Nivolumab Rechallenge After Immune-related Adverse Events in Patients With Unresectable Advanced or Recurrent Esophageal Cancer.

BACKGROUND/AIM: Rechallenge with immune checkpoint inhibitors following immune-related adverse events (irAEs) during the treatment of certain cancers reportedly has good efficacy. However, the subsequent clinical course of esophageal cancer remains unclear. This study investigated the nature of irAEs and the efficacy of a nivolumab rechallenge for patients with esophageal cancer. PATIENTS AND METHODS: This study retrospectively analyzed 44 patients with unresectable advanced or recurrent esophageal cancer who were treated with nivolumab as a second-line or later regimen and developed irAEs between February 2020 and May 2022. The cohort was divided into continuation, rechallenge, and discontinuation groups based on nivolumab administration after the occurrence of irAEs. The proportion of each group was investigated according to the type of irAEs. The progression-free and overall survival periods were retrospectively analyzed for each group. RESULTS: Among patients with skin-related irAEs, 78.6% continued nivolumab administration, 14.3% rechallenged, and 7.1% discontinued nivolumab. Among patients with gastrointestinal disorders, 30.8% continued, 46.2% rechallenged, and 23.1% discontinued nivolumab. Among patients with interstitial pneumonia, none continued, 55.6% rechallenged, and 44.4% discontinued nivolumab. In those with endocrine disorders, 83.3% continued, none rechallenged, and 16.7% discontinued nivolumab. The median progression-free survival after irAE occurrence in the continuation, rechallenge, and discontinuation groups was 210, 333, and 72.5 days, respectively (p=0.022), while the median overall survival after irAE occurrence was 714, 848, and 223 days, respectively (p=0.008). CONCLUSION: Rechallenge with nivolumab may be considerably effective, depending on the type and severity of irAEs, and may improve the prognosis of patients with unresectable advanced or recurrent esophageal cancer.

[Indication and Perioperative Management for Esophagectomy in Elderly Patients of Esophageal Cancer].

Esophagectomy is a highly invasive surgery for elderly patients. The incidence of esophageal cancer is relatively high among the aging population in Japan. Therefore, it is crucial to determine the indications for esophagectomy and implement effective pre- and post-operative management strategies, considering the reduced physical function often observed in elderly patients. In our study, approximately 20% of patients with stageⅡ/Ⅲ esophageal cancer underwent esophagectomy. When we assessed thesepatients using the estimation of physiologic ability and surgical stress (E-PASS) scoring system, we found that the E-PASS score was significantly lower in the group that underwent surgery compared to those who received chemotherapy, radiation, or palliative treatment. Evaluating the risk of esophagectomy using tools such as E-PASS or others is crucial in establishing appropriate indications and ensuring patient safety. Regarding the perioperative period, our study revealed that the complication rate did not differ significantly between patients aged 74 years or younger and those aged 75 years or older. However, patients aged 75 years or older experienced significantly longer total and post-hospital stays. This prolonged postoperative stay in elderly patients can be attributed to a decline in activities of daily living (ADL) following esophagectomy, primarily due to their lower physical function. These results emphasize the importance of considering the potential decline in ADL resulting from lower physical function in elderly patients during perioperative management. Establishing multidisciplinary perioperative teams and rehabilitation programs can enhance the quality of life for patients after esophagectomy.

Deep learning-based diagnostic model for predicting complications after gastrectomy.

BACKGROUND: Gastric cancer is one of the leading causes of cancer deaths, and gastrectomy with lymph node dissection is the mainstay of treatment. Despite clinician efforts and advances in surgical methods, the incidence of complications after gastrectomy remains 10%-20% including fatalities. To the best of our knowledge, this is the first report on utilization of a deep learning method to build a new artificial intelligence model that could help surgeons diagnose these complications. METHODS: A neural network was constructed with a total of 4000 variables. Clinical, surgical, and pathological data of patients who underwent radical gastrectomy at our institute were collected to maintain a deep learning model. We optimized the parameters of the neural network to diagnose whether these patients would develop complications after gastrectomy or not. RESULTS: Seventy percent of the data was used to optimize the neural network parameters, and the rest was used to validate the model. A model that maximized the receiver operating characteristics (ROC) area under the curve (AUC) for validation of the data was extracted. The ROC-AUC, sensitivity, and specificity of the model to diagnose all complications were 0.8 vs 0.7, 81% vs 50%, and 69% vs 75%, for the teaching and validation data, respectively. CONCLUSIONS: A predictive model for postoperative complications after radical gastrectomy was successfully constructed using the deep learning method. This model can help surgeons accurately predict the incidence of complications on postoperative day 3.

