bluuebunny/crossref_metadata_2025 huggingface dataset:
PS02.034: EFFICACY AND SAFETY OF SALVAGE PHOTODYNAMIC THERAPY USING TALAPORFIN SODIUM FOR LOCAL FAILURE AFTER CHEMORADIOTHERAPY IN PATIENTS WITH ESOPHAGEAL CANCER
Authors: Amanuma Yusuke , Ohashi Shinya , Tamaoki Masashi , Horimatsu Takahiro , Muto Manabu
Published: September 2018

Background

We previously conducted an investigator-initiated trial of photodynamic therapy (PDT) using talaporfin sodium (talaporfin-PDT) and laser irradiation (PD-laser) against local failure after chemoradiotherapy (CRT) in patients with esophageal cancer (EC) and reported a high local complete response rate (L-CR) (88.5%) (Yano et al., Oncotarget 2017). Thereafter, talaporfin-PDT has been applied clinically as a salvage treatment for local failure after CRT in Japan since October 2015. The current study retrospectively reviewed the efficacy and safety of talaporfin-PDT in patients who underwent this treatment in our clinical practice.

Methods

This study was a single-center retrospective observational study. Patients who received salvage talaporfin-PDT for local failure of EC limited to T1–2 after definitive CRT or radiotherapy from May 2011 to July 2017 in our hospital were included. PDT was applied with an intravenous administration of talaporfin sodium (40 mg/kg) followed 4 h later by diode laser irradiation at 100 J/cm2. The primary and secondary endpoints were the rate of L-CR and the safety of PDT, respectively. The criteria for L-CR were as follows: 1) no residual tumor, 2) disappearance of post-PDT ulcer and scar formation, and 3) disappearance of cancer cells as assessed histologically.

Results

Thirty-one patients were analyzed in this study (26 men, 5 women, median age: 68 years). Histological types were squamous cell carcinoma and adenocarcinoma (30 and 1 patients, respectively). The failure patterns of lesions after CRT were recurrence after achieving a CR and residual lesion just after CRT (25 and 6 patients, respectively). The recurrent T stages were T1a, T1b, and T2 (1, 18, and 12 patients, respectively). The median total laser exposure dose was 500 J (range: 200–900). The L-CR rates were 84.2% (16/19), 41.7% (5/12), and 61.3% (19/31) in patients with T1, T2, and all stages, respectively. No severe adverse events greater than grade 3 related to PDT were observed. Although four patients had grade 2 esophageal stenosis after PDT, the stenosis was controlled by endoscopic balloon dilation.

Conclusion

Salvage talaporfin-PDT is a safe and curative treatment for local failure, especially stage T1, after CRT in patients with EC.

Disclosure

All authors have declared no conflicts of interest.
PS02.035: CIRCUMFERENTIAL ENDOSCOPIC SUBMUCOSAL DISSECTION OF A LARGE SUPERFICIAL OESOPHAGUS SQUAMOUS CELL CANCER WITHOUT STRICTURES ON FOLLOW-UP
Authors: Baldaque-Silva Francisco , Konradsson Magnus , Wang Naning , Omae Masami
Published: September 2018

Description

The optimal treatment for oesophageal superficial squamous cell cancer (SCC) is end bloc resection, that in large lesions is only possible with endoscopic submucosal dissection (ESD). Resections larger than 3cm, in the upper esophagus and encompassing more than 3/4 of the luminal circumference, are associated with high stricture rate. That risk is virtually 100% in cases of circumferential ESD. High focus had been given to preventive measurements such as steroids injection, oral steroids or cell sheet transplantation. Usually highly osmotic substances such as Glicerol ® are used for subepitelial lifting. Hyaluronic acid has high viscosity and anti-inflammatory proprieties, that due to its high cost is not widely used in ESD or is used in low concentration formulas and low volume. We report a case of a 7.5 cm long circumferential oesophageal ESD performed with injection of a high volume and concentration of hyaluronic acid that was not associated with stricture in the follow-up. A 73 years-old male patient was referred to our clinic due to the presence of a long superficial lesion and biopsies positive for SCC. We performed chromoendoscopy with lugol that revealed the presence of a ca 6cm long Paris IIa-b, circumferential SCC in the middle esophagus with ‘Tatami-no-me ‘and ‘pink-color’ signs, without ulcers or other endoscopic signs of deep invasion. The PET-CT was negative for metastasis. After multidisciplinary conference and patient's consent an ESD was performed under full narcosis using Dualknife ® and hyaluronic acid for subepitelial injection. A 7.5 cm circumferential ESD specimen was resected and the patient was discharged at day 3 without complications under proton pump Inhibitors and a step-down dose of 30mg/d of oral prednisolone. The pathological result revealed R0 resection of a SCC with invasion of the superficial muscularis mucosae (T1a) and no lymphovascular engagement. The follow-up at 2, 5, 8 weeks and 6, 9 and 12 months revealed the absence of stricture. There was no cancer recurrence in the last follow-up (1 year). Long circumferential ESD of oesophageal SCC is possible with curative intent. The combination of PPI, oral steroids and high volume/concentration of hyaluronic acid, avoided stricture formation in this case.

Disclosure

All authors have declared no conflicts of interest.
PS02.037: NETWORK AND PATHWAY-BASED ANALYSIS OF GENES ASSOCIATED WITH ESOPHAGEAL SQUAMOUS CELL CARCINOMA
Authors: He Wenwu , Han Yongtao , Yuan Kun , Lin Peng
Published: September 2018

Background

As a highly malignant and aggressive tumor, Esophageal Squamous Cell Carcinoma (ESCC) is not sensitive to chemoradiotherapy and chemotherapy. Although diagnostic methods and treatments have improved over the last few years, the 5-year survival rate of ESCC patients remains generally poor. The development of high-throughput technology has witnessed the great achievements in localization ESCC related genes/proteins, and many genes/proteins are considered as potential targets for detection or treatment. To take a further quest for a thorough understanding of the biological processes involved in the pathogenesis of ESCC at the molecular level, the potential pathogenesis of ESCC needs to be deciphered at a phylogenetic level.

