karnofsky performance status ≥ 60, and life expectancy >12 weeks, and with adequate organ functions of the bone marrow, liver, kidney and heart were recuited in our study. albumin-bound paclitaxel was administered alone or combined with capecitabine, TS-1, trastuzumab or cetuxizumb. The total doses of albumin-bound paclitaxel were 200-400 mg (130-260 mg/m(2)), divided on days 1, 8 or days 1,8, and 15, given intravenously during 30 minutes of a 21-day cycle. Tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.0. The adverse events (AE) were graded according to National Cancer Institute-Common Toxicity Criteria (NCI-CTC) 3.0 version. RESULTS: From July 2009 to Octobor 2012, the total of 25 patients were treated and completed 65 cycles of chemotherapy (median: 2 cycles, and range: 0.5-7). The median age was 57 years (range: 38-79). The majority of the patients were with non-gastroesophageal junction cancers and had metastasic disease with lymph nodes and peritoneum. Eleven patients were chemotherapy naive and the others had accepted previous systemic therapy for advanced disease. 16 patients were evaluable for clinical response. No complete response was observed and partial response (PR) was achieved in 5 patients. Five patients had stable disease and 6 patients progressed. Among the chemotherapy naive patients, 8 patients were evaluable for response, 3 patients had partial response (37.5%) and 1 patient had stable disease (tumor shrink). The clinical response rate was 50%. Time to treatment failure (TTF)was 3.7 months(95% CI 2.32-5.08) and time to death (TTD)was 7.9 months (95% CI 5.17-10.63). No statistical differences in TTF and TTD were observed between the untreated and the retreated patients or the monotherapy and the combination therapy groups. All the patients were suitable for safety assessment. Most toxicities were mild with grades 1/2. Hematologic AEs were more common with leucopenia and neutropenia. Meanwhile, nausea/vomiting, fatigue, peripheral neuropathy were the most common non-hematologic AEs. No allergic reaction or treatment-related deaths were recorded. CONCLUSION: AGC patients could benefit from albumin-bound paclitaxel with lower dose level than breast cancer patients. Additional phase I/II studies of albumin-bound paclitaxel in gastric cancer are warranted.

Neutrophil count and the inflammation-based glasgow prognostic score predict survival in patients with advanced gastric cancer receiving first-line chemotherapy.

PURPOSE: To explore the value of systemic inflammatory markers as independent prognostic factors and the extent these markers improve prognostic classification for patients with inoperable advanced or metastatic gastric cancer (GC) receiving palliative chemotherapy. METHODS: We studied the prognostic value of systemic inflammatory factors such as circulating white blood cell count and its components as well as that combined to form inflammation-based prognostic scores (Glasgow Prognostic Score (GPS), Neutrophil-Lymphocyte Ratio (NLR), Platelet Lymphocyte Ratio (PLR), Prognostic Index (PI) and Prognostic Nutritional Index (PNI)) in 384 patients with inoperable advanced or metastatic gastric cancer (GC) receiving first-line chemotherapy. Univariate and multivariate analyses were performed to examine the impact of inflammatory markers on overall survival (OS). RESULTS: Univariate analysis revealed that an elevated white blood cell, neutrophil and/or platelet count, a decreased lymphocyte count, a low serum albumin concentration, and high CRP concentration, as well as elevated NLR/PLR , GPS, PI, PNI were significant predictors of shorter OS. Multivariate analysis demonstrated that only elevated neutrophil count (HR 3.696, p=0.003) and higher GPS (HR 1.621, p=0.01) were independent predictors of poor OS. CONCLUSION: This study demonstrated elevated pretreatment neutrophil count and high GPS to be independent predictors of shorter OS in inoperable advanced or metastatic GC patients treated with first-line chemotherapy. Upon validation of these data in independent studies, stratification of patients using these markers in future clinical trials is recommended.

A phase II study of triweekly paclitaxel and capecitabine combination therapy in patients with fluoropyrimidine-platinum-resistant metastatic gastric adenocarcinoma.

