Nivolumab receptor occupancy on effector regulatory T cells predicts clinical benefit.

Immune checkpoint inhibitor discovery represents a turning point in cancer treatment. However, the response rates of solid tumors remain ~10%-30%; consequently, prognostic and immune-related adverse event (irAE) predictors are being explored. The programmed cell death protein 1 (PD-1) receptor occupancy (RO) of PD-1 inhibitors depends on the number of peripheral blood lymphocytes and their PD-1 expression levels, suggesting that the RO may be related to efficacy and adverse events. As PD-1 inhibition affects each T-cell subset differently, the RO of each cell population must be characterized. However, relevant data have not been reported, and the prognostic relevance of this parameter is not known. In this study, we aimed to clarify the association between the nivolumab RO in each T-cell population and patient prognosis and reveal the development of irAEs in nivolumab-treated patients. Thirty-two patients were included in the study, and the mean follow-up period was 364 days. The nivolumab RO on effector regulatory T cells (eTregs) was significantly lower in the group that presented clinical benefits, and a significant negative association was observed between PD-1 occupancy on eTregs and all-cause mortality. The results suggest that the nivolumab RO on eTregs may be a prognostic factor in PD-1 inhibitor therapy, implying that the inhibition of PD-1/PD-ligand 1 (PD-L1) signaling on eTregs may attenuate antitumor effects.

Butyricimonas is a key gut microbiome component for predicting postoperative recurrence of esophageal cancer.

BACKGROUND: Recently, intestinal bacteria have attracted attention as factors affecting the prognosis of patients with cancer. However, the intestinal microbiome is composed of several hundred types of bacteria, necessitating the development of an analytical method that can allow the use of this information as a highly accurate biomarker. In this study, we investigated whether the preoperative intestinal bacterial profile in patients with esophageal cancer who underwent surgery after preoperative chemotherapy could be used as a biomarker of postoperative recurrence of esophageal cancer. METHODS: We determined the gut microbiome of the patients using 16S rRNA metagenome sequencing, followed by statistical analysis. Simultaneously, we performed a machine learning analysis using a random forest model with hyperparameter tuning and compared the data obtained. RESULTS: Statistical and machine learning analyses revealed two common bacterial genera, Butyricimonas and Actinomyces, which were abundant in cases with recurrent esophageal cancer. Butyricimonas primarily produces butyrate, whereas Actinomyces are oral bacteria whose function in the gut is unknown. CONCLUSION: Our results indicate that Butyricimonas spp. may be a biomarker of postoperative recurrence of esophageal cancer. Although the extent of the involvement of these bacteria in immune regulation remains unknown, future research should investigate their presence in other pathological conditions. Such research could potentially lead to a better understanding of the immunological impact of these bacteria on patients with cancer and their application as biomarkers.

Usefulness of an Artificial Intelligence Model in Recognizing Recurrent Laryngeal Nerves During Robot-Assisted Minimally Invasive Esophagectomy.

BACKGROUND: Recurrent laryngeal nerve (RLN) palsy is a common complication in esophagectomy and its main risk factor is reportedly intraoperative procedure associated with surgeons' experience. We aimed to improve surgeons' recognition of the RLN during robot-assisted minimally invasive esophagectomy (RAMIE) by developing an artificial intelligence (AI) model. METHODS: We used 120 RAMIE videos from four institutions to develop an AI model and eight other surgical videos from another institution for AI model evaluation. AI performance was measured using the Intersection over Union (IoU). Furthermore, to verify the AI's clinical validity, we conducted the two experiments on the early identification of RLN and recognition of its location by eight trainee surgeons with or without AI. RESULTS: The IoUs for AI recognition of the right and left RLNs were 0.40 ± 0.26 and 0.34 ± 0.27, respectively. The recognition of the right RLN presence in the beginning of right RLN lymph node dissection (LND) by surgeons with AI (81.3%) was significantly more accurate (p = 0.004) than that by surgeons without AI (46.9%). The IoU of right RLN during right RLN LND recognized by surgeons with AI (0.59 ± 0.18) was significantly higher (p = 0.010) than that by surgeons without AI (0.40 ± 0.29). CONCLUSIONS: Surgeons' recognition of anatomical structures in RAMIE was improved by our AI system with high accuracy. Especially in right RLN LND, surgeons could recognize the RLN more quickly and accurately by using the AI model.

