Field carcinogenesis and biological significance of the potential of the bystander effect: carcinogenesis, therapeutic response, and tissue regeneration.

The "bystander effect" is a transmission phenomenon mediating communication from target to non-target cells, as well as cell-to-cell interactions between neighboring and distantly located cells. In this narrative review, we describe the fundamental and clinical significance of the bystander effect with respect to cell-to-cell interactions in carcinogenesis, therapeutic response, and tissue regeneration. In carcinogenesis, the bystander effect mediates communications between tumor microenvironments and non-malignant epithelial cells and has been suggested to impact heterogeneous tumorigenic cells in tumors and cancerized fields. In therapeutic response, the bystander effect mediates communications between drug-sensitive and drug-resistant cells and may transmit both drug efficacy and resistance. Therefore, control of therapeutic response transmission via the bystander effect might offer a promising future cancer treatment. Finally, in tissue regeneration, circulating cells and stromal cells may differentiate into various cells for the purpose of tissue regeneration under direction of the bystander effect arising from surrounding cells in a defective space. We hope that the findings we present will promote the development of innovative cancer therapies and tissue regeneration methodologies from the viewpoint of cell-to-cell interactions through the bystander effect.

CD36 Expression Is Associated with Cancer Aggressiveness and Energy Source in Esophageal Squamous Cell Carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is an important cause of cancer-related death worldwide. CD36, a long-chain fatty acid (FA) receptor, can initiate metastasis in human oral squamous cell carcinoma (SCC), and its expression is associated with poor prognosis in several cancers. The clinical significance of CD36 expression and its function in ESCC remain unknown. METHODS: We examined the clinical significance of CD36 expression in 160 ESCC samples using immunohistochemical staining. Functional analysis was performed to determine the association between CD36 and ESCC characteristics (proliferative ability, invasive ability, and energy source dependency). RESULTS: Thirty (18.8%) ESCC cases showed high CD36 expression, indicating a significant association with progression. CD36 suppression inhibited proliferation and invasiveness in ESCC cells. ESCC cells with CD36 suppression used specific essential amino acids (EAAs) as energy sources. Cell viability depended on FAs under CD36 expression. The viability of ESCC cells with CD36 suppression depended on EAAs but not FAs. CONCLUSIONS: CD36 may be a good biomarker and therapeutic target in ESCC. Our data provide new insights into the basic mechanism of CD36-dependent energy utilization for ESCC survival. CD36 might be a key regulator of the dependency of FAs as energy source in ESCC cells.

Uptake of positron emission tomography tracers reflects the tumor immune status in esophageal squamous cell carcinoma.

The relationship between the local immune status and cancer metabolism regarding 18 F-FDG and 18 F-FAMT uptake in esophageal squamous cell carcinoma (ESCC) remains unknown. The present study examined the correlations between tumor immune status, clinicopathological factors, and positron emission tomography (PET) tracer uptake in ESCC. Forty-one ESCC patients who underwent 18 F-FDG PET and 18 F-FAMT PET before surgery were enrolled in the study. Immunohistochemistry was conducted for programmed death 1 (PD-1), CD8, Ki-67, CD34, GLUT1 (18 F-FDG transporter) and LAT1 (18 F-FAMT transporter). ESCC specimens with high tumoral PD-L1 and high CD8-positive lymphocytes were considered to have "hot tumor immune status." High PD-L1 expression (53.7%) was significantly associated with tumor/lymphatic/venous invasion (P = 0.028, 0.032 and 0.018), stage (P = 0.041), CD8-positive lymphocytes (P < 0.001), GLUT1 (P < 0.001), LAT1 expression (P = 0.006), Ki-67 labelling index (P = 0.009) and CD34-positive vessel counts (P < 0.001). SUVmax of 18 F-FDG was significantly higher in high PD-L1 cases than in low PD-L1 cases (P = 0.009). SUVmax of 18 F-FAMT was significantly higher in high PD-L1 (P < 0.001), high CD8 (P = 0.012) and hot tumor groups (P = 0.028) than in other groups. High SUVmax of 18 F-FAMT (≥4.15) was identified as the only predictor of hot tumor immune status. High PET tracer uptake was significantly associated with cancer aggressiveness and hot tumor immune status in ESCC. PET imaging may be an effective tool to predict tumor immune status in ESCC with respect to immune checkpoint inhibitor sensitivity.

