Effectiveness of Etoposide and Cisplatin vs Irinotecan and Cisplatin Therapy for Patients With Advanced Neuroendocrine Carcinoma of the Digestive System: The TOPIC-NEC Phase 3 Randomized Clinical Trial.

Importance: Etoposide plus cisplatin (EP) and irinotecan plus cisplatin (IP) are commonly used as community standard regimens for advanced neuroendocrine carcinoma (NEC). Objective: To identify whether EP or IP is a more effective regimen in terms of overall survival (OS) in patients with advanced NEC of the digestive system. Design, Setting, and Participants: This open-label phase 3 randomized clinical trial enrolled chemotherapy-naive patients aged 20 to 75 years who had recurrent or unresectable NEC (according to the 2010 World Health Organization classification system) arising from the gastrointestinal tract, hepatobiliary system, or pancreas. Participants were enrolled across 50 institutions in Japan between August 8, 2014, and March 6, 2020. Interventions: In the EP arm, etoposide (100 mg/m2/d on days 1, 2, and 3) and cisplatin (80 mg/m2/d on day 1) were administered every 3 weeks. In the IP arm, irinotecan (60 mg/m2/d on days 1, 8, and 15) and cisplatin (60 mg/m2/d on day 1) were administered every 4 weeks. Main Outcomes and Measures: The primary end point was OS. In total, data from 170 patients were analyzed to detect a hazard ratio (HR) of 0.67 (median OS of 8 and 12 months in inferior and superior arms, respectively) with a 2-sided α of 10% and power of 80%. The pathologic findings were centrally reviewed following treatment initiation. Results: Among the 170 patients included (median [range] age, 64 [29-75] years; 117 [68.8%] male), median OS was 12.5 months in the EP arm and 10.9 months in the IP arm (HR, 1.04; 90% CI, 0.79-1.37; P = .80). The median progression-free survival was 5.6 (95% CI, 4.1-6.9) months in the EP arm and 5.1 (95% CI, 3.3-5.7) months in the IP arm (HR, 1.06; 95% CI, 0.78-1.45). A subgroup analysis of OS demonstrated that EP produced more favorable OS in patients with poorly differentiated NEC of pancreatic origin (HR, 4.10; 95% CI, 1.26-13.31). The common grade 3 and 4 adverse events in the EP vs IP arms were neutropenia (75 of 82 [91.5%] patients vs 44 of 82 [53.7%] patients), leukocytopenia (50 of 82 [61.0%] patients vs 25 of 82 [30.5%] patients), and febrile neutropenia (FN) (22 of 82 [26.8%] patients vs 10 of 82 [12.2%] patients). While incidence of FN was initially high in the EP arm, primary prophylactic use of granulocyte colony-stimulating factor effectively reduced the incidence of FN. Conclusions and Relevance: Results of this randomized clinical trial demonstrate that both EP and IP remain the standard first-line chemotherapy options. Although AEs were generally manageable, grade 3 and 4 AEs were more common in the EP arm. Trial Registration: Japan Registry of Clinical Trials: jRCTs031180005; UMIN Clinical Trials Registry: UMIN000014795.

A novel imaging technology to assess oxygen saturation of the gastric conduit in thoracic esophagectomy.

BACKGROUND: Real-time evaluation of blood perfusion is important when selecting the site of anastomosis during thoracic esophagectomy. This study investigated a novel imaging technology that assesses tissue oxygen saturation (StO2) in the gastric conduit and examined its efficacy. METHODS: Fifty-one patients undergoing thoracic esophagectomy for esophageal cancer who underwent intraoperative StO2 endoscopic imaging to assess the gastric conduit for the optimal site of anastomosis were examined. Efficacy of oxygen saturation imaging and patient outcomes were analyzed. RESULTS: All 51 patients underwent esophagectomy without intraoperative problems. Mean StO2 in the gastric tube was highest at the pre-pylorus area and then gradually decreased proceeding toward the tip. StO2 was well preserved in areas supplied by the right gastroepiploic artery but low in other areas. Anastomotic sites were selected based on StO2 imaging and tension considerations; most were located within 3 cm of the end of the right gastroepiploic artery. Three patients developed postoperative anastomotic leakage (5.8%). Mean StO2 at the point of anastomosis was significantly lower in the patients who experienced leakage than in those who did not (P = 0.04). CONCLUSION: Intraoperative endoscopic StO2 imaging is useful in esophageal cancer patients undergoing thoracic esophagectomy to determine the optimal site for anastomosis to minimize the risk of anastomotic leakage.

