Robot Assisted Laparoscopy Combined with Thoracoscopy in the Treatment of Hepatocellular Carcinoma with Inferior Vena Cava Tumor Thrombus.

BACKGROUND: Facing the 0.7-22% incidence rate of hepatocellular carcinoma (HCC) with inferior vena cava tumor thrombus (IVCTT), there are usually no obvious symptoms and signs when the tumor thrombus completely blocks the IVCTT in the early stage.1.J Gastroenterol. 29:41-46;2.Hepatogastroenterology. 41:154-157;3.Clin Cardiol. 19:211-213; Once diagnosed, it is the end-stage manifestation without unified treatment for HCC with IVCTT, bringing poor prognosis. Without active treatment, the median survival time is only 3 months. Previous scholars believed that patients with IVCTT should not adopt active surgical treatment. With the advance of technology, active surgical treatment has significantly lengthened the survival time with IVCTT.4.Ann Surg Oncol. 20:914-22;5.World J Surg Oncol. 11:259;6.Hepatogastroenterology. 58:1694-1699; However, for patients with HCC and IVCTT, open surgery was always selected in the past by opening the diaphragm through the combined thoracoabdominal incision to block the superior and subhepatic vena cava, leading long incision and huge trauma. With the development of minimally invasive techniques, laparoscopy thoracoscopy has showed great advantages in the treatment of HCC with IVCTT. A patient underwent laparoscopic with thoracoscopic resection of tumor and cancer thrombectomy after neoadjuvant therapy and then survived after follow-up.7.Ann Surg Oncol. 29:5548-5549 Therefore, it used as a first reported case of robot-assisted laparoscopic with thoracoscopic treatment of HCC complicated inferior vena cava cancer thrombectomy. METHODS: A 41-year-old man had a liver space-occupying lesion discovered during his medical examination 2 months ago. The diagnosis of HCC with IVCTT was confirmed by enhanced CT and biopsy specimen in the first hospitalization. A combination of TACE, targeted therapy, and immunotherapy plan was applied for the patient after multidisciplinary treatment (MDT). Specifically, Lenvatinib was taken orally 8 mg daily and 160 mg of toripalimab was given intravenously every 3 weeks. His reexamination CT showed that the tumor was more advanced after 2 months of treatment. The surgical operation was performed based on comprehensive consideration. The patient was placed in the left lateral decubitus position, and a thoracoscopic prefabricated the inferior vena cava above diaphragm blocking device was pulled out of the incision. The patient was switched to a supine position with the head of the bed raised 30 degrees. The gallbladder was removed first after entering the abdominal cavity, then prefabricated first hilar blocking band. Sterile rubber glove edges and hemo-lock were used to fabricate the blocking device. The novel hepatic inflow occlusion device is a safe, reliable, and convenient technique that is associated with favorable perioperative outcomes and low risk of conversion.8.Surg Endosc. 34:2807-2813 The liver along the middle hepatic vein was cut to expose the anterior wall of the inferior vena cava, then prefabricated posterior inferior vena cava blocking belt and right hepatic vein blocking belt. Finally, the first portal of liver, right hepatic vein, retrohepatic inferior vena cava, and inferior vena cava above diaphragm were blocked in sequence, so that accomplishing tumor resection and thrombectomy of inferior vena cava. It should be emphasized that before the inferior vena cava is completely sutured, the retrohepatic inferior vena cava blocking device should be released to allow blood flow to flush the inferior vena cava. Moreover, transesophageal ultrasound is required to real-time monitor inferior vena cava blood flow and IVCTT. Some images of the operation are shown in Fig. 1. Fig. 1 (a) Layout of the trocar. ①Make a 3cm small incision between the right anterior axillary line and the midaxillary line, parallel to the fourth and fifth intercostal spaces; a puncture hole in the next intercostal space for endoscope; ②2cm above the intersection of umbilicus horizontal line and axillary front line; ③Intersection of right clavicular midline and umbilical horizontal line; ④Superior margin of umbilicus; ⑤The midpoint of '④ & ⑥'; ⑥2cm below the intersection of left clavicular midline and left costal margin. (b) Prefabricated the inferior vena cava blocking device above diaphragm by thoracoscopic. (c) The smooth tumor thrombus protruding into the inferior vena cava RESULTS: It took 475 min to finish the operation, and the loss of blood was estimated as 300 ml. The patient was discharged from hospital 8 days after the operation without postoperative complication. HCC was confirmed by postoperative pathology. CONCLUSIONS: Robot surgical system reduces the limitations of laparoscopic surgery by offering a stable three-dimensional view, 10-times-enlarged image, restored eye-hand axis, and excellent dexterity with the endowristed instruments, which has several advantages over open operation such as diminished blood loss, reduced morbidity, and shorter hospital stay.9.Chirurg. 88:7-11;10.BMC Surg. 11:2;11.Minerva Chir. 64:135-146; Furthermore, it could favor the operative feasibility of difficult resections reducing the conversion rate and playing a role to extend the indications of liver resection to minimally invasive approaches. It may provide new curative options in patients deemed inoperable with conventional surgery, such as HCC with IVCTT.12.Biosci Trends. 16:178-188;13.J Hepatobiliary Pancreat Sci. 29:1108-1123.

