Objective
This report presents the essence in practice of Japanese methods and tradition in surgery for esophageal cancer.
Methods
The etiology of esophageal cancer and the concepts of ...lymphadenectomy in esophagectomy, in neoadjuvant treatments, and in stage classifications are compared between Western countries and Japan.
Results
With respect to the type and relative incidence of esophageal cancer, in Western countries, adenocarcinoma in the lower thoracic esophagus and in the cardia is common, and among esophageal surgeons, there remains some controversy over the extent of lymphadenectomy. On the other hand, in Japan, squamous cell carcinoma in the middle thoracic esophagus is common, and concerning lymphadenectomy, Japanese esophageal surgeons consider that three-field lymphadenectomy is superior to other types of lymphadenectomy. In Japan, surgeons believe that most patients with esophageal cancer even those having lymph node metastasis can be best treated using esophagectomy and lymphadenectomy.
Conclusions
In Japan, the tradition in esophageal surgery places great significance on lymphadenectomy. The ways and procedures for esophageal cancer surgery, the neoadjuvant and adjuvant treatments, the Japanese Classification of Esophageal Cancer, the Esophageal Cancer Practice Guidelines, and other scientific reports are all based on a close combination of esophagectomy with lymphadenectomy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
I would herein like to look back upon surgery for esophageal cancer, particularly on lymphadenectomy, and to speculate a little on the future prospects for esophageal surgery. There are two schools ...of thought on lymphadenectomy in esophageal cancer: one believes in en bloc esophagectomy, which is commonly performed in Western countries; the other believes in three-field lymphadenectomy, which is commonly performed in Japan. We esophageal surgeons at Kurume University have contributed to some advances in three-field lymphadenectomy. For example, we initiated functional mediastinal dissection to ensure patient safety, and we proposed the lymph node compartment theory to assess the clinical importance of regional nodes. Oncological surgery has progressed in terms of its safety, radicality and functional preservation, leading to improved quality-of-life for patients after surgery. This then evolved to the current development of multimodal and individualized tailor-made treatments. I believe that surgery for esophageal cancer will become bipolarized in the future. One strand will evolve as salvage surgery for residual or recurrent tumors, which non-surgical therapies have failed to cure, and the other strand will evolve as less invasive surgery, adjuvant surgery, for cancers at the relatively early stage, for which micro-metastasis can be cured by non-surgical therapies.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The first successful resection of a cancer in the thoracic esophagus was performed by Franz Torek around one hundred years ago. Awareness of developments in surgery and the early history can ...stimulate and foster innovation among surgeons, as well as promote a deeper appreciation of the pioneers of the methods still used today. Here we report the conditions leading to Torek’s operation performed in 1913. In the operation, anesthesia was achieved by tracheal insufflation. Ernst Sauerbruch, a surgeon in Germany, first developed a negative-pressure chamber for anesthesia in 1903 and subsequently used this in many open-chest operations. Then in 1909 Samuel Meltzer, a physiologist in New York, proposed ventilation through an intratracheal tube while under anesthesia. Soon afterwards, Sauerbruch gave his chamber to Willey Meyer, a surgeon in the New York German Hospital, who reported Sauerbruch’s success in operations in the American journal. The negative-pressure chamber was sent to the Meltzer’s laboratory where Meltzer demonstrated that tracheal insufflation was superior to the negative-pressure chamber for open thoracic operations. These findings were conveyed to Meyer and to Franz Torek, a surgeon in the New York German Hospital and a colleague of Meyer, who succeeded in the historical first resection of a cancer in the thoracic esophagus according to Meltzer.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background & Aims Esophageal squamous cell carcinoma (ESCC) is the predominant form of esophageal cancer in Japan. Smoking and drinking alcohol are environmental risk factors for ESCC, whereas single ...nucleotide polymorphisms in ADH1B and ALDH2 , which increase harmful intermediates produced by drinking alcohol, are genetic risk factors. We conducted a large-scale genomic analysis of ESCCs from patients in Japan to determine the mutational landscape of this cancer. Methods We performed whole-exome sequence analysis of tumor and nontumor esophageal tissues collected from 144 patients with ESCC who underwent surgery at 5 hospitals in Japan. We also performed single-nucleotide polymorphism array-based copy number profile and germline genotype analyses of polymorphisms in ADH1B and ALDH2 . Polymorphisms in CYP2A6, which increase harmful effects of smoking, were analyzed. Functions of TET2 mutants were evaluated in KYSE410 and HEK293FT cells. Results A high proportion of mutations in the 144 tumor samples were C to T substitution in CpG dinucleotides (called the CpG signature) and C to G/T substitutions with a flanking 5′ thymine (called the APOBEC signature). Based on mutational signatures, patients were assigned to 3 groups, which associated with environmental (drinking and smoking) and genetic (polymorphisms in ALDH2 and CYP2A6 ) factors. Many tumors contained mutations in genes that regulate the cell cycle ( TP53, CCND1, CDKN2A , FBXW7 ); epigenetic processes ( MLL2, EP300, CREBBP , TET2 ); and the NOTCH ( NOTCH1 , NOTCH3 ), WNT ( FAT1 , YAP1 , AJUBA ) and receptor-tyrosine kinase−phosphoinositide 3-kinase signaling pathways ( PIK3CA , EGFR , ERBB2 ). Mutations in EP300 and TET2 correlated with shorter survival times, and mutations in ZNF750 associated with an increased number of mutations of the APOBEC signature. Expression of mutant forms of TET2 did not increase cellular levels of 5-hydroxymethylcytosine in HEK293FT cells, whereas knockdown of TET2 increased the invasive activity of KYSE410 ESCC cells. Computational analyses associated the mutations in NFE2L2 we identified with transcriptional activation of its target genes. Conclusions We associated environmental and genetic factors with base substitution patterns of somatic mutations and provide a registry of genes and pathways that are disrupted in ESCCs. These findings might be used to design specific treatments for patients with esophageal squamous cancers.
