Lymphoepithelioma-like esophageal carcinoma with macroscopic reduction.

Esophageal lymphoepithelioma-like carcinoma (LELC) is extremely rare. We report the first case of esophageal LELC showing macroscopic reduction. A 67-year-old male presented with dysphagia and, by endoscopic examination, was found to have a significantly raised tumor of 10 mm in diameter in the thoracic esophagus. The biopsied material showed esophageal cancer. We performed endoscopic submucosal dissection. However, the tumor became flattened, similar to a scar, in only 2 mo. Histologically, the carcinoma cells had infiltrated the submucosal layer. Prominent infiltration of T lymphoid cells that stained positive for CD8 was observed around the carcinoma cells. Therefore, this lesion was considered to be an LELC with poorly differentiated squamous cells. Because the margin was positive, an esophagectomy was performed. Carcinoma cells were detected in the neck in one lymph node. The staging was T1N0M1b. However, the patient has been well, without adjuvant therapy or recurrence, for more than 5 years.

Identification of a novel SEREX antigen family, ECSA, in esophageal squamous cell carcinoma.

BACKGROUND: Diagnosis of esophageal squamous cell carcinoma (SCC) may improve with early diagnosis. Currently it is difficult to diagnose SCC in the early stage because there is a limited number of tumor markers available. RESULTS: Fifty-two esophageal SCC SEREX antigens were identified by SEREX (serological identification of antigens by recombinant cDNA expression cloning) using a cDNA phage library and sera of patients with esophageal SCC. Sequence analysis revealed that three of these antigens were similar in amino acid sequences, and they were designated as ECSA (esophageal carcinoma SEREX antigen)-1, -2 and -3. The ECSA family was also similar to an EST clone, hepatocellular carcinoma-associated antigen 25a (HCA25a). Serum antibody levels to ECSA-1, -2 and -3 were significantly higher in patients with esophageal SCC than in healthy donors. Based on the conserved amino acid sequences, three peptides were synthesized and used for enzyme-linked immunosorbent assays (ELISA). The serum antibody levels against one of these peptides were significantly higher in patients with esophageal SCC. This peptide sequence was also conserved in FAM119A, GOSR1 and BBS5, suggesting that these are also ECSA family members. Reverse transcription followed by quantitative PCR analysis showed that the mRNA expression levels of ECSA-1, -2 and -3 and FAM119A but not of HCA25a, GOSR1 and BBS5 were frequently elevated in esophageal SCC tissues. CONCLUSIONS: We have identified a new gene family designated ECSA. Serum antibodies against the conserved domain of the ECSA family may be a promising tumor marker for esophageal SCC.

Viral shedding after p53 adenoviral gene therapy in 10 cases of esophageal cancer.

We detected adenoviral DNA fragments in excretions of 10 esophageal cancer patients by DNA-PCR after tumor injection of Ad-CMV-vector. A total of 220 samples consisting of feces, gargling saliva, urine, and blood plasma were assessed. A total of 29.7% of feces samples and 13.2% of gargling saliva samples were positive for adenoviral DNA fragments, but 89.7% of the positive feces samples and all of the positive gargling saliva samples turned negative on day 12 after tumor injection. Although adenoviral DNA fragments may be pathogen-free, patients' feces and gargling saliva contain adenoviral DNA fragments for 12 days after injection.

Impact of lymph node involvement in T2 or T3 thoracic esophageal squamous cell carcinoma.

BACKGROUND/AIMS: Treatment strategy for T2/ T3 esophageal carcinoma has become controversial because of recent improvements in chemoradiation therapy. Only a few study analyzed the prognostic impact of clinicopathological factors for surgical outcome of patients with esophageal carcinoma focused on T2/T3 tumors. METHODOLOGY: Subjects of this study were 187 patients with pathological T2 (n = 46) or pathological T3 (n = 141) thoracic esophageal squamous cell carcinoma who received surgical treatment without neoadjuvant therapy. The impact of clinicopathological factors on survival was evaluated by univariate and multivariate analysis. RESULTS: Overall 5-year survival rate of all patients was 38%. Dismal 5-year overall survival rates were observed in patients with 5 or more positive nodes (11%). Multivariate analysis indicated that lymph node metastases (hazard ratio; 2.07, 95%IC, 1.20-3.56, p < 0.01) and the number of metastatic nodes (hazard ratio; 1.77, 95%IC, 1.11-2.82, p = 0.02) were independent risk factors for poor survival. However, tumor depth itself was not an independent risk factor for survival. CONCLUSIONS: Although survival of patients with pathological T2 or T3 was partly dependent on tumor depth, it was mainly dependent on lymph node status. Multiple positive nodes were independent risk factors for poor survival.

