Safety and Effectiveness of High-Precision Hyperthermic Intraperitoneal Perfusion Chemotherapy in Peritoneal Carcinomatosis: A Real-World Study.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) has been reported to effectively control peritoneal carcinomatosis (PC) in various patient populations, but there is a lack of real-world data. This study aimed to examine the safety and effectiveness of HIPEC in patients with PC in a real-world setting. METHODS: This was a retrospective study of patients with PC treated with the high-precision BR-TRG-I type HIPEC device between December 2006 and December 2016. Vital signs during HIPEC and adverse events were recorded. Effectiveness was evaluated by total objective remission rate (ORR), which was based on ascites' remission 4 weeks after HIPEC. RESULTS: A total of 1,200 patients were included. There were 518 males and 682 females, with a mean age of 58.6 ± 6.5 years (range, 32-76 years). Among the patients, 93.6% of the patients (1123/1200) successfully received the three sessions of HIPEC, 158 had massive ascites. The changes of vital signs during HIPEC were within acceptable ranges, and patients only had a transient fever and abdominal distension. Regarding the HIPEC-related complications, hemorrhage was observed in seven (0.6%) patients, anastomotic leakage in four (0.5%), and intestinal obstruction in eight (0.7%). Nine (0.8%, 9/1200) patients had CTCAE grade IV bone marrow suppression, and three (0.3%, 3/1200) patients had severe renal failure (SRF), which were considered to be drug-related. The ORR of malignant ascites was 95.6% (151/158). CONCLUSION: This real-world study strongly suggests that HIPEC was safe in treating PC patients with a low rate of adverse events and leads to benefits in PC patients with massive malignant ascites.

Knockdown of lncRNA ZNRD1-AS1 suppresses gastric cancer cell proliferation and metastasis by targeting the miR-9-5p/HSP90AA1 axis.

LncRNAs play an important role in a variety of biological processes, such as cancer pathogenesis. The lncRNA zinc ribbon domain containing 1 antisense RNA 1 (ZNRD1-AS1) is a natural antisense transcript of ZNRD1. In this study, we found that ZNRD1-AS1 levels were significantly upregulated in gastric cancer tissues compared to those in adjacent healthy gastric tissues. ZNRD1-AS1 levels were correlated with lymph node metastasis, distal metastasis, and TNM stage, but were not correlated with age and sex. ZNRD1-AS1 knockdown suppressed cell proliferation, migration, and invasion, and promoted apoptosis. ZNRD1-AS1 overexpression had the opposite effect. ZNRD1-AS1 knockdown suppressed tumor growth and pulmonary metastasis in a nude mouse model ZNRD1-AS1 can bind to miR-9-5p and ZNRD1-AS1 knockdown can decrease the protein level of heat shock protein 90 alpha family class A member 1 (HSP90AA1), which is the target of miR-9-5p. The miR-9-5p inhibitor rescued the effect of ZNRD1-AS1 knockdown, and the mutant of miR-9-5p binding site on ZNRD1-AS1 sequence blocked the effect of ZNRD1-AS1 overexpression. In conclusion, ZNRD1-AS1 levels were upregulated in gastric cancer tissues, and knockdown of ZNRD1-AS1 suppressed gastric cancer cell proliferation and metastasis by targeting the miR-9-5p/HSP90AA1 axis. Our findings provide novel insights into the mechanism underlying the role of ZNRD1-AS1 in gastric cancer.

Prognostic and clinicopathological value of PD-L2 in lung cancer: A meta-analysis.

