Evaluation and treatment results of trimodality therapy for advanced esophageal squamous cell carcinoma.

OBJECTIVES: The prognosis for highly advanced esophageal squamous cell carcinoma (ESCC) remains poor, and there is currently no standard treatment. The purpose of this study was to examine the benefits of trimodality therapy [chemoradiation plus surgery, (CRT + S)] by evaluating the surgical outcomes of patients with ESCC in Keiyukai Sapporo Hospital, Japan. We assessed the preoperative and postoperative adverse events, treatment effects of preoperative CRT, metastatic diagnosis of the dissected lymph nodes, and survival. PATIENTS AND METHODS: Between 2012 and 2018, 148 patients with highly advanced ESCC who underwent preoperative CRT + S were analyzed for diagnosis and staging, preoperative complications, clinical and histopathological effects of CRT in the resected specimens, survival rates, and recurrences. RESULTS: The grade 3 and higher complications of preoperative CRT were neutropenia in 3 cases and thrombocytopenia in 1 case. Among the postoperative complications, there were 2 cases (1.4%) of direct surgical death, only tracheobronchial bleeding and liver failure. Using the 11th edition of the classification of esophageal cancer by the Japanese Esophageal Society, 60 patients (40.5%) were classified as grade 3 (negative for cancer cells, pathological complete response). However, 20 of them (33.3%) had metastatic tumor cells in the lymph nodes. The overall 5-year survival rate was 58.5%. Including references to the pathological findings and recurrence patterns, there is no effective diagnostic method for selecting the subsequent approach based on the effectiveness of CRT. CONCLUSION: Planned surgery following CRT was the only solution for achieving better treatment results. CRT + S is a promising treatment with low direct surgical mortality.

Larynx-preserving hybrid surgery with endoscopic laryngopharyngeal surgery and open surgery for cervical esophageal cancer invading pharynx.

Larynx preserving hybrid surgery with endoscopic laryngopharyngeal surgery and open surgery (HELPS) was created for resectable cervical esophageal cancer (CEC) invading the hypopharynx. This study aimed to verify the effectiveness and to evaluate the feasibility of the new HELPS treatment method. Between 2014 and 2018, 19 patients with CEC invading the hypopharynx were treated with HELPS. The postoperative complications and survival rates were reviewed. Postoperative recurrent laryngeal nerve paralysis occurred in four patients. All patients consumed food orally without a feeding tube at the time of the discharge. The median follow-up period was 27 months. The 2- and 3-year overall survival rates were 94.7 and 71.5%, respectively. HELPS, a new surgical treatment method that utilizes endoscopic surgery, is effective, feasible and beneficial for preserving the larynx in patients with CEC even if the tumor invaded the pharynx.

Impact of Preoperative Skeletal Muscle Mass and Nutritional Status on Short-and Long-Term Outcomes After Esophagectomy for Esophageal Cancer: A Retrospective Observational Study : Impact of Psoas Muscle Mass and Body Mass on Esophagectomy.

BACKGROUND: Preoperative muscle volume and body mass index (BMI) are associated with postoperative outcomes. Because esophagectomy for esophageal cancer (EC) is associated with high morbidity and because EC has a poor prognosis, this study investigated the association of preoperative skeletal muscle mass and nutritional status with postoperative outcomes. METHODS: The study analyzed 483 patients who underwent esophagectomy from 2009 to 2012. The cross-sectional area of the psoas muscle index (PMI) was measured at the third lumbar vertebral level using computed tomography. Clavien-Dindo classifications were used to analyze postoperative complications. Because skeletal muscle mass varies according to sex, all analyses were performed accordingly (390 males, 93 females). RESULTS: For male patients, BMI was a significant multivariate factor, and PMI, a univariate factor, predicted postoperative complications and overall survival (OS). Using a preoperative nutritional and muscular (PNM) score derived from BMI and PMI results (patients were allocated 1 point if their BMI was < 18.5 kg/m2 and 1 point if their PMI was < 600 mm2/m2, for a possible maximum total of 2 points), male patients were categorized as high risk (score 2), moderate risk (score 1), or low risk (score 0). In the low-risk group, anastomotic leakage was significantly less (p = 0.01), and the 3-year OS was significantly better (p < 0.01). On the other hand, in female patients, neither BMI nor PMI was a significant factor for postoperative outcomes. CONCLUSIONS: For male patients, the PNM score is a promising tool for predicting postoperative outcomes and identifying patients requiring preoperative nutritional intervention and rehabilitation.