Identification of Makorin 1 as a novel SEREX antigen of esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (SCC) represents one of the most malignant tumors. To improve the poor prognosis, it is necessary to diagnose esophageal SCC at early stages using new tumor markers. SEREX (serological identification of antigens by recombinant cDNA expression cloning) is suitable for large-scale screening of tumor antigens and has been applied for various types of human tumors. METHODS: Tumor markers of esophageal squamous cell carcinoma (SCC) were screened by SEREX method. The presence of serum anti-makorin 1 (MKRN1) antibodies (s-MKRN1-Abs) was examined by Western blotting using bacterially expressed MKRN1 protein. The expression levels of MKRN1 mRNA in tissues were examined by RT-PCR. The biological activity of MKRN1 was examined by transfection of ras-NIH3T3 mouse fibroblasts with MKRN1 cDNA. Major ubiquitinated proteins in MKRN1-transfected cells were identified by immunoprecipitation with anti-ubiquitin antibody followed by mass spectrometry. RESULTS: MKRN1 was identified as a novel SEREX antigen of esophageal SCC. Although a total of 18 (25%) of 73 patients with esophageal SCC had s-MKRN1-Abs, none of the 43 healthy donors had a detectable level of s-MKRN1-Abs. There was no correlation between the presence of s-MKRN1-Abs and clinicopathological variables other than histological grading. Well-differentiated tumors were associated significantly with the presence of s-MKRN1-Abs in the patients. The mRNA levels of MKRN1 were frequently higher in esophageal SCC tissues than in the peripheral normal esophageal mucosa. Stable transfection of ras-NIH3T3 cells with MKRN1 cDNA induced prominent morphological changes such as enlargement of the cell body and spreading. Ubiquitination of 80- and 82-kDa proteins were clearly observed in MKRN1-transfected cells but not in the parental cells, which were identified as L-FILIP (filamin A interacting protein 1). CONCLUSION: MKRN1 is a novel SEREX antigen of esophageal SCC, and s-NKRN1-Abs can be a candidate of diagnostic markers of esophageal SCC with high specificity. It is plausible that MKRN1 is involved in carcinogenesis of the well-differentiated type of tumors possibly via ubiquitination of L-FILIP.

Detection of anti-CUEC-23 antibodies in serum of patients with esophageal squamous cell carcinoma: a possible new serum marker for esophageal cancer.

BACKGROUND: Serological identification of antigens by recombinant cDNA expression cloning (SEREX) is an established method for detecting new tumor-specific antigens. Antibodies to SEREX antigens may be useful for the detection of esophageal squamous cell carcinoma (SCC). METHODS: A phage cDNA library of a human esophageal SCC cell line was screened using sera of patients with esophageal SCC. The presence and levels of serum antibodies to SEREX antigens were established by Western blotting and enzyme-linked immunosorbent assay (ELISA) using purified recombinant antigen proteins, respectively. RESULTS: The newly identified esophageal SCC antigen is encoded by a novel gene located on chromosome 1, here designated CUEC-23. Serum CUEC-23-antibodies (s-CUEC-23-Abs) were detected in 14 of 54 patients with esophageal SCC (26%) by Western blot analysis. Esophageal SCCs were positive for s-CUEC-23-Abs together with CEA, SCC-Ag or CYFRA21-1 in 44, 41 and 52% of cases, respectively. There was no detectable association between the presence of s-CUEC-23-Abs and clinicopathological variables. ELISA showed that the levels of s-CUEC-23-Abs were significantly higher in patients with esophageal SCC than in healthy volunteers (17% in the former using the mean+3 SD of s-CUEC-23-Abs in healthy controls as the cutoff). CONCLUSION: A new tumor antigen, CUEC-23, was identified by SEREX screening. s-CUEC-23-Abs might be a useful serum marker to detect esophageal SCC.

