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Background & Aims Oropharyngeal and esophageal squamous cell carcinomas, especially the latter, are a lethal disease, featuring intratumoral cancer cell heterogeneity and therapy resistance. To facilitate cancer therapy in personalized medicine, three-dimensional (3D) organoids may be useful for functional characterization of cancer cells ex vivo. We investigated the feasibility and the utility of patient-derived 3D organoids of esophageal and oropharyngeal squamous cell carcinomas. Methods We generated 3D organoids from paired biopsies representing tumors and adjacent normal mucosa from therapy-naïve patients and cell lines. We evaluated growth and structures of 3D organoids treated with 5-fluorouracil ex vivo. Results Tumor-derived 3D organoids were grown successfully from 15 out of 21 patients (71.4%) and passaged with recapitulation of the histopathology of the original tumors. Successful formation of tumor-derived 3D organoids was associated significantly with poor response to presurgical neoadjuvant chemotherapy or chemoradiation therapy in informative patients (P = 0.0357, progressive and stable diseases, n = 10 vs. partial response, n = 6). The 3D organoid formation capability and 5-fluorouracil resistance were accounted for by cancer cells with high CD44 expression and autophagy, respectively. Such cancer cells were found to be enriched in patient-derived 3D organoids surviving 5-fluorouracil treatment. Conclusions The single cell-based 3D organoid system may serve as a highly efficient platform to explore cancer therapeutics and therapy resistance mechanisms in conjunction with morphological and functional assays with implications for translation in personalized medicine., Graphical abstract

Background Anti-HER2 therapy has not demonstrated a survival advantage in the second-line setting of patients with HER2-positive gastric cancer. We conducted this study to assess changes in HER2 status and to identify possible biomarkers for acquired resistance after the use of trastuzumab as the first-line therapy. Patients and methods Patients with advanced or recurrent HER2-positive gastric adenocarcinoma who were diagnosed with progressive disease after the first-line trastuzumab-based therapy and developed pathologically confirmed adenocarcinoma within 3 months after completion of trastuzumab-based therapy were enrolled in this study. We collected re-biopsied samples from the HER2-positive patients who had developed resistance to trastuzumab and re-evaluated their HER2 status. Amplification of EGFR and c-met, as well as PIK3CA mutation, were comparatively analysed when samples were available. Results Among 33 eligible patients, loss of HER2 was identified in 20 patients (60.6%) with refractory disease. Immunohistochemistry showed that the rate of HER2 overexpression was greatly reduced after therapy (pre-HER2 3+: 24 [72.7%] vs. post-HER2 3+: 13 [39.4%]). We found that the use of fixatives other than 10% neutral buffered formalin significantly reduced the HER2-positive rate. EGFR amplification, c-met amplification and PIK3CA mutation before and after trastuzumab-based therapy were observed in 10.3% and 3.8%, 17.9% and 4.2% and 4.0% and 4.2% of cases, respectively. Conclusion Re-evaluation of HER2 status is needed to determine the appropriate use of anti-HER2–targeted therapy after disease progression. Our results also highlight the importance of formalin fixation conditions for HER2 testing.

Background Severe mental disorders are thought to affect the diagnosis and treatment of breast cancer because of their lower awareness and understanding of the disease and their reduced ability to cooperate with medical staff. We analyzed the clinical features of patients with breast cancer and pre-existing mental disorders such as schizophrenia, dementia, and intellectual disability. Patients and methods: We reviewed the records of 46 patients who were diagnosed with schizophrenia, dementia, or intellectual disability, before being diagnosed with breast cancer. Three patients had more than 2 mental disorders. All patients underwent curative surgical treatment between September 1992 and January 2015. Patients' clinicopathological information was compared with a control group of 727 breast-cancer patients without mental disorders seen during the same period. Results Patients with mental disorders were less likely to be aware of their own breast cancer; the lesions were often found by other people such as family, care staff, and medical staff. Breast cancer patients with mental disorders had significantly more advanced T factors and overall stage at the time of surgery than their counterparts without mental illness, more patients underwent total mastectomy, and fewer patients underwent postoperative adjuvant chemotherapy and radiation. Biological markers such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression were not significantly different between groups. Disease-free survival and overall survival were not significantly different between groups. Conclusion Patients with mental disorders receive less postoperative adjuvant chemotherapy; however, their outcomes were not worse than those of patients without mental disorders.

