Three-dimensional imaging of intramural perineural invasion in colorectal cancer: Three-dimensional reconstruction approach with multiple immunohistochemically stained sections.

Perineural invasion (PNI) at Auerbach's plexus in colorectal cancer (CRC), known as intramural PNI, is associated with adverse prognostic outcomes. This study aimed to characterize the three-dimensional (3D) architecture of CRC with intramural PNI and to evaluate the morphological features of tumor invasion around nerve tissue. Serial tissue sections from two cases of CRC were stained with cytokeratin AE1/AE3 and an anti-S-100 protein antibody. 3D models were reconstructed by scanning the virtual slides. In one case, intramural PNI was observed at the horizontal invasive front. The 3D reconstruction model showed tumor cells that appeared to infiltrate along the nervous meshwork, the structure of which was preserved. In the other case, intramural PNI was observed both at and behind the horizontal invasive front, and the 3D reconstruction model showed that the tumor cells appeared to be involved with nerve cells at the focal part of the horizontal invasive front. However, the nervous meshwork structure was not well identified in cancer-involved areas. This is the first study to characterize the 3D structure of tumor invasion around nerve tissue in CRC, demonstrating the morphological features of intramural PNI in CRC.

[A Case of Severe Aortic Thrombosis during the First Chemotherapy Regimen of CapeOX plus Bevacizumab for Metastatic Colon Cancer].

A 61-year-old man underwent CapeOX plus bevacizumab chemotherapyafter right hemicolectomyfor metastatic ascending colon cancer. On the 7th dayafter the first administration, he had sudden abdominal pain and nausea. Contrast-enhanced computed tomographyrevealed aortic thrombosis and a superior mesenteric artery(SMA)embolism that was considered to be associated with bevacizumab. Bevacizumab was discontinued and anticoagulation therapyusing heparin and urokinase was performed. Brain infarction of the left middle cerebral arteryoccurred on the 15th dayafter the first administration and thrombectomywas performed. Anticoagulation therapyusing heparin, bayaspirin, and edoxaban tosilate hydrate was performed. The aortic thrombosis and SMA embolism resolved with treatment, but the patient died following an increase in peritoneal dissemination. It should be noted that unexpectedlysevere aortic thrombosis occurred during the first administration of CapeOX plus bevacizumab for metastatic colon cancer.

Clinical significance of programmed cell death-ligand 1 expression and the immune microenvironment at the invasive front of colorectal cancers with high microsatellite instability.

Immunotherapy is reportedly effective in colorectal cancers (CRCs) with high microsatellite instability (MSI-H); however, the specific cell types that respond to immune checkpoint therapy are unclear. Herein, we aimed to examine the expression of programmed cell death-ligand 1 (PD-L1) and related proteins in MSI-H and microsatellite-stable (MSS) CRCs to investigate the immune microenvironment at the tumor's invasive front. The MSI status was retrospectively assessed in 499 patients undergoing surgical resection of primary CRC; of these, 48 were classified as MSI-H. Propensity score matching was performed, and tissues from 36 and 37 patients with MSI-H and MSS CRCs, respectively, were immunohistochemically evaluated for PD-L1, PD-1, CD8 and CD68. PD-L1 expression was evaluated separately for tumor cells (PD-L1 [T]) and tumor-infiltrating myeloid cells in the stroma (PD-L1 [I]). PD-L1 (T) was positive in only 5.4% and 36.1% of MSS and MSI-H CRCs, while PD-L1 (I) was positive in 27% and 72.2% of these CRCs, respectively. The PD-L1 (T) and PD-L1 (I) expression levels in MSI-H CRCs significantly correlated with poor differentiation, lymphatic invasion and vascular invasion (p < 0.05), and with early-stage adenocarcinoma and high budding grade (p < 0.05), respectively. Significantly more PD-L1 (I), CD8-positive cells and CD68-positive macrophages were present at the invasive front than in the central tumor in MSI-H CRCs (p < 0.005). PD-L1 was expressed on both tumor cells and CD68/CD163-positive (M2) macrophages at the invasive front of MSI-H CRCs. In conclusion, PD-L1-positive tumor cells and M2-type tumor-associated macrophages may contribute to tumor invasion and immune escape at the invasive front.

A novel histological examination with dynamic three-dimensional reconstruction from multiple immunohistochemically stained sections of a PD-L1-positive colon cancer.