Methods

The interaction of these genes was explored by collecting genes associated with ESCC, using gene enrichment assays, pathway enrichment assays, pathway crosstalk analysis and extraction of ESCC-specific subnetwork to describe the relevant biochemical processes.

Results

Through GO enrichment analysis, many molecular functions related to response to chemical, cellular response to stimulus and cell proliferation were found to be significantly enriched in ESCC-related genes. The results of pathway and pathway crosstalk analysis showed that pathways associated with multiple malignant tumors, the immune system and metabolic processes were significantly enriched in ESCC-related genes. Through the analysis of specific subnetwork, we obtained some novel ESCC-related potential genes, such as MUC13, GSTO1, FIN, GRB2, CDC25C and so on.

Conclusion

The molecular mechanism of ESCC is extremely complex. Some inducing factors change the expression status of many genes. The abnormal expression of genes mediates the biological processes involved in immunity and metabolism, apoptosis and cell proliferation, leading to the occurrence of tumors. Gene MUC13, RYK, FIN may be potential prognostic indicators of ESCC. GRB2 and CDC25C may be potential targets of ESCC in proliferation. Our work may provide valuable information for understanding the molecular mechanisms for the development of ESCC.

Disclosure

All authors have declared no conflicts of interest.
PS02.038: SAFETY AND EFFICACY OF REPETITIVE PHOTODYNAMIC THERAPY FOR RESIDUAL ESOPHAGEAL CANCER LESIONS AFTER INITIAL PHOTODYNAMIC THERAPY
Authors: Tamaoki Masashi , Amanuma Yusuke , Horimatsu Takahiro , Ohashi Shinya , Muto Manabu
Published: September 2018

Background

Photodynamic therapy (PDT) is an effective salvage treatment for local failure after chemoradiotherapy in patients with esophageal cancers. However, the treatment strategy for local failure after initial PDT has not been established, and the safety and efficacy of repetitive PDT for such lesions are also unknown.

Methods

We retrospectively investigated 33 esophageal cancer patients who received initial salvage PDT at Kyoto University Hospital between May 2012 and November 2017. Additionally, we examined the treatment outcomes of those patients who received repetitive PDT.

Results

Twenty-one patients (64%) achieved local complete response (CR) by initial PDT, and local recurrence did not occur in those patients. Eleven patients (33%) had residual lesions after initial PDT. Among these, 7 patients were treated with repetitive PDT, 2 patients selected best supportive care, 1 patient was treated with surgery, and 1 patient was treated with chemotherapy. Five of the 7 patients who received repetitive PDT were treated with talaporfin sodium, and 2 patients were treated with porfimer sodium. The median age of the patients who received repetitive PDT was 70 years old, and all patients were men. Regarding histology, 6 patients were squamous cell carcinoma and 1 patient was adenocarcinoma. The median period from initial PDT to repetitive PDT was 3 months (range 1–4). Lesion depth before initial PDT was T1 in 3 patients and T2 in 4 patients. Lesion depth before repetitive PDT was T1 in 5 patients, and T2 in 2 patients. Local CR rate in 7 patients treated with repetitive PDT was 42.9% (3/7). Additionally, local CR rate in T1 cases was 60% and 0% in T2 cases. Adverse events of grade 3 or higher were not observed in any patient.

Conclusion

Repetitive salvage PDT was considered to be an effective and safe treatment option in residual T1 lesions after initial PDT for local failure of esophageal cancer treated with chemoradiotherapy.

Disclosure

All authors have declared no conflicts of interest.
PS02.040: EXPRESSION OF INTESTINAL/NON-INTESTINAL DIFFERENTIATION MARKERS IN ADENOCARCINOMAS OF THE ESOPHAGUS CORRELATES WITH ESOPHAGO-GASTRIC INTESTINAL METAPLASIA
Authors: Bonora Elena , Isidori Federica , Lugaresi Marialuisa , Sala Claudia , Malvi Deborah , Fittipaldi Silvia , Castellani Gastone , Räsänen Jari , D’Errico Antonietta , Fiocca Roberto , Mattioli Sandro
Published: September 2018

Background

Esophageal adenocarcinomas (EAC), grouped according to the presence (+ )/absence (-) of intestinal metaplasia in esophagus (BIM) and stomach (GIM) differ in terms of nodal metastatic patterns and survival. We studied the differentiation profile in BIM/GIM categories.

Methods

In 77 EAC surgical specimens we assessed CDX-2, CK7, CK20, MUC1, MUC2, MUC5A/C, MUC6 antibodies. The expression of such markers was correlated with: BIM + GIM- (Barrett-like), BIM-GIM- (cardiopyloric-like), BIM-GIM + (gastric-like).

Results

CDX2 (P = 0.0481), CK7 (P = 0.0150), MUC2 (P = 0.0395) were differently expressed (Kruskall-Wallis test) in BIM/GIM categories. Binary relations (Mann-Whitney test) showed that CDX2 was more expressed in BIM + /GIM- than in BIM-/GIM- (P = 0.0046) tumors; CK7 was more expressed in BIM-/GIM- than in BIM-/GIM + (P = 0.0020) and in BIM + /GIM- than in BIM-/GIM + (P = 0.0101); MUC2 was more expressed in BIM + /GIM- than in BIM-/GIM- (P = 0.0061). The other investigated markers were randomly distributed among BIM/GIM categories.

