Strategies and Recent Advances on Improving Efficient Antitumor of Lenvatinib Based on Nanoparticle Delivery System.

Lenvatinib (LVN) is a potentially effective multiple-targeted receptor tyrosine kinase inhibitor approved for treating hepatocellular carcinoma, metastatic renal cell carcinoma and thyroid cancer. Nonetheless, poor pharmacokinetic properties including poor water solubility and rapid metabolic, complex tumor microenvironment, and drug resistance have impeded its satisfactory therapeutic efficacy. This article comprehensively reviews the uses of nanotechnology in LVN to improve antitumor effects. With the characteristic of high modifiability and loading capacity of the nano-drug delivery system, an active targeting approach, controllable drug release, and biomimetic strategies have been devised to deliver LVN to target tumors in sequence, compensating for the lack of passive targeting. The existing applications and advances of LVN in improving therapeutic efficacy include improving longer-term efficiency, achieving higher efficiency, combination therapy, tracking and diagnosing application and reducing toxicity. Therefore, using multiple strategies combined with photothermal, photodynamic, and immunoregulatory therapies potentially overcomes multi-drug resistance, regulates unfavorable tumor microenvironment, and yields higher synergistic antitumor effects. In brief, the nano-LVN delivery system has brought light to the war against cancer while at the same time improving the antitumor effect. More intelligent and multifunctional nanoparticles should be investigated and further converted into clinical applications in the future.

Pemigatinib in previously treated Chinese patients with locally advanced or metastatic cholangiocarcinoma carrying FGFR2 fusions or rearrangements: A phase II study.

OBJECTIVE: This study evaluated the antitumor activity and safety of pemigatinib in previously treated Chinese patients with advanced cholangiocarcinoma and fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements. BACKGROUND: Pemigatinib provided clinical benefits for previously treated patients with cholangiocarcinoma carrying FGFR2 fusions or rearrangements and was approved for this indication in multiple countries. METHODS: In this ongoing, multicenter, single-arm, phase II study, adult patients with locally advanced or metastatic cholangiocarcinoma carrying centrally confirmed FGFR2 fusions or rearrangements who had progressed on ≥1 systemic therapy received 13.5 mg oral pemigatinib once daily (3-week cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was objective response rate (ORR) assessed by an independent radiology review committee. RESULTS: As of January 29, 2021, 31 patients were enrolled. The median follow-up was 5.1 months (range, 1.5-9.3). Among 30 patients with FGFR2 fusions or rearrangements evaluated for efficacy, 15 patients achieved partial response (ORR, 50.0%; 95% confidence interval [CI], 31.3-68.7); 15 achieved stable disease, contributing to a disease control rate of 100% (95% CI, 88.4-100). The median time to response was 1.4 months (95% CI, 1.3-1.4), the median duration of response was not reached, and the median progression-free survival was 6.3 months (95% CI, 4.9-not estimable [NE]). Eight (25.8%) of 31 patients had ≥grade 3 treatment-emergent adverse events. Hyperphosphatemia, hypophosphatasemia, nail toxicities, and ocular disorders were mostly

Overexpression of rhophilin 2 promotes pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is the seventh leading cause of global cancer deaths. In recent years, targeted therapy has been used for pancreatic cancer; however, the drugs available for use in targeted therapy for pancreatic cancer are still very limited. Hence, identification of novel targeted molecules for PDAC is required. Rhophilin 2 (RHPN2) was proven to be a driver gene in glioblastoma. However, the function of RHPN2 in PDAC remains unknown. In the present study, the function of RHPN2 was investigated. The RHPN2 levels were overexpressed by pcDNA3.1-RHPN2 and downregulated by si-RHPN2. Cell proliferation was assessed using the MTT assay and apoptosis was assessed using flow cytometry. The results revealed that high RHPN2 levels in PDAC tissue were correlated with a low overall survival rate of patients with PDAC. Inhibition of RHPN2 reduced SW1990 and PANC1 proliferation and increased the rate of apoptosis. Network analysis demonstrated that centrosomal protein 78 expression was negatively correlated with RHPN2 expression. In conclusion, the present study demonstrated that RHPN2 may promote PDAC making it a potential candidate for targeted therapy.

