Yoichi Tabira

Indications for three-field dissection followed by esophagectomy for advanced carcinoma of the thoracic esophagus

OBJECTIVE The aim of this study was to evaluate the indication for 3-field lymphadenectomy (3-field dissection) followed by esophagectomy for locally advanced carcinoma of the thoracic esophagus in the presence of lymph node metastasis. METHODS From January 1983 to December 1995, 86 patients with thoracic esophageal carcinoma invading muscularis propria or adventitia underwent radical subtotal esophagectomy after preoperative chemotherapy. Forty-six of the 86 patients underwent a 2-field dissection (mediastinal and abdominal nodes, group A), and 40 patients underwent a 3-field dissection (bilateral cervical, mediastinal, and abdominal nodes, group B). Survival curves were compared between the 2 groups after stratification according to the degree of lymph node involvement (number of positive nodes and involvement of intrathoracic or intrathoracic recurrent nerve chain nodes). Potential prognostic factors of these 86 patients were evaluated by means of Cox regression analysis. RESULTS There were no significant differences in age, sex ratio, depth of tumor invasion, pTNM classification, or number of positive nodes between the 2 groups. Among patients with positive intrathoracic nodes, the 5-year survival of group B (42%) was significantly longer than that of group A (13%, generalized Wilcoxon test P =.02). Among patients with 1 to 4 positive nodes, the 5-year survival of group B (54%) was significantly higher than that of group A (22%, P =.01). Multivariate analysis revealed the number of positive nodes, age, and pT4 stage to be significant predictors of survival in patients with thoracic esophageal carcinoma. CONCLUSIONS Three-field dissection for advanced carcinoma of the thoracic esophagus is effective in patients with 1 to 4 positive nodes.

Recurrent nerve nodal involvement is associated with cervical nodal metastasis in thoracic esophageal carcinoma

BACKGROUND Because three-field dissection for esophageal carcinoma is one of the most invasive operations, this procedure should be selected only when strictly indicated; but there are no useful criteria for it. The goal of this study was to identify the useful clinicopathologic factors for indicating three-field dissection. STUDY DESIGN In this study, we reviewed the survival of patients after three-field dissection and identified factors associated with metastases in cervical nodes (CN), especially internal jugular nodes and supraclavicular nodes. Eighty-six patients who underwent curative esophagectomy with three-field dissection for squamous cell carcinoma of the thoracic esophagus were enrolled in this study. Survival rates were compared with respect to the presence of nodal metastasis. The relationship between recurrent nerve nodal (RNN) involvement and CN metastasis (bilateral internal jugular nodes, supraclavicular nodes, or both) was examined. Clinicopathologic factors possibly influencing CN metastasis were studied by multivariate logistic regression analysis. RESULTS The overall 5-year survival rate was 45.1%. The 5-year survival rate for patients without metastatic nodes was 67.5%, for patients with one to four metastatic nodes it was 53.1%, and for patients with five or more it was 9.1 %. The prognosis of those with five or more metastatic nodes was significantly poorer than those of the other two groups. In the positive-node group, the 5-year survival rate for patients with RNN metastasis was 21.7%, and for patients with negative RNN it was 47.0% (p = 0.2). In the positive-node group, the 5-year survival rate for patients with positive CN was 13.7% and for patients with negative CN it was 45.8% (p = 0.01). Fifty-six (88.9%) of 63 patients without RNN metastasis had no CN metastasis in contrast to 13 of 23 patients (56.5%) with RNN metastasis who had no CN metastasis (p = 0.001). The positive predictive value, negative predictive value, sensitivity, and specificity were 43.5%, 88.8%, 58.8%, and 81.2%, respectively. The number of metastatic nodes (5 or more versus 0-4) (odds ratio: 2.9, 95% Confidence Interval (CI) = 1.6-5.5, p = 0.0008) and RNN involvement (odds ratio: 4.5, 95% CI = 1.3-15.9, p = 0.02) were the significant factors associated with CN metastasis in the multivariate analysis. CONCLUSIONS RNN involvement is associated with CN metastasis as is the number of metastatic nodes and may be an indicator for the selection of three-field dissection in thoracic esophageal carcinoma.