Background Among gastrointestinal cancers, the prognosis of pancreatic cancer is one of the poorest, with a large number of patients being diagnosed with unresectable tumors at the first visit to a doctor. The aims of the present study were to investigate the circulating tumor cells (CTC) in peripheral blood in order to assess their clinical significance in patients with pancreatic cancer. Methods Sixty-five patients with advanced pancreatic cancer were enrolled. Borderline resectable pancreatic tumor patients were 9, and Unresectable patients were 56. The CellSearch system was used to isolate and enumerate CTCs. Results CTCs were identified in 21 out of 65 patients (32.3%) with only unresectable tumors. The overall survival rate was significantly lower in unresectable patients with than in those without CTCs ( P = 0.0051). CTC positivity was significantly higher in patients with than in those without liver metastasis. A multivariate analysis identified the presence or absence of CTCs as an independent prognostic factor. Follow-up blood specimens were obtained from 40 patients treated with chemotherapy or chemoradiotherapy. The incidences of CTC positivity at three months after beginning of treatments in patients with progressive disease and stable disease or a partial response were 45.4% and 24.1%, respectively. The overall survival rate was significantly lower in patients with than in those without CTCs even after treatments ( P = 0.045). Conclusion CTC numbers represents a useful tool for predicting prognoses and therapeutic responses to chemotherapy among patients with advanced pancreatic cancer.

An association between inflammatory/immunonutritional status and patient prognosis has been reported in various types of cancer. The aim of this study was to evaluate the utility of inflammatory/immunonutritional factors as therapeutic predictors for patients with locally advanced pancreatic cancer treated with chemoradiotherapy (CRT).Ninety-six patients with histologically proven locally advanced pancreatic adenocarcinoma who underwent CRT were enrolled in this study. We evaluated significance of inflammation-based factors as predictors of therapeutic effect and prognosis.The median progression free survival (PFS) and overall survival (OS) of all patients was 10 and 18 months, respectively. A Glasgow prognostic score (GPS) of 2 and plasma fibrinogen levels ≥ 400 mg/dL were independent predictors of poor PFS and OS. A prognostic nutritional index (PNI) ≥ 45 was a predictor of a significantly better reduction rate of the primary tumor. The prognosis between patients with GPS 0/1 and fibrinogen400 mg/dL, GPS 2 or fibrinogen ≥400 mg/dL, and GPS 2 and fibrinogen ≥400 mg/dL were significantly different. Patients with GPS 2 and/or plasma fibrinogen ≥ 400 mg/dL had significantly higher incidence of metastasis within 6 months after CRT.GPS, fibrinogen, PNI are useful therapeutic and prognostic predictors in patients with locally advanced pancreatic cancer treated with CRT.

Background Human leukocyte antigen (HLA)-F is a nonclassical HLA class I molecule that shows aberrant expression in cancer cells. Although the clinical implications of HLA-F expression in cancer patients have been described, the specific significance of this antigen in gastrointestinal cancer remains unclear. The present study examined the expression pattern and clinical implications of HLA-F in gastric adenocarcinoma. Patients and methods HLA-F expression was assessed in 179 patients by immunohistochemistry, and its association with clinical parameters including patient survival was analyzed. Results HLA-F expression was positive in 30.7% (55/179) of patients and in 50.0% (90/179) of peritumoral infiltrating lymphocytes. HLA-F expression in gastric adenocarcinoma was significantly correlated with the depth of invasion, nodal involvement, and lymphatic and venous invasions (P < 0.01, all). HLA-F positivity of infiltrating cells near the tumor showed no correlation with clinicopathological features. HLA-F–positive patients had a significantly worse prognosis than HLA-F–negative patients (P = 0.012). However, HLA-F expression was not an independent prognostic factor in multivariate analysis. Conclusions The present study provides the first evidence that neo-HLA-F expression is of clinical significance in gastric adenocarcinoma. HLA-F expression in gastric adenocarcinoma may promote the aggressive behavior of tumors by suppressing the activity of antitumor immune effector cells.