Inhibition of AMPK/PFKFB3 mediated glycolysis synergizes with penfluridol to suppress gallbladder cancer growth.

BACKGROUND: Penfluridol (PF) is an FDA-approved antipsychotic drug that has recently been shown to have anticancer activity. However, the anticancer effects and underlying mechanisms of PF are not well-established in gallbladder cancer (GBC). METHODS: The anticancer efficacy of PF on GBC was investigated via a series of cell functions experiments, including cell viability, colony formation, apoptosis assays, and so on. The corresponding signaling changes after PF treatment were explored by western blotting. Then, nude mice were utilized to study and test the anticancer activity of PF in vivo. Besides, glucose consumption and lactic production assays were used to detect the glycolysis alteration. RESULTS: In this study, we discovered that PF greatly inhibited the proliferation and invasion ability of GBC cells (GBCs). The glucose consumption and lactic generation ability of GBCs were dramatically elevated following PF treatment. Additionally, we discovered that inhibiting glycolysis could improve PF's anticancer efficacy. Further studies established that the activation of the AMPK/PFKFB3 signaling pathway medicated glycolysis after PF treatment. We proved mechanistically that inhibition of AMPK/PFKFB3 singling pathway mediated glycolysis was a potential synergetic strategy to improve the anticancer efficacy of PF on GBC. CONCLUSIONS: By inhibiting AMPK, the anticancer effects of PF on GBCs were amplified. As a result, our investigations shed new light on the possibility of repurposing PF as an anticancer drug for GBC, and AMPK inhibition in combination with PF may represent a novel therapeutic strategy for GBC. Video abstract.

Comparison of laparoscopic proximal gastrectomy with double-tract reconstruction and laparoscopic total gastrectomy for proximal gastric cancer with stage cT1-2.

ABSTRACT: This study aimed to evaluate the feasibility and nutritional benefits of laparoscopic proximal gastrectomy (LPG) with double-tract reconstruction (DTR) in comparison with laparoscopic total gastrectomy (LTG).The demographic, clinical, and pathological data and postoperative nutritional status of patients undergoing LPG with DTR (n = 21) or LTG (n = 26) at Sir Run Run Shaw Hospital between January 2016 and January 2019 were retrospectively reviewed and compared.The operative time in the LPG group was slightly longer than that in the LTG group; however, the difference was not statistically significant. Blood loss was not significantly different between groups. The mean number of retrieved lymph nodes was higher in the LTG group than in the LPG group (P = .02). The time to first flatus, postoperative hospital stay, and postoperative complications were comparable between the groups. During the 3-year postoperative follow-up, a statistically significant decrease in hemoglobin level was observed in the LTG group. There were no differences between the two groups of patients before and after the operation regarding albumin levels. The mean vitamin B12 level was higher in the LPG group than in the LTG group from 12 to 18 months postoperatively.LPG with DTR is an acceptable procedure for patients with upper gastric cancer. LPG with DTR has numerous potential advantages in preserving the physiological and nutritional functions of the remnant stomach and the conservation of the gastric reservoir.

Anlotinib combined with PD-1 blockade for the treatment of lung cancer: a real-world retrospective study in China.

