Correlation between TXNRD1/HO-1 expression and response to neoadjuvant chemoradiation therapy in patients with esophageal squamous cell carcinoma.

BACKGROUND: Thioredoxin reductase 1 (TXNRD1) and heme oxygenase-1 (HO-1) are both involved in the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and play key roles in antioxidant responses. In patients with esophageal squamous cell carcinoma (ESCC), the correlation between the expression of these two proteins and the therapeutic response to neoadjuvant chemoradiation therapy (NACRT), as well as the difference in their expression after chemoradiotherapy, remains unknown. METHODS: Proteins involved in the Nrf2 pathway were immunolocalized in carcinoma cells in ESCC patients on NACRT with 5-fluorouracil and cisplatin, followed by esophagectomy. The 8-hydroxydeoxyguanosine (8-OHdG) levels were used to quantify reactive oxygen species. The changes in immunoreactivity before and after NACRT (Δ) were assessed. RESULTS: Tumor reduction following NACRT was significantly attenuated in pre-therapeutic biopsy specimens associated with high HO-1 status. TXNRD1Δ, HO-1Δ, and 8-OHdGΔ were significantly different in the ineffective and effective groups. The overall survival was significantly lower in high Nrf2 and TXNRD1 groups. In addition, high TXNRD1 expression was an independent prognostic factor in the multivariate analysis of overall survival. CONCLUSIONS: The study findings indicate that HO-1 status in pre-therapeutic biopsy specimens could predict response to NACRT, and TXNRD1 status could predict overall survival of ESCC patients.

GR, Sgk1, and NDRG1 in esophageal squamous cell carcinoma: their correlation with therapeutic outcome of neoadjuvant chemotherapy.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a highly malignant neoplasm. The glucocorticoid (GC)-glucocorticoid receptor (GR) pathway plays pivotal roles in cellular response to various stresses of tumor cells, including chemotherapy. However, the status of the GC-GR pathway in ESCC, including its correlation with chemotherapeutic responses, is largely unknown. METHODS: GR, serum-and glucocorticoid-regulated kinase 1 (Sgk1), and N-myc down regulation gene 1 (NDRG1) were immunolocalized in 98 patients with ESCC who had undergone esophagectomy following neoadjuvant chemotherapy (NAC) with 2 courses of 5-fluorouracil + cisplatin. We also examined biopsy specimens before NAC in 42 cases and compared the results between those before and after NAC. RESULTS: Overall survival (OS) of the patients treated with surgery following NAC was significantly shorter in the group with high GR than that with low GR status (P = 0.0473). Both OS and disease-free survival (DFS) were significantly shorter in both Sgk1- and NDRG1-high groups than in the low groups (OS: Sgk1, P = 0.0055; NDRG1, P = 0.0021; DFS: Sgk1, P = 0.0240; NDRG1, P = 0.0086). Biopsy specimens before NAC showed significantly shorter DFS in the high Sgk1 group (P = 0.0095), while both OS and DFS were shorter in the high NDRG1 group (OS, P = 0.0233; DFS, P = 0.0006) than in the respective low groups. In the high NDRG1 group of biopsy specimens before NAC, the tumor reduction rate by NAC was significantly attenuated (P = 0.021). CONCLUSIONS: High GR, Sgk1, and NDRG1 statuses in ESCC after NAC was significantly associated with an overall worse prognosis, with no significant changes in their expression levels before and after NAC. Therefore, increased activity of the GC-GR pathway with enhanced induction of Sgk1 and NDRG1 in carcinoma cells play pivotal roles in tumor progression and development of chemo-resistance in patients with ESCC undergoing NAC.

Glucocorticoid receptor and serum- and glucocorticoid-induced kinase-1 in esophageal adenocarcinoma and adjacent Barrett's esophagus.