Conversion surgery for esophageal and esophagogastric junction cancer.

As a result of the recent advances in first-line treatment including chemotherapy, radiation therapy, targeted therapy, and immune checkpoint inhibitor immunotherapy (ICI) for locally advanced/metastatic initially unresectable esophageal and esophagogastric junction cancer, surgery aiming at cure after initial treatment, so-called "conversion surgery" has become more common in this field. Several studies have indicated encouraging survival outcomes for patients after conversion surgery with R0 resection. However, various issues, such the utility and the safety of conversion surgery remain unclear. In this review, we will focus on the surgical treatment for initially unresectable esophageal and esophagogastric junction cancer after first- or later- line treatment and review recent evidence regarding the safety and the efficacy of conversion surgery. Multidisciplinary treatment including surgery may serve as a novel treatment strategy for esophageal and esophagogastric junction cancer, thus provide a curative treatment option and potentially contribute to better prognosis for initially untreatable diseases.

Modification of the lesser curvature incision line enhanced gastric conduit perfusion as determined by indocyanine green fluorescence imaging and decreased the incidence of anastomotic leakage following esophagectomy.

AIM: This study aimed to investigate the effectiveness of a modified incision line on the lesser curvature for gastric conduit formation during esophagectomy in enhancing the perfusion of gastric conduit as determined by indocyanine green fluorescence imaging and reducing the incidence of anastomotic leakage. METHODS: A total of 272 patients who underwent esophagectomy at our institute between 2014 and 2022 were enrolled in this study. These patients were divided based on two different types of cutlines on the lesser curvature: conventional group (n = 141) following the traditional cutline and modified group (n = 131) adopting a modified cutline. Gastric conduit perfusion was assessed by ICG fluorescence imaging, and clinical outcomes after esophagectomy were evaluated. RESULTS: The distance from the pylorus to the cutline was significantly longer in the modified group compared with the conventional group (median: 9.0 cm vs. 5.0 cm, p < 0.001). The blood flow speed in the gastric conduit wall was significantly higher in the modified group than that in the conventional group (median: 2.81 cm/s vs. 2.54 cm/s, p = 0.001). Furthermore, anastomotic leakage was significantly lower (p = 0.024) and hospital stay was significantly shorter (p < 0.001) in the modified group compared with the conventional group. Multivariate analysis identified blood flow speed in the gastric conduit wall as the only variable significantly associated with anastomotic leakage. CONCLUSIONS: ICG fluorescence imaging is a feasible, reliable method for the assessment of gastric conduit perfusion. Modified lesser curvature cutline could enhance gastric conduit perfusion, promote blood circulation around the anastomotic site, and reduce the risk of anastomotic leakage after esophagectomy.

Usefulness of skeletal muscle measurement by computed tomography in patients with esophageal cancer: changes in skeletal muscle mass due to neoadjuvant therapy and the effect on the prognosis.

PURPOSE: This analysis was performed to clarify the usefulness of skeletal muscle measurements using computed tomography (CT) in patients with esophageal cancer and the effect of treatment-induced changes in the skeletal muscle mass on the prognosis. METHODS: Ninety-seven male patients who underwent thoracoscopic esophagectomy for esophageal squamous cell carcinoma were included in the study. The preoperative CT images were analyzed retrospectively. RESULTS: In a survival analysis performed according to the preoperative data of skeletal muscle, the low-skeletal muscle index (l-SMI) group had a poorer outcome than the normal skeletal muscle index (n-SMI) group in terms of both the overall survival (OS) and the relapse-free survival (RFS) (OS: P < 0.01, RFS: P = 0.01). In the multivariate analysis for the OS, preoperative l-SMI was an independent predictor (hazard ratio: 3.68, 95% confidence interval 1.32-10.2, P = 0.01). In patients who underwent neoadjuvant therapy (NAT), the SMI was significantly reduced after NAT (P < 0.01). The preoperative skeletal muscle area on CT was strongly correlated with the results of a bioelectrical impedance analysis (BIA) (ρ = 0.77, P < 0.01). CONCLUSIONS: A decreased preoperative skeletal muscle mass was associated with a poor outcome. In patients who underwent NAT, the SMI was significantly reduced after NAT. An analysis of the skeletal muscle mass using CT images was found to be useful for providing data that corresponded with BIA data.

