3cDe-Net: a cervical cancer cell detection network based on an improved backbone network and multiscale feature fusion.

BACKGROUND: Cervical cancer cell detection is an essential means of cervical cancer screening. However, for thin-prep cytology test (TCT)-based images, the detection accuracies of traditional computer-aided detection algorithms are typically low due to the overlapping of cells with blurred cytoplasmic boundaries. Some typical deep learning-based detection methods, e.g., ResNets and Inception-V3, are not always efficient for cervical images due to the differences between cervical cancer cell images and natural images. As a result, these traditional networks are difficult to directly apply to the clinical practice of cervical cancer screening. METHOD: We propose a cervical cancer cell detection network (3cDe-Net) based on an improved backbone network and multiscale feature fusion; the proposed network consists of the backbone network and a detection head. In the backbone network, a dilated convolution and a group convolution are introduced to improve the resolution and expression ability of the model. In the detection head, multiscale features are obtained based on a feature pyramid fusion network to ensure the accurate capture of small cells; then, based on the Faster region-based convolutional neural network (R-CNN), adaptive cervical cancer cell anchors are generated via unsupervised clustering. Furthermore, a new balanced L1-based loss function is defined, which reduces the unbalanced sample contribution loss. RESULT: Baselines including ResNet-50, ResNet-101, Inception-v3, ResNet-152 and the feature concatenation network are used on two different datasets (the Data-T and Herlev datasets), and the final quantitative results show the effectiveness of the proposed dilated convolution ResNet (DC-ResNet) backbone network. Furthermore, experiments conducted on both datasets show that the proposed 3cDe-Net, based on the optimal anchors, the defined new loss function, and DC-ResNet, outperforms existing methods and achieves a mean average precision (mAP) of 50.4%. By performing a horizontal comparison of the cells on an image, the category and location information of cancer cells can be obtained concurrently. CONCLUSION: The proposed 3cDe-Net can detect cancer cells and their locations on multicell pictures. The model directly processes and analyses samples at the picture level rather than at the cellular level, which is more efficient. In clinical settings, the mechanical workloads of doctors can be reduced, and their focus can be placed on higher-level review work.

Insulin gene enhancer protein 1 mediates glycolysis and tumorigenesis of gastric cancer through regulating glucose transporter 4.

BACKGROUND: Insulin gene enhancer protein 1, (ISL1), a LIM-homeodomain transcription factor, is involved in multiple tumors and is associated with insulin secretion and metabolic phenotypes. However, the role of ISL1 in stimulating glycolysis to promote tumorigenesis in gastric cancer (GC) is unclear. In this study, we aimed to characterize the expression pattern of ISL1 in GC patients and explore its molecular biological mechanism in glycolysis and tumorigenesis. METHODS: We analyzed the expression and clinical significance of ISL1 in GC using immunohistochemistry and real-time polymerase chain reaction (PCR). Flow cytometry and IncuCyte assays were used to measure cell proliferation after ISL1 knockdown. RNA-sequencing was performed to identify differentially expressed genes, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and Gene Set Enrichment Analysis (GSEA) to reveal key signaling pathways likely regulated by ISL1 in GC. Alteration of the glycolytic ability of GC cells with ISL1 knockdown was validated by measuring the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) and by detecting glucose consumption and lactate production. The expression of glucose transporter 4 (GLUT4) and ISL1 was assessed by Western blotting, immunohistochemistry, and immunofluorescent microscopy. The luciferase reporter activity and chromatin immunoprecipitation assays were performed to determine the transcriptional regulation of ISL1 on GLUT4. RESULTS: High levels of ISL1 and GLUT4 expression was associated with short survival of GC patients. ISL1 knockdown inhibited cell proliferation both in vitro and in vivo. KEGG analysis and GSEA for RNA-sequencing data indicated impairment of the glycolysis pathway in GC cells with ISL1 knockdown, which was validated by reduced glucose uptake and lactate production, decreased ECAR, and increased OCR. Mechanistic investigation indicated that ISL1 transcriptionally regulated GLUT4 through binding to its promoter. CONCLUSION: ISL1 facilitates glycolysis and tumorigenesis in GC via the transcriptional regulation of GLUT4.

