ACT001 can prevent and reverse tamoxifen resistance in human breast cancer cell lines by inhibiting NF-κB activation.

Endocrine therapy is one of the main treatments for estrogen receptor-positive breast cancers. Tamoxifen is the most commonly used drug for endocrine therapy. However, primary or acquired tamoxifen resistance occurs in a large proportion of breast cancer patients, leading to therapeutic failure. We found that the combination of tamoxifen and ACT001, a nuclear factor-κB (NF-κB) signaling pathway inhibitor, effectively inhibited the proliferation of both tamoxifen-sensitive and tamoxifen-resistant cells. The tamoxifen-resistant cell line MCF7R/LCC9 showed active NF-κB signaling and high apoptosis-related gene transcription, especially for antiapoptotic genes, which could be diminished by treatment with ACT001. These results demonstrate that ACT001 can prevent and reverse tamoxifen resistance by inhibiting NF-κB activation.

[Comparison of the Predictive Values of Eight Staging Systems for Primary Liver Cancer in Prognosis of Combined Hepatocellular-cholangiocellular Carcinoma Patients after Surgery].

OBJECTIVE: To compare the predictive values of eight staging systems for primary liver cancer in the prognosis of combined hepatocellular-cholangiocellular carcinoma (cHCC-CC) patients after surgery. METHODS: The clinical data of 54 cHCC-CC patients who underwent hepatectomy or liver transplantation from May 2005 to Augest 2013 in Chinese PLA General Hospital were collected. We evaluated the prognostic value of the Okuda staging system, Cancer of the Liver Italian Program (CLIP) score, French staging system, Barcelona Clinic Liver Cancer (BCLC) staging system, 7th edition of tumour-node-metastasis (TNM) staging system for hepatocellular carcinoma and intrahepatic cholangiocarcinoma (ICC), Japan Integrated Staging (JIS) score, and Chinese University Prognostic Index. The distribution, Kaplan-Meier method, Log-rank test, and area under a receiver operating characteristic curve were used to compare the prognosis-predicting ability of these different staging systems in 54 cHCC-CC patients after surgery. RESULTS: The TNM staging system for ICC and JIS score had a better distribution of cases. The 12-and 24-month survivals of the entire cohort were 65.5% and 56.3%, respectively. A Log-rank test showed that there was a significant difference existing in the cumulative survival rates of different stage patients when using TNM staging system for ICC (stage 1 vs. stage 2, P=0.012; stage 2 vs. stage 3-4, P=0.002), Okuda staging system (stage 1 vs. stage 2, P=0.025), and French staging system (stage A and stage B, P=0.045). The 12-and 24-month area under curve of TNM staging system for ICC, BCLC staging system, JIS score, and CLIP score were 0.836 and 0.847, 0.744 and 0.780, 0.723 and 0.764, and 0.710 and 0.786, respectively. CONCLUSION: The 7th edition of TNM staging system for ICC has superior prognostic value to other seven staging systems in cHCC-CC patients undergoing surgical treatment.

Contrast-enhanced ultrasound may distinguish gallbladder adenoma from cholesterol polyps: a prospective case-control study.

PURPOSE: The aim of this study was to find the independent risk factors related with gallbladder (GB) adenoma compared to cholesterol polyp by contrast-enhanced ultrasound (CEUS). MATERIALS AND METHODS: Between January 2010 and September 2014, a total of 122 consecutive patients undergoing cholecystectomy for GB polypoid lesions were enrolled. Before cholecystectomy, each patient underwent conventional US and CEUS examination and all image features were documented. The patients were divided into adenoma group and cholesterol polyp group according to the pathological findings. All the image features between two groups were statistically compared. RESULTS: There were differences in patient age, lesion size, echogenicity, and vascularity of lesion between two groups (P < 0.05). There were differences in stalk width and enhancement intensity between the two groups (P < 0.05). Multiple logistic regression analysis proved that enhancement intensity, stalk of lesion, and vascularity were the independent risk factors related with GB adenoma (P < 0.05). CONCLUSIONS: CEUS could offer useful information to distinguish adenoma from cholesterol polyp. The treatment algorithm for gallbladder polyp lesions would likely benefit from CEUS as a routine imaging investigation, especially in cases where the polyp is larger than 1 cm.

The evolution of liver-directed treatments for hepatic colorectal metastases.

