Rintaro Yoshida

Advances in esophageal cancer surgery in Japan: An analysis of 1000 consecutive patients treated at a single institute

BACKGROUND In Japan, most esophageal cancers are squamous cell carcinomas, and the results of esophagectomy have improved remarkably in recent years. The object of this study was to evaluate advances in operative therapy for esophageal cancer in Japan. METHOD We evaluated mortality, morbidity, and prognosis in 1000 consecutive patients who underwent esophagectomy for esophageal cancer at a single institution in Japan. The patients were divided into 3 groups according to the period when esophagectomy was performed: Group I (n = 197), 1964-1980; group II (n = 432), 1981-1993; and group III (n = 371), 1993-2006. RESULTS The incidence of squamous cell carcinoma was 94%. The morbidity rates were 62%, 38%, and 33 %, in groups I, II, and III, respectively (P < 0.01, groups I vs II and III), and the in-hospital mortality rates were 14.2%, 5.1%, and 2.4%, respectively (P < 0.01, between each group). The 5-year overall survival rate was 30% (14%, 27%, and 46% in groups I, II, and III, respectively; P < 0.0001). Multivariate analysis revealed age, gender, depth of invasion, node metastasis, distant metastasis, curability, extent of lymphadenectomy, resectability, and the period when the operation was performed as independent prognostic factors. CONCLUSION Generally, esophagectomy has been performed safely without critical complications; however, the prognosis has improved remarkably with advances in surgical techniques and treatment modalities.

Alcohol drinking, cigarette smoking, and the development of squamous cell carcinoma of the esophagus: epidemiology, clinical findings, and prevention

Both cigarette smoking and alcohol drinking are well-established risk factors for esophageal squamous cell carcinoma (ESCC), and the relationship of dose to cancer risk has already been described. Furthermore, the synergistic effect of these two factors has been reported. Our case–control study revealed the odds ratio of ESCC to be 50.1 for those who were both heavy smokers and heavy drinkers in comparison to people who neither drank nor smoked. In patients with ESCC, head and neck cancers as well as dysplastic lesions are frequently observed. Heavy smoking and heavy drinking are closely related to such multicentric carcinogenesis events in the upper aerodigestive tract (UADT), including the esophagus and head andneck region. Polymorphisms in acetaldehyde dehydrogenase 2 (ALDH2) are reported to be a key event in deciding individual susceptibility to UADT cancer. Patients with inactive ALDH2, in whom facial flushing is usually observed after the drinking of alcohol, are at high risk for ESCC as well as multiple UADT cancers. For the early detection of the disease, effective follow up using endoscopy with Lugol staining or narrow band imaging endoscopy is strongly recommended for high-risk populations, such as smokers, heavy drinkers, people with experience of flushing after the drinking of alcohol, and patients with UADT cancer.

Concurrent genetic alterations in DNA polymerase proofreading and mismatch repair in human colorectal cancer

Genomic sequences encoding the 3′ exonuclease (proofreading) domains of both replicative DNA polymerases, pol delta and pol epsilon, were explored simultaneously in human colorectal carcinomas including six established cell lines. Three unequivocal sequence alterations, including one previously reported, were found, and all these were considered as dysfunctional mutations in light of the local amino-acid sequences. In particular, the F367S mutation found in the POLE gene encoding the pol epsilon catalytic subunit, which includes the proofreading domain, is the first found in human diseases. Surprisingly, the tumours carrying these proofreading domain mutations were all defective in DNA mismatch repair (MMR). In addition to the two cell lines with acknowledged MMR gene mutations, the third tumour was also demonstrated to harbour a distinct mutation in MLH1, and indeed exhibited a microsatellite-unstable phenotype. These findings suggest that, in concert with MMR deficiency, defective polymerase proofreading may also contribute to the mutator phenotype observed in human colorectal cancer. Our observations may suggest previously unrecognised complexities in the molecular abnormalities underlying the mutator phenotype in human neoplasms.

Esophagectomy in patients 80 years of age and older with carcinoma of the thoracic esophagus

BackgroundThe purpose of this study was to clarify the indications for an esophagectomy in elderly patients (especially patients over 80 years of age) with esophageal cancer.MethodsA total of 668 patients with thoracic esophageal cancer who underwent an esophagectomy by the transthoracic approach were divided into three groups according to age, namely, groups I (>80 years, n = 16), II (70–79 years, n = 158), and III (≤69 years, n = 494). In group I, surgery was only done in patients with PS 0 or 1, as well as normal cardiac and pulmonary functions.ResultsThe incidence of preoperative pulmonary risk was 16% and 7% in groups II and III, respectively (P < 0.01). The morbidity rates of group II and III were 42% and 32%, respectively (P < 0.05). Pulmonary complications occurred in 18% and 10%, respectively, and cardiovascular complications occurred in 11% and 4%, respectively (P < 0.01). In group I, the morbidity and 30-day mortality rates were 25% and 0%, respectively, and pulmonary and cardiovascular complications occurred only in one patient each (6%). No significant differences were observed in cause-specific survival.ConclusionsIn the elderly, preoperative pulmonary risk is frequently present, and careful perioperative management is needed while paying special attention to pulmonary and cardiovascular complications. However, when the indications for surgery can be strictly determined, an esophagectomy is considered a viable treatment alternative with satisfactory prognosis even in patients 80 years of age and older without any increased morbidity or mortality.