Covered stent placement for hepatic artery pseudoaneurysm.

PURPOSE: To evaluate the efficacy and safety of covered stent placement for the treatment of hepatic artery pseudoaneurysm (HAP). METHODS: Between March 2006 and March 2019, 17 consecutive patients underwent emergency covered stent placement for treatment of HAP. There were 12 men and 5 women aged 24-71 years, with an average age of 49.4 years. Eleven patients had undergone Whipple procedure, 3 had hepatic abscess following hepatectomy, 2 had undergone hepatectomy under extracorporeal circulation, and 1 had received surgical exploration after a car accident. The average interval from surgical intervention to massive bleeding was 15.3 days (range: 6-35 days). After HAP was confirmed by angiography, 1-3 covered stent grafts (3-8 mm in diameter and 13 mm-5 cm in length) were implanted. Adequate drainage, anti-infection treatment, and symptomatic treatment were offered after stent placement, and no anticoagulation or antiplatelet drug was used. RESULTS: The interventions were successful in all 17 patients. Angiography revealed pseudoaneurysms in common hepatic artery in 16 patients (in gastroduodenal artery stumps in 4 patients) and hemorrhage from a ruptured right hepatic artery in 1 patient. All patients were successfully implanted with 1-3 covered stent grafts. Bleeding was completely controlled in 12 patients (stent diameter: 4.5-8 mm). Four patients (stent diameter: 3-4.5 mm) experienced bleeding recurrence 1 h to 3 days after stent implantation, and type 1 endoleaks were identified during second angiography. Finally, these 4 patients died of multiple organ failure 2-10 days after embolization/blockage. The remaining patient suffered from abdominal hemorrhage again 2 weeks after stent implantation, and second angiography showed hemorrhage from a branch of the superior mesenteric artery; no bleeding occurred after embolization. Thirteen patients survived at discharge, and the average length of hospital stay was 26.53 days (range: 11-58 days). The average follow-up time was 23 months (range: 16-37 months), during which 6 patients died of tumor progression. No bleeding recurred during the follow-up period, and routine color Doppler ultrasound revealed that the common hepatic artery was patent and the blood flow was smooth at the stent implantation site. CONCLUSION: Covered stent placement is a safe and effective alternative for treating HAP patients with high risk of severe complications after hepatic artery embolization. Larger stent grafts (> 4 mm in diameter) may achieve better prognosis.

Simultaneous transarterial chemoembolization and radiofrequency ablation for large hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common cancer and a leading cause of tumor-related death. Patients with large HCC (≥ 8 cm) are at an advanced stage and have poor prognosis, and hepatic resection may not be suitable, and the incidence of postoperative recurrence is high. AIM: To evaluate recurrence and mid-term survival of patients with large HCC treated by transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA). METHODS: This was a retrospective study. From 2010 to 2013, 46 consecutive patients with large HCC were treated with simultaneous TACE and RFA. Thirty-five of 46 patients had a single tumor. Progression-free survival (PFS) and overall survival (OS) were analyzed at 2 years and 3 years, respectively. RESULTS: Forty-six patients treated by simultaneous TACE and RFA had no significant complications and treatment was successful. After 3 years, median PFS and OS were 10.21 ± 1.58 mo and 26.44 ± 2.26 mo, retrospectively. The survival rate was 67.5% after 2 years and 55.67% after 3 years. CONCLUSION: These preliminary data show that simultaneous TACE and RFA are safe and effective for large HCC.

General versus local anesthesia for percutaneous radiofrequency ablation of hepatocellular carcinoma at unusual regions.

