Monitoring of Current Cancer Therapy by Positron Emission Tomography and Possible Role of Radiomics Assessment.

Evaluation of cancer therapy with imaging is crucial as a surrogate marker of effectiveness and survival. The unique response patterns to therapy with immune-checkpoint inhibitors have facilitated the revision of response evaluation criteria using FDG-PET, because the immune response recalls reactive cells such as activated T-cells and macrophages, which show increased glucose metabolism and apparent progression on morphological imaging. Cellular metabolism and function are critical determinants of the viability of active cells in the tumor microenvironment, which would be novel targets of therapies, such as tumor immunity, metabolism, and genetic mutation. Considering tumor heterogeneity and variation in therapy response specific to the mechanisms of therapy, appropriate response evaluation is required. Radiomics approaches, which combine objective image features with a machine learning algorithm as well as pathologic and genetic data, have remarkably progressed over the past decade, and PET radiomics has increased quality and reliability based on the prosperous publications and standardization initiatives. PET and multimodal imaging will play a definitive role in personalized therapeutic strategies by the precise monitoring in future cancer therapy.

Determination of brain tumor recurrence using 11 C-methionine positron emission tomography after radiotherapy.

We conducted a prospective multicenter trial to compare the usefulness of 11 C-methionine (MET) and 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for identifying tumor recurrence. Patients with clinically suspected tumor recurrence after radiotherapy underwent both 11 C-MET and 18 F-FDG PET. When a lesion showed a visually detected uptake of either tracer, it was surgically resected for histopathological analysis. Patients with a lesion negative to both tracers were revaluated by magnetic resonance imaging (MRI) at 3 months after the PET studies. The primary outcome measure was the sensitivity of each tracer in cases with histopathologically confirmed recurrence, as determined by the McNemar test. Sixty-one cases were enrolled, and 56 cases could be evaluated. The 38 cases where the lesions showed uptake of either 11 C-MET or 18 F-FDG underwent surgery; 32 of these cases were confirmed to be subject to recurrence. Eighteen cases where the lesions showed uptake of neither tracer received follow-up MRI; the lesion size increased in one of these cases. Among the cases with histologically confirmed recurrence, the sensitivities of 11 C-MET PET and 18 F-FDG PET were 0.97 (32/33, 95% confidence interval [CI]: 0.85-0.99) and 0.48 (16/33, 95% CI: 0.33-0.65), respectively, and the difference was statistically significant (P < .0001). The diagnostic accuracy of 11 C-MET PET was significantly better than that of 18 F-FDG PET (87.5% vs. 69.6%, P = .033). No examination-related adverse events were observed. The results of the study demonstrated that 11 C-MET PET was superior to 18 F-FDG PET for discriminating between tumor recurrence and radiation-induced necrosis.

Prognostic impact of preoperative FDG-PET positive lymph nodes in lung cancer.

BACKGROUND: 2-[18F] Fluoro-D-deoxyglucose positron emission tomography (FDG-PET) is an appropriate diagnostic procedure for staging lung cancer. However, accurate evaluation of lymph node (LN) metastases by PET is controversial owing to false-positive/-negative FDG uptake results. The prognostic significance of both false-negative and false-positive LNs on FDG-PET remains to be determined. METHODS: A total of 235 patients with lung cancer were retrospectively analyzed. Maximum standardized uptake values (SUVmax) of the lymph nodes were compared with pathological LN metastases to correlate PET findings with clinicopathological variables and patients' outcomes. RESULTS: When SUVmax ≥ 4 was defined as PET-positive for LN metastasis, sensitivity, specificity, and accuracy were 46.0%, 79.5%, and 72.3%, respectively. False-negative cases and pathological n0 cases were significantly younger, had primary tumors that were smaller or lower SUVmax, and adenocarcinomas compared with false-positive and pathological n+ cases. The difference in survival time between patients with abnormal FDG uptake in the LN and those without was larger than that between pathological LN metastases and no pathological metastases in patients with adenocarcinoma. Multivariate analysis by the Cox proportional hazard model identified smoker, EGFR/ALK negative and LN positive on PET as significant adverse prognostic factors, rather than pathological n-stage. CONCLUSIONS: Abnormal FDG uptake in the LN is an important prognostic factor. Increased glucose metabolism on FDG-PET appears to be a more efficient postoperative prognostic marker than pathological n-stage in patients with lung cancer.

