Fibroblast activation protein-targeted near-infrared photoimmunotherapy depletes immunosuppressive cancer-associated fibroblasts and remodels local tumor immunity.

BACKGROUND: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a critical role in tumor immunosuppression. However, targeted depletion of CAFs is difficult due to their diverse cells of origin and the resulting lack of specific surface markers. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that leads to rapid cell membrane damage. METHODS: In this study, we used anti-mouse fibroblast activation protein (FAP) antibody to target FAP+ CAFs (FAP-targeted NIR-PIT) and investigated whether this therapy could suppress tumor progression and improve tumor immunity. RESULTS: FAP-targeted NIR-PIT induced specific cell death in CAFs without damaging adjacent normal cells. Furthermore, FAP-targeted NIR-PIT treated mice showed significant tumor regression in the CAF-rich tumor model accompanied by an increase in CD8+ tumor infiltrating lymphocytes (TILs). Moreover, treated tumors showed increased levels of IFN-γ, TNF-α, and IL-2 in CD8+ TILs compared with non-treated tumors, suggesting enhanced antitumor immunity. CONCLUSIONS: Cancers with FAP-positive CAFs in their TME grow rapidly and FAP-targeted NIR-PIT not only suppresses their growth but improves tumor immunosuppression. Thus, FAP-targeted NIR-PIT is a potential therapeutic strategy for selectively targeting the TME of CAF+ tumors.

Overcoming cancer-associated fibroblast-induced immunosuppression by anti-interleukin-6 receptor antibody.

Cancer-associated fibroblasts (CAFs) are a critical component of the tumor microenvironment and play a central role in tumor progression. Previously, we reported that CAFs might induce tumor immunosuppression via interleukin-6 (IL-6) and promote tumor progression by blocking local IL-6 in the tumor microenvironment with neutralizing antibody. Here, we explore whether an anti-IL-6 receptor antibody could be used as systemic therapy to treat cancer, and further investigate the mechanisms by which IL-6 induces tumor immunosuppression. In clinical samples, IL-6 expression was significantly correlated with α-smooth muscle actin expression, and high IL-6 cases showed tumor immunosuppression. Multivariate analysis showed that IL-6 expression was an independent prognostic factor. In vitro, IL-6 contributed to cell proliferation and differentiation into CAFs. Moreover, IL-6 increased hypoxia-inducible factor 1α (HIF1α) expression and induced tumor immunosuppression by enhancing glucose uptake by cancer cells and competing for glucose with immune cells. MR16-1, a rodent analog of anti-IL-6 receptor antibody, overcame CAF-induced immunosuppression and suppressed tumor progression in immunocompetent murine cancer models by regulating HIF1α activation in vivo. The anti-IL-6 receptor antibody could be systemically employed to overcome tumor immunosuppression and improve patient survival with various cancers. Furthermore, the tumor immunosuppression was suggested to be induced by IL-6 via HIF1α activation.

PD-L1-expressing cancer-associated fibroblasts induce tumor immunosuppression and contribute to poor clinical outcome in esophageal cancer.

The programmed cell death 1 protein (PD-1)/programmed cell death ligand 1 (PD-L1) axis plays a crucial role in tumor immunosuppression, while the cancer-associated fibroblasts (CAFs) have various tumor-promoting functions. To determine the advantage of immunotherapy, the relationship between the cancer cells and the CAFs was evaluated in terms of the PD-1/PD-L1 axis. Overall, 140 cases of esophageal cancer underwent an immunohistochemical analysis of the PD-L1 expression and its association with the expression of the α smooth muscle actin, fibroblast activation protein, CD8, and forkhead box P3 (FoxP3) positive cells. The relationship between the cancer cells and the CAFs was evaluated in vitro, and the effect of the anti-PD-L1 antibody was evaluated using a syngeneic mouse model. A survival analysis showed that the PD-L1+ CAF group had worse survival than the PD-L1- group. In vitro and in vivo, direct interaction between the cancer cells and the CAFs showed a mutually upregulated PD-L1 expression. In vivo, the anti-PD-L1 antibody increased the number of dead CAFs and cancer cells, resulting in increased CD8+ T cells and decreased FoxP3+ regulatory T cells. We demonstrated that the PD-L1-expressing CAFs lead to poor outcomes in patients with esophageal cancer. The cancer cells and the CAFs mutually enhanced the PD-L1 expression and induced tumor immunosuppression. Therefore, the PD-L1-expressing CAFs may be good targets for cancer therapy, inhibiting tumor progression and improving host tumor immunity.