OBJECTIVE: The prognostic role of programmed death ligand-2 (PD-L2) expression in lung cancer has been widely studied, however, the results are controversial. Accordingly, we investigated the prognostic and clinicopathological value of PD-L2 in patients with lung cancer in this meta-analysis. METHODS: Relevant studies were systematically searched in the PubMed, Web of Science, EMBASE, ClinicalTrials.gov., Scopus, and Cochrane Library until July 10, 2020. The hazard ratio (HR), odds ratio (OR), and their corresponding 95% confidence intervals (CIs) were calculated. RESULTS: Thirteen studies with 3107 participants were included. High PD-L2 expression was associated with poor overall survival (OS) (HR 1.248, 95% CI: 1.071-1.455, p = 0.004) and worse disease-free survival (DFS)/progression-free survival (PFS)/relapse-free survival (RFS) (HR 1.224, 95% CI: 1.058-1.417, p = 0.007) in lung cancer. Furthermore, unfavorable OS was found in lung adenocarcinoma (HR 1.349, 95% CI: 1.051-1.731, p = 0.019), but not in other pathological types (HR 1.192, 95% CI: 0.982-1.447 p = 0.076) with higher PD-L2 expression in our subgroup analysis. Concerning the clinicopathological characteristics, high PD-L2 expression was associated with smoking (OR 0.725, 95% CI: 0.591-0.890, p = 0.002) and PD-L1 (OR 1.607, 95% CI:1.115-2.314, p = 0.011) and vascular invasion (OR 1.500, 95% CI: 1.022-2.203, p = 0.039). CONCLUSION: PD-L2 overexpression might predict a poor prognosis in lung cancer patients after surgery. PD-L2 expression might be a potential biomarker for PD-1/PD-L1-targeted immunotherapy in lung cancer, which should be investigated in future studies.

Cytoreductive surgery and HIPEC for malignant ascites from colorectal cancer - a randomized study.

INTRODUCTION: The efficacy of different timings of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in controlling malignant ascites caused by peritoneal carcinomatosis of colorectal cancer (CRC) is not well defined. The study aims to investigate the clinical efficacy and safety of different timings of CRS with HIPEC for malignant ascites caused by peritoneal carcinomatosis from CRC. MATERIALS AND METHODS: This was a preliminary randomized controlled study performed at the Intracelom Hyperthermic Perfusion Therapy Center of the Cancer Hospital of Guangzhou Medical University (China) from December 2008 to December 2016. The patients were randomized to: CRS, followed by HIPEC (CRS+HIPEC; n = 14), and ultrasound-guided HIPEC, followed by CRS 1 to 2 weeks later (HIPEC+ delayed cytoreductive surgery (dCRS) group, n = 14). The endpoints were complete remission rate of ascites, successful complete CRS rate, and overall survival. RESULTS: Malignant ascites in all patients showed complete remission; the total effective rate was 100%. Complete CRS was not feasible in any patient. The median follow-up of the 2 groups was 41.9 and 42.3 months in the CRS+HIPEC and HIPEC+dCRS groups, respectively. Overall survival was 14.5 (95%CI: 7-19 months) and 14.3 months (95%CI: 4-21 months) (P > .05). The adverse effects of HIPEC were manageable. CONCLUSIONS: CRS+HIPEC and HIPEC+dCRS have the same efficacy in controlling malignant ascites caused by CRC and peritoneal carcinomatosis. The timing of CRS and HIPEC does not prolong the survival of patients with peritoneal carcinomatosis from CRC, even when a complete CRS is not feasible.

Laparoscopic Hyperthermic Intraperitoneal Perfusion Chemotherapy for Patients With Malignant Ascites Secondary to Unresectable Gastric Cancer.

BACKGROUND: To compare the efficacy of 3 chemotherapeutic combinations for laparoscopic hyperthermic intraperitoneal perfusion chemotherapy (HIPPC) in the treatment of malignant ascites secondary to unresectable gastric cancer (GC). MATERIALS AND METHODS: From January 2010 to December 2013, 38 GC patients were randomly divided into 3 groups and treated by laparoscopic HIPPC with 1 of the 3 following chemotherapy combinations: raltitrexed (Ra) with oxaliplatin (L-OHP), Ra with cisplatin (DDP), and Ra with mitomycin C (MMC). Perioperative complications, patients' quality of life, and survival were recorded and compared among the 3 groups. RESULTS: The intraoperative course was successful in all patients, and no perioperative death or complication related to laparoscopic HIPPC was documented. The median follow-up period was 9 months and the median survival was 7.5 months for all patients. Patients in the Ra/L-OHP group had a median survival of 8.7 months, the Ra/DDP group had a median survival of 5.6 months, and the Ra/MMC group had a median survival of 7.5 months. Patients' median survival in the Ra/L-OHP group and Ra/MMC group is significantly longer than Ra/DDP group (P<0.05). No significant difference was found in total remission rate of ascites, increase in the Karnofsky performance scale, and incidence rate of port-site metastases among the 3 groups. CONCLUSIONS: Laparoscopy-assisted HIPPC provide modest yet encouraging efficacy for malignant ascites secondary to disseminated GC. Our preliminary data indicate that the chemotherapeutical combination of Ra/L-OHP and Ra/MMC might be more beneficial compared with Ra/DDP in terms of patients' survival.

