Yoshihiro Kakeji

Clinical significance of salvage esophagectomy for remnant or recurrent cancer following definitive chemoradiotherapy

BackgroundThe purpose of this study was to clarify the effect of preoperative chemoradiotherapy (CRT) for esophageal cancer on the postoperative course, and to determine the clinical significance of salvage esophagectomy after definitive CRT.MethodsBased on their preoperative treatment, 477 patients with esophageal cancer were classified into three groups: 253 patients who received surgery alone (Group I), 197 who received planned CRT (30–45xa0Gy, Group II), and 27 who received a salvage esophagectomy (radiation ≥60xa0Gy, Group III).ResultsPostoperative complications developed in 25, 40, and 59% of the patients in Groups I, II, and III, respectively, with pulmonary complications developing in 10, 15, and 30%, and anastomotic leakage developing in 13, 23, and 37%, respectively. Mortality rates were 2.4, 2.0, and 7.4%, respectively. Multivariate analysis revealed preoperative therapy to be an independent factor associated with postoperative risks: the odds ratios (ORs) of Groups II and III compared to Group I were 1.8 and 4.0 for pulmonary complications, while they were 1.9 and 2.8, respectively, for anastomotic leakage. No critical complications developed in the 14 patients who received salvage surgery performed with strict surgical indications after 2005. The survival of Group III was not significantly different from that of Groups I and II. Most patients who received an R1/R2 resection after definitive CRT died within 2xa0years after salvage surgery.ConclusionsPreoperative CRT is associated with postoperative complications especially in patients with R2 resection, while long-term survival can be achieved after R0 resections. Salvage surgery should be considered for carefully selected patients in whom R0 resection can be achieved.

In-hospital mortality after a surgical resection for esophageal cancer: analyses of the associated factors and historical changes.

BackgroundResections for esophageal cancer are invasive, with high mortality and morbidity rates. The object of this study was to clarify the factors associated with in-hospital death while also evaluating any associated historical changes in the characteristics of such deaths.MethodsThe factors associated with mortality were examined by logistic regression analysis in 1106 patients who underwent an esophagectomy for esophageal cancer. The historical changes in the characteristics of in-hospital deaths were also evaluated.ResultsA multivariate analysis revealed that not only undergoing an esophagectomy before 1979, but also a patient’s age (odds ratio 1.070 for every increase in age by year) and an incomplete resection (odds ratio 2.265) were independent factors associated with in-hospital death. The in-hospital mortality rates were 16.1%, 5.8%, 2.5%, and 3.1%, while the 30-day mortality rates were 9.2%, 2.2%, 0.8%, and 0.3% during 1964–1979, the 1980s, the 1990s, and the 2000s, respectively. Eight patients had preoperative comorbidities among 11 patients who died in the hospital after 1997. The mortality rate was 5.5% in patients with any comorbidities, while it was 1.3% in patients without any comorbidities (Pxa0=xa00.026). The most common direct cause of in-hospital death was previous pulmonary complications; however, cancer progression has recently become the most common cause.ConclusionsTo prevent in-hospital mortality after an esophagectomy, strict indications for surgery and careful perioperative management are important, especially in high-risk patients with advanced esophageal cancer.

Impact of FOXA1 expression on the prognosis of patients with hormone receptor-positive breast cancer.

BackgroundAssessing indications for adjuvant chemotherapy (CT) in patients with hormone receptor (HR)-positive/human epidermal receptor 2 (HER2)-negative breast cancer remains a challenge for oncologists. In this study, we evaluated whether forkhead-box protein A1 (FOXA1) expression was a prognostic and predictive marker for HR-positive breast cancer.MethodsFOXA1 expression was analyzed immunohistochemically in 239 primary breast cancers. Associations between FOXA1 expression and clinicopathological characteristics and prognosis were evaluated.ResultsFOXA1 expression was positively correlated with estrogen receptor (ER) (Pxa0<xa00.0001) and progesterone receptor (PR) expression (Pxa0=xa00.0011), and inversely correlated with nuclear grade (Pxa0=xa00.0048) and Ki67 index (Pxa0=xa00.0112). High FOXA1 was associated with longer recurrence-free survival (RFS) in all cases (Pxa0<xa00.0001) and in ER-positive cases (Pxa0<xa00.0001), but not in ER-negative cases. In addition, FOXA1 expression was associated with good prognosis, regardless of the Ki67 index, in HR-positive cases. FOXA1 was an independent prognostic factor on multivariate analysis in all cases and in ER-positive cases. Among HR-positive/HER2-negative cases with high FOXA1 expression, there was no difference in RFS between those given hormone therapy (HT) alone and those given CT plus HT.ConclusionsIn HR-positive breast cancer, FOXA1 expression was significantly associated with good prognosis. FOXA1 expression may be a useful marker for HR-positive/HER2-negative breast cancer to identify patients with good prognosis who may not require CT.

