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Focal adhesion kinase (FAK) is often up-regulated in a variety of malignancies, including gastrointestinal stromal tumor (GIST), and its overexpression seems to be associated with tumor progressiveness and poor prognosis. GIST is well known to have a mutation to c-KIT; thus, a specific c-KIT inhibitor (imatinib) is recognized as the first-line chemotherapy for GIST, although a certain type of c-KIT mutation reveals a resistance to imatinib due to as yet uncertain molecular mechanisms. To assess the c-KIT mutation-related variation of cellular responses to imatinib, murine lymphocyte-derived Ba/F3 cells, which are stably transduced with different types of c-KIT mutation, were treated with either imatinib or a FAK inhibitor (TAE226), and their antitumor effects were determined in vitro and in vivo. A mutation at exon 11 (KITdel559-560) displayed a high sensitivity to imatinib, whereas that at exon 17 (KIT820Tyr) showed a significant resistance to imatinib in vitro and in vivo. KIT820Tyr cells appeared to maintain the activities of FAK and AKT under the imatinib treatment, suggesting that FAK might play a role in cell survival in imatinib-resistant cells. When FAK activity in those cells was inhibited by TAE226, cell growth was equally suppressed and the cells underwent apoptosis regardless of the c-KIT mutation types. Oral administration of TAE226 significantly diminished tumor growth in nude mice bearing KIT820Tyr xenografts. In summary, c-KIT mutation at exon 17 displayed a resistance to imatinib with maintained activations of FAK and subsequent survival signals. Targeting FAK could be a potential therapeutic strategy for imatinib-resistant GISTs. [Mol Cancer Ther 2009;8(1):127–34]

Purpose: Focal adhesion kinase (FAK) regulates integrin and growth factor–mediated signaling pathways to enhance cell migration, proliferation, and survival, and its up-regulation correlates malignant grade and poor outcome in several types of cancer. In this study, we aimed to raise a potential therapeutic strategy using a FAK inhibitor for Barrett's esophageal adenocarcinoma.Experimental Design: The expression status of FAK in clinical Barrett's esophageal adenocarcinoma tissues was determined by immunohistochemistry. Cultured esophageal adenocarcinoma cells were treated with TAE226, a specific FAK inhibitor with an additional effect of inhibiting insulin-like growth factor-I receptor (IGF-IR), to assess its anticancer effect in vitro. Western blot was carried out to explore a participating signaling pathway for TAE226-induced cell death. Furthermore, TAE226 was orally administered to s.c. xenograft animals to investigate its anticancer effect in vivo.Results: Strong expression of FAK was found in 94.0% of Barrett's esophageal adenocarcinoma compared with 17.9% of Barrett's epithelia, suggesting that FAK might play a critical role in the progression of Barrett's esophageal adenocarcinoma. When esophageal adenocarcinoma cells were treated with TAE226, cell proliferation and migration were greatly inhibited with an apparent structural change of actin fiber and a loss of cell adhesion. The activities of FAK, IGF-IR, and AKT were suppressed by TAE226 and subsequent dephosphorylation of BAD at Ser136 occurred, resulting in caspase-mediated apoptosis. In vivo tumor volume was significantly reduced by oral administration of TAE226.Conclusions: These results suggest that TAE226, a dual tyrosine kinase inhibitor for FAK and IGF-IR, could become a new remedy for Barrett's esophageal adenocarcinoma.

Supplementary Table S1 from Inhibition of focal adhesion kinase as a potential therapeutic strategy for imatinib-resistant gastrointestinal stromal tumor

Supplementary Table 1 from Dual Tyrosine Kinase Inhibitor for Focal Adhesion Kinase and Insulin-like Growth Factor-I Receptor Exhibits Anticancer Effect in Esophageal Adenocarcinoma In vitro and In vivo

Supplementary Figure and Movie Legends from Tumorigenic Conversion of Primary Human Esophageal Epithelial Cells Using Oncogene Combinations in the Absence of Exogenous Ras