[A Case of Unresectable Thoracic Esophageal Cancer Responding Well to Multimodal Therapy Including 5-FU plus CDDP plus Pembrolizumab].

A 51-year-old male presented with swelling on the left side of his neck. A diagnosis of thoracic esophageal cancer(Lt type 5a, squamous cell carcinoma, T3N4[16LN]M1[skin, bone, retroperitoneum, lung], cStage Ⅳb)was made, and treatment with a combination of 5-FU plus CDDP and pembrolizumab was initiated. After the 1st round of chemotherapy, there was an increase in metastases in the left cervical lymph node and skin, along with the development of back pain because of an L3 lumbar spine metastasis. Palliative radiotherapy(Σ24 Gy/6 Fr)was administered for all lesions. Subsequently, pembrolizumab was administered for the persistent decline in white blood cell and neutrophil counts. After 6 courses of pembrolizumab, computed tomography(CT)revealed an absence of lesions. Positron emission tomography/CT demonstrated no significant accumulation, prompting a diagnosis of complete response(CR). The patient is currently under pembrolizumab therapy and continues to remain in a state of CR.

[A Case of Suspected Pure Red Cell Aplasia Due to Nivolumab Treatment for Unresectable Esophageal Cancer].

Immune checkpoint inhibitor(ICI)combination therapy is the first-line of treatment for unresectable or recurrent esophageal cancer. The frequency and mechanism of immune-related adverse events(irAEs)associated with ICI are still unclear and may require differentiation from other diseases. The present study examined a patient with unresectable, advanced esophageal cancer treated with cisplatin plus 5-fluorouracil(CF)plus nivolumab as the first-line treatment. CF therapy was discontinued after 1 course owing to adverse events. Nivolumab was continued, but progressive anemia stemming from pure red cell aplasia(PRCA), an irAE of nivolumab administration, was observed. Nivolumab was discontinued, but later, interstitial pneumonia also developed, and pulse steroid therapy was begun. After steroid tapering, both the PRCA and interstitial pneumonia improved. At present, about 6 months have elapsed since the last nivolumab administration without any PRCA recurrence or evidence of tumor progression.

The impact of lymphadenectomy on lymph node recurrence after performing various treatments for esophageal squamous cell carcinoma.

BACKGROUND: Treatment for regional lymph node recurrence after initial treatment for esophageal squamous cell carcinoma (ESCC) differs among institutions. Though some retrospective cohort studies have shown that lymphadenectomy for cervical lymph node recurrence is safe and leads to long-term survival, the efficacy remains unclear. In this study, we investigated the long-term outcomes of patients who underwent lymphadenectomy for regional recurrence after treatment for ESCC. PATIENTS AND METHODS: We retrieved 20 cases in which lymphadenectomy was performed for lymph node recurrence after initial treatment for ESCC in our hospital from January 2003 to December 2016. Initial treatments included esophagectomy, endoscopic resection (ER) and chemoradiotherapy/chemotherapy (CRT/CT). Overall survival (OS) and recurrence-free survival (RFS) after lymphadenectomy were calculated by the Kaplan-Meier method. We also used a univariate analysis with a Cox proportional hazards model to determine factors influencing the long-term outcomes. RESULTS: The five-year OS and RFS of patients who underwent secondary lymphadenectomy for recurrence after initial treatment were 50.0% and 26.7%, respectively. The five-year overall survival rates of patients who received esophagectomy, ER and CRT/CT as initial treatments, were 40.0%, 75.0% and 50.0%, respectively. The five-year OS rates of patients with Stage I and Stage II-IVB at initial treatments were 83.3% and 33.3%, respectively. CONCLUSIONS: Lymphadenectomy for regional recurrence after initial treatment for ESCC is effective to some degree. Patients with regional recurrence after initial treatment for Stage I ESCC have a good prognosis; thus, lymphadenectomy should be considered for these cases.

Preliminary study for developing a navigation system for gastric cancer surgery using artificial intelligence.

PURPOSE: We are attempting to develop a navigation system for safe and effective peripancreatic lymphadenectomy in gastric cancer surgery. As a preliminary study, we examined whether or not the peripancreatic dissection line could be learned by a machine learning model (MLM). METHODS: Among the 41 patients with gastric cancer who underwent radical gastrectomy between April 2019 and January 2020, we selected 6 in whom the pancreatic contour was relatively easy to trace. The pancreatic contour was annotated by a trainer surgeon in 1242 images captured from the video recordings. The MLM was trained using the annotated images from five of the six patients. The pancreatic contour was then segmented by the trained MLM using images from the remaining patient. The same procedure was repeated for all six combinations. RESULTS: The median maximum intersection over union of each image was 0.708, which was higher than the threshold (0.5). However, the pancreatic contour was misidentified in parts where fatty tissue or thin vessels overlaid the pancreas in some cases. CONCLUSION: The contour of the pancreas could be traced relatively well using the trained MLM. Further investigations and training of the system are needed to develop a practical navigation system.