Prognosis and prognostic factors of esophageal spindle cell carcinoma treated by esophagectomy: a retrospective single-institution analysis.

BACKGROUND: Esophageal spindle cell carcinoma (ESpCC) is a malignant tumor composed of sarcomatous components. ESpCC is treated as a squamous cell carcinoma. However, because ESpCC is a rare tumor, little is known regarding its prognosis. This study aimed to analyze patients with ESpCC who were surgically treated at our hospital, determine the validity of surgery, and identify factors that indicate a prognosis. METHODS: Treatment characteristics, overall survival (OS), and recurrence-free survival (RFS) of 28 patients with ESpCC who underwent surgery at our hospital between 1990 and 2016 were assessed. Furthermore, factors associated with OS and RFS were analyzed. RESULTS: Subtotal esophagectomy with 3-field lymph node dissection and lower esophagectomy with 2-field lymph node dissection were performed in 25 and 3 patients, respectively. Chemotherapy was administered as preoperative therapy to two patients. Postoperative therapy, comprising radiotherapy and chemotherapy, was administered to three and nine patients, respectively. The 3- and 5-year RFS were 66.4% and 61.6% and the 3- and 5-year OS were 73% and 61.9%, respectively. Macroscopic type was identified as a prognostic factor. In terms of OS, prognosis was significantly worse in ulcerative-type ESpCC than in the polypoid type. CONCLUSION: The 5-year OS of ESpCC mainly treated with surgical therapy was 61.9%. However, prognosis was poor in some patients with ulcerative-type ESpCC according to macroscopic type. In the future, it will be necessary to accumulate more cases and investigate therapeutic strategies added to surgery to improve prognosis.

A randomized controlled trial of endoscopic steroid injection for prophylaxis of esophageal stenoses after extensive endoscopic submucosal dissection.

BACKGROUND: Esophageal stenosis following endoscopic submucosal dissection (ESD) is a serious adverse event that makes subsequent management more difficult. METHODS: This parallel, randomized, controlled, open-label study was designed to examine whether local steroid injection is an effective prophylactic treatment for esophageal stenoses following extensive ESD. This single center trial was conducted at the Keiyukai Hospital, a tertiary care center for gastrointestinal disease in Japan [University Hospital Medical Network Clinical Trial Registry (UMIN-CTR) on 15 September 2011 (UMIN000006327)]. Thirty-two patients with mucosal defects involving ≥75% of the esophageal circumference were randomized to receive a single dose of triamcinolone acetonide injections (n = 16) or be treated conventionally (n = 16). The primary outcome was the frequency of stricture requiring endoscopic dilatation; the surrogate primary endpoint was the number of dilatation sessions needed. Secondary outcomes included adverse event rates, the minimum diameter of the stenotic area and the duration of the course of dilatation treatments. RESULTS: The frequency of stricture was not significantly different between the groups because of insufficient statistical power, but the number of dilatation sessions required was significantly less in the steroid group (6.1 sessions [95% confidence interval, CI 2.8-9.4] versus 12.5 [95% CI 7.1-17.9] sessions in the control group; P = 0.04). The perforation rate was similar in both groups. The minimum diameter of stenotic lumens was significantly greater in the treatment group than controls (11.0 mm versus 7.1 mm, respectively; P = 0.01). The perforation rate was not significantly different between the groups (1.0% versus 0.5% in the treatment and control group, respectively). Steroid injection was effective in cases of mucosal defects encompassing the entire esophageal circumference. CONCLUSIONS: Prophylactic endoscopic steroid injection appears to be a safe means of relieving the severity of esophageal stenoses following extensive ESD.