Insulin-like Growth Factor-I Prevents Gut Atrophy and Maintains Intestinal Integrity in Septic Rats

BACKGROUND The effects of insulin-like growth factor-I (IGF-I) on gut metabolism, structure, and barrier function as well as its general anabolic effects were investigated in septic rats. METHODS Thirty-three male Wistar rats that underwent cecal ligation were randomly divided into one of the following two groups: (1) received only total parenteral nutrition (control group) or (2) received total parenteral nutrition with IGF-I (IGF group) at a dose of 4 mg/kg/d for 3 days. RESULTS During the 3-day period, the body weight of rats in the IGF group increased significantly over that of rats in the control group (17.1 +/- 2.6 vs 5.8 +/- 4.6 g, p < .01). The total and free IGF-I plasma concentrations were significantly higher in the IGF group than in the control group. The cumulative nitrogen balance was significantly more positive for the IGF group (423.9 +/- 24.3 mg of nitrogen) than for the control group (290.8 +/- 26.0 mg of nitrogen). The weights of thymus, spleen, and kidneys were significantly increased in the IGF group compared with weights in the control group. Treatment with IGF-I improved the gut mucosal weight in all regions of the gut examined, including duodenum, jejunum, ileum, and colon. Histologic and biochemical analyses of the jejunum showed greater villus height and crypt depth and higher mucosal DNA and protein content in the IGF group. The arterial concentration of endotoxin was not significantly different between the two groups, whereas its level in portal blood was significantly lower in the IGF group (23.2 +/- 9.9 pg/mL) than in the control group (95.5 +/- 37.9 pg/mL), an indication that IGF-I treatment decreased the amount of endotoxin that traversed the gut barrier. CONCLUSIONS These results indicate that IGF-I can improve gut metabolism and reduce mucosal atrophy and that it may play a role in maintaining the gut barrier function in sepsis.

NE-dlg, a mammalian homolog of Drosophila dlg tumor suppressor, induces growth suppression and impairment of cell adhesion: Possible involvement of down-regulation of β-catenin by NE-dlg expression

Membrane‐associated guanylate kinases (MAGUKs) are known to function as scaffolds for forming multiprotein complexes at the synaptic junctions of neuronal cells and at sites of epithelial cell‐cell contact. In Drosophila, mutations of the lethal (1)‐discs large (dlg) gene, which encodes a MAGUK protein, leads to post‐synaptic structure defects in neuronal cells and neoplastic overgrowth of epithelial cells. We previously showed that NE‐dlg (neuronal and endocrine dlg), a human homolog of the dlg, plays a crucial role in formation of synaptic structure in human neuronal cells. Here we demonstrate that NE‐dlg, similar to Drosophila dlg, is involved in regulation of cell cycle progression and adhesive ability of non‐neuronal cells. Overexpression of NE‐dlg in proliferating cells including various cancer cell lines induced growth suppression and impairment of cell adhesive ability. Furthermore, NE‐dlg overexpression caused the down‐regulation of β‐catenin in cancer cells regardless of mutations in the APC (adenomatous polyposis coli) gene. The PDZ domains of NE‐dlg were found to be essential for the growth suppression, loss of adhesive property and down‐regulation of β‐catenin. We propose that NE‐dlg regulates the cell growth and adhesive ability by controlling the level of β‐catenin through an APC‐independent pathway. Inactivation of NE‐dlg may therefore contribute to development and/or progression of human neoplasms. Int. J. Cancer 86:480–488, 2000.