Overexpression of Rhophilin Rho GTPase-binding protein 2 promotes hepatocellular carcinoma.

Hepatocellular carcinoma is a serious public health problem in China. The mortality rate associated with the majority of cancer types has decreased as a result of targeted therapy. However, the mortality rates associated with hepatocellular carcinoma have not improved; therefore, the identification of new molecular targets is required for the development of novel targeted therapies. In the present study, a new molecular target, Rhophilin Rho GTPase-binding protein 2 (RHPN2), was identified. The levels of RHPN2 protein in tumor tissues were assessed via immunohistochemistry, while the mRNA levels were analyzed via reverse transcription-quantitative PCR. Additionally, cell viability was tested via MTT analysis. RHPN2 expression was upregulated in hepatocellular carcinoma tissues compared with that of matched adjacent normal tissues. More importantly, low expression of RHPN2 in patients with hepatocellular carcinoma was associated with an improved prognosis rate compared with patients with high expression. Downregulation of RHPN2 reduced the proliferation of hepatocellular carcinoma cells and increased the rate of apoptosis, whereas overexpression of RHPN2 demonstrated the opposite effects. Hepatocyte nuclear factor 1α was implicated in the mechanism of RHPN2. Overall, these data indicated that overexpression of RHPN2 may promote hepatocellular carcinoma.

Long non-coding RNA CASC2 upregulates PTEN to suppress pancreatic carcinoma cell metastasis by downregulating miR-21.

BACKGROUND: The mechanism of pancreatic cancer metastasis remains poorly understood. Recently, lncRNA CASC2 has been demonstrated to be a tumor suppressor in various types of cancer. This study aimed to explore the mechanism of CASC2 in the regulation of pancreatic cancer metastasis. METHODS: The expression levels of CASC2 and miR-21 in pancreatic cells were detected by qRT-PCR. Using specific expression vectors, including mimics or shRNA, the expression levels of CASC2, miR-21 and PTEN in pancreatic cells were altered. The association between CASC2, miR-21 and PTEN was detected. Then, cell migration and invasion were assessed using the transwell assay. RESULTS: CASC2 expression was downregulated in the pancreatic cancer cell lines CAPAN-1, BxPC-3, JF305, PANC-1 and SW1990 compared with levels in normal human pancreatic HPDE6-C7 cells. CACS2 overexpression inhibited the migration and invasion of PANC-1 cells and significantly inhibited the expression of miR-21 and PTEN. MiR-21 was a direct target of CACS2. The overexpression of miR-21 significantly abolished the antimetastatic effects of CASC2 on PANC-1 cells. Moreover, the downregulation of PTEN significantly abolished the antimetastatic effects of CASC2. CONCLUSION: CASC2 functions as a tumor suppressor in pancreatic cancer cells to inhibit tumor cell migration and invasion. Our work revealed a novel regulatory mechanism of the CASC2/miR-21/PTEN axis that may be important in pancreatic cancer.

Evaluation of psychometric properties of needs assessment tools in cancer patients: A systematic literature review.