Pathophysiology of Vomiting and Esophageal Perforation in Boerhaave's Syndrome.

BACKGROUND AND AIMS: Boerhaave's syndrome, involving esophagus rupture, is considered a pathological response to vomiting that may occur just before perforation. However, the mechanism of vomiting and occurrence of this disease have not been clearly demonstrated. METHODS: We identified patients with esophageal perforation between 1995 and 2017 and reviewed endoscopic findings at retching during upper gastrointestinal endoscopy. Finally, we proposed a theory for the underlying pathological mechanism. RESULTS: We retrospectively investigated 10 patients with esophageal perforation between 1995 and 2017. All patients presented after vomiting associated with large volumes of food and alcohol intake. Nine were treated by primary closure of the perforation and drainage of the thoracic cavity, and one was conservatively treated. In all cases, the perforations were longitudinal tears (1-4 cm) and located in the left of the esophagus, just above the gastric cardia. CONCLUSIONS: We hypothesize that vomiting occurred by retrograde propagation of gastrointestinal motor contraction from the jejunum to the gastric antrum, followed by prolapse of the gastric fornix mucosal into the esophagus. Subsequent esophageal perforation probably resulted from excessive prolapse due to strong contraction and destruction of the muscularis mucosa of the left side of abdominal esophagus, with longitudinal stretching of the whole left esophageal wall due to traction. We also propose that Boerhaave's syndrome is defined as "post-emetic esophageal perforation" to ensure broader recognition and more expedient diagnosis and treatment. Remaining conditions without any definite causes may be labeled "idiopathic" or "spontaneous" rupture of the esophagus.

Elucidation of the Anatomical Mechanism of Nodal Skip Metastasis in Superficial Thoracic Esophageal Squamous Cell Carcinoma.

BACKGROUND: Lymph node metastasis (LNM) is a standard mechanism of cancer progression in esophageal squamous cell carcinoma (ESCC). We aimed to clarify the anatomical mechanism of skip nodal metastasis to mediastinal zones by analyzing the relationship between LNM to sentinel zones and lymphatic vessel counts in the muscle layer adjacent to the outer esophagus. METHODS: We examined the surgical records of 287 patients with ESCC who underwent potentially curative surgery (three-field lymphadenectomy) and whole esophagi, including pharynges and stomachs from 10 cadavers, to determine the number of lymphatic vessels in the intra-outer longitudinal muscle layer adjacent to the outer esophagus of the cervical (Ce), upper thoracic, middle thoracic (Mt), lower thoracic (Lt), and abdominal esophagi (Ae). RESULTS: The frequency of LNM to the middle mediastinal and supraclavicular zones, including the Mt and Ce, respectively, was lower than to the upper and lower mediastinal and abdominal zone in patients with superficial and advanced thoracic ESCC. In cadavers, the lymphatic vessel counts of the intra-outer longitudinal muscle layer in the Mt and Ce were significantly lower than those of the Lt and Ae, suggesting that lymphatic flow toward the outside of the Mt and Ce was not more abundant than to other sites. CONCLUSION: Our anatomical data suggested that the absence of intra-muscle lymphatic vessels in the middle mediastinal and supraclavicular zones causes skip LNM in patients with thoracic ESCC. Thus, standard esophagectomy with lymph node dissection, including distant zones, may be appropriate for treating patients with superficial thoracic ESCC.

Correlation between high FBXW7 expression in pretreatment biopsy specimens and good response to chemoradiation therapy in patients with locally advanced esophageal cancer: A retrospective study.