The liver is the most common site of metastases from colorectal cancer. Over the past 3 decades, surgical resection has proved to be the most effective and potentially curative therapy for such metastases. This article will review the current practice of hepatic resection for colorectal liver metastases, including the possibility of combined resection of hepatic metastases at the time of resection of the primary cancer. Effective use of neoadjuvant and adjuvant chemotherapy has further expanded the pool of treatable patients. Most recently, ablative therapies based on needle-delivered thermoablation or radiation therapy have become additional weapons for effective treatment. The relative roles and combined use of these local therapies will be highlighted in this article. Overall, the recent combined advances in surgery, radiation therapy, ablative therapy, and chemotherapy have provided more patients with a chance for long-term survival.

Simultaneously high prevalences of hepatitis B and C virus infections in a population in Putian County, China.

This study investigated a rare area of endemicity with a high prevalence of both hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, in Putian County, China. Among 1,050 subjects, the overall prevalence of HBsAg seropositivity was 15.8%, and that of anti-HCV seropositivity was 28.9%. Intrafamilial viral transmission might be the major cause of the high prevalence of HBV infection in this region. However, HCV infection was shown to be associated with the use of inadequately sterilized medical equipment.

[Application of persistent methylene blue dyeing method for anatomic hepatectomy of hepatocellular carcinoma with bile duct tumor thrombi].

OBJECTIVE: To evaluate the role of anatomic hepatectomy of hepatocellular carcinoma with bile duct tumor thrombi by application of persistent methylene blue dyeing method. METHODS: From January 2009 to February 2011, 11 hepatocellular carcinoma patients with bile duct tumor thrombi underwent anatomic hepatectomy with removal of the biliary tumor thrombus. There were 10 male and 1 female patients. The average age was 49 years (ranging from 31 to 67 years). The initial symptom of 9 out of the 11 patients was jaundice. After anatomy and ligation of Glissonean pedicle of pre-resection segment, methylene blue was injected into its far-end portal vein in order to dye the segment. RESULTS: Persistent methylene blue dyeing method was successful in all patients. Primary foci were found in all patients. Hepatectomy were performed, including 4 patients of segmentectomy, 3 patients of subsegmentectomy, 2 patients of hemihepatectomy, and 2 patients of hepatic sectionectomy. The mean operation time and blood loss was 137 minutes and 246 ml respectively. Severe complications such as liver function failure and sub-diaphragm abscess was avoided in all patients. No perioperative death. Post-operation radiotherapy was performed on 2 patients . Over a mean follow-up time of 14.6 months, liver cancer recurrence occurred in 2 patients, abdomen seeding metastasis in 1 patient, bile duct tumor thrombi recurrence in 1 case, and 2 patients died. CONCLUSIONS: Anatomic hepatectomy of hepatocellular carcinoma with bile duct tumor thrombi by application of persistent methylene blue dyeing method can make resection more precise and improve curative effect.

[Analysis of Related Factors of Autologous Peripheral Hematopoietic Stem Cell Mobilization in Patients with Lymphoma and Myeloma].

OBJECTIVE: To explore the related factors affecting of autologous peripheral hematopoietic stem cell mobilization in patients with single center lymphoma and multiple myeloma. METHODS: The clinical total of 30 patients with lymphoma or multiple myeloma who underwent autologous peripheral hematopoietic stem cell mobilization and transplantation in the Affiliated Hospital of Jiangsu University from March 2012 to December 2021 were retrospectively analyzed, including the patients' age, gender, disease type, chemotherapy course, mobilization scheme, collection times, CD34+ cell count, adverse events, days of neutrophil and platelet implantation after transplantation. The related factors affecting to the mobilization efficiency of peripheral blood stem cells was analyzed. RESULTS: The mobilization scheme had a significant effect on the mobilization success rate of CD34+ cells. The mobilization success rate and optimal mobilization rate of intermediate-dose VP-16+G-CSF were higher than that of high-dose VP-16+G-CSF (P<0.05); the mobilization success rate of patients with previous chemotherapy courses ≤4 was higher than that of patients with chemotherapy courses >4 (100% vs 72.22%, P<0.05); the mobilization success rate of lymphoma patients was lower than that of myeloma patients (66.67% vs 94.44%, P<0.05); the mobilization success rate of lymphoma patients who received intermediate-dose VP-16+G-CSF was higher than that received high-dose VP-16+G-CSF patients (100% vs 42.86%, P<0.05). Patients' gender, age, time from diagnosis to mobilization and disease status had no significant effect on the efficiency of stem cell mobilization. Fifteen patients (50%) had febrile neutropenia during stem cell mobilization. There was no statistical difference in the incidence of febrile neutropenia between the two mobilization schemes (P>0.05); the incidence of severe thrombocytopenia in intermediate-dose VP-16+G-CSF group was higher than that in high-dose VP-16+G-CSF group (P<0.05). There was no statistical difference in the time of granulocyte implantation and platelet implantation after stem cell transplantation in patients with different mobilization schemes (P>0.05). CONCLUSION: Mobilization regime, the number of previous chemotherapy course and disease type affect the mobilization efficiency of stem cells. Intermediate dose VP-16+G-CSF can improve the mobilization efficiency of stem cell in lymphoma patients, but should pay attention to the risk of bleeding.