AIMS: The aim of this study is to compare the efficacy and safety of percutaneous radiofrequency ablation (RFA) under general anesthesia or local anesthesia plus intraoperative analgesia in the treatment of hepatocellular carcinoma (HCC) at unusual regions. SUBJECTS AND METHODS: From July 2012 to October 2019, 83 consecutive patients with 107 HCC lesions were treated with interventional radiology therapy. The lesions were located at some unusual regions such as diaphragmatic surface, hepatic hilum, hepatic subcapsular region, tissues near inferior vena cava, and tissues near the colon. General anesthesia was applied in 57 cases (general anesthesia group) and local anesthesia plus intraoperative analgesia was used in 26 cases (local anesthesia group). All patients were treated with transcatheter arterial chemoembolization, followed immediately by RFA. The rate of tumor inactivation, time used for placing RF needles to the scheduled sites, pain score, and complications were analyzed. STATISTICAL ANALYSIS USED: All continuous variables were tested for the normal/nonnormal distribution by Kolmogorov-Smirnov test. The t-test was used to analyze the normal distribution variables; the Mann-Whitney U-test was used to measure nonnormal distribution variables; and the Chi-square test for categorical variables. P < 0.05 was considered statistically significant. RESULTS: The treatments were successful in all patients, including 51 cases of complete response (CR) and 6 cases of partial response (PR) in the general anesthesia group and 18 cases of CR and 8 cases of PR in the local anesthesia group (P = 0.049). The time used for placing the needles to the scheduled sites was 1-5 min (mean 2 min) in the general anesthesia group and 2-9 min (mean 4 min) in the local analgesia group (P < 0.001). The pain scores ranged from 0 to 2 points (mean 1 point) in the general anesthesia group and 2-9 points (mean 5 points) in the local anesthesia group (P < 0.001). With regard to complications, seven cases had pneumothorax and four cases had slight hepatic subcapsular hemorrhage in the general anesthesia group and four cases of pneumothorax and three cases of slight hepatic subcapsular hemorrhage in the local anesthesia group, and the difference was not statistically significant between the two groups (P = 0.715). CONCLUSIONS: For HCC located at unusual regions, general anesthesia is superior to local anesthesia plus intraoperative analgesia in percutaneous RFA in reducing the difficulty of the procedure and improving the safety of RFA.

Significance of HER2 protein expression and HER2 gene amplification in colorectal adenocarcinomas.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is an oncogenic driver, and a well-established therapeutic target in breast and gastric cancers. While the role of HER2 as a prognostic biomarker in colorectal adenocarcinomas (CRCs) remains uncertain, its relevance as a therapeutic target has been established. We undertook the present study to evaluate the frequency of HER2 expression in CRC and to correlate it with various clinicopathological variables. AIM: To correlate HER2 protein expression and HER2 gene amplification with clinicopathological features and survival in surgically resected CRC. METHODS: About 1195 consecutive surgically resected CRCs were analyzed by immunohistochemical staining (IHC) to assess HER2 protein expression, and 141 selected tumors were further evaluated by fluorescence in situ hybridization (FISH) to assess HER2 gene amplification. Follow-up information was available for 1058 patients, and using this information we investigated the prevalence of HER2 protein overexpression and gene amplification in a large series of surgically resected CRCs, and evaluated the relationship between overexpression and clinicopathological parameters and prognosis. RESULTS: HER2 IHC scores of 3+, 2+, 1+, and 0 were seen in 31 (2.6%), 105 (8.8%), 475 (39.7%), and 584 (48.9%) tumors, respectively. HER2 gene amplification was seen in 24/29 tumors with an IHC score of 3+ (82.8%; unreadable in 2/31), 12/102 tumors with an IHC score of 2+ (11.8%; unreadable in 2/104), and 0 tumors with IHC score of 1+ (0/10). HER2 gene amplification was seen in 36/1191 tumors (3.0%; unreadable in 4/1195). Among the tumors with HER2 IHC scores of 3+ and 2+, the mean percentage of tumor cells with positive IHC staining was 90% (median 100%, range 40%-100%) and 67% (median 75%, range 5%-95%), respectively (P < 0.05). Among tumors with IHC scores of 2+, those with HER2 gene amplification had a higher number of tumors cells with positive IHC staining (n = 12, mean 93%, median 95%, range 90%-95%) than those without (n = 90, mean 70%, median 50%, range 5%-95%) (P < 0.05). HER2 gene status was significantly associated with distant tumor metastasis and stage (P = 0.028 and 0.025). HER2 protein overexpression as measured by IHC or HER2 gene amplification as measured by FISH was not associated with overall survival (OS) or disease-specific survival for the overall group of 1058 patients. However, further stratification revealed that among patients with tubular adenocarcinomas who were 65 years old or younger (n = 601), those exhibiting HER2 gene amplification had a shorter OS than those without (mean: 47.9 mo vs 65.1 mo, P = 0.04). Among those patients with moderately to poorly differentiated tubular adenocarcinomas, those with positive HER2 tumor IHC scores (2+, 3+) had a shorter mean OS than those with negative HER2 IHC scores (0, 1+) (47.2 mo vs 64.8 mo, P = 0.033). Moreover, among patients with T2 to T4 stage tumors, those with positive HER2 IHC scores also had a shorter mean OS than those with negative HER2 IHC scores (47.1 mo vs 64.8 mo, P = 0.031). CONCLUSION: HER2 protein levels are correlated with clinical outcomes, and positive HER2 expression as measured by IHC confers a worse prognosis in those patients 65 years old or younger with tubular adenocarcinomas.