Detectability of Malignant Lesions by Whole-Body Magnetic Resonance Imaging Using Whole-Body Integrated Positron Emission Tomography/Magnetic Resonance Imaging.

PURPOSE: To assess the diagnostic ability of whole-body magnetic resonance imaging (MRI) using integrated positron emission tomography/MRI(PET/MRI). METHODS: Axial T2-weighted image (T2WI), diffusion-weighted imaging (DWI), coronal T1-weighted image (T1WI), axial volumetric interpolated breath-hold examination in the lung field, and 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG-PET) were evaluated in combination with T2WI alone, T2WI + DWI, T2WI + DWI + T1WI, T2WI + DWI + T1WI + volumetric interpolated breath-hold examination (all MRI images), and all MRI + FDG-PET. RESULTS: A total of 370 lesions were observed in 90 (62.5%) of the 144 patients. The lesion-based sensitivities were 62%, 74%, 74%, 76%, and 94%, and the patient-based sensitivities were 70%, 77%, 77%, 77%, and 81% using T2WI, T2WI + DWI, T2WI + DWI + T1WI, all MRI, and all MRI + FDG-PET, respectively. There were significant differences in the lesion-based sensitivity between T2WI and other sequence combinations and between all MRI and all MRI + FDG-PET. No significant differences were observed between any combinations among the patient-based sensitivities. CONCLUSION: The sensitivity of whole-body MRI was lower when lesion based, but almost equivalent when patient based compared with PET/MRI.

Efficacy of system l amino acid transporter 1 inhibition as a therapeutic target in esophageal squamous cell carcinoma.

System l amino acid transporter 1 (LAT1) is highly expressed in various types of human cancer, and contributes to cancer growth and survival. Recently, we have shown that LAT1 expression is closely related to the growth and aggressiveness of esophageal cancer, and is an independent marker of poor prognosis. However, it remains unclear whether LAT1 inhibition could suppress esophageal cancer growth. In this study, we investigated the tumor-suppressive effects of the inhibition of LAT1. Both LAT1 and CD98, which covalently associates to LAT1 on the membrane, were expressed in human esophageal cancer cell lines KYSE30 and KYSE150. Quantitative PCR analysis showed that the expression of LAT1 was much higher than other subtypes of LAT. A selective inhibitor of LAT, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), suppressed cellular uptake of l-14 C-leucine and cell proliferation in a dose-dependent manner. It also suppressed phosphorylation of mammalian target of rapamycin, 4E-BP1, and p70S6K protein, and induced cell cycle arrest at G1 phase. These results suggest that suppression of both mammalian target of rapamycin signaling and cell cycle progression is involved in BCH-induced growth inhibition. In tumor-bearing mice, daily treatment with BCH significantly delayed tumor growth and decreased glucose metabolism, indicating that LAT1 inhibition potentially suppresses esophageal cancer growth in vivo. Thus, our results suggest that LAT1 inhibition could be a promising molecular target for the esophageal cancer therapy.

Specific transport of 3-fluoro-l-α-methyl-tyrosine by LAT1 explains its specificity to malignant tumors in imaging.

3-(18)F-l-α-methyl-tyrosine ([18F]FAMT), a PET probe for tumor imaging, has advantages of high cancer-specificity and lower physiologic background. FAMT-PET has been proved useful in clinical studies for the prediction of prognosis, the assessment of therapy response and the differentiation of malignant tumors from inflammation and benign lesions. The tumor uptake of [18F]FAMT in PET is strongly correlated with the expression of L-type amino acid transporter 1 (LAT1), an isoform of system L upregulated in cancers. In this study, to assess the transporter-mediated mechanisms in FAMT uptake by tumors, we examined amino acid transporters for FAMT transport. We synthesized [14C]FAMT and measured its transport by human amino acid transporters expressed in Xenopus oocytes. The transport of FAMT was compared with that of l-methionine, a well-studied amino acid PET probe. The significance of LAT1 in FAMT uptake by tumor cells was confirmed by siRNA knockdown. Among amino acid transporters, [14C]FAMT was specifically transported by LAT1, whereas l-[14C]methionine was taken up by most of the transporters. Km of LAT1-mediated [14C]FAMT transport was 72.7 µM, similar to that for endogenous substrates. Knockdown of LAT1 resulted in the marked reduction of [14C]FAMT transport in HeLa S3 cells, confirming the contribution of LAT1 in FAMT uptake by tumor cells. FAMT is highly specific to cancer-type amino acid transporter LAT1, which explains the cancer-specific accumulation of [18F]FAMT in PET. This, vice versa, further supports the cancer-specific expression of LAT1. This study has established FAMT as a LAT1-specific molecular probe to monitor the expression of a potential tumor biomarker LAT1.