[The Effect of Doxycycline on the Expression of MMP-2 and MMP-9 in Multiple Myeloma].

OBJECTIVE: To investigate the expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in multiple myeloma (MM) patients, and analyze the effect of doxycycline (DOX) on the expression of MMP-2 and MMP-9 in MM cells. METHODS: The peripheral blood and bone marrow samples of MM patients were collected, and the patients were divided into three groups: newly diagnosed group, remission group and relapsed/refractory group, while the peripheral blood samples of 34 health people and the bone marrow samples of 17 IDA patients were selected as normal control and control group. The levels of MMP-2 and MMP-9 were detected by ELISA. The protein levels of MMP-2 and MMP-9 in H929 cells treated by different concentrations of DOX were analyzed by Western blot. After H929 cells was treated by Akt inhibitor MK-2206 2HCl in combination with DOX, Western blot was used to detect the levels of MMP-2 and MMP-9. RESULTS: The levels of MMP-2 and MMP-9 in newly diagnosed MM patients were higher than those in control (P<0.05), while for the patients in the remission group were decreased, but still higher than those in control. The levels of MMP-2 and MMP-9 were increased again for the patients in relapsed/refractory group, and showed no significant difference as compared with those in newly diagnosed group. The levels of MMP-2 and MMP-9 could be inhibited by 10 mg/L and 15 mg/L DOX treated by H929 cell. The protein levels of MMP-2 and MMP-9 showed no altered in H929 cells treated by 5 nmol/L MK-2206 2HCl alone. DOX exerted more profound inhibitory effect to MMP-2 and MMP-9 expression in H929 cells when Akt inhibitor MK-2206 2HCl was combined with DOX. CONCLUSION: The levels of MMP-2 and MMP-9 are increased in MM patients and related to the disease status of MM. DOX can inhibit the expression of MMP-2 and MMP-9 in MM cells, and antagonizing its activation of Akt signaling pathway can further enhance the inhibitory effect.

A proposed modification for the Barcelona Clinic Liver Cancer staging system: Adding bile duct tumor thrombus status in patients with hepatocellular carcinoma.

BACKGROUND: The Barcelona Clinic Liver Cancer (BCLC) staging system is widely applied to stage hepatocellular carcinoma (HCC). However, it may be inaccurate when applied to East Asian HCC patients. In this study, a large Chinese HCC cohort was analyzed to evaluate possible modifications for the BCLC staging system. METHODS: Between January 1995 and December 2009, 622 HCC patients who underwent hepatectomy were enrolled. Prognostic risk factors were analyzed using univariate and multivariate analyses. The ability of the modified system to predict survival was evaluated by determining the area under the receiver operating characteristic curve. RESULTS: Patients without bile duct tumor thrombus (BDTT; 1-, 3- and 5-year overall survival, 80%, 60% and 48%, respectively) showed a substantial survival advantage over those with BDTT (1-, 3- and 5-year overall survival, 77%, 42% and 23%, respectively; χ2 = 6.280, P = 0.012). In BCLC stage 0-A patients, significant differences were identified between the BDTT group and the non-BDTT group, while no such differences were found in BCLC stage B patients. Based on this finding, BCLC stage 0-A BDTT patients were recategorized into stage B. The modified BCLC classification featured better performance in the prediction of overall survival than the original system (modified BCLC χ2 = 53.596, P < 0.001; original BCLC χ2 = 46.335, P < 0.001). The ability to predict mortality was also slightly higher using the modified BCLC system. CONCLUSIONS: Modification of the BCLC system to include BDTT status might further enhance its prognostic ability.

[Impact of surgical operation-related factors on long-term survival of patients with hepatocellular carcinoma after hepatectomy].