BACKGROUND AND OBJECTIVES: Esophageal squamous cell carcinoma (ESCC) exhibits good reactivity to chemoradiation therapy (CRT). The dysregulation of F-Box and WD Repeat Domain Containing 7 (FBXW7) is associated with therapeutic resistance in cancer cells. However, the correlation between FBXW7 expression and CRT sensitivity in patients with clinical ESCC has been investigated only in few studies. Therefore, this study aimed to elucidate the significance of FBXW7 expression in pretreatment biopsy specimens from patients with ESCC receiving CRT. METHODS: We investigated the relationship between FBXW7 expression and CRT sensitivity in 30 pretreatment biopsy specimens with histological grades of post-CRT surgically resected tumors. Furthermore, we evaluated the effects of high FBXW7 expression on the sensitivity to cytotoxic agents, including docetaxel and nedaplatin, and radiation in ESCC cells in vitro. RESULTS: High FBXW7 expression before CRT correlated with a good pathological CRT response in patients with advanced ESCC (P < .05). Further, our in vitro data showed that both chemo and radiation sensitivity increased in TE-8 and KYSE140 cells overexpressing FBXW7 compared with mock cells because of the degradation of the anti-apoptotic protein MCL1. CONCLUSIONS: The evaluation of FBXW7 expression before CRT treatment is a potential predictor of good responders among patients with ESCC receiving CRT.

[High-resolution Manometry for Esophageal Motility Disorders].

High-resolution manometry (HRM) has significant contribution in the field of esophageal motility disorders recently. The development of HRM has categorized various esophageal motility disorders focusing on patterns of esophageal motor function. Additionally, the Chicago classification criteria are widely used for manometric diagnosis. HRM provides functional imaging of the esophagus. HRM has closely spaced pressure sensors and displays pressure variations as pressure topography plots. In the analysis of HRM according to the Chicago classification, a hierarchical categorization of motility disorders is made after evaluation of the individual swallow patterns. First the lower esophageal sphincter (LES) function, and subsequently the esophageal pressure patterns are used to make a diagnosis. The hierarchical flow-chart has 4 groups; (1) incomplete LES relaxation( achalasia or esophagogastric junction outflow obstruction), (2) major motility disorders, (3) minor motility disorders, (4) normal esophageal motility. HRM is the gold standard for diagnosis of esophageal motility disorders.

Elevated expression of ΔNp63 in advanced esophageal squamous cell carcinoma.

This study aims to explore the expression level of ΔNp63 in esophageal squamous cell carcinoma (ESCC). To investigate the association between ΔNp63 (p40) expression and ESCC biology, we compared the levels of ΔNp63 expression in normal and tumor tissues, with a specific focus on the diagnostic value of ΔNp63 in ESCC. We analyzed 160 consecutive patients with ESCC who underwent surgical resection without neoadjuvant chemotherapy at Gunma University Hospital (Maebashi, Japan) between September 2000 and January 2010. The clinicopathological characteristics and survival of patients were subclassified based on the expression of ΔNp63 as determined by immunohistochemistry, indicating that ΔNp63 was highly expressed in 75.6% (121/160) of ESCC patients. Clinicopathological analysis of ΔNp63 expression showed that ΔNp63-positive tumors significantly correlated with two important clinical parameters: T factor (P = 0.0316) and venous invasion (P = 0.0195). The 5-year overall survival rates of advanced ESCC patients with positive and negative expression of ΔNp63 were 35.6% and 71.7%, respectively. Multivariate analysis revealed that the expression of ΔNp63 was identified as an independent prognostic factor (P = 0.0049) in advanced ESCC. In line with this, ΔNp63α-transduced ESCC cell lines increased tumor growth in a soft agar colony formation assay. We report here for the first time that ΔNp63 expression increases the oncogenic potential of ESCC and is an independent marker for predicting poor outcome in advanced ESCC. Our findings suggest that ΔNp63 could serve as a new diagnostic marker for ESCC and might be a relevant therapeutic target for the treatment of patients with this disease.