BACKGROUND: Although randomized trials have shown a survival benefit of second-line chemotherapy (SLC) in metastatic gastric adenocarcinoma (MGA), no standard regimen has yet been established. Paclitaxel acts synergistically with capecitabine. In this phase II study, we evaluated the efficacy and safety of paclitaxel/capecitabine (PX) as an SLC regimen for patients with fluoropyrimidine-resistant MGA. MATERIALS AND METHODS: Patients were eligible if the tumor progressed to fluoropyrimidine-based regimens or relapsed within 6 months after completion of therapy with adjuvant fluoropyrimidines. Treatment consisted of paclitaxel (80 mg/m 2 , days 1 and 8) and capecitabine (1000 mg/m 2 , bid, days 1-14), called PX, every 3 weeks. The primary endpoint was the objective response rate (ORR). Thirty-five patients were required according to the statistical design, and PX combination would be rejected if fewer than five patients responded. RESULTS: From November 2004 to May 2007, 36 eligible patients were enrolled. Among them, 35 (97.2%) had previously received platinum/fluoropyrimidine as first-line therapy. Response was assessed in 35 patients; 10 partial responses were obtained, resulting in an ORR of 28.5%. The median progression-free survival was 5.0 months, and the median overall survival was 11.1 months. The most frequent grade 3/4 toxicity was neutropenia, observed in 11.1% of the patients. CONCLUSIONS: PX regimen was clearly demonstrated to be active and safe for fluoropyrimidine-platinum-resistant MGA, and further evaluation in future phase III trials is warranted.

Efficacy of imatinib dose escalation in Chinese gastrointestinal stromal tumor patients.

AIM: To investigate the efficacy and safety of imatinib dose escalation in Chinese patients with advanced gastrointestinal stromal tumor (GIST). METHODS: Advanced GIST patients previously failing 400 mg imatinib treatment were enrolled in this study. Patients received imatinib with dose escalation to 600 mg/d, and further dose escalation to 800 mg/d if imatinib 600 mg/d failed. Progression-free survival, overall survival, clinical efficacy, c-kit/PDGFRA genotype and safety were evaluated. RESULTS: 52 patients were enrolled in this study. For the 47 evaluable patients receiving imatinib (600 mg/d), the disease control rate was 40.4%, and the median progression-free survival for all patients was 17 wk (95% CI: 3.9-30.1). The median overall survival after dose escalation was 81 wk (95% CI: 36.2-125.8). Adverse events, mainly edema, fatigue, granulocytopenia and skin rash were tolerable. However, further dose escalation (800 mg/d) in 14 cases was ineffective, with disease progression and severe adverse events. Among 30 cases examined for gene mutations, patients with exon 9 mutations experienced a better progression-free survival of 47 wk. CONCLUSION: Imatinib dose escalation to 600 mg/d is more appropriate for Chinese patients and may achieve further survival benefit.

[Meta-analyses of oxaliplatin-based chemotherapy versus cisplatin-based chemotherapy in advanced gastric cancer].

OBJECTIVE: To analyze whether Oxaliplatin (OXA) is effective in advanced gastric cancer. METHODS: Clinical trials of OXA-based chemotherapy (treatment group) versus DDP-based chemotherapy (control group) in advanced gastric cancer which published in 6 years were retrieved from China National Knowledge Infrastructure (CNKI), Wanfang Data, VIP information database and PubMed of U.S. National Library of Medicine and NIH. Review Manager 4.2 was used for meta-analysis and main outcome measure included objective response rate, survival and toxicities. RESULTS: There were 2121 patients (1062 cases in treatment group and 1059 cases in control group) from 16 controlled clinical trials were enrolled. Response rate increased (46.3% vs 40.6%, OR = 1.28, P = 0.006) and 1-year survival rate increased (44.6% vs 39.3%, OR = 1.25, P = 0.04) in treatment group than that of control group. Peripheral neurotoxicity was more frequently observed in treatment group (70.6% vs 21.9%, OR = 10.76, P < 0.01) while anemia and nausea/vomiting were reversed (58.0% vs 70.1%, 61.4% vs 75.6% respectively, both P < 0.05). CONCLUSION: Oxaliplatin-based chemotherapy is well-tolerated and more effective than cisplatin in advanced gastric cancer.

