Protocol of a pilot randomized clinical trial to evaluate nutritional support and rehabilitation on prevention of skeletal muscle mass loss during neoadjuvant chemotherapy in patients with esophageal cancer.

BACKGROUND: Subtotal esophagectomy with lymph node dissection followed by neoadjuvant chemotherapy (NAC) is the standard treatment for stage II-III esophageal cancer. Esophagectomy is still associated with high morbidity rates, and reducing these rates remains challenging. Among several complications, postoperative pneumonia (PP) is sometimes fatal, which has been reportedly caused by sarcopenia. Thus, nutritional support and rehabilitation may be promising for preventing skeletal muscle mass loss and reduce the incidence of PP. METHODS: This single-center, randomized, open-label, pilot trial will randomize a total of 40 patients with esophageal cancer in a 1:1 ratio either to ISOCAL Clear + rehabilitation arm or only rehabilitation arm. Although all patients will be educated about rehabilitation by a specialized physician and will be asked to undergo the prespecified rehabilitation program, patients treated with ISOCAL Clear + rehabilitation arm will be supplemented by 400 mL of ISOCAL Clear (Nestlé Japan Ltd, Tokyo, Japan) per day during two courses of NAC with docetaxel, cisplatin, and fluorouracil. Body composition will be assessed using Inbody (Inbody Co., Ltd., Tokyo, Japan) just before starting NAC and surgery. The primary endpoint is the change of skeletal muscle index (SMI) during NAC. Secondary endpoints include (i) body weight, total skeletal muscle mass, appendicular skeletal muscle mass, and lean body mass index changes; (ii) the percentage of ISOCAL Clear continuation; (iii) appetite evaluation; (iv) the percentage of targeted calorie achievement; (v) adverse events of NAC; (vi) postoperative complication rates; and (vii) postoperative hospital stay. DISCUSSION: This prospective trial assesses the efficacy of nutritional support in addition to rehabilitation during NAC for patients with esophageal cancer. The results will be utilized in assessing whether the effects of nutritional support by ISOCAL Clear are promising or not and in planning future larger clinical trials.

An 8-mm port site hernia after robotic-assisted ileocecal resection: a case report.

BACKGROUND: Robotic-assisted surgery is steadily becoming more prominent. The majority of reports regarding port site hernias (PSHs) have involved laparoscopic procedures. Currently, it is common to suture the fascia at port sites that are 10 mm or larger; however, the closure of 5-mm port sites is not considered mandatory. The da Vinci® surgical system (Intuitive Surgical Inc., Sunnyvale, CA, USA) utilizes a distinctive 8-mm port. We report a case of an early-onset PSH at an 8-mm port site after robotic-assisted ileocecal resection. CASE PRESENTATION: A 74-year-old male patient with a body mass index of 19.7 kg/m2 was diagnosed with cecal cancer and underwent robotic-assisted ileocecal resection. A 3-cm midline incision was made at the umbilicus for insufflation. Under laparoscopic visualization, three ports (12 mm, 8 mm, and 8 mm) were inserted in the lower abdomen. An 8-mm port was inserted in the left subcostal region, and a 5-mm port was inserted in the left lateral abdomen. The procedure was performed without significant intraoperative complications. The fascia was closed only at the umbilicus and 12-mm port site; the fascia at the 8-mm port sites was not closed. The patient was initially discharged without complications; however, on postoperative day 11, the patient was urgently hospitalized again because of PSH incarceration. After manual reduction, the fascia was sutured closed under local anesthesia. The hernial defect was small and barely allowed the insertion of a little finger. There was no evidence of compression or significant damage to the fascia. On postoperative day 27, the patient was discharged after experiencing good recovery. CONCLUSIONS: Robotic-assisted colectomy could contribute to the risk of PSHs because of its surgical characteristics. Although routine closure of the fascia at 8-mm port sites is not mandatory, it may be beneficial in certain cases.

Prognostic significance of connective tissue growth factor expression in stromal cells in patients with diffuse­type gastric cancer.