To investigate pathways of human esophageal squamous cell transformation, we generated esophageal tumor cells using human telomerase– and SV40-immortalized primary esophageal epithelial cells (EPC2) by overexpression of selected combinations of oncogenes. H-Ras, c-Myc, or Akt, but not epidermal growth factor receptor (EGFR), induced transformed colonies in soft agar. By contrast, bioluminescence imaging of genetically altered immortalized esophageal cells revealed that Akt, EGFR, or H-Ras, but not c-Myc, resulted in tumor formation in immunodeficient mice. H-Ras-driven tumors showed highly tumorigenic phenotypes with 2.6 ± 0.6 days for doubling, whereas Akt and EGFR tumors doubled every 9.5 ± 1.6 and 6.1 ± 1.2 days, respectively. H-Ras-driven tumors expressed the hypoxia-inducible factor target Glut1, whereas Akt- or EGFR-driven tumors had evidence of angiogenesis and no detectable Glut1 expression. Proliferation rates among these tumors were similar, but there was reduced apoptosis in the more aggressive H-Ras-driven tumors that also developed aneuploidy and multiple centrosomes. c-Myc overexpression did not result in tumorigenic conversion but introduction of Bcl-XL into c-Myc-expressing cells generated tumors. Although cytokeratin expression was typical of squamous carcinoma, gene expression profiling was done to compare the four different types of engineered tumors with human esophageal squamous cell carcinomas and adenocarcinomas. Interestingly, c-Myc plus Bcl-XL transformants mimicked squamous carcinomas, whereas H-Ras-, EGFR-, and Akt-driven tumors were similar to adenocarcinomas in their molecular profiles. These genetically engineered models may provide new platforms for understanding human esophagus cancer and may assist in the evaluation of new therapies. (Cancer Res 2006; 66(21): 10415-24)

Supplementary Table 2 from Somatic Hypermethylation of MSH2 Is a Frequent Event in Lynch Syndrome Colorectal Cancers

Gene therapy and virotherapy are one of the approaches used to treat malignant pleural mesothelioma. To improve the efficiency of targeting malignant mesothelioma cells, we designed a novel system using the promoter of the CREBBP/EP300 inhibitory protein 1 (CRI1), a gene specifically expressed in malignant pleural mesothelioma. Four tandem repeats of the CRI1 promoter (CRI1−138 4x) caused significantly high promoter activity in malignant pleural mesothelioma cells but little promoter activity in normal mesothelial cells and normal fibroblasts. The recombinant adenoviral vector expressing proapoptotic BH3-interacting death agonist or early region 1A driven by the CRI1−138 4x promoter induced cell death in malignant mesothelioma cells but not in normal cells. Moreover, these viruses showed antitumor effects in a mesothelioma xenograft mouse model. Here, we describe a novel strategy to target malignant mesothelioma using the CRI1−138 4x promoter system. [Cancer Res 2008;68(17):7120–9]

Supplementary Movie from Tumorigenic Conversion of Primary Human Esophageal Epithelial Cells Using Oncogene Combinations in the Absence of Exogenous Ras

Supplementary Figures 1-2, Tables 1-2 from Tumorigenic Conversion of Primary Human Esophageal Epithelial Cells Using Oncogene Combinations in the Absence of Exogenous Ras

Supplementary Figure 1 from Malignant Pleural Mesothelioma–Targeted CREBBP/EP300 Inhibitory Protein 1 Promoter System for Gene Therapy and Virotherapy

Supplementary Table 1 from Somatic Hypermethylation of MSH2 Is a Frequent Event in Lynch Syndrome Colorectal Cancers

Esophageal squamous cell carcinoma (ESCC) is the seventh most common cancer and the sixth leading cause of cancer-related death worldwide, and has a male preponderance. The gender-based differences in clinical presentation and risk factor exposure are not fully studied. The aim of this study was to compare males and females with this disease. We retrospectively investigated the clinical data of 503 consecutive patients with ESCC from April 2011 to December 2019. Data collected included patient demographics, clinical presentation, pathology and risk factor exposure. We analyzed the differences in clinical characteristics and risk factor exposure between males and females with ESCC. Four hundred and sixty-nine patients with ESCC were included. The male to female ratio was 4.6:1. There was no significant difference in clinical presentation and pathology. There were significant differences between risk factor exposure between the two genders: smoking and alcohol consumption was an association in more than 90% of males but in less than 50% of females. The analysis including all patients showed no significant difference in survival rates, but when limited to patients with stage 3 or higher disease, survival rates were significantly higher in females (Figure). Smoking and alcohol consumption, traditionally considered risk factors, are less associated with female patients with ESCC, and other environmental risk factors might be more involved in this gender.