'The parachute method': A novel technique for laparoscopic tumour handling.

Aims and Objectives: Although laparoscopic surgery for submucosal tumours (SMTs) may require multiple support threads, the traction direction of a single thread is only one option and cannot be freely changed. To solve this problem, we introduced a novel innovative technique for tumour handling, named 'the parachute method'. Subjects and Methods: Prior to suturing, the surrounding vessel was treated when the tumour was located near the lesser or greater curvature. A monofilament thread was ligated in the serous muscle layer along the peritumoural markings with approximately five stitches in a row, with moderate deflection. Next, the other monofilament thread was passed through the deflection and ligated; this resembled a parachute shape that could be pulled in any direction over the entire circumference with uniform tension. Results: We performed this procedure in three patients with extramural growth-type gastrointestinal stromal tumours of approximately 2-3 cm. The median suturing time was 10 minutes. Laparoscopic local resection of the stomach was safely performed, and the patients were discharged without any complications. Conclusion: In this study, we demonstrate a novel, simple, inexpensive, useful and reasonable technique for handling SMTs, named 'the parachute method'. We believe that this technique will have additional applications in cooperative surgery with endoscopy.

Neoadjuvant chemotherapy for locally advanced esophageal cancer comparing cisplatin and 5-fluorouracil versus docetaxel plus cisplatin and 5-fluorouracil: a propensity score matching analysis.

BACKGROUND: The standard treatment for locally advanced esophageal cancer is preoperative chemotherapy with cisplatin and 5-fluorouracil (CF), followed by surgery. Although docetaxel plus cisplatin and 5-fluorouracil (DCF) has been reported to have favorable outcomes, no study has compared its therapeutic efficacy to that of standard treatment. This study aimed to compare the therapeutic effects of CF and DCF in the real world by matching patient background factors using propensity scores. METHODS: We retrospectively reviewed the data of 237 patients with esophageal squamous cell carcinoma who underwent esophagectomy between January 2008 and December 2018. Patients were divided into two groups based on the preoperative chemotherapy regimens of CF (79 patients) or DCF (158 patients), and 49 matched pairs were finally analyzed using propensity score matching. Short- and long-term outcomes were compared between groups. RESULTS: After matching, although no significant differences in survival were observed among the groups, patients receiving DCF showed a significantly high histological response (P < 0.001). Subgroup analyses demonstrated that DCF therapy had better overall survival (P = 0.046) and relapse-free survival (P = 0.010) among pathological T3 and T4 cases. Whereas, adverse effects of chemotherapy were more frequent in the DCF group. CONCLUSIONS: Patients receiving DCF had higher pathological response and better survival than those receiving CF, especially in pathological T3 and T4 cases matched using propensity scores. Thus, the DCF regimen might be an effective treatment for locally advanced esophageal cancer. However, the adverse side effects of chemotherapy remain high and should be handled appropriately.

Nanog is a promising chemoresistant stemness marker and therapeutic target by iron chelators for esophageal cancer.

Esophageal cancer is a disease showing poor prognosis. Although combination chemotherapy using cisplatin (CDDP) and 5-fluorouracil is standard for unresectable esophageal cancer, the response rate is 35%. Cancer stem cells (CSCs) and inflammation are reportedly responsible for the poor prognosis of esophageal cancer. However, comprehensive analyses have not been conducted and proposals for progress remain lacking. Iron is known to be a key factor in the stemness of CSCs. Our study focused on the therapeutic potential of iron control using iron chelators for CSCs in esophageal cancer. Among 134 immunohistochemically analyzed cases, Nanog expression was high in 98 cases and low in 36 cases. High Nanog expression correlated with low overall and disease-free survivals. The iron chelators deferasirox (DFX) and SP10 suppressed the proliferation and expression of stemness markers in TE8 and OE33 cells. DFX and SP10 did not induce compensatory interleukin (IL)-6 secretion, although CDDP did result in high induction. Moreover, BBI608 and SSZ, as other CSC-targeting drugs, could not suppress the expression of stemness markers. Overall, Nanog expression appears related to poor prognosis in esophageal cancer patients, and inhibition of stemness and compensatory IL-6 secretion by iron chelators may offer a novel therapeutic strategy for esophageal cancer.