Utility of double endoscopic intraluminal operation for esophageal cancer.

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

Impact of the Level of Anastomosis on Reflux Esophagitis Following Esophagectomy with Gastric Tube Reconstruction.

BACKGROUND: Among patients who undergo gastric tube reconstruction after esophagectomy, it is generally accepted that the incidence of reflux esophagitis (RE) is significantly lower in patients with neck anastomosis than in those with intrathoracic anastomosis. However, the true impact of the level of anastomosis on RE currently remains unclear. METHODS: We examined 53 patients with thoracic esophageal cancer underwent radical esophagectomy with gastric tube reconstruction and neck anastomosis. The level of anastomosis was assessed by measuring the distance from the sternal notch to the stapled ring by computed tomography. The relative level of anastomosis was calculated by the distance from the sternal notch to the most caudal side of the stapled ring (mm)/height (cm). RESULTS: The relative level of anastomosis in 30 (56.6%) patients showed <0, which indicated that anastomosis in these patients was located at a lower level than the sternal notch. The mean relative level of anastomosis was significantly lower in patients with RE (grade A to D) than in those without RE (grade N) (-0.062 vs. -0.012 mm/cm, respectively; p = 0.043). RE was more severe with a lower relative level of anastomosis (p for trends = 0.044). CONCLUSIONS: The level of anastomosis in patients with gastric tube reconstruction following esophagectomy was associated with the incidence of RE. The displacement of anastomosis into the thoracic cavity was detected in approximately half of the patients with neck anastomosis. RE was more severe with a lower level of anastomosis, even in patients with neck anastomosis.

SKIP interacts with c-Myc and Menin to promote HIV-1 Tat transactivation.

The Ski-interacting protein SKIP/SNW1 associates with the P-TEFb/CDK9 elongation factor and coactivates inducible genes, including HIV-1. We show here that SKIP also associates with c-Myc and Menin, a subunit of the MLL1 histone methyltransferase (H3K4me3) complex and that HIV-1 Tat transactivation requires c-Myc and Menin, but not MLL1 or H3K4me3. RNAi-ChIP experiments reveal that SKIP acts downstream of Tat:P-TEFb to recruit c-Myc and its partner TRRAP, a scaffold for histone acetyltransferases, to the HIV-1 promoter. By contrast, SKIP is recruited by the RNF20 H2B ubiquitin ligase to the basal HIV-1 promoter in a step that is bypassed by Tat and downregulated by c-Myc. Of interest, we find that SKIP and P-TEFb are dispensable for UV stress-induced HIV-1 transcription, which is strongly upregulated by treating cells with the CDK9 inhibitor flavopiridol. Thus, SKIP acts with c-Myc and Menin to promote HIV-1 Tat:P-TEFb transcription at an elongation step that is bypassed under stress.

Cysteine inhibits the fibrillisation and cytotoxicity of amyloid-ß 40 and 42: implications for the contribution of the thiophilic interaction.

Inhibitors of amyloid fibril formation have been at the centre of intense research efforts for the prevention of amyloidosis. Here, we hypothesise that a specific non-covalent interaction, the thiophilic interaction between the side chain of an aromatic residue in a polypeptide and a sulphur atom of the compound, effectively inhibits amyloid fibril formation. Fluorescence spectroscopy and transmission electron microscopy revealed that sulphur compounds, particularly Cys, inhibit the fibrillisation of amyloid-ß 1-40 (Aß40) and 1-42 (Aß42). Interestingly, aggregates of Aß40 and Aß42 induced by Cys were less cytotoxic than those induced by catechin, which is the most typical inhibitor of amyloid fibril formation. Because the essential amino acid, Cys, is an abundant molecule in the blood and cytosol, our data provide a new basis for the prevention of amyloid-related diseases and the elucidation of the mechanism of these diseases.