Eosinophilic gastroenteritis (EGE) can present findings on computed tomography (CT) images that resemble malignant tumors. EGE is generally treated with systemic oral steroid administration, which is reportedly effective in relieving symptoms at least temporarily. Here, we report a case of EGE that mimicked malignant lymphoma in a gastroduodenal lesion, in which treatment with a potassium-competitive acid blocker without systemic oral steroid administration relieved the symptoms and reversed the initial image findings. A 56-year-old woman became aware of discomfort in her epigastric region, which gradually worsened. This case showed antroduodenal wall thickness, which mimicked a malignant lymphoma with increased F-18 fluorodeoxyglucose (FDG) uptake by positron emission tomography/computed tomography (PET/CT). An upper gastrointestinal endoscopy revealed protruding erosions in the antrum and severe edematous changes in the duodenum. Extensibility of the normal gastric wall by insufflation also occurred. However, an abdominal ultrasound indicated wall thickening with a preserved wall structure. Histological examinations showed a large amount of eosinophil infiltration, mainly in the gastroduodenal mucosa, without malignant cells. Thus, we made a final diagnosis of EGE. The patient was then administered 20 mg vonoprazan fumarate per day because she refused steroid treatment and because the pathological lesion was also localized from the duodenum to the antrum. After 3 weeks of potassium-competitive acid blocker treatment, her symptoms were alleviated, and the degree and extent of thickening of the gastroduodenal wall in upper gastrointestinal endoscopy and ultrasonographic image findings had remarkably improved.

Ischemic enteritis (IE) is a rare disorder which is caused by inadequate blood flow to small intestine. The diagnostic procedure of this disease has not sufficiently established because of its rarity. Here, we report a case of IE in a hemodialysis-dependent 70-year-old man and summarize the diagnostic options for IE. The patient was admitted to our hospital because of acute abdominal distention and vomiting. He presented with mild tenderness in the lower abdomen and slightly elevated C-reactive protein level as revealed by blood tests. Radiographic imaging showed small bowel obstruction due to a stricture in the distal ileum. Contrast-enhanced abdominal ultrasonography revealed a 7-cm stenotic site with increased intestinal wall thickening, which preserved mucosal blood perfusion. Elastography revealed a highly elastic alteration of the stenotic lesion, indicating benign fibrotic changes resulting from chronic insufficient blood flow. Based on a clinical diagnosis of IE with fibrous stenosis, a partial ileostomy was performed. After surgical treatment, oral intake was initiated without recurrence of intestinal obstruction. Pathological findings revealed deep ulceration with inflammatory cell infiltration at the stenotic site. Occlusion and hyalinization of the venules in the submucosal layer indicated IE. In addition to current case, we reviewed past case reports of IE. Through this case presentation and literature review, we summarize the usefulness and safety of transabdominal ultrasonography for diagnosing IE.

Objective Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is overexpressed in a subset of malignant cells. However, it remains unknown whether ROR1 is targetable in malignant mesothelioma (MM). Therefore, in this study, we investigated the effects of ROR1 inhibition in mesothelioma cells. Materials and methods Growth inhibition, colony formation, apoptosis, and mRNA/protein levels using siRNA-transfected MM cells were evaluated. Cluster analysis using Gene Expression Omnibus repository of transcriptomic information was also performed. Results Our results indicated that in three (H2052, H2452, and MESO-1) among four MM cell lines, ROR1 inhibition had anti-proliferative and apoptotic effects and suppressed the activation of AKT and STAT3. Although growth inhibition by siROR1 was minimal in another mesothelioma cell line (H28), colony formation was significantly suppressed. Microarray, quantitative polymerase chain reaction, and Western blot analyses showed that there were differences in the suppression of mRNA and proteins between H2452 and H28 cells transfected with siROR1 compared with those transfected with control siRNA. Cluster analysis further showed that MM tumors had relatively high ROR1 expression, although the cluster in them was different from that in MM cell lines. Thymidylate synthase, a target of pemetrexed, was downregulated in H2452 cells transfected with siROR1. Accordingly, a combination of pemetrexed with siROR1 was found to be effective in the three MM cell lines we studied. Conclusion Our findings may provide novel therapeutic insight into the treatment of advanced MM.

