[Gallbladder carcinosarcoma associated with pancreaticobiliary maljunction with biliary dilation:a case report].

A 68-year-old female patient was referred to our hospital with acute cholangitis. Computed tomography revealed common bile duct dilatation, gallbladder fundal tumor, and gallbladder wall thickening attached to the tumor. Cholangiography revealed pancreaticobiliary maljunction with biliary dilation. The patient was diagnosed with pancreaticobiliary maljunction with biliary dilation and gallbladder cancer and underwent liver S4b+5 and bile duct resection and reconstruction. Pathological results revealed that the gallbladder fundal tumor included sarcoma, and the gallbladder wall thickening had adenocarcinoma;thus, the patient was diagnosed with gallbladder carcinosarcoma.

Primary pure squamous cell carcinoma of the gallbladder.

SummarySquamous cell carcinoma (SCC) is an uncommon and frequently aggressive subtype of gallbladder cancer known for its poor outcomes compared with other gallbladder tumours. Gallbladder SCC typically presents as higher grade and more advanced than adenocarcinoma, resulting in lower estimated survival. Early recognition of these tumours is ideal, but infrequently achieved. Herein is a case of a male patient in his 80s with new onset abdominal pain who was initially diagnosed with cholecystitis, but diagnostic imaging revealed a gallbladder mass. Surgical resection and pathology revealed pure SCC of the gallbladder without local organ invasion or metastatic disease. Pure SCC histology of the gallbladder is rare, with limited studies on clinical presentation, natural history, and optimal treatment.

Should we suspect gallbladder cancer if which CT finding is observed in patients with localized gallbladder wall thickening?

PURPOSE: To identify high-risk computed tomography (CT) features for predicting gallbladder (GB) cancer in patients presenting with localized GB wall thickening. METHODS: This retrospective analysis included 120 patients (mean age: 63.9 ± 10.0 years; 51 men) exhibiting localized GB wall thickening on CT scans obtained between January 2008 and May 2017. Two radiologists independently evaluated CT imaging features for predicting GB cancer. The diagnostic performance of significant imaging features and their combinations was evaluated. High-risk CT features ranked by accuracy were delineated for predicting GB cancer. RESULTS: This study included 55 patients with GB cancer and 65 with benign GB conditions. The top-four most accurate CT imaging features for predicting GB cancer were identified: heterogeneously enhancing single layer or strongly enhancing thick inner layer; GB wall thickness > 6.5 mm; hyperenhancement on arterial phase; and absence of intramural small cystic lesions (accuracies of 90.0 %, 88.3 %, 85.0 %, and 85.0 %, respectively). The combination of any three high-risk features exhibited the highest accuracy (94.2 %). The presence of any high-risk feature yielded a sensitivity of 100 %, whereas that of all high-risk features indicated a specificity of 100 %. CONCLUSION: CT imaging features, whether alone or in combination, could effectively and accurately predict GB cancer among patients with localized GB wall thickening. This finding holds significance in guiding decisions regarding further diagnostic tests and treatment planning.

Contributions of endoscopic ultrasonography-guided tissue acquisition (EUS-TA) to the diagnostics of biliary stricture and gallbladder lesions.

Endoscopic ultrasonography (EUS) provides high spatial resolution and more detailed images than other diagnostic modalities. Furthermore, EUS-guided tissue acquisition (EUS-TA), such as EUS-guided fine needle aspiration or biopsy (EUS-FNA/FNB), is an indispensable tool in pancreaticobiliary disease diagnostics, supporting a conclusive pathological diagnosis. In this review, we evaluate the current status and the usefulness of EUS-TA for the diagnostics of the following biliary tract diseases: (A) biliary stricture diagnostics, (B) biliary tract cancer (BTC) itself, and (C) staging of advanced BTC. Previous reports have shown that EUS-FNA for biliary lesions is a safe procedure that is useful in differentiating biliary cancer from benign lesions and in the staging of BTC. On the other hand, the diagnostic performance of EUS-TA for bile duct lesions is reported to be similar to that of transpapillary biopsy. Overall, EUS-TA for biliary lesions may be a safe and effective method, but it should be performed with an understanding of the risk of serious adverse events such as bile leakage and peritoneal dissemination of cancer. It is recommended for distal biliary stricture lesions for which endoscopic retrograde cholangiopancreatography cannot confirm the diagnosis or gallbladder lesions if they do not require the needle to pass through the biliary lumen.