BACKGROUND: Although a wide range of needs assessment tools for cancer patients have been developed, no standardized and commonly accepted instruments were recommended to use in clinical care. This systematic review was conducted to assess the quality of psychometric properties of needs assessment tools among cancer patients in order to help oncology healthcare professionals select the most appropriate needs assessment tools in routine clinical practice. METHODS: Searches were conducted in the electronic databases of PUBMED from 1966, CINAHL from 1960, EMBASE from 1980 and PsychINFO from 1967 as well as additional sources. The quality of psychometric properties of the recruited needs assessment tools was evaluated using the agreed quality criteria for measurement properties of health status questionnaires. RESULTS: Thirty-seven studies which evaluated the psychometric properties of 20 needs assessment tools were identified. Internal consistency was tested in 32 studies with 9 studies indicating negative rating and 4 studies intermediate rating. Less than half of the studies (13 studies) assessed test-retest reliability, and only 4 studies reported positive rating. Content validity was the most tested psychometric property appraised in 33 studies and indicated positive rating in all the evaluated studies. Structural validity was adequately evaluated in 28 studies with 23 studies reporting intermediate rating. More than half of the studies (29 studies) tested hypothesis testing and 13 studies were rated positive. Cross-cultural validity results were obtained in 13 studies with 7 studies showing negative rating. No data was available on measurement error and criterion validity. Only one study appraised responsiveness and showed intermediate rating. The Supportive Care Needs Survey-Short Form (SCNS-SF) is the most widely used instrument for needs assessment in cancer patients. It had strong evidence for internal consistency, content validity, structural validity and hypothesis testing, and moderate evidence for reliability and cross-cultural validity. Cancer Survivors' Unmet Needs Measure (CaSUN) reported strong or moderate evidence for internal consistency, reliability, content and structural validity, and hypothesis testing. Furthermore, Supportive Cancer Care Needs Assessment Tool for Indigenous People (SCNAT-IP) had strong evidence for content validity, and moderate evidence for internal consistency, structural validity and hypothesis testing. CONCLUSIONS: Despite several needs assessment tools exist to assess care needs in cancer patients, further improvement of already existing and promising instruments is recommended.

MiR-132 promotes the proliferation, invasion and migration of human pancreatic carcinoma by inhibition of the tumor suppressor gene PTEN.

MicroRNA (miRNAs) emerges as key oncogene or tumor suppressor in a variety of cancers including pancreatic carcinoma. In this study, we detected the role of miR-132 in development and progression of pancreatic cancer and the underlying mechanism. First, the expression of miR-132 in pancreatic carcinoma and adjacent non-cancerous tissues were detected by qRT-PCR. Then, the role of miR-132 in biological function of pancreatic carcinoma cells was investigated. Our results identified that miR-132 was generally upregulated in pancreatic carcinoma, and phosphatase and tensin homolog (PTEN) was generally downregulated. miR-132 and PTEN were associated with advanced tumor size, lymph node metastasis and Tumor-Nodes-Metastases (TNM) stage of pancreatic carcinoma. Downregulation of miR-132 inhibited proliferation, migration and invasion of pancreatic carcinoma cells. In contrast, overexpression of miR-132 promoted proliferation, migration and invasion of pancreatic carcinoma cells. The luciferase reporter system demonstrated PTEN is a direct target of miR-132. Overexpression of PTEN abrogated the induction of miR-132 on proliferation, migration and invasion of pancreatic carcinoma cells. Taken together, miR-132 promotes the proliferation, invasion and migration of human pancreatic cancer by inhibition of PTEN, and could be a tumor oncogene in development and progression of pancreatic carcinoma, and might be a candidate prognostic biomarker and a promising target for new treatment of human pancreatic cancer.

Fibrosis-4 Model Influences Results of Patients with Hepatocellular Carcinoma Undergoing Hepatectomy.

BACKGROUND: Several noninvasive models based on routine laboratory index have been developed to predict liver fibrosis. Our aim is to discuss whether these indexes could predict prognosis in patients with hepatocellular carcinoma undergoing hepatectomy. METHODS: This study retrospectively enrolled 788 consecutive hepatocellular carcinoma patients undergoing liver resection in the cohort. Univariate and multivariate analysis were used to identify the risk factors of complications, survival, and disease-free survival. RESULTS: Fibrosis-4 index had the best prediction ability for cirrhosis among other noninvasive models. Both the univariate and multivariate analyses showed that fibrosis-4 was independent risk factor for survival and disease-free survival. With the optimal cutoff value of 3.15, patients with fibrosis-4 ⩾3.15 had higher postoperative hepatic insufficiency (P=0.006) and worse survival than the fibrosis-4<3.15 group. The corresponding 1-year, 3-year, and 5-year overall survival were 80.9%, 56.3%, and 44.6% in the High fibrosis-4 group and were 86.5%, 69.9%, and 63.2% in the Low fibrosis-4 group, respectively (P<0.001). Worse disease-free survival was also observed in the fibrosis-4 ⩾3.15 group; the corresponding 1-year, 3-year, and 5-year disease-free survival were 74.9%, 45.3%, and 24.6% for the fibrosis-4 ⩾3.15 group and were 81.8%, 54.9%, and 34.4% for the fibrosis-4<3.15 group (P=0.009). CONCLUSIONS: Fibrosis-4 is useful for assessing the short-term and long-term results for hepatocellular carcinoma patients with liver resection.