Preventive effect on delayed gastric emptying of preserving the infra-pyloric vein in laparoscopic pylorus-preserving gastrectomy for early gastric cancer.

BACKGROUND: Pylorus-preserving gastrectomy (PPG) has the postoperative advantages of a better quality of life and less weight loss than distal gastrectomy. However, postoperative delayed gastric emptying (DGE) due to antral hypomotility can be a problem. Although preserving the infra-pyloric vein (IPV) is reported to improve congestion of the antrum and prevent DGE, the benefits of this procedure have not been confirmed. The present study aimed to clarify the preventive effect on DGE of preserving the IPV. METHODS: A total of 148 patients [IPV-preserved (IPVP): 78 patients and IPV-non-preserved (IPVN): 70 patients] who underwent laparoscopic and robotic PPG (LRPPG) for early gastric cancer were enrolled in this study. The clinicopathologic characteristics and incidence of DGE were compared between the groups. The nutritional risk index (NRI) at 1, 2, and 3 years after the operation and the relapse-free survival (RFS) were also compared. RESULTS: There were no significant differences in the clinicopathological characteristics between the two groups. DGE was observed in 15 of 148 patients (10.1%). The incidence of DGE did not differ markedly between the 2 groups (IPVP vs. IPVN; 11.5% vs. 8.6% p = 0.596). There were no significant differences in other complications between the groups either (IPVP vs. IPVN; 19.2% vs. 21.4%; p = 0.838). The NRI and 3-year RFS were not significantly different between the two groups. CONCLUSION: Regarding LRPPG, preserving the IPV did not help prevent DGE and resulted in no significant difference in the outcomes.

Risk factor of mediastinal lymph node metastasis of Siewert type I and II esophagogastric junction carcinomas.

BACKGROUND: Incidence of esophagogastric junction (EGJ) carcinoma has been increasing worldwide. Several studies revealed that the distance from the EGJ to the proximal edge of the primary tumor (esophageal invasion: EI) may be a significant indicator of metastasis in the mediastinal lymph nodes in patients with Siewert type II carcinomas. However, few studies have been conducted in patients with carcinomas located at Siewert type II sequentially to upper carcinomas (Siewert type I) for mediastinal metastasis regardless of histological types. METHODS: This was a single-center retrospective cohort study. EGJ carcinomas located at Siewert type I and II regions including both squamous cell carcinoma (SCC) and adenocarcinoma were analyzed in terms of lymph node metastasis patterns. RESULTS: We included 121 patients in this study. Thirty-three (27.3%) patients had SCC. In multivariate analysis, the distance of EI (> 20 mm) was an independent risk factor (OR 11.80, p = 0.005) for lower mediastinal lymph node metastasis. In terms of above the middle mediastinal metastasis, the distance of EI (> 30 m), histological type (SCC), and tumor size (> 40 mm) were risk factors in univariate analysis. Furthermore, EI was significant (OR 13.50, p = 0.026) in multivariate analysis. CONCLUSIONS: The distance of EI was the independent risk factor for mediastinal lymph node metastasis, especially > 20 mm related with a higher risk for mediastinal lymph node metastasis. Furthermore, EGJ carcinoma patients who have EI > 30 mm, large SCC carcinoma, and multiple lymph node metastasis might be considered the middle-upper mediastinal lymph node dissection by transthoracic approach.

Risk Factors for Postoperative Delirium After Gastrectomy in Gastric Cancer Patients.

