Pembrolizumab Versus Placebo as Second-Line Therapy in Patients From Asia With Advanced Hepatocellular Carcinoma: A Randomized, Double-Blind, Phase III Trial.

PURPOSE: We evaluated the efficacy and safety of pembrolizumab in patients from Asia with previously treated advanced hepatocellular carcinoma (HCC). METHODS: In a double-blind, phase III trial, 453 patients with advanced HCC and progression during or after treatment with or intolerance to sorafenib or oxaliplatin-based chemotherapy were randomly assigned in a 2:1 ratio to receive pembrolizumab (200 mg) or placebo once every 3 weeks for ≤ 35 cycles plus best supportive care. The primary end point was overall survival (one-sided significance threshold, P = .0193 [final analysis]). Secondary end points included progression-free survival (PFS) and objective response rate (ORR; one-sided significance threshold, P = .0134 and .0091, respectively [second interim analysis]; RECIST version 1.1, by blinded independent central review). RESULTS: Median overall survival was longer in the pembrolizumab group than in the placebo group (14.6 v 13.0 months; hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P = .0180). Median PFS was also longer in the pembrolizumab group than in the placebo group (2.6 v 2.3 months; hazard ratio for progression or death, 0.74; 95% CI, 0.60 to 0.92; P = .0032). ORR was greater in the pembrolizumab group (12.7% [95% CI, 9.1 to 17.0]) than in the placebo group (1.3% [95% CI, 0.2 to 4.6]; P < .0001). Treatment-related adverse events occurred in 66.9% of patients (grade 3, 12.0%; grade 4, 1.3%; grade 5, 1.0%) in the pembrolizumab group and 49.7% of patients (grade 3, 5.9%; grade 4, 0%; grade 5, 0%) in the placebo group. CONCLUSION: In patients from Asia with previously treated advanced HCC, pembrolizumab significantly prolonged overall survival and PFS, and ORR was greater versus placebo.

Clinical and biomarker analyses of sintilimab versus chemotherapy as second-line therapy for advanced or metastatic esophageal squamous cell carcinoma: a randomized, open-label phase 2 study (ORIENT-2).

This randomized, open-label, multi-center phase 2 study (NCT03116152) assessed sintilimab, a PD-1 inhibitor, versus chemotherapy in patients with esophageal squamous cell carcinoma after first-line chemotherapy. The primary endpoint was overall survival (OS), while exploratory endpoint was the association of biomarkers with efficacy. The median OS in the sintilimab group was significantly improved compared with the chemotherapy group (median OS 7.2 vs.6.2 months; P = 0.032; HR = 0.70; 95% CI, 0.50-0.97). Incidence of treatment-related adverse events of grade 3-5 was lower with sintilimab than with chemotherapy (20.2 vs. 39.1%). Patients with high T-cell receptor (TCR) clonality and low molecular tumor burden index (mTBI) showed the longest median OS (15.0 months). Patients with NLR < 3 at 6 weeks post-treatment had a significantly prolonged median OS (16.6 months) compared with NLR ≥ 3. The results demonstrate a significant improvement in OS of sintilimab compared to chemotherapy as second-line treatment for advanced or metastatic ESCC.

Camrelizumab Combined with Chemotherapy Followed by Camrelizumab plus Apatinib as First-line Therapy for Advanced Gastric or Gastroesophageal Junction Adenocarcinoma.