Clinicopathological and molecular characteristics of serrated lesions in Japanese elderly patients.

BACKGROUND: The population in Japan is aging more rapidly than in any other country. However, no studies have determined the characteristics of the large population of elderly patients with colorectal tumors. Therefore, we examined the clinicopathological and molecular features of these tumors in elderly patients. METHODS: In total, 1,627 colorectal tumors (393 serrated lesions, 277 non-serrated adenomas and 957 colorectal cancers) were acquired from patients. Tumor specimens were analyzed for BRAF and KRAS mutations, CpG island methylator phenotype-specific promoters (CACNA1G, CDKN2A, IGF2 and RUNX3), IGFBP7, MGMT, MLH1 and RASSF2 methylation, microsatellite instability (MSI) and microRNA- 31 (miR-31). RESULTS: The frequency of elderly patients (aged ≥75 years) with sessile serrated adenomas (SSAs) with cytological dysplasia was higher than that of those with other serrated lesions and non-serrated adenomas (p < 0.0001). In elderly patients, all SSAs were located in the proximal colon (particularly the cecum to ascending colon). High miR-31 expression, MLH1 methylation and MSI-high status were more frequently detected in SSAs from elderly patients than in those from non-elderly patients. In contrast, no significant differences were found between older age of onset and high-grade dysplasia for traditional serrated adenomas or non-serrated adenomas in any of these molecular alterations. CONCLUSION: In elderly patients, all SSAs were located in the proximal colon. Furthermore, cytological dysplasia and molecular alterations were more frequently detected in elderly patients with SSAs than in non-elderly patients. Thus, careful colonoscopic examinations of the proximal colon are necessary for elderly patients because SSAs in those patients may exhibit malignant potential.

Association of microRNA-31 with BRAF mutation, colorectal cancer survival and serrated pathway.

BRAF is an important gene in colorectal cancers (CRCs) that is associated with molecular characterization and resistance to targeted therapy. Although microRNAs (miRNAs) are useful biomarkers of various cancers, the association between miRNA and BRAF in CRCs is undefined. Therefore, this study was conducted to identify a relationship between specific miRNA molecules and BRAF mutation in CRCs and serrated lesions. miRNA array was used for the measurement of 760 miRNAs in 29 CRCs. To assess the identified miRNAs, quantitative reverse transcription-PCR was performed on 721 CRCs, 381 serrated lesions and 251 non-serrated adenomas. Moreover, proliferation and invasion assays were conducted using cell lines. miRNA array analysis revealed that microRNA-31 (miR-31)-5p was the most up-regulated miRNA in CRCs with mutated BRAF (V600E) compared with CRCs possessing wild-type BRAF (including cases with KRAS mutation). High miR-31 expression was associated with BRAF and KRAS mutations and proximal location (P < 0.0001). High miR-31 expression was related to cancer-specific mortality [multivariate hazard ratio = 2.06, 95% confidence interval: 1.36-3.09, P = 0.0008]. Functional analysis demonstrated that miR-31 inhibitor decreased cell invasion and proliferation. With regard to serrated lesions, high miR-31 expression was less frequently detected in hyperplastic polyps compared with other serrated lesions. In conclusion, associations were identified between miR-31, BRAF and prognosis in CRC. Transfection of miR-31 inhibitor had an antitumour effect. Thus, miR-31 may be a promising diagnostic biomarker and therapeutic target in colon cancers. Moreover, high miR-31 expression in serrated lesions suggested that miR-31 may be a key molecule in serrated pathway.