BACKGROUND: This study evaluated the efficacy and safety of anlotinib combined with programmed cell death protein 1 (PD-1) blockade for the treatment of small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: SCLC (n = 28) and NSCLC (n = 177) patients who received treatment at Hunan Cancer Hospital between June 1, 2019, and July 1, 2020, were retrospectively analyzed. Progression-free survival (PFS) and treatment responses were compared among patients who received combination therapy of anlotinib plus PD-1 inhibitor, or monotherapy of either chemotherapy or PD-1 inhibitor. Independent prognostic factors were identified by Cox regression analysis. RESULTS: Patients with relapsed SCLC who received anlotinib plus PD-1 inhibitor as a ≥ second-line therapy (n = 14) had a significantly longer PFS than those who received PD-1 inhibitor alone (n = 14, 5.0 vs. 3.0 months; P = 0.005). For patients with previously untreated wild-type NSCLC, the combination therapy in the first-line setting (n = 6) provided a marginally longer PFS than mono-chemotherapy (n = 6, 8.0 vs. 3.0 months; P = 0.075). For patients with relapsed NSCLC, the combination therapy in the ≥ second-line setting (n = 62) resulted in significantly higher objective response rate (19.3 vs. 5.0 vs. 2.4%; P = 0.013) and longer PFS (8.0 vs. 2.0 vs. 2.0 months; P <0.001) as compared to monotherapy of either chemotherapy (n = 41) or PD-1 inhibitor (n = 62). Anlotinib and PD-1 blockade combination therapy was an independent predictive factor of longer PFS (P <0.001). CONCLUSION: The combination of anlotinib and PD-1 inhibitor has promising efficacy and manageable toxicity as a second- or later-line treatment of relapsed NSCLC and possibly for relapsed SCLC.

CircRNA-SORE mediates sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1.

Sorafenib is the first-line chemotherapeutic therapy for advanced hepatocellular carcinoma (HCC). However, sorafenib resistance significantly limits its therapeutic efficacy, and the mechanisms underlying resistance have not been fully clarified. Here we report that a circular RNA, circRNA-SORE (a circular RNA upregulated in sorafenib-resistant HCC cells), plays a significant role in sorafenib resistance in HCC. We found that circRNA-SORE is upregulated in sorafenib-resistant HCC cells and depletion of circRNA-SORE substantially increases the cell-killing ability of sorafenib. Further studies revealed that circRNA-SORE binds the master oncogenic protein YBX1 in the cytoplasm, which prevents YBX1 nuclear interaction with the E3 ubiquitin ligase PRP19 and thus blocks PRP19-mediated YBX1 degradation. Moreover, our in vitro and in vivo results suggest that circRNA-SORE is transported by exosomes to spread sorafenib resistance among HCC cells. Using different HCC mouse models, we demonstrated that silencing circRNA-SORE by injection of siRNA could substantially overcome sorafenib resistance. Our study provides a proof-of-concept demonstration for a potential strategy to overcome sorafenib resistance in HCC patients by targeting circRNA-SORE or YBX1.

Olaparib and enzalutamide synergistically suppress HCC progression via the AR-mediated miR-146a-5p/BRCA1 signaling.

Hepatocellular carcinoma (HCC) is one of most common cancers worldwide, however, the treatment for advanced HCC remains unsatisfactory. We focused on the function of the androgen receptor (AR) in HCC and tried to find new treatment strategy based on antiandrogen enzalutamide (Enz). Here, we found that olaparib, a FDA-approved PARP inhibitor, could enhance the cytotoxicity in HCC cells with a lower BRCA1 expression, and suppressing the AR with either Enz or AR-shRNA could further increase the olaparib sensitivity to better suppress the HCC cell growth via a synergistic mechanism that may involve suppressing the expression of BRCA1 and other DNA damage response (DDR) genes. Mechanism studies revealed that Enz/AR signaling might transcriptionally regulate the miR-146a-5p expression via binding to the Androgen Response Elements on its 5' promoter region, which could then lead to suppress the homologous recombination-related BRCA1 expression via direct binding to the mRNA 3'UTR. Preclinical studies using an in vivo mouse model also demonstrated that combining Enz plus olaparib led to better suppression of the HCC progression. Together, these in vitro/in vivo data suggest that combining Enz and olaparib may help in the development of a novel therapy to better suppress the HCC progression.

TR4 nuclear receptor suppresses HCC cell invasion via downregulating the EphA2 expression.