SMARCA4-Deficient Poorly Differentiated Adenocarcinoma of the Gallbladder.

ABSTRACT: A 64-year-old woman presented with chest pain while eating and was referred to our hospital. Physical examination revealed abdominal distension, tenderness, and lower-extremity edema. Imaging revealed a large gallbladder tumor infiltrating the liver, with ascites and pleural effusion. A biopsy confirmed a poorly differentiated adenocarcinoma with SMARCA4 deficiency (cT3N2M1, cStage IV). Chemotherapy was ineffective and led to tumor progression. The patient died 9 months later. Recently, attention has been paid to SMARCA4 deficiency, which is a genetic mutation found in tumors. Here, we report on poorly differentiated adenocarcinomas of the gallbladder based on imaging findings, including FDG PET.

Discrimination between benign and malignant gallbladder lesions on enhanced CT imaging using radiomics.

BACKGROUND: Gallbladder cancer is a rare but aggressive malignancy that is often diagnosed at an advanced stage and is associated with poor outcomes. PURPOSE: To develop a radiomics model to discriminate between benign and malignant gallbladder lesions using enhanced computed tomography (CT) imaging. MATERIAL AND METHODS: All patients had a preoperative contrast-enhanced CT scan, which was independently analyzed by two radiologists. Regions of interest were manually delineated on portal venous phase images, and radiomics features were extracted. Feature selection was performed using mRMR and LASSO methods. The patients were randomly divided into training and test groups at a ratio of 7:3. Clinical and radiomics parameters were identified in the training group, three models were constructed, and the models' prediction accuracy and ability were evaluated using AUC and calibration curves. RESULTS: In the training group, the AUCs of the clinical model and radiomics model were 0.914 and 0.968, and that of the nomogram model was 0.980, respectively. There were statistically significant differences in diagnostic accuracy between nomograms and radiomics features (P <0.05). There was no significant difference in diagnostic accuracy between the nomograms and clinical features (P >0.05) or between the clinical features and radiomics features (P >0.05). In the testing group, the AUC of the clinical model and radiomics model were 0.904 and 0.941, and that of the nomogram model was 0.948, respectively. There was no significant difference in diagnostic accuracy between the three groups (P >0.05). CONCLUSION: It was suggested that radiomics analysis using enhanced CT imaging can effectively discriminate between benign and malignant gallbladder lesions.

Prediction of neoplastic gallbladder polyps in patients with different age level based on preoperative ultrasound: a multi-center retrospective real-world study.

BACKGROUND: The prevalence of neoplastic polyps in gallbladder polyps (GPs) increases sharply with age and is associated with gallbladder carcinoma (GBC). This study aims to predict neoplastic polyps and provide appropriate treatment strategies based on preoperative ultrasound features in patients with different age level. METHODS: According to the age classification of WHO, 1523 patients with GPs who underwent cholecystectomy from January 2015 to December 2019 at 11 tertiary hospitals in China were divided into young adults group (n=622), middle-aged group (n=665) and elderly group (n=236). Linear scoring models were established based on independent risk variables screened by the Logistic regression model in different age groups. The area under ROC (AUC) to evaluate the predictive ability of linear scoring models, long- and short- diameter of GPs. RESULTS: Independent risk factors for neoplastic polyps included the number of polyps, polyp size (long diameter), and fundus in the young adults and elderly groups, while the number of polyps, polyp size (long diameter), and polyp size (short diameter) in the middle-aged groups. In different age groups, the AUCs of its linear scoring model were higher than the AUCs of the long- and short- diameter of GPs for differentiating neoplastic and non-neoplastic polyps (all P<0.05), and Hosmer-Lemeshow goodness of fit test showed that the prediction accuracy of the linear scoring models was higher than the long- and short- diameter of GPs (all P>0.05). CONCLUSION: The linear scoring models of the young adults, middle-aged and elderly groups can effectively distinguish neoplastic polyps from non-neoplastic polyps based on preoperative ultrasound features.

The value of CT radiomics combined with deep transfer learning in predicting the nature of gallbladder polypoid lesions.

