Satoru Motoyama

Expression of histone deacetylase 1 correlates with a poor prognosis in patients with adenocarcinoma of the lung.

UNLABELLED Histone deacetylase (HDAC) inhibitors (HDACis) are now attracting attention as promising therapeutic agents for the treatment of cancer. However, the relation between HDAC1 expression and the clinicopathological characteristics of non-small cell lung cancer (NSCLC) is not well understood. We therefore investigated the relationship between HDAC1 expression by tumors and the clinicopathological characteristics of patients with adenocarcinoma of the lung. METHODS We used semi-quantitative real time reverse transcription polymerase chain reaction to assess expression of HDAC1 mRNA in tumor samples from 93 patients with adenocarcinoma of the lung. We then correlated HDAC1 mRNA levels with known clinicopathological factors. RESULTS We found that the 5-year disease-free survival rate among patients strongly expressing HDAC1 was significantly poorer than among those expressing lower levels (P=0.005 by log-rank test). Multivariate Cox proportional hazard analyses revealed that being male (hazard ratio, 3.56; 95% CI, 1.58-8.42; P=0.002), nodal metastasis (hazard ratio, 7.98; 95% CI, 2.99-22.1; P<.001) and HDAC1 (hazard ratio, 2.17; 95% CI, 1.04-4.84; P=0.039) were all independent factors affecting 5-year disease-free survival. CONCLUSION Stronger HDAC1 expression by tumor cells is an independent predictor of a poor prognosis in patients with adenocarcinoma of the lung.

Hand-Sewn Cervical Anastomosis Versus Stapled Intrathoracic Anastomosis After Esophagectomy for Middle or Lower Thoracic Esophageal Cancer: A Prospective Randomized Controlled Study

PurposeThe type of anastomosis and its outcome can affect postoperative morbidity, mortality, and quality of life after esophagectomy. We compared the outcomes of cervical hand-sewn anastomosis (CHS) and intrathoracic stapled anastomosis (ITS) performed after esophagectomy and gastric reconstruction.MethodsThirty-two patients with middle or lower thoracic esophageal cancer were prospectively randomized to undergo CHS (n = 18) or ITS (n = 14) after esophagectomy. We compared clinical data, postoperative symptoms, and long-term survival in the two groups.ResultsThe rates of anastomotic leak and stricture in the CHS and ITS groups were 16.7% versus 7.1% and 0% versus 14.2%, respectively, which do not represent significant differences. The respective rates of recurrent laryngeal nerve palsy were 38.8% versus 7.1% (P < 0.05), and proximal esophageal resection was 15 mm longer (P < 0.05) in the CHS group. There were no significant differences in symptoms 6 months after surgery, or in the overall 5-year survival rates (72.2% and 85.7%, respectively).ConclusionsThe two methods of anastomosis yielded similar anastomotic outcomes. Although the incidence of recurrent laryngeal nerve injury was higher after CHS, and proximal esophageal resection was longer, this had little impact on postoperative symptoms and long-term survival.

Inhibition of heat shock protein 90 sensitizes melanoma cells to thermosensitive ferromagnetic particle-mediated hyperthermia with low Curie temperature

Heat shock protein (Hsp) 90 is a key regulator of a variety of oncogene products and cell‐signaling molecules, and the therapeutic benefit of its inhibition in combination with radiation or chemotherapy has been investigated. In addition, hyperthermia has been used for many years to treat various malignant tumors. We previously described a system in which hyperthermia was induced using thermosensitive ferromagnetic particles (FMP) with a Curie temperature (Tc = 43˚C) low enough to mediate automatic temperature control, and demonstrated its antitumor effect in a mouse melanoma model. In the present study, we examined the antitumor effects of combining a Hsp90 inhibitor (geldanamycin; GA) with FMP‐mediated hyperthermia. In cultured B16 melanoma cells, GA exerted an antitumor effect by increasing the cells’ susceptibility to hyperthermia and reducing expression of Akt. In an in vivo study, melanoma cells were subcutaneously injected into the backs of C57BL/6 mice. FMP were then injected into the resultant tumors, and the mice were divided into four groups: group I, no treatment (control); group II, one hyperthermia treatment; group III, GA alone; and group IV, GA with hyperthermia. When exposed to a magnetic field, the temperature of tissues containing FMP increased and stabilized at the Tc. In group IV, complete regression of tumors was observed in five of nine mice (56%), whereas no tumor regression was seen in groups I–III. Our findings suggest that inhibition of Hsp90 with hyperthermia increases its antitumor effect. Thus, the combination of FMP‐mediated, self‐regulating hyperthermia with Hsp90 inhibition has important implications for the treatment of cancer. (Cancer Sci 2009; 100: 558–564)

CRP Genetic Polymorphism Is Associated with Lymph Node Metastasis in Thoracic Esophageal Squamous Cell Cancer