Accelerated growth signals and low tumor-infiltrating lymphocyte levels predict poor outcome in T4 esophageal squamous cell carcinoma

BACKGROUND Little is known about the biological nature of T4 esophageal carcinoma growth signals and host defenses. METHODS Paraffin-embedded sections from 78 patients with T2 to T4 esophageal squamous cell carcinoma who underwent operation were analyzed with immunohistochemistry. RESULTS Positive cyclin A showed a significantly greater increase in T4 tumors than in those of other stages, and negative p27 showed a significantly greater decrease in T4 tumors than in large T3 stage tumors (tumor size > or = 4.0 cm). Patients with low-grade tumor-infiltrating lymphocyte (TIL) density showed a significantly greater decrease in T4 than in T2. The combination of p27 and cyclin A was a significant independent prognostic factor among T and N factors in multivariate analysis. TIL density was an independent prognostic factor among immunonutritional variables such as serum albumin concentration and the number of total blood lymphocytes. CONCLUSIONS T4 esophageal squamous cell carcinoma has a poor prognosis, which is associated with increased p27-negative and cyclin A-positive growth signals in the tumor and with low TIL density in the host.

Effect of Administered Human Growth Hormone on Protein Metabolism in Septic Rats

The effect of administered human growth hormone (hGH) on protein metabolism in septic rats was investigated. Fifty-three male Wistar rates with SVC cannulation were divided into four groups. Group I (n = 10) underwent sham-operation. Sepsis was induced by cecal ligation in group II (n = 19), group III (n = 10), and group IV (n = 14). Isocaloric, isonitrogenous glucose/amino acids were infused for 4 days. hGH was administered in group III (100 mU/day) and group IV (200 mU/day) every day. Cumulative nitrogen balance (mg/kg) in group IV was significantly higher than in group II (p less than 0.01): group I, 1264 +/- 355; group II, 117 +/- 693; group III, 92 +/- 735; group IV, 1001 +/- 279. Cumulative urinary excretion of 3-methylhistidine (3-MH, mg/kg) did not differ between group II and group IV: group I, 6.2 +/- 0.9; group II, 12.0 +/- 2.2; group III, 13.4 +/- 2.9; group IV, 10.5 +/- 2.3. Serum albumin level in group IV (1.8 +/- 0.2 g/dl) was significantly higher than in group II (1.5 +/- 0.2 g/dl) (p less than 0.01). Blood urea nitrogen level in group IV (12.6 +/- 2.3 mg/dl) was significantly lower than in group II (18.8 +/- 7.4 mg/dl) (p less than 0.05). Although serum levels of glucose, insulin, triglyceride, and phospholipid were higher in sepsis groups than in sham-operated group, those levels did not differ among sepsis groups. Administration of hGH, 200 mU/day, resulted in marked nitrogen retention and had little effect on 3-MH excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Quality of life after esophagectomy for cancer: An assessment using the questionnaire with the face scale

AbstractPurpose. The face scale has not been used as a global parameter of quality of life (QOL). The aims of this study were to assess the QOL of patients after esophagectomy for cancer and to examine whether a face scale is useful as a global parameter of QOL. Method. Seventy-one patients without postoperative recurrence after curative esophagectomy answered the questionnaire with the face scale and food intake. We calculated the QOL score (its full mark: 85) and examined the correlation between the QOL score and other parameters including the face scale. Result. The duration of the postoperative period ranged from 8 to 253 months (median 87 months). Gastric pullups at the left cervix were selected in 66 patients. The retrosternal route was performed in 55 patients. The mean QOL score was 64.2 (range 33–84). There was the significant positive correlation between QOL score and the face scale (P < 0.0001). The quantity of meal intake decreased in 55 patients (77.55%) by more than 50% compared with their healthy state. About a half of the subjects still suffered from the swallowing problems and a decreased food intake. Conclusion. The face scale is correlative with the total QOL score after an esophagectomy and is useful as a global parameter of the QOL.