Post-Progression Survival Highly Influences Overall Survival in Driver Gene Mutation/Translocation Negative or Unknown Type of Non-Small Cell Lung Cancer.

INTRODUCTION: In stage I-III non-small cell lung cancer (NSCLC), which is considered operable, surgical resection is the most efficacious treatment and is considered to provide a cure. However, after complete surgical resection, approximately 50% of patients with stage I-IIIA NSCLC experience recurrence and death. Once postoperative recurrence of NSCLC occurs, the prognosis is significantly poor, and the course of treatment after recurrence may influence overall survival (OS). Consequently, we investigated the relationship between relapse-free survival (RFS), post-progression survival (PPS), and OS in patients with postoperative recurrence of NSCLC with driver gene mutation/translocation negative or unknown status. METHODS: Between January 2007 and September 2019, 101 patients with driver gene mutation/translocation negative or unknown status of NSCLC who underwent complete resection and in whom recurrence occurred were analyzed. The associations between RFS, PPS, and OS were analyzed at the individual patient level. RESULTS: Linear regression and Spearman rank correlation analyses revealed that PPS was strongly associated with OS (r = 0.83, p < 0.0001, R2 = 0.71), whereas RFS was moderately correlated with OS (r = 0.65, p < 0.0001, R2 = 0.48). In the multivariate analysis, performance status at relapse, administration of immune checkpoint inhibitors, and radiotherapy for oligo-recurrences were significantly associated with PPS (p < 0.001). CONCLUSION: Current analysis of individual-level data of patients who underwent complete resection implied that PPS had a higher impact on OS than RFS in patients with postoperative recurrence of driver gene mutation/translocation negative or unknown status of NSCLC. Additionally, current perceptions indicate that treatment beyond progression after complete surgical resection might strongly affect OS.

Indocyanine green fluorescence imaging for evaluating blood flow in the reconstructed conduit after esophageal cancer surgery.

We investigated the effectiveness of indocyanine green (ICG) fluorescence blood flow imaging of the gastric conduit to evaluate anastomotic leakage after esophagectomy. We identified 19 articles using the PRISMA standard for systematic reviews. The more recent studies reported attempts at objective quantification of ICG fluorescence imaging, rather than qualitative assessment. Anastomotic leakage after esophagectomy occurred in 0-33% of the patients who underwent ICG fluorescence imaging. According to the six studies that compared the incidence of anastomotic leakage in the ICG group and the control group, it ranged from 0 to 18.3% in the ICG group and from 0 to 25.2% in the control group, respectively. Overall, the incidence of anastomotic leakage in the ICG group (8.4%) was lower than that in the control group (18.5%). Although the incidence of anastomotic leakage was as high as 43.1% in patients who did not undergo any intraoperative intervention for poor blood flow, it was only 24% in patients who underwent intraoperative intervention. This systematic review revealed that ICG fluorescence imaging may be a crucial adjunctive tool for reducing anastomotic leakage after esophagectomy, suggesting that it should be performed during esophageal reconstruction.

Usefulness of prone-position computed tomography as preoperative simulation prior to thoracoscopic esophagectomy for thoracic esophageal cancer.