The primary function of the esophagus is to facilitate bolus transport to the stomach. High-resolution manometry assesses the functions of esophageal motility, but not the clearance of bolus transit through the esophagus. The development of combined multichannel intraluminal impedance and manometry (MII-EM) has enabled simultaneous measurement of bolus transport and manometry. This study investigated the effects of bolus transit on esophageal motility disorders and its effect on the quality of life of patients with dysphagia. Methods A total of 810 wet swallows were reviewed and analyzed in 81 patients with dysphagia who underwent MII-EM. Incomplete bolus clearance (IBC) was defined based on impedance measurement. IBC was classified into four types (A: normal, B: incomplete clearance in the upper esophagus, C: incomplete clearance in the lower esophagus, D: incomplete clearance of the whole esophagus), and was also evaluated according to the appearance rate of complete bolus transit. Then, the clinical significance of IBC was determined by our previously validated dysphagia symptom score and the SF8 quality of life instrument (physical component summary and mental component summary). Results There were 16 cases of esophageal achalasia (Ach), 9 of esophagogastric junction outflow obstruction (EGJOO), 8 of distal esophageal spasm (DES), 7 of Jackhammer esophagus (JE), 2 of absent contractility (AC), 10 of ineffective esophageal motility (IEM) and 29 normal cases. The figure shows the breakdown of IBC for each disorder. Complete bolus transit was found in 27.8% in EGJOO, 52.5% in DES, 14.2% in JE, 4.0% in IEM, and 83.3% in normal; no CBT was found in Ach and AC. Patients with IBC had significantly higher dysphagia symptom scores (p Conclusion Patients with dysphagia with esophageal dysmotility were classified into two groups: those with and without IBC. Assessment of bolus transport is an important clinical marker for patients with dysphagia, because those with IBC had a significantly higher dysphagia symptom scores and impaired quality of life.

Dysphagia is a symptom suggestive of severe underlying pathology, although its causes include organic and non-organic disorders. A balance must be struck between the potential complications of any invasive investigation and its diagnostic utility, especially for elderly patients with dysphagia. The aim of this study was to investigate whether transabdominal ultrasonography (TUS) can differentiate among patients complaining of esophageal dysphagia including achalasia, distal esophageal spasms (DES), neoplasms involving the esophagogastric junction (EGJ) and healthy controls. Methods All patients complained of esophageal dysphagia, while healthy controls had no symptoms originating from esophagus. TUS was performed in 50 patients with achalasia, 17 DES patients, 10 patients with neoplasms, and 39 sex- and age-matched controls. All studies were performed with a 3.5 MHz real time curved array scanner and using an electronic caliper to measure esophageal wall thickness and the maximum esophageal diameter at 3 cm from EGJ. Manometric diagnoses were made based on the Chicago classification ver.3. The cutoff value of each TUS parameter was then calculated. Specificity and sensitivity in making a diagnosis of each disease were determined. Results There were significantly differences in the TUS parameters among four groups (Fig). The cutoff value of diameter of esophageal lumen to differentiate achalasia from other 3 groups was calculated as 13.1 mm (sensitivity, 0.96; specificity, 0.93), with an area under the curve (AUC) of 0.99, and that of esophageal wall thickness to differentiate both the tumor and DES groups from the other two groups was 3.5 mm (sensitivity, 0.64; specificity, 0.62), respectively. Using these parameters, sensitivity and specificity of diagnosis was 0.56 and 0.95 in achalasia, 1.00 and 0.24 in DES, and 1.00 and 0.21 in tumors. Conclusion TUS is a useful, non-invasive diagnostic aid in differentiating patients with primary achalasia from those with other causes of dysphagia.