BACKGROUND: Computed tomography (CT) radiomics combined with deep transfer learning was used to identify cholesterol and adenomatous gallbladder polyps that have not been well evaluated before surgery. PURPOSE: To investigate the potential of various machine learning models, incorporating radiomics and deep transfer learning, in predicting the nature of cholesterol and adenomatous gallbladder polyps. MATERIAL AND METHODS: A retrospective analysis was conducted on clinical and imaging data from 100 patients with cholesterol or adenomatous polyps confirmed by surgery and pathology at our hospital between September 2015 and February 2023. Preoperative contrast-enhanced CT radiomics combined with deep learning features were utilized, and t-tests and least absolute shrinkage and selection operator (LASSO) cross-validation were employed for feature selection. Subsequently, 11 machine learning algorithms were utilized to construct prediction models, and the area under the ROC curve (AUC), accuracy, and F1 measure were used to assess model performance, which was validated in a validation group. RESULTS: The Logistic algorithm demonstrated the most effective prediction in identifying polyp properties based on 10 radiomics combined with deep learning features, achieving the highest AUC (0.85 in the validation group, 95% confidence interval = 0.68-1.0). In addition, the accuracy (0.83 in the validation group) and F1 measure (0.76 in the validation group) also indicated strong performance. CONCLUSION: The machine learning radiomics combined with deep learning model based on enhanced CT proves valuable in predicting the characteristics of cholesterol and adenomatous gallbladder polyps. This approach provides a more reliable basis for preoperative diagnosis and treatment of these conditions.

Positive 18 F-FDG and Negative 68 Ga-FAPI-04 Findings in a Patient With Gallbladder Adenocarcinoma.

ABSTRACT: Radiolabeled fibroblast activation protein inhibitor (FAPI) is considered as a potential alternative agent to 18 F-FDG for tumor-specific imaging. We report 18 F-FDG and 68 Ga-FAPI-04 PET/MR findings in a 67-year-old woman with gallbladder adenocarcinoma. The lesions showed intense 18 F-FDG uptake but limited 68 Ga-FAPI-04 uptake in PET/MR. This case emphasizes the necessity for nuclear clinicians to exercise caution when assessing gallbladder lesions with limited 68 Ga-FAPI-04 uptake, underscoring the continued relevance of 18 F-FDG in this diagnostic domain.

Accuracy of preoperative T2 gallbladder tumor localization and the adequate surgical resection.

INTRODUCTION: The agreement between the radiologic and histopathologic tumor locations in T2 gallbladder cancer is critical. There is no consensus regarding the extent of curative resection by tumor locations. METHODS: Between January 2010 and December 2019, a consecutive series of 118 patients with pathological T2 gallbladder cancer who underwent surgery were retrospectively analyzed in terms of the accordance between radiologic and histopathologic tumor locations, the extents of hepatic resection and the numbers of harvested lymph nodes. Radical resection was defined as liver resection with harvesting of at least four lymph nodes. RESULTS: The accuracy of preoperative tumor localization was only 68%. After radical resection, the 5-year overall survival (OS) was 59.4%; after nonradical resection, the figure was 46.1% (p = 0.092). In subanalyses, the 5-year OS was marginally better for patients who underwent liver resection or from whom at least four lymph nodes were harvested than those who did not undergo liver resection or from whom three or fewer lymph nodes were harvested (58.2% vs. 39.4%, p = 0.072; 59.9% vs. 50.0%, p = 0.072, respectively). In patients with peritoneal side tumor, the 5-year OSs of those who did and did not undergo liver resection were 67% and 41.2%, respectively (p = 0.028). In multivariate analysis, perineural invasion and radical resection were independently prognostic of OS. CONCLUSION: The accuracy of preoperative tumor localization was 68%. Hepatic resection, lymph node dissection harvesting of at least four lymph nodes are required for curative resection for gallbladder cancer, regardless of tumor location.

Risk prediction and analysis of gallbladder polyps with deep neural network.

