Targeted therapy for intractable cancer on the basis of molecular profiles: An open-label, phase II basket trial (Long March Pathway).

Purpose: We evaluated he effects of molecular guided-targeted therapy for intractable cancer. Also, the epidemiology of druggable gene alterations in Chinese population was investigated. Materials and methods: The Long March Pathway (ClinicalTrials.gov identifier: NCT03239015) is a non-randomized, open-label, phase II trial consisting of several basket studies examining the molecular profiles of intractable cancers in the Chinese population. The trial aimed to 1) evaluate the efficacy of targeted therapy for intractable cancer and 2) identify the molecular epidemiology of the tier II gene alterations among Chinese pan-cancer patients. Results: In the first stage, molecular profiles of 520 intractable pan-cancer patients were identified, and 115 patients were identified to have tier II gene alterations. Then, 27 of these 115 patients received targeted therapy based on molecular profiles. The overall response rate (ORR) was 29.6% (8/27), and the disease control rate (DCR) was 44.4% (12/27). The median duration of response (DOR) was 4.80 months (95% CI, 3.33-27.2), and median progression-free survival (PFS) was 4.67 months (95% CI, 2.33-9.50). In the second stage, molecular epidemiology of 17,841 Chinese pan-cancer patients demonstrated that the frequency of tier II gene alterations across cancer types is 17.7%. Bladder cancer had the most tier-II alterations (26.1%), followed by breast cancer (22.4%), and non-small cell lung cancer (NSCLC; 20.2%). Conclusion: The Long March Pathway trial demonstrated a significant clinical benefit for intractable cancer from molecular-guided targeted therapy in the Chinese population. The frequency of tier II gene alterations across cancer types supports the feasibility of molecular-guided targeted therapy under basket trials.

Durable Clinical Response to ALK Tyrosine Kinase Inhibitors in Epithelioid Inflammatory Myofibroblastic Sarcoma Harboring PRRC2B-ALK Rearrangement: A Case Report.

Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm and patients with IMT tend to have a favorable outcome after complete surgical resection. However, some tumors of IMT cases have recurred and grown rapidly after successful surgery. Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a highly aggressive intra-abdominal IMT variant with epithelioid-to-round cell morphology. Currently, no standard therapy exists for recurrent or invasive IMTs and EIMS, but anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are recommended for those harboring ALK gene rearrangements. We herein report the first case of PRRC2B-ALK fusion associated IMTs with clinical and pathological manifestation matched the diagnosis criteria of EIMS and the durable clinical response of the sequential use of ALK TKIs (crizotinib, alectinib, ceritinib, and lorlatinib). A female patient with EIMS of the greater omentum was suffering from a rapid recurrence after cytoreductive surgery was done. Crizotinib was administered when PRRC2B-ALK fusion was detected, and partial response was achieved. The progression-free survival (PFS) of crizotinib was 5 months. Alectinib was administered based on the results of second next-generation sequencing (NGS) analysis, which identified the secondary mutation ALK R1192P. The best overall response of alectinib treatment was a partial response (PR) and the PFS was 5.5 months. Ceritinib was prescribed as third-line therapy after alectinib resistance with ALK L1196M mutation. PR was achieved and the PFS of ceritinib was 6 months. The patient was taking lorlatinib after ceritinib resistance and achieved a stable disease at 2 months with the PFS more than 5 months. The overall survival was more than two years as of the time of manuscript preparation. We describe an EIMS of greater omentum caused by PRRC2B-ALK fusion gene and showed durable clinical response to the sequential use of ALK TKIs.

Cetuximab and vemurafenib plus FOLFIRI (5-fluorouracil/leucovorin/irinotecan) for BRAF V600E-mutated advanced colorectal cancer (IMPROVEMENT): An open-label, single-arm, phase II trial.