Propensity-matched analysis of the efficacy of olanexidine gluconate versus chlorhexidine-alcohol as an antiseptic agent in thoracic esophagectomy.

BACKGROUND: In the present matched-cohort study, we investigated the efficacy of olanexidine gluconate in comparison with chlorhexidine-alcohol as an antiseptic agent in thoracic esophagectomy. METHODS: A total of 372 patients with esophageal cancer who were scheduled to undergo thoracic esophagectomy between 2016 and 2018 were assigned to one of two groups based on the preoperative antiseptic agent used in thoracic esophagectomy. We investigated the incidence of surgical site infectious complications in the propensity-matched cohort. RESULTS: Based on the propensity score, 116 patients prepared with 1.5% olanexidine gluconate and 114 patients prepared with 1.0% chlorhexidine-alcohol as surgical skin antisepsis were selected. No significant intergroup differences were observed with respect to incisional surgical site infection (0.8% in the olanexidine group versus 0.8% in the chlorhexidine group) and deep fascial/organ space surgical site infection (1.7%/10.3% in the olanexidine group versus 3.5%/15.7% in the chlorhexidine group, p = 0.39/p = 0.03). Notably, the respective incidences of surgical site infection except anastomotic leakage were 1.7% and 7.0% in the olanexidine and chlorhexidine groups (p = 0.04). CONCLUSIONS: Olanexidine gluconate was well tolerated and significantly reduced incidence of surgical site infection except anastomotic leakage in comparison with chlorhexidine-alcohol as an antiseptic agent in thoracic esophagectomy with three-field lymph node dissection.

Laparoscopic Synchronous Resection for Descending Colon Cancer and Tailgut Cyst.

A 67-year-old woman underwent polypectomy for a tumor at the descending colon. Pathologically, the tumor was diagnosed as adenocarcinoma with an invasion of 2000 µm. Computed tomography showed a swollen paracolic lymph node and a mass lesion in the presacral space. Magnetic resonance imaging revealed a multio-cular cystic lesion. On diagnosis of descending colon cancer and tailgut cyst, she underwent synchronous lapa-roscopic resection. Histopathologically, the colon cancer was diagnosed as pT1bN1M0, pStage IIIa. The pre-sacral cystic lesion was diagnosed as a nonmalignant tailgut cyst with negative surgical margin. The patient is currently doing well without recurrence at 28 months.

[Successful Resection Using a Posterior Approach of a Tailgut Cyst in the Retrorectal Space].

We present the case of a Tailgut cyst occurring in the retrorectal space that was curatively resected using a posterior approach. A 40-year-old man presented to the Kochi Health Sciences Center with the chief complaint of perineal incongruity. Pelvic magnetic resonance imaging revealed a multilocular cystic lesion in the retrorectal space, with high signal intensity on T2-weighted imaging. After diagnosing a Tailgut cyst, we performed resection of the tumor using a posterior approach. The lesion was removed en bloc with the coccyx. Histopathologically, the lesion was diagnosed as a non-malignant Tailgut cyst, and the surgical margin was negative. The patient is currently doing well without recurrence at 20 months.

Novel universally applicable technique for performing bilateral transcervical mediastinoscopic-assisted transhiatal laparoscopic esophagectomy: a truly minimally invasive procedure.

