Degree of histological differentiation is an important characteristic of cancers and may be associated with malignant potential. However, in squamous cell carcinomas, a key transcriptional factor ...regulating tumor differentiation is largely unknown. Chemoradiotherapy (CRT) is a standard treatment for locally advanced esophageal squamous cell carcinoma; however, the survival rate is still below 40%. From microarray data, single‐minded 2 (SIM2) was overexpressed in the epithelial subtype. Here, we investigated the correlation between SIM2 expression and its clinical implication, and in vitro and in vivo functions of SIM2 in tumor differentiation and in CRT sensitivity. Although SIM2 was suppressed in cancerous tissues, SIM2‐high ESCC showed a favorable prognosis in CRT. Transient SIM2 expression followed by 3D culture induced expression of differentiation markers and suppressed epithelial‐mesenchymal transition‐ and basal‐cell markers. Levels of PDPN‐high tumor basal cells and of expression of genes for DNA repair and antioxidant enzymes were reduced in stable transfectants, and they showed high CDDP and H2O2 sensitivities, and their xenografts showed a well‐differentiated histology. Reduction of tumor basal cells was restored by knockdown of aryl hydrocarbon receptor nuclear translocator (ARNT) that interacted with SIM2. Together, SIM2 increases CRT sensitivity through tumor differentiation by cooperation with ARNT.
In esophageal squamous cell carcinoma, we identified that expression of a transcriptional factor, single‐minded 2 (SIM2), is highly associated with favorable prognosis. A series of in vitro and in vivo studies showed SIM2 as a differentiation regulator and that SIM2 and ARNT cooperatively reduce PDPN‐positive malignant basal cells through differentiation and improve CRT sensitivity in squamous cell carcinoma.
Background
The sarcomatous variant of carcinoma is relatively rare in intrahepatic cholangiocarcinoma (ICC). Sarcomatous ICC (SICC) is associated with a poorer prognosis compared with ICC. SICC is ...rarely diagnosed before surgery due to non-descriptive findings; it progresses rapidly, resulting in miserable prognosis. Here, we report a case of rapidly progressing SICC that showed a clinically significant tumor growth rate.
Case presentation
A 77-year-old woman who had undergone ileocecal resection for cecal cancer 5 years previously was found to have elevated levels of the tumor marker carbohydrate antigen 19-9. Although an abdominal computed tomography (CT) scan did not detect any liver mass lesions until 3 months before this serum examination, the subsequent CT scan revealed a hypodensity 20 mm mass lesion in the right anterior section. Contrast-enhanced CT and magnetic resonance imaging revealed peripheral enhancement in the arterial-to-equilibrium phase. Fluorodeoxyglucose positron emission tomography revealed uptake in the lesion. None of the imaging modalities showed lymph node swelling or distant metastases. She underwent hepatectomy under the diagnosis of ICC or an atypical metastasis from previous cecal cancer. Although preoperative images showed no suspicious lymph node metastasis 3 weeks prior, the hilar lymph node swelled 3 cm and contained adenocarcinoma. Consequently, the patient underwent right anterior sectionectomy and lymph node dissection of the hepatoduodenal ligament. Histopathological examination revealed that the liver tumor was a poorly differentiated adenocarcinoma with sarcomatous pattern. While the patient received adjuvant gemcitabine and S-1 therapy, lymph node metastasis appeared in the mediastinum 13 months after the surgery. She received gemcitabine + cisplatin + S-1 therapy but died 20 months after surgery.
Conclusion
SICC and lymph node metastasis clinically appeared within 3 months and 3 weeks, respectively. Suspected ICC that rapidly progresses should be considered SICC and treated with early resection. SICC is often missed in clinical diagnosis and has a poor prognosis, even after curative resection. While an alternative strategy involving preoperative biopsy and neoadjuvant therapy may be beneficial, it should be approached with discretion due to the potential risks of tumor progression and peritoneal dissemination.
Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors. Although improvement in both surgical techniques and neoadjuvant chemotherapy has been achieved, the 5‐year ...survival rate of locally advanced tumors was, at best, still 55%. Therefore, elucidation of mechanisms of the malignancy is eagerly awaited. Epithelial‐mesenchymal transition (EMT) by transforming growth factor‐β (TGF‐β) has been reported to have critical biological roles for cancer cell stemness, whereas little is known about it in ESCC. In the current study, a transcriptional factor SIX1 was found to be aberrantly expressed in ESCCs. SIX1 cDNA transfection induced overexpression of transforming growth factors (TGFB1 and TGFB2) and its receptor (TGFBR2). Cell invasion was reduced by SIX1 knockdown and was increased in stable SIX1‐transfectants. Furthermore, the SIX1‐transfectants highly expressed tumor basal cell markers such as NGFR, SOX2, ALDH1A1, and PDPN. Although mock‐transfectants had only a 20% PDPN‐high population, SIX1‐transfectants had 60–70%. In two sets of 42 and 85 ESCC patients receiving surgery alone or neoadjuvant chemoradiotherapy followed by surgery, the cases with high SIX1 mRNA and protein expression level significantly showed a poor prognosis compared with those with low levels. These SIX1 high cases also expressed the above basal cell markers, but suppressed the differentiation markers. Finally, TGF‐β signaling blockade suppressed ESCC cell growth in association with the reduction of PDPN‐positive tumor basal cell population. The present results suggest that SIX1 accelerates self‐renewal of tumor basal cells, resulting in a poor prognosis for ESCC patients.