BACKGROUND: Current therapeutic regimens for patients with v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E-mutated colorectal cancer show unsatisfactory efficacy. To improve outcomes in this area, we assessed the safety and efficacy of a new protocol using vemurafenib and cetuximab combined with FOLFIRI (5-fluorouracil/leucovorin/irinotecan) in patients with BRAF V600E-mutated colorectal cancer. METHODS AND MATERIALS: This was an investigator-initiated, open-label, single-arm, phase II trial conducted in patients with BRAF V600E-mutated advanced colorectal cancer. Patients were eligible to receive FOLFIRI combined with vemurafenib and cetuximab. The primary end-point was the objective response rate, and the secondary end-points included disease control rate, progression-free survival, overall survival and safety. This trial is registered with ClinicalTrials.gov, NCT03727763. RESULTS: Between 12th January 2018, and 18th June 2021, we screened 27 patients, 21 of which were enrolled in this study. Efficacy analysis showed that objective response rates were 81.0% (17/21; 95% confidence interval [CI] 57.4-93.7) in the intention-to-treat population and 85.0% (17/20, 95%CI 61.0-96.0) in the per-protocol population; two patients achieved complete response, and 15 patients achieved a partial response. In the entire cohort, the median progression-free survival was 9.7 months (95%CI 6.3-10.9), and the median overall survival for all patients was 15.4 months (95%CI 8.5-15.4). The most common adverse events (grade 3 to 4) were neutropenia (8/21), anaemia (3/21) and skin rash (3/21). CONCLUSION: Vemurafenib and cetuximab can be safely combined with the FOLFIRI regimen, showing promising antitumour activity and tolerable toxicity in patients with BRAF V600E-mutated advanced colorectal cancer. This regimen warrants a further randomised study in phase III clinical trials.

Mechanism of Fuzheng Kang'ai Formula Regulating Tumor Microenvironment in Non-Small Cell Lung Cancer.

OBJECTIVE: To study the mechanism of Chinese herbal medicine Fuzheng Kang'ai Formula (, FZKA) on tumor microenvironment (TME). METHODS: CIBERSORTx was used for analysis of TME. Traditional Chinese Medicine Systems Pharmacology and Analysis Platform was applied to identify compounds-targets network and the Cancer Genome Atlas (TCGA) was employed to identify the differential expression genes (DEGs) between tumor and paracancerous tissues in lung adenocarcinoma (LUAD) from TCGA-LUAD. Additionally, DEGs with prognosis in LUAD was calculated by univariable and multivariate Cox regression. The core targets of FZKA were analyzed in lung adenocarcinoma TME. Protein-protein interaction database was employed to predict down-stream of target. Quantitative reverse transcription polymerase chain reaction was employed for biological experiment in A549, H1299 and PC9 cell lines. RESULTS: The active and resting mast cells were significantly associated with prognosis of LUAD (P<0.05). Of the targets, CCNA2 as an important target of FZKA (hazard ratio=1.41, 95% confidential interval: 1.01-2.01, P<0.05) was a prognostic target and significantly associated with mast cells. CCNA2 was positively correlated with mast cell activation and negatively correlated with mast cell resting state. BCL1L2, ACTL6A and ITGAV were down-stream of CCNA2, which were validated by qRT-PCR in A549 cell. CONCLUSION: FZKA could directly bind to CCNA2 and inhibit tumor growth by regulating CCNA2 downstream genes and TME of NSCLC closely related to CCNA2.

Aerobic Exercise Attenuates Pressure Overload-Induced Cardiac Dysfunction through Promoting Skeletal Muscle Microcirculation and Increasing Muscle Mass.