BACKGROUND: The procedure of mediastinoscopic-assisted transhiatal esophagectomy (MATE) is only performed in a few institutions, despite this being the ultimate form of minimally invasive surgery for performing esophagectomy for esophageal and esophagogastric cancer in that it entails no chest wall trauma. We have developed a novel, universally applicable, surgical procedure for performing bilateral transcervical mediastinoscopic-assisted transhiatal laparoscopic esophagectomy (BTC-MATLE) that is an improvement on standard MATE surgery for esophageal and esophagogastric cancer. METHODS: The patient is placed in a supine position under general anesthesia with bilateral lung ventilation. BTC-MATLE combined with mediastinoscopic and transhiatal laparoscopic esophagectomy with total mediastinal lymph node dissection are performed synchronously. After lymph node dissection along both recurrent laryngeal nerves through bilateral cervical skin incisions, bilateral transcervical mediastinoscopic esophagectomy is performed to avoid collision outside the cervical region and ensure operability even in patients with narrow mediastimun. Laparoscopic gastric mobilization and subsequent lower esophageal mobilization meet the bilateral transcervical mediastinoscopic esophagectomy at the border of the middle and lower third of the esophagus. The gastric tube is pulled up into the cervical region via a posterior mediastinal route and anastomosed in the neck. RESULTS: BTC-MATLE was performed on 16 high-risk patients (Charlson Comorbidity Index ≥ 3 in 14 patients and two octogenarians with complex comorbidities). Median operation time and postoperative hospital stay were 231 min and 15 days, respectively. R0 resection was achieved in 15 patients (94%), and there were no in-hospital deaths. CONCLUSIONS: BTC-MATLE, a procedure for performing minimally invasive esophagectomy, is likely to become the applicable form of MATE surgery for esophageal and esophagogastric cancer, even in high-risk patients because it is truly minimally invasive and has excellent short-term outcomes.

Novel minimally invasive approach to lymph node dissection around the left renal vein in patients with esophagogastric junction cancer.

The left renal vein lymph node (LRVLN) may be the extended locoregional node in esophagogastric junction cancer; however, only open-surgical methods of dissection have been reported. We therefore developed a novel minimally invasive laparoscopic method for LRVLN dissection. Following esophagectomy, the stomach was mobilized and LRVLN dissection was started by taping the pancreatic body using two silicone drains. The transverse mesocolon was then retracted through the superior duodenal fossa to expose the horizontal duodenum and permit LRVLN dissection. We carried out the procedure successfully in 17 patients with advanced esophagogastric cancer. The median total and laparoscopic operative times were 415 and 161 min, respectively. Postoperative esophagectomy-related complications occurred in six patients. The median estimated blood loss was 120 ml and hospital stay was 15 days. This minimally invasive laparoscopic LRVLN dissection method was safe and effective, and may support faster recovery and earlier postoperative adjuvant therapy in patients with esophagogastric junction cancer.

Totally Mechanical Collard Technique for Cervical Esophagogastric Anastomosis Reduces Stricture Formation Compared with Circular Stapled Anastomosis.

BACKGROUND: The optimal technique for cervical esophagogastric anastomosis in esophagectomy has not yet been established. Using circular stapled (CS) technique effectively reduces the incidence of anastomotic leakage and shortens the operating time; however, anastomotic stricture has been reported to be more common. The present study was performed to compare the clinical outcomes of the recently developed totally mechanical Collard (TMC) and CS anastomosis. METHODS: We retrospectively reviewed consecutive esophageal cancer cases who are undergoing transthoracic extended esophagectomy with gastric conduit reconstruction using cervical CS or TMC anastomosis from December 2013 to December 2016. Propensity score matching and multivariate regression were used to adjust for differences in baseline characteristics. RESULTS: Among 313 patients, 93 underwent CS anastomosis and 220 underwent TMC anastomosis. Stricture formation occurred in 59 patients (18.8%), significantly more often with the CS than TMC anastomosis (30.1% vs. 14.1%, p = 0.001). No significant differences were observed in the refractory stricture rate (9.7% vs. 5.0%, p = 0.134) or the anastomotic leakage rate (11.8% vs. 10.9%, p = 0.845) between the two groups. The propensity score matching cohort study including 86 pairs of patients confirmed a significantly lower stricture formation rate with the TMC than CS technique (27.9% vs. 14.0%, p = 0.038). In the multivariable analysis, anastomotic leakage, the CS technique, and a body mass index of ≥25 mg/m2 were independently associated with a risk of stricture formation. CONCLUSION: TMC technique contributed to a reduced rate of stricture formation compared with CS technique in cervical esophagogastric anastomosis.