PURPOSE: The incidence of postoperative delirium is reported to range from 9 to 87%; however, no report has focused on cases of postoperative delirium in gastric cancer surgery alone. Therefore, we investigated the incidence of and risk factors for postoperative delirium after gastrectomy in patients with gastric cancer. METHODS: A total of 1037 patients who underwent surgery were included in the study. Patients were divided into two groups-those with (delirium group) or without (non-delirium group) postoperative delirium-and their backgrounds were compared. The short-term outcomes and the overall survival were also investigated. RESULTS: Postoperative delirium was observed in 47 of 1037 patients (4.5%). A multivariate analysis revealed that male gender, age ≥ 75 years, a history of cerebrovascular disease, and the habitual use of sleeping pills were independent predictive factors for postoperative delirium. The postoperative hospital stay was significantly longer in the postoperative delirium group than in the non-delirium group. Postoperative delirium was significantly associated with postoperative complications. The 3-year overall survival was 74.3% in the delirium group and 85.5% in the non-delirium group (log-rank p = 0.006). A multivariate analysis revealed that postoperative delirium was an independent prognostic factor, along with the age and cancer stage. CONCLUSION: The incidence of postoperative delirium was 4.5% in gastric cancer patients. Male gender, age ≥ 75 years, a history of cerebrovascular disease, and the habitual use of narcoleptic agents were risk factors for postoperative delirium after gastrectomy in gastric cancer patients. Postoperative delirium was strongly associated with other postoperative complications and a poor survival after surgery.

Early detection of nonperitoneal recurrence may contribute to survival benefit after curative gastrectomy for gastric cancer.

BACKGROUND: There is no evidence that strict follow-up using cross-sectional imaging after curative gastrectomy benefits survival; however, nonperitoneal recurrence detected early might be treated with additional surgery. The present study examined whether early detection of recurrence by imaging modalities could increase survival, particularly in patients with nonperitoneal recurrence. METHODS: We retrospectively analyzed 218 patients with recurrent gastric cancer after curative gastrectomy performed from 2002 to 2014. The patients were divided into an asymptomatic group (n = 117) and a symptomatic group (n = 101), according to the presence of symptoms at the time of recurrence, to compare clinicopathological characteristics and long-term survival. RESULTS: Peritoneal recurrence was less frequent in the asymptomatic group (22.2%) than in the symptomatic group (62.4%), the median time to recurrence was shorter (12.7 months vs 18.9 months; P < 0.001), and the median survival time after recurrence was longer (18.7 months vs 7.5 months; P < 0.001). In the asymptomatic group, 10 of 117 patients (8.5%) received additional curative surgery after recurrence. Median overall survival after gastrectomy was not significantly different between the groups (30.1 months for the asymptomatic group vs 30.0 months for the symptomatic group; P = 0.132); however, it was significantly longer among asymptomatic patients with nonperitoneal recurrence compared with symptomatic patients (35.9 months vs 24.0 months; P = 0.039). CONCLUSIONS: The presence of symptoms at recurrence did not affect survival in patients with recurrent gastric cancer. However, detection of nonperitoneal recurrence before the appearance of symptoms may provide survival benefit. Therefore, regular follow-up, including use of imaging modalities, is recommended.

Near-infrared Photoimmunotherapy Targeting Cancer-Associated Fibroblasts in Patient-Derived Xenografts Using a Humanized Anti-Fibroblast Activation Protein Antibody.

Esophageal cancer remains a highly aggressive malignancy with a poor prognosis, despite ongoing advancements in treatments such as immunotherapy. The tumor microenvironment, particularly cancer-associated fibroblasts (CAF), plays a crucial role in driving the aggressiveness of esophageal cancer. In a previous study utilizing human-derived xenograft models, we successfully developed a novel cancer treatment that targeted CAFs with near-infrared photoimmunotherapy (NIR-PIT), as an adjuvant therapy. In this study, we sought to translate our findings toward clinical practice by employing patient-derived xenograft (PDX) models and utilizing humanized mAbs, specifically sibrotuzumab, which is an antihuman fibroblast activation protein (FAP) Ab and already being investigated in clinical trials as monotherapy. PDX models derived from patients with esophageal cancer were effectively established, preserving the expression of key biomarkers such as EGFR and FAP, as observed in primary tumors. The application of FAP-targeted NIR-PIT using sibrotuzumab, conjugated with the photosensitizer IR700DX, exhibited precise binding and selective elimination of FAP-expressing fibroblasts in vitro. Notably, in our in vivo investigations using both cell line-derived xenograft and PDX models, FAP-targeted NIR-PIT led to significant inhibition of tumor progression compared with control groups, all without inducing adverse events such as weight loss. Immunohistologic assessments revealed a substantial reduction in CAFs exclusively within the tumor microenvironment of both models, further supporting the efficacy of our approach. Thus, our study demonstrates the potential of CAF-targeted NIR-PIT employing sibrotuzumab as a promising therapeutic avenue for the clinical treatment of patients with esophageal cancer.