PURPOSE: Capecitabine plus oxaliplatin (CAPOX) is one of the standard first-line treatments for unresectable, advanced, or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. Camrelizumab shows promising antitumor activity in advanced or metastatic G/GEJ adenocarcinoma in a phase I study. We reported the outcomes of cohort 1 in a multicenter, open-label, phase II trial, which assessed camrelizumab in combination with CAPOX followed by camrelizumab plus apatinib as a first-line combination regimen for advanced or metastatic G/GEJ adenocarcinoma. PATIENTS AND METHODS: Systemic treatment-naïve patients with EGFR2-negative advanced or metastatic G/GEJ adenocarcinoma received initial camrelizumab plus CAPOX for 4-6 cycles, and patients without progressive disease were administrated subsequent camrelizumab plus apatinib. Primary endpoint was objective response rate (ORR). RESULTS: All 48 enrolled patients comprised the efficacy and safety analysis population. The ORR was 58.3% [95% confidence interval (CI), 43.2-72.4] with this combination regimen. Median duration of response was 5.7 months (95% CI, 4.4-8.3). Median overall survival was 14.9 months (95% CI, 13.0-18.6), and median progression-free survival was 6.8 months (95% CI, 5.6-9.5), respectively. The most common grade ≥3 treatment-related adverse events (>10%) were decreased platelet count (20.8%), decreased neutrophil count (18.8%), and hypertension (14.6%). Treatment-related death occurred in 1 patient (2.1%) due to abnormal hepatic function and interstitial lung disease. CONCLUSIONS: Camrelizumab combined with CAPOX followed by camrelizumab plus apatinib demonstrated encouraging antitumor activity and manageable toxicity as first-line therapy for patients with advanced or metastatic G/GEJ adenocarcinoma.

The relationship between treatment-induced hypertension and efficacy of anlotinib in recurrent or metastatic esophageal squamous cell carcinoma.

OBJECTIVE: In this post-hoc analysis, we evaluated anlotinib treatment-induced hypertension as a potential predictive factor of efficacy in esophageal squamous cell carcinoma (ESCC) patients. METHODS: A total of 109 patients enrolled in the anlotinib group in a phase 2 trial were included. The tumor response was assessed by computed tomography at week 3, week 6, and then every 6 weeks until progressive disease was observed. The primary endpoint of the study was progression free survival (PFS). The secondary endpoints included overall survival (OS) and objective response rate (ORR). RESULTS: In all patients, the median PFS was 3.02 months [95% confidence interval (CI): 2.63-3.65 months] and the OS was 6.11 months (95% CI: 4.40-7.79 months). The ORR was 7.34% (95% CI: 3.22%-13.95%). A total of 59 (54%) patients were diagnosed with treatment-induced hypertension (Group A), and the remaining patients (n = 50, 46%) were in Group B. Baseline prognostic factors were similar between the 2 groups. Patients in Group A had a longer PFS and OS and higher ORR. When stratifying patients using a previously known history of hypertension, treatment-induced hypertension was a predictor only for patients without previous hypertension, who had longer PFS [hazard ratio (HR): 0.40, 95% CI: 0.24-0.68] and OS (HR: 0.37, 95% CI: 0.21-0.67). CONCLUSIONS: We showed, for the first time, a correlation between treatment-induced hypertension and better prognoses in recurrent or metastatic ESCC patients treated with anlotinib, without a previously known history of hypertension. Treatment-induced hypertension may be a simple and low cost predictor for anlotinib antitumor efficacy in these patients, which may also reflect the intended target inhibition.

Anlotinib for previously treated advanced or metastatic esophageal squamous cell carcinoma: A double-blind randomized phase 2 trial.

BACKGROUND: Currently, there are no randomized trials on the effect of antiangiogenic therapy in patients with esophageal squamous cell carcinoma (ESCC). The following study investigated the efficacy and safety of anlotinib in patients with advanced ESCC who were previously treated with chemotherapy. METHODS: This randomized, placebo-controlled, double-blind phase 2 trial (NCT02649361) was conducted in 13 Chinese hospitals. Eligible patients were adults with histologically confirmed recurrent or metastatic ESCC who were previously treated with chemotherapy, and were randomly assigned (2:1) to receive oral anlotinib 12 mg or placebo on days 1-14 (repeated every 21 days). The primary endpoint was progression-free survival (PFS). RESULTS: One hundred and sixty-five patients were randomly assigned to the anlotinib (n = 110) or the placebo (n = 55) arm. Median PFS was 3.02 months (95% CI 2.63-3.65) in the anlotinib group and 1.41 months (95% CI 1.38-1.41) in the placebo group (hazard ratio 0.46 [95% CI 0.32-0.66]; p < 0.001). The most common treatment-related adverse events of grade 3 or 4 were hypertension (17 [16%] patients), decreased appetite (6 [6%] patients), and hyponatremia (4 [4%] patients) in the anlotinib group and decreased appetite (2 [4%] patients) in the placebo group. Three (3%) deaths in the anlotinib group were considered as drug related, while there were no treatment-related deaths in the placebo group. CONCLUSIONS: The use of anlotinib in previously treated, recurrent, or metastatic ESCC patients significantly improved PFS compared with placebo. Our findings suggest that antiangiogenesis might be an important therapeutic target in advanced ESCC. CLINICAL TRIALS REGISTRATION: Study of Anlotinib in Patients With Esophageal Squamous Cell Carcinoma (ALTER1102), NCT02649361.