OBJECTIVE: To evaluate the prognostic value of surgical operation-related factors in patients with hepatocellular carcinoma (HCC). METHODS: The clinical data of 234 patients after hepatic resection (214 men and 20 women) were retrospectively studied. Univariate and multivariate COX regression analyses were performed for surgical operation-related prognostic factors including age, gender, intraoperative blood loss, iatrogenic tumour rupture, transfusion, operation duration, hepatectomy extent, Pringle manoeuvre, with or without devarscularization, and complications (e.g. postoperative ascites, biliary leakage, incision infection, and pleural effusion). Kaplan-Meier and log-rank tests were used to compare survival rates. Kendall's tau bivariate analyses were used to examine the correlations of these surgical operation-related factors. RESULTS: Univariate COX regression analysis revealed that iatrogenic blood loss (chi2 = 19.721, P < 0.001), transfusion (chi2 = 7.769, P = 0.005), tumour rupture (chi2 = 6.401, P = 0.011), operation duration (chi2 = 4.793, P = 0.029), and postoperative ascites (chi2 = 4.452, P = 0.035) were statistically significant predictors in patients with HCC after hepatic resection. Multivariate COX regression analysis revealed that pathological factors, such as blood loss (RR: 2.138, 95% CI: 1.556-2.939), tumour rupture (RR: 2.260, 95% CI: 1.182-4.321), and postoperative ascites (RR: 1.648, 95% CI: 1.088-2.469), independently influenced the HCC prognosis. Blood loss correlated with transfusion (Kendall's tau = 0.416, P < 0.001). There was no correlation between hepatectomy extent and blood loss (Kendall's tau = 0.057, P = 0.383), while transfusion closely correlated with the hepatectomy extent (Kendall's tau = 0.185, P = 0.004). The postoperative ascites closely correlated with Child classification (Kendall's tau = 0.151, P = 0.024). CONCLUSIONS: The long-term survival of patients with HCC after hepatectomy may be improved by avoiding blood loss and iatrogenic tumour rupture. The indications of blood transfusion may not be strictly obeyed in some severe cases. Child class B and C cirrhotic patients may experience postoperative ascites and a worse prognosis, and therefore may be candidates for liver transplantation.

[Clinical related factors of portal vein tumor thrombosis in patients with hepatocellular carcinoma: a logistic regression analysis].

OBJECTIVE: To investigate the related factors of portal vein tumor thrombosis (PVTT) in patients with HCC. METHODS: A total number of 234 patients with hepatocellular carcinoma (HCC) were included in this retrospective study. Uni-variate and multi-variate logistic regression analysis were employed to analyze the association between PVTT and 18 routine clinical parameters. RESULTS: Among the 234 patients with HCC, 15% of patients (35/235) had PVTT. Univariate logistic regression analysis revealed significant association of age (P = 0.016), gamma glutamyl transferase (GGT, P = 0.003), number of segmental invasion (P = 0.007), microvascular invasion (P < 0.01), segment location of S2 (P = 0.001), S3 (P = 0.000), S4 (P = 0.004) and S6 (P = 0.016). Multivariate analysis shows potential significant predictors of PVTT in HCC were age (RR: 0.373; 95% CI: 0.146-0.954; P = 0.040), the tumor location of S3 (RR: 4.625; 95% CI: 1.916-11. 165;P = 0.001), GGT (RR: 4.091; 95% CI: 1.448-11.553; P = 0.008) and microvascular invasion (RR: 20.912; 95% CI: 4.745-92.172; P < 0.01). CONCLUSIONS: PVTT occurred more commonly in the younger (< 50 years old), and those with high level of GGT, segment location of S3 and microvascular invasion.

Zn(II)-curcumin protects against oxidative stress, deleterious changes in sperm parameters and histological alterations in a male mouse model of cyclophosphamide-induced reproductive damage.

The poor bioavailability and stability of curcumin limit its clinical application. A novel Zn(II)-curcumin complex was synthesized and its effects against cyclophosphamide (CP)-induced reproductive damage were compared with curcumin. Oral administration of Zn(II)-curcumin significantly prevented CP-induced elevation of malondialdehyde (MDA) level and reductions in superoxide dismutase (SOD) activity and glutathione (GSH) content in mouse testis. Zn(II)-curcumin significantly ameliorated CP-induced reductions in body and reproductive organs weights. Zn(II)-curcumin dose-dependently ameliorated CP-induced reproductive system impairments, by improving sperm parameters (sperm count, viability, motility) and reducing serum testosterone and histological alterations. Compared to curcumin at the same dose, Zn(II)-curcumin more effectively alleviated CP-induced reproductive injury, leading to a reduced severity of testicular pathologic changes, lower MDA level, elevated SOD activity and GSH content, and increased sperm parameters and serum testosterone. These results suggest Zn(II)-curcumin more effectively protects against CP-induced reproductive damage than curcumin alone due to a synergistic reduction in oxidative stress.