BACKGROUND: Aerobic exercise has been proven to have a positive effect on cardiac function after hypertension; however, the mechanism is not entirely clarified. Skeletal muscle mass and microcirculation are closely associated with blood pressure and cardiac function. OBJECTIVE: This study was designed to investigate the effects of aerobic exercise on the skeletal muscle capillary and muscle mass, to explore the possible mechanisms involved in exercise-induced mitigation of cardiac dysfunction in pressure overload mice. METHODS: In this study, 60 BALB/C mice aged 8 weeks were randomly divided into 3 groups: control (CON), TAC, and TAC plus exercise (TAE) group and utilized transverse aortic constriction (TAC) to establish hypertensive model; meanwhile, treadmill training is used for aerobic exercise. After 5 days of recovery, mice in the TAE group were subjected to 10-week aerobic exercise. Carotid pressure and cardiac function were examined before mice were executed by Millar catheter and ultrasound, respectively. Muscle mass of gastrocnemius was weighed; cross-sectional area and the number of capillaries of gastrocnemius were detected by HE and immunohistochemistry, respectively. The mRNA and protein levels of VEGF in skeletal muscle were determined by RT-PCR and western blot, respectively. RESULTS: We found that ① 10-week aerobic exercise counteracted hypertension and attenuated cardiac dysfunction in TAC-induced hypertensive mice; ② TAC decreased muscle mass of gastrocnemius and resulted in muscle atrophy, while 10-week aerobic exercise could reserve transverse aortic constriction-induced the decline of muscle mass and muscle atrophy; and ③ TAC reduced the number of capillaries and the protein level of VEGF in gastrocnemius, whereas 10-week aerobic exercise augmented the number of capillaries, the mRNA and protein levels of VEGF in mice were subjected to TAC surgery. CONCLUSIONS: This study indicates that 10-week aerobic exercise might fulfill its blood pressure-lowering effect via improving skeletal muscle microcirculation and increasing muscle mass.

The effectiveness of afatinib and osimertinib in a Chinese patient with advanced lung adenocarcinoma harboring a rare triple EGFR mutation (R670W/H835L/L833V): a case report and literature review.

In patients without tissue availability at presentation, the analysis of cell-free DNA derived from liquid biopsy samples, in particular from plasma, represents an established alternative for providing epidermal growth factor receptor (EGFR) mutational testing for treatment decision-making. Compared with quantitative polymerase chain reaction and digital polymerase chain reaction-targeted methods, next-generation sequencing can provide more information about tumor molecular alterations, especially EGFR mutations. Here, we present a case of a patient with non-small cell lung cancer (NSCLC) harboring 3 uncommon mutations of EGFR-R670W in exon 17 and H833V, and H835L in exon 21, as shown by next-generation sequencing of plasma cell-free DNA. To the best of our knowledge, this is the first case report of a patient harboring the R670W mutation. The patient responded well to second-generation tyrosine kinase inhibitors (TKIs). T790M is an acquired resistant mutation in patients with R670W, H833V, and H835L. This is also the first case of a patient harboring the H833V/H835L/T790M triple mutation; the patient had a good response to the third-generation TKI osimertinib. In this work, we also performed a literature review on the clinical characteristics of NSCLC patients with the H833V/H835L double mutation, together with a descriptive analysis about their response to EGFR TKI monotherapy as a first-line treatment, according to data from previous case reports. The results showed that the cohort of NSCLC patients with H833V/H835L responded well to EGFR TKIs; thus, before treatment in clinical practice, screening for EGFR mutations should be conducted and EGFR TKIs should be preferred in NSCLC patients with H833V/H835L mutations.

Adenosquamous carcinoma of the bile duct: a population-based study.

