Conversion surgery for metastatic gastric cancer at 2 years after initial diagnosis of cancer of unknown primary with metastasis of cervical lymph nodes and ovary: a case report.

BACKGROUND: Patients with stage IV gastric cancer have a poor prognosis despite improvements in intensive treatment regimens, including chemotherapy. Recently, conversion surgery has received much attention as it can provide long-term survival in stage IV gastric cancer patients who are responsive to chemotherapy. Herein, we describe the case of a patient who underwent conversion surgery for metastatic gastric cancer that was performed over 2 years after an initial diagnosis of cancer of unknown primary (CUP) with metastasis of the cervical lymph nodes and the ovary. CASE PRESENTATION: A 67-year-old woman with cervical lymphadenopathy was referred to our hospital. Computed tomography showed left cervical lymphadenopathy and bilateral ovarian enlargement. Endoscopic survey revealed no signs of malignancy in the upper or the lower gastrointestinal tract. Pathological findings after cervical lymphadenectomy revealed a signet-ring cell carcinoma and were suggestive of gastric cancer metastases. However, multiple evaluations yielded no evidence of gastric cancer and the patient was diagnosed with CUP. She was prescribed chemotherapy for gastric cancer and underwent bilateral oophorectomy after undergoing chemotherapy for 18 months. Pathologic analysis of oophorectomy tissue revealed findings identical to those seen in the cervical lymph nodes. At about 2 years after the initial diagnosis, an esophagogastroduodenoscopy revealed evidence of gastric cancer. We performed a distal gastrectomy with D2 lymphadenectomy. Her postoperative course was uneventful and she remains alive with no signs of disease recurrence at 3 months post-surgery. CONCLUSIONS: To the best of our knowledge, this is the first report describing successful conversion surgery for stage IV gastric cancer in a patient whose cancer was definitively diagnosed 2 years after an initial diagnosis of CUP.

Optimal timing for the resection of pulmonary metastases in patients with colorectal cancer.

This study aims to clarify the surgical treatment time of pulmonary metastasis in patients with colorectal cancer.Early relapse after resection of pulmonary metastasis is often encountered when the interval from the detection of pulmonary metastasis to pulmonary metastasectomy was short.In this retrospective analysis, data of patients with colorectal cancer who underwent surgical treatment of pulmonary metastasis at the Gunma Prefectural Cancer Center, Gunma, from April 2001 through September 2018 were evaluated. The patients were divided into 2 groups. We examined the interval period from the diagnosis of pulmonary metastasis to pulmonary metastasectomy. This period was divided into every 3 months, and the prognosis of each group was compared with clarify the appropriate timing of pulmonary metastasectomy.The primary endpoints were 5-year overall survival and recurrence-free survival rates.The most significant difference was observed when the cutoff value was 9 months (5-year recurrence-free survival 45.8% vs 85.6%, P < .01). No significant difference was found in any background factors between the 2 groups. Twenty-five patients (34.7%) experienced recurrence after pulmonary metastasectomy. The most common site of recurrence was the lung (48%). Among the 12 cases of recurrence of pulmonary metastasis, 11 cases belonged to the <9 months group. A multivariable survival analysis found that the interval period of <9 months was a significant predictor of recurrence.Our study suggests that clinical follow-up for 9 months prior pulmonary metastasectomy in colorectal patients would improve the prognosis.

Post-esophagectomy Adjuvant Chemotherapy Benefits Esophageal Cancer Patients.