AIMS: Programmed cell death-ligand 1 (PD-L1) expression is observed in patients with microsatellite instability-high (MSI-H) colon cancer, which is susceptible to immune checkpoint blockade. The aim of this study was to investigate the interrelationship between PD-L1-positive cells and cytotoxic T cells, lymphatic vessels and vascular endothelium by using histological examination with the three-dimensional (3D) reconstruction of a PD-L1-positive colon cancer. METHODS AND RESULTS: Serial sections of MSI-H colon cancer tissue were stained with haematoxylin and eosin (H&E) and Masson trichrome stains; immunohistochemical analysis of PD-L1, CD8, D2-40 and CD31 was performed. Several 3D models of MSI-H colon cancer were reconstructed with a 3D data visualisation system. Moreover, 18 serial sections were stained with PD-L1, cytokeratin AE1/AE3, CD45, CD31, CD68 and H&E in the same case to confirm that PD-L1 was expressed on tumour cells, CD31-positive cells and macrophages in the invasive frontal region. Notably, there was a peak in the expression of PD-L1 and CD31 in the invasive frontal region. D2-40-positive cells were abundant in the overall tumour stroma, and CD8-positive cells infiltrated the tumour parenchyma. PD-L1 was expressed on tumour cells in the parenchyma and other cells in the stroma. Additional staining of 18 consecutive sections revealed that the other cells were CD68-positive and CD45-positive macrophages and CD31-positive proliferating vascular endothelial cells. CONCLUSIONS: We confirmed that PD-L1 was highly expressed in the invasive frontal region in 3D models of MSI-H colon cancer tissue. This method can be useful for accurately evaluating the localisation of immune checkpoint molecules.

Neoadjuvant Chemoradiotherapy for Patients with cT3/Nearly T4 Esophageal Cancer: Is Sarcopenia Correlated with Postoperative Complications and Prognosis?

BACKGROUND: Since the clinical impact of sarcopenia on multimodal therapy for patients with esophageal cancer is not well understood, this study was conducted to determine the influence of sarcopenia on the efficacy of neoadjuvant chemoradiotherapy (NACRT) for locally advanced esophageal cancer. METHODS: The skeletal muscle index was quantified at the level of the third lumbar vertebra on computed tomography images, and sarcopenia was defined as a skeletal muscle index that was less than the average for each gender. We compared treatment outcomes in patients with cT3 and nearly T4 thoracic esophageal squamous cell carcinoma between the sarcopenia group (n = 85) and the non-sarcopenia group (n = 72). RESULTS: The 5-year survival rates were 33.4% in the non-sarcopenia group and 31.5% in the sarcopenia group; these differences were not significant. The prognosis of the patients with sarcopenia was worse than that of the patients without sarcopenia in the surgery-alone group, but there was no difference between patients with and without sarcopenia in the NACRT group. CONCLUSIONS: NACRT could be a useful option for patients with locally advanced esophageal squamous cell carcinoma, even for those with sarcopenia, without increasing the incidence of morbidity and mortality.

Sarcopenia is an independent predictor of complications after colorectal cancer surgery.

PURPOSE: The significance of sarcopenia after colorectal cancer (CRC) resection has only been discussed with relatively small samples or short follow-up periods. This study aimed to clarify the clinical significance of sarcopenia in a large-sample study. METHODS: We retrospectively analyzed the relationship between sarcopenia and clinical factors, surgical outcomes, and the survival in 494 patients who underwent CRC surgery between 2004 and 2013. Sarcopenia was defined based on the sex-specific skeletal muscle mass index measured by preoperative computed tomography. RESULTS: Sarcopenia was associated with sex (higher rate of male, P < 0.0001), and low body mass index (P < 0.0001), but not age or tumor stage. Sarcopenia was associated with higher incidence of all postoperative complications (P = 0.02), especially for patients with Clavien-Dindo classification grade ≥2 (CDC; P = 0.0007). Postoperative hospital stays were significantly longer for sarcopenic patients than for non-sarcopenic patients (P = 0.02). In a multivariate analysis, sarcopenia was an independent predictor for postoperative complications (P = 0.01, odds ratio 1.82, 95% confidence interval 1.13-3.00). Among postoperative complications (CDC grade ≥2), sarcopenia was correlated with non-surgical-site infections (P = 0.03). Sarcopenia was not correlated with the overall or recurrence-free survival. CONCLUSIONS: Sarcopenia was an independent predictive factor for postoperative complications after CRC surgery.