Transport of 3-fluoro-L-α-methyl-tyrosine (FAMT) by organic ion transporters explains renal background in [(18)F]FAMT positron emission tomography.

A PET tracer for tumor imaging, 3-(18)F-l-α-methyl-tyrosine ([(18)F]FAMT), has advantages of high cancer-specificity and low physiological background. In clinical studies, FAMT-PET has been proved useful for the detection of malignant tumors and their differentiation from inflammation and benign lesions. The tumor specific uptake of FAMT is due to its high-selectivity to cancer-type amino acid transporter LAT1 among amino acid transporters. In [(18)F]FAMT PET, kidney is the only organ that shows high physiological background. To reveal transporters involved in renal accumulation of FAMT, we have examined [(14)C]FAMT uptake on the organic ion transporters responsible for the uptake into tubular epithelial cells. We have found that OAT1, OAT10 and OCTN2 transport [(14)C]FAMT. The [(14)C]FAMT uptake was inhibited by probenecid, furosemide and ethacrynic acid, consistent with the properties of the transporters. The amino acid uptake inhibitor, 2-amino-2-norbornanecarboxylic acid (BCH), also inhibited the [(14)C]FAMT uptake, whereas OCTN2-mediated [(14)C]FAMT uptake was Na(+)-dependent. We propose that FAMT uptake by OAT1, OAT10 and OCTN2 into tubular epithelial cells could contribute to the renal accumulation of FAMT. The results from this study would provide clues to the treatments to reduce renal background and enhance tumor uptake as well as to designing PET tracers with less renal accumulation.

Radioisotope Therapy of Japan: Future Perspective and Recommendations.

In Japan, because of the rapid increase in the number of thyroid cancer patients and the recent severe shortage of radioisotope therapy wards, the prolonged waiting time for the admission to the radioisotope therapy wards has become a social problem. This situation is against one of the main purposes of the Cancer Control Promotion Plan of our nation, which is advocating an equal accessibility of medical care for the Japanese citizens. In 2015, diet discussions about the problems of radioisotope therapy took place and the prime minister stated that the promotion of radioisotope therapy is one of the most important issues in Japan, therefore further promotion of research and development is anticipated in this field. In this article, we have summarized the problems during radioisotope therapy, and have added our recommendations in the social and medical realizable countermeasures in future, according to the deep considerations of medical economy in Japan, an assumption of disease prevalence of thyroid cancer in the future, and the situations of foreign countries.

Clinicopathological significance of ASC amino acid transporter-2 expression in pancreatic ductal carcinoma.

AIMS: ASC amino acid transporter-2 (ASCT2) is highly expressed in cancer cells. However, the clinicopathological significance of ASCT2 expression in pancreatic cancer remains unclear. The aim of this study was to investigate the clinical significance of ASCT2 expression in pancreatic cancer. METHODS AND RESULTS: Ninety-seven patients with surgically resected pancreatic ductal adenocarcinoma were evaluated. Tumour sections were stained by immunohistochemistry for ASCT2, Ki67, CD34 (to determine microvessel density), phospho-AKT (p-AKT) and phospho-mammalian target of rapamycin (p-mTOR) expression. ASCT2 was expressed in 54% (52/97) of tumours. Statistically significant differences in patient age, T stage, N stage, lymphatic permeation, vascular invasion, Ki67, and CD34 and p-mTOR expression were observed between tumours with and without ASCT2 expression. Multivariate analysis confirmed that vascular invasion, ASCT2 expression and Ki67 expression were independent predictive factors for a poorer prognosis. CONCLUSIONS: ASCT2 expression plays an important role in tumour cell growth, and is a promising pathological marker for predicting a worse outcome in pancreatic cancer.

Expression of amino acid transporters (LAT1, ASCT2 and xCT) as clinical significance in hepatocellular carcinoma.