Flow cytometric method for in situ preparation of standard materials of a small defined number of microbial cells with colony-forming potentiality.

Standard materials of a small defined number of cells with colony-forming potentiality are essential for the rational validation of food microbiological methods. An in situ flow cytometric method using viable staining with 6-carboxyfluorescein diacetate (CFDA) and tryptic soy agar (TSA) was previously proposed and its feasibility was demonstrated with five strains. In this study, this method was applied to 16 strains to support its broad applicability. The cell sorting gate was previously determined based on the CFDA stainability alone. Now the structural properties of cells designated by forward and side-scattering intensities have been introduced as the second gating criteria. Under the optimum gate condition, 100 cells have been selected and sorted on TSA. Consequently, a 95% or higher colony-forming rate has been attained for every strain. A successful application to microaerophilic Campylobacter spp. is especially of great importance because it suggests further broader applicability.

Traumatic sigmoid colon rupture due to breast cancer metastasis: a case report.

The metastasis of breast cancer to the gastrointestinal tract is rare. Herein, we presented the case of an 85-year-old woman who had a history of invasive lobular carcinoma and experienced complete colon rupture due to relatively low-energy trauma. The patient underwent bilateral total mastectomy and axillary dissection following preoperative chemotherapy 6 years ago. She had a local recurrence 2 years after the surgery and underwent chemotherapy. Subsequently, the cancer metastasized to the thoracolumbar area and retroperitoneum. In addition, the patient fell from a height of 30 cm while hanging laundry and her abdomen hit a hose reel. Emergency surgery was performed, and the entire circumference of the sigmoid colon was ruptured. The ruptured colon lesion was resected, and the stump was closed. A double-barrel transverse colostomy was created as it was impossible to lift the stump up to the abdominal wall. Histopathological examination revealed the invasive lobular carcinoma metastasis and a linitis plastica-like change of the colon wall, which probably consequently weakened. In addition, minimal trauma can damage the gastrointestinal tract that had invasive lobular carcinoma metastasis.

A case of spontaneous esophageal submucosal hematoma.

A 78-year-old man visited a nearby hospital owing to chest pain triggered by vomiting. As computed tomography revealed suspected esophageal perforation, he was referred to our hospital. Upper gastrointestinal endoscopy showed blood coagula extending from the middle intra-thoracic to the esophago-cardiac junction (ECJ), and it was diagnosed as an esophageal submucosal hematoma. Conservative therapy was initiated by fasting and discontinuing oral anticoagulants. The lesion was monitored by upper gastrointestinal endoscopy. On day 12 of the symptom appearance, the hematoma had completely disappeared and on day 22, the patient was discharged from the hospital. In most cases, esophageal submucosal hematoma has a favorable course with preservative treatment. Esophageal submucosal hematoma should be considered as one of the differential diagnoses for chest pain triggered by vomiting.

Coexistence of superficial carcinogenesis of resident epithelium besides neuroendocrine neoplasm of the digestive tract.

BACKGROUND & AIMS: Mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) is a rare neuroendocrine neoplasm (NEN) comprising dual neuroendocrine and non-neuroendocrine components. Although the coexistence pattern of neuroendocrine and non-neuroendocrine components in definitive MiNEN is thought to overlap, there may be a coexistent pattern of both components, such as superficial carcinoma adjacent to NEN. The present study evaluated the histopathological findings of the coexistence pattern of superficial carcinomas adjacent to NENs in the esophagogastrointestinal tract. METHODS: From 2000 to 2019, 35 serial NEN resections of the esophagus (n = 9), stomach (n = 3), and large intestine (n = 23), respectively, were performed at Gunma University Hospital. Borderline areas between NEN and resident superficial epithelium were observed in the 35 serial NEN cases as well as two additional cases from affiliated hospitals. RESULTS: Among the 35 serial NEN samples, squamous cell carcinomatous/dysplastic components were identified 77.8% (7/9 cases) of esophageal NENs, and adenocarcinomatous areas were seen in 66.7% (2/3 cases) of gastric NENs and 26% (6/23 cases) of colorectal NENs. Thus, all superficial carcinomatous components adjacent to NENs were observed as squamous cell carcinoma/dysplasia in esophagus and adenocarcinoma in stomach and large intestine, which showed histological characteristics as the resident epithelial pattern in each organ. CONCLUSIONS: These findings suggested a potential "paratransformation" or "bystander effect" in resident epithelium by NENs. Thus, "bystander carcinogenesis" could be a pathogenic mechanism of resident epithelium transformation adjacent to NENs in the esophagogastrointestinal tract.