Early studies indicated that testicular nuclear receptor 4 (TR4) could function as a suppressor in the transcriptional regulation of the HBV core gene expression, which might then influence the development of hepatocellular carcinoma (HCC). The direct linkage between TR4 and HCC progression, however, remained unclear. Here, via a human clinical sample survey, we found that 13 of the 18 HCC patients studied had lower TR4 expression in metastatic lesions than in matched primary HCC lesions, suggesting that TR4 may play a negative role in HCC metastasis. Results from in vitro cell migration/invasion studied confirmed that TR4 could suppress HCC cell migration/invasion. Mechanism dissection revealed that TR4 might function through downregulating ephrin type-A receptor 2 (EphA2) expression at the transcriptional level via direct binding to the TR4REs located on the 5' promoter of EphA2 to suppress HCC cell migration/invasion. Targeting the EphA2 via EphA2-siRNA partially reversed the enhanced HCC cell migration/invasion with confirmed TR4 knockdown. Notably, results from preclinical studies using in vivo mouse model with orthotopic xenograft of HCC LM3 cells also confirmed the in vitro findings. Taking these findings together, preclinical studies using multiple in vitro HCC cell lines and an in vivo mouse model all led to the conclusion that TR4 may function as a suppressor of HCC metastasis and that targeting this newly identified TR4-EphA2 signaling may improve our ability to suppress HCC metastasis.

Increasing AR by HIF-2α inhibitor (PT-2385) overcomes the side-effects of sorafenib by suppressing hepatocellular carcinoma invasion via alteration of pSTAT3, pAKT and pERK signals.

Although sorafenib is currently used as a standard treatment for advanced hepatocellular carcinoma, low response rate, transient and limited efficacy, primary and acquired resistance and negative side-effects gain increasing attentions, suggesting the need for better efficacious combination therapy. Here, we demonstrated that the sorafenib-induced or hypoxia-induced hypoxia inducible factor (HIF)-2α could bind to an hypoxia responsive element within 500 bp region of androgen receptor (AR) promoter and thus transcriptionally suppress AR. Importantly, In vitro and In vivo studies suggested a specific and potent HIF-2α inhibitor, PT-2385, could significantly enhance sorafenib efficacy by suppressing HIF-2α, increasing AR and suppressing downstream pSTAT3/pAKT/pERK pathways. Clinical samples further confirmed the role of HIF-2α and AR. It is promising that PT-2385 could alleviate the undesirable side-effects of sorafenib treatment by sorafenib-PT-2385 combination therapy, which may shed light for late-stage HCC patients.

TR4 nuclear receptor enhances the cisplatin chemo-sensitivity via altering the ATF3 expression to better suppress HCC cell growth.

Early studies indicated that TR4 nuclear receptor (TR4) may play a key role to modulate the prostate cancer progression, its potential linkage to liver cancer progression, however, remains unclear. Here we found that higher TR4 expression in hepatocellular carcinoma (HCC) cells might enhance the efficacy of cisplatin chemotherapy to better suppress the HCC progression. Knocking down TR4 with TR4-siRNA in HCC Huh7 and Hep3B cells increased cisplatin chemotherapy resistance and overexpression of TR4 with TR4-cDNA in HCC LM3 and SNU387 cells increased cisplatin chemotherapy sensitivity. Mechanism dissection found that TR4 might function through altering the ATF3 expression at the transcriptional level to enhance the cisplatin chemotherapy sensitivity, and interrupting ATF3 expression via ATF3-siRNA reversed TR4-enhanced cisplatin chemotherapy sensitivity in HCC cells. The in vivo HCC mouse model using xenografted HCC LM3 cells also confirmed in vitro cell lines data showing TR4 enhanced the cisplatin chemotherapy sensitivity. Together, these results provided a new potential therapeutic approach via altering the TR4-ATF3 signals to increase the efficacy of cisplatin to better suppress the HCC progression.

Comparison of laparoscopic hepatectomy, percutaneous radiofrequency ablation and open hepatectomy in the treatment of small hepatocellular carcinoma.

OBJECTIVE: Three mainstream techniques--laparoscopic hepatectomy (LH), percutaneous radiofrequency ablation (pRFA), and open hepatectomy (OH)--were compared in this study, in terms of their efficacies in the treatment of small hepatocellular carcinoma (HCC). METHODS: A comparative study was performed within a total of 94 patients diagnosed with small HCC in our hospital from 2005 to 2010, who underwent LH (28), RFA (33), or OH (33). They had either a single tumor lesion of less than or up to three nodules with diameters of less than each. Outcomes were carefully evaluated throughout a 3-year follow-up interval and statistically interpreted. RESULTS: The pRFA group had a significantly lower disease-free survival rate compared with the two surgical groups (P=0.001) and significantly shorter overall survival (P=0.005), while the LH group and the OH group had no difference in survival results. For patients younger than 60 years old, surgical approaches offered a better long-term overall survival prognosis (P=0.008). There were no statistically significant differences among the three groups in overall survival for elderly patients (P=0.104). CONCLUSIONS: Among patients with small HCC, LH may provide better curative effects than pRFA without increasing complication rates. pRFA leads to faster recurrence than surgical resections. LH has similar therapeutic effects to OH and causes less trauma. For patients younger than 60 years old, LH may be the best curative treatment. Elderly patients may choose either surgery or pRFA.