The aim of this study is to analyze the risk factors associated with the development of adenomatous and malignant polyps in the gallbladder. Adenomatous polyps of the gallbladder are considered precancerous and have a high likelihood of progressing into malignancy. Preoperatively, distinguishing between benign gallbladder polyps, adenomatous polyps, and malignant polyps is challenging. Therefore, the objective is to develop a neural network model that utilizes these risk factors to accurately predict the nature of polyps. This predictive model can be employed to differentiate the nature of polyps before surgery, enhancing diagnostic accuracy. A retrospective study was done on patients who had cholecystectomy surgeries at the Department of Hepatobiliary Surgery of the Second People's Hospital of Shenzhen between January 2017 and December 2022. The patients' clinical characteristics, lab results, and ultrasonographic indices were examined. Using risk variables for the growth of adenomatous and malignant polyps in the gallbladder, a neural network model for predicting the kind of polyps will be created. A normalized confusion matrix, PR, and ROC curve were used to evaluate the performance of the model. In this comprehensive study, we meticulously analyzed a total of 287 cases of benign gallbladder polyps, 15 cases of adenomatous polyps, and 27 cases of malignant polyps. The data analysis revealed several significant findings. Specifically, hepatitis B core antibody (95% CI -0.237 to 0.061, p < 0.001), number of polyps (95% CI -0.214 to -0.052, p = 0.001), polyp size (95% CI 0.038 to 0.051, p < 0.001), wall thickness (95% CI 0.042 to 0.081, p < 0.001), and gallbladder size (95% CI 0.185 to 0.367, p < 0.001) emerged as independent predictors for gallbladder adenomatous polyps and malignant polyps. Based on these significant findings, we developed a predictive classification model for gallbladder polyps, represented as follows, Predictive classification model for GBPs = -0.149 * core antibody - 0.033 * number of polyps + 0.045 * polyp size + 0.061 * wall thickness + 0.276 * gallbladder size - 4.313. To assess the predictive efficiency of the model, we employed precision-recall (PR) and receiver operating characteristic (ROC) curves. The area under the curve (AUC) for the prediction model was 0.945 and 0.930, respectively, indicating excellent predictive capability. We determined that a polyp size of 10 mm served as the optimal cutoff value for diagnosing gallbladder adenoma, with a sensitivity of 81.5% and specificity of 60.0%. For the diagnosis of gallbladder cancer, the sensitivity and specificity were 81.5% and 92.5%, respectively. These findings highlight the potential of our predictive model and provide valuable insights into accurate diagnosis and risk assessment for gallbladder polyps. We identified several risk factors associated with the development of adenomatous and malignant polyps in the gallbladder, including hepatitis B core antibodies, polyp number, polyp size, wall thickness, and gallbladder size. To address the need for accurate prediction, we introduced a novel neural network learning algorithm. This algorithm utilizes the aforementioned risk factors to predict the nature of gallbladder polyps. By accurately identifying the nature of these polyps, our model can assist patients in making informed decisions regarding their treatment and management strategies. This innovative approach aims to improve patient outcomes and enhance the overall effectiveness of care.

Nonocclusive mesenteric ischemia (NOMI) on Roux limb after biliary reconstruction successfully treated by interventional radiology (IVR).

Nonocclusive mesenteric ischemia (NOMI) is a life-threatening disorder. Early diagnosis is challenging because NOMI lacks specific symptoms. A 52-year-old man who received extended cholecystectomy with Roux-en-Y hepaticojejunostomy for gallbladder cancer (GBC) presented to our hospital with nausea and vomiting. Neither tender nor peritoneal irritation sign was present on abdominal examination. Blood test exhibited marked leukocytosis (WBC:19,800/mm3). A contrast-enhanced abdominal computed tomography (CT) scan revealed remarkable wall thickening and lower contrast enhancement effect localized to Roux limb. On hospital day 2, abdominal arterial angiography revealed angio-spasm at marginal artery and arterial recta between 2nd jejunal artery and 3rd jejunal artery, leading us to the diagnosis of NOMI. We then administered continuous catheter-directed infusion of papaverine hydrochloride until hospital day 7. Furthermore, the patient was anticoagulated with intravenous unfractionated heparin and antithrombin agents for increasing D-dimer level and decreasing antithrombin III level. On hospital day 8, diluted oral nutrition diet was initiated and gradually advanced as tolerated. On hospital day 21, the patient was confirmed of improved laboratory test data and discharged with eating a regular diet. We experienced a rare case of NOMI on Roux limb after 2 years of extended cholecystectomy with hepaticojejunostomy for GBC, promptly diagnosed and successfully treated by interventional radiology (IVR).

Value of high frame rate contrast enhanced ultrasound in gallbladder wall thickening in non-acute setting.