Factors associated with risk for colorectal cancer recurrence after endoscopic resection of T1 tumors.

BACKGROUND & AIMS: More information is needed on the long-term outcomes of patients who undergo endoscopic resection of colorectal tumors. We evaluated recurrence of colorectal cancer (CRC) after endoscopic resection or a combination of endoscopic research and surgery for T1 colorectal tumors. METHODS: We conducted a retrospective study of 389 patients with T1 CRC treated by endoscopic resection from January 1989 to December 2008 in Sapporo, Japan. We compared outcomes between patients who underwent subsequent surgery (ER + SURG, n = 205) and those who did not (ER only, n = 184) and statistically adjusted baseline differences between the groups according to the propensity scores. RESULTS: There was almost no risk of cancer recurrence among patients without indications for surgery recommended by the Japanese Society for Cancer of the Colon and Rectum (these indications include tumors with vertical margins, deep submucosal invasion, lymphatic or venous invasion, poor differentiation, or high-grade budding). Among patients with indications for surgery, the cumulative risks of recurrence (CRRs) were 3.7% in the ER + SURG group and 20.1% in the ER only group (P = .001). However, the patients with only deep submucosal invasion had a low CRR, even without surgery (2.3% in the ER + SURG group and 3.4% in the ER only groups, P = .867). In contrast, patients with indications for surgery other than deep submucosal invasion (high-risk patients) had much better outcomes when they also underwent surgery (CRRs: 5.8% in the ER + SURG group vs 58.0% in the ER only group, P < .001). CONCLUSIONS: On the basis of a retrospective study of patients who underwent endoscopic resection for T1 CRC, those with tumors with only submucosal invasion are at low risk for cancer recurrence. However, patients with other high-risk tumor features have greater risks for cancer recurrence and benefit from subsequent surgery.

Diagnostic value of ¹8F-FDG PET/CT for lymph node metastasis of esophageal squamous cell carcinoma.

PURPOSE: This study investigated the diagnostic accuracy of hybrid positron-emission tomography/computed tomography (PET/CT) for lymph node (LN) metastasis of esophageal cancer. We also investigated the correlation between the size of metastatic nests and the detection by PET/CT. METHODS: Two hundred and fifty-eight patients with esophageal squamous cell carcinoma who underwent esophagectomy with two- or three-field radical lymphadenectomy were analyzed retrospectively. We compared the diagnosis of preoperative PET/CT to the postoperative histopathological examination by each anatomical field (n = 1,231) in all 258 patients. The metastatic LNs resected from PET/CT positive fields were classified as belonging to the PET/CT-N-positive group (n = 229) and those from negative fields as belonging to the PET/CT-N-negative group (n = 352). The cross-sectional areas of metastatic nests were measured in each metastatic LN. RESULTS: Of the 1,231 fields, 275 (22 %) were positive for metastasis, including 581 LNs from 408 regional LN stations. The sensitivity and specificity of PET/CT examined by each anatomical field were 25.8 and 97.8 %, respectively. The median area of metastatic nests was 17.7 mm2 in the PET/CT-N-positive group, and 7.7 mm2 in the PET/CT-N-negative group (p < 0.001). CONCLUSIONS: A significant correlation was suggested between the nest size and detection by PET/CT. Because of its low sensitivity, PET/CT alone is insufficient to determine the surgical procedures, especially when considering reduction surgery.

Vascular anatomical study of persistent descending mesocolon in patients undergoing laparoscopic surgery for colorectal cancer.