BACKGROUND/AIM: Postoperative chemotherapy is an absolutely imperative treatment for advanced esophageal cancer patients, while preoperative chemotherapy is the standard therapy for clinical stage II/III esophageal squamous cell carcinoma (ESCC) in Japan. The aim of this study was to report the effect of postoperative chemotherapy on survival after esophagectomy due to thoracic esophageal squamous cell carcinoma. PATIENTS AND METHODS: One hundred thirteen consecutive patients with esophageal carcinoma who underwent esophagectomy were included. Several regiments were performed at various times. RESULTS: Adjuvant chemotherapy brought a significantly superior overall survival (p=0.002), although there was no significant difference in cancer-specific survival (p=0.054) for clinical stage II or stage III esophageal cancer patients. Depth of invasion (p=0.003), number of lymph node metastases (p=0.048), and venous invasion (p<0.001) were risk factors for recurrence in the adjuvant-chemotherapy group with positive lymph nodes. Additionally, a not well-differentiated type, lymphatic and venous invasions were risk factors for recurrence in the surgery-alone group without positive lymph nodes. CONCLUSION: Postoperative adjuvant chemotherapy contributes to the prognosis of clinical stage II or III esophageal cancer patients.

Association of Preoperative Nutritional Status with Prognosis in Patients with Esophageal Cancer Undergoing Salvage Esophagectomy.

BACKGROUND: To investigate whether malnutrition is associated with poor prognosis of patients who undergo salvage esophagectomy. We examined the association between the preoperative prognostic nutritional index (PNI) and prognosis of patients who undergo salvage esophagectomy. PATIENTS AND METHODS: We conducted a single-center retrospective study and reviewed hospital patient records for tumor characteristics and patient outcomes. Univariate and multivariate survival analyses were carried out using the Cox proportional hazards regression model. RESULTS: Thirty-two patients with esophageal squamous cell carcinoma (ESCC) who underwent salvage esophagectomy between 1998 and 2015 at our Institute were included in this study. Univariate analysis revealed that clinical response (p=0.045), preoperative PNI (p<0.001), pT (p=0.024), pN (p=0.004), and residual tumors (p<0.001) were significant prognostic factor for overall survival. Multivariate analysis using age and these five variables found no independent prognostic factors. Multivariate analysis using three preoperative variables (age, clinical response, and preoperative PNI) revealed that PNI was an independent prognostic preoperative factor for overall survival (p=0.005). CONCLUSION: Preoperative nutritional status is associated with the prognosis of patients undergoing salvage esophagectomy.

18F-FAMT PET Is Useful to Distinguish between Specific Uptake and Nonspecific Uptake Compared to 18F-Flourodeoxyglucose Position Emission Tomography in Esophageal Cancer Patients.

BACKGROUND: L-[3-18F]-α-methyltyrosine (18F-FAMT) solely accumulates in tumor cells via an amino acid transport system. This selective uptake pattern results in a very high tumor-to-background ratio, enabling clear delineation of the tumor. The purpose of the present study was to assess the significance of 18F-FAMT PET, which shows little nonspecific uptake compared to 18F-flourodeoxyglucose position emission tomography (FDG PET) in esophageal cancer patients. METHODOLOGY: PET-CT studies with 18F-FAMT and 18F-FDG were performed as part of pretreatment work-up in 82 patients with histologically confirmed esophageal cancer. We evaluated nonspecific uptakes of 18F-FDG and 18F-FAMT PET. RESULTS: The nonspecific uptake of 18F-FAMT PET was lower than that of 18F-FDG PET (p = 0.282). In the operation group, 26.1% demonstrated nonspecific uptake in 18F-FDG PET, whereas only 2.38% (1 case) demonstrated nonspecific uptake in 18F-FAMT PET (p = 0.433). In the inoperable group, 47.5% showed nonspecific uptake in 18F-FDG PET, whereas 5.0% showed nonspecific uptake in 18F-FAMT PET (p = 0.079). CONCLUSION: A crucial point for the diagnostic value of PET is distinguishing specific and nonspecific uptake. 18F-FAMT-PET is a very superior modality with regard to the lower rate of nonspecific uptake in esophageal cancer.

Clinical Significance of Salvage Esophagectomy for Patients with Esophageal Cancer and Factors of Influencing Long-term Survival.