Prognostic Significance of Sarcopenia in Patients with Esophagogastric Junction Cancer or Upper Gastric Cancer.

BACKGROUND: The association between sarcopenia and postoperative outcomes for patients with gastrointestinal malignancies remains controversial. This study aimed to assess the impact of sarcopenia on short- and long-term outcomes after surgery for esophagogastric junction cancer (EGJC) or upper gastric cancer (UGC). METHODS: The study reviewed 148 patients with EGJC or UGC who underwent surgical resection. The patients were categorized into the sarcopenia group or the non-sarcopenia group according to their skeletal muscle index calculated using abdominal computed tomography images. The study compared clinicopathologic factors, postoperative complications, and prognosis between the two groups. RESULTS: Sarcopenia was present in 19 patients (32.2%) with EGJC and 23 patients (25.8%) with UGC. The 5-year overall survival (OS) and recurrence-free survival (RFS) rates were significantly poorer in the sarcopenia group than in the non-sarcopenia group (OS 85.5 vs 54.8%, P = 0.0010; RFS 78.7 vs 51.7%, P = 0.0054). The development of postoperative complications did not differ significantly between the two groups. Both the uni- and multivariate analyses showed that N stage (P < 0.0001) and sarcopenia (P = 0.0024 and 0.0293, respectively) were independent poor prognostic factors for OS. CONCLUSIONS: Sarcopenia was strongly associated with a poor long-term prognosis for patients with EGJC or UGC who underwent surgery. The results suggest that special attention might be needed during the development of treatment strategies for patients with sarcopenia who intend to undergo operations for EGJC and UGC.

Gluteal muscle metastasis with peritoneal dissemination from gastric cancer during postoperative adjuvant chemotherapy: a case report.

BACKGROUND: Skeletal muscle metastasis from gastric cancer is rare and has a poor prognosis. We reported a case of gluteal muscle metastasis with peritoneal dissemination from gastric cancer during postoperative adjuvant chemotherapy. CASE PRESENTATION: A 64-year-old man with gastric cancer underwent distal gastrectomy with D2 lymph node resection. The pathological diagnosis was poorly differentiated adenocarcinoma and signet cell carcinoma, T3N3bM0, Stage IIIC. Metastases were found in all regional lymph nodes, except 11p. The resection margin was negative. S-1 plus docetaxel therapy was administered as postoperative adjuvant chemotherapy. Six month post-operation, the patient presented with right gluteal muscle tenderness and abdominal distension. Computed tomography revealed a solid mass in the right gluteal muscle, a disseminated nodule on the abdominal wall, and massive ascites. Pathological examination of the gluteal muscle revealed signet cell carcinoma, similar to the resected gastric cancer. The tumor was diagnosed as gastric cancer metastases. Ascites cytology was class V. Thereafter, the patient underwent one course of capecitabine plus cisplatin combined with trastuzumab. Radiation therapy was also administered to relieve the pain of gluteal muscle metastasis. However, chemoradiotherapy was ineffective, and the patient died 2 months after the recurrence. CONCLUSIONS: Skeletal muscle metastasis and peritoneal dissemination during adjuvant chemotherapy indicated a poor prognosis.

"Energy-less technique" with mini-clips for recurrent laryngeal nerve lymph node dissection in prone thoracoscopic esophagectomy for esophageal cancer.

BACKGROUND: Meticulous recurrent laryngeal nerve (RLN) lymph node dissection in thoracoscopic esophagectomy for esophageal cancer often results in RLN paralysis. METHODS: We had attempted to simply cut the vessels around RLN sharply with scissors without using energy device in order to prevent RLN paralysis. However, these procedures often result in minor bleeding. Since we introduced the use of mini-clips for hemostasis before cutting the vessels with scissors, we herein compared the surgical results between before and after the introduction of use of mini-clips. RESULTS: With regard to RLN paralysis, the incidence was 24.0% in the before group; this incidence went down to 5.1% in the after group (P = 0.0259). Moreover, length of hospital stay after surgery was significantly shortened, from 36.1 days to 22.0 days, after the introduction of energy-less techniques with mini-clips (P = 0.0075). CONCLUSIONS: Our data demonstrated that this technique contributed to prevent RLN paralysis and to shorten the patient's length of hospital stay.