Efficacy of prewarming prophylaxis method for intraoperative hypothermia during thoracoscopic esophagectomy.

BACKGROUND: This study was performed to elucidate the clinical efficacy of the prewarming prophylaxis method for intraoperative hypothermia during thoracoscopic esophagectomy for esophageal cancer. METHODS: We enrolled 100 consecutive patients with esophageal cancer. Two patients in the prewarming group could not undergo thoracoscopic esophagectomy because of conversion to thoracotomy. The intraoperative core temperature was measured in 50 and 48 patients classified into the control and prewarming groups, respectively. Patients in the prewarming group wore a Bair Hugger warming gown (3 M, Maplewood, MN, USA) in the ward for 30 min before entering the operation room. The primary outcome measure was the difference in the intraoperative body core temperature between the control and prewarming groups, and the secondary outcome measure was the difference in postoperative infectious complications between the control and prewarming groups. RESULTS: The intraoperative core temperature was significantly different between the two groups at each 30-min time point from the starting of operation to the ending of the thoracic procedure (P < 0.001). The incidence of infectious surgical complications was not significantly different between the control and prewarming groups (30.0% vs. 14.6%, respectively; P = 0.11). CONCLUSION: The prewarming prophylaxis method was effective for maintaining normothermia during thoracoscopic esophagectomy.

Thoracoscopic esophagectomy with three-field lymphadenectomy for thoracic esophageal cancer in a patient with a double aortic arch: a report of a case.

BACKGROUND: We encountered an esophageal cancer patient with a double aortic arch (DAA) who underwent radical thoracoscopic esophagectomy with three-field lymph node dissection. A DAA generally makes it difficult to perform upper mediastinal lymph node dissection via both sides of the thoracic cavity. Furthermore, most patients with a DAA have a superior right aortic arch and right-sided descending aorta, which hampers radical esophagectomy with a typical right thoracic approach. We herein report our operative strategy of thoracoscopic esophagectomy via the left side of the thoracic cavity with a preceding cervical procedure. CASE PRESENTATION: A 64-year-old man was diagnosed with esophageal squamous cell carcinoma in the upper esophagus at clinical Stage IIB (cT1bN1M0) according to the UICC-TNM classification 7th edition. First, we planned the preceding cervical procedure to complete upper mediastinal lymph node dissection, as the DAA prevented a bilateral thoracic approach to the upper mediastinum. We then planned the left thoracoscopic procedure to perform lymph node dissection below the left aortic arch, as the patient in our case had a right side-dominant DAA and right-sided descending aorta, as is common in such patients. We identified the bilateral recurrent laryngeal nerves during upper mediastinal lymph node dissection in the preceding cervical procedure and ultimately successfully resected the patient's esophageal cancer. CONCLUSION: The cervical procedure preceding the left-thoracoscopic approach is reasonable for achieving radical esophagectomy for thoracic esophageal cancer in patients with a DAA.

Impact of pathologically assessing extranodal extension in the thoracic field on the prognosis of esophageal squamous cell carcinoma.

BACKGROUND: This study aimed to elucidate the impact of extranodal extension, pathologically assessed according to new diagnostic criteria, on the prognosis of esophageal squamous cell carcinoma. Extranodal extension has been shown to be a prognostic indicator for head and neck cancers; however, its utility in esophageal squamous cell carcinoma has not been demonstrated. METHODS: We enrolled 174 consecutive esophageal squamous cell carcinoma patients who had undergone esophagectomy with lymph node dissection in the three fields. Extranodal extensions from all metastatic lymph nodes were pathologically classified into grades 1-3. Then, relationships between extranodal extension and clinicopathologic factors, including overall survival and recurrence-free survival were examined. Recurrence patterns in the thoracic and abdominal fields were also examined. RESULTS: Kaplan-Meier analyses showed that patients with grades 2 and 3 extranodal extension showed significantly poorer recurrence-free survival compared with those with intranodal involvement of esophageal squamous cell carcinoma cells (P = .0041 and P = .0011, respectively). Patients with pN3b (newly defined in this study as including at least one lymph node with grade 2-3 extranodal extension regardless of region or number of metastatic lymph nodes) was associated with significantly shorter overall survival and recurrence-free survival (P < .001). Moreover, multivariate analyses indicated that patients with grades 2-3 extranodal extension showed significantly reduced recurrence-free survival in the thoracic but not in the abdominal field (thoracic: P = .047; abdominal: P = .15). CONCLUSION: This study suggests that the extranodal extension grading system proposed in this study is a novel predictor of overall survival and recurrence-free survival in esophageal squamous cell carcinoma.