Pathological identification of esophageal eosinophilia (EE) is considered to be most important and critical step for diagnosis of eosinophilic esophagitis (EoE). Although several endoscopic findings related with EoE have been reported, it is still difficult to exclude other causes of EE, such as gastroesophageal reflux disease. Here, we noted a novel endoscopic finding related with EoE termed ‘Caterpillar sign’. The aim of this study was to evaluate its clinical significance for the diagnosis of EoE. Methods One hundred and seventy-four patients who were endoscopically suspected with EoE at our hospital and affiliated institutions were enrolled. EoE was defined clinically by symptoms of esophageal dysfunction and histologically by the presence of EE [≧15 eosinophils/high power field (HPF)]. Endoscopic findings at baseline were retrospectively reviewed. ‘Caterpillar sign’ was defined as a stair-like, fragile, slight mucosal protruded lesion sandwiched between longitudinal furrows, such as the Caterpillar traces remaining on the ground (Figure). Furthermore, the clinicopathological features of patients having ‘Caterpillar sign’ were evaluated. Results One hundred and seventy-four patients (92 males, 82 females with mean age of 49.7) suspected with EoE were evaluated, of whom 60 (34.5%) was finally diagnosed as EoE. ‘Caterpillar sign’ was found in 48 patients (80.0%). Sensitivity and Specificity of ‘Caterpillar sign’ for the diagnosis of EoE was 0.80 (95% confidence interval [CI] 0.72–0.85) and 0.94 (95% CI 0.90–0.97), respectively. Furthermore, the presence of ‘Caterpillar sign’ was associated with degree of eosinophil infiltration (Caterpillar sign positive: 42.9 ± 49.3/HPF vs. Caterpillar sign negative: 6.7 ± 24.4/HPF, p Conclusion This novel finding termed ‘Caterpillar sign’ was clinically useful for the definitive diagnosis of EoE and associated with degree of eosinophil infiltration.

Highlights • Many recurrences occur after surgical resection of retroperitoneal liposarcoma. • Dedifferentiated liposarcoma in particular occasionally causes lung metastases. • In the case of no local recurrence, metastasectomy might be effective., Background The principle treatment for retroperitoneal liposarcoma is surgical resection, however there are many cases of recurrence. In addition to local recurrence, retroperitoneal liposarcoma, particularly dedifferentiated liposarcoma is known to occasionally cause lung metastases. Case report A 72-year-old woman with a diagnosis of retroperitoneal liposarcoma and probable right upper lobe early pulmonary adenocarcinoma underwent sequential local tumor resection and right upper lobectomy. Twenty months after liposarcoma resection, a computed tomography (CT) scan of the chest revealed a nodule located in the left lower lobe. A CT-guided biopsy was performed and she was subsequently diagnosed with pulmonary metastasis from retroperitoneal liposarcoma. The nodule enlarged chronologically, however a left lower lobectomy could not be performed because respiratory function after the right upper lobectomy was not sufficient. Therefore, in order to preserve the left superior segment (S6), the basal segments (S8+S9+S10) were resected. Seven months after the surgery, she is living a self-reliant life without recurrence of liposarcoma. Conclusion Here we have reported a case of pulmonary metastasis from retroperitoneal liposarcoma following limited surgery. In cases where respiratory function is limited, lower lobe segmentectomy can be an effective treatment. For the treatment of a single pulmonary metastasis from retroperitoneal liposarcoma, metastasectomy was considered to be effective as long as no local recurrence was seen after initial primary tumor resection.

Despite high expectations for lung tumoroids, they have not been applied in the clinic due to the difficulty of their long-term culture. Here, however, using AO (airway organoid) media developed by the Clevers laboratory, we succeeded in generating 3 lung tumoroid lines for long-term culture (>13 months) from 41 lung cancer cases (primary or metastatic). Use of nutlin-3a was key to selecting lung tumoroids that harbor mutant p53 in order to eliminate normal lung epithelial organoids. Next-generation sequencing (NGS) analysis indicated that each lung tumoroid carried BRAFG469A, TPM3-ROS1 or EGFRL858R/RB1E737*, respectively. Targeted therapies using small molecule drugs (trametinib/erlotinib for BRAFG469A, crizotinib/entrectinib for TPM3-ROS1 and ABT-263/YM-155 for EGFRL858R/RB1E737*) significantly suppressed the growth of each lung tumoroid line. AO media was superior to 3 different media developed by other laboratories. Our experience indicates that long-term lung tumoroid culture is feasible, allowing us to identify NGS-based therapeutic targets and determine the responsiveness to corresponding small molecule drugs.