PURPOSE: The study aimed to evaluate the usefulness of prone-position computed tomography (CT) for predicting relevant thoracic procedure outcomes in minimally invasive esophagectomy (MIE) for thoracic esophageal cancer. MATERIALS AND METHODS: A total of 59 patients underwent esophagectomy between May 2019 and December 2020 in Tokai University Hospital. Preoperative CT imaging was conducted with the patient in both the supine and prone positions, and the magnitude of change in the intramediastinal space was calculated. In the 56 patients (94.9%) who had undergone MIE, the effects of such a difference on the surgical outcomes were analyzed. RESULTS: A significant correlation of the magnitude of change in VE (distance between ventral aspect of the vertebral body and the midpoint of the esophagus) with the surgical outcome was revealed in the 17 patients (30.4%) in whom the magnitude of change in VE was over the 75th percentile. That is, in this subgroup, the magnitude of change in VE showed a negative correlation with the thoracic operation time (rs = - 0.57, p = 0.01) and blood loss during the thoracic procedure (rs = - 0.46, p = 0.01). Multivariate analysis identified a magnitude of change in VE ≥ 9 mm (OR = 0.14, p = 0.03) as an independent risk factor for postoperative pneumonia. CONCLUSIONS: This study indicates that preoperative prone-position CT imaging is useful for predicting the level of ease or difficulty of securing an adequate operative field, surgical outcomes, and the risk of postoperative pneumonia in MIE.

Immunotherapy for esophageal cancer: Where are we now and where can we go.

Immune checkpoint inhibitor therapy has dramatically improved patient prognosis, and thereby transformed the treatment in various cancer types including esophageal squamous cell carcinoma (ESCC) in the past decade. Monoclonal antibodies that selectively inhibit programmed cell death-1 (PD-1) activity has now become standard of care in the treatment of ESCC in metastatic settings, and has a high expectation to provide clinical benefit during perioperative period. Further, anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) monoclonal antibody has also been approved in the treatment of recurrent/metastatic ESCC in combination with anti-PD-1 antibody. Well understanding of the existing evidence of immune-based treatments for ESCC, as well as recent clinical trials on various combinations with chemotherapy for different clinical settings including neoadjuvant, adjuvant, and metastatic diseases, may provide future prospects of ESCC treatment for better patient outcomes.

Thoracoscopic McKeown esophagectomy in a patient with an azygos lobe.

BACKGROUND: The azygos lobe is a relatively rare anatomical variation, and there have been no reports, until date, of thoracoscopic McKeown esophagectomy for esophageal cancer in a patient with an azygos lobe. The azygos lobe can be diagnosed by chest X-ray or CT, and is usually not associated with any symptoms. However, surgeons should be aware that transthoracic surgical procedures in patients with an azygos lobe could be associated with a high risk of complications. CASE PRESENTATION: An 83-years-old man was brought to our emergency room with fever, severe headache, and difficulty in moving. MRI revealed a brain abscess, which was treated by abscess drainage and systemic antibiotic treatment. Further examinations to determine the cause of the brain abscess revealed esophageal cancer. In addition, CT revealed an azygos lobe in the right thoracic cavity. Although intrathoracic adhesions were anticipated on account of a previous history of bacterial pyothorax, we decided to perform esophagectomy via a thoracoscopic approach. Despite the difficulty in dissecting the intrathoracic adhesions, we were able to obtain the surgical field thoracoscopically. Then, we found the azygos lobe, as diagnosed preoperatively, and the azygos vein was supported by the mesentery draining into the superior vena cava. After dividing the mesentery, we clipped and cut the vessel, and both ends were further ligated. After these procedures, we safely performed esophagectomy with 3-field lymph node dissection. The postoperative course was uneventful, and the patient was discharged on the 21st postoperative day. CONCLUSIONS: Although there was a firm adhesion in the thoracic cavity, preoperative recognition of the azygos lobe could help in preventing intraoperative injury. Especially, esophageal surgeons are required to deal with the azygos lobe safely to avoid serious intraoperative injury.

MHC class I polypeptide-related sequence B shedding modulates pancreatic tumor immunity via the activation of NKG2DLow T cells.