Barrett's esophagus (BE) is a consequence of gastroesophageal reflux disease and is predisposed to esophageal adenocarcinoma (EAC). EAC is an exemplar model of inflammation-associated cancer. Glucocorticoids suppress inflammation through glucocorticoid receptor (GR) and serum- and glucocorticoid-induced kinase-1 (Sgk1) expressions. Therefore, we immunolocalized GR and Sgk1 in EAC and the adjacent BE tissues and studied their association with clinical disease course in 87 patients with EAC who underwent surgical resection (N = 58) or endoscopic submucosal dissection (N = 29). Low GR and Sgk1 expressions in adjacent BE tissues were associated with adverse clinical outcomes (P = 0.0008 and 0.034, respectively). Patients with low Sgk1 expression in EAC cells exhibited worse overall survival (P = 0.0018). In multivariate Cox regression analysis, low GR expression in the adjacent nonmalignant BE tissues was significantly associated with worse overall survival (P = 0.023). The present study indicated that evaluation of GR and Sgk1 expressions in both the EAC cells and adjacent nonmalignant BE tissues could help to predict clinical outcomes following endoscopic and surgical treatments. In particular, the GR status in BE tissues adjacent to EAC was an independent prognostic factor.

Esophageal Carcinosarcoma with Basaloid Squamous Cell Carcinoma: A Case Report and Review of the Literature.

Esophageal carcinosarcoma is a rare tumor composed of neoplastic squamous epithelium and sarcomatous spindle cells. The origin of spindle cells remains unknown; however, the majority of sarcomatous components are currently considered to be derived from existing carcinomatous cells via epithelial-mesenchymal transition (EMT). We report a case of esophageal carcinosarcoma harboring basaloid squamous cell carcinoma successfully treated with preoperative chemotherapy. A 78-year-old man complaining dysphagia was diagnosed as esophageal carcinosarcoma. After two courses of preoperative chemotherapy with cisplatin and 5-fluorouracil, curative esophagectomy with lymph node dissection was performed thoracoscopically. Histopathological findings of the resected specimen revealed the mixture of basaloid squamous cell carcinoma and sarcomatous spindle cells. A transitional zone between both components was also detected. As fibrosis was identified around both two components, the findings indicated that both carcinomatous and sarcomatous neoplasms disappeared by preoperative chemotherapy. Final pathological diagnosis was esophageal carcinosarcoma with basaloid squamous cell carcinoma. No recurrent lesions have been detected for 25 months after the surgery. Sarcomatous spindle cells could be derived from the components of basaloid squamous cell carcinoma in our present case due to the presence of histological transition between two components. In addition, the marked immunoreactivity of vimentin (an EMT marker) detected in the tumor cells of basaloid squamous cell carcinoma could be consistent with the concept of monoclonal origin via EMT. The regimen targeting squamous cell carcinoma could also be effective in the treatment of sarcomatous components. Preoperative therapy might achieve the improvement of clinical outcome of patients with esophageal carcinosarcoma.

Definitive chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) for advanced cervical esophageal cancer.

BACKGROUND: Recently, definitive chemoradiotherapy (dCRT) has become one of the essential treatment strategies for esophageal squamous cell carcinoma (ESCC) and has been especially gaining prevalence for cervical ESCC to preserve the larynx. Our department recently introduced dCRT concomitant with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) for treating advanced cervical ESCC. This study aims to assess the safety and outcomes of DCF-R in patients with advanced cervical ESCC. METHODS: We retrospectively assessed 11 patients with advanced cervical ESCC (clinical stage: II-IV, including T4b and/or M1 lymph node) who received DCF-R as the first-line treatment between December 2010 and February 2015. RESULTS: Our patient cohort comprised 8 males and 3 females (median age 68 years; range 54-76 years). The pretreatment clinical stage included stage II (1), stage III (7), and stage IV (3) cases [including 3 patients with T4b (2 trachea and 1 thyroid) and 3 patients with M1 lymph node]. We attained complete response (CR) in 10 patients and stable disease in 1 patient. Of 10 patients with CR, 5 experienced recurrence and 5 continued exhibiting CR. Furthermore, grade 3 or more adverse events included leucopenia (91%), neutropenia (91%), febrile neutropenia (45%), and pharyngeal pain (55%). While the 2-year overall survival rate was 72%, the 2-year recurrent-free survival rate was 64%, respectively. CONCLUSIONS: DCF-R treatment for advanced cervical esophageal cancer could be completed by the careful administration; although a strong blood toxicity might occur, this treatment may provide the chance to obtain favorable prognosis with larynx preservation.