LncRNA AC093818.1 accelerates gastric cancer metastasis by epigenetically promoting PDK1 expression.

Gastric cancer (GC) is a highly prevalent type of metastatic tumor. The mechanisms underlying GC metastasis are poorly understood. Some long noncoding RNAs (lncRNAs) reportedly play key roles in regulating metastasis of GC. However, the biological roles of five natural antisense lncRNAs (AC093818.1, CTD-2541M15.1, BC047644, RP11-597M12.1, and RP11-40A13.1) in GC metastasis remain unclear. In this study, the expression of these lncRNAs was measured by quantitative reverse transcription-polymerase chain reaction. Migration and invasion were evaluated by wound-healing and the Transwell assay, respectively. Stable cells were injected into the tail veins of nude mice. Sections of collected lung and liver tissues were stained using hematoxylin and eosin. Protein expression was analyzed by western blot. RNA immunoprecipitation (RIP) assay was used to verify whether the STAT3 and SP1 transcription factors bound to AC093818.1 in GC cells. Expression levels of the five lncRNAs, especially AC093818.1, were significantly upregulated in metastatic GC tissues relative to those in nonmetastatic GC tissues. AC093818.1 expression was correlated with invasion, lymphatic metastasis, distal metastasis, and tumor-node-metastasis stage. AC093818.1 expression was highly sensitive and specific in the diagnosis of metastatic or nonmetastatic GC. AC093818.1 overexpression promoted GC migration and invasion in vitro and in vivo. AC093818.1 overexpression increased PDK1, p-AKT1, and p-mTOR expression levels. AC093818.1 silencing decreased these expressions. AC093818.1 bound to transcription factors STAT3 and SP1, and SP1 or STAT3 silencing could alleviated the effect of AC093818.1 overexpression. The data demonstrate that lncRNA AC093818.1 accelerates gastric cancer metastasis by epigenetically promoting PDK1 expression. LncRNA AC093818.1 may be a potential therapeutic target for metastatic GC.

Hyperthermic intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis: A multicenter propensity score-matched cohort study.

OBJECTIVE: Systemic chemotherapy has limited efficacy in the treatment of peritoneal metastasis (PM) in gastric cancer (GC). Hyperthermic intraperitoneal chemotherapy (HIPEC) combined with complete cytoreductive surgery (CRS) has shown promising outcomes but remains controversial. The present study aimed to evaluate the safety and efficacy of HIPEC without CRS in GC patients with PM. METHODS: This retrospective propensity score-matched multicenter cohort study included GC patients with PM treated with either chemotherapy alone (Cx group) or with HIPEC combined with chemotherapy (HIPEC-Cx group) in four Chinese high-volume gastric medical centers between 2010 and 2017. The primary outcomes were median survival time (MST) and 3-year overall survival (OS). Propensity score matching was performed to compensate for controlling potential confounding effects and selection bias. RESULTS: Of 663 eligible patients, 498 were matched. The MST in the Cx and HIPEC-Cx groups was 10.8 and 15.9 months, respectively [hazard ratio (HR)=0.71, 95% confidence interval (95% CI), 0.58-0.88; P=0.002]. The 3-year OS rate was 10.1% (95% CI, 5.4%-14.8%) and 18.4% (95% CI, 12.3%-24.5%) in the Cx and HIPEC-Cx groups, respectively (P=0.017). The complication rates were comparable. The time to first flatus and length of hospital stay for patients undergoing HIPEC combined with chemotherapy was longer than that of chemotherapy alone (4.6±2.4 dvs. 2.7±1.8 d, P<0.001; 14.2±5.8 dvs. 11.4±7.7 d, P<0.001), respectively. The median follow-up period was 33.2 months. CONCLUSIONS: Compared with standard systemic chemotherapy, HIPEC combined with chemotherapy revealed a statistically significant survival benefit for GC patients with PM, without compromising patient safety.

Development of a high-precision bladder hyperthermic intracavitary chemotherapy device for bladder cancer and pharmacokinetic study.