INTRODUCTION: Adenosquamous carcinoma (ASC) of the bile duct is a rare diagnosis with poorly understood clinicopathological characteristics and disease progression, so identification of the features associated with ASC patient survival is warranted. MATERIALS AND METHODS: A population cohort study was performed using prospectively extracted data from the Surveillance, Epidemiology and End Results (SEER) database for patients with histological diagnoses of ASC of the bile duct from 1973 to 2013. RESULTS: A total of 106 patients with ASC of the bile duct were included (mean age 68.1±13.5 years). Lesions from 58 patients were in the extrahepatic bile duct and 34 were located at the ampulla of Vater. Fifty-seven patients were categorized with a regional stage, 15 had localized disease, and 30 had distant disease. Most (60.4%) patients received cancer-directed surgery, and radiation was performed in 14.1% of cases. The 1-year, 2-year, and 5-year overall survival (OS) for patients with ASC of the bile duct was 30.1%, 11.3%, and 3.7%, respectively. Cancer-directed surgery offered 10 additional months of OS for patients with ASC of the bile duct and median OS was 14.0, 6.0, and 6.0 months for ampulla of Vater, extrahepatic bile duct, and intrahepatic bile duct cases, respectively. A multivariate Cox analysis showed that lesions in the ampulla of Vater (HR=0.51, 95% CI 0.26-0.99) and having surgery (HR=0.34, 95% CI 0.14-0.81) were independent protective prognostic factors for these patients. CONCLUSION: Cancer-directed surgery and a primary lesion site of the ampulla of Vater may suggest favorable prognosis for patients with ASC of the bile duct.

C-Myc-dependent repression of two oncogenic miRNA clusters contributes to triptolide-induced cell death in hepatocellular carcinoma cells.

BACKGROUND: Triptolide is a structurally unique diterpene triepoxide with potent antitumor activity. However,the effect and mechanism of triptolide on hepatocellular carcinoma (HCC) is not well studied. METHODS: Cells were treated with triptolide, and the anti-HCC activity of triptolide was evaluated using flow cytometry, western blot, and xenograft studies. MicroRNA microarray and quantitative reverse-transcription polymerase chain reaction was used to identify differential microRNAs induced by triptolide. Chromatin immunoprecipitation assay was employed to study the interaction between c-Myc and genomic regions of miR106b-25. MicroRNAs overexpression and knockdown experiments were performed to determine the role of these microRNAs in triptolide-induced apoptosis. RESULTS: Triptolide inhibited cell proliferation and induced marked apoptosis in multiple HCC cell lines with different p53 status. Several signaling molecules involved in different pathways were altered after the treatment of triptolide. Xenograft tumor volume was significantly reduced in triptolide-treated group compared with vehicle control group. Two miRNA clusters, miR-17-92 and miR-106b-25, were significantly suppressed by triptolide, which resulted in the upregulation of their common target genes, including BIM, PTEN, and p21. In HCC samples, high levels of these miRNA clusters correlated with shorter recurrence free survival. Triptolide inhibited the expression of theses miRNAs in a c-Myc-dependent manner, which enhanced triptolide-induced cell death. We further showed that triptolide down-regulated the expression of c-Myc through targeting ERCC3, a newly identified triptolide-binding protein. CONCLUSIONS: The triptolide-induced modulation of c-Myc/miRNA clusters/target genes axis enhances its potent antitumor activity, which indicates that triptolide serves as an attractive chemotherapeutic agent against HCC.

Paralytic ileus due to a novel anticancer drug, nab-paclitaxel: A case report.

Nab-paclitaxel is a recently emerged chemotherapy drug, which is widely used for the treatment of multiple types of cancer. The prospects of this novel drug are very bright as a result of its higher efficacy and lower toxicity compared with paclitaxel. Hence, the side effect, even if rare, require attention in clinical practice. The present study described an unusual case of nab-paclitaxel-associated paralytic ileus. To the best of our knowledge, this is the first report to demonstrate that nab-paclitaxel may lead to acute intestinal obstruction. Since nab-paclitaxel will be used more frequently, this unusual side effect might be encountered by a clinical oncologist and must be treated correctly. This is the first reported case, to the best of our knowledge, of paralytic ileus caused by nab-paclitaxel, which will be widely used as a novel anticancer drug.

[Effects of the Combination of Emodin and 3'-Azido-3'-Deoxythymidine on Proliferation and Apoptosis in leukemia KG-1a cells Transfected with Egr-1 siRNA].