Prognostic Value of Intraoperative Blood Transfusion in Patients with Adenocarcinoma of the Esophagogastric Junction.

Background and objectives: Adenocarcinoma of the esophagogastric junction (AEG) has a complicated surgical anatomy, due to which it sometimes induces excessive intraoperative blood loss that necessitates intraoperative blood transfusion (BTF). However, few reports have focused on the impact of BTF on the survival outcomes of patients with AEG. We aimed to evaluate the impact of BTF on AEG prognosis. Materials andMethods: We included 63 patients who underwent surgical resection for AEG at our hospital between January 2010 and September 2020. Clinicopathological characteristics and survival outcomes were compared between patients with (n = 12) and without (n = 51) BTF. Multivariate analysis was performed to identify the independent prognostic factors for overall survival. Results: None of the patients who underwent minimally invasive surgery received BTF. Patients who received BTF had a significantly worse 5-year survival rate than those who did not (67.8% vs. 28.3%, p = 0.001). BTF was an independent risk factor for overall survival (hazard ratio: 3.90, 95% confidence interval 1.30-11.7), even after patients who underwent minimally invasive surgery were excluded. Conclusions: BTF adversely affected the survival outcomes of patients with AEG who underwent curative surgery. To avoid BTF, surgeons should strive to minimize intraoperative bleeding.

Mucosal Congestion on the First Day Following Endoscopy Predicts Anastomotic Stricture After Esophagectomy.

BACKGROUND: Anastomotic stricture is a relatively common postoperative complication after esophagectomy. Previous studies have indicated that impaired perioperative blood perfusion at the anastomosis is associated with the occurrence of stricture. Therefore, we analyzed the association between endoscopically assessed blood perfusion during the early postoperative period and anastomotic stricture. METHODS: This retrospective study evaluated patients who underwent esophagectomy at Tokyo Medical and Dental University between 2010 and 2015. The patients had undergone nasal endoscopy on the 1st and 8th postoperative days. The findings were used to evaluate blood perfusion at the anastomosis and gastric tube, which was classified based on mucosal color as ischemia (white) or congestion (blue or black). Univariate and multivariable logistic regression analyses were performed to identify risk factors for anastomotic stricture. RESULTS: The study included 197 patients and anastomotic stricture was observed in 60 patients (30.4%). The multivariable analysis revealed that postoperative gastric tube congestion was a risk factor for stricture (odds ratio [OR]: 6.440, 95% confidence interval [CI]: 2.660-15.600; p < 0.001). Lower risks of anastomotic stricture were associated with pathological stage III-IV disease (OR: 0.325, 95% CI: 0.161-0.656; p = 0.002). CONCLUSION: This study revealed that endoscopically detected congestion at the anastomosis on the first postoperative day was a risk factor for anastomotic stricture.

Clinical Impact of Primary Tumor Site in Stage IV Colorectal Cancer: A Statewide Cohort Study.

BACKGROUND/AIM: We investigated the clinical impact of the primary tumor site in stage IV colorectal cancer (CRC). PATIENTS AND METHODS: In this statewide multicenter retrospective cohort, patients with stage IV CRC from nine hospital-based cancer registries across the Fukushima Prefecture (2008-2015) were categorized based on three primary tumor sites: right colon cancer (RCC), left colon cancer (LCC), and rectal cancer. Overall survival was assessed using Cox regression analysis. RESULTS: A total of 1,211 patients were included. The most common clinical symptom was obstruction in LCC and bleeding in rectal cancer. Liver metastases were multiple and larger in LCC, while lung metastases were multiple in rectal cancer. Compared to LCC, the adjusted hazard ratio (HR) for overall survival was 1.19 [95% confidence interval (CI)=1.01-1.39, p=0.032] in RCC and 1.03 (95% CI=0.86-1.23, p=0.77) in rectal cancer. CONCLUSION: RCC was independently associated with a worse prognosis in stage IV CRC.

Preoperative lymphocyte-to-monocyte ratio is the most predictive inflammatory response marker of survival in gastric cancer.