A case of mixed adenoneuroendocrine carcinoma (MANEC) arising in Barrett's esophagus: literature and review.

BACKGROUND: Mixed adenoneuroendocrine carcinoma (MANEC) is defined as a neoplasm composed of both exocrine and endocrine carcinomas, each comprising at least 30% of the tumor. MANEC can occur in various organs of the gastrointestinal tract, including the esophagus, stomach, and colon. We herein provide the first case report of surgically resected MANEC arising in Barrett's esophagus (BE). CASE PRESENTATION: A 70-year-old man presenting with abdominal pain was referred to our hospital. Upper endoscopy showed a type 0-IIa + IIc elevated lesion adjacent to BE. According to a biopsy specimen, the elevated lesion was diagnosed as adenocarcinoma with neuroendocrine differentiation. No lymphatic or distant metastasis was detected in the preoperative examination. Laparoscopic distal esophagectomy and proximal gastrectomy were performed, and a diagnosis of MANEC in BE was determined according to the surgically resected specimen. CONCLUSIONS: A very rare case of MANEC in BE was detected. BE can be the origin of esophageal MANEC as well as adenocarcinoma. Due to the small number of esophageal or esophagogastric MANEC cases reported, further accumulation of such cases is necessary to recommend an optimal management strategy for esophageal or esophagogastric MANEC.

Chemoradiotherapy for Solitary Skeletal Muscle Metastasis from Oesophageal Cancer: Case Report and Brief Literature Review.

BACKGROUND: The incidence of skeletal muscle metastasis from oesophageal cancer is very low, and the treatment strategy has not been established. CASE REPORT: A 77-year-old man underwent oesophagectomy following neoadjuvant chemotherapy for oesophageal squamous cell carcinoma (CT-pT3 N0 M0, CT-pStage II). Fourteen months after surgery, he became aware of a subcutaneous tumour in his left forearm. Computed tomography and fluorodeoxyglucose positron-emission tomography revealed a 65×75 mm intramuscular nodular lesion with a standardized uptake value of 8.5. Further examination by biopsy strongly suggested this was a solitary metastasis from oesophageal cancer. The patient received chemoradiotherapy with two cycles of 5-fluorouracil combined with cisplatin and radiation. Clinical complete response was confirmed by imaging 7 months after chemoradiation and no recurrence has occurred at 20 months since chemoradiation. CONCLUSION: Radiotherapy or chemoradiotherapy can be an alternative locoregional therapy to surgery for solitary skeletal muscle metastasis.

Thoracoscopic plication for idiopathic eventration of the bilateral diaphragm: Report of a case.

INTRODUCTION: Diaphragmatic eventration, defined as permanent elevation of the diaphragm without defects, is a rare anomaly in adults. Trauma, neoplasms, infection, and degenerative disease are the most common causes of this condition, whereas idiopathic eventration of the diaphragm is relatively infrequent. PRESENTATION OF CASE: We herein present the rare case of an 85-year-old female with idiopathic eventration of the bilateral diaphragm. The patient demonstrated a rapidly progressive course with dyspnea; therefore, thoracoscopic surgery of the unilateral diaphragm was performed. She subsequently withdrew from home oxygen therapy, which had introduced preoperatively, and exhibited a significant improvement in her pulmonary function for one year after the operation. DISCUSSION: Various approaches for diaphragmatic plication have been reported, including open (transthoracic or transabdominal) and minimally invasive methods, such as thoracoscopic or laparoscopic plication. We consider thoracoscopic plication to be an effective minimally invasive method, although single-lung ventilation is required. CONCLUSION: We experienced a case in which thoracoscopic plication of the unilateral diaphragm resulted in adequate objective improvements in the pulmonary function in a patient with idiopathic eventration of the bilateral diaphragm.

Laparoscopic Total Gastrectomy for RGC: Four Case Reports.

Surgery for RGC can generally be difficult because of the severity of intra-abdominal adhesion due to past gastrectomy. Laparoscopic gastrectomy for RGC has been reported in some cases, but the adequacy of this procedure is still unclear. Herein we report four cases of RGC that underwent laparoscopic gastrectomy at our Hospital and discuss the benefit of the laparoscopic approach for RGC.