Decrease in chemosensitivity against anticancer drugs by an esophageal squamous cell carcinoma SEREX antigen, AISEC.

We performed SEREX (serological identification of antigens by recombinant cDNA expression cloning) using the sera of patients with esophageal squamous cell carcinoma (SCC), and examined whether some of the SEREX antigens can affect chemosensitivity against anticancer drugs. We isolated a novel gene which was designated as AISEC (antigen identified by SEREX for esophageal carcinoma). RT-PCR analysis showed that the mRNA expression levels of AISEC were higher in esophageal SCC tissues than in their normal counterparts. By transfection into activated Ha-ras-transformed NIH3T3 (ras-NIH) mouse fibroblasts, we isolated a clone, FAISEC-3, which stably expressed AISEC. FAISEC-3 cells were more resistant to anticancer drugs, such as mitomycin C, ifosfamide, vincristine, camptothecin and etoposide, than parental ras-NIH cells. Luciferase reporter assay after a transient transfection with AISEC cDNA or the control vector revealed that the transactivity of p53 was suppressed by AISEC in a dose-dependent manner. These results suggested that esophageal SCC tissues produce AISEC in increased amounts, which can reduce the chemosensitivity against anticancer drugs possibly by suppressing the p53 transactivation ability.

Mode of lymphadenectomy and surgical outcome of upper thoracic esophageal squamous cell carcinoma.

INTRODUCTION: Only a few studies have evaluated the impact of clinicopathological variables and cervical lymphadenectomy on survival in patients with upper thoracic esophageal squamous cell carcinoma (SCC). MATERIAL AND METHODS: From 1960 to 2005, a total of 167 consecutive patients with upper thoracic esophageal SCC underwent esophagectomy. Of these patients, 108 underwent surgery between 1960 and 1989 and 59 between 1990 and 2005. A total of 65 patients were treated with cervical lymphadenectomy. Univariate and multivariate analyses were performed to evaluate the impact of clinicopathological variables on surgical outcome and possible predictors for cervical lymph node metastasis. RESULTS AND DISCUSSION: The overall 5-year survival of the later period was significantly better than the former period (43% vs 13%, p < 0.01). Based on Cox's proportional hazards model, T3/T4 tumors, thoracic or abdominal node metastasis, venous invasion, residual cancer, absence of cervical lymphadenectomy, and hospital morbidity were independent risk factors for reduced survival in patients with upper thoracic esophageal SCC. A total of 31 (48%) of 65 patients who underwent cervical lymphadenectomy showed positive nodes in cervical field. CONCLUSION: Based on logistic regression analysis, T3/T4 tumors and recurrent nerve node metastasis were possible risk factors for cervical node metastasis.

Perioperative changes of serum p53 antibody titer is a predictor for survival in patients with esophageal squamous cell carcinoma.

BACKGROUND: Although the presence of serum p53 antibody (s-p53-Abs) before treatment has been shown to correlate with poor prognosis and lymph node metastasis in esophageal cancer, there has been little information about postoperative s-p53-Abs titer and perioperative changes of s-p53-Abs titers in patients with esophageal carcinoma. METHODS: A highly specific enzyme-linked immunosorbent assay was used to analyze s-p53-Abs in 110 patients with esophageal squamous cell carcinoma before and 1 month after surgery. The cutoff level of 1.3 U/ml was used to indicate seropositive patients. Impact of postoperative s-p53-Abs titer and perioperative changes of s-p53-Abs on survival was evaluated. RESULTS: Forty (36%) of 110 patients were positive for s-p53-Abs before surgery and 35 patients (32%) were positive after surgery. s-p53-Abs titer generally decreased after surgery. Among sero-positive patients, the patients who remained sero-positive after surgery (n = 28) had a worse prognosis than patients who showed sero-conversion (P = 0.02). Among sero-positive patients, the nondecreased titer group showed significantly unfavorable survival (P < 0.01). Multivariate analysis revealed that postoperative s-p53-Abs was an independent risk factor for worse overall survival (adjusted hazard ratio = 3.05; 95% confidence interval = 1.11-8.33; P = 0.03). CONCLUSIONS: Perioperative monitoring of s-p53-Abs titers was useful to identify patients with esophageal cancer with a high risk for tumor recurrence and a poor prognosis. Continuous sero-positive patients and/or nondecreased titer group, even after surgery, showed significantly unfavorable survival.