Connective tissue growth factor (CTGF) is a target gene of the Hippo signaling pathway. Its differential role in the histological types of gastric cancer (GC) remains unknown; therefore, the present study aimed to confirm the clinical significance of CTGF expression in cancer and stromal cells in patients with GC depending on the histological type. The present study enrolled 589 patients with GC. Immunohistochemistry was used to analyze CTGF expression in cancer and stromal cells. CTGF mRNA expression data and the corresponding clinical information of GC samples were collected from The Cancer Genome Atlas (TCGA) database. Subsequently, the associations between CTGF expression and several clinicopathological factors were investigated. In the present study, CTGF expression was mainly observed in the cytoplasm of cancer and stromal cells. CTGF expression in stromal cells was significantly associated with CTGF expression in cancer cells (P<0.001). CTGF positivity in stromal cells was also significantly associated with intestinal type, non-scirrhous type, tumor depth (T1-2), lymph node metastasis (negative), lymphatic invasion (negative) and tumor size (<5 cm). Low CTGF expression in stromal cells was independently associated with worse overall survival (OS). Furthermore, the OS of patients with low CTGF expression in stromal cells, especially in patients with diffuse-type GC, was significantly worse than patients with high CTGF expression (P=0.022). This trend was similar to that revealed by TCGA data analysis. In conclusion, low CTGF expression was associated with a significantly worse OS in patients with diffuse-type GC. These data indicated that CTGF, and its control by the Hippo pathway, may be considered potential treatment targets in diffuse-type GC.

The development of a risk assessment tool for patients with postoperative pneumonia after gastrectomy for gastric cancer.

BACKGROUND: Although frail patients are known to experience increased postoperative complications, this is unclear for postoperative pneumonia (POP). We investigated associations between frailty and POP in patients with gastric cancer (GC) undergoing gastrectomy. METHODS: In this prospective study conducted between August 2016 and December 2022, we preoperatively assessed frailty in 341 patients with GC undergoing gastrectomy using a frailty index (FI). Patients were divided into high FI vs low FI groups to examine frailty and pneumonia rates after gastrectomy for GC. RESULTS: Of 327 patients, 18 (5.5%) experienced POP after gastrectomy. Multivariate analyses showed that a high FI and total or proximal gastrectomy (TG/PG) were independent risk factors for POP (high FI: odds ratio [OR], 5.00; 95% CI, 1.77-15.54; TG/PG: OR, 3.07; 95% CI, 1.09-8.78). The proportion of patients with POP was 2.4% in those with nonhigh FI and non-TG/PG, 5.3% in those with nonhigh FI and TG/PG, 7.1% in those with high FI and non-TG/PG, and 28.0% in those with high FI and TG/PG (P < .001). The area under the receiver operating characteristic curve for this risk assessment for predicting POP was 0.740. CONCLUSION: In patients with GC undergoing gastrectomy, POP was independently associated with preoperatively high FI and TG/PG. Our simple POP risk assessment method, which combines these factors, may effectively predict and prepare patients for POP.

Study of Short-Term and Long-Term Outcomes Between Esophagogastrostomy and Double-Tract Reconstruction After Proximal Gastrectomy.

BACKGROUND: As the opportunities for proximal gastrectomy (PG) for early gastric cancer in the upper third stomach have been increasing, the safety and feasibility of PG have been a great concern in recent years. This study aimed to compare the short-term and long-term outcomes between patients who underwent esophagogastrostomy (EG) and those who underwent double-tract reconstruction (DTR) after PG. METHODS: We retrospectively reviewed the medical records of 34 patients who underwent EG and 39 who underwent DTR at our hospital between 2011 and 2022. We compared the procedure data and postoperative complications including anastomotic complications within 1 year after surgery as short-term outcomes and the rates of change in nutritional status, skeletal muscle mass, and 3-year survival as long-term outcomes. RESULTS: Although operation time of the DTR group was significantly longer than that of the EG group, there were no significant differences in postoperative complications between 2 groups. Regarding the endoscopic findings, the incidence of anastomotic stenosis and reflux esophagitis was significantly higher in the EG group than in the DTR group (26.5% vs 0%, p < 0.001; 15.2% vs 0%, p = 0.020). In long-term outcomes, there were no significant differences in body weight, BMI, laboratory data, and skeletal muscle mass index between 2 groups for 3 years. The 3-year overall survival rates of 2 groups were similar. CONCLUSION: DTR after PG could prevent the occurrence of anastomotic complications in comparison to EG. The long-term outcomes were similar between these 2 types of reconstruction.