Targeting Androgen Receptor (AR)→IL12A Signal Enhances Efficacy of Sorafenib plus NK Cells Immunotherapy to Better Suppress HCC Progression.

Gender disparity has long been considered as a key to fully understand hepatocellular carcinoma (HCC) development. At the same time, immunotherapy related to IL12 still need more investigation before being applied in clinical settings. The aim of this study is to investigate the influence of the androgen receptor (AR) on natural killer (NK) cell-related innate immune surveillance in liver cancer, and provide a novel therapeutic approach to suppress HCC via altering IL12A. By using in vitro cell cytotoxicity test and in vivo liver orthotopic xenograft mouse model, we identified the role of AR in modulating NK cell cytotoxicity. Luciferase report assay and chromatin immunoprecipitation assay were applied for mechanism dissection. IHC was performed for sample staining. Our results showed AR could suppress IL12A expression at the transcriptional level via direct binding to the IL12A promoter region that resulted in repressing efficacy of NK cell cytotoxicity against HCC, and sorafenib treatment could enhance IL12A signals via suppressing AR signals. These results not only help to explain the AR roles in the gender disparity of HCC but also provide a potential new therapy to better suppress HCC via combining sorafenib with NK cell-related immunotherapy. Mol Cancer Ther; 15(4); 731-42. ©2016 AACR.

Total laparoscopic left hepatectomy for primary hepatolithiasis: Eight-year experience in a single center.

BACKGROUND: Primary hepatolithiasis is prevalent in some Asian countries. Hepatectomy is a definitive treatment for this disease. Whether laparoscopic left hepatectomy (LLH) is suitable for primary hepatolithiasis remains controversial, because LLH is more challenging technically. The aim of this study was to evaluate the outcomes of LLH for primary hepatolithiasis in a single center. METHODS: This retrospective study included 96 consecutive patients who underwent LLH for primary hepatolithiasis in the Sir Run Run Shaw Hospital from May 2005 to December 2012. In addition, 105 patients who met the same inclusion criteria for LLH but underwent open left hepatectomy (OLH) for hepatolithiasis during the same period were reviewed for comparison. The patient characteristics, operative features, postoperative course, residual stone rate, and recurrent stone rate were analyzed. RESULTS: In the LLH group, 81 patients (84.4%) underwent total LLH and 15 (15.6%) were converted to open hepatectomy. The volume of intraoperative blood loss was less in the LLH than OLH group (383 ± 281 vs 554 ± 517 mL; P = .005). The intraoperative transfusion rate was also significantly lower in the LLH group (8.3% vs 30.5%; P < .001). There were no differences between the LLH and OLH groups in operation time, duration of postoperative hospitalization, postoperative complication rate, residual stone rate, or recurrent stone rate. CONCLUSION: In experienced hands, total LLH is a safe, effective, and promising treatment for patients with hepatolithiasis.

Adenoviral delivery of truncated MMP-8 fused with the hepatocyte growth factor mutant 1K1 ameliorates liver cirrhosis and promotes hepatocyte proliferation.

Liver cirrhosis is a chronic liver disease caused by chronic liver injury, which activates hepatic stellate cells (HSCs) and the secretion of extracellular matrix (ECM). Cirrhosis accounts for an extensive level of morbidity and mortality worldwide, largely due to lack of effective treatment options. In this study, we have constructed a fusion protein containing matrix metal-loproteinase 8 (MMP-8) and the human growth factor mutant 1K1 (designated cMMP8-1K1) and delivered it into hepatocytes and in vivo and in cell culture via intravenous injection of fusion protein-harboring adenovirus. In doing so, we found that the cMMP8-1K1 fusion protein promotes the proliferation of hepatocytes, likely resulting from the combined inhibition of type I collagen secretion and the degradation of the ECM in the HSCs. This fusion protein was also observed to ameliorate liver cirrhosis in our mouse model. These changes appear to be linked to changes in downstream gene expression. Taken together, these results suggest a possible strategy for the treatment of liver cirrhosis and additional work is warranted.