INTRODUCTION: Persistent descending mesocolon (PDM) is a rare congenital atypia of fixation of the descending colon, and currently, very few detailed studies exist on its vascular anatomy. This study was conducted to evaluate the features of the vascular anatomy of PDM to help avoid intraoperative lethal injury and subsequent postoperative complications in laparoscopic colorectal surgery. METHODS: We retrospectively analyzed the data of 534 patients who underwent laparoscopic left-sided colorectal surgery. PDM was diagnosed using preoperative axial computed tomography (CT) view. The vascular anatomical features were compared between PDM and non-PDM cases based on three-dimensional (3D)-CT angiography findings. Additionally, the perioperative short-term outcomes of laparoscopic surgery in the 534 patients were also compared between PDM and non-PDM cases. RESULTS: Of the total 534 patients, 13 patients (2.4%) presented with PDM. No branching pattern of the inferior mesenteric artery (IMA) specific to PDM was found. In the running direction of the IMA and sigmoidal colic artery (SA), the midline-shift of IMA and the right-shift of SA were significantly more in PDM than in non-PDM cases, respectively (38.5% vs. 2.5%, P ≤ .0001; 61.5% vs. 4.6%, P ≤ .0001). The perioperative short-term outcomes of laparoscopic surgery in the 534 patients were similar between PDM and non-PDM cases. CONCLUSION: Because changes in the direction of the vascular running are often observed due to adhesions and shortening of the mesentery in PDM cases, performing a detailed preoperative evaluation of vascular anatomy using imaging modalities such as 3D-CT angiography is important.

Characterization of an Opa interacting protein 5 involved in lung and esophageal carcinogenesis.

To identify potential molecular targets for diagnosis, treatment and/or prevention of lung and esophageal carcinomas, we screened for genes that were overexpressed in tumors through gene expression analyses of 120 lung cancers and 19 esophageal squamous-cell carcinomas using a cDNA microarray consisting of 27,648 cDNA or expressed sequence tags. In this process, we identified a gene, Opa interacting protein 5 (OIP5), to be highly transactivated in the majority of lung and esophageal cancers. Immunohistochemical staining using 336 archived non-small cell lung cancers and 305 esophageal squamous-cell carcinomas specimens demonstrated that OIP5 expression was significantly associated with poor prognosis of lung and esophageal cancer patients (P = 0.0053 and 0.0168, respectively), and multivariate analysis confirmed its independent prognostic value for non-small cell lung cancers (P = 0.0112). Suppression of OIP5 expression with siRNA effectively suppressed the growth of cancer cells, whereas the exogenous expression of OIP5 enhanced the growth of cancer cells. In addition, OIP5 protein is likely to be stabilized through its interaction with Raf1. OIP5 is a promising target for developing new prognostic biomarkers and anti-cancer drugs.

Endoscopic resection as an independent predictive factor of local control in patients with T1bN0M0 esophageal squamous cell carcinoma treated with chemoradiotherapy: a retrospective study.

BACKGROUND: Although chemoradiotherapy (CRT) is one of the curative treatments for thoracic esophageal squamous cell carcinoma (ESCC) with submucosal invasion, the risk of local recurrence after CRT remains a clinical problem. This retrospective study aimed to analyze the predictive factors for local recurrence after CRT. METHODS: Ninety-one patients with clinical or pathological (c/p) T1bN0M0 thoracic ESCC who underwent CRT from 2004 to 2017 in our institution were analyzed retrospectively. Sixty-three patients were diagnosed with pathological T1b after undergoing initial endoscopic resection (ER) and treated with additional CRT; meanwhile, 28 patients were clinically diagnosed with T1b and underwent definitive CRT. We investigated the predictors of disease-specific survival (DSS) and local recurrence-free survival (LRFS) by performing univariate and multivariate analyses. RESULTS: The median observation period was 59.8 months. The 5-year DSS and LRFS rates were 84.3% (95% confidence interval [CI]: 76.1-92.5) and 87.1% (95% CI: 79.1-95.1), respectively. The multivariate analysis revealed no significant predictors associated with DSS. On the contrary, ER (hazard ratio [HR]: 0.11, 95% CI: 0.02-0.48, p = 0.003) and tumor length (HR: 6.78, 95% CI: 1.28-36.05, p = 0.025) were recognized as independent predictive factors for LRFS. During follow-up, recurrence was observed in 18 patients (19.8%). With regard to the patterns of relapse, local recurrence was the most common in 11 patients, and salvage ER was performed in 9 of 11 patients. CONCLUSIONS: ER and tumor length were independent predictive factors for LRFS. Our study suggested that performance of ER prior to CRT improved the local control in patients with c/p T1bN0M0 ESCC. In addition, most of the patients who experienced local recurrence were treated with salvage ER, which contributed to preserving the organs.