Impact of a robotic system on intra-abdominal infectious complications after minimally invasive gastrectomy in patients with gastric cancer: A propensity score matching analysis regarding visceral obesity.

Background: The efficacy of robotic gastrectomy (RG) on postoperative complications in patients with gastric cancer (GC) is unclear in terms of the volume of intra-abdominal fat tissue. Patients and Methods: We enrolled 403 patients with GC who had minimally invasive surgery between January 2015 and July 2022. During this time, 197 RG and 206 laparoscopic gastrectomies (LG) were performed on the study participants. According to the computed tomography scan, patients were defined as having or not having visceral obesity based on the visceral fatty area (VFA). In each high and low VFA group, we compared short-term outcomes between the RG group and LG group. Results: After PS matching for patients with high VFA, the two groups were well matched, with 71 cases in both the RG and LG groups. The median surgical time in the RG group was significantly longer (420 vs. 365 min, p < 0.001). However, the RG group had a significantly lower rate of severe intra-abdominal infectious complications (IAIC), such as anastomotic leakage, pancreatic fistula, and intra-abdominal abscess (1.4% vs. 15.4%, p = 0.004). However, among the 77 patients with low VFA values, we found no significant difference in the rate of severe IAIC between the two groups (1.1% in the RG group vs. 2.6% in the LG group, p = 1.00). Conclusion: RG may be a viable alternative to LG because of the lower postoperative IAIC for patients with visceral obesity and GC. However, RG may not benefit non-obese patients.

An Improvement of Exertional Dyspnea by the Reintroduction of Anti-EGFR Antibody in Patients with Metastatic Rectal Cancer Who Developed Cancerous Lymphangiopathy: A Case Report.

Introduction: Reexposure to anti-EGFR antibodies, such as a reintroduction or rechallenge with anti-EGFR antibodies, has attracted much attention in the field of metastatic colorectal cancer. A reintroduction of anti-EGFR antibodies often shows good therapeutic outcomes, as most patients eligible for such reintroduction discontinued treatment due to adverse events despite a good treatment response during front-line treatment. We herein report a case demonstrating an improvement in exertional dyspnea after the reintroduction of anti-EGFR antibody in a patient with metastatic rectal cancer who developed cancerous lymphangiopathy. Case Presentation: A 68-year-old man who had undergone curative surgery for stage IIIB rectal cancer was diagnosed with multiple lung metastases. During the late-line treatment, respiratory failure developed because of multiple lung metastases and cancerous lymphangiopathy. Two months after the initiation of irinotecan + cetuximab, which had been discontinued due to acneiform eruptions despite a good treatment response as a first-line treatment, his dyspnea and performance status dramatically improved. Conclusion: This case indicates that the reintroduction of anti-EGFR antibody to patients who have discontinued anti-EGFR antibody due to skin toxicity despite a good treatment response is a very useful treatment option for metastatic colorectal cancer.

Effects of an artificial pancreas on postoperative inflammation in patients with esophageal cancer.

PURPOSES: Subtotal esophagectomy for esophageal cancer (EC) is associated with high morbidity rates. Tight glycemic control using an artificial pancreas (AP) is one of the promising strategies to reduce postoperative inflammation and morbidities. However, the effects of tight glycemic control using AP in patients with EC are yet to be fully elucidated. METHOD: This study reviewed 96 patients with EC who underwent subtotal esophagectomy. The postoperative inflammation parameters and morbidity rates were compared between patients who used the AP (n = 27) or not (control group, n = 69). AP is a closed-loop system that comprises a continuous glucose monitor and an insulin pump. RESULTS: The numbers of white blood cells (WBC) and Neutrophils (Neut) were noted to be lower in the AP group than in the control group, but with no significant difference. The ratio in which the number of WBC, Neut, and CRP on each postoperative day (POD) was divided by those tested preoperatively was used to standardize the results. The ratio of WBC and Neut on 1POD was significantly lower in the AP group than in the control group. The rate of surgical site infection was lower in the AP group than in the control group. CONCLUSION: AP significantly decreased WBC and Neut on 1POD; this suggests the beneficial effects of AP in alleviating postoperative inflammation.