DOES NEOADJUVANT CHEMOTHERAPY FOR CARCINOMA IN THE THORACIC ESOPHAGUS INCREASE POSTOPERATIVE MORBIDITY

OBJECTIVES The aims of this study were to examine whether neoadjuvant chemotherapy for a carcinoma in the thoracic esophagus increased the incidence of postoperative complications, and which clinicopathological factors may affect postoperative complications after esophagectomy. SUBJECTS AND METHODS One hundred and forty-four patients who underwent neoadjuvant chemotherapy followed by esophagectomy for a carcinoma in the thoracic esophagus were reviewed in a retrospective study. Ninety-six patients received neoadjuvant chemotherapy and 48 did not. The postoperative complications were grouped either general complications (Complications A) or surgery-related complications (Complications B). Complications A consisted of pulmonary, cardiac, hepatic, renal, and neurological complications, and catheter sepsis. Complications B consisted of a gastrointestinal tract leak, gastrointestinal tract necrosis, an intrathoracic or intraabdominal abscess, hemorrhage, ileus, and vocal cord palsy. In these two categories of complications, 17 factors obtained from subjects were compared between patients with complications and those without by univariate and multivariate analyses. RESULTS The patient characteristics did not differ between patients who received neoadjuvant chemotherapy and those without. The preoperative serum albumin level was higher in patients without complication than in those with complication in both two categories of complications (Complications A: p = 0.001, Complications B: p = 0.05). The proportion of patients who received neoadjuvant chemotherapy did not differ between patients with complication and those without complication in either category of complications. Multivariate analysis showed that preoperative Onoderas Prognostic Nutritional Index was the only factor reducing the incidence of complications A (p = 0.02, Odds ratio: 0.63). CONCLUSION Neoadjuvant chemotherapy was well tolerated and was not associated with any increased morbidity or mortality after esophagectomy for a carcinoma in the thoracic esophagus.