BACKGROUND: Bladder hyperthermic intracavitary chemotherapy (HIVEC) has good effectiveness for bladder cancer, but conventional HIVEC systems lack precision and convenient application. To test the safety of a new HIVEC device (BR-TRG-II-type) in pigs and to perform a preliminary clinical trial in patients with bladder cancer. METHODS: This device was tested on six pigs to optimize the temperature and time parameters. Then, 165 patients (HIVEC after transurethral resection (TUR), n = 128; or HIVEC, n = 37) treated between December 2006 and December 2016 were recruited. Mitomycin C (MMC) was the chemotherapeutic agent. A serum pharmacokinetic study was performed. The primary endpoints were tumor recurrence, disease-free survival (DFS), and cumulative incidence rate (CIR) during follow-up. The adverse effects were graded. RESULTS: The animal experiment showed that 45 °C for 1 h was optimal. HIVEC was successful, with the infusion tube temperature stably controlled at about 45 °C, and outlet tube temperature of about 43 °C in all patients, for three sessions. Serum MMC levels gradually increased during HIVEC and decreased thereafter. The mean DFS was 39 ± 3.21 months (ranging from 8 to 78 months), and the DFS rate was 89.1% during follow-up. No adverse events occurred. CONCLUSION: The use of the BR-TRG-II-type HIVEC device is feasible for the treatment of bladder cancer. Future clinical trials in patients with different stages of bladder cancer will further confirm the clinical usefulness of this device. TRIAL REGISTRATION: chictr.org.cn: ChiCTR1900022099 (registered on Mar. 252,019). Retrospectively registered.

Thermo-chemotherapy inhibits the proliferation and metastasis of gastric cancer cells via suppression of EIF5A2 expression.

PURPOSE: Thermo-chemotherapy (TCT) is a new approach for the treatment of cancer that combines chemotherapy with thermotherapy. In the present study, we investigated the relationship between eukaryotic translation initiation factor 5A2 (EIF5A2) and TCT sensitivity in gastric cancer (GC) to further illuminate the molecular mechanism underlying the effect of TCT on GC. METHODS: A TCT cell model was constructed, and EIF5A2 was silenced or overexpressed by infection with a lentivirus expressing either EIF5A2 or EIF5A2 shRNA. Then, RT-qPCR, Western blotting, and immunohistochemistry assays were performed to evaluate the changes in the expression levels of EIF5A2, c-myc, vimentin, and E-cadherin. Cell proliferation and xenograft assays were conducted to evaluate the effect on cell proliferation. Finally, wound-healing and Transwell invasion assays were performed to evaluate the effects on migration and invasion. RESULTS: TCT reduced EIF5A2 expression at both the mRNA and protein levels. It also inhibited cell proliferation, migration, and invasion, downregulated the expression of c-myc and vimentin, and increased the expression of E-cadherin in both MKN28 and MKN45 cells. Silencing of EIF5A2 enhanced the above effects of TCT on MKN28 and MKN45 cells, while overexpression of EIF5A2 had the opposite effects. In addition, EIF5A2 overexpression weakened the inhibitory effect of TCT on tumor growth in vivo as well as the effects on c-myc, vimentin, and E-cadherin. CONCLUSION: TCT inhibits GC cell proliferation and metastasis by suppressing EIF5A2 expression. Our results provide new insights into our understanding of the molecular mechanism underlying the effects of TCT in GC.

Ascites do not affect the rate of complete cytoreductive surgery and prognosis in patients with primary ovarian cancer with ascites treated with hyperthermic intraperitoneal chemotherapy.

Cytoreductive surgery (CRS) is the current standard therapy procedure for patients with advanced ovarian cancer (OC), but numerous patients with OC are complicated with ascites. The aim of the present study was to assess whether massive ascites affect the rate of complete CRS and prognosis for patients with primary OC treated with hyperthermic intraperitoneal chemotherapy (HIPEC). Between December 2006 and December 2015, 1,293 patients with primary OC from the Intracelom Hyperthermic Perfusion Therapy Center of the Cancer Hospital of Guangzhou Medical University prospective database were treated with CRS combined with HIPEC. A total of 1,225 patients were without malignant ascites or small amounts of ascites and 68 had massive malignant ascites. The rate of complete CRS, overall survival (OS), disease-free survival (DFS) and resolution of ascites for patients with massive ascites were analyzed between patients without/small ascites, and with massive ascites. Complete CRS was successful in 86.8% (1,063/1,225) of patients without/small ascites, and 85.3% (58/68) of patients with massive ascites. No statistical differences were identified in complete CRS success between patients with ascites and patients without/small ascites (P=0.080). For patients with massive ascites, all symptoms exhibited regression; the total objective remission rate was 100% (68/68), even for patients with incomplete CRS (10/68) (P=0.100). The mean OS was 58 months and the mean DFS was 26 months in patients without/small ascite, vs. 57 months and 28 months in patients with massive ascites. No significant differences were noted in median DFS and median OS between patients with ascites, and patients without/small ascites (All P>0.05). In conclusion, the results of the present study suggest that ascites does not affect the rate of complete CRS and the prognosis of patients with massive ascites following HIPEC. CRS is suitable for the majority of patients with primary OC and massive ascites.