Natural killer group 2 member D ligands (NKG2DLs) are expressed as stress response proteins in cancer cells. NKG2DLs induce immune cell activation or tumor escape responses, depending on their expression. Human pancreatic cancer cells, PANC-1, express membrane MHC class I polypeptide-related sequence A/B (mMICA/B), whereas soluble MICB (sMICB) is detected in the culture supernatant. We hypothesized that sMICB saturates NKG2D in NKG2DLow T cells and inhibits the activation signal from mMICB to NKG2D. Knockdown of MICB by siRNA reduced sMICB level, downregulated mMICB expression, maintained NKG2DLow T cell activation, and inhibited NKG2DHigh T cell activation. To maintain mMICB expression and downregulate sMICB expression, we inhibited a disintegrin and metalloproteinase (ADAM), a metalloproteinase that sheds MICB. Subsequently, the shedding of MICB was prevented using ADAM17 inhibitors, and the activation of NKG2DLow T cells was maintained. In vivo xenograft model revealed that NKG2DHigh T cells have superior anti-tumor activity. These results elucidate the mechanism of immune escape via sMICB and show potential for the activation of NKG2DLow T cells within the tumor microenvironment.

Isobutyric acid enhances the anti-tumour effect of anti-PD-1 antibody.

The low response rate of immune checkpoint inhibitors (ICIs) is a challenge. The efficacy of ICIs is influenced by the tumour microenvironment, which is controlled by the gut microbiota. In particular, intestinal bacteria and their metabolites, such as short chain fatty acids (SCFAs), are important regulators of cancer immunity; however, our knowledge on the effects of individual SCFAs remains limited. Here, we show that isobutyric acid has the strongest effect among SCFAs on both immune activity and tumour growth. In vitro, cancer cell numbers were suppressed by approximately 75% in humans and mice compared with those in controls. Oral administration of isobutyric acid to carcinoma-bearing mice enhanced the effect of anti-PD-1 immunotherapy, reducing tumour volume by approximately 80% and 60% compared with those in the control group and anti-PD-1 antibody alone group, respectively. Taken together, these findings may support the development of novel cancer therapies that can improve the response rate to ICIs.

Current status and future perspectives for the treatment of resectable locally advanced esophagogastric junction cancer: A narrative review.

Incidence rates for esophagogastric junction cancer are rising rapidly worldwide possibly due to the economic development and demographic changes. Therefore, increased attention has been paid to the prevention, diagnosis, and the treatment of esophagogastric junction cancer. Although there are discrepancies in the treatment strategy between Asian and Western countries, surgery remains the mainstay of treatment for esophagogastric junction cancer. Recent developments of perioperative multidisciplinary treatment may lead to better therapeutic effect, higher complete resection rate, and better control of the residual diseases, thus result in prolonged prognosis. In this review, we will focus on the treatment of locally advanced resectable esophagogastric junction cancer, and discuss the current status and future perspectives of the perioperative treatment including chemotherapy, radiation therapy, and immunotherapy, as well as the surgical strategy. Better understanding of the latest treatment strategy and future overlook may enable to standardize and individualize the treatment for esophagogastric junction cancer, thus leading to better prognosis for those patients.

Effective Postoperative Surveillance Protocol after Thoracoscopic Esophagectomy Focusing on Symptoms in Patients with Esophageal Cancer.

BACKGROUND: The optimal postoperative surveillance protocol after esophagectomy for patients with esophageal cancer has still not been established. We investigated the risk factors for recurrence of esophageal cancer to devise an appropriate surveillance protocol. We focused on the appearance and worsening of symptoms to determine if additional imaging examinations should be performed. STUDY DESIGN: We enrolled 416 patients with esophageal and esophagogastric junctional cancer who had undergone thoracoscopic esophagectomy at Tokai University Hospital. Outpatient visits for the patients are usually scheduled at least 4 times per year with CT imaging and blood biochemical examination. We evaluated the time to recurrence after esophagectomy, especially the correlation of this parameter with the appearance and worsening of symptoms during the postoperative outpatient follow-up. RESULTS: Of the 416 patients, recurrence occurred in 127 patients (30.5%). The median time to recurrence was 6 months after esophagectomy; recurrence occurred within 24 months in 112 patients (88%), and 51 of these patients (40%) developed some new symptom(s) (symptomatic group) before the diagnosis of recurrence. The number of patients who developed recurrence within 6 months was significantly higher in the symptomatic group compared with that in the asymptomatic group (66.7% vs 46.0%, p = 0.02). The overall survival in the symptomatic group was significantly shorter than that in the asymptomatic group (p < 0.001). CONCLUSIONS: We advocate an effective surveillance protocol depending on the appearance and worsening of symptoms to diagnose recurrence of esophageal cancer; we recommend routine imaging examinations every 6 months and clinical outpatient follow-up at even shorter intervals for the first 24 months after esophagectomy.