Copy-neutral loss of heterozygosity at the p53 locus in carcinogenesis of esophageal squamous cell carcinomas associated with p53 mutations

Purpose: LOH at the p53 locus has been reported to be associated with esophageal squamous cell carcinogenesis. The aim of this study is to identify potential mechanisms resulting in LOH around the p53 locus in its carcinogenesis. Experimental Design: We investigated 10 esophageal cancer cell lines and 91 surgically resected specimens, examining them for LOH at the p53 locus on chromosome 17. We examined the p53 gene by using microsatellite analysis, comparative genomic hybridization (CGH), FISH, and single-nucleotide polymorphism–CGH (SNP–CGH). Results: In an analysis of specimens by microsatellite markers, a close positive correlation was found between p53 mutations and LOH at the p53 locus (P < 0.01). Although four cell lines were found to be homozygous for p53 mutations, LOH at the p53 locus was not detected by CGH. Among two p53 mutant cancer cell lines and five p53 mutant/LOH cancer specimens analyzed by FISH, both the cell lines and four of the specimens exhibited no obvious copy number loss at the p53 locus. SNP–CGH analysis, which allows both determination of DNA copy number and detection of copy-neutral LOH, showed that LOHs without copy number change were caused by whole or large chromosomal alteration. Conclusions: LOH without copy number change at the p53 locus was observed in p53 mutant esophageal squamous cell carcinomas. Our data suggest that copy-neutral LOH occurring as a result of chromosomal instability might be the major mechanism for inactivation of the intact allele in esophageal squamous cell carcinogenesis associated with p53 mutation. Clin Cancer Res; 17(7); 1731–40. ©2011 AACR.

Patterns and time of recurrence after complete resection of esophageal cancer

PurposeThe results and outcomes of surgical resection for esophageal carcinoma have improved remarkably in recent years; however, recurrence still frequently develops, even after complete resection. The purpose of this study is to clarify the characteristics of recurrence in this patient population.MethodsAmong 208 patients, who underwent R0 resection for esophageal carcinoma, recurrence developed in 61. Clinical data were available for 56 of these patients, who were the subjects of this study. We evaluated the time, patterns, and treatment of recurrence in these patients.ResultsRecurrence developed within 1 and 2xa0years after esophagectomy in 71 and 84% of the patients, respectively, and was classified as loco-regional (54%), hematogenous (36%), or mixed type (10%). The prognosis of patients with loco-regional recurrence tended to be better than that of those with distant metastasis, although the difference was not significant (Pxa0=xa00.088). Patients with recurrence treated by chemotherapy alone or multimodal therapy, such as radiation or surgery combined with systemic chemotherapy, survived significantly longer than those with untreatable recurrence (Pxa0=xa00.016).ConclusionThese findings reinforce the importance of careful follow-up for both loco-regional and hematogenous recurrence after esophagectomy, particularly during the first 2xa0years.

Lymph node metastasis from cancer of the esophagogastric junction, and determination of the appropriate nodal dissection

PurposeBoth squamous cell carcinomas and adenocarcinomas can develop in the esophagogastric junction. To clarify the appropriate lymph node dissection range, lymph node metastases from cancers in the esophagogastric junction were investigated.MethodsThe nodal metastases were analyzed in 64 patients with squamous cell carcinoma and 129 with adenocarcinoma according to Siewert’s classification, which is based on topographic anatomical criteria for adenocarcinoma.ResultsThe squamous cell carcinomas located above the esophagocardial junction had more frequent metastasis to the lower and middle mediastinal lymph nodes in proportion to the depth of the tumor. Nodal metastasis was also often detected in the abdominal lymph nodes. In contrast, adenocarcinomas metastasized less frequently to the mediastinal lymph nodes, and the metastatic rates in the abdominal nodes were higher than those from squamous cell carcinoma.ConclusionEsophagectomy with mediastinal and abdominal lymph node dissection is considered to be an appropriate approach for surgical resection of squamous cell carcinomas, whereas transhiatally extended gastrectomy with lower mediastinal and abdominal lymph node dissection is recommended for the treatment of adenocarcinomas.