Hyperthermia enhances radiosensitivity of colorectal cancer cells through ROS inducing autophagic cell death.

Hyperthermia (HT) enhances the anti-cancer effects of radiotherapy (RT), but the precise biochemical mechanisms involved are unclear. This study was aim to investigate if mild HT sensitizes colorectal cancer cells to RT through reactive oxygen species (ROS)-inducing autophagic cell death in a mice model of HCT116 human colorectal cancer. HCT116 mice model were randomly divided into five groups: mock group, hyperthermia group (HT), radiotherapy group (RT), HT + RT group, and HT + RT +N-acetyl L-cysteine (NAC) group (HT + CT + NAC). After four weeks of treatment, cancer growth inhibition, rate and mitochondrial membrane potential were measured with MTT and JC-1 assays, respectively, while ROS were estimated fluorimetrically. The relationship of these parameters to expressions of autophagy-related genes Beclin1, LC3B, and mTOR was analyzed. Gene expression was measured by Real-Time polymerase chain reaction (RT-PCR). There were significant increases in ROS levels and mitochondrial membrane potential in the HT + RT group. ROS levels in the HT + RT group increased more significantly than in any other group. In contrast, ROS levels in the HT + RT + NAC group were significantly decreased relative to the HT + RT group. The number of autophagic bodies in HT + RT group was higher than that of mock group. There were significant increases in the expression of Beclin1 and LC3B genes, while mTOR expression was significantly decreased in the HT + CT group. Treatment with NAC reversed the pattern of these changes. These results indicate that HT enhances the radiosensitivity of colorectal cancer cells to RT through ROS inducing autophagic cell death.

BRD4 promotes gastric cancer progression through the transcriptional and epigenetic regulation of c-MYC.

Although the significance of BRD4 in the epigenetic memory and cancer genesis has been intensively investigated, little is known about its function and potential roles during the generation and progression of gastric cancer. We report here that BRD4 increases the proliferation and represses the apoptosis of gastric cancer cells through activating c-MYC via transcriptional and epigenetic regulation mechanisms. Expression analyses in both small and large cohort of sample show that BRD4 is highly expressed in gastric cancer tissues/cells when compared with the adjacent non-tumor tissues/normal cells. We also find a positive correlation between the expression of BRD4 and c-MYC in patient samples. The repression of BRD4 by siRNAs leads to the down-regulation of c-MYC in gastric cancer cells. Chromatin immunoprecipitation-qPCR and luciferase assays show that BRD4 binds to and coordinately activates c-MYC promoter, indicating that c-MYC is transcriptional target of BRD4 and BRD4 regulates its basal expression. Further evidence show that the histone acetylation inhibitor reduces the binding of BRD4 as well as the histone activation level on c-MYC promoter, and leads to the down-regulation of c-MYC, suggesting that BRD4 regulates the expression of c-MYC through epigenetic mechanism. Functionally, the suppression of BRD4 leads to growth inhibition and apoptosis in gastric cancer cells. Force expression of c-MYC alongside with BRD4 repression rescue the anti-cancer effects caused by BRD4 repression. Collectively, our data not only uncovered the mechanism of BRD4 in regulating the proliferation of gastric cancer cells but also provides a new therapeutic strategy for this type of cancer.

Long noncoding RNA LINC00673 epigenetically suppresses KLF4 by interacting with EZH2 and DNMT1 in gastric cancer.