Feasibility of hyperspectral analysis for discrimination of rabbit liver VX2 tumor.

BACKGROUND: Hepatocellular carcinoma is one of the most common malignant tumors worldwide. Currently, the most accurate diagnosis imaging modality for hepatocellular carcinoma is enhanced magnetic resonance imaging. However, it is still difficult to distinguish cirrhosis lesions, and novel diagnosis modalities are still needed. AIM: To investigate the feasibility of hyperspectral analysis for discrimination of rabbit liver VX2 tumor. METHODS: In this study, a rabbit liver VX2 tumor model was established. After laparotomy, under direct view, VX2 tumor tissue and normal liver tissue were subjected to hyperspectral analysis. RESULTS: The spectral signature of the liver tumor was clearly distinguishable from that of the normal tissue, simply from the original spectral curves. Specifically, two absorption peaks at 600-900 nm wavelength in normal tissue disappeared but a new reflection peak appeared in the tumor. The average optical reflection at the whole waveband of 400-1800 nm in liver tumor was higher than that of the normal tissue. CONCLUSION: Hyperspectral analysis can differentiate rabbit VX2 tumors. Further research will continue to perform hyperspectral imaging to obtain more information for differentiation of liver cancer from normal tissue.

Feasibility of terahertz imaging for discrimination of human hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and novel methods for early/rapid diagnosis of HCC are needed. Terahertz (THz) spectroscopy is considered to have the potential to distinguish between normal liver tissue and HCC tissue; however, there are few reports on it. We conduct this observational study to explore the feasibility of THz imaging for the diagnosis of HCC. AIM: To evaluate the feasibility of THz for discriminating between HCC and normal liver tissues using fresh tissue specimens obtained from HCC patients who had undergone surgery. METHODS: Normal liver tissue and HCC tissue were cryosectioned into 50 µm-thick slices and placed on cover glass. Two adjacent tissue sections were separated subjected to histopathological examination by hematoxylin and eosin staining or THz transmission examination, and THz images were compared with pathologically mapped images. We determined the typical tumor and normal liver tissue regions by pathological examination; the corresponding areas of adjacent sections were examined by THz transmission. RESULTS: The transmission rate of HCC tissue was 0.15-0.25, and the transmission rate of typical HCC tissue was about 0.2. THz transmittance in normal liver tissue is slightly higher than 0.4, but there were many influencing factors, including the degree of liver cirrhosis, fat components, ice crystals in frozen sections, and apoptosis. CONCLUSION: In conclusion, this study shows that THz imaging can detect HCC tissue. Further research will yield more detailed data of the THz transmission rates of HCC tissue with different degrees of differentiation.