[Efficacy of chemotherapy combined with bevacizumab for unresectable advanced or recurrent colorectal cancer].

Systemic treatment for metastatic or advanced colorectal cancer(mCRC)has remarkably progressed during recent years. All previously untreated mCRC patients at our institution between November, 2007 and June, 2010 were retrospectively evaluated. Of 72 patients, 39 were treated with chemotherapy alone, and 33 were treated with chemotherapy plus bevacizumab(BV). The median progression-free survival(mPFS)was 329 days in the group given chemotherapy plus BV, compared with 209 days in the group given chemotherapy alone(p=0. 0189). In sub-group analysis of those treated with chemotherapy plus BV, mPFS between 70 y/o

Desmoid tumor occurrence following gastric cancer surgery: A report of two cases.

INTRODUCTION AND IMPORTANCE: While rare, desmoid tumors can develop after abdominal surgery and are difficult to differentiate from recurrent tumors following cancer resection. In this report, we describe two cases of desmoid tumors that occurred following gastric cancer procedures and were successfully treated with surgical resection. CASE PRESENTATION: In Case 1, a 77-year-old woman underwent open distal gastrectomy for gastric cancer followed by Roux-en-Y reconstruction. The pathological diagnosis was stage IIB T3N1M0 disease. Four years postsurgically, computed tomography (CT) revealed a 2.4 cm tumor lesion in the upper abdomen. Desmoid tumor was the most suspected tumor, for which a resection with partial resection of the jejunum was performed. In case 2, a 60-year-old man underwent open distal gastrectomy for gastric cancer and Billroth I reconstruction; the pathological diagnosis was T1aN0M0 stage IA. Two years later, CT revealed a 4.0 cm tumor lesion in the upper abdomen. As in Case 1, desmoid tumor was most suspected, a tumor resection with partial resection of the jejunum was performed. Based on the pathological findings, the tumors were diagnosed as desmoid tumor. There had been no recurrence of either gastric cancer or the desmoid tumor in both cases. CLINICAL DISCUSSION: Although active surveillance has been recommended for desmoid tumors recently, surgical resection is appropriate when recurrence cannot be ruled out. CONCLUSIONS: Desmoid tumors should be included in the differential diagnosis when intra-abdominal tumors occur after surgery for gastric cancer. Complete resection with adequate margins can prevent desmoid recurrence.

Surgical resection of a retroperitoneal liposarcoma producing insulin-like growth factor II: a case report.

BACKGROUND: Tumor-produced high molecular weight insulin-like growth factor-II (big insulin-like growth factor-II) is considered to cause non-islet cell tumor hypoglycemia. This paper presents a case of surgically resected retroperitoneal liposarcoma that produced big insulin-like growth factor-II. CASE PRESENTATION: Here, we report the case of a 62-year-old woman who presented with an abdominal mass and hypoglycemia. Non-islet cell tumor hypoglycemia due to retroperitoneal liposarcoma was suspected. After complete resection of the tumor, the patient's hypoglycemia improved and big insulin-like growth factor-II disappeared in the molecular weight analysis of serum insulin-like growth factor-II by western blotting. The patient had no tumor recurrence or reappearance of hypoglycemia 16 months after the operation without any adjuvant therapy. CONCLUSIONS: Although insulin-like growth factor-II-producing tumors are generally large and difficult to operate on, surgical resection is currently the most effective and only treatment; thus, it is essential to attempt resection aggressively.

Conventional Cancer Therapies Can Accelerate Malignant Potential of Cancer Cells by Activating Cancer-Associated Fibroblasts in Esophageal Cancer Models.