Mucosal lymphatic vessels of the esophagus distant from the cancer margin: morphometrical analysis using 27 surgically removed specimens of squamous cell carcinoma located in the upper or middle thoracic esophagus.

PURPOSE: To clarify the configuration of the esophageal mucosal lymphatics distant from cancer using D2-40 immunohistochemistry. METHODS: D2-40 immunohistochemistry for human lymphatic epithelium was performed at sites about 10 cm anal from the pathologically examined margin of upper or mid- thoracic squamous cell carcinoma (27 patients). We measured the entire length of mucosal lymphatic vessels within a x10 objective field (1.2 mm along the muscularis mucosae). RESULTS: The present morphometrical study demonstrated significant individual differences in the amount of mucosal lymphatic vessels, within a range of more than 10-fold (8.4 mm-0.8 mm within an objective field). However, the difference in length of the mucosal lymphatic epithelium did not correlate with either N-factor, T-factor including cancer depth or prognosis. CONCLUSION: A higher density of pre-existing mucosal lymphatic vessels may not always be correlated with larger numbers of nodal metastases. Lymphatic proliferation or dilation induced by cancer seems to occur irrespective of whether pre-existing vessels are rich or sparse.

Involvement of epithelial cell transforming sequence-2 oncoantigen in lung and esophageal cancer progression.

PURPOSE: This study aims to isolate potential molecular targets for diagnosis, treatment, and/or prevention of lung and esophageal carcinomas. EXPERIMENTAL DESIGN: We screened for genes that were frequently overexpressed in the tumors through gene expression profile analyses of 101 lung cancers and 19 esophageal squamous cell carcinomas (ESCC) by cDNA microarray consisting of 27,648 genes or expressed sequence tags. In this process, we identified epithelial cell transforming sequence 2 (ECT2) as a candidate. Tumor tissue microarray was applied to examine the expression of ECT2 protein in 242 archived non-small-cell lung cancers (NSCLC) and 240 ESCC specimens and to investigate its prognostic value. A role of ECT2 in lung and esophageal cancer cell growth and/or survival was examined by small interfering RNA experiments. Cellular invasive activity of ECT2 in mammalian cells was examined using Matrigel assays. RESULTS: Northern blot and immunohistochemical analyses detected expression of ECT2 only in testis among 23 normal tissues. Immunohistochemical staining showed that a high level of ECT2 expression was associated with poor prognosis for patients with NSCLC (P = 0.0004) as well as ESCC (P = 0.0088). Multivariate analysis indicated it to be an independent prognostic factor for NSCLC (P = 0.0005). Knockdown of ECT2 expression by small interfering RNAs effectively suppressed lung and esophageal cancer cell growth. In addition, induction of exogenous expression of ECT2 in mammalian cells promoted cellular invasive activity. CONCLUSIONS: ECT2 cancer-testis antigen is likely to be a prognostic biomarker in clinic and a potential therapeutic target for the development of anticancer drugs and cancer vaccines for lung and esophageal cancers.

A novel method, digital genome scanning detects KRAS gene amplification in gastric cancers: involvement of overexpressed wild-type KRAS in downstream signaling and cancer cell growth.