Involvement of CX3CR1+ cells appearing in the abdominal cavity in the immunosuppressive environment immediately after gastric cancer surgery.

BACKGROUND: Gastric cancer is primarily treated by surgery; however, little is known about the changes in the intraperitoneal immune environment and the prognostic impact of surgery. Surgical stress and cancer-associated inflammation cause immune cells to mobilize into the abdominal cavity via numerous cytokines. One such cytokine, CX3CR1, has various immune-related functions that remain to be fully explained. We characterized the intraperitoneal immune environment by investigating CX3CR1+ cells in intraperitoneal lavage fluid during gastric cancer surgery. METHODS: Lavage fluid samples were obtained from a total of 41 patients who underwent gastrectomy. The relative expression of various genes was analyzed using quantitative real-time PCR. The association of each gene expression with clinicopathological features and surgical outcomes was examined. The fraction of CX3CR1+ cells was analyzed by flow cytometry. Cytokine profiles in lavage fluid samples were investigated using a cytometric beads array. RESULTS: CX3CR1high patients exhibited higher levels of perioperative inflammation in blood tests and more recurrences than CX3CR1low patients. CX3CR1high patients tended to exhibit higher pathological T and N stage than CX3CR1low patients. CX3CR1 was primarily expressed on myeloid-derived suppressor cells and tumor-associated macrophages. In particular, polymorphonuclear myeloid-derived suppressor cells were associated with perioperative inflammation, pathological N, and recurrences. These immunosuppressive cells were associated with a trend toward unfavorable prognosis. Moreover, CX3CR1 expression was correlated with programmed death-1 expression. CONCLUSIONS: Our results suggest that CX3CR1+ cells are associated with an acute inflammatory response, tumor-promotion, and recurrence. CX3CR1 expression could be taken advantage of as a beneficial therapeutic target for improving immunosuppressive state in the future. In addition, analysis of intra-abdominal CX3CR1+ cells could be useful for characterizing the immune environment after gastric cancer surgery.

Optimal extent of lymph node dissection for high-risk gastric cancer stratified by a national clinical database risk calculator.

BACKGROUND: For patients with gastric cancer, a well-balanced treatment that considers both oncological aspects and surgical risk is demanded. This study aimed to explore the optimal extent of lymph node dissection (LND) for patients with gastric cancer according to surgical risk, stratified by the risk calculator system produced by the Japan National Clinical Database (NCD). PATIENTS AND METHODS: We retrospectively evaluated 187 patients who underwent radical gastrectomy for gastric cancer. Using the median predicted anastomotic leak rate obtained by the NCD risk calculator as the cutoff value, we classified 97 and 90 patients as having high and low risks, respectively. RESULTS: In low-risk patients, although limited LND reduced the postoperative intraabdominal infectious complications (IAIC), multivariate analysis revealed standard LND as an independent prognostic factor that improved Relapse-free survival (RFS). In high-risk patients, the rates of postoperative IAIC and RFS were similar between standard and limited LND. Pancreatic fistula was not observed in the limited dissection group. CONCLUSION: Limited LND might be the optimal treatment strategy for patients with gastric cancer with high surgical risk.

Enabling Personalization for Digital Cognitive Stimulation to Support Communication With People With Dementia: Pilot Intervention Study as a Prelude to AI Development.