Growth of MCF-7 breast cancer cells and efficacy of anti-angiogenic agents in a hydroxyethyl chitosan/glycidyl methacrylate hydrogel.

BACKGROUND: Breast cancer negatively affects women's health worldwide. The tumour microenvironment plays a critical role in tumour initiation, proliferation, and metastasis. Cancer cells are traditionally grown in two-dimensional (2D) cultures as monolayers on a flat solid surface lacking cell-cell and cell-matrix interactions. These experimental conditions deviate from the clinical situation. Improved experimental systems that can mimic the in vivo situation are required to discover new therapies, particularly for anti-angiogenic agents that mainly target intercellular factors and play an essential role in treating some cancers. METHODS: Chitosan can be modified to construct three-dimensional (3D) tumour models. Here, we report an in vitro 3D tumour model using a hydroxyethyl chitosan/glycidyl methacrylate (HECS-GMA) hydrogel produced by a series of chitosan modifications. Parameters relating to cell morphology, viability, proliferation, and migration were analysed using breast cancer MCF-7 cells. In a xenograft model, secretion of angiogenesis-related growth factors and the anti-angiogenic efficacy of Endostar and Bevacizumab in cells grown in HECS-GMA hydrogels were assessed by immunohistochemistry. RESULTS: Hydroxyethyl chitosan/glycidyl methacrylate hydrogels had a highly porous microstructure, mechanical properties, swelling ratio, and morphology consistent with a 3D tumour model. Compared with a 2D monolayer culture, breast cancer MCF-7 cells residing in the HECS-GMA hydrogels grew as tumour-like clusters in a 3D formation. In a xenograft model, MCF-7 cells cultured in the HECS-GMA hydrogels had increased secretion of angiogenesis-related growth factors. Recombinant human endostatin (Endostar), but not Bevacizumab (Avastin), was an effective anti-angiogenic agent in HECS-GMA hydrogels. CONCLUSIONS: The HECS-GMA hydrogel provided a 3D tumour model that mimicked the in vivo cancer microenvironment and supported the growth of MCF7 cells better than traditional tissue culture plates. The HECS-GMA hydrogel may offer an improved platform to minimize the gap between traditional tissue culture plates and clinical applicability. In addition, the anti-angiogenic efficacy of drugs such as Endostar and Bevacizumab can be more comprehensively studied and assessed in HECS-GMA hydrogels.

Selective colorectal cancer cell lysates enhance the immune function of mature dendritic cells in vitro.