Conclusion

The greater expression of intestinal markers (CDX2-MUC2) in Barrett's intestinal metaplasia associated tumors (BIM + /GIM-) compared to those with no intestinal metaplasia (BIM-/GIM-) is consistent with their predominant intestinal differentiation. In contrast, CK7, although mostly expressed in tumors not associated with intestinal metaplasia (BIM-/GIM-) was less efficient in distinguishing them from those associated with Barrett's metaplasia (BIM + /GIM-) while showed the lowest level of expression in tumors associated with gastric intestinal metaplasia (BIM-/GIM + ). In conclusion, intestinal (CDX2-MUC2) and non-intestinal (CK7) differentiation markers appear to be expressed differently in BIM/GIM categories. Those findings support the opportunity to investigate further biology of these tumors in view of clinical-prognostic implications.

Disclosure

All authors have declared no conflicts of interest.
PS02.042: PROGNOSTIC ROLE OF HPV INFECTION IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA
Authors: Bognar Laura , Bellyei Szabolcs , Hegedus Ivett , Gombos Katalin , Horvath Ors , Vereczkei Andras , Pozsgai Eva , Papp Andras
Published: September 2018

Background

The aims of this study were to evaluate whether HPV infection has a prognostic role in patients with esophageal squamous cell carcinoma who underwent oncological treatment and also to correlate the heat shock proteins (Hsp) 90, 27 and 16.2 and growth hormone-releasing hormone receptor (GHRH-R) expression patterns of the pre-treatment tumor biopsies with the HPV status and with the oncological response.

Methods

Pre-treatment tumor biopsies of 74 patients with locally advanced esophageal squamous cell carcinoma were processed retrospectively. The presence of HPV was detected by chromogenic in situ hybridization. Hsp and GHRH-R expressions were determined using immunohistochemistry. Following neoadjuvant or definitive radiochemotherapy, the patients were restaged according to the Response Evaluation Criteria in Solid Tumors. The correlation between the HPV status, response and Hsp and GHRH-R expressions were evaluated.

Results

Fourteen (19%) patients were HPV-positive. HPV-positive patients were more likely to respond poorly to multimodal therapy (71.4% were non-responders vs. 28.6% responders) and had shorter overall survival compared to HPV-negative patients (median survival of 6 months vs. 7 months), although the difference was not significant (Log Rank P = 0.898). A significantly higher number of HPV-positive patients expressed Hsp 90 and 16.2 at high levels (85.7% and 71.4%, respectively) than at low levels. Higher levels of Hsp expressions resulted in poorer response to therapy and worse overall survival.

Conclusion

We found that HPV infection resulted in poor response to therapy and decreased overall survival, and therefore proved to be a negative prognostic factor in patients with esophageal squamous cell carcinoma. There was a linear correlation between levels of Hsp 90 and 16.2 expression and HPV positivity.

Disclosure

All authors have declared no conflicts of interest.
PS02.043: OVEREXPRESSION OF HSP27 AND HSP70 ARE ASSOCIATED WITH DECREASED SURVIVAL AMONG PATIENTS WITH ESOPHAGEAL ADENOCARCINOMA
Authors: Söderström Henna , Kauppi Juha , Räsänen Jari , Rantanen Tuomo
Published: September 2018

Background

Heat shock protein (HSP) 27 and 70 overexpression is associated with several malignancies but reports of their incidence and association with survival among patients with esophageal carcinoma (EC) are scarce. COX-2 expression is induced by inflammation, and it has been linked to a Barrett's esophagus and a wide variety of cancers. High COX-2 expression has been linked to poor survival in EC but results regarding association to clinicopathological factors are conflicting.

Methods

Immunohistochemical analysis for HSP27, HSP70 and COX-2 was performed on 97 cancer cases, 19 Barrett cases and 5 controls treated between 1990 - 2007. Data was gathered from patient records and survival data was acquired in December 2015.

Results

Higher tumor stage was significantly associated with poorer survival (P < 0001), which was independent of HSP27, HSP70 and COX-2 immunostaining. HSP27 was moderately or strongly positive in 61,8% of the cancer cases, which was significantly associated to poorer survival (25,6 and 19 months versus 65,1 in weakly positive samples) (P = 0,01). Similar results were seen for HSP70, for which 30,4% of the cases were stained moderately or strong positive, and survival was 15 and 17,3 months compared to 41,7 months in weakly stained cases. COX-2 was negative in 83,3% of the cancer cases, and none of the samples had strong COX-2 immunostaining. COX-2 did not correlate with survival.

Conclusion

Moderate or high HSP27 and HSP70 staining intensities were associated with poor survival among patients with esophageal adenocarcinoma, which is now reported for the first time. According to previous studies opposite conclusions for esophageal squamous cell carcinoma was found. COX-2 did not impact survival in our study even though it's been found to be a negative prognostic factor in several previous studies.

Disclosure

All authors have declared no conflicts of interest.
PS02.044: A BARRETT’S CELL CULTURE MODEL, SHOWING AN INCREASED ACID TOLERABILITY OF ESOPHAGEAL ADENOCARCINOMA CELLS
Authors: Thieme René , Storz Lucie , Rolfs Franziska , Eichfeld Uwe , Dietrich Arne , Hoffmeister Albrecht , Jansen-Winkeln Boris , Gockel Ines
Published: September 2018

Background

Inflammation is a common in esophageal adenocarcinoma (EAC). The response of EAC to common chemotherapeutic regimes is relatively low and the 5-years-survival is poor. The influence of acidic reflux on the viability of esophageal adenocarcinoma cells is unknown.

Methods

We investigated the influence of acidified medium conditions (pH3; pH3.5; pH4) in a Barrett's cell culture model, using six cell lines representing the Barrett's sequence from normal esophageal epithelium (EPC1 and EPC2), metaplasia (CP-A), dysplasia (CP-B) and EAC (OE33 and OE19) for their tolerability against an acid pulse of 15 and 30 min as well as expression profile of the Nrf2-Keap1-signalling pathway and their downstream targets.