OBJECTIVE: This study was aimed to investigate the effects of emodin combined with 3'-azido-3'-deoxythymidine (AZT) on proliferation and apoptosis of leukemia cell line KG-1a cells and its mechanism. METHODS: KG-1a cells were transfected with Egr-1 siRNA by electroporation and divided into blank control (KG-1a), nonspecific control (KG-1a/NC) and Egr-1 siRNA (KG-1a/siRNA) groups. Transfection efficiency was tested through fluorescence microscopy and flow cytometry and the transfection effect was detected by using qPCR. The cell proliferation rate was detected with MTT method. After the cells were treated with 10 µmol/L of emodin, 3200 or 1600 µmol/L of AZT and their combinations, the proliferation inhibition rates and the apoptosis rates of cells in 3 groups were detected with MTT method and FCM, respectively. RESULTS: The transfection efficiency of Egr-1 siRNA was found to reach more than 59.21%; as compared with blank control(KG-1a) and nonspectic control(KG-1a/NC), the cell proliferation in Egr-1 siRNA group significantly reduced (P<0.01). The combination of emodin and AZT had considerable synergistic inhibitory effects on proliferation of normal KG-1a cells and nonspecific control(KG-1a NC) cells, but the synergistic effects disappeared after Egr-1 gene silencing. CONCLUSION: The effects of the combination of emodin and AZT on proliferation and apoptosis may be related with Egr-1.

Overexpression of SLC38A1 is associated with poorer prognosis in Chinese patients with gastric cancer.

BACKGROUND: Current literature has demonstrated that host glutamine depletion facilitates tumorigenesis. Likewise, the glutamine transporter SLC38A1 is putatively associated with malignant transformation and tumor progression. Taken together, this forms the premise for undertaking the current study. The twofold aim of this study was to provide insight into whether or not a variance in the expression of SLC38A1 exists between human gastric cancer and healthy human tissues, and to determine how silencing the SLC38A1 gene could affect the proliferation, viability, migration, and invasion of gastric cancer cells. METHODS: Immunohistochemical staining was used to analyze the expression of SLC38A1 in gastric cancer tissues and adjacent healthy mucosa in 896 patients with pathologically confirmed gastric cancer who had underwent R0 resection. SH-10-TC cells (a gastric cancer cell line) were used to examine whether silencing SLC38A1 with siRNA could affect cell viability, migration and invasion. RESULTS: The SLC38A1 protein was very low or undetectable in healthy gastric mucosa. In contrast, strong staining of SLC38A1 protein was found in the cytoplasm in 495 out of the 896 gastric cancer samples. More pronounced SLC38A1 expression in gastric cancer tissues was significantly associated with age, differentiation status, lymph node metastasis, TNM stage and PCNA (proliferating cell nuclear antigen) expression. Upon univariate survival analysis, SLC38A1 expression was correlated with poor survival. Multivariate survival analysis revealed that SLC38A1 was an independent prognostic factor. CONCLUSION: SLC38A1 is overexpressed in gastric cancer, which suggests that it is contributory to tumor progression. These results encourage the exploration of SLC38A1 as a target for intervention in gastric cancer.

[Clinical observation of prophylactic lactulose for prevention of oral morphine-induced constipation].