BACKGROUND/AIM: Definitive chemoradiotherapy (CRT) without planned surgery has been recently widely used as a therapeutic option for locally advanced esophageal cancer. Salvage esophagectomy can offer the chance of prolonged survival for patients who have locoregional failure after definitive CRT, but many clinicians oppose the use of surgery due to the associated excessive morbidity and mortality. The aim of this study was to identify patients who are good candidates for salvage surgery by investigating factors influencing long-term survival. PATIENTS AND METHODS: A total of 40 patients underwent concurrent CRT or RT followed by esophagectomy for residual tumor or locoregional recurrence of esophageal squamous cell carcinoma without distant organ metastasis at the Department of General Surgical Science, Gunma University, Gunma, Japan, and were included in this study. As short-term outcomes after salvage esophagectomy, pulmonary and cardiovascular complications, anastomotic leakage, and chylothorax, and the length of postoperative stay were evaluated. Survival rates were calculated using the Kaplan-Meier method, and the Cox proportional hazards model was used for univariate and multivariate analyses of disease-specific survival. RESULTS: Postoperative complications were noted in 20 patients (50%), and pulmonary complications were the most common (25%), followed by anastomotic leakage (20%). There was also one case of in-hospital death, caused by multiple organ failure due to chylothorax. Univariate analysis revealed that sex, clinical residual tumor, CRT response, pathological tumor depth, and pathological residual tumor were significant factors affecting disease-specific survival (p=0.034, p=0.009, p=0.014, p=0.020, and p=0.026, respectively). Moreover, multivariate analysis demonstrated that clinical residual tumor was the only independent factor influencing disease-specific survival (p=0.036). Thirteen patients (32.5%) died from other illnesses after salvage surgery, 53.8% patients from pneumonia. CONCLUSION: Based on long-term survival, recurrence rather than residual tumor after definitive CRT was a favorable indicator for salvage esophagectomy. Not only management of postoperative morbidity and curative operation but, also long-term rigorous outpatient management, including respiratory rehabilitation to reduce pneumonia, is necessary.

High stathmin 1 expression is associated with poor prognosis and chemoradiation resistance in esophageal squamous cell carcinoma.

Stathmin 1 (STMN1) is a major cytosolic phosphoprotein regulating microtubule dynamics, thereby playing an important role in cancer progression and resistance to microtubule-binding anticancer agents. We assessed the prognostic significance of STMN1 expression and STMN1-associated resistance to docetaxel and radiation in esophageal squamous cell carcinoma (ESCC) patients. STMN1 expression was evaluated by immunohistochemistry in 172 surgical specimens. The association of STMN1 expression with chemoradiation resistance using docetaxel was examined by comparing expression in 15 biopsy specimens obtained before neoadjuvant therapy to histological grades of post-therapy surgically resected tumors. We also evaluated the effects of STMN1 on sensitivity to docetaxel and radiation in ESCC cell lines. High STMN1 immunoexpression was significantly associated with tumor depth, lymph node metastasis, lymphatic invasion and venous invasion. Survival rates were significantly lower in ESCC patients with high STMN1 expression than in those with low STMN1 expression. Multivariable analysis showed that high STMN1 expression was an independent factor for poor survival. High STMN1 expression was also associated with poor response to neoadjuvant chemoradiotherapy using docetaxel. Knockdown of STMN1 expression enhanced ESCC cell line sensitivity to docetaxel and radiation. STMN1 appears critical for ESCC invasiveness and predicts an unfavorable prognosis in ESCC.

TNFAIP3 overexpression is an independent factor for poor survival in esophageal squamous cell carcinoma.