SOX2 and Rb1 in esophageal small-cell carcinoma: their possible involvement in pathogenesis.

Clinicopathological features and pathogenesis of esophageal small-cell carcinoma remain unclear. We hypothesized common cellular origin and pathogenesis in small-cell carcinoma of esophagus and lung associated with SOX2 overexpression and loss of Rb1. Expression of squamous-basal markers (CK5/6 and p40), glandular markers (CK18 and CEA), SOX2, and Rb1 were evaluated in 15 esophageal small-cell carcinomas, 46 poorly differentiated squamous cell carcinomas, and 88 small-cell lung carcinoma, as well as 16 embryonic esophagus. Esophageal small-cell carcinoma expressed higher levels of glandular markers and lower levels of squamous-basal markers than poorly differentiated squamous cell carcinoma. No significant differences were observed in immunohistochemistry profiles between small-cell carcinoma of the esophagus and the lung. SOX2 expression was high in esophageal small-cell carcinoma (70%±33% of nuclei), small-cell lung carcinoma (70%±26%), and the embryonic esophagus (75%±4%), and it was significantly lower in poorly differentiated squamous cell carcinoma (29%±28%). Rb1 expression was significantly lower in esophageal small-cell carcinoma (0.3%±1%), small-cell lung carcinoma (2%±6%), and the embryonic esophagus (7%±5%), and it was significantly higher in poorly differentiated squamous cell carcinoma (51%±24%). The immunohistochemistry profiles of small-cell carcinoma of the esophagus and the lung are highly similar. The loss of Rb1 function is a key contributor to the pathogenesis of both neoplasms. In addition, SOX2 overexpression observed in esophageal and lung small-cell carcinoma as well as in the embryonic esophagus indicated that esophageal small-cell carcinoma may arise from embryonic-like stem cells in the esophageal epithelium. The two distinct differentiation patterns (neuroendocrine and glandular) of esophageal small-cell carcinoma further support the fact that SOX2 has a pivotal role in the differentiation of pluripotent stem cells into esophageal small-cell carcinoma cells.

c-Met in esophageal squamous cell carcinoma: an independent prognostic factor and potential therapeutic target.

BACKGROUND: c-Met is widely known as a poor prognostic factor in various human malignancies. Previous studies have suggested the involvement of c-Met and/or its ligand, hepatocyte growth factor (HGF), in esophageal squamous cell carcinoma (ESCC), but the correlation between c-Met status and clinical outcome remains unclear. Furthermore, the identification of a novel molecular therapeutic target might potentially help improve the clinical outcome of ESCC patients. METHODS: The expression of c-Met and HGF was immunohistochemically assessed in 104 surgically obtained tissue specimens. The correlation between c-Met/HGF expression and patients' clinicopathological features, including survival, was evaluated. We also investigated changes in cell functions and protein expression of c-Met and its downstream signaling pathway components under treatments with HGF and/or c-Met inhibitor in ESCC cell lines. RESULTS: Elevated expression of c-Met was significantly correlated with tumor depth and pathological stage. Patients with high c-Met expression had significantly worse survival. In addition, multivariate analysis identified the high expression of c-Met as an independent prognostic factor. Treatment with c-Met inhibitor under HGF stimulation significantly inhibited the invasive capacity of an ESCC cell line with elevated c-Met mRNA expression. Moreover, c-Met and its downstream signaling inactivation was also detected after treatment with c-Met inhibitor. CONCLUSIONS: The results of our study identified c-Met expression as an independent prognostic factor in ESCC patients and demonstrated that c-Met could be a potential molecular therapeutic target for the treatment of ESCC with elevated c-Met expression.

Decreased expression of ARID1A contributes to infiltrative growth of esophageal squamous cell carcinoma.