ISL1 predicts poor outcomes for patients with gastric cancer and drives tumor progression through binding to the ZEB1 promoter together with SETD7.

ISL1, a LIM-homeodomain transcription factor, serves as a biomarker of metastasis in multiple tumors. However, the function and underlying mechanisms of ISL1 in gastric cancer (GC) have not been fully elucidated. Here we found that ISL1 was frequently overexpressed in GC FFPE samples (104/196, 53.06%), and associated with worse clinical outcomes. Furthermore, the overexpression of ISL1 and loss-of-function of ISL1 influenced cell proliferation, invasion and migration in vitro and in vivo, including GC patient-derived xenograft models. We used ChIP-seq and RNA-seq to identify that ISL1 influenced the regulation of H3K4 methylation and bound to ZEB1, a key regulator of the epithelial-mesenchymal transition (EMT). Meanwhile, we validated ISL1 as activating ZEB1 promoter through influencing H3K4me3. We confirmed that a complex between ISL1 and SETD7 (a histone H3K4-specific methyltransferase) can directly bind to the ZEB1 promoter to activate its expression in GC cells by immunoprecipitation, mass spectrometry, and ChIP-re-ChIP. Moreover, ZEB1 expression was significantly positively correlated with ISL1 and was positively associated with a worse outcome in primary GC specimens. Our paper uncovers a molecular mechanism of ISL1 promoting metastasis of GC through binding to the ZEB1 promoter together with co-factor SETD7. ISL1 might be a potential prognostic biomarker of GC.

CT during celiac artery angiography for localization of clinically suspected small insulinomas.

BACKGROUND: To identify location and number of insulinomas before operation is very important for improving the cure rate. The objective of the study was to assess performance of CT during celiac artery angiography for preoperative localization of clinically suspected small insulinomas (< 2 cm in diameter). METHODS: From January 2013 to November 2016, 42 patients with hypoglycemic symptoms underwent celiac artery angiography, superior mesenteric artery angiography and CT during celiac artery angiography by a combined CT/digital subtraction angiography system, MIYABI Angio CT plus an Artiszeeceiling (SIEMENS, Germany). Patient group consisted of 13 males and 29 females, age 17-69 years (average, 45.4 ± 13.5 y). After diagnosis, all 42 patients were operated. Obtained images were retrospectively analyzed and compared with findings from post-operation pathology. RESULTS: All interventional radiology procedures were performed successfully with no complications. Sensitivity of angiography alone for insulinoma was 76.1% (32/42), at combined CT/digital subtraction angiography, 4 more nodules were found (sensitivity, 85.7%, 36/42), while 6 false-negatives were observed (all false negative lesions were less than 2 cm). A total of 64 ml to 80 ml contrast media was used per patient. CONCLUSION: CT during celiac artery angiography is a sensitive diagnostic procedure for localizing insulinomas. Combined with angiography, it can prioritize the pancreatic region for exploration and guide a pancreatic resection. TRIAL REGISTRATION: Ethical approval was obtained from the Hospital Research Ethics Committee. Informed consent was obtained from all patients included in the study. Duan Feng, Bai Yan-hua and Cui Li are co-first authors.

Combined transcatheter arterial chemoembolization and radiofrequency ablation in single-session for solitary hepatocellular carcinoma larger than 7 cm.