Long non-coding RNAs (lncRNAs), a variety of transcripts without protein coding ability, have recently been reported to play vital roles in gastric cancer (GC) development and progression. However, the biological role of long non-coding RNA LINC00673 in GC is not fully known. In the study, we found that LINC00673 expression was dramatically higher in gastric cancer tissues compared with adjacent normal tissues, and positively associated with lymph node metastasis, distant metastasis and TNM stage in patients. Higher LINC00673 expression predicted poor disease-free survival (DFS) and overall survival (OS) in GC patients. By univariate and multivariate Cox analysis, the results confirmed that higher LINC00673 expression was an independent risk factor of prognosis in patients. Knockdown of endogenous LINC00673 significantly inhibited cell proliferation, colony formation number, cell migration and invasion in GC. Furthermore, knockdown of endogenous LINC00673 reduced the expression levels of PCNA, CyclinD1 and CDK2 in GC cells. RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) proved that LINC00673 suppressed KLF4 expression by interacting with EZH2 and DNMT1 in GC cells. Moreover, we confirmed that LINC00673 promoted cell proliferation and invasion by partly repressing KLF4 expression in GC. Taken together, these results indicated that LINC00673 may be a prognostic biomarker and therapeutic target for GC patients.

Mild hyperthermia enhances sensitivity of gastric cancer cells to chemotherapy through reactive oxygen species-induced autophagic death.

Mild hyperthermia enhances anti-cancer effects of chemotherapy, but the precise biochemical mechanisms involved are not clear. This study was carried out to investigate whether mild hyperthermia sensitizes gastric cancer cells to chemotherapy through reactive oxygen species-induced autophagic death. In total, 20 BABL/c mice of MKN-45 human gastric cancer tumor model were divided into hyperthermia + chemotherapy group, hyperthermia group, chemotherapy group, N-acetyl-L-cysteine group, and mock group. Reactive oxygen species production and expression of autophagy-related genes Beclin1, LC3B, and mammalian target of rapamycin were determined. The relationships between tumor growth regression, expression of autophagy-related genes, and reactive oxygen species production were evaluated. Tumor size and wet weight of hyperthermia + chemotherapy group was significantly decreased relative to values from hyperthermia group, chemotherapy group, N-acetyl-L-cysteine group, and mock group ( F = 6.92, p < 0.01 and F = 5.36, p < 0.01, respectively). Reactive oxygen species production was significantly higher in hyperthermia + chemotherapy group than in hyperthermia, chemotherapy, and mock groups. The expression levels of Beclin1 and LC3B were significantly higher, while those of mammalian target of rapamycin were significantly lower in hyperthermia + chemotherapy group than in hyperthermia, chemotherapy, and mock groups. Tumor growth regression was consistent with changes in reactive oxygen species production and expression of autophagy-related genes. N-acetyl-L-cysteine inhibited changes in the expression of the autophagy-related genes and also suppressed reactive oxygen species production and tumor growth. Hyperthermia + chemotherapy increase expression of autophagy-related genes Beclin1 and LC3B, decrease expression of mammalian target of rapamycin, and concomitantly increase reactive oxygen species generation. These results strongly indicate that mild hyperthermia enhances sensitivity of gastric cancer cells to chemotherapy through reactive oxygen species-induced autophagic death.

Bladder intracavitary hyperthermic perfusion chemotherapy for the prevention of recurrence of non-muscle invasive bladder cancer after transurethral resection.

Preventing the recurrence of non-muscle invasive bladder cancer (NMIBC) post-transurethral resection (TUR) remains challenging. The aim of the present study was to investigate the effectiveness and safety of bladder intracavitary hyperthermic perfusion chemotherapy (BHPC) for prevention of NMIBC recurrence post-TUR. Between December 2006 and December 2014, 53 patients with NMIBC who underwent TUR were randomly assigned to receive BHPC (BHPC group, 28 patients) or intravesical chemotherapy alone (chemotherapy group, 25 patients) at the Intracelom Hyperthermic Perfusion Therapy Center of Guangzhou Medical University Cancer Hospital (Guangzhou, China). BHPC was performed by combining perfusion-based hyperthermia with chemotherapeutic agent mitomycin C (MMC) in the bladder, and the chemotherapy group of patients received bladder MMC perfusion. The concentration of MMC in the perfusion fluid and serum were assessed at different time-points. Tumor recurrence, disease-free survival (DFS), and side-effects were recorded and compared between the 2 groups. Results revealed that BHPC was performed smoothly, at ~44̊C in the bladder cavity. Patients tolerated BHPC, and no side-effects were observed. Both BHPC and intravesical chemotherapy achieved a high MMC concentration in the bladder perfusion liquid, but low MMC concentration in the serum, although serum MMC concentrations in the BHPC group were significantly higher (P<0.05). The tumor recurrence rate was significantly lower (10.7 vs. 28.0%; P=0.02) and the DFS period was significantly longer (37±1.2 vs. 19±0.9 months; P=0.001) in the BHPC group than in the chemotherapy group. Our results demonstrated that BHPC is safe and effective for preventing NMIBC recurrence post-TUR and prolongs DFS.