The aim of the present study was to determine the most effective antigen with which to mature dendritic cells (DCs). The immune function of DCs loaded with lysates from three different colorectal cancer cell lines was compared. DCs were induced using granulocyte macrophage colony­stimulating factor, interleukin (IL)­4 and tumor necrosis factor-α from the peripheral blood mononuclear cells of patients with colorectal cancer, and loaded with lysates from Colo320, SW480 and SW620 colorectal cancer cell lines, respectively. Autogenous T cells were co­cultured with mature DCs. Surface markers and the secretory function of mature DCs and stimulated T cells were then analyzed. MTT assays were used to evaluate the killing capacity of autogenous cytotoxic T lymphocytes (CTLs). Compared with control, cluster of differentiation (CD)1a, CD83 and CD86, and human leukocyte antigen­DR expression levels were significantly higher in DCs matured using cancer cell lysates. In addition, IL­12 secretion levels were elevated. Autogenous T cells stimulated with DCs that were matured using cancer cell lysates showed a higher proliferation capacity, increased interferon-γ secretion levels and stronger cytotoxic abilities compared with control cells. Among the three cell lines, SW480 lysates were most effective at promoting DC and T cell function. The results showed that SW480 lysates are more efficient than Colo320 and SW620 lysates in inducing DC immune function and activating the antitumor function of autogenous T cells.

[Effect of nursing intervention on improving quality of life of patients with advanced schistosomiasis].

OBJECTIVE: To evaluate the effect of nursing intervention on the quality of life of patients with advanced schistosomiasis. METHODS: A total of 226 cases of advanced schistosomiasis were randomly divided into a control group and an experimental group (113 cases each). The patients in the control group received the conventional nursing, while the patients in the experimental group received the conventional nursing plus other interventions such as the health education, psychological counseling and diet guidance. The complications and scores of life quality of the patients in the 2 groups were observed and compared. RESULTS: The awareness of knowledge about the disease improved from 67.7% to 98.9%, the incidence of complications decreased from 28.3% to 13.3%, and the scores of life quality improved significantly in the experimental group, which were much better than those in the control group. CONCLUSION: The nursing intervention on the quality of life of patients with advanced schistosomiasis is effective.

[Role of oxidative stress and thioredoxin in gastric cancer].

OBJECTIVE: To explore the role of oxidative stress and the antioxidant protein thioredoxin in the tumorigenesis and progression of gastric cancer. METHODS: The plasma levels of adenosine deaminase (ADA), glutathione peroxidase (GPX), superoxide dismutase (SOD), and advanced oxidation protein products (AOPP) were determined by colorimetry, and the plasma levels of thioredoxin were determined by enzyme-linked immunosorbent assay (ELISA) in 48 gastric cancer patients and 30 healthy subjects. RT-PCR assay was employed to examine the expression levels of thioredoxin mRNA in the tissue samples of the patients. RESULTS: Compared with the healthy controls, patients with gastric cancer had significantly increased plasma levels of ADA and AOPP (P<0.05), decreased plasma GPX level (P<0.05), and similar plasma SOD levels. The plasma levels of thioredoxin were significantly higher in patients with gastric cancer than in the healthy controls (P<0.05). Thioredoxin levels was not associated with gender, age, degree of tumor cell differentiation, invasion depth, or lymph node metastasis (P>0.05), but was correlated to distant tumor metastasis (P<0.05). The expression of Trx mRNA was significantly higher in gastric carcinoma than in normal gastric tissue (P<0.05). CONCLUSION: Gastric cancer patients have high levels of oxidative stress and thioredoxin expression, and the latter is related to distant metastasis of the tumor.

[A pilot study of weekly versus 3-week docetaxel in combination with capecitabine in patients with anthracycline-pretreated metastatic breast cancer].

OBJECTIVE: To evaluate the efficacy and safety of weekly or 3-week docetaxel in combination with capecitabine. METHODS: 83 Patients with at least one measurable lesion were randomized to receive the treatment arms: docetaxel 37.5 mg/m(2) on days 1 and 8, oral capecitabine 950 mg/m(2) twice daily on days 1-14 (Group A); docetaxel 75 mg/m(2) on days 1, oral capecitabine 950 mg/m(2) twice daily on days 1-14 (Group B). Each cycle was repeated every 3 weeks. RESULTS: Eighty-three patients were enrolled, 78 eligible for tumor assessment. The overall clinical response rate of all groups was 61.4% (51/83). There was no progressive disease (PD) after two cycles. Efficacy outcomes were similar in the two groups. The response rate of group A and B were 61.8% (21/34) and 61.2% (30/49) respectively. There were no drug-related deaths observed. Neutropenia was the most common toxicity. In all, the frequency of Grade 3/4 neutropenia were 45.8% (38/83), but Grade 3/4 neutropenia of Group B 55.1% (27/49) was higher than Group A 32.4% (11/34), P = 0.04. CONCLUSION: The study confirmed the superior activity of docetaxe-capecitabine combination therapy in anthracycline resistant MBC, and comparing with 3-week schedule, weekly docetaxel plus capecitabine has same high efficacy with a favourable safety profile.