Tumor necrosis factor α induced protein 3 (TNFAIP3) is a protein that is induced by TNF-mediated NF-κB activation and has a dual function in regulating NF-κB. TNFAIP3 is associated with inflammatory carcinogenesis in many cancer types. However, the clinical significance of TNFAIP3 expression and function in esophageal squamous cell carcinoma (ESCC) has not yet been reported. We examined 149 ESCC tissue specimens to determine the clinical significance of TNFAIP3 by immunohistochemistry. Western blot analyses were used to detect TNFAIP3 expression in TE-1, TE-8, TE-15 and KYSE-70 ESCC cells and in Het-1A, a non-cancerous esophageal cell line. TNFAIP3 protein knockdown was conducted using small-interfering RNA to investigate its impact on cell proliferation, migration and invasion. Significant correlations between TNFAIP3 expression and differentiation (P=0.04) among clinicopathological characteristics of ESCC patients were demonstrated, and high TNFAIP3 expression was associated with poor survival (P=0.02). Moreover, multivariate analysis result showed that high TNFAIP3 expression was an independent factor for poor survival (P=0.04). In vitro analysis showed high expression of TNFAIP3 protein in TE-15 cells and low expression in Het-1A cells. Furthermore, the proliferation, migration and invasion of TE-15 cells after TNFAIP3 suppression by siRNA were significantly reduced. These findings suggest that TNFAIP3 protein may be an independent prognostic marker for poor survival, and a promising target for ESCC therapy.

Utility of double endoscopic intraluminal operation for esophageal cancer.

OBJECTIVES: Endoscopic submucosal dissection (ESD) is a more difficult technique for esophageal cancer than for gastric cancer because the working space for esophageal ESD is small. Further, the difficulty level gradually increases depending on the size of the carcinoma. To overcome these difficulties, double endoscopic intraluminal operation (DEILO), which enables the resection of mucosal lesions using two fine endoscopes and monopolar shears, was reported previously. Here, we report the utility of DEILO for esophageal cancer. METHODS: A total of 26 esophageal cancer patients (19 men and seven women) with 26 lesions treated using DEILO between 2011 and 2014 at Gunma University Hospital were included. We evaluated the utility and safety of DEILO for early esophageal cancer. RESULTS: For all patients (100%), the DEILO procedure was performed successfully, and en bloc resection was achieved. The median operation time, postoperative hospital stay, and the longitudinal dimension of resected specimens were 123 min (range 45-236 min), 5 days, and 32 mm, respectively. Perioperative perforation, pneumothorax, and mediastinal emphysema were not recognized. Only one patient was diagnosed with a postoperative hemorrhage, but the bleeding was successfully treated by bleeding vessel coagulation. CONCLUSION: DEILO has good utility as a technique of ESD for early esophageal cancers. Additional improvement and advancement of the procedure will increase the indication of DEILO.

TGFBI Expression in Cancer Stromal Cells is Associated with Poor Prognosis and Hematogenous Recurrence in Esophageal Squamous Cell Carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is an important cause of cancer-related death worldwide. To improve prognoses in patients with ESCC, we evaluated the potential of transforming growth factor-beta-induced protein (TGFBI), which is overexpressed in ESCC, as a therapeutic candidate. METHODS: We examined the clinical significance of TBFBI in 102 ESCC samples using real-time RT-PCR. Immunohistochemical studies were conducted to examine the localization of TGFBI. Knockdown of TGFBI in cocultured fibroblasts was performed to determine the roles of TGFBI in migration and invasion. RESULTS: The level of TGFBI in ESCC tissues was higher than that in normal tissues. The high TGFBI expression group (n = 16) had higher TGFB1 expression and more frequent hematogenous recurrence than the low-expression group (n = 86). High TGFBI expression was an independent prognostic factor in patients with ESCC. TGFBI was mainly localized in stromal cells of ESCC. Moreover, suppression of TGFBI in fibroblasts inhibited the migration and invasion capacity of TE8 ESCC cells. CONCLUSIONS: High TGFBI expression in ESCC tissues could be a powerful biomarker of poor prognosis and hematogenous recurrence. TGFBI in stromal cells might be a promising molecular target for ESCC treatment.

Nuclear PROX1 is Associated with Hypoxia-Inducible Factor 1α Expression and Cancer Progression in Esophageal Squamous Cell Carcinoma.