BACKGROUND: Ultrasound (US) has been widely used in screening and differential diagnosis of gallbladder wall thickening (GWT). However, the sensitivity and specificity for diagnosing wall-thickening type gallbladder cancer are limited, leading to delayed treatment or overtreatment. We aim to explore the value of high frame rate contrast enhanced ultrasound (H-CEUS) in distinguishing wall-thickening type gallbladder cancer (malignant) from GWT mimicking malignancy (benign). METHODS: This retrospective study enrolled consecutive patients with non-acute GWT who underwent US and H-CEUS examination before cholecystectomy. Clinical information, US image and H-CEUS image characteristics between malignant and benign GWT were compared. The independent risk factors for malignant GWT on H-CEUS images were selected by multivariate logistic regression analysis. The diagnostic performance of H-CEUS in determining malignant GWT was compared with that of the gallbladder reporting and data system (GB-RADS) score. RESULTS: Forty-six patients included 30 benign GWTs and 16 malignant GWTs. Only mural layering and interface with liver on US images were significantly different between malignant and benign GWT (P < 0.05). Differences in enhancement direction, vascular morphology, serous layer continuity, wash-out time and mural layering in the venous phase of GWT on H-CEUS images were significant between malignant and benign GWT (P < 0.05). The sensitivity, specificity and accuracy of H-CEUS based on enhancement direction, vascular morphology and wash-out time in the diagnosis of malignant GWT were 93.75%, 90.00%, and 91.30%, respectively. However, the sensitivity, specificity and accuracy of the GB-RADS score were only 68.75%, 73.33% and 71.74%, respectively. The area under ROC curve (AUC) of H-CEUS was significantly higher than that of the GB-RADS score (AUC = 0.965 vs. 0.756). CONCLUSIONS: H-CEUS can accurately detect enhancement direction, vascular morphology and wash-out time of GWT, with a higher diagnostic performance than the GB-RADS score in determining wall-thickening type gallbladder cancer. This study provides a novel imaging means with high accuracy for the diagnosis of wall-thickening type gallbladder cancer, thus may be better avoiding delayed treatment or overtreatment.

Rare Findings of Gallbladder Metastasis From Cutaneous Melanoma on 18 F-FDG PET/CT Imaging.

ABSTRACT: We present the imaging findings of a 77-year-old man with a history of malignant cutis melanoma that metastasized to the gallbladder. A restaging 18 F-FDG PET/CT scan showed uneven thickening and elevated 18 F-FDG uptake in the gallbladder wall. Subsequently, the patient underwent laparoscopic cholecystectomy, and histopathologic findings confirmed the diagnosis of metastatic melanoma of the gallbladder.

Gallbladder carcinoma presenting with disseminated bony metastasis.

Gallbladder cancer (GBC) is the 23rd most common cancer worldwide and one of the three leading cancers in North and Northeast India. GBC has inferior outcomes due to its advanced presentation and poor response to chemotherapy. The approximate 5-year survival rate for metastatic GBC is less than 5%, with a median survival of around 6 months. Distant metastases from GBC to the bones happen in the later part of the natural history of the disease. Presentation with bony metastasis is infrequent, and less than 25 cases have been reported. Our case was an elderly man in his 70s who presented with back pain and, on workup, was detected to have adenocarcinoma of the gall bladder with disseminated lytic bony metastasis without any visceral metastasis. This case describes the natural history of such cases and discusses the role of bone scan or fluorodeoxyglucose positron emission tomography in the workup for GBC.

Percutaneous cholecystostomy: an unusual route of dissemination of gallbladder carcinoma.

A 78-year-old male with high-risk surgical presented severe acute cholecystitis and required cholecystostomy. The patient was referred later for assessment of the surgical treatment. A cholangio-MRI revealed a lesion on the gallbladder fundus with hepatic lesions suggestive of metastatic gallbladder carcinoma, which was confirmed in the histological analysis. The tumor progressed despite the chemotherapy through the cholecystostomy tract and developed peritoneal carcinomatosis. The patient did not respond to chemotherapy and he died 12 months later.

Mixed adenoneuroendocrine carcinoma of the gallbladder.