Thoracoscopic esophagectomy for stenosis of thoracic esophagus due to acute esophageal necrosis associated with alcoholic ketoacidosis.

Acute esophageal necrosis (AEN) is a rare disease characterized by the appearance of diffuse black mucosa on upper gastrointestinal endoscopy; the condition often progresses to esophageal stenosis in the chronic phase. A 70-year-old man was admitted to a neighborhood hospital with the diagnosis of alcoholic ketoacidosis and an upper gastrointestinal endoscopy performed to investigate the symptom of esophageal tightness revealed AEN. The patient developed esophageal stenosis with scarring in the chronic phase and was referred to our hospital for surgery 6 months after the diagnosis of AEN. We performed thoracoscopic esophagectomy with the patient in the prone position. Although the esophagus was thickened and strong adhesions were present around the esophagus due to inflammation, we were able to complete the surgical procedure thoracoscopically. In patients presenting with benign esophageal stenosis developing after AEN, thoracoscopic esophagectomy may be a useful treatment option, even in the presence of severe fibrosis.

Turicibacter and Acidaminococcus predict immune-related adverse events and efficacy of immune checkpoint inhibitor.

Introduction: Immune checkpoint inhibitors have had a major impact on cancer treatment. Gut microbiota plays a major role in the cancer microenvironment, affecting treatment response. The gut microbiota is highly individual, and varies with factors, such as age and race. Gut microbiota composition in Japanese cancer patients and the efficacy of immunotherapy remain unknown. Methods: We investigated the gut microbiota of 26 patients with solid tumors prior to immune checkpoint inhibitor monotherapy to identify bacteria involved in the efficacy of these drugs and immune-related adverse events (irAEs). Results: The genera Prevotella and Parabacteroides were relatively common in the group showing efficacy towards the anti-PD-1 antibody treatment (effective group). The proportions of Catenibacterium (P = 0.022) and Turicibacter (P = 0.049) were significantly higher in the effective group than in the ineffective group. In addition, the proportion of Desulfovibrion (P = 0.033) was significantly higher in the ineffective group. Next, they were divided into irAE and non-irAE groups. The proportions of Turicibacter (P = 0.001) and Acidaminococcus (P = 0.001) were significantly higher in the group with irAEs than in those without, while the proportions of Blautia (P = 0.013) and the unclassified Clostridiales (P = 0.027) were significantly higher in the group without irAEs than those with. Furthermore, within the Effective group, Acidaminococcus and Turicibacter (both P = 0.001) were more abundant in the subgroup with irAEs than in those without them. In contrast, Blautia (P = 0.021) and Bilophila (P= 0.033) were statistically significantly more common in those without irAEs. Discussion: Our Study suggests that the analysis of the gut microbiota may provide future predictive markers for the efficacy of cancer immunotherapy or the selection of candidates for fecal transplantation for cancer immunotherapy.

Multimodal Treatment Strategies to Improve the Prognosis of Locally Advanced Thoracic Esophageal Squamous Cell Carcinoma: A Narrative Review.

