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BACKGROUND: Patients with metastatic uveal melanoma (MUM) in the liver usually die within 1 year. The development of new treatments for MUM has been limited by the lack of diverse MUM cell lines and appropriate animal models. We previously reported that orthotopic xenograft mouse models established by direct injection of MUM cells into the liver were useful for the analysis associated with tumor microenvironment in the liver. However, considering that patients with UM metastasize to the liver hematogenously, direct liver injection model might not be suitable for investigation on various mechanisms of liver metastasis. Here, we aim to establish new orthotopic xenograft models via hematogenous dissemination of tumor cells to the liver, and to compare their characteristics with the hepatic injection model. We also determine if hepatic tumors could be effectively monitored with non-invasive live imaging. METHODS: tdtTomate-labeled, patient-derived MUM cells were injected into the liver, spleen or tail vein of immunodeficient NSG mice. Tumor growth was serially assessed with In Vivo Imaging System (IVIS) images once every week. Established hepatic tumors were evaluated with CT scan and then analyzed histologically. RESULTS: We found that splenic injection could consistently establish hepatic tumors. Non-invasive imaging showed that the splenic injection model had more consistent and stronger fluorescent intensity compared to the hepatic injection model. There were no significant differences in tumor growth between splenic injection with splenectomy and without splenectomy. The splenic injection established hepatic tumors diffusely throughout the liver, while the hepatic injection of tumor cells established a single localized tumor. Long-term monitoring of tumor development showed that tumor growth, tumor distribution in the liver, and overall survival depended on the number of tumor cells injected to the spleen. CONCLUSION: We established a new orthotopic hepatic metastatic xenograft mouse model by splenic injection of MUM cells. The growth of orthotopic hepatic tumors could be monitored with non-invasive IVIS imaging. Moreover, we evaluated the therapeutic effect of a MEK inhibitor by using this model. Our findings suggest that our new orthotopic liver metastatic mouse model may be useful for preclinical drug screening experiments and for the analysis of liver metastasis mechanisms.

Nodal status is well known to be the most important prognostic factor for esophageal cancer patients, even if they are treated with neoadjuvant therapy. To establish an optimal postoperative adjuvant strategy for patients, we aimed to more accurately predict the prognosis of patients and systemic recurrence by using clinicopathological factors, including nodal status, in patients with esophageal cancer who received neoadjuvant chemotherapy. The clinicopathological factors associated with survival and systemic recurrence were investigated in 488 patients with esophageal squamous cell carcinoma who received neoadjuvant chemotherapy. Overall survival differed according to tumor depth, nodal status, tumor regression, and lymphovascular (LV) invasion. In the multivariate analysis, nodal status and LV invasion were identified as independent prognostic factors (P  < 0.0001, P  = 0.0008). Nodal status was also identified as an independent factor associated with systemic recurrence, although LV invasion was a borderline factor (P  = 0.066). In each pN stage, patients with LV invasion showed significantly worse overall survival than those without LV invasion (pN0: P  = 0.036, pN1: P  = 0.0044, pN2: P  = 0.0194, pN3: P  = 0.0054). Patients with LV invasion were also more likely to have systemic, and any recurrence than those without LV invasion in each pN stage. Pathological nodal status and LV invasion were the most important predictors of survival and systemic recurrence in patients with esophageal cancer who underwent neoadjuvant chemotherapy followed by surgery. This finding could provide useful information about selecting candidates for adjuvant therapy among these patients. Our analysis showed that LV invasion was an independent prognostic factor in patients with esophageal cancer who underwent neoadjuvant chemotherapy and that combining LV invasion with pathological nodal status makes it possible to stratify the prognosis in those patients. [ABSTRACT FROM AUTHOR]

Introduction: Metastatic or unresectable locally advanced oesophageal cancer remains a disease with high mortality. More recently, pembrolizumab plus chemotherapy has been indicated as the first-line treatment for those patients, but the predictive factors for treatment efficacy remain controversial. This study investigated the clinical utility of early tumour shrinkage (ETS) and depth of response (DpR) in metastatic or unresectable oesophageal cancer treated with pembrolizumab plus CF therapy. Methods: ETS and DpR, defined as the percent decreases at the second evaluation and the percentage of the maximal tumour shrinkage during treatment, were measured in 53 eligible patients. The ETS and DpR cut-off values were 20% and 30%, respectively, based on survival outcomes. Results: Twenty-seven patients (51%) were treatment naïve, while 26 (49%) had received any treatment before initiating pembrolizumab plus CF therapy. The median progression-free survival (PFS) and overall survival for ETS ≥20% and <20% were 12.7 and 5.5 months and 14.4 and 8.2 months and 12.7 and 4.9 months and 14.4 and 8.0 months for DpR ≥30% and <30%, respectively. ETS <20% showed early tumour growth, whereas ETS ≥20% had a good response rate with sufficient longer response duration. In addition, an ETS cut-off of 20% predicted the best overall response and was not associated with prior treatment. In multivariable analysis, ETS ≥20% and DpR ≥30% were independent factors of longer PFS. Conclusion: Our findings suggest that an ETS is a promising on-treatment marker for early prediction of further sensitivity to pembrolizumab plus CF therapy. [ABSTRACT FROM AUTHOR]