BACKGROUND: Transcription factor prospero homeobox 1 (PROX1) has been identified as a master regulator of lymphangiogenesis associated with metastasis. Although PROX1 expression has been investigated in several cancers, its clinical significance remains controversial and needs further validation. In this study, we investigated the clinical and functional significance of PROX1 and PROX1 regulator hypoxia-inducible factor 1α (HIF1α) in esophageal squamous cell carcinoma (ESCC). METHODS: A total of 117 samples from ESCC patients were analyzed for PROX1, HIF1α, and E-cadherin expression by immunohistochemistry; correlation with clinicopathological characteristics was determined. PROX1 function was evaluated in PROX1 small interfering RNA (siRNA)-transfected human ESCC cells in vitro by assessing cell proliferation and migration. RESULTS: PROX1 expression was higher in ESCC than in normal tissues. Patients with higher PROX1 expression (n = 26) had increased nuclear accumulation of HIF1α (p = 0.004) and more advanced metastasis, both lymph node (N factor; p = 0.09) and hematogenous (M factor; p = 0.04), than those with lower PROX1 expression (n = 91). In addition, high PROX1 and HIF1α expression correlated with low levels of E-cadherin, an epithelial cell marker. Analysis of overall and cancer-specific survival indicated that elevated PROX1 expression was significantly correlated with poor prognosis (p = 0.0064). PROX1 downregulation in ESCC cells inhibited cellular proliferation and migration (p < 0.05). Hypoxia restored PROX1 levels that were reduced by PROX1-specific siRNA. CONCLUSION: Our data suggest that high expression of PROX1 in ESCC could be used as an indicator of poor prognosis, and that PROX1 is a promising candidate molecular target for ESCC treatment.

Usefulness of 18f-Fluorodeoxyglucose Positron Emission Tomography for Predicting the Pathological Response of Neoadjuvant Chemoradiotherapy for T4 Esophageal Squamous Cell Carcinoma.

BACKGROUND/AIMS: The purpose of this study is to assess the efficacy of 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) in predicting the pathological response of neoadjuvant chemoradiation (CRT) for clinically diagnosed T4 esophageal squamous cell carcinoma (SCC). METHODOLOGY: We examined 32 patients with T4 thoracic esophageal SCC who received neoadjuvant CRT followed by surgery. RESULTS: Pathological complete response (pCR) was achieved in 7 patients (21.9%). pCR was significant correlated with standardized uptake value (SUV) after neoadjuvant CRT (P = 0.034) and SUV decrease (%) (P = 0.030). The optimal cut-off values to predict pCR were 2.25 for SUV after neoadjuvant CRT and 79.3 for SUV decrease (%). Of note, no patients who did not reach both cut-off values achieved pCR. Conclusions: SUV after CRT and SUV decrease (%) in FDG-PET of the primary tumor are useful tools to predict pathological response of neoadjuvant CRT for T4 esophageal SCC.

L-[3-¹8F]-α-methyltyrosine uptake by lymph node metastasis is a predictor of complete response to CRT in esophageal cancer.

BACKGROUND/AIM: The amino acid positron emission tomography (PET) tracer [(18)F]-3-fluoro-alpha-methyltyrosine ((18)F-FAMT) is known to be highly specific for malignancies. We evaluated the accumulation of (18)F-FDG or (18)F-FAMT in lymph nodes (LN) prior to definitive chemoradiotherapy (CRT) for esophageal cancer. PATIENTS AND METHODS: We retrospectively reviewed 30 patients with esophageal squamous cell carcinoma. All patients received definitive CRT. The relationship between the accumulation of (18)F-FDG PET or (18)F-FAMT PET in LNs prior to CRT and clinical outcomes was assessed. RESULTS: A correlation was observed between LNs in which most of (18)F-FAMT was accumulated and complete response (CR) rate, but was not for (18)F-FDG. Additionally, for (18)F-FAMT, the CR rate was significantly higher in the LN accumulated lesion ≤ 1 group than in the LN accumulated lesion >2 group. DISCUSSION: To predict the outcome of definitive CRT in patients with esophageal cancer, it is important to evaluate the LN status.

Use of pre-treatment 18F-FAMT PET to predict patient survival in squamous cell carcinoma of the esophagus treated by curative surgery.