Non-occlusive mesenteric ischemia associated with enteral feeding after esophagectomy for esophageal cancer: report of two cases and review of the literature.

BACKGROUND: Non-occlusive mesenteric ischemia (NOMI) is a rare but life-threatening complication of early postoperative enteral feeding. We herein report two patients who developed NOMI during enteral feeding after esophagectomy. CASE PRESENTATION: In case 1, a 75-year-old man with no medical history was diagnosed with multiple primary cancers of the esophagus, stomach, and kidney. He underwent percutaneous endoscopic gastrostomy tube placement followed by thoracoscopic esophagectomy and cervical esophagostomy placement as the first-stage operation. Gastrostomy feeding was started on postoperative day (POD) 3 with a polymeric formula (ENSURE H®). On POD 7, he developed acute abdominal pain and distension with bloody drainage through the gastrostomy tube. Dynamic computed tomography showed massive hepatic portal venous gas and pneumatosis intestinalis. Angiography showed diffuse spasms in the branches of the superior mesenteric artery. Under a diagnosis of NOMI, we started intra-arterial infusion of papaverine and prostaglandin E1. His symptoms improved, and he was discharged on POD 48. In case 2, a 68-year-old man with diabetes and atrial fibrillation was diagnosed with esophageal cancer. His medical history was significant for pylorus-preserving gastrectomy for gastric cancer and small bowel resection for trauma. He underwent thoracoscopic esophagectomy, open total gastrectomy, colonic reconstruction, and jejunostomy tube placement. Adhesiolysis for abdominal severe adhesions caused by previous operations was difficult. Jejunostomy feeding was started on POD 3 with a polymeric formula (Racol®). On POD 7, he developed persistent diarrhea and cervical anastomotic leakage. On POD 9, he developed acute abdominal pain and distension with bloody drainage through the jejunostomy tube. Dynamic computed tomography showed the same findings as in case 1. Under a diagnosis of NOMI, we started intravenous infusion of papaverine and prostaglandin E1. His symptoms improved, and he was discharged on POD 28. CONCLUSIONS: The causes of feeding-related NOMI may include the use of a high-osmolarity formula, preoperative malnutrition, abdominal adhesiolysis, systemic inflammation after anastomotic leakage, and a medical history of diabetes and atrial fibrillation. NOMI should be considered as a differential diagnosis in patients with these risk factors and clinical features such as acute abdominal pain and distension during enteral feeding.

Internal hernia to the retrosternal space is a rare complication after minimally invasive esophagectomy: three case reports.

BACKGROUND: Minimally invasive esophagectomy is considered a beneficial approach to esophageal cancer, although a hiatal hernia occurs more frequently in this approach than in open esophagectomy with reconstruction via the mediastinal route. Development of an internal hernia to the retrosternal space is not a recognized complication of reconstruction via the retrosternal route after esophagectomy. We herein report three cases of the development of an internal hernia to the retrosternal space after minimally invasive esophagectomy. CASE PRESENTATION: Thoracolaparoscopic esophagectomy with cervical anastomosis by retrosternal route reconstruction was performed in all three cases. All patients were men ranging in age from 60 to 80 years. Two patients had abdominal pain, and one had experienced syncope. All patients were diagnosed by computed tomography with an internal hernia to the retrosternal space and thoracic cavity (retrosternal hernia) without ischemic change to the incarcerated intestine. Two patients received medical therapy to relieve their intra-abdominal pressure, which allowed for a successful reduction of the intestine into the abdomen. Open laparotomy was performed to repair the hernia in the third patient. After reducing the intestine into the abdomen, reefing of the retrosternal orifice was performed, and the gastric conduit was anchored to the abdominal wall. No relapse occurred in three cases throughout follow-up. CONCLUSION: Hiatal hernia is a well-recognized complication after minimally invasive esophagectomy; however, retrosternal hernia is a rare complication following this procedure. Based on the present report, if no ischemic change is present in the herniated intestine, two types of potentially curative treatments are available: medical or surgical. As minimally invasive esophagectomy is performed more frequently, retrosternal hernia may become an increasingly more common complication in the near future.