Have surgical outcomes of pathologic T4 esophageal squamous cell carcinoma really improved? Analysis of 268 cases during 45 years of experience.

BACKGROUND: Because invasion to an adjacent organ (T4) indicates highly advanced disease, and most surgeons avoid esophagectomy, the prognostic impact of clinicopathologic factors for survival of these patients after esophagectomy has rarely been analyzed. STUDY DESIGN: From 1960 to 2005, a total of 268 patients with esophageal squamous cell carcinoma underwent esophagectomy for pathologic T4 disease (pT4). The impact of clinicopathologic factors on survival was evaluated by univariate and multivariate analysis. Changes in surgical outcomes and longterm survival between the earlier period (1960 to 1989) and the later period (1990 to 2005) were analyzed. RESULTS: Overall survival rates of all patients were 25% at 1 year, 10% at 3 years, and 5% at 5 years. The survival curve of the later group was significantly better than that of the earlier group (p < 0.01). Multivariate analysis indicated that venous invasion (hazards ratio, 1.76; 95% CI, 1.33 to 2.33, p < 0.01) and presence of a postoperative complication (hazards ratio, 2.62; 95% CI, 1.96 to 3.51, p < 0.01) were independent risk factors for poor overall survival. Presence of residual cancer was also an independent risk factor for poor cause-specific survival (hazards ratio, 2.40; 95% CI, 1.23 to 4.69, p=0.01). Venous invasion and intramural metastasis were risk factors for residual cancer. A total of 38 (14%) patients, 15 in the early period and 23 in the later period, underwent complete resection (R0). Although overall survival after R0 resection in the later period improved slightly, cancer-related survival rates were similar in both periods. CONCLUSIONS: Although overall survival of patients with pT4 improved after 1990, this improvement might be mainly dependent on curability of the resection.

Long-term results after dissection of positive thoracic lymph nodes in patients with esophageal squamous cell carcinoma.

BACKGROUND: Although thoracic lymph node metastasis in patients with thoracic esophageal squamous cell carcinoma (SCC) has been reported to be a negative risk factor for long-term survival, only a few studies have evaluated the clinicopathologic difference between the impact of metastasis to the paraesophageal lymph nodes and to the nonparaesophageal lymph nodes. The purpose of this study was to evaluate surgical outcome after the clearance of metastatic thoracic lymph nodes. METHODS: Retrospectively reviewed were 164 consecutive patients with thoracic esophageal SCC who had not had preoperative treatment and underwent surgery from 1980 to 2005 and were found to have thoracic lymph node metastases. Of these patients, 83 underwent surgery from 1980 to 1994 and 81 from 1995 to 2005. Univariate and multivariate analyses were performed to evaluate the impact of nonparaesophageal lymph node metastasis on survival. RESULTS: Univariate analysis revealed that T3/T4 tumors and the presence of nonparaesophageal node metastases were associated with only a 20% overall five-year survival rate. The overall five-year survival for the most recent period was significantly better than for the former period (42% vs. 13%, p<0.01). Based on a multivariate analysis of prognostic impact of each nonparaesophageal node, the presence of metastatic subcarinal and/or posterior mediastinal nodes was an independent risk factor for reduced survival. CONCLUSION: Surgical outcome for patients with thoracic esophageal cancer and metastatic thoracic lymph nodes has improved during the last 25 years. Although postoperative chemotherapy might improve survival, the presence of T3/T4 tumors and/or metastatic nonparaesophageal nodes were unfavorable factors for survival.

Sensitization against anticancer drugs by transfection with UBE2I variant gene into ras-NIH3H3 mouse fibroblasts.