Objectives The first aim of this study was to elucidate the detection rate of esophagogastroduodenoscopy (EGD) in patients complaining of dysphagia with esophageal motility disorders; the second was to clarify the useful parameters of EGD associated with esophageal motility disorders. Methods Participants included 380 patients who underwent EGD before high-resolution manometry (HRM) for dysphagia. EGD findings were investigated according to the following five parameters: resistance when passing through the esophagogastric junction (EGJ), residue in the esophageal lumen, esophageal dilation, and spastic and nonocclusive contractions. HRM diagnoses were based on the Chicago classification (v3.0). Results The percentage of abnormal EGD findings was 64.4% among patients with esophageal motility disorders, and the results differed for each esophageal motility disorder. The rate of abnormal EGD for both EGJ outflow obstruction and major disorders of peristalsis was significantly higher than that for manometrically normal subjects. On multivariate analysis, resistance when passing through EGJ, residue in the esophageal lumen, spastic and nonocclusive contraction were significantly associated with esophageal motility disorders. The sensitivity, specificity, positive predictive value, and negative predictive value of these parameters for detection of esophageal motility disorders were 75.1%, 86.6%, 84.8% and 77.8%, respectively. Conclusion Esophagogastric junction outflow obstruction and major disorders of peristalsis can be screened with EGD. Among several endoscopic parameters, resistance when passing through EGJ, residue in the esophageal lumen, spastic and nonocclusive contraction are considered significantly useful indicators.

A 26-year-old man with right lower mandibular and chest pain, fever, and respiratory distress was urgently transported to our hospital. CT images revealed gas collection and an abscess from the neck to the mediastinum with bilateral pleural effusion. Descending necrotizing mediastinitis (DNM) induced by an odontogenic infection of a right mandibular molar abscess was diagnosed. The cervical and mediastinal areas were drained, extensive debridement was performed, necrotic tissue was excised, and broad-spectrum antibiotics were administered immediately. Prompt diagnosis and intensive care were necessary for managing the DNM, and the patient was discharged with no comorbidities.

Purpose of the guidelines The primary objective of these guidelines is to provide general clinicians with information that would guide them to make informed choices of the available diagnosis/treatment strategies for esophageal cancer (intended for malignant esophageal tumors of epithelial origin, not for any other non-epithelial malignant tumors of the esophagus or metastatic esophageal malignant tumors). Furthermore, these guidelines are also intended as an aid for healthcare professionals other than the physicians, patients, and patients’ family members, to obtain an understanding of the fundamental principles of the diagnosis and treatment of esophageal cancer. These guidelines are intended to allow physicians to undertake diagnosis and treatment of esophageal cancer by sharing the information contained in the guidelines and promote mutual understanding among the healthcare professionals, patients, and their family members.