Safety and efficacy of hydroxyethyl starch 6% 130/0.4/9 solution versus 5% human serum albumin in thoracic esophagectomy with 3-field lymph nodes dissection.

PURPOSE: We investigated the safety and efficacy of administering hydroxyethyl starch 6% 130/0.4/9 (HES130/0.4/9) versus 5% human serum albumin (HSA), perioperatively, to patients undergoing thoracic esophagectomy with 3-field lymph-node dissection for esophageal cancer. METHODS: The subjects of this study were 262 patients, scheduled to undergo thoracic esophagectomy for esophageal cancer, who were assigned to one of two groups based on the fluid replacement therapy. We compared the intraoperative and immediate postoperative hemodynamics and incidence of complications in the two groups. RESULTS: Neither group suffered any adverse events. No significant differences were observed in systolic/diastolic blood pressure, heart rate, incidence of postoperative complications, postoperative urine output, or serum creatinine levels, between the groups. A mild postoperative increase (×1.5 increase) in serum creatinine levels was seen in 9.5% and 9.5% of patients in the HSA and HES130/0.4/9 groups, respectively (p = 0.99), and a moderate postoperative increase (×2.0 increase) was seen in 4.4% and 3.1%, respectively (p = 0.84). Univariate and multivariate analyses revealed that the administration of hydroxyethyl starch was not associated with a postoperative increase in serum creatinine levels. CONCLUSION: Hydroxyethyl starch 6% 130/0.4/9 was well tolerated and comparable to albumin with respect to its effect on renal function during thoracic esophagectomy with 3-field lymph-node dissection.

A case report of postoperative VRSA enteritis: Effective management of rifampicin for vancomycin resistant Staphylococcus aureus enteritis after esophagectomy and colon reconstruction.

INTRODUCTION: Vancomycin is one of the most widely used antibiotics for the treatment of serious infectious caused by methicillin-resistant Staphylococcus aureus (MRSA). However, reduced susceptibility of S. aureus to vancomycin has been observed in recent years. We report on a case of vancomycin resistant methicillin-resistant Staphylococcus aureus (VRSA) enteritis after colon reconstruction followed by esophagectomy and completion gastrectomy, with extended lymph node dissection for esophageal squamous cell carcinoma. PRESENTATION OF CASE: A 66-year old male was referred to our hospital for esophageal carcinoma of clinical stage T3 N0 M0, Stage IIA. From the postoperative day 3, the patient reported heavy watery stools on more then 10 occasions and high fever, and was diagnosed with the methicillin-resistant Staphylococcus aureus (MRSA) enteritis. We administered vancomycin to treat the enteritis, although a subsequent stool culture indicated VRSA instead of MRSA. Rifampincin treatment was initiated and the patient's symptoms improved. DISCUSSION: In this case report, this patient underwent esophagectomy, total resection of the gastric remnant, and colon reconstruction, and it is likely that methicillin-resistant Staphylococcus aureus (MRSA) from the upper airway system, which is not exposed to gastric acid, proliferated in the interposed colon and resulted in MRSA enteritis. CONCLUSIONS: Rifampicin represents an effective treatment strategy for postoperative VRSA enteritis.

Postoperative pulmonary complications and thoracocentesis associated with early versus late chest tube removal after thoracic esophagectomy with three-field dissection: a propensity score matching analysis.