Terlipressin in the treatment of hepatorenal syndrome: A systematic review and meta-analysis.

BACKGROUND: Hepatorenal syndrome is a fatal complication of advanced cirrhosis. Terlipressin is the most widely used treatment method, however, the therapy effects remain inconsonant. We aim to systematically assess the safety and efficacy of terlipressin for hepatorenal syndrome. METHODS: We conducted a systematic review and meta-analysis. Randomized controlled trials involving terlipressin for hepatorenal syndrome were included in a systematic literature search. Two authors independently assessed the studies for inclusion and extracted the data. A meta-analysis was conducted to estimate the safety and efficacy of terlipressin for hepatorenal syndrome. RESULTS: A total of 18 randomized controlled trials including 1011 patients were included. Hepatorenal syndrome reverse rate was 42.0% in the terlipressin group and 26.2% in the non-terlipressin group. Terlipressin had greater hepatorenal syndrome reverse rate and renal function improvement rate than placebo and octreotide in the management of HRS. Comparing to norepinephrine, terlipressin had similar efficacy, but with more adverse events. No significant difference of the efficacy was found between terlipressin and dopamine treatment. The subgroup analysis for type 1 HRS had the above same results, except that the adverse events were not significant different between norepinephrine group and terlipressin group. CONCLUSIONS: Terlipressin was superior to placebo and octreotide for reversal of hepatorenal syndrome and improving renal function, but it had no superiority comparing to norepinephrine.

Immediate postoperative Fibrosis-4 predicts postoperative liver failure for patients with hepatocellular carcinoma undergoing curative surgery.

BACKGROUND: Postoperative liver failure remains the main complication and predominant cause of hepatectomy-related mortality for patients undergoing liver resection. AIM: Our aim is to investigate whether immediate postoperative Fibrosis-4 could predict postoperative liver failure. METHODS: We retrospectively enrolled 1353 consecutive hepatocellular carcinoma patients undergoing radical resection. The characteristics and clinical outcomes were compared between patients with high and low immediate postoperative Fibrosis-4. Risk factors for hepatic failure were evaluated by univariate and multivariate analysis. RESULTS: Using a receiver operating characteristic curve, immediate postoperative Fibrosis-4 showed good prediction ability for postoperative liver failure (AUROC=0.647, P<0.001). With the optimal cut-off value of 5.9, the high postoperative Fibrosis-4 group (Fibrosis-4<5.9) had higher postoperative complication (39.1% vs 28.6%, P<0.001), mortality (2.8% vs 0.6%, P<0.001) and liver failure (13.9% vs 6.2%, P<0.001). In addition, patients with high Fibrosis-4 had worse and delayed recovery of liver function. By univariate and multivariate analysis, Fibrosis-4, as well as liver removed volume, total bilirubin and albumin was identified as independent risk factor for postoperative liver failure. CONCLUSIONS: Immediate postoperative Fibrosis-4 showed good prediction ability for postoperative liver failure, and required measure should be taken to prevent liver failure when high postoperative Fibrosis-4 appeared.

Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma patients after curative resection, a systematic review and meta-analysis.