BackgroundLymph node involvement is the most important prognostic factor in thoracic esophageal cancer. A more accurate molecular technique for diagnosing lymph node metastasis and a better understanding of the molecular mechanisms governing lymph node metastasis would be highly desirable. The purpose of this study is to examine the association between inflammation-related genetic polymorphisms and lymph node metastasis.MethodsThe study participants were 113 Japanese patients undergoing curative surgery for thoracic esophageal squamous cell cancer. DNA was extracted from blood samples and genetic polymorphisms in C-reactive protein (CRP), tumor necrosis factor (TNF)-α and -β, interferon (IFN)-γ, transforming growth factor (TGF)- β, interleukin (IL)-1β, IL-1 receptor antagonist, IL-2, IL-4, IL-6, IL-6 receptor, IL-10, and IL-12β were investigated using the polymerase chain reaction–restriction fragment length polymorphism method. We then assessed the association between inflammation-related genes and lymph node metastasis.ResultsFor CRP 1846C>T polymorphism, the frequency of the 1846T/T genotype was significantly higher in patients with lymph node metastasis (P = 0.0043), and the odds ratio (3.040) derived from logistic regression models indicated that the 1846T/T genotype significantly increases the likelihood of lymph node metastasis. In submucosal cancer, the utility of CRP 1846C>T polymorphism for predicting lymph node involvement was superior to usual methods (computed tomography and ultrasonography), with positive and negative predictive values of 69% and 75%, respectively.ConclusionsThese findings suggest that CRP polymorphism is a potentially effective predictor of lymph node metastasis and may thus be useful for deciding on treatment strategy.

Self-regulating hyperthermia induced using thermosensitive ferromagnetic material with a low Curie temperature

Hyperthermia has been used for many years to treat a variety of malignant tumors. The Curie temperature (Tc) is a transition point at which magnetic materials lose their magnetic properties, causing a cessation of current and thus heat production. The Tc enables automatic temperature control throughout a tumor as a result of the self‐regulating nature of the thermosensitive material. We have developed a method of magnetically‐induced hyperthermia using thermosensitive ferromagnetic particles (FMPs) with low Tc (43°C), enough to mediate automatic temperature control. B16 melanoma cells were subcutaneously injected into the backs of C57BL/6 mice, after which tumors were allowed to grow to 5 mm in diameter. FMPs were then injected into the tumors, and the mice were divided into three groups: group I (no hyperthermia, control); group II (one hyperthermia treatment); and group III (hyperthermia twice a week for 4 weeks). When exposed to a magnetic field, the FMPs showed a sharp rise in heat production, reaching the Tc in tissue within 7 min, after which the tissue temperature stabilized at approximately the Tc. In groups I and II, all mice died within 30–45 days. In group III, however, 6 of 10 mice remained alive 120 days after beginning treatment. Our findings suggest that repeated treatment with magnetically‐induced self‐regulating hyperthermia, mediated by FMPs with a low Tc, is an effective means of suppressing melanoma growth. A key advantage of this hyperthermia system is that it is minimally invasive, requiring only a single injection for repeated treatments with automatic temperature control. (Cancer Sci 2008; 99: 805–809)

Phase II Study of Personalized Peptide Vaccination for Previously Treated Advanced Colorectal Cancer

Kibe and colleagues report the safety and benefit in a phase II study of 60 pretreated, advanced colorectal cancer (CRC) patients of personalized vaccines comprising HLA-matched peptides selected from preexisting host immunity, providing a new approach of personalized immunotherapy for refractory CRC. The prognosis of advanced colorectal cancer (aCRC) remains poor, and development of new therapeutic approaches, including immunotherapy, is needed urgently. Herein we report on our phase II study of personalized peptide vaccination (PPV) in 60 previously treated patients with aCRC, who had failed at least one regimen of standard chemotherapy and/or targeted therapy. For PPV, a maximum of four HLA-matched peptides were individually selected from a pool of 31 different peptide candidates based on preexisting host immunity, and administered subcutaneously without severe adverse events. Boosting of IgG and cytotoxic T lymphocyte (CTL) responses specific to the administered peptides was observed in 49% and 63%, respectively, of the patients, who completed the first cycles of six vaccinations. Median overall survival (OS) time was 498 days, with 1- and 2-year survival rates of 53% and 22%, respectively. Multivariate Cox regression analysis of prevaccination factors showed that plasma IL6, IP-10, and BAFF levels were significantly prognostic for OS [hazard ratio (HR), 1.508, P = 0.043; HR, 1.579, P = 0.024; HR, 0.509, P = 0.002, respectively]. In addition, increased peptide-specific CTL responses after vaccination were significantly predictive of favorable OS (HR, 0.231; P = 0.021), suggesting a causal relationship between biologic and clinical efficacy of PPV. On the basis of the safety profile and potential clinical efficacy, we believe that clinical trials of PPV would be warranted for previously treated patients with aCRC. Cancer Immunol Res; 2(12); 1154–62. ©2014 AACR.