AIM: Amino acid transporters play an important role in tumor progression and survival of cancer cells. However, the prognostic significance of L-type amino acid transporter 1 (LAT1), system ASC amino acid transporter-2 (ASCT2) and xCT expression in patients with hepatocellular carcinoma (HCC) remains unclear. The aim of this study is to investigate the clinicopathological significance of these amino acid transporters in patients with HCC. METHODS: We examined 84 patients with surgically resected HCC. Tumor sections were stained by immunohistochemistry for LAT1, ASCT2, xCT, 4F2hc/CD98hc (4F2hc), Ki-67 and microvessel density (MVD) determined by CD34. RESULTS: LAT1, 4F2hc, ASCT2 and xCT were positively expressed in 61% (50/84), 77% (65/84), 63% (53/84) and 65% (55/84), respectively. Positive LAT1 expression was significantly associated with 4F2hc expression, Ki-67 and the serum albumin. By univariate analysis, LAT1 expression, disease stage and albumin had a significant relationship with overall survival. Tumor size, disease stage, portal vein invasion, albumin and α-fetoprotein had a significant relationship with progression-free survival. Multivariate analysis confirmed that LAT1 expression is an independent and significant prognostic factor for predicting worse outcome after surgery. CONCLUSION: LAT1 can serve as a significant prognostic marker for predicting negative prognosis after surgery.

Expression of L-type amino acid transporter 1 (LAT1) as a prognostic and therapeutic indicator in multiple myeloma.

L-type amino-acid transporter 1 (LAT1) plays a key role in cell growth and survival. To determine the prognostic significance of LAT1 in multiple myeloma (MM), we investigated the expression of LAT1 and its functional subunit, 4Fc heavy chain (CD98), on myeloma cells by immunohistochemistry in 100 newly diagnosed MM patients. High expression (moderate or strong staining intensity) of LAT1 and CD98 was detected in 56% and 45% of patients, respectively. The LAT1 expression score was positively correlated with Ki-67 index (r = 0.631, P < 0.001), and there was a statistically significant difference in Durie-Salmon stage between patients with high and low LAT1 expression (P = 0.03). In 43 patients treated with melphalan and prednisolone, the overall response rate was significantly higher in the high LAT1 expression group (60.0%) than in the low LAT1 expression group (17.6%) (P = 0.03). Multivariate analysis confirmed that high expression of LAT1 was a significant prognostic factor for predicting poor overall survival independently from the International Staging System (both P = 0.01). Here, we show that the overexpression of LAT1 is significantly associated with high proliferation and poor prognosis in newly diagnosed MM patients. Thus, LAT1 may be a promising pathological marker for identifying high-risk MM.

Effects and safety of ¹³¹I-metaiodobenzylguanidine (MIBG) radiotherapy in malignant neuroendocrine tumors: results from a multicenter observational registry.

Effective treatments for malignant neuroendocrine tumors are under development. While iodine-131 metaiodobenzylguanidine (¹³¹I-MIBG) radiotherapy has been used in the treatment of malignant neuroendocrine tumors, there are few studies evaluating its therapeutic effects and safety in a multicenter cohort. In the current study, we sought to evaluate the effects and safety of ¹³¹I-MIBG therapy for conditions including malignant pheochromocytoma and paraganglioma within a multicenter cohort. Forty-eight malignant neuroendocrine tumors (37 pheochromocytoma and 11 paraganglioma) from four centers underwent clinical ¹³¹I-MIBG radiotherapy. The tumor responses were observed before and 3 to 6 months after the ¹³¹I-MIBG radiotherapy in accordance with RECIST criteria. We also evaluated the data for any adverse effects. The four centers performed a total of 87 ¹³¹I-MIBG treatments on 48 patients between January 2000 and March 2009. Of the treatments, 65 were evaluable using RECIST criteria. One partial response (PR), 40 stable disease (SD), and 9 progressive disease (PD) in malignant pheochromocytoma were observed after each treatment. Fourteen SD and one PD-were observed in paraganglioma. Patients with normal hypertension (systolic blood pressure (BP) > 130 mmHg) showed significantly reduced systolic BP after the initial follow-up (n=10, 138.1±8.2 to 129.5±13.5 mmHg, P=0.03). In adult neuroendocrine tumors with a treatment-basis analysis, there were side effects following 41 treatments (47.1%) and most of them (90.2%) were minor. In this multicenter registry, PR or SD was achieved in 84.6% of the treatment occasions in adult neuroendocrine tumors through ¹³¹I-MIBG radiotherapy. This indicated that most of the ¹³¹I-MIBG radiotherapy was performed safely without significant side effects.