[Pilot study on the correlation between high incidence of CD44+/CD24 -/low/ABCG2- cells and poor prognosis in breast cancer].

OBJECTIVE: To explore whether the CD44+/CD24(-/low)/ABCG2(-) (ATP binding cassette superfamily G member 2) cells are associated with prognosis and clinical response in breast cancer patients. METHODS: We investigated the paraffin-embedded tissues of 43 breast cancer patients with (23 cases) and without (20 cases) recurrences. Double-staining immunohistochemistry (IHC) was applied for the detection of CD44+/CD24(-/low) cells and single-staining IHC for ABCG2. Flow cytometry was used to analyze the CD45(-)/CD44+/CD24(-/low)/ABCG2(-) cells in 4 mL peripheral blood of patients with metastasis breast cancer and 11 healthy female volunteers as controls. RESULTS: The positive rate of ABCG2 in recurrence-group was higher but with no difference compared with controls (78.3 % vs 60.0%, P = 0.32). Double-staining IHC revealed that the percentage of CD44(+)/CD24(-/low) cells was higher in recurrence-group than non-recurrence group(65.2% vs 35.0%, P = 0.048)and higher percentage of CD44+/CD24(-/low) cells was significant associated with poor overall survival(P = 0.031). Patients with higher percentage of CD44+/CD24(-/low) cells have shorter disease free survival (DFS), but have no statistical significance. Flow cytometry revealed that the CD45(-)/CD44+/CD24(- /low)/ABCG2(-) cells were higher in breast cancer patients than those of the volunteers (median 679/10(5) cells vs 12/10(5) cells). The cell number of this subset was affected by chemotherapy but was not statistically consistent with clinical response. CONCLUSION: Our study suggests that CD44+/CD24(-/low) breast cancer stem cells in tumor tissue may be associated with poor prognosis. The incidence of CD44+/CD24(-/low)/ABCG2(-) cells in peripheral blood is more frequent in breast cancer patients but further investigation should be made to explore the relationship of this subset and disease prognosis.

[Efficacy of gemcitabine-based chemotherapy on advanced pancreatic cancer].

BACKGROUND & OBJECTIVE: Advanced pancreatic cancer has a poor prognosis. Gemcitabine (GEM) can improve the quality of life of pancreatic cancer patients. However, the efficacy of gemcitabine-based combination chemotherapy is uncertain. This study was to compare the efficacy of GEM-based combination therapy and GEM alone on advanced pancreatic cancer. METHODS: Clinical data of 40 patients with pathologically or clinically diagnosed advanced pancreatic cancer were analyzed. Of the 40 patients, 15 were treated with GEM (1,000 mg/m(2)) alone weekly for 7 weeks followed by a 2-week rest, then received cycles of 3-week administration with 1-week rest; 25 were treated with GEM (1,000 mg/m(2)) weekly for 2 weeks plus 5-fluorouracil (5-FU) (425-600 mg/m(2)) as bolus at Day 1-5 or 120-hour infusion every 21 days, or cisplatin (DDP) (30-37.5 mg/m(2)) at Day 1-2 every 21 days, or oxaliplatin (85-130 mg/m(2)) at Day 1 every 21 days, or capecitabine (1,000 mg/m(2)) twice a day at Day 1-14 every 21 days, respectively. The survival was analyzed by Kaplan-Meier method. Median time to progression (mTTP), clinical benefit response (CBR), disease control rate, median overall survival (mOS) and toxicity were assessed according to World Health Organization criteria. RESULTS: The rate of CBR was 56.0% in GEM-combination group and 46.7% in GEM alone group. There were no significant differences in disease control rate, mOS, CBR, and adverse events between the two groups (all P>0.05). However, for the patients with stage III-IV advanced pancreatic cancer, the disease control rate was higher in GEM-combination group than in GEM alone group (75.0% vs. 45.5%, P=0.13). CONCLUSION: GEM-combination regimens and GEM alone have similar efficacy, and lead to similar clinical benefit response and mOS for the patients with advanced pancreatic cancer.