Hyperthermic Intraperitoneal Perfusion Chemotherapy and Cytoreductive Surgery for Controlling Malignant Ascites From Ovarian Cancer.

BACKGROUND: Malignant ascites, a complication often seen in patients with ovarian cancer (OC), is difficult to treat, but hyperthermic intraperitoneal chemotherapy (HIPEC) has a good efficacy. OBJECTIVE: The aim of this study was to assess the efficacy of cytoreductive surgery (CRS) combined with HIPEC for controlling malignant ascites from OC. MATERIALS AND METHODS: From December 2009 until December 2014, 53 patients with OC and malignant ascites were treated with CRS and HIPEC. Patients in good health condition were treated with CRS followed by HIPEC (CRS + HIPEC), and patients in poor health condition were treated initially with B-mode ultrasound-guided HIPEC followed by delayed CRS upon improvement of their health condition (HIPEC + delayed CRS). Resolution of ascites, complete CRS, overall survival, and disease-free survival were analyzed. RESULTS: All patients showed ascites regression. The total objective remission rate was 100%, even for patients in the poor condition group before CRS. Complete CRS was successful in 30 (88.23%) of 34 patients in the good condition group, and 17 (89.47%) of 19 patients in the poor condition group (P > 0.05). Median disease-free survival and median overall survival were 21 and 39 months in the good condition group, and 22 and 38 months in the poor condition group, respectively (P > 0.05). CONCLUSIONS: Hyperthermic intraperitoneal chemotherapy is effective at controlling ascites in patients with OC, even for patients in poor condition before CRS, or when complete CRS is not feasible. Furthermore, the regression of ascites appears not to be dependent on complete resection.

Autophagic death induced by thermo­chemotherapy in gastric cancer cells results from the reactive oxygen species pathway.

Gastric cancer is the third leading type of cancer and has the third leading cancer­associated mortality in China. The mechanism of thermo­chemotherapy in gastric cancer cells remains to be elucidated. The present study aimed to investigate the role of autophagic cell death in the thermo­chemotherapy of gastric cancer. The current study included four groups: An empty control group, a hyperthermia group, a chemotherapy (oxaliplatin) group, and a thermo­chemotherapy group. Cell viability was analyzed by the MTS assay. Production of intracellular reactive oxygen species (ROS) was quantified by flow cytometry. Autophagy­associated proteins, Beclin 1, microtubule­associated protein 1A/1B­light chain (LC3B) and mammalian target of rapamycin (mTOR), were determined by western blot analysis. The results indicated that thermo­chemotherapy markedly increased intracellular ROS production, and decreased mitochondrial membrane potential. The transmission electron microscopy results indicated that thermo­chemotherapy induced production of autophagic bodies. In addition, thermo­chemotherapy­induced cell damage at the cellular and animal levels indicated a notable increase in the expression of the autophagy­associated genes, LC3B and Beclin 1. A negative correlation between mTOR expression and autophagy was also identified, which demonstrates that thermo­chemotherapy induces autophagic cell death by activating the autophagy­associated signaling pathways. The results of the present study demonstrated that the ROS level is important in autophagic death of the gastric carcinoma cells, and the increased ROS level, induced by thermo­chemotherapy treatment, induced autophagy in gastric carcinoma cells.

miR-409-3p sensitizes colon cancer cells to oxaliplatin by inhibiting Beclin-1-mediated autophagy.