The history of esophageal surgery in Japan can be divided into three periods, an era of safety from 1930 to 1980, an era of radicality from 1980 to 2000, and the era of quality of life (QOL) from ...2000 to the present. The treatment for T4 cancers of the thoracic esophagus has also changed over time from preoperative radiotherapy, combined resection of the neighboring organs with esophagectomy, and to definitive chemoradiotherapy (dCRT) with salvage surgery. At present, almost all patients with an unresectable T4 esophageal cancer receives dCRT. However, there are many patients with a residual or recurrent tumor after dCRT. Salvage surgery for such patients often results in incomplete resection of the tumor because the tumor involves the trachea and/or aorta. New techniques to enable the resection of such neighboring organs even during salvage surgery are needed. In the future, the mainstay of treatment for esophageal cancer will be CRT with the foreseeable progress in new drugs and new techniques of radiotherapy. Surgery will be indicated for a local failure after CRT, while combined resection of the neighboring organs will be necessary to treat a local failure after CRT for T4 cancers. New surgical techniques have to be developed through some application of new devices and equipment.
Advanced esophageal tumors have been a challenge for surgery since the very beginning, and these challenges continue still today. In the early period of three-field lymphadenectomy (late 1980s), ...there was no special attention paid to tracheal necrosis after such an extended operation. In 1988, we reported functional mediastinal dissection preserving the right bronchial artery to prevent such complications. In 1993, we reported that the survival after three-field lymphadenectomy was better than that after en-bloc esophagectomy, and then the lymph node compartment classification based on the metastatic rate and the survival rate. This concept was introduced into the 9th edition of the Guidelines for Clinical and Pathologic Studies on Carcinoma of the Esophagus published in 1999. In early 1980s, combined resection of the neighboring organs was initiated for a locally advanced esophageal cancer. Almost all patients who underwent such an operation, however, died of metastasis in the short-term after surgery without any additional treatment. In 1987, we reported several types of tracheal repair using the latissimus dorsi muscle flap, as a less-invasive surgery that enabled adjuvant or additive therapy, after resection of the trachea involved by cancer. Then in 2004, we demonstrated that the canine aorta could be resected even immediately after aortic stenting. This suggests that an esophageal cancer involving the aorta can be resected using a new technique. To meet the challenges posed by advanced esophageal cancer, the help of other specialized fields besides esophageal surgery is needed: “The specialist must know everything of something, something of everything.”
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Mucosal (T1a) and submucosal (T1b) squamous cell carcinoma of the esophagus (ESCC) have often been analyzed together and are staged as the same category in the UICC/TNM staging system. The ...difference in surgical outcomes between T1a and T1b ESCC therefore remains unclear. The purpose of this study was to examine the differences in surgical outcomes between T1a and T1b ESCC, and to investigate the prognostic factors in T1 ESCC.
Methods
A prospectively maintained database identified 145 previously untreated patients with pT1 ESCC who underwent radical transthoracic (
n
= 134) or transhiatal esophagectomy (
n
= 11). Median follow-up was 108 months.
Results
Of the 145 patients, 35 (24 %) had pT1a cancer and 110 (76 %) had pT1b cancer. Lymph node metastasis was present in 45 patients (31 %): 3 patients with pT1a cancer and 42 patients with pT1b cancer (
P
= 0.0003). The 5-year survival rate for the whole group was 77 %. The 5-year survival rate of the T1a patients was 94 % compared with 72 % for the T1b patients (
P
= 0.0282). In multivariate analysis, only the depth of tumor invasion (pT1a vs. pT1b) was an independent prognostic factor (hazard ratio 2.358; 95 % confidence interval 1.009–5.513;
P
= 0.0477).