hSSTR2 expression and octreotide treatment reverses multidrug resistance of BxPC-3 human pancreatic cancer cells.

Pancreatic cancer is generally refractory to most chemotherapeutic agents. We investigated whether hSSTR2 expression and octreotide treatment reverse multidrug resistance of human pancreatic cancer cells. We used pancreatic cancer cells that were transfected by using a lentivirus expression system, which allowed stable expression of the hSSTR2 gene in the pancreatic cancer cells. BxPC-3 cells were transfected with hSSTR2 through a lentivirus vector pWP XL-MOD-SSTR2 in order to enable the expression of hSSTR2. The transfected cells were treated with different concentrations of octreotide and with the chemotherapeutic agents cisplatin, epirubicin, fluorouracil and gemcitabine. The changes in IC50 following treatment with chemotherapeutic agents were determined, and the expression of different MDR indicating marker genes, multidrug resistance gene-1 (MDR1), multidrug resistance-associated protein 2 (MRP2), and lung resistance-related protein (LRP), were evaluated. Octreotide treatment of the transfected cells significantly decreased the IC50 of chemotherapeutic agents in a dose-dependent manner. hSSTR2 gene transfection decreased MDR1, MRP2 and LRP expression by 57, 47 and 56%, respectively (P<0.01), and octreotide treatment (1.6 microg/ml) for 48 h, decreased it further by 88, 73 and 87<, respectively (P<0.01). These data suggested that the down-regulation of MDR genes is responsible for the improvement in the chemotherapeutic sensitivity of hSSTR2-expressing pancreatic cancer cells, when these cells are subjected to octreotide treatment.

[Immunopotentiation of novel adjuvant SWZY on the poorly immunogenic murine melanoma vaccine].

AIM: To evaluate the immunopotentiation of novel adjuvant SWZY on the cancer vaccine of poorly immunogenic melanoma. METHODS: C57BL/6 mice immunized with inactivated D5 melanoma cells were divided into 6 groups: the control without adjuvants, with FCA, FCA+IL-2+GM-CSF, FIA+IL-2+GM-CSF, FIA+SWZY, and FIA+SWZY+IL-2+GM-CSF. Three days after completion of immunization, DTH response, specific killing activity of splenocytes and the level of IFN-gamma and IL-10 in serum and splenocytes' culture supernatant were assayed in half of the mice in each group. The rest were subject to live D5 tumor cell challenge. Three weeks after tumor inoculation, the same immunological parameters were measured. RESULTS: DTH response, splenocytes' killing activity of all the experimental groups were markedly higher than those in the control group (P<0.05), but decreased as the tumor grew larger. The level of IFN-gamma in serum or splenocyte culture supernatant of each experimental group was significantly higher than that of the control (P<0.05) before tumor formation, whereas IL-10 level was lower than that of the control (P<0.05). After tumor formation, the level of IFN-gamma in all groups decreased while that of IL-10 increased in general, but the levels of IFN-gamma and IL-10 in group FCA and FIA+SWZY didn't change very much. CONCLUSION: All kinds of adjuvants can enhance the cell-mediated immune response against poorly immunogenic tumor to some extent. The novel adjuvant SWZY can strengthen immunoresponses similar to FCA. With few harmful side-effect, SWZY might be a promising adjuvant for cancer vaccine.

[Expression of dihydropyrimidine dehydrogenase in human colorectal carcinoma and its clinical implications].