BACKGROUND: Cytokine-induced killer cells have been used as an adjuvant treatment for hepatocellular carcinoma with curative treatment. However, the outcomes remain controversial. AIM: We conducted this meta-analysis to assess the safety and efficacy of cytokine-induced killer cells. METHODS: Randomized controlled trials on cytokine-induced killer cells for hepatocellular carcinoma after curative treatments were identified by electronic searches. A meta-analysis was carried out to examine disease-free survival, overall survival rate and adverse effect. RESULTS: Six randomized controlled trials with 844 patients (85.9% with hepatitis B or C) were included. Our meta-analysis showed that cytokine-induced killer cells can not only improve the 1-year (RR=1.23, P<0.001), 2-year (RR=1.37, P<0.001) and 3-year (RR=1.35, P=0.004) disease-free survival, but also improve the 1-year (RR=1.08, P=0.001), 2-year (RR=1.14, P<0.001) and 3-year (RR=1.15, P=0.02) overall survival. However, it failed to affect the 4-year and 5-year disease-free survival and overall survival (P>0.05). At the same time, cytokine-induced killer cells treatment was proved to be a safe strategy with the comparable adverse events comparing to the control group (P=0.39). CONCLUSIONS: This review provides the best available evidence that adjuvant cytokine-induced killer cells treatment can be safely used to improve the early disease-free survival and survival of hepatitis B or C related hepatocellular carcinoma.

The tumor suppressor role of miR-4782-3p in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortalities in China. Although advances have been made in treatments, the prognosis of HCC patients has not improved significantly. MicroRNAs (miRNA) play important roles in all stage of the progress of HCC. miR-4782-3p takes part in the pathogenesis of non-small cell lung cancer (NSCLC). However, the role of miR-4782-3p in HCC remains unknown. In the present study, we found that miR-4782-3p had low expression in HCC tissues. The low expression of miR-4782-3p indicated shorter survival of HCC patients. Moreover, the low expression of miR-4782-3p promoted HCC cells growth and inhibited cell apoptosis. We confirmed that USP14 was targeted by miR-4782-3p in HCC cells.

A Left-Sided Approach for Resection of Hepatic Caudate Lobe Hemangioma: Two Case Reports and a Literature Review.

Resection of the hemangioma located in the caudate lobe is a major challenge in current liver surgery. This study aimed to present our surgical technique for this condition. Two consecutive patients with symptomatic hepatic hemangioma undergoing caudate lobectomy were investigated retrospectively. First, all the blood inflow of hemangioma from the portal vein and the hepatic artery at the base of the umbilical fissure was dissected. After the tumors became soft and tender, the short hepatic veins and the ligaments between the secondary porta hepatis were severed. At last the tumors were resected from the right lobe of the liver. The whole process was finished by a left-sided approach. Blood lost in Case 1 was 1650 mL because of ligature failing in one short hepatic vein, and in the other case, 210 mL. Operation time was 236 minutes and 130 minutes, respectively. Postoperative hospital stays were 11 and 5 days, respectively. The diameter of tumors was 9.0 cm and 6.5 cm. Case 1 required blood transfusion during surgery. No complications such as biliary fistula, postoperative bleeding, and liver failure occurred. The left-sided approach produced the best results for caudate lobe resection in our cases. The patients who recovered are living well and asymptomatic. Caudate lobectomy can be performed safely and quickly by a left-sided approach, which is carried out with optimized perioperative management and innovative surgical technique.

Case analysis of complete remission of advanced hepatocellular carcinoma achieved with sorafenib.