PURPOSE: To evaluate the safety of early chest tube removal after thoracic esophagectomy with three-field dissection. METHODS: This prospective cohort study evaluated patients who underwent thoracic esophagectomy with three-field dissection during 2013-2015. Patients were divided into two groups according to whether they underwent early or late chest tube removal. Propensity score matching in a 1:1 ratio was applied. We compared the incidences of postoperative pulmonary complications and thoracocentesis in the two groups. RESULTS: After propensity score matching, 89 patients in each group were analyzed. There was no significant difference between the groups in the incidences of pulmonary complications or thoracocentesis. Significantly more patients achieved first mobilization within 15 h postoperatively in the early removal group (89.8%) than in the late removal group (52%, p < 0.01). Multivariate analysis revealed that early chest tube removal was not a risk factor for pulmonary complications or thoracocentesis. Independent risk factors for pulmonary complications were a history of pulmonary disease (odds ratio: 0.81 [0.63-0.98]; p = 0.02) and neoadjuvant chemotherapy (odds ratio: 0.67 [0.32-0.96]; p = 0.04). CONCLUSION: Early chest tube removal is as safe and feasible as late chest tube removal after thoracic esophagectomy with three-field dissection.

CBP501 induces immunogenic tumor cell death and CD8 T cell infiltration into tumors in combination with platinum, and increases the efficacy of immune checkpoint inhibitors against tumors in mice.

CBP501, a calmodulin-binding peptide, is an anti-cancer drug candidate and functions as an enhancer of platinum uptake into cancer cells. Here we show that CBP501 promotes immunogenic cell death (ICD) in combination with platinum agents. CBP501 enhanced a clinically relevant low dose of cisplatin (CDDP) in vitro as evidenced by upregulation of ICD markers, including cell surface calreticulin exposure and release of high-mobility group protein box-1. Synergistic induction of ICD by CDDP plus CBP501 as compared to CDDP alone was confirmed in the well-established vaccination assay. Furthermore, cotreatment of CDDP plus CBP501 significantly reduced the tumor growth and upregulated the percentage of tumor infiltrating CD8+ T cell in vivo. Importantly, the antitumor effect of CDDP plus CBP501 was significantly reduced by anti-CD8 antibody treatment. Based on this novel effect of CBP501, we analyzed the combination treatment with immune checkpoint inhibitors in vivo. Mice treated with CBP501 in combination with CDDP and anti-PD-1 or anti-PD-L1 showed an additive antitumor effect. These results support the conclusion that CBP501 enhances CDDP-induced ICD in vitro and in vivo. The findings also support the further clinical development of the CBP501 for enhancing the antitumor activity of immune checkpoint inhibitors in combination with CDDP.

CBP501 suppresses macrophage induced cancer stem cell like features and metastases.

CBP501 is an anti-cancer drug candidate which has been shown to increase cis-diamminedichloro-platinum (II) (CDDP) uptake into cancer cell through calmodulin (CaM) inhibition. However, the effects of CBP501 on the cells in the tumor microenvironment have not been addressed. Here, we investigated new aspects of the potential anti-tumor mechanism of action of CBP501 by examining its effects on the macrophages. Macrophages contribute to cancer-related inflammation and sequential production of cytokines such as IL-6 and TNF-α which cause various biological processes that promote tumor initiation, growth and metastasis (1). These processes include the epithelial to mesenchymal transition (EMT) and cancer stem cell (CSC) formation, which are well-known, key events for metastasis. The present work demonstrates that CBP501 suppresses lipopolysaccharide (LPS)-induced production of IL-6, IL-10 and TNF-α by macrophages. CBP501 also suppressed formation of the tumor spheroids by culturing with conditioned medium from the LPS-stimulated macrophage cell line RAW264.7. Moreover, CBP501 suppressed expression of ABCG2, a marker for CSCs, by inhibiting the interaction between cancer cells expressing VCAM-1 and macrophages expressing VLA-4. Consistently with these results, CBP501 in vivo suppressed metastases of a tumor cell line, 4T1, one which is insensitive to combination treatment of CBP501 and CDDP in vitro. Taken together, these results offer potential new, unanticipated advantages of CBP501 treatment in anti-tumor therapy through a mechanism that entails the suppression of interactions between macrophages and cancer cells with suppression of sequential CSC-like cell formation in the tumor microenvironment.