BACKGROUND: Gastric cancer is the third most common malignancy affecting the general population worldwide. Aberrant activation of KRAS is a key factor in the development of many types of tumor, however, oncogenic mutations of KRAS are infrequent in gastric cancer. We have developed a novel quantitative method of analysis of DNA copy number, termed digital genome scanning (DGS), which is based on the enumeration of short restriction fragments, and does not involve PCR or hybridization. In the current study, we used DGS to survey copy-number alterations in gastric cancer cells. METHODS: DGS of gastric cancer cell lines was performed using the sequences of 5000 to 15000 restriction fragments. We screened 20 gastric cancer cell lines and 86 primary gastric tumors for KRAS amplification by quantitative PCR, and investigated KRAS amplification at the DNA, mRNA and protein levels by mutational analysis, real-time PCR, immunoblot analysis, GTP-RAS pull-down assay and immunohistochemical analysis. The effect of KRAS knock-down on the activation of p44/42 MAP kinase and AKT and on cell growth were examined by immunoblot and colorimetric assay, respectively. RESULTS: DGS analysis of the HSC45 gastric cancer cell line revealed the amplification of a 500-kb region on chromosome 12p12.1, which contains the KRAS gene locus. Amplification of the KRAS locus was detected in 15% (3/20) of gastric cancer cell lines (8-18-fold amplification) and 4.7% (4/86) of primary gastric tumors (8-50-fold amplification). KRAS mutations were identified in two of the three cell lines in which KRAS was amplified, but were not detected in any of the primary tumors. Overexpression of KRAS protein correlated directly with increased KRAS copy number. The level of GTP-bound KRAS was elevated following serum stimulation in cells with amplified wild-type KRAS, but not in cells with amplified mutant KRAS. Knock-down of KRAS in gastric cancer cells that carried amplified wild-type KRAS resulted in the inhibition of cell growth and suppression of p44/42 MAP kinase and AKT activity. CONCLUSION: Our study highlights the utility of DGS for identification of copy-number alterations. Using DGS, we identified KRAS as a gene that is amplified in human gastric cancer. We demonstrated that gene amplification likely forms the molecular basis of overactivation of KRAS in gastric cancer. Additional studies using a larger cohort of gastric cancer specimens are required to determine the diagnostic and therapeutic implications of KRAS amplification and overexpression.

Can hybrid FDG-PET/CT detect subclinical lymph node metastasis of esophageal cancer appropriately and contribute to radiation treatment planning? A comparison of image-based and pathological findings.

BACKGROUND: We aimed to determine the appropriateness of adding 18F-fluorodeoxyglucose (FDG)-positronemission tomography (PET) to computed tomography (CT) and other pre-existing diagnostic imaging modalities for detecting subclinical lymph node metastasis of esophageal cancer, by comparing images from these modalities with the results of histopathological analysis. METHODS: Twenty patients who received radical surgery for squamous cell carcinoma of the esophagus were examined by PET-CT, and endoscopic ultrasound (EUS) examination before surgery. Based on these diagnostic modalities, the clinical target volume (CTV) was set as the gross tumor volume (GTV) plus a 1-cm margin. Histopathological diagnosis was performed in all patients immediately after resection. RESULTS: Fifty-three (3.0%) of 1764 nodes in the 20 patients were histopathologically positive for cancer cells. The CTV was not adequate to cover these histopathologically detected positive lymph nodes in 8 of 20 patients on CT, 5 of 20 on CT+EUS, 7 of 20 on PET-CT, and 5 of 20 on PET-CT+EUS. CONCLUSION: The detection rate of subclinical lymph node metastasis did not improve with the use of PET-CT, for either the cervical and supraclavicular, mediastinal, or abdominal regions. It is not recommended to use FDG-PET or PET-CT alone as a diagnostic tool to determine CTV if pathologically involved lymphatic regions are to be included in the CTV in the treatment protocol. The accuracy of PET-CT must be further improved in order to better detect positive nodes and improve the definition of the CTV.

The value of narrow band imaging for early detection of laryngeal cancer.