BACKGROUND: To evaluate the feasibility and security of complete remission (CR) of advanced hepatocellular carcinoma (HCC) achieved with sorafenib treatment, and investigate the previously described predictive factors in CR. METHODS: The case of a patient who achieved CR of advanced HCC with sorafenib treatment was analyzed. The case analysis was performed by a literature review of relevant reports retrieved from the PubMed database. RESULTS: A 58-year-old male patient achieved CR of advanced HCC after 23 weeks of oral treatment with sorafenib alone for 41 months and maintained CR for more than 35 months. Eleven reports worldwide have documented a total of twelve patients who achieved CR of advanced HCC, including six with nonsurgical oral sorafenib treatment, four with surgical resection in the descent stage following oral sorafenib treatment and two with oral sorafenib treatment for postoperative metastasis. CONCLUSIONS: For unresectable advanced HCC, sorafenib can significantly improve progression-free survival and overall survival, achieving CR in some cases. In addition, surgical resection of advanced HCC in the descent stage is possible following oral sorafenib treatment. For patients with postoperative distant metastasis of HCC, sorafenib treatment also provides clinical benefits and can even achieve CR. Besides, long-term sorafenib administration is safe, and patients should continually receive sorafenib to avoid recurrence after complete remission of cancer. Furthermore, early HFSR, rapid decline of AFP levels and rapid tumor shrinking observed by imaging are known parameters describing sorafenib's effects. Finally, it is important to assess the gene locus of sorafenib sensitivity in HCC patients in future research.

[The effects of transferring DPC4-adenovirus on pancreatic adenocarcinoma cells].

OBJECTIVE: To observe the effect of transferring DPC4-adenovirus on pancreatic cells. METHODS: The recombined wild DPC4 gene and replication-deficiency adenovirus was transfected into cultured pancreatic adenocarcinoma cells and exograft pancreatic adenocarcinoma at the axillary flank of nude mice. The expression of objective gene was evaluated by flow cytometry and immunohistological chemistry assay. The cell cycle was also measured by flow cytometry. The related data were collected and analyzed with statistical methods. RESULTS: in viro, the suppression rate of transferring DPC4-adenovirus on cultured pancreatic adenocarcinoma cells was 30% on the fourth day. The fluorescence intensity of PD cells, P cells, HD cells, PA (Pc-3-Adenovirus) cells was higher than that of HS766T cells and HA cells (P<0.05). After transfection, PD cells proliferated most slowly, while H and HA proliferated most quickly (P<0.05). Significant difference was seen between the volume of exograft tumor of the controlled group and that of the treatment group (P<0.05). After transfection, the proliferation of cultured pancreatic adenocarcinoma cells was suppressed, the cells of G1 phase increased obviously (P<0.05) while the cells of S phase decreased (P<0.05), although no obvious increase of apoptosic cell number was observed. CONCLUSION: The DPC4-adenovirus can be transfected into pancreatic adenocarcinoma cells effectively. It could suppress the proliferation of pancreatic adenocarcinoma cells in vivo and in vitro.

Modified techniques of heterotopic total small intestinal transplantation in rats.

AIM: To establish a successful model of heterotopic total small intestinal transplantation (SIT) in rats in order to reduce the complications and increase the survival rate. METHODS: A total of 196 Wistar rats underwent heterotopic SIT with microsurgical technique. Technical modifications included shortening fasting time and supplying energy before surgery, administering optimal volume of crystalloid fluid to the donor and recipient during surgical procedures, reducing mechanical and ischemic injuries to donor intestine, revascularizing small intestinal graft with a combination of conventional aorta to aorta anastomosis and a cuffed portal vein to left renal vein anastomosis which resulted in an acceptably short warm ischemic time, and also an adequate blood supply and drainage of the graft. RESULTS: The average time for the donor surgery was 86 min +/- 20 min, the mean operative time for the recipient was 115 min +/-20 min and warm ischemia time was shortened to 40 min +/- 5 min. There was a shorter revascularizing time of the graft, the abdominal aorta (AA) to AA anastomosis being 21 min +/- 10 min, and the cuffed portal vein (PV) to the renal vein anastomosis being 5 min +/- 5 min. The one-week survival rate of 98 rats with SIT was 88.78% (87/98), without thrombosis and stenosis of anastomosis. The longest survival time of recipient rats was more than 389 days after SIT, the rats were maintaining normal weight, with perfect intestinal function and intact intestinal histology. CONCLUSION: These modified techniques for SIT would remarkably reduce the complications and improve survival rate in rats, which provided a potentially more consistent and practical model for experimental and clinical studies.