The clinical outcome for esophageal squamous cell carcinoma (ESCC) patients is often poor because of the invasive nature of this tumor type. AT-rich interactive domain 1A (ARID1A) functions as a tumor suppressor, and its gene mutation has been reported in various human malignancies. ARID1A is a non-catalytic subunit of the SWItch/Sucrose Non Fermentable (SWI/SNF) chromatin-remodeling complex that regulates gene transcription. Decreased expression of ARID1A protein has been reported to decrease the expression of E-cadherin, an adhesion protein. However, the correlation between ARID1A and E-cadherin expression status in ESCC remains largely unknown. To address this issue, we examined the expression of ARID1A and E-cadherin in tumor specimens excised from 83 ESCC patients using immunohistochemical analysis. The intensity of the ARID1A immunoreactivity was significantly lower in tumors with a growth pattern characterized by ill-defined borders than that in tumors with an expansive growth pattern having a well-demarcated border or tumors with an intermediate growth pattern. Thus, decreased ARID1A immunoreactivity correlated with infiltrative growth of ESCC. In contrast, E-cadherin status did not correlate with the infiltrative growth pattern of ESCC. Moreover, ARID1A expression status did not significantly correlate with any of other clinicopathological factors, E-cadherin expression levels, or the clinical outcome of the patients. On the other hand, the patients with tumors expressing low levels of E-cadherin exhibited significantly lower survival rates than those with high expression. In conclusion, reduced ARID1A expression in tumor tissues contributes to infiltrative growth of ESCC, irrespective of E-cadherin expression levels.

[A rare case of lymphangitis carcinomatosa of the lung due to primary pulmonary adenocarcinoma with intestinal differentiation successfully treated with chemotherapy].

We report a rare case of lymphangitis carcinomatosa in a 66-year-old man with a relatively long survival of 18 months following chemotherapy.The patient initially presented with dyspnea and lower abdominal pain.Subsequent colonoscopy detected adenocarcinoma of the descending colon, and computed tomography (CT) demonstrated indications of lymphangitis carcinomatosa of the lung.Therefore, the patient was diagnosed with pulmonary metastasis due to colon cancer and administered chemotherapy.The performance status (PS) of patients with lymphangitis carcinomatosa is usually dismal.This patient's PS was also poor, but dyspnea markedly improved following chemotherapy, and a subsequent CT revealed disappearance of radiological findings of lymphangitis carcinomatosa.However, subsequent immunocytochemistry analysis using the cell transfer method in bronchoalveolar lavage fluid specimens revealed diffuse positivity for cytokeratin (CK) 7, while the colon carcinoma was negative for CK7.The difference in CK7 immunoreactivity between the bronchoalveolar lavage fluid and biopsy specimen of the colon indicated that the lymphangitis carcinomatosa in this patient could be reasonably postulated to be caused by a synchronous primary pulmonary adenocarcinoma with intestinal differentiation.However, an autopsy could not be performed to test this hypothesis.

Blood flow ratio in the gastric conduit measured by laser Doppler flowmetry: A predictor of anastomotic leakage after esophagectomy.

Background: Anastomotic leakage after esophagectomy is a common complication. Laser Doppler flowmetry (LDF) can quantitatively evaluate the blood flow in the gastric conduit. Methods: A total of 326 patients who underwent thoracoscopic/robot-assisted esophagectomy followed by gastric conduit reconstruction and end-to-side anastomosis were enrolled. We divided the gastric conduit into zones I (dominated by the right gastroepiploic vessels), II (dominated by the left gastroepiploic vessels), and III (perfused with short gastric vessels). Before pulling up the gastric conduit to the neck, LDF values were measured at the pylorus, the border between zones I and II (zone I/II), the border between zones II and III (zone II/III), and the gastric conduit tip (tip). The blood flow ratio was calculated as the LDF value divided by the LDF value at the pylorus. Results: Anastomotic leakage developed in 32 of 326 patients. Leakage was significantly associated with the blood flow ratio at the tip (p < 0.001), but not at zone I/II, zone II/III, and the anastomotic site. The receiver-operating characteristic curve analysis identified an anastomotic leakage cutoff ratio of 0.41 (at the tip). A multivariate Cox analysis showed that a blood flow ratio <0.41 at the tip was an independent risk factor for anastomotic leakage (p < 0.001). Conclusion: Anastomotic leakage after esophagectomy was significantly associated with the blood flow ratio at the tip of the gastric conduit. Preservation of the blood supply to the tip via the gastric wall might contribute to a decreased incidence of anastomotic leakage.