Outcome of histologically node-negative esophageal squamous cell carcinoma

The outcome of node-negative esophageal carcinoma and the prognostic significance of lymph node micrometastasis remain unknown. The aim of this retrospective study was to clarify these two points. A series of 98 patients who underwent curative operation for histologically node-negative (pNO in TNM classification) esophageal carcinoma were enrolled in the study. We reviewed the cause of death of these patients. The survival curves were calculated and compared after stratifications according to clinicopathologic parameters. Lymph node micrometastasis in the patients with recurrences was examined using immunohistochemical staining of cytokeratin. Their ages ranged from 45 to 83 years (mean 64.3 years). There were 83 men and 15 women. Altogether, 54 patients were still alive, and 44 had died. A total of 9 patients died from recurrence of their esophageal carcinoma, 33 died from other causes (pneumonia 11, extraesophageal carcinoma 7, and so on), and 2 died from unknown causes. Eight patients had locoregionai recurrences, and two patients had distant recurrences. The overall survival rate for the 98 patients was 58.2%. The survival for patients with pT2 or pT3 tumors was significantly worse than for those with pTis or pTl tumors (p=0.02, log-rank test). Other clinicopathologic factors did not affect the prognosis. Immunohistochemical study found no lymph node micrometastasis in 365 lymph nodes resected from the patients with recurrences. Only the depth of tumor invasion affected the outcome of patients with node-negative esophageal carcinoma. Altogether, 75% of patients died of other causes without recurrence, with the two main causes of death being pulmonary complications and extraesophageal carcinoma in these patients. Lymph node micrometastasis was not associated with recurrence in this series.RésuméL’évolution des cancers de lœsophage NO et la signification des micrométastases ganglionnaires resent inconnues. Le but de cette étude rétrospective a été de clarifier ces deux problèmes. Nous avons inclus dans cette étude, 98 patients qui ont eu une résection à visée curative pour un cncer de l’œsophage (pNO selon la classificaton TNM). Nous avons revu les causes de mortalité chez ces patients. Les courbes de survie ont été calculées et comparées après stratification selon les données clinicopathologiques. Les micrométastases ganglionnaires chez les patients récidives ont été déterminées par une coloration immunohistochimique de la cytokératine. L’àge des patients allait de 45 à 83 ans (moyenne: 65.3 ans). Il y avait 83 hommes et 15 femmes. Cinquante-quatre patients étaient en vie et 44 patients étaient décédés. Neuf patients sont décédés d’une récidive de leur cancer le l’œsophage, 33 sont décédés d’autres causes (principalement une infection pulmonaire:n=11, ou un cancer extra-esophagien: n=7) alors que deux patients sont décédés de cause inconnue. Huit patients ont eu une récidive locorégionale et deux, une récidive à distance. La survie globale pour les 98 patients a été de 58.2%. La survie des patients ayant des tumeurs pT2 ou pT3 a été significativement moins bonne que pour les tumeurs pTis ou pT1 (p=0.02, test du log-rank). Les autres facteurs clinicopathologiques n’ont pas affecté le pronostic. Par l’étude immunohistochimique aucune micrométastase n’a été retrouvée parmi 365 ganglions réséqués chez des patients ayant eu une récidive. Seule la profondeur d’invasion tumorale a influené l’évolution de la maladie chez les patients NO. Parmi les patients décédés, 75% étaient sans récidive; les deux causes principales étant des complications pulmonaires et un cancer extra-esophagien. Dans cette série, les micrométastases n’ont jamais été la cause de récidive.ResumenNo están bien establecidos ni la evolución ni el resultado final del carcinoma escamocelular del esófago con ganglios negativos, tampoco el significado pronóstico de las micrometástasis ganglionares. El propósito de este estudio retrospectivo fue aclarar estos interrogantes. Noventa y ocho pacientes sometidos a operación curativa por carcinoma esofágico con ganglios histológicmente negativos (pNO en la clasificación TNM) fueron incorporados en el estudio. Se revisaron las causas de muerte y se calcularon las curvas de supervivencia para compararlas luego de la estratificación según parámetros clínico patológicos. El estudio de los ganglios para determinar micrometástasis fue hecho en los pacientes que desarrollaron recurrencia mediante coloración immunohistológica de queratina. Las edades oscilaron entre 45 y 83 años (promedio: 65.3); hubo 83 hombres y 15 mujeres. Cincuenta y dos pacientes están vivos, 44 murieron. Nueve murieron por carcinoma recurrente, 33 por otras causas (neumonía 11, carcinoma extraesofágico 7, etc.) y dos por causa desconocida. Ocho presentaron recurrencia local-regional y dos metástasis distantes. La tasa global de supervivencia para los 98 pacientes fue 58.2%. La supervivencia en los pacientes con neoplasmas pT2 o pT3 fue significativamente peor que en los pTis o pT1 (p=0.02). Otros factores clínicos y patológicos no demostraron efecto sobre el pronóstico. El estudio immunohistoquímico no reveló micrometástasis ganglionares en 365 ganglios resecados de pacientes con recurrencias. Sólo la profundidad de la invasión tumoral afectó la evolución final en estos carcinomas esofágicos con ganglios negativos. Setenta y cinco por ciento de los pacientes murieron por causas diferentes de la recurrencia tumoral, y las dos causas principales de muerte fueron la complicación pulmonar y el carcinoma extraesofágico en los pacientes libres de recurrencia. La presencia de micrometástasis ganglionares no apareció asociada con recurrencia en esta serie.

Prognostic value of mitotic metaphase rate in oesophageal cancer

OBJECTIVE To assess the prognostic value of the mitotic metaphase rate in patients with oesophageal cancer. DESIGN Retrospective study. SETTING University hospital, Japan. SUBJECTS 41 patients with oesophageal cancer. INTERVENTIONS We calculated the ratio of mitotic metaphase to anaphase cells among tumour cells in sections stained with haematoxylin and eosin, a ratio that shows the status of mitotic metaphase-anaphase transition. The DNA ploidy pattern was examined by flow cytometry. MAIN OUTCOME MEASURE Correlation between survival and mitotic metaphase rate. RESULTS A high mitotic metaphase rate was correlated with vascular invasion and is expected to be a useful prognostic factor. DNA diploidy combined with a low rate was an independent favorable prognostic factor. CONCLUSION Mitotic metaphase rate is a useful index of malignant potential, independent of DNA ploidy. It can distinguish high malignant potential from low in a diploid tumour, which has a poor prognosis that is equal to that of the aneuploidy tumour.