Esophageal cancer is the seventh most common malignancy and sixth most common cause of cancer-related death globally. Esophageal squamous cell carcinoma (ESCC) with aortic or tracheal invasion is considered unresectable, and has an extremely poor prognosis; its standard treatment is definitive chemoradiotherapy (dCRT). In recent years, induction chemotherapy (ICT) has been reported to yield high response rates for locally advanced ESCC, and the efficacy and safety of ICT followed by conversion surgery (CS) have been investigated. Multimodal treatment, combining surgery with induction chemoradiotherapy (ICRT) or ICT, is necessary to improve ESCC prognosis. CS is generally performed for locally advanced ECC after ICRT or ICT when tumor downstaging is achieved, although its prognostic benefit remains controversial. The Japan Clinical Oncology Group (JCOG) has conducted a three-arm phase III randomized controlled trial (JCOG1510) to confirm the superiority of DCF (docetaxel, cisplatin, and 5-fluorouracil) ICT, over conventional dCRT, among patients with initially unresectable ESCC. In recent years, researchers have reported favorable outcomes of induction therapy followed by CS and salvage surgery, after dCRT or systemic immunochemotherapy. In this review, we will describe the latest developments in the multimodal treatment including chemotherapy, CRT, surgery, and immunotherapy, which may improve oncological and survival outcomes for patients with cT4 ESCC.

Impact of Subclassification of Serosal Invasion on the Survival of Patients With T4a Gastric Cancer.

BACKGROUND/AIM: In the Japanese Classification of Gastric Carcinoma, T4a gastric cancer is defined as tumor invasion contiguous to the serosa or penetrating the serosa with exposure to the peritoneal cavity. The aim of this study was to assess the impact of T4a subclassification of gastric cancer on survival. PATIENTS AND METHODS: A total of 326 patients with T4a cancer who had undergone gastrectomy were enrolled. The T4a tumors were classified into two groups: serosa-contiguous or serosa-exposed. RESULTS: The serosa-exposed group had a significantly worse prognosis, and multivariate analysis identified the T4a subclass as an independent prognostic factor. Analysis of the risk factors for recurrence identified the T4a subclass as a significant risk factor for peritoneal recurrence in patients undergoing curative gastrectomy. CONCLUSION: The serosa-contiguous and serosa-exposed subgroups of T4a gastric cancer showed different biological behaviors. These groups may need to be treated as separate.

Three resected cases of esophageal carcinoma considered as being secondary solid tumors after bone marrow transplantation.

BACKGROUND: Bone marrow transplantation is now an established treatment for some hematopoietic disorders and hematopoietic malignancies, and secondary solid tumors that develop after bone marrow transplantation have begun to attract attention. CASE PRESENTATION: Herein, we report 3 cases of esophageal carcinoma that developed after bone marrow transplantation. Case 1: 40-year-old female received cyclophosphamide and total body irradiation at 12 Gy for acute myeloid leukemia, followed by related bone marrow transplantation. She developed chronic graft-versus-host disease manifesting as pulmonary complications and was administered cyclosporine. Nine years after the transplantation, she was diagnosed as having esophageal carcinoma Stage II and underwent radical surgery. She died of the primary disease 17 months after the surgery. Case 2: A 45-year-old male patient received cyclophosphamide, VP-16 and total body irradiation at 13.2 Gy for acute lymphocytic leukemia, followed by related bone marrow transplantation. He developed chronic graft-versus-host disease manifesting as liver dysfunction. Fifteen years after the transplantation, he was diagnosed as having esophageal carcinoma Stage II and underwent radical surgery. Seven months after the surgery, he died of the primary disease. Case 3: A 30-year-old female patient received cyclophosphamide and total body irradiation at 3 Gy for Fanconi anemia, followed by unrelated bone marrow transplantation. She developed chronic graft-versus-host disease manifesting as a rash and was administered tacrolimus and methotrexate. Fifteen years after the transplantation, she was diagnosed as having esophageal carcinoma Stage III and underwent radical surgery. She died of sepsis 7 months after the surgery. CONCLUSION: The esophageal carcinomas developing after bone marrow transplantation had the characteristics of secondary solid tumors in all 3 patients, such as early onset, after total body irradiation, association with chronic graft-versus-host disease, and history of use of immunosuppressive drugs. Patients undergoing bone marrow transplantation require long-term follow-up after the transplantation, considering the possible development of secondary solid tumors, and in regard to secondary solid tumors developing in the gastrointestinal tract, it must be borne in mind that the risk of esophageal carcinoma is particularly high.