Kiyotomi Maruyama

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)

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.

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.

Tumoral CRP expression in thoracic esophageal squamous cell cancers is associated with poor outcomes.

PurposeCancer cells reportedly produce C-reactive protein (CRP) locally within tumors. The aim of this study was to determine whether tumoral CRP is associated with clinical outcome and recurrence in thoracic esophageal squamous cell cancer.MethodsThe subjects included 73 Japanese patients with thoracic esophageal squamous cell cancer (pathological Stage IIA–IV) that had not been treated preoperatively with either chemotherapy or radiotherapy. Tumoral CRP expression in resected specimens of tumor tissue was assessed by immunohistochemistry. The survival rate following surgery, the rates and patterns of recurrence, and the serum CRP levels before treatment and at recurrence were analyzed in patients with and without tumoral CRP expression.ResultsFifty-nine percent of the study participants (43/73) were positive for tumoral CRP expression, and the remaining 41% (30/73) were negative. No significant difference in clinicopathological factors was observed between the tumoral CRP-positive and CRP-negative groups; however, patients expressing tumoral CRP showed significantly poorer survival and recurrence rates. A multivariate analysis showed that tumoral CRP expression was an independent factor contributing to the likelihood of a poor outcome.ConclusionTumoral CRP is associated with a poor outcome in thoracic esophageal squamous cell cancer. Tumoral CRP could therefore be an important target for the treatment of this disease.

REG I enhances chemo- and radiosensitivity in squamous cell esophageal cancer cells.

Identification of reliable markers of chemo‐ and radiosensitivity and the key molecules that enhance the susceptibility of squamous esophageal cancer cells to anticancer treatments would be highly desirable. To test whether regenerating gene (REG) I expression enhances chemo‐ and radiosensitivity in esophageal squamous cell carcinoma cells, we used MTT (3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyltetrazolium bromide) assays to compare the chemo‐ and radiosensitivities of untransfected TE‐5 and TE‐9 cells with those of cells stably transfected with REG Iα and Iβ. We then used flow cytometry to determine whether REG I expression alters cell cycle progression. No REG I mRNA or protein were detected in untransfected TE‐5 and TE‐9 cells. Transfection with REG Iα and Iβ led to strong expression of both REG I mRNA and protein in TE‐5 and TE‐9 cells, which in turn led to significant increases in both chemo‐ and radiosensitivity. Cell cycle progression was unaffected by REG I expression. REG I thus appears to enhance the chemo‐ and radiosensitivity of squamous esophageal cancer cells, which suggests that it may be a useful target for improved and more individualized treatments for patients with esophageal squamous cell carcinoma. (Cancer Sci 2008; 99: 2491–2495)

IGFBP3 and BAG1 enhance radiation-induced apoptosis in squamous esophageal cancer cells

Identification of reliable markers of radiosensitivity and the key molecules that enhance the susceptibility of esophageal cancer cells to anticancer treatments would be highly desirable. To identify molecules that confer radiosensitivity to esophageal squamous carcinoma cells, we assessed the radiosensitivities of the TE-5, TE-9 and TE-12 cloneA1 cell lines. TE-12 cloneA1 cells showed significantly greater susceptibility to radiotherapy at 5 and 10Gy than either TE-5 or TE-9 cells. Consistent with that finding, 24h after irradiation (5Gy), TE-12 cloneA1 cells showed higher levels of caspase 3/7 activity than TE-5 or TE-9 cells. When we used DNA microarrays to compare the gene expression profiles of TE-5 and TE-12 cloneA1 cells, we found that the mRNA and protein expression of insulin-like growth factor binding protein 3 (IGFBP3) and Bcl-2-associated athanogene 1 (BAG1) was five or more times higher in TE-12 cloneA1 cells than TE-5 cells. Conversely, knocking down expression of IGFBP3 and BAG1 mRNA in TE-12 cloneA1 cells using small interfering RNA (siRNA) significantly reduced radiosensitivity. These data suggest that IGFBP3 and BAG1 may be key markers of radiosensitivity that enhance the susceptibility of squamous cell esophageal cancer to radiotherapy. IGFBP3 and BAG1 may thus be useful targets for improved and more individualized treatments for patients with esophageal squamous cell carcinoma.

C-Reactive Protein 1059G>CGenetic Polymorphism Influences Serum C-Reactive Protein Levels after Esophagectomy in Patients with Thoracic Esophageal Cancer

BACKGROUND Little is known about how C-reactive protein (CRP) genetic polymorphisms influence the rise in serum CRP levels seen after surgery. The purpose of this study was to assess the association between CRP polymorphisms and acute-phase serum CRP levels after esophagectomy for thoracic esophageal cancer. STUDY DESIGN We enrolled 110 patients who underwent curative esophagectomy without neoadjuvant treatment between 2003 and 2008. Using peripheral blood samples collected from the patients, polymorphisms for CRP, tumor necrosis factor, interferon-gamma, tumor growth factor-beta1, interleukin (IL)-1beta, IL-1 receptor antagonist, IL-2, IL-4, IL-6, IL-6 receptor, IL-10, and IL-12beta were all investigated to determine which, if any, affect postoperative serum CRP levels and clinical outcomes. RESULTS Although preoperative serum CRP levels did not differ, 12 hours after esophagectomy, serum CRP levels were significantly higher in patients carrying the CRP 1059G/G genotype than in those with the 1059G/C genotype (111 +/- 35 mg/L versus 78 +/- 17 mg/L; p = 0.0266), and after 36 hours CRP levels remained higher in those with the 1059G/G genotype (217 +/- 63 mg/L versus 140 +/- 51 mg/L; p = 0.0020). Logistic regression models revealed that patients carrying the CRP 1059G/G genotype had a significantly higher likelihood of a postesophagectomy increase in serum CRP, although the CRP 1059G>C genetic polymorphism had no effect on clinical outcomes. None of the other cytokine genetic polymorphisms influenced postoperative serum CRP levels. CONCLUSIONS Our findings suggest that the CRP 1059G>C genetic polymorphism is 1 determinant of serum CRP levels after major surgery.