A diagnostic pitfall; Small cell carcinoma-like features in basaloid squamous cell carcinoma of the esophagus.

Esophageal basaloid squamous cell carcinoma may resemble small cell carcinoma biopsy specimens and cause difficulties in pathology diagnosis. We aimed to clarify the clinicopathological significance of small cell carcinoma-like morphologies in basaloid squamous cell carcinoma. Thirty biopsy specimens of esophageal basaloid squamous cell carcinoma were reviewed and compared with 13 matched surgical specimens. Small cell carcinoma-like features, such as diffuse growth, nuclear molding, or nuclear crush artifact, were identified in 80% (24/30) of the biopsies and in 77% (10/13) of the surgery specimens, but in a proportionally much smaller area in the surgical specimens than in the biopsy samples. The presence of a small cell carcinoma-like feature had no impact on patients´ outcome. Immunohistochemically, synaptophysin and chromogranin A were consistently negative, while CD56 was expressed in 42% (10/24) of basaloid squamous cell carcinomas with small cell carcinoma-like features. p16, a highly sensitive marker for small cell carcinoma, was also expressed in 8% (2/24). p40 was expressed in all cases of basaloid squamous cell carcinoma. In conclusion, small cell carcinoma-like features are frequent and conspicuous in biopsies, which are probably caused by exogenous factors such as friction and external pressure that occur in biopsy procedure and in the tumor environment. Small cell carcinoma-like features may lead to a misinterpretation of a true small cell carcinoma, if CD56 is the only neuroendocrine marker expressed. p16 expression may also be detected in basaloid squamous cell carcinoma.

Distinguishing Killian-Jamieson diverticulum from Zenker's diverticulum.

BACKGROUND: Killian-Jamieson diverticulum, which is a relatively rare pharyngoesophageal diverticulum, is difficult to distinguish from Zenker's diverticulum. Because major points of the relevant surgical procedures for these two entities differ, it is important to make an accurate diagnosis. We herein report a case of Killian-Jamieson diverticulum initially diagnosed as Zenker's diverticulum. CASE PRESENTATION: A 56-year-old man complaining of discomfort during swallowing was diagnosed with pharyngoesophageal diverticulum. He was initially diagnosed with Zenker's diverticulum before surgery, but the diverticulum actually arose from the left side of the esophageal wall, at the level of the cricoid cartilage and below the cricopharyngeal muscle. We therefore ultimately diagnosed this case as Killian-Jamieson diverticulum during surgery, and were able to preserve the muscle above the diverticulum, which would normally have to be cut when treating a case of Zenker's diverticulum. CONCLUSION: To make an accurate diagnosis, clinical and surgical findings are important to consider, including the location of the diverticulum and the relationship between the diverticula and cricopharyngeal muscles or between the diverticula, thyroid cartilage and cricoid cartilage.

Correlation between KRAS Mutation and CTLA-4 mRNA Expression in Circulating Tumour Cells: Clinical Implications in Colorectal Cancer.