Results

The Barrett's sequence was characterized by an increase of acid tolerability in the more advanced cells of this sequence. The squamous epithelium cell line EPC1 has shown the highest susceptibility with a decrease of 75% of cell viability, when treated with pH4 medium for 15min, while dysplastic and EAC cells had shown only a decrease of 10–25%. The lowest susceptibility was observed in the EAC cell line OE33, which had also 90% living cell in pH3 medium after 15min and had almost 30% living cells after 30min, when all other investigated cell lines showed no more living cells. Additionally, treatment with acidified medium was accompanied with an increase of the Nrf2 target gene hemeoxygensae-1.

Conclusion

We could show an increased tolerability against acidified medium (pH3) in cells representing advanced Barrett's esophagus stages, accompanied by an activation of Keap1-Nrf2-signalling pathway. However, acidic reflux may influence inflammation and chemo-sensitivity of the EAC.

Disclosure

All authors have declared no conflicts of interest.
PS02.045: EXPRESSION AND CLINICAL SIGNIFICANCE OF LEUCINE-RICH REPEAT-CONTAINING PROTEIN 8A (LRRC8A) IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA
Authors: Konishi Tomoki , Shiozaki Atsushi , Fujiwara Hitoshi , Konishi Hirotaka , Kudo Michihiro , Shoda Katsutoshi , Kosuga Toshiyuki , Arita Tomohiro , Morimura Ryo , Murayama Yasutoshi , Kuriu Yoshiaki , Ikoma Hisashi , Kubota Takeshi , Nakanishi Masayoshi , Okamoto Kazuma , Otsuji Eigo
Published: September 2018

Background

All cells have regulatory volume decrease (RVD) function to maintain cell volume. When the cell volume changes, the anion channels on the cell membrane are activated and keep constant cell volume due to water flow. Leucine-Rich Repeat-Containing protein 8 A (LRRC8A) was first reported in 2014 as the main constituent protein of this anion channel. In normal tissues, LRRC8A is thought to control cell volume regulation and is thought to be involved in cell cycle and death. However, its expression and significance in esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we examined to investigate the clinicopathological significance of its expression in ESCC and the role of LRRC8A in tumor function.

Methods

An immunohistochemical analysis was performed on 64 patients with ESCC who underwent curative surgery in our department. We carried out knockdown using siRNA to evaluate the role of LRRC8A in ESCC cells.

Results

LRRC8A was expressed in the cell membrane and cytoplasm of cancer cells. We divided ESCC patients into 2 groups by referring to the staining scores; a high expression group with staining scores ≥ 1.0, n = 53, and a low expression group with staining scores < 1.0, n = 11. In correlation analysis with clinicopathologic factors, high LRRC8A expression tended to have a positive correlation with the presence or absence of lymph node metastasis (P = 0.059). In the survival analysis, the 5-year overall survival rate of patients with high LRRC8A expression (43.4%) was significantly lower than that of patients with low LRRC8A expression (90.0%) (P = 0.013). Cox proportional hazard analysis showed that high LRRC8A expression was an independent poor prognostic factor (P = 0.013, HR = 6.67). LRRC8A was strongly expressed in TE15 and KYSE170 human ESCC cells. The depletion of LRRC8A using siRNA inhibited cell proliferation, migration, invasion and induced apoptosis.

Conclusion

The LRRC8A expression is related to worse prognosis in ESCC patients and regulates tumor progression. Nest step, we will carry out further investigation to reveal how to regulate tumor function by microarray analysis.

Disclosure

All authors have declared no conflicts of interest.
PS02.046: UNRAVELING TUMOR HETEROGENEITY OF ESOPHAGEAL ADENOCARCINOMA (EAC) THROUGH HIGH-THROUGHPUT OF SORTED TUMOR CELL POPULATIONS
Authors: Bonora Elena , Isidori Federica , Bozzarelli Isotta , Lugaresi Marialuisa , Malvi Deborah , Söderström Henna , Bolognesi Chiara , Forcato Claudio , D’Errico Antonietta , Fiocca Roberto , Seri Marco , Krishnadath Kausilia , Mattioli Sandro
Published: September 2018

Background

In EAC clinical, histological, immune-histochemical and genetic patterns were documented, which support the existence of biologically different sub populations. We studied genetic intra/inter tumor heterogeneity of EAC with a new technology based on sorting of specific cell populations.

Methods

Formalin embedded material obtained from 16 EAC surgical specimens, classified according to the presence/absence of intestinal metaplasia in esophagus (BIM) and stomach (GIM) in BIM + GIM- (Barret's like), BIM-GIM- (cardio-pyloric like), BIM—GIM + (gastric like) types, was processed using a high-throughput cell sorting technology. Stromal and tumor cell populations were sorted based on antibodies against vimentin/pan-cytokeratin and on DNA content. Targeted resequencing on DNA extracted from the sorted cells was performed for 63 cancer-related genes (OncoSeek panel).

Results

In 11/16 (68.75%) of cases a mutation in TP53 was detected, and in 2 we observed CDKN2A (TP53 regulator) mutations. In Barret's like and Gastric like sub types only mutations of TP53 or TP53regulator genes were present. In pyloric like type TP53 and/or other different mutations of whom 2 in HNF1A were detected (Figure 1).

Conclusion

Selective sorting led to new patterns of EAC tumor mutational status and heterogeneity, among others somatic mutations in HNF1A not previously found. Parallel analysis of unsorted samples failed to detect these specific mutations. The cardio-pyloric like sub type contains mutational patterns different than those of Barret's and gastric like types. Further research on additional cases is necessary to confirm these findings.

Disclosure

All authors have declared no conflicts of interest.
PS02.048: DECREASED EXPRESSION OF PRSS27 IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA
Authors: Terayama Masayoshi , Hagiwara Teruki , Yamada Kazuhiko , Soma Daisuke , Nohara Kyoko , Yamashita Satoshi , Kokudo Norihiro , Dohi Taeko , Kawamura Yuki I
Published: September 2018

Background

Alcohol drinking and smoking are substantial risk factors of esophageal squamous cell carcinoma (ESCC) and are supposed to induce genetic mutations and epigenetic disorders, including aberrant DNA methylation. Previously, we have conducted transcriptome and methylome analyses of a paired specimen of ESCC and adjacent non-cancerous tissues and found that both gene expression and promotor methylation of PRSS27 were perturbed in ESCC. PRSS27 was a trypsin-like serine protease (also known as marapsin) and expressed in normal esophagus; however, little is known about the significance of PRSS27 expression in ESCC. In this study, we evaluated the expression of PRSS27 in many ESCC cases in relation with clinical features and the prognosis.