Conclusions
After esophagectomy, the prognosis of patients with pT1b ESCC is significantly worse than that of patients with pT1a ESCC. Infiltration into the submucosa is the only independent prognostic factor affecting survival. These findings suggested that T1a and T1b ESCC could be staged separately in the next version of UICC/TNM staging system.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Objective
In Japan, no region has introduced primary HPV testing for cervical cancer screening. We assessed the diagnostic value and possible harm of HPV testing in Japan.
Methods
This ...cross‐sectional study with historical controls used cytology‐based screening and co‐testing data in Japan. As surrogate indicators of possible harm, colposcopy referral rate and cervical intraepithelial neoplasm (CIN) 1 detection rates were calculated. As surrogate indicators with diagnostic values, the detection rates of CIN2 or greater (CIN2+) and CIN3+ were calculated.
Results
The data of 297 970 women (182 697 for cytology‐based, 115 273 for co‐testing) were examined. The detection rates of CIN1, CIN2+, and CIN3+ were significantly higher in the co‐testing group than in the cytology‐based group (P < 0.001, P < 0.0001, P < 0.01, respectively). Between ages 25–49, CIN2+ detection rates were significantly higher in the co‐testing group than in the cytology‐based group (P < 0.05 for each 5‐year age group). Between ages 30–49, CIN3+ detection rates were significantly higher in the co‐testing group than in the cytology‐based group (P < 0.05 for each 5‐year age group).
Conclusion
Limiting the target age group may minimize the possible harm of screening. Cytology/HPV co‐testing may be useful in Japanese populations if balance is maintained between benefit and harm.
Cytology/HPV co‐testing may be useful in Japanese populations if efforts are made to achieve a balance between associated benefits and possible harm.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Purpose
It is sometimes difficult to differentiate between high signals originating from a reverse flow on magnetic resonance angiography (MRA) and occult arteriovenous shunting. We attempted to ...determine whether arterial spin labeling (ASL) can be used to discriminate reversal of venous flow from arteriovenous shunting for high-signal venous sinuses on MR angiography.
Methods
Two radiologists evaluated the signals of the venous sinus on MRA and ASL obtained from 364 cases without arteriovenous shunting. In addition, the findings on MRA were compared with those on ASL in an additional 13 patients who had dural arteriovenous fistula (DAVF).
Results
In the 364 cases (728 sides) without arteriovenous shunting, a high signal due to reverse flow in the cavernous sinuses (CS) was observed on 99 sides (13.6%) on MRA and none on ASL. Of these cases, a high signal in the sigmoid sinus, transverse sinus, and internal jugular vein was seen on 3, 3, and 8 sides, respectively. All of these venous sinuses showed a high signal from the reverse flow on MRA images.
Conclusion
ASL is a simple and useful MR imaging sequence for differentiating between reversal of venous flow and CS DAVF. In the sigmoid and transverse sinus, ASL showed false-positives due to the reverse flow from the jugular vein, which may be a limitation of which radiologists should be aware.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Background
The importance of mesenchymal characteristics has not been fully elucidated in esophageal cancer.
Methods
Ten normal and 77 tumor specimens were collected. Microarray analysis was ...performed to analyze the expression patterns of epithelial markers, mesenchymal markers, epithelial mesenchymal transition (EMT)-related genes and stem cell markers. RT-PCR analysis was conducted to confirm the results of microarray analysis. Immunohistochemical analysis was performed to verify the level of protein expression. Statistical analysis was performed to investigate the correlation between selected genes and clinicopathological factors.
Results
Microarray analysis showed that epithelial markers were significantly down-regulated whereas mesenchymal markers and EMT transcription factors were up-regulated in cancer cells. Two types of gene expression patterns were found in the clustering analysis, type 1 tumors and type 2 tumors. Type 1 tumor clusters did not reveal a fixed gene expression pattern whereas type 2 tumor clusters revealed up-regulation of mesenchymal markers EMT inducers and related genes. Vimentin and fibronectin were selected to distinguish between tumor types 1 and 2. Type 2 tumors showed significantly larger tumor sizes (
p
< 0.0001), wider ranges of lymph node metastasis (
p
= 0.0057), and a more severe clinical stage (
p
< 0.0001) than did type 1 tumors. The prognosis of patients with type 2 tumors was significantly worse than that of patients with type 1 tumors. Univariate and multivariate analyses revealed that classification of type 2 tumors was an independent prognostic factor.
Conclusions
The analysis of mesenchymal markers in esophageal cancer is useful in distinguishing patients with a poor prognosis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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