PURPOSE: Systemic inflammatory responses play a key role in cancer progression, and detecting the predictive inflammatory response markers is needed. The present study explored inflammatory response markers capable of predicting survival in patients with gastric cancer. METHODS: We enrolled 264 patients, who underwent curative gastrectomy for clinical stage (cStage) I-III gastric cancer between 2012 and 2015. The cut-off point of eight preoperative inflammatory response markers was determined by receiver operating characteristic (ROC) curve analysis. The marker with the highest Harrell's concordance index (C-index) was adopted for subsequent univariate and multivariate analyses using the Cox proportional-hazards model. RESULTS: Among eight representative inflammatory response markers, lymphocyte-to-monocyte ratio (LMR; cut-off point, 4.60) achieved the highest C-index (0.633). The 5-year survival rate was significantly worse in patients with LMR < 4.60 than in those with LMR ≥ 4.60 (67.5% versus 89.0%, P < 0.001). In multivariate analysis, LMR < 4.60 was identified as an independent prognostic factor (hazard ratio: 2.372; 95% confidence interval: 1.266-4.442; P = 0.007). CONCLUSION: In this study, LMR had the strongest ability to predict the survival of patients with gastric cancer among other inflammatory response markers, with lower LMRs being associated with poor survival following curative gastrectomy.

Impact of Preoperative Time Interval on Survival in Patients With Gastric Cancer.

BACKGROUND: A time interval between diagnosis and surgery for gastric cancer is necessary, although its impact on survival remains controversial. We evaluated the impact of preoperative time interval on survival in gastric cancer patients. METHODS: We enrolled 332 patients who underwent curative gastrectomy for clinical stage (cStage) I-III gastric cancer between 2012 and 2015. We separately analyzed early- (cStage I) and advanced-stage (cStages II and III) patients. Early-stage patients were divided according to preoperative time interval: short (≤ 42 days) and long (> 42 days) groups. Advanced-stage patients were also divided into short (≤ 21 days) and long (> 21 days) groups. We compared the survival between the short and long groups in early- and advanced-stage patients. RESULTS: The median preoperative time interval was 29 days, and no significant differences were found in patient characteristics between the short and long groups in early- and advanced-stage patients. In early-stage patients, the 5-year survival rates of the short and long groups were 86.5% and 88.4%, respectively (P = 0.917). In advanced-stage patients, the 5-year survival rates were 72.1% and 70.0%, respectively (P = 0.552). In multivariate analysis, a longer time interval was not selected as an independent prognostic factor in early- and advanced-stage patients. CONCLUSIONS: In this study, survival difference was not found based upon preoperative time interval. The results do not affirm the delay of treatment without reason, however, imperative extension of preoperative time interval may be justified from the standpoint of long-term survival.

The evaluation of the gastric tube blood flow by indocyanine green fluorescence angiography during esophagectomy: a multicenter prospective study.

OBJECTIVE: We determined the anastomotic site during gastric tube reconstruction in esophagectomy according to the "90-to 60-s rule" using indocyanine green (ICG) fluorescence angiography. We evaluated its safety and efficacy in a prospective multicenter setting. METHODS: We enrolled 129 patients who underwent subtotal esophagectomy for esophageal cancer. ICG fluorescence angiography was performed after making a wide gastric tube, and the time from the initial enhancement of the right gastroepiploic artery to the tip of the gastric tube was used as a parameter. Esophago-gastro anastomosis was made at the area that was enhanced within 90 s (preferably within 60 s). The enhancement time and the incidence of anastomotic leakage were compared. RESULTS: In all cases, anastomosis was made at the site enhanced within 90 s. Anastomotic leakage was found in only 4 (3.1%) of 129 cases; specifically, it was detected in 3 (2.4%) of 126 cases whose anastomotic site was enhanced within 60 s and in 1 (33.3%) of 3 cases where the enhancement time exceeded 60 s (p = 0.09). CONCLUSIONS: Determining the anastomotic site using the 90-to 60-s rule with ICG imaging in gastric tube reconstruction helps reduce the rate of anastomotic leakage.

Histological changes in the human esophagus following triamcinolone injection to prevent esophageal stricture after endoscopic submucosal dissection.