TGF‐β signaling blockade suppressed ESCC cell growth in association with the reduction of PDPN‐positive tumor basal cell population. The present results suggest that SIX1 accelerates self‐renewal of tumor basal cells, resulting in a poor prognosis for ESCC patients.
Diffuse-type solid tumors are often composed of a high proportion of rarely proliferating (i.e., dormant) cancer cells, strongly indicating the involvement of cancer stem cells (CSCs) Although ...diffuse-type gastric cancer (GC) patients have a poor prognosis due to high-frequent development of peritoneal dissemination (PD), it is limited knowledge that the PD-associated CSCs and efficacy of CSC-targeting therapy in diffuse-type GC. In this study, we established highly metastatic GC cell lines by in vivo selection designed for the enrichment of PD-associated GC cells. By microarray analysis, we found C-X-C chemokine receptor type 4 (CXCR4) can be a novel marker for highly metastatic CSCs, since CXCR4-positive cells can grow anchorage-independently, initiate tumors in mice, be resistant to cytotoxic drug, and produce differentiated daughter cells. In clinical samples, these CXCR4-positive cells were found from not only late metastasis stage (accumulated ascites) but also earlier stage (peritoneal washings). Moreover, treatment with transforming growth factor-β enhanced the anti-cancer effect of docetaxel via induction of cell differentiation/asymmetric cell division of the CXCR4-positive gastric CSCs even in a dormant state. Therefore, differentiation inducers hold promise for obtaining the maximum therapeutic outcome from currently available anti-cancer drugs through re-cycling of CSCs.
Hepatic arterial infusion chemotherapy (HAIC) for liver metastases (LMs) from breast cancer is not a standard of care, but its effectiveness in patients with extensive LMs who cannot tolerate ...systemic therapy has been reported. Herein, we report a case of breast cancer LMs that were controlled by anthracycline-based HAIC. A 46-year-old woman with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer who had multiple LMs and bone metastases underwent seven lines of systemic therapy (paclitaxel/bevacizumab for 38 months; letrozole, nivolumab/fulvestrant, eribulin, gemcitabine/vinorelbine, high-dose toremifene/abemaciclib, and capecitabine for 21 months in total). However, owing to its adverse effects and the continued progression of the LMs, systemic therapy was switched to HAIC (40 mg/body epirubicin on day 1, 4 mg/body mitomycin C on days 1 and 15, and 500 mg/body 5-fluorouracil on days 1, 8, and 15; 28-day courses). In response to HAIC, the LMs remarkably regressed and were controlled for 17 months without severe adverse effects. HAIC was stopped when multiple brain metastases arose, and the patient died 2 months later. This case suggests that HAIC is a reasonable option for patients with extensive LMs, even in the late stage of treatment. HAIC recipients should be carefully selected through multidisciplinary discussions as the survival benefits of HAIC over systemic treatment remain unclear. Our findings identify a potential window for the use of traditional chemotherapeutic agents such as anthracyclines. Novel strategies to improve drug delivery are warranted in the future.
The prognosis of patients with advanced diffuse‐type gastric cancer (GC), especially scirrhous gastric cancer (SGC) remains extremely poor. Peritoneal carcinomatosis is a frequent form of metastasis ...of SGC. With survival rates of patients with peritoneal metastasis at 3 and 5 years being only 9.8% and 0%, respectively, development of a new treatment is urgently crucial. For such development, the establishment of a therapeutic mouse model is required. Among the 11 GC cell lines we examined, HSC‐60 showed the most well‐preserved expression profiles of the Hedgehog and epithelial‐mesenchymal transition pathways found in primary SGCs. After six cycles of harvest of ascitic tumor cells and their orthotopic inoculation in scid mice, a highly metastatic subclone of HSC‐60, 60As6 was obtained, by means of which we successfully developed peritoneal metastasis model mice. The mice treated with small interfering (si) RNA targeting NEDD1, which encodes a gamma‐tubulin ring complex‐binding protein, by the atelocollagen‐mediated delivery system showed a significantly prolonged survival. Our mouse model could thus be useful for the development of a new therapeutic modality. Intraperitoneal administration of siRNAs of targeted genes such as NEDD1 could provide a new opportunity in the treatment of the peritoneal metastasis of SGC.