Methods

ESCC tissue specimens were obtained from 80 patients who had undergone esophagectomy between April 2008 and December 2016 in our hospital and were subjected to immunostaining for PRSS27. ESCC cases were classified into PRSS27-negative and PRSS27-positive groups and difference of clinical features and the prognosis between the groups was analyzed.

Results

The mRNA expression of PRSS27 was significantly decreased in ESCC compared with those in matched normal mucosa (P < 0.0001). Histologically, PRSS27 was highly expressed in spinous cells of suprabasal cell layer but not in basal cell layer of normal esophageal mucosa. In contrast, 37 of 80 (47%) ESCC exhibited decreased intensity of PRSS27 staining when compared with that in normal mucosa, and 53% (43/80) of ESCC showed almost no staining of PRSS27. Although the prognosis of PRSS27-positive cases were worse in trend than that of PRSS27-negative cases, there was no significant difference (P = 0.0763)

Conclusion

PRSS27 gene and protein expression was both downregulated in ESCC; its functional significance in relation to malignancy is underinvestigation.

Disclosure

All authors have declared no conflicts of interest.
PS02.049: HIGH GPX1 EXPRESSION PROMOTES ESOPHAGEAL SQUAMOUS CELL CARCINOMA INVASION, MIGRATION, PROLIFERATION AND CISPLATIN-RESISTANCE BUT CAN BE REDUCED BY VITAMIN D
Authors: Gan Xiangfeng , Chen Ju , Chen Baishen
Published: September 2018

Background

Esophageal cancer is one of the most common cancers worldwide. Despite recent progress in the devel- opment of novel therapies, esophageal carcinoma remains an aggressive cancer associated with a poor prognosis. The glutathione peroxidase 1 (GPX1) gene located on chromosome 3p21.3 is associated with the cancer of several organs. According to available information, GPX1, a gene downstream of NF-κB, is considered to exert adverse ef- fects on tumour progression and enhance malignancy in some cancers but has not been reported in esophageal cancer. It is also reported that vitamin D (Vit. D), a widely used drug in the clinical setting, could suppress GPX1 expression through the NF-κB pathway. Thus, it is speculated that Vit. D could reduce malignancy in esophageal cancer by altering the NF-κB pathway.

Methods

Selection GPX1 high expression EC109 and EC9706 cell line K150, and K180 low expression cell lines transfected with siRNA and vector. Using RT-PCR to detect cell transfection efficiency GPX1’s, Western blot detect the expression of uPA, MMP-2, NF-κB, and CCK-8 assay inhibition or overexpression on GPX1 on ESCC cell cisplatin resistance and proliferation. Transwell assay inhibition or over-expression of GPX1 on invasive ability of ESCC cells.

Results

By CCK-8 and transwell law found within the cells expressing low GPX1 ESCC can inhibit cell proliferation, cisplatin resistance, invasion and migration, high GPX1 when the opposite phenomenon can be observed. Western blot GPX1 down when found, PTEN, Bax activity rises, PDK-1, AKT, Bcl-2, uPA, MMP-2 expression decreased, vimentin, E-cadherin, ß-catenin, snail is no significant change. After Vit.D treatment, CCK-8 assay showed that cell proliferation and drug resistance was significantly inhibited; Transwell showed cell invasion and migration also decreased. Cells was detected by Western blot after transfection, cells, PTEN, Bax increased activity, p65, PDK-1, AKT, Bcl-2, uPA, MMP-2 expression decreased, vimentin, E-cadherin, ß-catenin, snail is no significant change.

Conclusion

Treatment with vitamin D can downregulate GPX1, thus decreasing tumour cell capacity for invasion, migration, proliferation and cisplatin resistance via the NF-κB pathway. Vitamin D, already commonly used in clinical therapy, could play a greater role in the treatment of esophageal cancer patients.

Disclosure

All authors have declared no conflicts of interest.
PS02.050: TUMOR LOCATION IS AN INDEPENDENT PROGNOSTIC FACTOR OF ESOPHAGEAL ADENOCARCINOMA BASED ON THE EIGHTH EDITION OF TNM STAGING SYSTEM IN CHINESE PATIENTS
Authors: Lin Yidan , Deng Hanyu
Published: September 2018

Background

Whether tumor location has any impact on the survival of esophageal adenocarcinoma patients remains controversial. In this study, we tried to investigate the prognostic value of tumor location for esophageal adenocarcinoma based on the eight edition of TNM staging system, which modified the description for positioning the esophagogastric junction (EGJ)tumor, in Chinese patients for the first time.

Methods

A retrospective analysis of patients who underwent esophagectomy for esophageal adenocarcinoma was conducted. Data for analysis included demographic data, comorbidity, pathologic findings, surgical approach, adjuvant therapy, and survival time. Tumor location was simply categorized into two groups (adenocarcinomas at EGJ and adenocarcinomas at other sites of esophagus). Both univariate and multivariate analyses were applied. Propensity-score matched (PSM) analysis was also conducted to eliminate the bias effects of confounding factors during comparison.

Results

A total of 107 patients from January 2009 to December 2015 was included for analysis. After a median follow-up time of 60.0 months, the median survival time of those patients was 41.0 months. In the univariate analysis, adenocarcinomas in the EGJ (P = 0.047), early pT stages (P = 0.030), and moderate/well differentiation (P = 0.022) were significantly correlated with better survival. In the multivariate analysis, tumor site [hazard ratio (HR) = 0.545; 95% confidence interval (CI) = 0.302–0.985], pT stage (HR = 0.295; 95% CI = 0.123–0.708), and tumor differentiation (HR = 0.458; 95% CI = 0.244–0.861) were significant independent prognostic factors for overall survival of those esophageal adenocarcinoma patients. After adjusted by PSM, adenocarcinoma at the EGJ still yielded significantly longer survival than those at other sites of esophagus (P = 0.026).