BACKGROUND: Maintaining good communication and engagement between people with dementia and their caregivers is a major challenge in dementia care. Cognitive stimulation is a psychosocial intervention that supports communication and engagement, and several digital applications for cognitive stimulation have been developed. Personalization is an important factor for obtaining sustainable benefits, but the time and effort required to personalize and optimize applications often makes them difficult for routine use by nonspecialist caregivers and families. Although artificial intelligence (AI) has great potential to support automation of the personalization process, its use is largely unexplored because of the lack of suitable data from which to develop and train machine learning models. OBJECTIVE: This pilot study aims to evaluate a digital application called Aikomi in Japanese care homes for its potential to (1) create and deliver personalized cognitive stimulation programs to promote communication and engagement between people with dementia and usual care staff and (2) capture meaningful personalized data suitable for the development of AI systems. METHODS: A modular technology platform was developed and used to create personalized programs for 15 people with dementia living in 4 residential care facilities in Japan with the cooperation of a family member or care staff. A single intervention with the program was conducted with the person with dementia together with a care staff member, and for some participants, smell stimulation was provided using selected smell sticks in conjunction with the digital program. All sessions were recorded using a video camera, and the combined personalized data obtained by the platform were analyzed. RESULTS: Most people with dementia (10/15, 67%) showed high levels of engagement (>40 on Engagement of a Person with Dementia Scale), and there were no incidences of negative reactions toward the programs. Care staff reported that some participants showed extended concentration and spontaneous communication while using Aikomi, which was not their usual behavior. Smell stimulation promoted engagement for some participants even when they were unable to identify the smell. No changes in well-being were observed following the intervention according to the Mental Function Impairment Scale. The level of response to each type of content in the stimulation program varied greatly according to the person with dementia, and personalized data captured by the Aikomi platform enabled understanding of correlations between stimulation content and responses for each participant. CONCLUSIONS: This study suggests that the Aikomi digital application is acceptable for use by persons with dementia and care staff and may have the potential to promote communication and engagement. The platform captures personalized data, which can provide suitable input for machine learning. Further investigation of Aikomi will be conducted to develop AI systems and create personalized digital cognitive stimulation applications that can be easily used by nonspecialist caregivers.

The Effect of Bidirectional Barbed Sutures on the Duration of Common Enterotomy Closure in Intracorporeal Anastomosis.

BACKGROUND/AIM: The adoption of intracorporeal anastomosis in minimally invasive surgery for colon cancer has gradually expanded owing to its many advantages. However, intracorporeal anastomosis has the disadvantage of a longer operative time than extracorporeal anastomosis. One reason that intracorporeal anastomosis takes longer to perform is the closure of the common enterotomy. The present study evaluated the effect of bidirectional barbed sutures on the duration of common enterotomy closure in intracorporeal anastomosis for minimally invasive colectomy. MATERIALS AND METHODS: The time required for common enterotomy closure was measured with a simulator using an intestinal model. A two-layer suture with continuous full-thickness suture followed by a continuous serosal-muscular suture was adopted. The time required to close the common enterotomy using two unidirectional barbed sutures and one bidirectional barbed suture was measured five times each. RESULTS: The duration of common enterotomy closure using bidirectional barbed suture was significantly shorter than that using two conventional barbed sutures. CONCLUSION: Bidirectional barbed sutures are useful for closing the common enterotomy in intracorporeal anastomosis for minimally invasive colectomy.

Evaluation of Intraoperative Neural Monitoring During Thoracoscopic Surgery for Esophageal Cancer.