Combination strategies of KRAS inhibition with immunotherapy in treating advanced or recurrent colorectal carcinoma (CRC) may need to be assessed in circulating tumour cells (CTCs) to achieve better clinical outcomes. This study aimed to investigate the genomic variations of KRAS in CTCs and matched CRC tissues and compared mRNA expression of KRAS and CTLA-4 between wild-type and KRAS-mutated CTCs and CRC tissues. Clinicopathological correlations were also compared. Six known mutations of KRAS were identified at both codon 12 and codon 13 (c.35G>T/G12V, c.35G>A7/G12D, c.35G>C/G12A, c.34G>A/G12S, c.38G>C/G13A, and c.38G>A/G13D). Three CTC samples harboured the identified mutations (16.7%; 3/18), while fifteen matched primary tumour tissues (65.2%, 15/23) showed the mutations. CTCs harbouring the KRAS variant were different from matched CRC tissue. All the mutations were heterozygous. Though insignificant, CTLA-4 mRNA expression was higher in patients carrying KRAS mutations. Patients harbouring KRAS mutations in CTCs were more likely to have poorly differentiated tumours (p = 0.039) and with lymph node metastasis (p = 0.027) and perineural invasion (p = 0.014). KRAS mutations in CTCs were also significantly correlated with overall pathological stages (p = 0.027). These findings imply the genetic basis of KRAS with immunotherapeutic target molecules based on a real-time platform. This study also suggests the highly heterogeneous nature of cancer cells, which may facilitate the assessment of clonal dynamics across a single patient's disease.

Pancreatic neuroendocrine neoplasms: Updates on genomic changes in inherited tumour syndromes and sporadic tumours based on WHO classification.

Pancreatic neuroendocrine neoplasms (PanNENs) are the neuroendocrine neoplasms with greatest rate of increase in incidence. Approximately 10% of PanNENs arise as inherited tumour syndromes which include multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 4, von Hippel-Lindau syndrome, neurofibromatosis type1, tuberous sclerosis complex 1/2, Cowden syndrome, and Glucagon cell hyperplasia and neoplasia as well as familial insulinomatosis. In sporadic PanNENs, driver mutations in MEN1, DAXX/ATRX and mTOR pathway genes are associated with development and progression in pancreatic neuroendocrine tumours. The other changes are in VEGF pathway, Notch pathway, germline mutations in MUTYH, CHEK2, BRCA2, PHLDA3 as well as other genetic alterations. On the other hand, pancreatic neuroendocrine carcinomas share similar genetic alterations with ductal adenocarcinomas, e.g., TP53, RB1 or KRAS. In addition, microRNA and changes in immune microenvironment were noted in PanNENs. Updates on these genetic knowledges contribute to the development of management strategies for patients with PanNENs.

Minimally Invasive Surgery for Sternoclavicular Joint Infection with Osteomyelitis, Large Abscesses, and Mediastinitis.

Background: Sternoclavicular joint infections require en bloc resection for radical cure; however, this aggressive procedure may result in multiple adverse events. Therefore, performing minimally invasive surgery is desirable. In this report, we describe a case of sternoclavicular joint infection complicated by osteomyelitis, large abscesses, and mediastinitis that was successfully treated with incision and drainage. Case Presentation. A 42-year-old man with no medical history presented to our hospital with complaints of painful swelling in the left chest wall and acute dyspnea. Computed tomography revealed arthritis of the left sternoclavicular joint, osteomyelitis of the clavicle and sternum, anterior mediastinitis, and abscesses in the neck, chest wall, and retrosternal and extrapleural spaces. Gram staining of the aspirated pus revealed clusters of gram-positive cocci. A diagnosis of Staphylococcus aureus sternoclavicular joint infection with locoregional spread was made. Emergency surgery was performed following adequate resuscitation. A skin incision was made in the second intercostal space. The joint capsule was widely opened, necrotic tissue was curetted, and closed suction drains were placed in the abscess cavities and connected to a negative pressure system. The wound was then closed using primary sutures. The postoperative course was uneventful. Methicillin-sensitive Staphylococcus aureus was cultured from the pus. The patient was discharged on postoperative day 14. Osteomyelitis worsened within a few weeks after surgery but recovered with wound management and six weeks of antibiotic therapy. The patient has had no recurrence of infection for two years. Conclusions: Incision and drainage proved to be an effective minimally invasive surgical treatment for sternoclavicular joint infection with osteomyelitis, large abscesses, and mediastinitis caused by methicillin-sensitive Staphylococcus aureus.

Murine Double Minute 2 Antagonist Nutlin-3 Enhanced Chemosensitivity in Esophageal Squamous Cell Carcinoma.