Two-Stage Operation for High-Risk Patients with Thoracic Esophageal Cancer: An Old Operation Revisited

PurposeAn esophagectomy followed by reconstruction for esophageal cancer is a highly aggressive operation. The purpose of this study was to justify a two-stage operation for high-risk patients with esophageal cancer.MethodsThe clinical results of 27 patients who underwent two-stage operation were compared with 118 patients who underwent a simultaneous resection and reconstruction (control subjects). The reasons for the selection of the two-stage operation were underlying general disease in 13 patients (liver dysfunction, nxa0=xa06; pulmonary disease, nxa0=xa03; poor performance status, nxa0=xa02; diabetes and renal failure, nxa0=xa01 each) and high-risk operation in 14 other patients (colon interposition, nxa0=xa07; salvage operation after definitive chemoradiotherapy, nxa0=xa04; and intraoperative events, nxa0=xa03). The patients initially underwent an esophagectomy and a cervical esophagostomy. Reconstruction was usually performed 2–3xa0weeks later.ResultsThe patients in the two-stage group were older than the control patients (mean 67.8 vs. 61.6xa0years old). The morbidity rate of the two-stage operation was 29.6%, which was not statistically different than control patients (32.2%). Postoperative complications in the two-stage operation were anastomotic leakage in 5 patients, and pneumonia and wound infection in 1 patient each. No patient experienced in-hospital death. The survival rates were not statistically different between the two groups.ConclusionA two-stage operation is a safe operation that prevents the occurrence of critical postoperative complications, and it thus may be considered an important treatment strategy for high-risk patients with esophageal cancer.

Loss of p53 in esophageal squamous cell carcinoma and the correlation with survival: analyses of gene mutations, protein expression, and loss of heterozygosity in Japanese patients.

A high frequency of p53 protein expression or gene mutation has been reported in the early stages of esophageal squamous cell carcinoma (ESCC), and thus loss of p53 function is thought to be very important in esophageal carcinogenesis. However, there is controversy surrounding the correlation between p53 dysfunction and ESCC tumor progression. The complexity arises from the different modalities, such as mutation analysis, immunohistochemistry, and the detection of loss of heterozygosity (LOH) at the p53 genomic locus.

Laparoscopic resection for gastrointestinal stromal tumors in the stomach

PurposeGastrointestinal stromal tumors (GISTs) should be surgically resected, even those smaller than 5xa0cm in size, which is the threshold of clinical malignancy for submucosal tumors (SMTs) in the gastrointestinal tract. This study reviewed the use of laparoscopic surgery for gastric partial resection of GISTs or SMTs that were suspected to be GISTs.MethodsEighteen patients underwent laparoscopic partial resection of the stomach for GISTs or SMTs. The tumor location was confirmed by intraluminal endoscopy. One-half of the circumference around the tumor was dissected, and the tumor was turned toward the abdominal cavity. The nonresected part of the tumor and the edge of the incision line was lifted up using forceps, and the incision line was closed using laparoscopic stapling devices.ResultsTwo cases were diagnosed as GIST by endoscopic biopsy. Six patients underwent endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) examinations, which diagnosed five GISTs. There were 18 tumors smaller than 5xa0cm, including 10 GISTs, 4 leiomyomas, 3 schwannomas, and one heterotopic pancreas.ConclusionsEndoscopic ultrasound-guided FNAB is recommended for definite preoperative diagnosis of histopathologically unknown SMTs to determine the indications for surgery. The laparoscopic approach with the assistance of endoscopy is useful for improving the curability, with minimal invasiveness for the partial resection of GISTs.

ATR–Chk1 signaling pathway and homologous recombinational repair protect cells from 5-fluorouracil cytotoxicity

5-Fluorouracil (5-FU) has long been a mainstay antimetabolite chemotherapeutic drug for the treatment of major solid tumors, particularly colorectal cancer. 5-FU is processed intracellularly to yield active metabolites that compromise RNA and DNA metabolism. However, the mechanisms responsible for its cytotoxicity are not fully understood. From the phenotypic analysis of mutant chicken B lymphoma DT40 cells, we found that homologous recombinational repair (HRR), involving Rad54 and BRCA2, and the ATR-Chk1 signaling pathway, involving Rad9 and Rad17, significantly contribute to 5-FU tolerance. 5-FU induced γH2AX nuclear foci, which were colocalized with the key HRR factor Rad51, but not with DNA double-strand breaks (DSBs), in a dose-dependent manner as cells accumulated in the S phase. Inhibition of Chk1 kinase by UCN-01 increased 5-FU-induced γH2AX and enhanced 5-FU cytotoxicity not only in wild-type cells but also in Rad54- or BRCA2-deficient cells, suggesting that HRR and Chk1 kinase have non-overlapping roles in 5-FU tolerance. 5-FU-induced Chk1 phosphorylation was significantly impaired in Rad9- or Rad17-deficient cells, and severe γH2AX nuclear foci and DSBs were formed, which was followed by apoptosis. Finally, inhibition of Chk1 kinase by UCN-01 increased 5-FU-induced γH2AX nuclear foci and enhanced 5-FU cytotoxicity in Rad9- or Rad17-deficient cells. These results suggest that Rad9- and Rad17-independent activation of the ATR-Chk1 signaling pathway also significantly contributes to 5-FU tolerance.