// Etsuko Yokota 1 , Tomoki Yamatsuji 1 , Munenori Takaoka 1 , Minoru Haisa 1 , Nagio Takigawa 2 , Noriko Miyake 3 , Tomoko Ikeda 3 , Tomoaki Mori 4 , Serika Ohno 4 , Takashi Sera 4 , Takuya Fukazawa 1 and Yoshio Naomoto 1 1 Department of General Surgery, Kawasaki Medical School, Okayama, 700-8505, Japan 2 Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, 700-8505, Japan 3 General Medical Center Research Unit, Kawasaki Medical School, Okayama, 700-8505, Japan 4 Department of Applied Chemistry and Biotechnology, Faculty of Engineering, Okayama University, Okayama, 700-8530, Japan Correspondence to: Takuya Fukazawa, email: fukazawat@aol.com Takashi Sera, email: sera@cc.okayama-u.ac.jp Keywords: artificial transcription factor (ATF), SOX2, squamous cell carcinoma, molecular targeted therapy Received: July 05, 2017 Accepted: September 20, 2017 Published: October 05, 2017 ABSTRACT SOX2 is a transcription factor essential for early mammalian development and for the maintenance of stem cells. Recently, SOX2 was identified as a lineage specific oncogene, recurrently amplified and activated in lung and esophageal squamous cell carcinoma (SCC). In this study, we have developed a zinc finger-based artificial transcription factor (ATF) to selectively suppress SOX2 expression in cancer cells and termed the system ATF/ SOX2 . We engineered the ATF using six zinc finger arrays designed to target a 19 bp site in the SOX2 distal promoter and a KOX transcriptional repressor domain. A recombinant adenoviral vector Ad-ATF/ SOX2 that expresses ATF/ SOX2 suppressed SOX2 at the mRNA and protein levels in lung and esophageal SCC cells expressing SOX2. In these kinds of cells, Ad-ATF/ SOX2 decreased cell proliferation and colony formation more effectively than the recombinant adenoviral vector Ad-sh SOX2 , which expresses SOX2 short hairpin RNA (sh SOX2 ). Ad-ATF/ SOX2 induced the cell cycle inhibitor CDKN1A more strongly than Ad-sh SOX2 . Importantly, the ATF did not suppress the cell viability of normal human cells. Moreover, Ad-ATF/ SOX2 effectively inhibited tumor growth in a lung SCC xenograft mouse model. These results indicate that ATF/ SOX2 would lead to the development of an effective molecular-targeted therapy for lung and esophageal SCC.

Smoking cigarettes and drinking alcoholic beverages are considered very important risk factors for adverse health effects, such as many types of cancer and cardiovascular disease. In this study, we evaluated the influence of smoking and drinking cessation on risk of esophageal cancer, by means of meta-analysis. We extracted 205 studies by conducting a systematic literature search. Thirty-five studies that estimated risk reduction following smoking cessation and 18 studies conducted following drinking cessation were identified in the literature review. Former smokers had a significantly lower summary risk ratio (RR) than current smokers [RR 0.74, 95% confidence interval (CI) 0.68–0.80]. In subgroup analysis of Japanese smokers, squamous cell carcinoma, and adenocarcinoma, RRs for former smokers versus current smokers were 0.65 (95% CI 0.51–0.83), 0.60 (95% CI 0.50–0.72), and 0.93 (95% CI 0.84–1.03), respectively. The summary RR between former alcohol drinkers and current drinkers was not significant (RR 1.09, 95% CI 0.94–1.26). In our analysis of time since drinking cessation, drinkers who had stopped consuming alcohol for 5 years or more had a significantly lower summary RR than current drinkers (RR 0.78, 95% CI 0.66–0.93). Summary RR for drinkers who stopped for 10 years or more versus current drinkers was 0.65 (95% CI 0.57–0.74). Our investigation found that smoking cessation lowers esophageal cancer incidence. We also found that esophageal cancer incidence risk could be decreased in current drinkers by cessation of alcohol consumption for 5 years or more.

Patient: Female, 56 Final Diagnosis: Birt-Hogg-Dubé syndrome Symptoms: Dyspnea Medication: — Clinical Procedure: — Specialty: Pulmonology Objective: Rare disease Background: Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder clinically characterized by pulmonary cysts, spontaneous pneumothorax, renal cell cancer, and skin fibrofolliculomas. The disorder is caused by germline mutations in the FLCN gene. Case Report: A 56-year-old female was admitted to our hospital with a diagnosis of bilateral spontaneous pneumothorax. A computed tomography (CT) scan of the chest revealed bilateral multiple bullae predominantly located in the subpleural and mediastinal areas in the bilateral upper and lower lobes. Although she was cured by thoracic cavity drainage, she underwent resection of bilateral lung bullae because she had a prior history of right pneumothorax at 37- and 45-years of age. She had no signs of renal tumor but had fibrofolliculoma in her face and a family history of pneumothorax, we therefore suspected BHD syndrome. DNA sequence analyses determined that there was a two base pair deletion in exon 4 of the FLCN gene, confirming the diagnosis of BHD syndrome. Conclusions: Here we report a case of BHD syndrome with a previously unreported FLCN mutation.