We evaluate the value of laryngoscopy using narrow band imaging (NBI) system in the diagnosis of precancerous and cancerous laryngeal lesions. Thirty-four patients were suspected of having a total of 35 precancerous or cancerous laryngeal lesions among patients receiving conventional white-light laryngoscopy. All 34 patients underwent laryngoscopy with NBI system to determine whether those lesions were malignant before biopsy procedure. The diagnostic criteria of malignancy by NBI view was the presence of demarcated brownish area with scattered brown spots in the lesion. Histopathologic results were retrospectively compared with results of determination of malignancy made by NBI view. Of the 23 lesions histopathologically proved to be malignancies, 21 lesions were classified as malignant by NBI view. Sensitivity and specificity for the diagnosis of malignancy by means of NBI view compared with histopathologic results were 91.3% for sensitivity and 91.6% for specificity. NBI endoscopy seems to be a very promising diagnostic tool in the diagnosis of laryngeal malignant disease.

Dikkopf-1 as a novel serologic and prognostic biomarker for lung and esophageal carcinomas.

Gene expression profile analysis of lung and esophageal carcinomas revealed that Dikkopf-1 (DKK1) was highly transactivated in the great majority of lung cancers and esophageal squamous cell carcinomas (ESCC). Immunohistochemical staining using tumor tissue microarrays consisting of 279 archived non-small cell lung cancers (NSCLC) and 280 ESCC specimens showed that a high level of DKK1 expression was associated with poor prognosis of patients with NSCLC as well as ESCC, and multivariate analysis confirmed its independent prognostic value for NSCLC. In addition, we identified that exogenous expression of DKK1 increased the migratory activity of mammalian cells, suggesting that DKK1 may play a significant role in progression of human cancer. We established an ELISA system to measure serum levels of DKK1 and found that serum DKK1 levels were significantly higher in lung and esophageal cancer patients than in healthy controls. The proportion of the DKK1-positive cases was 126 of 180 (70.0%) NSCLC, 59 of 85 (69.4%) SCLC, and 51 of 81 (63.0%) ESCC patients, whereas only 10 of 207 (4.8%) healthy volunteers were falsely diagnosed as positive. A combined ELISA assays for both DKK1 and carcinoembryonic antigen increased sensitivity and classified 82.2% of the NSCLC patients as positive whereas only 7.7% of healthy volunteers were falsely diagnosed to be positive. The use of both DKK1 and ProGRP increased sensitivity to detect SCLCs up to 89.4%, whereas false-positive rate in healthy donors was only 6.3%. Our data imply that DKK1 should be useful as a novel diagnostic/prognostic biomarker in clinic and probably as a therapeutic target for lung and esophageal cancer.

Lymph Node Metastasis From Gastroesophageal Cancer Successfully Treated by Nivolumab: A Case Report of a Young Patient.

Background: Immuno-oncology is a novel target of cancer therapy. Nivolumab is a monoclonal anti-programed death-1 antibody recently used to treat patients with chemotherapy-resistant gastric and gastroesophageal cancer. Although the disease control rate is reported to be very high, few cases demonstrate a complete response. Case Presentation: A 25-year-old man diagnosed with gastroesophageal cancer was treated with chemotherapy followed by surgical resection. Pathological diagnosis was poorly differentiated adenocarcinoma with distant lymph node metastasis. Residual lymph node metastasis was treated with nivolumab monotherapy, resulting in complete disappearance. No recurrence has been observed for 2 years since discontinuation of nivolumab. This rare case was additionally subjected to pathological and genetic analysis, suggesting that a high tumor mutation burden (10.7 mutations/Mb) might be associated with sensitivity to nivolumab. Summary: We reported a case of advanced gastroesophageal junction cancer with distal lymph node metastasis that was successfully treated with chemotherapy, surgical resection, and nivolumab therapy. An aggressive search for biomarkers implying benefit effects of nivolumab should be performed.