Although lymph node metastasis is one of the important prognostic factors for patients with gastric cancer, the clinical significance of micrometastasis remains controversial. In the 6th edition of the TMN classification, micrometastases were classified as micrometastasis (MM) and isolated tumor cells (ITC) according to its greatest dimension. The accurate diagnosis of micrometastases is required when considering less invasive surgery, especially in early stage of gastric cancer. Since generating useful information about micrometastases by conventional RT-PCR is time-consuming, this procedure is not useful for rapid diagnosis during surgery. Recently some new methods of genetic diagnosis have reduced the amount of time required to obtain information about micrometastases in lymph nodes to 30–40min. Such methodology can be clinically applied during less invasive surgery. The sentinel node (SN) concept has recently been applied to gastric cancer and SN navigation surgery (SNNS) is ideal for reduction of lymphadenectomy in patients with early gastric cancer. However, we should think about some conditions to establish SN concept for gastric cancer: the particle size of radioisotope, relationship between metastatic area and RI uptake, and the diagnosis of micrometastases by various method such as histological examination, immunostaining and RT-PCR. Here, we described the current status of MM and ITC in the lymph nodes and the SN concept in gastric cancer.

The 6th edition of the TNM classification has recently defined "sentinel nodes (SN)," "micrometastasis," and "isolated tumor cells (ITC)." The present study examines the frequency and proliferative activity of such metastases with focus on the SNs of gastric cancer.We enrolled 133 patients with cT1-2 tumors (cT1: 104, cT2: 29) and mapped SNs. Lymph node metastases were examined by routine histology and by immunohistochemistry with anti-cytokeratin. We used the Ki-67 antibody to detect the primary tumor and lymph node metastases to evaluate proliferative activity.The number of patients with SNs metastases and metastatic SNs was 19 and 52, respectively. The frequencies of macrometastasis, micrometastasis, and ITC were 48%, 25%, and 27%, respectively. Ki-67 expression in the tumor closely correlated with lymphatic invasion (P = 0.0001), venous invasion (P0.0001), and lymph node metastasis (P0.0001). Cells in 96% of macrometastases, 92% of micrometastases, and 29% of ITCs were Ki-67 positive.We showed that micrometastasis and some ITCs in SNs had proliferative activity. We suggest that micrometastasis and ITCs should be removed, especially during SN navigation surgery, until their clinical significance is clarified.

Sentinel node navigation surgery has been introduced for the treatment of gastrointestinal tumor. As few studies have examined relationships between metastatic area and radioisotope uptake in sentinel nodes, the present study examined this relationship for gastric and esophageal cancers.Subjects comprised 43 patients (esophageal cancer, n = 19; gastric cancer, n = 24) withor =3 lymph node metastases in whom sentinel node mapping with radio-guided methods was performed. Radioisotope uptake was measured after surgery for all dissected lymph nodes. Metastatic area was calculated using the following formula: metastatic area (%) = (area of metastasis/total area of lymph node) x 100. Based on radioisotope uptake, lymph nodes were divided into RI(-) and RI(+) groups.In 35 patients,or =1 metastatic node was present among the sentinel nodes. In 1 patient, no sentinel nodes were detected. No lymph node metastasis was found in sentinel nodes in the remaining seven patients. Lymph nodes were diagnosed as metastatic using preoperative imaging. Mean (+/-SD) metastatic area was significantly higher for RI(-) (68.3 +/- 20.5%) than for RI(+) (15.1 +/- 20.8%; P0.0001). Radioisotope uptake was decreased in lymph nodes with60% metastatic area.The fact that radioisotope uptake is not detectable in some lymph nodes with60% metastatic area must be considered when planning sentinel node navigation surgery.

Background Sentinel node navigation surgery (SNNS) has recently been introduced for various types of carcinoma. Numerous radioisotopes are used as tracers for SNNS. However, few reports have examined particle sizes of isotope colloids used in SNNS. Materials and methods Tin and phytate colloids were used in the present study. Isotonic sodium chloride and tin solutions were mixed ratios of 1:4, 1:2, 1:1, 2:1, and 4:1. Calcium solution and Tc-phytate were mixed at ratios of 1:4, 1:2, 1:1, 2:1 and 4:1. Particle size was measured using a Coulter Model N4SD Sub-micron Particle Analyzer. Results When isotonic sodium chloride and tin solutions were mixed at ratios of 1:4, 1:2, 1:1, 2:1, and 4:1, particle size was 47 ± 9, 96 ± 10, 712 ± 83, 925 ± 66 and 1079 ± 132 nm, respectively. As the ratio of tin solution decreased, colloid particle size increased. Particle size of phytate colloid varied from 174 ± 39 nm to 1222 ± 283 nm, according to calcium concentration. Phytate colloid particle size became larger as the ratio of phytate solution decreased. Conclusions We ascertained that the particle size of tin and phytate colloids is controllable by manipulating the conditions under which the colloids form. These results will offer useful information when SNNS is performed.