AIMS: To evaluate technical feasibility and treatment results of combined transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) in single-session for solitary hepatocellular carcinoma (HCC) larger than 7 cm in diameter. METHODS: Institutional review board approved this retrospective study. Written informed consent was obtained from all patients. Between June 2007 and July 2013, 87 patients (75 men, 12 women; mean age, 55.5 years ± 15.0) with solitary HCC with a mean maximum diameter of 9.5 cm ± 2.4 (range, 7.1-13.5 cm) not feasible for surgical resection underwent combined TACE and RFA in a single-session. Immediately following TACE, RFA was performed under fluoroscopy and CB-CT guidance. The primary endpoint was overall survival (OS). The secondary endpoints were technical safety and local tumor progression (LTP) rates. OS and time to progression (TTP) were analyzed with the Kaplan-Meier method. Univariate and multivariate analyses were performed to identify prognostic factors affecting OS and TTP. RESULTS: Technical success of combined TACE and RFA in a single-session was achieved in all patients (100%). On 1-month follow-up MRI, complete response (CR) was observed in 76 of 87 patients (87.4 %), partial response (PR) in 8 and stable disease (SD) in 3 patients. The median follow-up period was 49.5 months (interquartile range, 30.0-70.0 months). The median OS was 39 months (range, 15-86 months). The cumulative OS rates at 1, 3 and 5 years were 100%, 65.5% and 47.5%, respectively. The estimated 1, 3 and 5 year LTP rates were 0 %, 29.9% and 55.2 %, respectively. Univariate and multivariate analyses showed a tumor larger than 10.0 cm (P < 0.05) and presence of portal vein branch invasion (P < 0.05) led to the worst prognosis. No major complications were noted. CONCLUSIONS: Combined use of TACE and RFA in single-session is a safe and effective option in the treatment of patients with solitary large HCC (> 7 cm) not amenable to surgery.

Transarterial Embolization for Treatment of Symptomatic Polycystic Liver Disease: More than 2-year Follow-up.

BACKGROUND: Currently, treatment of symptomatic polycystic liver disease (PLD) is still a challenging problem, especially for these patients who are not feasible for surgery. Minimally invasive options such as laparoscopic fenestration and percutaneous cyst aspiration with sclerotherapy demonstrated disappointing results due to multiple lesions. Because the cysts in PLD are mostly supplied from hepatic arteries but not from portal veins, transcatheter arterial embolization (TAE) of the hepatic artery branches that supply the major hepatic cysts can lead to shrinkage of the cyst and liver size, relieve symptoms, and improve nutritional status. This study aimed to evaluate the effectiveness of TAE with a mixture of N-butyl-2-cyanoacrylate (NBCA) and iodized oil for patients with severe symptomatic PLD during a more than 2-year follow-up. METHODS: Institutional review board had approved this study. Written informed consent was obtained from all patients. From February 2007 to December 2014, twenty-three patients (20 women and 3 men; mean age, 49.0 ± 14.5 years) infeasible for surgical treatments underwent TAE. Changes in the abdominal circumferences, volumes of intrahepatic cysts, hepatic parenchyma volume, and whole liver, clinical symptoms, laboratory data, and complications were evaluated after TAE. RESULTS: Technical success was achieved in all cases. No procedure-related major complications occurred. The median follow-up period after TAE was 48.5 months (interquartile range, 30.0-72.0 months). PLD-related severe symptoms were improved remarkably in 86% of the treated patients; TAE failed to benefit in four patients (four patients did not benefit from TAE). The mean maximum abdominal circumference decreased significantly from 106.0 ± 8.0 cm to 87.0 ± 15.0 cm (P = 0.021). The mean intrahepatic cystic volume reduction rates compared with pre-TAE were 36% at 12 months, 37% at 24 months, and 38% at 36 months after TAE (P < 0.05). The mean liver volume reduction rates were 32% at 12 months, 31% at 24 months, and 33% at 36 months (P < 0.05). CONCLUSIONS: TAE with the mixture of NBCA and iodized oil appears to be a safe and effective treatment method for patients with symptomatic PLD, especially for those who are not good candidates for surgical treatments, to improve both hepatic volume and hepatic cysts volume.