CD98 is a promising prognostic biomarker in biliary tract cancer.

CD98 has been described to play a crucial role in tumor progression and survival. However, the role of CD98 in biliary tract cancer remains unclear. We found that 36.7% of all patients with biliary tract cancer had a high CD98 expression. Statistical analysis using Spearman's rank correlation showed that CD98 was significantly correlated with L-type amino acid transporter 1 (LAT1, r=0.562, P<0.001), Ki-67 (r=0.230, P=0.006) and CD34 (r=0.290, P=0.005). Multivariate analysis confirmed that a high CD98 expression was an independent prognostic factor for predicting poor outcome. CD98 is closely associated with tumor growth, biological aggressiveness, and survival of patients. With these data we proposed that CD98 expression is necessary for the development and pathogenesis of biliary tract cancer.

The influence of revised ordinance on radiation protection management in Japanese hospitals: device deployment and involvement of radiology technologists.

PURPOSE: This study evaluates the impact of the 2021 revision of Japan's Ordinance on the Prevention of Ionizing Radiation Hazards on radiation protection practices, focusing on the deployment of radiation protection devices and the involvement of radiology technologists in Japanese hospitals. METHODS: A two-phase web-based questionnaire survey was conducted among hospitals registered as training facilities with the Japanese Radiological Society. The survey included 53 questions covering facility information, radiation worker management, training, and working environment. RESULTS: The use of lens-specific dosimeters significantly increased post-revision (p = 0.005). Protective eyewear availability showed minor improvements, particularly in angiographic rooms (p = 0.019). The involvement of radiology technologists remained high in angiographic rooms but showed no significant changes in endoscopy and fluoroscopy rooms. Larger hospitals exhibited better compliance with protective measures, though gaps in resource allocation persisted. CONCLUSION: The ordinance revision led to significant improvements in dosimeter usage but only minor changes in protective eyewear deployment and technologist involvement.

Radiation Exposure Characteristics among Healthcare Workers: Before and After Japan's Ordinance Revision.

ABSTRACT: Radioactive materials and ionizing radiation have both medical value and disease risks, necessitating radiation dose measurement and risk reduction strategies. The International Commission on Radiological Protection (ICRP) lowered the lens of the eye exposure limit, leading to Japan's revised "Ionizing Radiation Ordinance." However, the effects on radiation exposure in medical settings and compliance feasibility remain unclear. To examine the impact of the revision to the "Ionizing Radiation Ordinance" and use it for measures to reduce exposure to radiation, a comprehensive analysis was conducted on data collected from Nagasaki University Hospital, Hiroshima University Hospital, and Fukushima Medical University Hospital in 2018, 2020, and April to September 2021. This included information on age, sex, occupation, department, and monthly radiation doses of workers, aiming to assess the impact of the revision to the "Ionizing Radiation Ordinance" on radiation exposure before and after its enforcement. Out of 9,076 cases studied, 7,963 (87.7%) had radiation doses below the measurable limit throughout the year. Only 292 cases (3.2%) exceeded 1 mSv y -1 , with 9 doctors and 2 radiological technologists surpassing 5 mSv y -1 . Radiological technologists showed significantly higher doses compared to doctors, dentists, and nurses (p < 0.01), while male subjects had significantly higher exposure doses than females (p < 0.01). No significant changes in radiation exposure were observed before and after the revision of the Ionizing Radiation Ordinance; however, variations in radiation exposure control were noted, particularly among nurses and radiological technologists, suggesting the impact of the revision and the need for tailored countermeasures to reduce radiation dose in each group.

Occupational radiation exposure among medical personnel in university and general hospitals in Japan.