Esophageal cancer is one of the most aggressive tumors, and the outcome remains poor. One contributing factor is the presence of tumors that are less responsive or have increased malignancy when treated with conventional chemotherapy, radiotherapy, or a combination of these. Cancer-associated fibroblasts (CAFs) play an important role in the tumor microenvironment. Focusing on conventional cancer therapies, we investigated how CAFs acquire therapeutic resistance and how they affect tumor malignancy. In this study, low-dose chemotherapy or radiotherapy-induced normal fibroblasts showed enhanced activation of CAFs markers, fibroblast activation protein, and α-smooth muscle actin, indicating the acquisition of malignancy in fibroblasts. Furthermore, CAFs activated by radiotherapy induce phenotypic changes in cancer cells, increasing their proliferation, migration, and invasion abilities. In in vivo peritoneal dissemination models, the total number of tumor nodules in the abdominal cavity was significantly increased in the co-inoculation group of cancer cells and resistant fibroblasts compared to that in the co-inoculation group of cancer cells and normal fibroblasts. In conclusion, we demonstrated that conventional cancer therapy causes anti-therapeutic effects via the activation of fibroblasts, resulting in CAFs. It is important to select or combine modalities of esophageal cancer treatment, recognizing that inappropriate radiotherapy and chemotherapy can lead to resistance in CAF-rich tumors.

Dual-targeted near-infrared photoimmunotherapy for esophageal cancer and cancer-associated fibroblasts in the tumor microenvironment.

Cancer-associated fibroblasts (CAFs) play a significant role in tumor progression within the tumor microenvironment. Previously, we used near-infrared photoimmunotherapy (NIR-PIT), a next-generation cancer cell-targeted phototherapy, to establish CAF-targeted NIR-PIT. In this study, we investigated whether dual-targeted NIR-PIT, targeting cancer cells and CAFs, could be a therapeutic strategy. A total of 132 cases of esophageal cancer were analyzed for epidermal growth factor receptor (EGFR), human epidermal growth factor 2 (HER2), and fibroblast activation protein (FAP) expression using immunohistochemistry. Human esophageal cancer cells and CAFs were co-cultured and treated with single- or dual-targeted NIR-PIT in vitro. These cells were co-inoculated into BALB/c-nu/nu mice and the tumors were treated with single-targeted NIR-PIT or dual-targeted NIR-PIT in vivo. Survival analysis showed FAP- or EGFR-high patients had worse survival than patients with low expression of FAP or EGFR (log-rank, P < 0.001 and P = 0.074, respectively), while no difference was observed in HER2 status. In vitro, dual (EGFR/FAP)-targeted NIR-PIT induced specific therapeutic effects in cancer cells and CAFs along with suppressing tumor growth in vivo, whereas single-targeted NIR-PIT did not show any significance. Moreover, these experiments demonstrated that dual-targeted NIR-PIT could treat cancer cells and CAFs simultaneously with a single NIR light irradiation. We demonstrated the relationship between EGFR/FAP expression and prognosis of patients with esophageal cancer and the stronger therapeutic effect of dual-targeted NIR-PIT than single-targeted NIR-PIT in experimental models. Thus, dual-targeted NIR-PIT might be a promising therapeutic strategy for cancer treatment.

Severe reflux esophagitis after total gastrectomy successfully treated by transposition of the jejunojejunal anastomosis: a report of two cases.

BACKGROUND: Reflux esophagitis after total gastrectomy is often difficult to treat. In this report, we describe two cases of reflux esophagitis that were refractory to medical therapy and successfully treated by transposition of the jejunojejunal anastomosis. CASE PRESENTATION: Case 1: A 66-year-old man underwent total gastrectomy and cholecystectomy for gastric cancer, and Roux-en-Y (RY) reconstruction was performed. The pathological diagnosis was T4aN3aM0 stage IIIC. Five months later, esophagogastroduodenoscopy identified reflux esophagitis. Although he was treated with various oral medications and was hospitalized six times, he lost 19 kg of weight. Finally, the patient was reoperated 3 years postoperatively. Intraoperative findings showed that there was no evidence of recurrence or severe adhesions that could have caused obstruction, and the anastomotic distance between the esophagojejunostomy and the jejunojejunostomy was approximately 40 cm. The jejunojejunostomy was re-anastomosed to increase the distance to 100 cm. Two years and 6 months after the reoperation, there was no recurrence of reflux esophagitis, and the patient's weight increased by 14 kg. Case 2: A 68-year-old woman underwent total gastrectomy and cholecystectomy for gastric cancer, and RY reconstruction was performed. The pathological diagnosis was T4aN0M0 stage IIB. Similar to Case 1, the patient was diagnosed with reflux esophagitis 5 months later. She lost 23 kg of weight and was reoperated at 6 months postoperatively. Intraoperative findings showed that there was no evidence of recurrence or severe adhesions, and transposition of the jejunojejunostomy was performed to increase the distance between anastomoses from 40 to 100 cm. Two years and 8 months after the reoperation, there was no recurrence of reflux esophagitis, and her weight increased by 15 kg. CONCLUSIONS: Transposition of the jejunojejunostomy was an effective treatment for medication-resistant severe reflux esophagitis after total gastrectomy.