Outcome and Treatment Strategy for Mid- and Lower-Thoracic Esophageal Cancer Recurring Locally in the Lymph Nodes of the Neck

The aim of the present study was to assess the outcome of treatment for patients with recurrent mid- and lower-thoracic esophageal cancers in whom recurrence was localized to the lymph nodes of the neck, and to determine the best strategy for further treatment. Between 1989 and 2001, 270 patients with mid- and lower-thoracic esophageal cancer underwent curative esophagectomy; 90 of those patients had a cancer recurrence. Our focus was on lymph node recurrence, especially when the recurrent cancers were localized to the lymph nodes in the neck. The outcomes of those patients and the efficacy of the strategies used to treat the recurrent cancers were determined. In 43 patients (48%), recurrent cancer initially appeared in the lymph nodes. Among the 43 patients, 15 (35%) had localized neck recurrence. The time between tumor recurrence and death among the 15 patients with localized neck recurrence was significantly longer than among the 28 patients with other recurrence patterns. In addition, 15 patients underwent lymph node resection, while 28 patients were treated non-surgically. The time between tumor recurrence and death was significantly longer in patients treated surgically. Of the 15 patients in whom recurrence affected the neck lymph nodes only, 10 (67%) were treated surgically; their 2-year survival rate after recurrence was 45%. The outcomes of recurrent esophageal cancers localized to the lymph nodes of the neck were better than those seen with other recurrence patterns, and salvage resection followed by chemoradiation therapy would seem to be indicated for those patients.

Cancer of the gastric tube reconstructed through the posterior mediastinal route after radical surgery for esophageal cancer.

Among 750 patients diagnosed with esophageal carcinoma in our department between 1972 and 1997, we reviewed our 10 cases in which cancer occurred within gastric tubes reconstructed through the posterior mediastinal route after radical surgery for esophageal cancer. The interval between esophagectomy and cancer onset in the reconstructed gastric tube was relatively long (mean interval: 72 months). Five of our 10 subjects had gastric tube cancer detected at follow-up endoscopy. Four underwent total or partial gastric tube resection with open thoracotomy using colonic or jejunal reconstruction; 3 underwent endoscopic resection. To the best of our knowledge, this is the first report on patients undergoing total resection of gastric tubes reconstructed through the posterior mediastinal route after esophagectomy and rereconstruction using the pedicled colon for the gastric tube cancer.

Extravascular lung water measured using single transpulmonary thermodilution reflects perioperative pulmonary edema induced by esophagectomy.

Pulmonary edema is the most frequent postoperative complication following esophagectomy for thoracic esophageal cancer. We enrolled 23 patients who underwent esophagectomy with extended lymph node dissection for thoracic esophageal cancer in a prospective observational clinical trial. We used the PiCCO device to measure extravascular lung water with the aim of determining whether it correlates with the respiratory index and whether it is predictive of pulmonary complications. Based on constant criteria, the tracheal tubes of 11 patients were removed on the morning of postoperative day 1 (extubation group), while 12 patients remained intubated (intubation group). These two groups significantly differed in that all patients in the extubation group recovered without any pulmonary complications, whereas 4 patients (33%) in the intubation group developed pulmonary complications. The extravascular lung water measured using PiCCO correlated significantly with the respiratory index. In the intubation group, both extravascular lung water and respiratory index were elevated 12 h after surgery and were even higher 24 h after surgery. The extravascular lung water measured using PiCCO reflects the level of postoperative pulmonary edema and predicts the pulmonary complications induced by esophagectomy with extended lymph node dissection.

Inhibition of dendritic cell migration by transforming growth factor-β1 increases tumor-draining lymph node metastasis

BackgroundTransforming growth factor (TGF)-β is known to be produced by progressor tumors and to immobilize dendritic cells (DCs) within those tumors. Moreover, although TGF-β1 has been shown to promote tumor progression, there is still no direct, in vivo evidence as to whether TGF-β1 is able to directly induce distant metastasis.MethodsTo address that issue and investigate the mechanism by which TGF-β1 suppresses DC activity, we subdermally inoculated mouse ears with squamous cell carcinoma cells stably expressing TGF-β1 or empty vector (mock).ResultsThe numbers of DCs within lymph nodes draining the resultant TGF-β1-expressing tumors was significantly lower than within nodes draining tumors not expressing TGF-β1. We then injected fluorescently labeled bone marrow-derived dendritic cells into the tumors, and subsequent analysis confirmed that the tumors were the source of the DCs within the tumor-draining lymph nodes, and that there were significantly fewer immature DCs within the nodes draining TGF-β1-expressing tumors than within nodes draining tumors not expressing TGF-β1. In addition, 14 days after tumor cell inoculation, lymph node metastasis occurred more frequently in mice inoculated with TGF-β1 transfectants than in those inoculated with the mock transfectants.ConclusionsThese findings provide new evidence that tumor-derived TGF-β1 inhibits migration of DCs from tumors to their draining lymph nodes, and this immunosuppressive effect of TGF-β1 increases the likelihood of metastasis in the affected nodes.