Conclusion

Tumor location was an independent prognostic factor for esophageal adenocarcinoma based on the eighth edition of TNM staging system in Chinese patients, which indicates that different surgical therapeutic modalities should be applied for esophageal adenocarcinoma with different tumor locations.

Disclosure

All authors have declared no conflicts of interest.
PS02.054: EXPRESSION OF THE DESMOSOME-RELATED MOLECULE PERIPLAKIN IS ASSOCIATED WITH ADVANCED STAGE AND POOR PROGNOSIS OF ESOPHAGEAL SQUAMOUS CELL CARCINOMA
Authors: Yamada Kazuhiko , Hagiwara Teruki , Sezaki Takuhito , Igari Toru , Yokoi Chizu , Nohara Kyoko , Terayama Masahiro , Kataoka Atsuko , Yamashita Satoshi , Dohi Taeko , Kawamura Yuki I , Kokudo Norihiro
Published: September 2018

Background

Our previous report showed that periplakin (PPL), a member of the plakin family of proteins, was expressed in all the normal esophageal squamous cells, except the Ki67 + basal cell layer; however, PPL-negative cells were observed in esophageal squamous cell carcinoma (ESCC) tissue samples and the proportion of PPL-positive areas in tumors showed considerable variation. In this study, we analyzed the relationships between PPL expression in tumors and the clinicopathological features of ESCC.

Methods

PPL expression was evaluated by immunostaining ESCC samples from 70 patients who underwent surgery and we classi ed the samples into PPL-negative and PPL-positive groups based on the proportion of PPL-positive areas in tumors, and the relationships among PPL expression, clinical features, and the ESCC prognosis were analyzed. ESCC cell line KYSE270 cells were stably transfected with the PPL expression vector and their growth was assessed by colony formation assay and subcutaneous xenografts in athymic mice.

Results

As found in our previous study, decreased PPL staining intensity was observed in all of the cancer tissues analyzed, compared with that observed in paired normal esophageal mucosae; however, the PPL-positive group (the percentage of PPL-positive tumor cells was > 20% on immunostaining) exhibited positive associations with the pT classi cation (larger primary tumor) (P = 0.029), pN classi cation (lymph node metastasis) (P = 0.0462), and advanced stages of cancer (P = 0.0253). High PPL expression was observed in all of 26 lymph node metastases analyzed. Furthermore, patients with PPL-positive tumors showed poor postoperative prognosis compared to those with PPL-negative ones. Forced expression of PPL in the KYSE270 ESCC cell line induced a strati ed structure and colony formation. In addition, PPL-transfected cells formed larger tumors in nude mice than mock-transfected cells, suggesting that relatively high PPL expression in tumors may facilitate cell-cell adhesion by desmosome formation and eventual cell growth in vivo.

Conclusion

PPL expression was generally reduced in ESCC compared with paired non-cancer tissue; however, relatively high levels of PPL expression in tumors correlated with tumor progression, lymph node metastasis, advanced stage cancer, and a poor prognosis.

Disclosure

All authors have declared no conflicts of interest.
PS02.061: TRANILAST: SPECIFIC INHIBITOR OF TRPV2 IS THERAPEUTIC AGENT OF ESOPHAGEAL CANCER STEM CELLS
Authors: Katsurahara Keita , Shiozaki Atsushi , Kudou Michihiro , Shoda Katsutoshi , Arita Tomohiro , Konishi Hirotaka , Morimura Ryo , Murayama Yasutoshi , Kuriu Yoshiaki , Kubota Takeshi , Ikoma Hisashi , Nakanishi Masayoshi , Okamoto Kazuma , Otsuji Eigo
Published: September 2018

Background

Recent studies revealed that membrane proteins, such as ion transporters, are specifically activated in cancer stem cells (CSCs). Therefore, these molecules are receiving a great attention as new chemotherapeutic targets of malignant tumor. This study aimed to investigate the expression and activity of ion transport-related molecules in CSCs of esophageal squamous cell carcinoma (ESCC).

Methods

We sorted cells with high expression of ALDH1A1 via FACS, and then, CSCs were generated using the sphere formation assay. The gene expression profiles of CSCs were examined using a microarray analysis. Candidate genes of membrane proteins activated in CSCs were selected based on that microarray data. Anticancer effects induced by inhibition of the selected proteins were examined.

Results

ALDH1A1 mRNA and protein levels were certainly upregulated in CSCs compared with non-CSCs. Obtained CSCs were resistant to Cisplatin and had the ability of re-differentiation. The results of the microarray analysis revealed that expressions of 50 genes of plasma membrane proteins were changed in CSCs, and that several genes related to ion channels, including transient receptor potential cation channel subfamily V member 2 (TRPV2), were upregulated. The upregulation of TRPV2 mRNA were also validated in CSCs derived from two types of esophageal cancer cell lines using RT-PCR method. Tranilast, which is specific TRPV2 inhibitor, was more cytotoxic at lower concentration in CSCs than in non-CSCs, and effectively decreased the number of tumorspheres. Further, Tranilast significantly decreased the cell population with high ALDH1A1 expression in esophageal cancer cells.

Conclusion

The results of the present study suggest that TRPV2 is involved in the maintenance of CSCs, and Tranilast, which is specific inhibitor of TRPV2, becomes a promising targeted therapeutic agent against ESCC.