Extra-nodal metastasis should be classified separately from lymph node metastasis in gastric cancer.

INTRODUCTION: Extra-nodal metastasis (ENM) is defined as a tumor nodule without histological evidence of a lymph node structure. Although ENM has pathological features distinct from those of metastatic lymph nodes, both ENM and metastatic lymph nodes are considered within the same category in the pathological nodal (pN) classification. This study aimed to clarify the clinicopathological characteristics and prognostic relevance of ENM in gastric cancer patients who underwent curative gastrectomy. MATERIALS AND METHODS: We retrospectively evaluated 1207 Japanese patients who underwent curative gastrectomy at a single center between January 2009 and December 2013. All resected specimens were fixed in 10% formalin, processed, and stained using hematoxylin and eosin, and subsequently reviewed by two pathologists. Survival times were analyzed using the Kaplan-Meier method, and independent prognostic factors were identified using a Cox proportional hazards regression model. RESULTS: Patients who were ENM-positive had significantly poorer overall survival; multivariable analysis revealed that independent prognostic factors were older age (hazard ratio [HR]: 3.68, 95% confidence interval [CI]: 2.60-5.20), higher pathological tumor classification (HR: 2.28, 95% CI: 1.43-3.62), presence of metastatic lymph nodes (HR: 1.57, 95% CI: 1.0-2.36), and ENM-positive status (HR: 2.33, 95% CI: 1.48-3.66). ENM-positive patients had similar survival outcomes to those of ENM-negative patients with ≥16 metastatic lymph nodes. CONCLUSIONS: Among Japanese patients with gastric cancer who underwent curative gastrectomy, ENM was an independent prognostic factor with a prognostic significance different from that of lymph node metastasis. These results suggest that ENM and lymph node metastasis should be classified separately.

Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer.

Cancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment. CAFs have the multifunctionality which strongly support cancer progression and the acquisition of therapeutic resistance by cancer cells. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that uses a highly selective monoclonal antibody (mAb)-photosensitizer conjugate. We developed fibroblast activation protein (FAP)-targeted NIR-PIT, in which IR700 was conjugated to a FAP-specific antibody to target CAFs (CAFs-targeted NIR-PIT: CAFs-PIT). Thus, we hypothesized that the control of CAFs could overcome the resistance to conventional chemotherapy in esophageal cancer (EC). In this study, we evaluated whether EC cell acquisition of stronger malignant characteristics and refractoriness to chemoradiotherapy are mediated by CAFs. Next, we assessed whether the resistance could be rescued by eliminating CAF stimulation by CAFs-PIT in vitro and in vivo. Cancer cells acquired chemoradiotherapy resistance via CAF stimulation in vitro and 5-fluorouracil (FU) resistance in CAF-coinoculated tumor models in vivo. CAF stimulation promoted the migration/invasion of cancer cells and a stem-like phenotype in vitro, which were rescued by elimination of CAF stimulation. CAFs-PIT had a highly selective effect on CAFs in vitro. Finally, CAF elimination by CAFs-PIT in vivo demonstrated that the combination of 5-FU and NIR-PIT succeeded in producing 70.9% tumor reduction, while 5-FU alone achieved only 13.3% reduction, suggesting the recovery of 5-FU sensitivity in CAF-rich tumors. In conclusion, CAFs-PIT could overcome therapeutic resistance via CAF elimination. The combined use of novel targeted CAFs-PIT with conventional anticancer treatments can be expected to provide a more effective and sensible treatment strategy.