BACKGROUND/AIM: Recurrent laryngeal nerve paralysis (RLNP) induces aspiration pneumonia and reduces the patient's quality of life. To decrease the incidence of RLNP, we performed intraoperative neural monitoring (IONM) during thoracoscopic surgery for esophageal cancer and evaluated its usefulness. PATIENTS AND METHODS: A total of 737 consecutive patients who underwent thoracoscopic surgery for esophageal cancer were enrolled in this study. Between May 1995 and March 2016, thoracoscopic esophagectomies were performed using video-assisted thoracoscopic surgery (VATS) with a small incision, whereas from April to June 2023, we used positive pressure pneumothorax with port placement only [minimum invasive esophagectomy (MIE)]. A total of 110 consecutive patients who underwent thoracoscopic surgery with IONM (IONM group) were retrospectively compared with those who underwent VATS or MIE without IONM (No-IONM group). RESULTS: The incidence of RLNP [Clavien-Dindo (CD) classification of ≥1] on postoperative day (POD) 5 was 13.9% in the IONM group, which was significantly lower than that of the no-IONM group (31.2%, p<0.001). Even when comparing only patients who underwent MIE, the incidence of RLNP on POD5 was 13.9% in the IONM group, which was significantly lower than that in the no-IONM group (26.2%, p=0.035). The incidence of postoperative pneumonia (CD ≥2) was 10.9% in the IONM group, which was significantly lower than that in the no-IONM group (26.1%, p=0.005). Bilateral RLNP did not occur in any of the IONM groups. CONCLUSION: IONM is a useful tool for reducing RLNP incidence and postoperative pneumonia after thoracoscopic surgery for esophageal cancer.

Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis.

The metabolic and signaling pathways regulating aggressive mesenchymal colorectal cancer (CRC) initiation and progression through the serrated route are largely unknown. Although relatively well characterized as BRAF mutant cancers, their poor response to current targeted therapy, difficult preneoplastic detection, and challenging endoscopic resection make the identification of their metabolic requirements a priority. Here, we demonstrate that the phosphorylation of SCAP by the atypical PKC (aPKC), PKCλ/ι promotes its degradation and inhibits the processing and activation of SREBP2, the master regulator of cholesterol biosynthesis. We show that the upregulation of SREBP2 and cholesterol by reduced aPKC levels is essential for controlling metaplasia and generating the most aggressive cell subpopulation in serrated tumors in mice and humans. Since these alterations are also detected prior to neoplastic transformation, together with the sensitivity of these tumors to cholesterol metabolism inhibitors, our data indicate that targeting cholesterol biosynthesis is a potential mechanism for serrated chemoprevention.

Usefulness of intraoperative ultrasound examination for laparoscopic right-side colon cancer surgery: a propensity score-matched study.

Complete mesocolic excision (CME) with central vascular ligation (CVL) in laparoscopic surgery for right-sided colon cancer (RSCC) requires a precise understanding of the vascular anatomy. The efficacy of intraoperative ultrasound (IUS) in the identification of blood vessels for RSCC surgery was not evaluated. The aim of this study was to compare the intraoperative and short-term outcomes of CME with CVL with or without IUS by laparoscopic surgery for RSCC. We performed IUS on 26 patients of RSCC and compared with a total of 124 patients who underwent the surgery for RSCC at our institution. Propensity score matching (PSM) was performed to reduce the confounding effects to imbalances in the use of IUS. The IUS identified the main feeding artery and the accompanying vein in all 26 cases. After PSM, the amount of intraoperative blood loss in the IUS group was significantly lower than that in the conventional group (5 ml vs. 30 ml, p = 0.035) and no significant difference of the postoperative complications was observed. The IUS reduced the risk of bleeding in the surgery for RSCC. The IUS is a safe and feasible technique that help the surgeons for anatomical understandings under real-time condition in the laparoscopic surgery of RSCC.

Preoperative Frailty Assessed Comprehensively by a Questionnaire Predicts a Poor Survival Following Curative Resection of Gastric Cancer.

Background/Aim: The concept of frailty has been attracting attention as a comprehensive indicator of the various effects of aging, but no conclusion has been reached on how to evaluate it. The present study investigated the adverse effect of preoperative frailty on short- and long-term outcomes in patients with gastric cancer using a questionnaire about frailty. Patients and Methods: One hundred and twenty-five patients with pathological stage (p Stage) I/II/III who underwent radical gastrectomy for gastric cancer at the Department of Gastroenterological Surgery, Osaka, Japan from April 2015 to December 2016 were enrolled in this study. The frailty index (FI) was calculated by dividing the total score of 50 questions consisting of 1 point per question by 50. The study used multiple logistic regression analysis with 5-year overall survival (OS) as the endpoint to create a receiver operating characteristic (ROC) curve to determine the cut-off point for the FI. The short- and long-term outcomes of the frail and non-frail groups were then compared, and prognostic factors for OS were examined. Results: Regarding the short-term outcomes, the postoperative complication rates did not differ significantly between the two groups. Regarding the 5-year OS rates of the patients with p Stages II/III, the outcomes in the frail group were significantly poorer than those in the non-frail group. In the multivariate analysis of OS, frailty was independently associated with unfavorable outcomes in patients with p Stages II/III gastric cancer. Conclusion: Frailty evaluation in this study may be useful in predicting long-term prognosis in patients undergoing surgical treatment for advanced gastric cancer.