We previously performed SEREX (serological identification of antigens by recombinant expression cloning) using the sera of patients with esophageal squamous cell carcinoma (SCC), and isolated a variant clone (AK093616) of ubiquitin-conjugating enzyme E21 (UBE2I). This clone was tentatively designated as UBE2I-v5 and analyzed for biological function by transient transfection of the cDNA into activated Ha-ras-transformed NIH3T3 (ras-NIH) mouse fibroblasts. Chemosensitivity to 92 cytotoxic drugs was compared between UBE2I-v5-transfected cells and the parental ras-NIH cells. The UBE2I-v5-transfected cells were more sensitive than the parental cells to anticancer drugs such as vincristine (VCR), mitoxantrone (MIT) and etoposide (VP16). The regression analysis of the total chemosensitivity pattern of UBE2I-vS-transfected cells revealed that the function of UBE2I-v5 was positively related to RPA2 (replication protein A2), Rho-GDI (Rho guanine nucleotide dissociation inhibitor a), FUS (putative tumor suppressor) and TKT (transketolase) but negatively related to Per-1 (period-I), Ran (nuclear Ras-related protein), PTEN (phosphatase and tensin homolog), C/EBPalpha (CCAAT/enhancer binding protein a) and the tumor suppressor p53. Thus, it is possible that UBE21-v5 plays a role in carcinogenesis by suppressing the function of CIEBPa and/or p53 via RPA2-like activity.

Is the surgical stress associated with worse survival in patients with esophageal cancer?--Analysis of colon substitution for 37 patients with remnant stomach.

BACKGROUND/AIMS: Colon substitution is a standard method of reconstruction, although an aggressive surgery, for patients with esophageal carcinoma who have remnant stomach. Presence of postoperative complication was reported to be a risk factor for worse survival in the patients with esophageal cancer. We evaluated the affect of this surgical stress on the postoperative course and long-term survival of patients with esophageal carcinoma. METHODOLOGY: Between 1980 and 2002, a total of 37 patients with primary thoracic esophageal squamous cell carcinoma, who had history of gastrectomy due to gastric ulcer, underwent R0 esophagectomy followed by colon substitution (colon group). The clinical affect of colon substitution was retrospectively evaluated in comparison with gastric substitution as the control group (stomach group). RESULTS: The postoperative hospital morbidity rate was significantly higher in the patients with remnant stomach than in the control group. Although the clinicopathological features in both groups were similar, except operative time and bleeding volume, the overall and cause-specific survival of the remnant stomach group were significantly worse than those of the control group. Multivariate analysis suggested that remnant stomach was an independent risk factor for a worse survival. CONCLUSIONS: Surgical stress and postoperative complications, resulted by colon substitution for the patients with remnant stomach, might be associated with worse survival of patients with esophageal cancer.

Surgical outcome of patients with thoracic esophageal cancer positive for cervical lymph nodes.

BACKGROUND/AIMS: Although cervical lymph nodes were classified as distant metastases in patients with thoracic esophageal cancer, not a few patients survive more than five-years. The purpose of this study was to predict patients with good prognosis among thoracic esophageal cancer patients with cervical node metastases. METHODOLOGY: From 1983 to 2002, 312 consecutive patients with thoracic esophageal squamous cell carcinoma underwent curative surgery with 3-field lymph node dissection (3FLD). A total of 88 (28%) of 312 patients were diagnosed with cervical lymph node metastases. Univariate and multivariate analyses were carried out to evaluate the impact of clinico-pathological factors on the survival of these patients. RESULTS: Overall five-year survival rate of 88 patients with cervical lymph node metastases was 26%. Univariate analysis revealed that following groups showed more than 40% overall five-years survival rate; female patients, patients with T1, T2 tumors and patients without thoracic node metastases. These variables were also independent good prognostic factors in multivariate analysis. CONCLUSIONS: Although cervical lymph node metastases was risk factors for worse survival, female patients, patients with T1, T2 tumors and patients without thoracic node metastases showed acceptable overall survival after 3FLD.

Surgical outcome of elderly patients 75 years of age and older with thoracic esophageal carcinoma.