Disclosure

All authors have declared no conflicts of interest.
PS02.062: CONFOCAL LASER ENDOMICROSCOPY IN THE ASSESSMENT OF PERSISTENT/RECURRENT INTESTINAL METAPLASIA/NEOPLASIA AFTER ENDOSCOPIC TREATMENT OF BORN
Authors: Krajciova Jana , Kollar Marek , Maluskova Jana , Kment Martin , Vackova Zuzana , Spicak Julius , Martinek Jan
Published: September 2018

Background

Patients after endoscopic treatment of Barrett's esophagus related neoplasia (BORN) should undergo regular endoscopic surveillance with biopsies to detect recurrent intestinal metaplasia (IM) or neoplasia (N). Probe-based confocal laser endomicroscopy (pCLE) offers detailed examination of cellular structures and may examine larger areas compared to standard biopsy.

Methods

A single center, prospective, controlled and pathologist-blinded (still ongoing) study in patients undergoing surveillance endoscopy after endoscopic treatment of BORN. pCLE images were obtained from the neo-Z-line (in few cases including macroscopically visible tongues), the cardia and the esophagus. Thereafter, standard biopsies were taken and sent for histopathological analysis (minimally 4 biopsies from macroscopically normal neo-Z-line, 2 biopsies from the cardia and the esophagus and targeted biopsies from visible abnormalities, if present).

Results

We examined 34 patients, from these 14 patients (41%) had the initial diagnosis of low-grade intraepithelial neoplasia (LGIN), 8 patients (24%) had high-grade intraepithelial neoplasia (HGIN) and 12 patients (35%) had an early adenocarcinoma (EAC). Three patients (9%) underwent endoscopic resection (ER), in 18 patients (53%) we performed ER or dissection of all visible lesions followed by radiofrequency ablation (RFA), and 13 patients (38%) had RFA as a single treatment modality.

Persistent/recurrent IM was detected only at the level of neo-Z-line in 8 patients (24%, 8/34 pts) by both methods. pCLE but not biopsies detected persistent/recurrent IM in 2 patients (6%, 2/34), another 2 patients had IM present in biopsies but not in pCLE. pCLE diagnosed one patient with recurrent LGIN in a macroscopic visible tongue arising from neo-Z-line, which was not confirmed in biopsies (there was only agreement in persistent IM detected by both methods).

Sensitivity and specificity of pCLE in detection of persistent/recurrent IM was 80% (95% CI 44–98) and 92% (95% CI 73–99), respectively, with a positive predictive value of 80% (95% CI 51–94) and a negative predictive value of 92% (95% CI 76–98). Agreement of pCLE and histopathological findings was 88%.

Conclusion

pCLE seems comparable to standard biopsies in detection of persistent/recurrent IM after endoscopic treatment of BORN. Nevertheless, these results need to be confirmed in a larger cohort of patients.

Disclosure

All authors have declared no conflicts of interest.
PS02.063: FALSE POSITIVE CASES OF FDG-PET/CT IN METASTASIS OF ESOPHAGEAL SQUAMOUS CELL CARCINOMA
Authors: Naomoto Yoshio , Yamatsuji Tomoki , Takaoka Munenori , Haisa Minoru , Manabe Noriaki
Published: September 2018

Background

PET-CTs are useful for diagnosing primary and metastatic lesions of esophageal cancer. Although the number of cases are few, false positives exist in which an inflammatory tumor mass and a non-specific tumor mass are difficult to differentiate.

Methods

The subjects had suspected metastasis from a PET-CT which occurred before the operation of esophageal cancer. However, after surgery, biopsy and/or follow-up observation, only the cases that were confirmed as metastasis negative were considered to be PET-CT false positives.

Results

There were three cases of preoperative PET/CT false positives. Bone metastasis was originally suspected in two cases, but they were later found to be bone metastasis negative after a preoperative bone biopsy and clinical course observation. The other cases suspected of mediastinal lymph node metastasis was diagnosed as inflammatory lymphadenopathy by a pathological examination.

Conclusion

Conducting a PET/CT is useful when diagnosing esophageal cancer metastasis, but there should be an awareness of the possibility of false positives.

Disclosure

All authors have declared no conflicts of interest.
PS02.064: ACCURACY OF F-18-FDG-PET/CT IN MONITORING TUMOUR RESPONSE AFTER NEOADJUVANT CHEMORADIOTHERAPY IN PATIENTS WITH OESOPHAGEAL CANCER
Authors: Valkema Maria , Noordman B , Wijnhoven Bas P L , Spaander M C W , Lagarde Sjoerd M , Ruurda Jelle , Nieuwenhuijzen Grard A P , Van Berge Henegouwen M I , Sosef M N , Siersema P D , Van Lanschot J J B , Valkema R
Published: September 2018

Background

Neoadjuvant chemoradiotherapy (nCRT) induces a pathologically complete response in approximately 30% of patients with oesophageal cancer. To explore the possibility of safe postponement of surgery, accurate clinical response evaluations are needed to exclude residual disease. The present study aims to assess the value of F-18-FDG-PET/CT for the detection of residual tumour (> 10% tumour cells = TRG3–4 vs. no vital cells = TRG1) or metastases after nCRT.

Methods

FDG-PET/CT at baseline and 12 weeks after nCRT was performed according to the European Association of Nuclear Medicine guidelines 1.0 (2.3MBq/kg F-18-FDG; scanning 60 ± 5min.) and the protocol of the preSANO study. Qualitative analysis included sensitive reading of presence of residual tumour and/or metastases. A lesion was considered FDG-positive, when any uptake in the lesion itself was above the adjacent oesophageal background uptake. Quantitatively, SUV/lean body mass (SUL) measurements at tumour, lymph nodes, oesophagus, liver and bloodpool were recorded and compared with pathology (resection specimen: gold standard).