BACKGROUND: Locoregional steroid injection prevents post-endoscopic submucosal dissection (ESD) esophageal stricture, but histological changes that occur following steroid injection in the human esophagus are unclear. This study investigated the histopathological characteristics caused by locoregional triamcinolone acetonide (TA) injection using human esophagectomy specimens. METHODS: From January 2014 to December 2019, among 297 patients (373 lesions) who underwent esophageal ESD, 13 patients who underwent additional esophagectomy after ESD were examined. Seven patients (TA group) with wide excisions were injected with TA after ESD and another six patients (Non-TA group) with smaller tumors were not injected with TA. The clinical background of these patients and histopathological features of ESD ulcer scar obtained from esophagectomy specimens were retrospectively investigated. RESULTS: The circumferential rate of ESD excision was more than three-quarters in all cases in the TA group, whereas it was less than three-quarters in the Non-TA group. No other statistical difference in the clinical background was found between the two groups. The subepithelial fibrous tissue of the ESD ulcer scar in the TA group was significantly thinner than that in the Non-TA group (P < 0.05). There was no significant difference in the thickness of the regenerated epithelium and muscularis propria layer of the ESD ulcer scar. CONCLUSIONS: Histological finding of thinning of the subepithelial fibrous tissue of ESD ulcer scar in the human esophagus after TA injection was obtained. This suggests that TA suppresses the proliferation of the fibrous tissue of the subepithelial layer to help prevent esophageal stricture after widespread ESD in the human esophagus.

[Neoadjuvant Chemoradiotherapy for Locally Advanced Carcinoma Associated with Anal Fistula].

The patient was a 59-year-old man. He was admitted to our hospital because of increasing anal pain with induration of the perianal region. There were large secondary orifices with mucous discharge on the left side of the perineal resion and buttock. We diagnosed adenocarcinoma on analysis of a biopsy specimen from induration of the perianal region. Pelvic CT and MRI showed that the tumor spreaded within the pelvis, with invasion of the prostate and sacrum. We performed neoadjuvant chemoradiotherapy preoperatively. After chemoradiotherapy, the tumor reduced in size greatly. We performed abdominoperineal resection and massive resection of skin of the perianal region. The defect of the pelvic floor and perianal skin was repaired using skin flap. The surgical margin was tumor free. Neoadjuvant chemoradiotherapy was considered effective for locally advanced carcinoma associated with anal fistula.

Is a Central Venous Catheter Necessary for the Perioperative Management of Esophagectomy? A Prospective Randomized Pilot Study Comparing Two Different Perioperative Regimens.

BACKGROUND/AIMS: Our prospective randomized study examined the possibility of perioperative management of esophagectomy without a central venous catheter (CVC). METHODS: Forty patients who underwent esophagectomy for esophageal cancer were divided into the total parenteral nutrition (TPN; receiving conventional perioperative management via a CVC) and peripheral parenteral nutrition (PPN; receiving perioperative management without a CVC) groups. Albumin and retinol-binding protein (RBP) levels were used as measurements of the nutritional status. Early postoperative complications and catheter-related complications were also evaluated. RESULTS: The actual calories administered per kg of body weight and the albumin and RBP levels did not significantly differ between the groups. Additionally, there was no significant difference in the morbidity of early postoperative complications between the groups. Catheter-related complications were observed in 4 patients in the TPN group (2 catheter infections, 1 case of thrombosis, and 1 case of iatrogenic pneumothorax), and 4 cases of peripheral phlebitis occurred in the PPN group. The incidence of catheter-related complications did not significantly differ between the groups. CONCLUSIONS: Perioperative management without a CVC can be safely performed in esophagectomy patients, and the decision to insert a CVC should be made based on the patient's perioperative condition.

Relationships between Micro-Vascular and Iodine-Staining Patterns in the Vicinity of the Tumor Front of Superficial Esophageal Squamous Carcinoma.

OBJECTIVE: The aim of the present study was to clarify differences between micro-vascular and iodine-staining patterns in the vicinity of the tumor fronts of superficial esophageal squamous cell carcinomas (ESCCs). METHODS: Ten consecutive patients with ESCCs who were treated by endoscopic submucosal dissection (ESD) were enrolled. At the edge of the iodine-unstained area, we observed 183 sites in total using image-enhanced magnifying endoscopy. We classified the micro-vascular and iodine-staining patterns into three types: Type A, in which the line of vascular change matched the border of the iodine-unstained area; Type B, in which the border of the iodine-unstained area extended beyond the line of vascular change; Type C, in which the line of vascular change extended beyond the border of the iodine-unstained area. Then, by examining histopathological sections, we compared the diameter of intra-papillary capillary loops (IPCLs) in cancerous areas and normal squamous epithelium. RESULTS: We investigated 160 sites that the adequate quality of pictures were obtained. There was no case in which the line of vascular change completely matched the whole circumference of the border of an iodine-unstained area. Among the 160 sites, type A was recognized at 76 sites (47.5%), type B at 79 sites (49.4%), and type C at 5 sites (3.1%). Histological examination showed that the mean diameter of the IPCLs in normal squamous epithelium was 16.2±3.7 µm, whereas that of IPCLs in cancerous lesions was 21.0±4.4 µm. CONCLUSIONS: The development of iodine-unstained areas tends to precede any changes in the vascularity of the esophageal surface epithelium.