Acute lung injury following an esophagectomy for esophageal cancer, with special reference to the clinical factors and cytokine levels of peripheral blood and pleural drainage fluid

Acute lung injury (ALI) is one of most serious complications to occur after an esophagectomy for esophageal cancer. However, the pathogenesis of ALI is still unclear. The cytokine levels of pleural drainage fluid as well as peripheral blood were measured in 27 patients who had undergone an extended radical esophagectomy. Both the clinical factors and cytokine levels were compared between 11 patients with (group I) and 16 without ALI (group II). ALI occurred more frequently in patients who underwent colon interposition than in those who received a gastric tube reconstruction (86%vs 25%, P = 0.009). The operation time of group I was significantly longer than that of group II. A logistic regression analysis revealed colon interposition to be an independent factor associated with the ALI (P < 0.05). Postoperative anastomotic leakage and systemic inflammatory response syndrome (SIRS) occurred more frequently in group I than in group II (P < 0.01). Both the serum interleukin-6 (IL-6) and IL-8 levels of group I were significantly higher than those of group II. IL-1beta and tumor necrosis factor-alpha were undetectable in the peripheral blood, whereas they were detectable in the pleural effusion. The IL-1beta of pleural effusion was higher in group I than group II. In conclusion, greater surgical stress, such as a longer operative time, is thus considered to be associated with the first attack of ALI. The adverse events developing in the extra-thoracic site, such as necrosis and local infection around anastomosis may therefore be the second attack. Furthermore, ALI may cause not only SIRS but also other complications such as anastomotic leakage.

High expression of BUBR1 is one of the factors for inducing DNA aneuploidy and progression in gastric cancer

(Cancer Sci 2010; 101: 639–645)

The difference in p53 mutations between cancers of the upper and lower gastrointestinal tract.

Background:p53 gene mutations have been reported in over half of all human cancers and they appear to occur in the early stage of cancer, thus indicating the important role that such mutations may play in the carcinogenesis of the digestive tract. This study investigated the differences in p53 abnormalities between cancers of the upper and lower gastrointestinal tract. Materials and Methods: The DNA of 354 specimens of gastrointestinal cancer (esophagus 85, stomach 112, colon 157) was extracted and then p53 gene mutations were investigated by direct sequencing; the loss of heterozygosity was also synchronously analyzed in all cases. Results: (1) p53 gene mutation: p53 gene mutations were found in 41 samples (48.2%) in the esophagus, 18 samples (16.0%) in the stomach and 36 samples (22.9%) in the colon. p53 mutations were more frequently identified in well-differentiated cancers and a close correlation was recognized between p53 mutations and loss of heterozygosity. (2) Mutation spectrum: the ratio of transversion was 43.9% in esophagus, 33.3% in stomach and 25.0% in the colon tumors. Reciprocally, the ratio of transition was 31.7, 66.7, and 72.2%, respectively. Discussion: The frequency of p53 transversion mutations was extremely high in the upper digestive tract, whereas transition mutations were more frequently observed in the lower digestive tract. The investigation of the spectrum of mutations in p53 is therefore expected to lead to a better understanding of the agents responsible for inducing cancer.

Aberrant hypermethylation of the promoter region of the CHFR gene is rare in primary breast cancer

SummaryTaxanes are among the most active agents and they are now known to be an indispensable component in chemotherapy for breast cancer. However, some patients are resistant to taxanes and the identification of the molecular characteristics that can predict the sensitivity to taxanes would be useful in selecting the most appropriate patients to receive taxane therapy. Taxanes are antimicrotubular agents that promote microtubular assembly and stabilize microtubules by preventing depolymerization. They interfere with normal mitotic transition and causes cell cycle arrest in the G2-M metaphase. CHFR (checkpoint with forkhead-associated and ring finger) is a recently identified gene, which functions as an important checkpoint protein early in G2-M transition. Its activation delays the cell cycle in prophase and promotes cell survival in response to the mitotic stress induced by either nocodazole or taxane. CHFR is frequently downregulated in human cancers, mostly owing to the hypermethylation of its promoter region. CHFR downregulation has been found in primary cancers or in the established tumor cells of various origins, such as the lung, colon, esophagus, and stomach. The aberrant hypermethylation of CHFR promoter appears to be a good molecular marker to predict sensitivity to taxanes in gastric, lung, and colon cancer. A downregulation of CHFR was observed in breast cancer cells, however, no apparent promoter hypermethylation has yet been reported. In addition, an alteration of the CHFR expression or aberrant promoter hypermethylation in primary breast cancer has not been fully investigated. In this study, we examined the methylation status of the promoter region of CHFR gene in 110 primary breast cancers. We observed the hypermethylation of the CHFR promoter region in only one case (0.9%). We herein show that the aberrant hypermethylation of this region is quite a rare event in primary breast carcinoma.

Surgical Removal of a Denture with Sharp Clasps Impacted in the Cervicothoracic Esophagus : Report of Three Cases

We report three cases of successful surgical removal of a denture with sharp clasps impacted in the cervical esophagus. Patient 1 was a 57-year-old woman institutionalized for over 30 years for schizophrenia, patient 2 was a 62-year-old man hospitalized for brain paralysis, and patient 3 was a 64-year-old man suffering cerebral hemorrhage sequelae. All three patients swallowed a denture accidentally. Chest X-rays showed the denture with sharp clasps in the cervicothoracic region of the esophagus, and endoscopy revealed that it was lodged in the esophageal mucosa. The denture was subsequently removed by cervical esophagotomy. All three patients had a good clinical postoperative course without any complications. Thus, we recommend surgery via a cervical approach to remove a denture with sharp clasps impacted in the cervicothoracic esophagus, with intraoperative endoscopic examination for esophageal injury.

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.