Usefulness of Biopsy Specimens for Evaluating CD103+ Tumor-resident Memory T Cells in Esophageal Cancer.

BACKGROUND/AIM: CD103+ tissue-resident memory T cells (TRM) in tumor sites are associated with a favorable prognosis and predict the effectiveness of immune checkpoint inhibitors. The detection of CD103+ TRM infiltration in biopsy samples could be beneficial for patients without surgical indications. However, the usefulness of TRM detection in biopsy tissue and the difference in TRM status between biopsy and surgical specimens' post-neoadjuvant chemotherapy have not been elucidated. In the present study, we aimed to elucidate whether we can detect TRM in biopsy specimens and the impact of chemotherapy on TRM infiltration. MATERIALS AND METHODS: Tissue sections were obtained from 46 patients with esophageal cancer who received neoadjuvant chemotherapy and underwent radical esophagectomy in 2017. Immunohistochemistry was performed using an anti-CD103 antibody for biopsy and surgical specimens. We examined the relationship between CD103 expression, clinicopathological features, and prognosis for each patient. RESULTS: TRM infiltration was detected in the biopsy specimens. CD103 expression in biopsy specimens correlated with that in surgical specimens. Although there was no statistical significance in clinicopathological findings between CD103high and CD103low, patients with CD103high biopsy specimens exhibited favorable prognosis. The number of CD103+ cells was increased by chemotherapy: though with no survival benefit. CONCLUSION: Regardless of surgical indication, we were able to determine the TRM status even in biopsy specimens. CD103 evaluation at biopsy may be more useful and practical than evaluation in surgical specimens, enabling prediction of prognosis and response to immune therapy.

Significance of CD103+ tissue-resident memory T cells for predicting the effectiveness of immune checkpoint inhibitors in esophageal cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs), including nivolumab, have been approved to treat esophageal cancer. However, these remedies are not fit for all patients with esophageal cancer; therefore, a predictive surrogate marker is needed to assess their effectiveness. CD103+CD8+ tumor-infiltrating lymphocytes, defined as tissue-resident memory T cells (TRM), are promising indicators of response to ICIs, but it remains to be elucidated. This study investigated the association between the efficacy of ICIs and TRM. METHODS: The relationships between TRM infiltrating esophageal cancer, clinicopathological features, and prognosis after nivolumab initiation were examined using immunostaining. Tissue samples were obtained from surgically resected specimens of 37 patients with esophageal cancer who received nivolumab as a secondary or subsequent therapy. In addition, TRM infiltration was compared with programmed death-ligand 1 (PD-L1) expression and blood count parameters as predictors of nivolumab effectiveness. RESULTS: TRM-rich patients had a significant survival benefit after nivolumab initiation (12-months overall survival 70.8% vs 37.2%, p = 0.0485; 12-months progression-free survival 31.2% vs 0%, p = 0.0153) and experienced immune-related adverse events more frequently than TRM-poor patients (6 vs 2 patients). TRM infiltration was weakly correlated with PD-L1 positivity (r = 0.374, p = 0.022), but TRM may indicate more sensitive response to ICIs than PD-L1 expression in this study. Some blood test parameters also weakly correlated with TRM but did not impact prognosis. CONCLUSIONS: TRM-rich patients have a favorable prognosis after nivolumab initiation. Our results suggest that TRM are vital for antitumor immunity and are a promising predictor of ICIs effectiveness.