BACKGROUND: This study aimed to evaluate the surgical outcome of esophagectomy in patients 75 years of age and older with thoracic esophageal carcinoma. PATIENTS AND METHODS: Between 1980 and 2002, 55 (46%) of 120 patients 75 years of age and older with thoracic esophageal carcinoma underwent an esophagectomy. The risk factors that resulted in decreased survival were analyzed by both univariate and multivariate analyses. Differences in surgical outcome and long-term survival between the earlier time period (1980-1989) and later time period (1990-2002) were analyzed separately. RESULTS: Overall resection rate in elderly patients in both periods was similar (44%, earlier period; 46%, later period). Postoperative complications significantly reduced long-term survival [adjusted hazard ratio for death, 4.05; 95% confidence interval (CI), 1.70-9.62; P < 0.01). Surgical blood loss greater than 1,000 ml was less frequently observed in the later period than in the earlier period (19% vs. 54%, P = 0.01). The postoperative morbidity rate was lower in the later than in the earlier period (29% vs. 63%, P = 0.02). Overall 5-year survival rate was significantly higher in the later period than in the earlier period (57% vs. 18%, P < 0.01). CONCLUSIONS: Elderly patients who underwent an esophagectomy in the later period appeared to manifest less neoadjuvant treatment, less surgical stress, fewer postoperative complications, and a better long-term survival than those treated in the earlier period.

Surgical outcome after the clearance of abdominal metastatic lymph nodes in 138 patients with thoracic esophageal carcinoma.

BACKGROUND: Although abdominal lymph node metastasis in patients with thoracic esophageal squamous cell carcinoma (SCC) has been reported to be a risk factor to reduce long-term survival, only a few studies have so far evaluated the clinicopathologic factors among this group of patients. The purpose of this study was to evaluate the patients' surgical outcome after the clearance of metastatic abdominal nodes. PATIENTS AND METHODS: From 1980 to 2002, 550 consecutive patients with thoracic esophageal SCC underwent surgery with an abdominal lymph node dissection. A total of 138 patients with abdominal lymph node metastases were curatively resected. Those patients, including 62 from 1980 to 1989 and 76 from 1990 to 2002, were retrospectively reviewed. Univariate and multivariate analyses were performed to evaluate the impact of clinicopathologic factors on the survival of these patients. RESULTS: The overall 5-year survival rate of the 138 patients with abdominal lymph node metastases was 23%. A univariate analysis revealed that the following groups showed a greater than 30% overall 5-year survival rate: patients with T1 or T2 tumors, patients without thoracic node metastases, and those with poorly differentiated type tumors. Good prognostic factors based on a multivariate analysis were the most recent time period of surgery and 4 or fewer positive nodes. CONCLUSION: Among the patients with abdominal lymph node metastases, those with T1 or T2 tumors, patients without thoracic node metastases, and patients with 4 or fewer positive nodes showed an acceptable overall survival after a curative resection.

Serum anti-myomegalin antibodies in patients with esophageal squamous cell carcinoma.

In order to identify new serum markers of esophageal squamous cell carcinoma (SCC), we performed serological identification of antigens by recombinant cDNA expression cloning (SEREX). E. coli was transformed with a lambdaZAPII phage cDNA library prepared from mRNA of an esophageal cancer cell line (T.Tn), and IPTG-induced cDNA products were screened for interaction with antibodies in allogeneic sera of patients with esophageal SCC. We identified myomegalin (MMGL, phosphodiesterase 4D interacting protein/PDE4DIP) as a new SEREX antigen for esophageal SCC. Western blot analysis revealed that serum anti-myomegalin antibodies (s-MMGL-Abs) were present in 43 (47%) of 91 patients, but in only one (2.2%) of 45 healthy controls. Of the 21 patients with stage I disease, 8 (38%) were sero-positive. The positive rate of s-MMGL-Abs was greater than those of other conventional tumor markers. Reverse transcription-PCR analysis suggested that alternative splicing from myomegalin variant 1 to variant 5 may explain, in part, the development of s-MMGL-Abs. Although the presence of s-MMGL-Abs was not related to any clinicopathological features of the patients, multivariate analysis indicated that the presence of s-MMGL-Abs was significantly associated with a favorable prognosis. Consequently, s-MMGL-Abs may be a useful tumor marker to diagnose and establish a prognosis in patients with esophageal SCC.