BACKGROUND: [18F]-3-fluoro-alpha-methyl tyrosine (18F-FAMT) as an amino acid tracer in positron emission tomography (PET) has been widely investigated in several tumor types. Herein we investigated the clinical significance of 18F-FAMT PET uptake as a prognostic marker together in our updated data of patients with esophageal cancer. PATIENTS AND METHODS: We retrospectively assessed the treatment outcomes of 42 patients with histologically-confirmed esophageal cancer. The survival rate was analyzed using the median peak standardized uptake value (SUV) with 2.2 as the cut-off value. RESULTS: FAMT uptakes were significantly correlated with factors reflecting tumor progression. Moreover, a significant correlation was observed between FAMT uptake and disease-free survival (p=0.023). Moreover, on evaluation of individual lymph node groups, the specificity and positive predictive value were significantly higher for 18F-FAMT-PET than for 18F-FDG-PET and computed tomography (CT). CONCLUSION: 18F-FAMT is an important pre-treatment diagnostic modality and its accumulation is a good predictor of disease-free survival (DFS) in patients with operable esophageal cancer.

L-[3-18F]-α-methyltyrosine accumulation as a definitive chemoradiotherapy response predictor in patients with esophageal cancer.

AIMS: L-[3-(18)F]-α-Methyltyrosine ((18)F-FAMT) has high specificity for malignant tumors on positron emission tomography (PET), and its role and potential usefulness has been previously investigated in operable esophageal carcinoma. We aimed to assess the ability of (18)F-FAMT PET to predict the response of esophageal cancer to definitive chemoradiotherapy. PATIENTS AND METHODS: We retrospectively reviewed 40 patients with esophageal cancer imaged with (18)F-FAMT PET. The relationship between (18)F-FAMT PET uptake before chemoradiotherapy and clinical outcomes was assessed. RESULTS: The primary tumor was visualized in 95% patients. (18)F-FAMT uptake was significantly positively correlated with lymph node metastasis. The low-(18)F-FAMT accumulation group had significantly higher complete response (CR) rates than did the high-accumulation group. The addition of a lymph node metastasis category with low (18)F-FAMT uptake provides a more precise predictor of CR. CONCLUSION: (18)F-FAMT uptake prior to treatment is a good predictor of CR rate after CRT for esophageal cancer.

[Re-thoracotomy for intrathoracic complications after esophagectomy for esophageal cancer].

We reviewed the indications for re-thoracotomy after esophagectomy for esophageal cancer. Hemothorax, chylothorax, tracheobronchial injury (fistula), pneumothorax, and pyothorax were the main causes of re-thoracotomy. Indications for emergency thoracotomy were as follows. 1)Hemothorax:bleeding through the chest drain continuing at >100 ml/hour for ≥5 hour, or in cases when normal blood pressure cannot be maintained without blood transfusion. 2)Chylothorax:in cases with ≥1.5 l/day of chyle drainage for >5 days under conservative treatment. Healing is not seen for 14 days after conservative treatment. Nutritional status of the patient has worsened. 3)Tracheobronchial injury:at 1st respiration state should be understood. After we maintain the patient's airway, fistula is treated by closure and plombage with omentum or muscle flap. Appropriate diagnosis and timing are important for re-thoracotomy for complications after esophagectomy.

Management of Barrett's esophageal carcinoma.

Barrett's esophagus (BE) is the premalignant lesion from which esophageal adenocarcinoma near the esophagogastric junction arises. The management of BE and the treatment of Barrett's esophageal adenocarcinoma (BEA) are important clinical issues in Europe and the United States. As the Helicobacter pylori infection rate in Japan is decreasing in the younger population, the incidence of BE and adenocarcinoma arising from BE may start increasing. Thus, we review the current status of BEA and its management. Magnifying endoscopy with narrow-band imaging is important for diagnosing dysplasia arising from BE. In Japan, adenocarcinoma arising from BE is managed the same way as squamous cell carcinoma in the same location. Strategies to prevent BEA may include medication such as non-steroidal anti-inflammatory drugs and proton pump inhibitors, and anti-reflux surgery. Understanding the pathophysiology of BE will help to reduce the incidence of BEA.