A 58-year-old woman presented with a 1-day history of abdominal pain. Abdominal CT showed an oval soft tissue density mass in the fundus of the gallbladder (red arrow), approximately 4.0 cm × 3.0 cm in size. The level of cancer antigen 199 was elevated (275.80 U/mL; normal level, 0.0-27.0 U/mL). Other tumor markers were normal including alpha fetoprotein, carcinoembryonic antigen. Abdominal magnetic resonance imaging demonstrated the mass with characteristic of mixed signals, containing marked enhanced ingredient (yellow arrow) and poor blood supply ingredient (blue arrow). Radical cholecystectomy, partial liver resection, and regional lymphadenectomy were performed. Pathological examination indicated mixed adenoneuroendocrine carcinoma, with the following immunohistochemistry results: CD56 (+) (Figure 1F), Syn (+) (Figure 1G), CK19 (+) (Figure 1H), CgA (+), MLHL (+), PMS2 (+), MSH2 (+), MSH6 (+), Ki-67 (60%+).

Risk stratification model for incidentally detected gallbladder polyps: A multicentre study.

PURPOSE: We aimed to develop a 4-level risk stratification model using a scoring system based on conventional ultrasound to improve the diagnosis of gallbladder polyp. METHOD: Patients with histopathologically confirmed gallbladder polyps were consecutively recruited from three medical centres. Conventional ultrasound findings and clinical characteristics were acquired prior to cholecystectomy. Risk factors for neoplastic and malignant polyps were used to build a risk stratification system via interobserver agreement and multivariate logistic regression analysis. The model was retrospectively trained using 264 pre-surgical samples and prospectively validated using 106 pre-surgical samples. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC) and malignant polyp rate. RESULTS: In total, 370 patients (mean age, 51.68 ± 14.41 years, 156 men) were enrolled in this study. Size (≥12 mm), shape (oblate or round), single, vascularity, gallbladder stone or sludge were considered risk factors for neoplastic polyps. Size (≥14 mm), shape (oblate), single, disrupted gallbladder wall, and gallbladder stone or sludge were risk factors for malignant polyps (all p < 0.05). In the scoring system, the sensitivity, specificity, and AUC of score ≥ 9 in diagnosing neoplastic polyps were 0.766, 0.788, and 0.876 respectively; and the sensitivity, specificity, and AUC of score ≥ 15 in diagnosing malignant polyps were 0.844, 0.926, and 0.949 respectively. In our model, the malignancy rates at the four levels were 0 % (0/24), 1.28 % (2/156), 9.26 % (5/54), and 70.37 % (38/54), respectively. CONCLUSIONS: The 4-level risk stratification model based on conventional ultrasound imaging showed excellent performance in classifying gallbladder polyps.

Proposal for a new morphological "combined type" of gallbladder cancer: description of radiopathological characteristics and comparison with other morphological types.

OBJECTIVE: To describe the radiopathological characteristics of a new morphological "combined type" of gallbladder cancer (GBC) and compare it with the mass replacing gallbladder and thickening types of GBC. MATERIALS AND METHODS: The imaging and pathological details of consecutive patients with GBC between August 2020 and December 2022 were retrospectively reviewed. Two radiologists reviewed computed tomography/magnetic resonance imaging in consensus for the morphological type of GBC. The radiologists classified GBC as mass replacing gallbladder, wall thickening, and combined type. The combined type was defined as a mass arising from the thickened wall of an adequately distended gallbladder that extended exophytically into the adjacent liver parenchyma. The presence of calculi, site, and size of lesion, biliary/portal vein involvement, liver, lymph node, and omental metastases was compared among the various types. The pathological characteristics were also compared. RESULTS: Of the 481 patients (median age 55 years, 63.2% females) included in the study, mass replacing gallbladder, wall thickening, and combined-type GBC were seen in 42.8% (206/481), 40.5% (195/481), and 16.6% (80/481) of patients, respectively. In the combined type of GBC, biliary/portal vein involvement was seen in 63.7% (51/80) and 7.5% (6/80) of patients. Liver, lymph node, and omental metastases were seen in 67.5% (54/80), 40% (32/80), and 41.2% (33/80) patients, respectively. Liver metastases were significantly more common in the combined type (p = 0.002). There were no significant differences in pathological characteristics among the various types. CONCLUSION: Combined-type GBC is less common than the mass replacing gallbladder and thickening types and is associated with a higher risk of liver metastases.