Location and clinical impact of solitary lymph node metastasis in patients with thoracic esophageal carcinoma.

BACKGROUND: The location and clinical impact of solitary lymph node metastasis from thoracic esophageal carcinoma have not been evaluated sufficiently. METHODS: A consecutive series of 91 patients with a solitary positive lymph node who underwent curative surgery for thoracic esophageal carcinoma was investigated. The prognostic impact was evaluated by univariate analysis and multivariate analysis using Cox's proportional hazards model. RESULTS: A total of 52 (57%) of the 91 patients showed a solitary positive node beyond the thorax. While 29% of the patients with an upper thoracic tumor showed a cervical node, 13% of the patients with a middle tumor and none of the patients with a lower tumor showed a cervical node. Tumor depth and venous invasion were found to be independent risk factors for poor survival. CONCLUSIONS: The solitary positive lymph nodes were broadly distributed depending on the tumor location and tumor depth. Tumor depth and venous invasion were risk factors for poor survival in these patients.

Impact of the number and extent of positive lymph nodes in 200 patients with thoracic esophageal squamous cell carcinoma after three-field lymph node dissection.

BACKGROUND: Subtotal esophagectomy with three-field lymph node dissection (3FLD) has been reported to improve survival in patients with thoracic esophageal squamous cell carcinoma (SCC). The purpose of this study was to evaluate the prognostic impact of the extent and number of positive lymph nodes for long-term survival of patients who underwent 3FLD. METHODS: From January 1983 to December 2002, a total of 200 patients with thoracic esophageal SCC underwent 3FLD without any neoadjuvant therapy. The prognostic impact of the extent and number of positive lymph nodes was evaluated by both univariate and multivariate analysis. RESULTS: The extent of positive nodes associated with a 5-year survival were as follows: none, 69%; one-field, 50%; two-field, 29%; and three-field, 11%. The number of positive nodes associated with 5-year survival were as follows: single node, 65%; two-nodes, 51%; and more than three-nodes, 20%. Among patients with cervical lymphatic spreading, patients with upper tumors showed significantly better survival than patients with lower tumors (P=0.036). Multivariate analysis indicated that number of positive nodes and the abdominal node status were independent prognostic factors among lymph node status. CONCLUSIONS: Together, number and extent of positive lymph nodes can be considered an independent predictor of a high risk of recurrence. Although cervical lymphatic spreading was risk factor for worse survival, patients with upper tumors may have survival benefit after cervical lymph node dissection.

Phase I/II adenoviral p53 gene therapy for chemoradiation resistant advanced esophageal squamous cell carcinoma.

We investigated the feasibility, safety, biological activity and therapeutic efficacy of adenovirus-mediated p53 gene transfer in patients with chemoradiation resistant advanced esophageal carcinoma. Eligible patients were not surgical candidates and had measurable, advanced squamous cell carcinoma of the esophagus that was resistant to chemoradiation therapy. On a 28-day cycle, intratumoral injections of Ad5CMV-p53 (INGN 201; ADVEXIN) were administered on days 1 and 3 at four dose levels (10 x 10(11) particles to 25 x 10(11) particles) and treated for up to five cycles. Ten patients received a total of 26 cycles with no dose-limiting toxicity. Administration of multiple courses was feasible and well-tolerated. Local tumor responses revealed stable disease in nine cases and progressive disease in one case. The overall responses were stable in six and progressive in four cases. Using polymerase chain reaction (PCR) analyses, gene transfer and p53 specific transgene expression were detected in tumor biopsy tissue from all patients. mRNA levels of p53, p21 and MDM2 increased in all but one case. Three patients showed absence of disease upon repeat biopsies. Substantial improvement in swallowing was observed in one patient with stenotic lesions. Intratumoral injection of Ad5CMV-p53 is safe, feasible and biologically active when administered in multiple doses to patients with esophageal cancer. Observations from this study indicate that this treatment results in local antitumor effects in chemoradiation resistant esophageal squamous cell carcinoma.