BACKGROUND/AIM: Murine double minute 2 (MDM2) is well known to inhibit p53 function and its over-expression is associated with poor prognosis in several human malignancies. Nutlin-3, a small-molecule inhibitor of MDM2, exerts antitumor effects on various solid tumors harboring wild-type p53. We aimed to clarify its effects on esophageal cancer. MATERIALS AND METHODS: We first examined the potential antitumor effects of nutlin-3 according to MDM2 status using esophageal carcinoma cell lines (KYSE 170/180). We then immunolocalized MDM2 immunoreactivity in 62 surgical cases of esophageal squamous cell carcinoma undergoing neoadjuvant chemotherapy followed by esophagectomy and correlated the findings with clinicopathological variables. RESULTS: MDM2 mRNA expression in KYSE 170 was significantly higher than that in KYSE 180 cells. No significant changes were detected in both cell lines when nutlin-3 was added. However, cell proliferation was significantly decreased in KYSE 170 cells treated with nutlin-3 and cisplatin compared to cisplatin alone but not in KYSE 180. MDM2 immunoreactivity was also significantly associated with poor sensitivity to neoadjuvant chemotherapy in the cases examined. CONCLUSION: The combination of nutlin-3 with chemotherapeutic agents may become a novel therapeutic strategy in esophageal cancer over-expressing MDM2.

Perioperative Administration of Cystine and Theanine Suppresses Inflammation and Facilitates Early Rehabilitation and Recovery after Esophagectomy: A Randomized, Double-Blind, Controlled Clinical Trial.

Oral administration of cystine and theanine (CT) increases glutathione levels to modulate the inflammatory response, which has yet to be sufficiently explored for patients' recovery and early rehabilitation. We planned a randomized, double-blind, placebo-controlled trial to determine whether perioperative oral administration of CT promotes recovery after esophagectomy. Patients were randomized into either CT or placebo groups, who received preoperative and postoperative treatments for 4 and 13 days, respectively. The main outcome measures were triaxial accelerometer readings, inflammation indicators, a 6 min walk test (6MWT), and a quality of life questionnaire (QoR-40). The study involved 32 patients. Although the CT group (n = 16) showed better patient activity across the investigated period, there was no significant difference between the two groups. However, white blood cell count on postoperative days (POD) 2 and 10, neutrophil count (POD 2, 7, and 10), and C-reactive protein level (POD 13) in the CT group were significantly lower than in the placebo group. Furthermore, 6MWT on POD 7 and QoR-40 on POD 13 were significantly higher in the CT group than those in the placebo group. This study suggests that perioperative administration of CT may contribute to early recovery and rehabilitation after esophagectomy via suppression of inflammatory response.

HO-1 in lymph node metastasis predicted overall survival in patients with esophageal squamous cell carcinoma receiving neoadjuvant chemoradiation therapy.

BACKGROUND: Lymph node metastasis is one of the pivotal factors of the clinical outcomes of patients with esophageal cancer receiving neoadjuvant chemoradiation therapy (NACRT). Both the nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathway and heme oxygenase-1 (HO-1) are frequently upregulated in various human malignancies and associated with resistance to chemoradiation therapy, subsequently resulting in adverse clinical outcomes. However, the Nrf2 and HO-1 status in lymph node metastasis and their differences between primary and metastatic lesions are unknown. AIMS: To examine the levels of Nrf2 signaling proteins and HO-1 in primary and metastatic lesions of patients with esophageal squamous cell carcinoma using immunohistochemistry. METHODS AND RESULTS: We immunolocalized Nrf2 signaling proteins in 69 patients with lymph node metastases, who received NACRT with 5-fluorouracil and cisplatin before esophagectomy. We also compared the findings between primary and metastatic lesions. Residual lymph node metastases were detected in 30 patients and among them, both primary and metastatic lesions were available for evaluation in 25 patients. Subsequently, we correlated the results with patients' survival. Nrf2, HO-1, and the Ki-67 labeling index were all significantly lower in the patients with lymph node metastases than in those with primary tumors. Carcinoma cells with high HO-1 levels were significantly associated with pathological resistance to NACRT. These results suggested that overall and disease-free survival of esophageal squamous cell carcinoma were significantly associated with both pN2 and high HO-1 levels, respectively. CONCLUSIONS: Protein expression in the Nrf2 pathway was significantly lower in patients with lymph node metastases than in those with primary lesions. HO-1 levels in lymph node metastases could be used to predict the eventual clinical outcome of patients with esophageal cancer receiving NACRT.