The chemoresistance of colon cancer cells limits the efficacy of chemotherapy. miR-409-3p has been shown to be downregulated in various types of cancer. In the present study, we examined the role of miR-409-3p in colon cancer as well as the effects of miR­409-3p on the sensitivity of colon cancer cells to oxaliplatin. The expression of miR-409 was significantly downregulated in the human colon cancer cell lines compared with the normal colon epithelial cells. Importantly, the miR-409-3p expression levels were lower in human colon cancer patient samples than in normal colon tissues. Moreover, we observed a negative correlation between the miR­409-3p levels and resistance to oxaliplatin: the oxaliplatin-resistant colon cancer cells exhibited significantly downregulated miR­409-3p levels, but higher autophagic activity than the oxaliplatin-sensitive cells. Using bioinformatics analysis, we predicted that miR­409-3p miRNA binds to the key autophagy gene encoding Beclin-1. Our findings indicated that the overexpression of miR­409-3p inhibited Beclin-1 expression and autophagic activity by binding to the 3'-untranslated region of Beclin-1 mRNA. In addition, the overexpression of miR­409-3p enhanced the chemosensitivity of the oxaliplatin-sensitive and oxaliplatin-resistant colon cancer cells. The restoration of Beclin-1 abrogated these effects of miR­409-3p. In a xenograft model using nude mice, we examined the effects of miR­409-3p on tumor growth during chemotherapy. miR­409-3p overexpression sensitized the tumor to chemotherapy, while inhibiting chemotherapy-induced autophagy in a manner dependent on Beclin-1. The findings of our study suggest that miR-409-3p is capable of enhancing the chemosensitivity of colon cancer cells by inhibiting Beclin-1-mediated autophagy.

Efficacy and safety of ultrasound-guided continuous hyperthermic intraperitoneal perfusion chemotherapy for the treatment of malignant ascites: a midterm study of 36 patients.

BACKGROUND: This study aimed to evaluate the efficacy and safety of ultrasound-guided continuous hyperthermic intraperitoneal perfusion chemotherapy (CHIPC) for the treatment of malignant ascites (MA). METHODS: Between July 2011 and June 2013, 36 MA patients were prospectively and consecutively hospitalized for three cycles of elective CHIPC under ultrasound guidance, maintained at a constant flow rate of 400-600 mL/min normal saline containing 5-fluorouracil plus mitomycin or carboplatin and at a constant temperature of 43°C±0.2°C, for 90 minutes. Main outcome measures were ascites resolution, Karnofsky performance status (KPS), and serum tumor biomarkers at 2 weeks after the last cycle of CHIPC. All the patients underwent uneventful CHIPC as scheduled, and vital signs remained stable over CHIPC. RESULTS: At 2 weeks after the last cycle of CHIPC, MA completely and partially resolved in 26 (72.2%) patients and eight (22.2%) patients, respectively; mean KPS score increased from pretreatment 61±9 to posttreatment 76±9 (P<0.001), and serum carcinoembryonic antigen and carbohydrate antigens 12-5 and 19-9 significantly decreased (all P<0.01). CONCLUSION: The current study indicated that ultrasound-guided CHIPC is an effective and safe palliative treatment modality for MA with respect to MA resolution, patient's general well-being, and systemic disease control. The long-term benefit of CHIPC on overall survival remains to be investigated in MA patients.

Laparoscopic Hyperthermic Intraperitoneal Perfusion Chemotherapy for Patients with Malignant Ascites Secondary to Unresectable Gastric Cancer.

BACKGROUND: To compare the efficacy of three chemotherapeutic combinations for laparoscopic hyperthermic intraperitoneal perfusion chemotherapy (HIPPC) in the treatment of malignant ascites secondary to unresectable gastric cancer (GC). MATERIALS AND METHODS: From January 2010 to December 2013, 38 GC patients were randomly divided into three groups and treated by laparoscopic HIPPC with one of the three following chemotherapy combinations: raltitrexed (Ra) with oxaliplatin [trans-(±)-diaminocyclohexane oxalatoplatinum (l-OHP)], Ra with cisplatin (DDP), and Ra with mitomycin C (MMC). Perioperative complications, patients' quality of life, and survival were recorded and compared among the three groups. RESULTS: The intraoperative course was successful in all patients, and no perioperative death or complication related to laparoscopic HIPPC was documented. The median follow-up period was 9 months, and the median survival was 7.5 months for all patients. Patients in the Ra/l-OHP group had a median survival of 8.7 months, the Ra/DDP group had a median survival of 5.6 months, and the Ra/MMC group had a median survival of 7.5 months. Patients' median survival in the Ra/l-OHP group and Ra/MMC group was significantly longer than in the Ra/DDP group (P < .05). No significant difference was found in total remission rate of ascites, increase in the Karnofsky Performance Scale, and incidence rate of port-site metastases among the three groups. CONCLUSIONS: Laparoscopy-assisted HIPPC provides modest yet encouraging efficacy for malignant ascites secondary to disseminated GC. Our preliminary data indicate that the chemotherapeutic combination of Ra/l-OHP and Ra/MMC might be more beneficial compared with Ra/DDP in terms of patients' survival.