Definitive chemoradiotherapy (CRT) is a less invasive therapy for esophageal squamous cell carcinoma (ESCC). Five-year survival rate of locally advanced ESCC patients by definitive CRT were 37%. We ...previously reported that tumor-specific cytotoxic T-lymphocyte (CTL) activation signatures were preferentially found in long-term survivors. However, it is unknown whether the CTL activation is actually driven by CRT. We compared gene expression profiles among pre- and post-treatment biopsy specimens of 30 ESCC patients and 121 pre-treatment ESCC biopsy specimens. In the complete response (CR) cases, 999 overexpressed genes including at least 234 tumor-specific CTL-activation associated genes such as IFNG, PRF1, and GZMB, were found in post-treatment biopsy specimens. Clustering analysis using expression profiles of these 234 genes allowed us to distinguish the immune-activated cases, designating them as I-type, from other cases. However, despite the better CR rate in the I-type, overall survival was not significantly better in both these 30 cases and another 121 cases. Further comparative study identified a series of epithelial to mesenchymal transition-related genes overexpressed in the early relapse cases. Importantly, the clinical outcome of CDH2-negative cases in the I-type was significantly better than that of the CDH2-positive cases in the I-type. Furthermore, NK cells, which were activated by neutrophils-producing S100A8/S100A9, and CTLs were suggested to cooperatively enhance the effect of CRT in the CDH2-negative I-type. These results suggested that CTL gene activation may provide a prognostic advantage in ESCCs with epithelial characteristics.
In Asian and Pacific regions, economic growth in the last decade has propelled the use of air-conditioners for space cooling along with the use of reversible heat pumps for year round space ...conditioning. This has led to the rapid increase of electricity demand for air conditioning in summer. To cope with the increasing power demand and the requirement for efficient energy use for space conditioning, governments and energy supply utilities have encouraged effective use and leveling of power load using a heat pump with thermal storage systems and gas cooling systems, by enacting financial and promotional supports. Status and trends of heat pumps in Asian and Pacific regions, related to the use of heat pumps for space heating and cooling were surveyed from the view points of climate, energy consumption, technologies, markets and promotion measures.
Dans les régions asiatiques et du Pacifique, la forte croissance économique de ces dernières décennies a donné lieu à une forte expansion dans l'utilisation des pompes à chaleur réversibles pour le chauffage et le conditionnement d'air toute l'année. La consommation d'électricité estivale liée au conditionnement d'air a également fortement augmenté. Afin de faire face à la demande d'électricité accrue et aux exigences en termes d'utilisation efficace d'énergie dans les applications de chauffage et de conditionnement d'air, les gouvernements et les fournisseurs d'énergie ont favorisé l'utilisation efficace et l'écrõtage des pointes à l'aide de pompes à chaleur reliées à des systèmes d'accumulation thermique, et de systèmes de refroidissement à gaz par le moyen de promotions et de l'instauration d'incitations financières. L'auteur donne une vue d'ensemble de la situation actuelle et les tendances dans les régions asiatiques et du Pacifique : il examine l'utilisation des pompes à chaleur dans les applications de chauffage et de conditionnement d'air, tenant compte des facteurs climatiques, de la consommation d'énergie, des technologies, des marchés et des mesures favorisant l'utilisation des pompes à chaleur.
Surgical samples have long been used as important subjects for cancer research. In accordance with an increase of neoadjuvant therapy, biopsy samples have recently become imperative for cancer ...transcriptome. On the other hand, both biopsy and surgical samples are available for expression profiling for predicting clinical outcome by adjuvant therapy; however, it is still unclear whether surgical sample expression profiles are useful for prediction via biopsy samples, because little has been done about comparative gene expression profiling between the two kinds of samples.
A total of 166 samples (77 biopsy and 89 surgical) of normal and malignant lesions of the esophagus were analyzed by microarrays. Gene expression profiles were compared between biopsy and surgical samples. Artificially induced epithelial-mesenchymal transition (aiEMT) was found in the surgical samples, and also occurred in mouse esophageal epithelial cell layers under an ischemic condition. Identification of clinically significant subgroups was thought to be disrupted by the disorder of the expression profile through this aiEMT.
This study will evoke the fundamental misinterpretation including underestimation of the prognostic evaluation power of markers by overestimation of EMT IN past cancer research, and will furnish some advice for the near future as follows: 1) Understanding how long the tissues were under an ischemic condition. 2) Prevalence of biopsy samples for in vivo expression profiling with low biases on basic and clinical research. 3) Checking cancer cell contents and normal- or necrotic-tissue contamination in biopsy samples for prevalence.
About 50% of patients who have a permanent stoma experience some degree of parastomal hernia formation. To prevent this complication, the extraperitoneal route is considered to be more effective than ...the transperitoneal route in the case of open colorectal surgery. This technique also has superiority in avoiding postoperative intestinal obstruction. Although laparoscopic surgery for rectal cancer has not been proved to be as safe as open surgery by a randomized-controlled trial, some studies have shown the equality of long-term results with laparoscopic low anterior resection and laparoscopic abdominoperineal resection. It is anticipated that cases of laparoscopic abdominoperineal resection will increase in the near future. However, a laparoscopic technique for creation of a permanent stoma has hardly been discussed. Most operative procedures for laparoscopic stoma creation have been performed with transperitoneal route, which may cause parastomal hernia and/or intestinal obstruction. This report describes a laparoscopic technique for permanent sigmoid stoma creation through the extraperitoneal approach.
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