Results

Some 129 of 207 patients with FDG-avid tumours at baseline proceeded to FDG-PET/CT at around 12 weeks after nCRT just before surgery. Forty-one of 129 patients had TRG3–4, of whom 6 were missed on FDG-PET/CT (15% false negative) with SULmax 2.07 ± 0.25, SUL-ratio tumour/oesophagus (SULR) 1.35 ± 0.14. Sensitivity for TRG2–3-4 vs. TRG1 was 57/71 (80%). SULmax and SULR of FDG-positives were 3.76 ± 1.33 and 1.82 ± 0.69 respectively, compared to SULmax 2.21 ± 0.42 and SULR 1.31 ± 0.22 in FDG-negatives. Distant metastases were detected in 18 of 190 (10%) patients. Of all patients with postponed surgery, 12 had ≥ 1 additional FDG-PET/CT during follow-up (25–49.7 weeks after nCRT). Eventually, 4 patients underwent surgery. Three of 4 had increased FDG-signal and TRG3–4; 1 patient had decreased FDG-signal and no tumour left (TRG1).

Conclusion

FDG-PET/CT at around 12 weeks after nCRT misses TRG3–4 tumours in 15% and detects residual TRG2–3-4 in 80%. Furthermore, PET-CT detects distant metastases in 10% of patients after nCRT. These data indicate that serial FDG-PET may become valuable in an active surveillance approach.

Disclosure

All authors have declared no conflicts of interest.
PS02.065: UTILITY OF FDG-PET TO PREDICT LONG TERM PROGNOSIS FOR PATIENTS WITH ESOPHAGEAL CANCER RECEIVING NEOADJUVANT CHEMORADIOTHERAPY FOLLOWED BY SURGERY
Authors: Emi Manabu , Hamai Yoichi , Ibuki Yuta , Okada Morihito
Published: September 2018

Background

There are no prognostic factor for patients with esophagectomy using neoadjvant chemoradiotherapy (nCRT) except for the pathological complete response (pCR). This study aimed to determine the ability of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) to predict prognosis of trimodality therapy on esophageal squamous cell carcinoma (ESCC).

Methods

A series of 90 patients with esophageal squamous cell carcinoma without cervical esophageal underwent sub-total esophagectomy after neoadjvant chemoradiotherapy in the period between October 2006 and January 2013 at our institution. The study included 119 (75 men, 15 women; median age,67) patients with locally advanced ESCC (Stage IB/IIAB/IIIABC/IV: 3/14/64/9). The responses were monitored using FDG-PET before and after nCRT followed by surgery. FDG-PET complete response (PET-CR) after chemoradiotherapy was defined as standardized uptake value less than 2.5. Prognostic factors were determined by uni- and multivariate analysis.

Results

The 5-year overall survival (OS) rates of all patients were 55.3%. Thirty-nine (43.3%) patients achieved a pathological complete response (pCR) after nCRT. Sixty-five percent achieved a PET-CR. PET-CR did not predict for improved outcomes for trimodality therapy (5-year OS 61.5% vs 43.8% P = 0.137).The optimal cutoffs for the rate of decreases in the maximum standard uptake value (SUVmax) determined from receiver operating characteristic (ROC) curves were 75 (AUC, 0.64; 95% CI, 0.54–0.75; P = 0.01) for predicting a pCR. A nonsignificant association was seen in prognosis at the the rate of decreases in SUVmax (P = 0.0823).The PET negative lymph nodes before treatment group showed a higher OS than in the PET-N positive group (5-Y OS 75.0% vs 46.9% P = 0.0036). Multivariate Cox regression analyses identified pCR (hazard ratio [HR], 3.271; confidence interval [CI], 1.568–6.828) and PET-N negative (HR 0.311, CI 0.163–0.592), as the prognostic factor.

Conclusion

Analysis of SUVmax of the primary tumor and lymph node before and after nCRT revealed that PET-N positive before treatment is long term prognostic factor.

Disclosure

All authors have declared no conflicts of interest.
PS02.066: ROLE OF 18F-FDG-PET/CT IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA AFTER NEOADJUVANT CHEMORADIOTHERAPY
Authors: Hirashima Tadahiro , Sasaki Ken , Uchikado Yasuto , Omoto Itaru , Osako Yusaku , Okumura Hiroshi , Setoyama Tetsuro , Owaki Tetsuhiro , Natsugoe Shoji
Published: September 2018

Background

The aim of this study was to assess the role of 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (FDG-PET/CT) in predicting pathological response and survival in patients with esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant chemoradiotherapy (nCRT).

Methods

Thirty patients with advanced ESCC received nCRT followed by surgery, and underwent FDG-PET/CT twice before and after nCRT. We compared the results of FDG-PET/CT with the pathological results and prognosis.

Results

Pathological response was found to correlate with the maximum standardised uptake value (SUVmax) after nCRT and the rate of decrease of SUVmax. Using univariate analysis, pN, SUVmax after nCRT and the rate of decrease of SUVmax were found to be prognostic factors. Multivariate analysis revealed that only pN was an independent prognostic factor

Conclusion

The prediction of pathological response and prognosis using FDG-PET/CT is not as reliable as pathological detection of lymph node metastasis, but could be a useful method contributing to treatment decisions. Neoadjuvant chemoradiotherapy (nCRT) plus surgery has been shown to improve survival rates and should be regarded as a standard of care for patients with locally advanced esophageal squamous cell carcinoma (ESCC). Appropriate evaluation of nCRT efficacy based on noninvasive parameters might help in individualizing treatments for patients with ESCC. 18F-fluorodeoxyglucose positronemission tomography/computed tomography (FDG-PET/CT) reflects tumor cell viability based on enhanced FDG uptake as a result of increased glucose metabolism. FDG-PET/CT is useful for the staging of advanced ESCC before treatment, and for evaluating the response to nCRT; however, findings from currently available studies in this regard are controversial. In the present study, we examined the role and usefulness of FDG-PET/CT in decisions regarding staging, prediction of histopathological response, and overall survival in patients with advanced ESCC treated with nCRT; this was achieved by analyzing the maximum standardized uptake value (SUVmax) before and after treatment, and the rate of decrease of SUVmax.

Disclosure

All authors have declared no conflicts of interest.