OBJECTIVE: This study aimed to compare the occupational radiation exposure of medical workers between general hospitals and university hospitals. METHODS: Radiation exposure data from three hospitals in Hiroshima city, including one university hospital and two general hospitals, were collected using personal dosimeters. Monthly radiation doses were analyzed, and the annual sum of radiation exposure dose was calculated for 538 subjects in general hospitals and 1224 subjects in the university hospital. To assess the impact of locality, additional data from Nagasaki University Hospital and Fukushima Medical University Hospital were included for comparative analysis. Professional affiliations, such as doctors, nurses, and radiological technologists, were considered in the evaluation. RESULTS: The study revealed slight but significant differences in radiation doses between general and university hospitals. In general hospitals, except for radiological technologists, a slightly higher radiation dose was observed compared to university hospitals. Despite the annual increase in the use of medical radiation, the majority of hospital workers in both settings adhered to safety guidelines, with occupational radiation exposure remaining below the limit of detection (LOD). Workers who involved in fluoroscopic procedure, whether at university or general hospitals, had higher radiation doses than those who did not. CONCLUSION: The study's primary conclusion is that workers in general hospitals experience a slight but significantly higher radiation dose and a lower percentage below the LOD compared to university hospitals. The observed difference is attributed to the greater workload at general hospitals than at university hospitals, and also may be due to the different nature of university hospital and general hospital. University hospitals, characterized by greater academic orientation, tend to benefit from comprehensive support systems, specialized expertise, and advanced technology, leading to more structured and regulated radiation control. These findings provide a basis for targeted interventions, improved safety protocols.

Diagnostic usefulness of ¹8F-FAMT PET and L-type amino acid transporter 1 (LAT1) expression in oral squamous cell carcinoma.

PURPOSE: L-[3-(18)F]-α-Methyltyrosine ((18)F-FAMT) was developed as an amino acid tracer for PET imaging to provide better specificity than 2-[(18)F]fluoro-2-deoxy-D-glucose ((18)F-FDG) PET for cancer diagnosis. We investigated the diagnostic usefulness of (18)F-FAMT in oral squamous cell carcinoma (OSCC). The correlation between tumour uptake of (18)F-FAMT and L-type amino acid transporter 1 (LAT1) expression was determined. METHODS: The study group comprised 68 OSCC patients who underwent both (18)F-FAMT and (18)F-FDG PET. Resected tumour sections were stained by immunohistochemistry for LAT1, CD98 and Ki-67, and microvessel density was determined in terms of CD34 and p53 expression. RESULTS: The sensitivity of primary tumour detection by (18)F-FAMT and (18)F-FDG PET was 98 % and 100 %, respectively. The sensitivity, specificity and accuracy of (18)F-FAMT PET for detecting malignant lymph nodes were 68 %, 99 % and 97 %, respectively, and equivalent values for (18)F-FDG PET were 84 %, 94 % and 94 %, respectively. The specificity and accuracy of (18)F-FAMT were significantly higher than those of (18)F-FDG. The uptake of (18)F-FAMT was significantly correlated with LAT1 expression, cell proliferation and advanced stage. The expression of LAT1 in OSCC cells was closely correlated with CD98 levels, cell proliferation and angiogenesis. CONCLUSION: (18)F-FAMT PET showed higher specificity for detecting malignant lesions than (18)F-FDG PET. The uptake of (18)F-FAMT by OSCC cells can be determined by the presence of LAT1 expression and tumour cell proliferation.

Clinical significance of L-type amino acid transporter 1 expression as a prognostic marker and potential of new targeting therapy in biliary tract cancer.

BACKGROUND: The expression of L-type amino acid transporter 1 (LAT1) has been described to play essential roles in tumor cell growth and survival. However, it remains unclear about the clinicopathological significance of LAT1 expression in biliary tract cancer. This study was conducted to determine biological significance of LAT1 expression and investigate whether LAT1 could be a prognostic biomarker for biliary tract cancer. METHODS: A total of 139 consecutive patients with resected pathologic stage I-IV biliary tract adenocarcinoma were retrospectively reviewed. Tumor specimens were stained by immunohistochemistry for LAT1, Ki-67, microvessel density determined by CD34, and p53; and prognosis of patients was correlated. Biological significance of LAT1 expression was investigated by in vitro and in vivo experiments with LAT inhibitor, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) using cholangiocarcinoma cell line. RESULTS: In total patients, high LAT1 expressions were recognized in 64.0%. The expression of LAT1 was closely correlated with lymphatic metastases, cell proliferation and angiogenesis, and was a significant indicator for predicting poor outcome after surgery. LAT1 expression was a significant independent predictor by multivariate analysis. Both in vitro and in vivo preliminary experiments indicated that BCH significantly suppressed growth of the tumor and yielded an additive therapeutic efficacy to gemcitabine and 5-FU. CONCLUSIONS: High expression of LAT1 is a promising pathological marker to predict the outcome in patients with biliary tract adenocarcinoma. Inhibition of LAT1 may be an effective targeted therapy for this distressing disease.