Effects of injured and dead cells of Escherichia coli on the colony-forming rate of live cells.

Osmotic stress-induced injured cells of Escherichia coli were prepared by sorting live cells onto tryptic soy agar (TSA) containing 10-50% sucrose. The time course of colony-forming rate (CFR%) was analyzed. A time delay in colony formation indicated a sublethal effect. The final CFR level at 24 h indicated the relative number of culturable cells irrespective of injury. A value of (100-CFR)% at 24 h indicated a lethal effect. When cells were grown on TSA containing 10% sucrose, the time delay was 4 h and the lethal effect was 4%. However, dead cells inhibited the growth of live cells. Physical contact with insoluble matter derived from dead cells or dead cells themselves might have caused growth inhibition. These findings highlight a novel perspective on colony count methods in practical situations, such as when sampling foods containing a high concentration of sucrose.

Comparative study on recurrence pattern and treatment method after radical esophagectomy for esophageal cancer.

Background : With regard to the recurrence of esophageal cancer after surgery, the prognosis has improved with the progress of multimodal perioperative treatment. In this study, the recurrence pattern, treatment method, and prognosis of recurrent cases following esophageal cancer surgery were retrospectively examined. Materials and Methods : Three hundred seven patients with histologically proven squamous cell carcinoma, adenocarcinoma, and others were enrolled in the study. With respect to clinicopathologic factors and recurrence patterns, recurrence risk factors, recurrence period, treatment for recurrence, and prognosis were investigated.Results : Ninety two percent of all recurrent cases were observed within two years after radical esophagectomy. Locoregional recurrence, distant recurrence, and mixed recurrence were observed in 38 (35%), 56 (51%), and 16 (14%) cases, respectively. Patients with lymph node metastasis showed a significantly longer survival in comparison to those with metastasis to other organs (p = 0.0032). When analyzed using the treatment method, patients who underwent surgery (only surgery or additional postoperative chemotherapy) exhibited better survival in comparison to those who underwent other treatments. Discussion : Detailed and strict follow-up within two years are necessary in cases with deeper than muscular invasion, cases with extensive lymph node metastasis, or cases with lymphatic or vascular invasion. J. Med. Invest. 68 : 129-135, February, 2021.

Resistance to Preoperative Oral Care Is Associated With Postoperative Pneumonia After Oesophageal Cancer Surgery.

BACKGROUND/AIM: Postoperative pneumonia is a serious complication of major oesophageal surgery. We aimed to clarify the association between the degree of improvement in oral hygiene by perioperative oral care and postoperative pneumonia in oesophageal cancer patients. PATIENTS AND METHODS: Oesophageal cancer patients (n=129) who underwent esophagectomy received perioperative oral care. Their oral hygiene was evaluated using the Oral Assessment Guide (OAG). The relationship between perioperative OAG scores and postoperative complications was analysed. RESULTS: The average OAG scores before starting oral care, pre-operation, and post-operation were 11.0±1.7, 9.1±1.5, and 11.2±3.0, respectively (p<0.001). An increase in preoperative OAG scores was independently associated with postoperative pneumonia on multivariate analysis (p=0.027). CONCLUSION: Preoperative oral care improves oral hygiene in patients undergoing oesophageal cancer surgery. No improvement in oral hygiene despite preoperative oral care was an independent predictor of postoperative pneumonia.