Hepatectomy for hepatocellular carcinoma in the era of liver transplantation.

The aim of management of hepatocellular carcinoma (HCC) is to improve the prognosis of the patients by radical resection and preserve remnant liver function. Although liver transplantation is associated with a lower tumor recurrence rate, this benefit is counteracted by long-term complications. Therefore, hepatectomy could be the first choice of treatment in selected patients with HCC. However, the higher frequency of tumor recurrence and the lower rate of resectability after hepatectomy for HCC led to an unsatisfactory prognosis. New strategies are required to improve the long-term outcome of HCC after hepatectomy. In this paper, we introduce some strategies to increase the low rate of resectability and reduce the high rate of tumor recurrence. Some aggressive treatments for tumor recurrence to extend long-term survival are also involved. We believe that hepatectomy combined with other therapies, such as portal vein embolization, transarterial chemoembolization, radioembolization, antiviral treatment, radiofrequency ablation and salvage transplantation, is a promising treatment modality for HCC and may improve survival greatly.

A meta-analysis of the long-term effects of chronic pancreatitis surgical treatments: duodenum-preserving pancreatic head resection versus pancreatoduodenectomy.

BACKGROUND: Surgery is regarded as the most effective treatment to relieve pain and reduce complications in chronic pancreatitis (CP). Two major strategies exist: duodenum-preserving pancreatic head resection (DPPHR) and pancreatoduodenectomy (PD). Many studies suggest that DPPHR offers advantages during surgery and in the short-term; however, the long-term effects have not been thoroughly investigated. We analyzed the long-term outcomes of DPPHR and PD, over follow-up times of at least 1 year, to determine the optimal surgical treatment for CP. METHODS: We systemically reviewed all CP surgical treatment reports, and only included randomized controlled trials (RCT) comparing DPPHR and PD, excluding unqualified studies using several pre-specified criteria. When multiple publications of a single trial were found, the most comprehensive current data were selected. Characteristics of the study populations and long-term postoperative outcome parameters were collected. The quality of the studies and data was analyzed using RevMan 4.2 software. RESULTS: Five trials were qualified for meta-analysis, with 261 participants in total (114 in the DPPHR group and 147 in the PD group). There were no significant differences in the age, gender, or indications for surgery of each group. At the mean of 5.7-year (1 - 14 years) follow-up examination, DPPHR and PD resulted in equally effective pain relief, exocrine and endocrine function, and similar mortality rates (P > 0.05); however, DPPHR patients had improved global quality of life and weight gain, and reduced diarrhea and fatigue (P < 0.05). CONCLUSION: DPPHR and PD result in equal pain relief, mortality, and pancreatic function; however, DPPHR provides superior long-term outcomes.

[Apoptosis and its mechanisms of spleen CD4⁺ CD25⁺ regulatory T cells in severe aplastic anemia mouse model].

OBJECTIVE: To explore the apoptosis and its mechanisms of spleen CD4⁺ CD25⁺ regulatory T (Treg) cells in severe aplastic anemia (SAA) mouse model induced by interferon (IFN-γ) in combination with busulphan (BU). METHODS: The BALB/c female mice SAA model was induced by intraperitoneal injection with IFN-γ and intragastric administration with BU (combined group, n=16), with BU group (n=16), IFN-γ group (n=16) and normal group (n=16) as controls. Spleen Treg cells were purified by using of immunomagnetic beads. Apoptosis was detected by flow cytometry. AKt and TGF-ß expression was measured by Western blot. RESULTS: Apoptosis of spleen Treg cells in combined group [(33.21±0.65)%] was significantly higher than that in BU group [(21.58±0.64)%], IFN-γ group [(17.62±1.05)%], and control[(27.38±1.89)%] (P<0.05). A significantly lower expression of AKt and TGF-ß protein was also seen in combined group (0.30±0.05 and 0.17±0.05), as compared to the other three groups (P<0.05). CONCLUSION: Excessive apoptosis of Treg cells was found in SAA mouse model, which may be a cause of Treg cells decrease in patients with AA. The down-regulated expression of AKt and TGF-ß could play a role in increased apoptosis of Treg cells. Our data may provide a new treatment strategy in AA.