OBJECTIVE: To evaluate the effects of different doses of lactulose on preventing oral morphine-induced constipation. METHODS: From January 2011 to May 2012, a total of 112 patients received oral lactulose solution to prevent morphine-induced constipation at our hospital and their clinical data were retrospectively analyzed. The doses of morphine were adjusted according to the pain scores and lactulose was taken simultaneously. There were 52 males and 60 females. They were randomized into Group 30 ml/d (n = 40), Group 60 ml/d (n = 43) and Group 90 ml/d (n = 29). The incidences of constipation and adverse reactions were obtained at 1 week after the start of medicine. The measurement data were analyzed with analysis of variance. And the enumeration data were analyzed with χ(2), Kruskal-Wallis and Mann-Whitney U tests. RESULTS: The incidence of constipation was 67.5% (27/40) in Group 30 ml/d, 46.5% (20/43) in Group 60 ml/d, and 37.9% (11/29) in Group 90 ml/d. And there were statistical differences (P = 0.036). The incidence of constipation in Group 30 ml was significantly higher than Group 90 ml/d (P = 0.015). No statistical difference existed in the incidence of constipation between Groups 30 ml/d and 60 ml/d (P = 0.054) or Groups 60 ml/d and 90 ml/d (P = 0.471). The incidence of vomiting was 34.5% (10/29) in Group 90 ml/d and it was significantly higher than 10.0% (4/40) in Group 30 ml/d (P = 0.013) and 9.3% (4/43) in Group 60 ml/d (P = 0.009). No statistical difference existed in the incidence of vomiting between Groups 30 ml/d and 60 ml/d (P = 0.915). The incidence of diarrhea was 17.2% (5/29) in Group 90 ml/d and it was significantly higher than 0 (0/40) in Group 30 ml/d (P = 0.007). No statistical difference existed in the incidence of diarrhea between Groups 30 ml/d and 60 ml/d (4.7% (2/43), P = 0.170) or Groups 60 ml/d and 90 ml/d (P = 0.072). CONCLUSION: The correct dosage of lactulose for the prevention of oral morphine-induced constipation is 60 ml/d.

Inhibiting effects of total saponins of panax ginseng on immune maturation of dendritic cells induced by oxidized-low density lipoprotein.

Total saponins of panax ginseng (TSPG) are the major active components in panax ginseng. Dendritic cells (DCs) play an active role in the immunological processes related to atherosclerosis. The purpose of this study was to determine the effect and possible mechanisms of TSPG on the maturation and immune function of DCs. Compared with those untreated, the DCs pre-treated with TSPG and then induced by oxidized-LDL exhibited a significantly lower expression of the maturation-associated markers of CD40, CD86, HLA-DR, and CD1a, together with an increased endocytosic function as well as decreased secretions of cytokine. However, silencing the expression of PPARgamma in DCs, the inhibitory effect of TSPG on the maturation DCs was significantly reduced. In conclusion, TSPG could inhibit the maturation of DCs induced by oxidized-LDL which suggests beneficial effects on atherosclerosis and this effect was partly dependent on the PPARgamma pathway at least.

[Protective effect of tongxinluo superfines on angiotensin II caused renal injury in rat].

OBJECTIVE: To explore the renal protective effect of Tongxinluo (TXL) and its mechanism of action. METHODS: Eight-week old SD rats were divided into the sham-operated group (A), the model group (B) and the TXL group, 6 rats in each group. Angiotensin II (Ang II) was administered slowly (200 ng/kg per min) to rats in group B and C via subcutaneously embedded osmotic pump to make them stimulative model of renal injury, while to rats in group A, pump embedding with saline infusion. After modeling, TXL was given to group C by gastric perfusion in dosage of 0.8 g/kg per day. And the following indexes were observed 14 days later: configuration of renal arterial endothelium by transmission electron microscope; pathologic figure of kidney with HE stain; renal apoptosis by TUNEL; expression of p53 and p22phox by RT-PCR;and level of reactive oxygen species (ROS) in kidney. RESULTS: Different degree of congestion, swelling, denudation of endothelial cell in renal arterial endothelial cell; glomerular matrix proliferation and partial glomerular atrophy with tendency of fibrosis; increased renal parenchymal apoptosis; enhanced expression of p53 and p22phox; and elevated ROS were found in model animals. All the above-mentioned abnormalities, including glomerular injury, renal cell apoptosis, as well as the increased p53, p22phox expressions and ROS production were all alleviated in group C after TXL treatment. CONCLUSION: TXL could protect renal against Ang II injury, and it may be realized by inhibiting NADPH-ROS/p53 pathways and suppressing cell apoptosis in renal parenchyma.