An extremely rare case of desmoplastic fibroblastoma exhibiting rapid growth in the chest wall: a case report.

BACKGROUND: Desmoplastic fibroblastoma is an uncommon, benign, fibrous tumor exhibiting infiltrative growth. Most of these tumors are small, slow-growing, and develop as subcutaneous lesions in the extremities. Cases of desmoplastic fibroblastoma in the chest wall are quite rare, and the preoperative diagnosis of such cases remains challenging as these tumors can mimic the characteristics of desmoid-type fibromatosis, which often occurs in the chest wall. We aimed to describe a rare case of desmoplastic fibroblastoma exhibiting rapid growth in the chest wall of a patient that was successfully treated with marginal excision only by diagnostic imaging before surgery. CASE PRESENTATION: A 79-year-old man was admitted to our hospital after experiencing right shoulder pain lasting for a few months. A 4 × 4 × 2 cm mass was incidentally detected at the right second rib two years prior. Chest computed tomography revealed a well-defined homogeneous mass with a muscle-like density along the right lateral chest wall, the size of which had increased to 12 × 10 × 4.5 cm in two years. Dynamic contrast-enhanced computed tomography revealed abundant vascularity at the periphery of the tumor. Magnetic resonance imaging revealed iso-intensity to muscle on T1-weighted images, slightly high intensity on T2-weighted images, and rim-like contrast enhancement at the periphery of the tumor, with uniform thickness on gadolinium-enhanced T1-weighted images with fat suppression. Rim-like contrast enhancement is an imaging feature that can distinguish cases of desmoplastic fibroblastoma from desmoid-type fibromatosis. We diagnosed the tumor as desmoplastic fibroblastoma by diagnostic imaging without tissue biopsy. Marginal excision with videoscopic assistance was performed through a small incision. The pathological diagnosis was desmoplastic fibroblastoma. The patient's postoperative course was uneventful, and his shoulder pain was relieved after the surgery. CONCLUSIONS: Desmoplastic fibroblastoma in the chest wall is extremely rare, but should be considered in the differential diagnosis when desmoid-type fibromatosis is clinically suspected. Gadolinium-enhanced magnetic resonance imaging is helpful in confirming the differential diagnosis.

Pancreatic neuroendocrine neoplasms: Clinicopathological features and pathological staging.

The nomenclature and classification of pancreatic neuroendocrine neoplasms has evolved in the last 15 years based on the advances in knowledge of the genomics, clinical behaviour and response to therapies. The current 2019 World Health Organization classification of pancreatic neuroendocrine neoplasms categorises them into three groups; pancreatic neuroendocrine tumours (PanNETs)(grade 1 grade 2, grade 3), pancreatic neuroendocrine carcinomas and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) based on the mitotic rate, Ki-67 index, morphological differentiation and/or co-existing tissue subtype. PanNETs are also classified into non-functional NET, insulinoma, gastrinoma, VIPoma, glucagonoma, somatostatinoma, ACTH-producing NET and serotonin producing NET based on hormone production and clinical manifestations. A portion of the cases were associated with genetic syndromes such as multiple neuroendocrine neoplasia 1 (MEN 1), neurofibromatosis and Von Hippel-Lindau syndrome. In view of the distinctive pathology and clinical behaviour of PanNENs, the current 8th AJCC/UICC staging system has separated prognostic staging grouping for PanNETs from the pancreatic neuroendocrine carcinomas or MiNENs. Pancreatic neuroendocrine carcinomas and MiNENs are staged according to the prognostic stage grouping for exocrine pancreatic carcinoma. The new stage grouping of PanNETs was validated to have survival curves separated between different prognostic groups. This refined histological and staging would lead to appropriate selections of treatment strategies for the patients with pancreatic neuroendocrine neoplasms.