OBJECTIVE: The study was to explore the dihydropyrimidine dehydrogenase (DPD) expression level in human colorectal carcinoma and its clinical implications. METHODS: Fifty-three patients with colorectal carcinoma were detected by immunohistochemical stain. These patients had undergone radical surgical treatment in the First Hospital of Xi'an Jiaotong University and had been followed up for 5 years after the operation. cases Twenty-two had received 5-fluorouracil-based adjuvant chemotherapy. RESULTS: DPD expression was predominantly observed in the cytoplasm of the tumor cells, and also partly in the nucleus. The positive rate of DPD expression was 73.58% (39/53). DPD expression in patients with different histopathology was obviously different (P < 0.05). There was no significant correlation between the expression of DPD and the efficacy of chemotherapy. By Kaplan-Meier methods, the survival patients with of negative DPD expression was longer than those with positive DPD expression, and then five-year survival rates were 12.97% and 42.86%, respectively (P < 0.05). The prognosis of patients with positive DPD expression was significantly poorer outcome than that of patients with negative DPD expression. CONCLUSION: These findings suggest that DPD expression might be one of the important prognostic parameters for colorectal cancer patients.

B7 molecule mRNA expression in colorectal carcinoma.

AIM: To observe the status of tumor-associated B(7) molecule mRNA expression in human colorectal cancer tissue by in situ hybridization. METHODS: The mRNA expression patterns of cancer-associated B(7-1),B(7)H(1),B(7)H(2),ICOS in 22 specimens of human colorectal cancer tissue were monitored by in situ hybridization (ISH) with digoxin-labeled oligonucleotide probes. RESULTS: B(7-1),B(7)H(1),B(7)H(2),ICOS mRNA were detected in both cancer cells and tumor infiltrating lymphocytes (TIL). The mRNA expression level of these molecules in tumor cells was higher than that in TIL (0.76+/-0.54 - 1.62+/-0.82 vs 0.38+/-0.19 - 0.65+/-0.33, P<0.001). There was no relationship between expression level of tested B(7) family molecules and patients' sex, age, differentiation status of cancer and regional lymph node metastasis. CONCLUSION: Th2 cytokine predominant in tumor microenvironment might be related to the expression of B(7)H(1),B(7)H(2) co-signal molecules in tumor cells and TIL.

[Expression of thymidine phosphorylase in human colorectal carcinoma and its clinical significance].

BACKGROUND & OBJECTIVE: Angiogenesis has been well known to be a factor related to the tumor growth and metastasis. Recent studies have reported that thymidine phosphorylase (TP) is identical with platelet-derived endothelial cell growth factor. It not only plays a role in the induction of the tumor angiogenesis, but also enhances the chemotherapeutical sensitivity of the tumor cells to prodrug of 5-fluorouracil. However, until now, the complete identity of view about the function of TP expression in colorectal carcinoma and its prognostic significance has not been reached. The present study was to explore the TP expression level in human colorectal carcinoma and its clinical significance. METHODS: Seventy archived samples of the patients with colorectal carcinoma were detected by immunohistochemical staining. These patients had undergone radical surgical treatment at the First Hospital of Xi'an Jiaotong University and had been followed up for 5 years after operation. RESULTS: TP expression was predominantly observed in the cytoplasm of the tumor cells. The positive rate was 57.14%(40/70). TP expression levels in the patients with different Dukes, stages and histopathological grades showed obvious difference (P=0.007 and 0.002, respectively). By Kaplan-Meier methods, the survival of TP positive expression group was shorter than that of TP negative expression group, and the five-year survival rates of TP positive expression group and TP negative expression group were 33.33% and 73.33% (P=0.000). The results indicated that the prognosis of the patients with TP positive expression was poorer than that of patients with TP negative expression. CONCLUSION: These findings suggest that TP expression might be one of the important prognostic indicators for colorectal carcinoma patients, and TP detection in colorectal carcinoma patients might served as a parameter for designing therapeutic schedule and choosing prodrug of 5-fluorouracil.