Introduction: Curative esophagectomy is not always possible in patients with locally advanced esophageal cancer. However, few studies have investigated patients who underwent non-curative surgery with intraoperative judgment. This study aimed to investigate patient characteristics and clinical outcomes for patients undergoing non-curative surgery and compare them between non-resectional and non-radical surgery. Methods: Among 989 consecutive patients with thoracic esophageal squamous cell carcinoma who were preoperatively expected for curative esophagectomy, 66 who were eligible for non-curative surgery were included in this study. Results: Intraoperative diagnosis of T4b accounted for 93% of the reasons for the failure of curative surgery. In those patients, esophageal cancer locally invaded into the aortobronchial constriction (70%), trachea (25%), or pulmonary vein (5%). Lymph node metastasis mainly invaded into the trachea (50%) or bronchus (28%). The overall survival of patients with non-curative surgery was 51.5%, 25.7%, and 10.4% at 6, 12, and 24 months after surgery, respectively. Although there were no differences in preoperative patient characteristics between non-resectional and non-radical surgery, distant metastasis, especially pleural dissemination, was significantly observed in T4b patients due to esophageal cancer with non-radical surgery than those with non-resectional surgery (35% vs. 15%, p = 0.002). Even in patients with non-curative surgery, R1 resection and postoperative chemoradiotherapy were identified as independent factors for survival 1 year after surgery (p = 0.047, and 0.019). Conclusions: T4b tumor located in aortobronchial constriction or trachea/bronchus makes it difficult to diagnose whether it is resectable or unresectable. Moreover, surgical procedures and perioperative treatment were deeply associated with the clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: The optimal extent of lymph-node (LN) dissection in esophageal cancer has not been established. Although the frequency and patterns of recurrence in each regional LN station after radical dissection are important in determining the regional LNs of thoracic esophageal cancer to be routinely dissected, this information has not been investigated sufficiently. We studied the significance of dissection at each LN station based on their recurrence patterns. Methods: Six hundred and twelve patients with esophageal cancer who underwent curative esophagectomy were studied. The incidence and pattern of recurrence (systemic or non-systemic) at each regional LN station were analyzed. To compare the significance of dissection among regional LNs, the efficacy index (EI) was also calculated. Results: Regional LN recurrence was diagnosed in 101 (16.5%) patients. Among the regional LNs, recurrent laryngeal nerve, paraesophageal, and perigastric LNs showed higher EIs (3.1–6.7). Pretracheal and posterior thoracic para-aortic LNs showed low EIs (0–0.2). Supraclavicular LNs had moderate EIs (1.7–2.0). The recurrence rate was highest in the pretracheal LN, followed by the supraclavicular LNs. The majority (81.8%) of the pretracheal LN had a systemic recurrence, while about half (right: 60.0%, left: 43.8%) of the supraclavicular LNs had a systemic recurrence. Conclusion: Due to the high incidence of systemic recurrence or low EI for pretracheal and posterior thoracic para-aortic LNs, we suggest that these LN stations be regarded as non-regional LNs and be excluded from routine dissection. Supraclavicular LNs may also be excluded from routinely dissected stations. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to investigate long‐term changes in bone mineral density (BMD) after esophagectomy, identify the risk factors for postoperative osteoporosis in patients with esophageal cancer and survival outcomes related to osteoporosis. Methods: We retrospectively evaluated BMD changes for 197 consecutive patients with thoracic esophageal cancer who were disease‐free for 5 years after radical esophagectomy. Osteoporosis was diagnosed using computed tomography with an L1 attenuation threshold of ≤110 HU. Survival analysis was performed on 381 consecutive patients with 5‐year follow‐up after radical esophagectomy. Results: BMD decreased annually after esophagectomy. The median attenuation (HU) was 134.2 before surgery and 135.2, 127.4, 123.3, 115.2, 105.6, and 102.4 at 6 months and 1, 2, 3, 4, and 5 years after surgery, respectively. Osteoporosis was diagnosed in 25.9% patients before surgery and 23.3%, 29.4%, 40.1%, 46.7%, 54.8%, and 60.4% patients with osteoporosis were observed at 6 months and 1, 2, 3, 4, and 5 years after surgery, respectively. Postoperative BMD did not decrease in patients aged ≤54 years, those who had never been smokers, and those with no weight loss after esophagectomy. Multivariate analysis identified that age (≥65 years) at surgery and smoking history were independent risk factors for osteoporosis at 5 years after esophagectomy. Patients with preoperative osteoporosis tended to have worse prognosis in disease‐free survival and overall survival than those without osteoporosis, who were more likely to die due to non‐esophageal cancer. Conclusion: Esophageal cancer survivors are more likely to develop osteoporosis after esophagectomy, and preoperative osteoporosis might be associated with prognosis. [ABSTRACT FROM AUTHOR]