The association between the tumor microenvironment (TME) and treatment response or survival has been a recent focus in several types of cancer. However, most study materials are resected specimens ...that were completely modified by prior chemotherapy; therefore, the unmodified host immune condition has not yet been clarified. The aim of the present study was to evaluate the relationship between TME assessed in pre–therapeutic biopsy samples and chemoresistance in esophageal cancer (EC). A total of 86 endoscopic biopsy samples from EC patients who received neoadjuvant chemotherapy (NAC) prior to surgery were evaluated for the number of intratumoral CD4+ lymphocytes (with/without Foxp3 expression), CD8+ lymphocytes (with/without PD‐1 expression), monocytes (CD14+) and macrophages (CD86+, CD163+ and CD206+) by multiplex immunohistochemistry (IHC). The number of tumor‐infiltrating CD206+ macrophages I significantly correlated with cT, cM, cStage and neutrophil/lymphocyte ratio (NLR), whereas the number of lymphocytes (including expression of Foxp3 and PD‐1) was not associated with clinico‐pathological features. The high infiltration of CD163+ or CD206+ macrophages was significantly associated with poor pathological response to NAC (P = 0.0057 and 0.0196, respectively). Expression of arginase‐1 in CD163+ macrophages tended to be higher in non–responders (29.4% vs 18.2%, P = 0.17). In addition, patients with high infiltration of M2 macrophages exhibited unfavorable overall survival compared to those without high infiltration of M2 macrophages (5‐year overall survival 57.2% vs 71.0%, P = 0.0498). Thus, a comprehensive analysis of TME using multiplex IHC revealed that M2 macrophage infiltration would be useful in predicting the response to NAC and long‐term survival in EC patients.
The present study confirmed that pre–therapeutic M2 macrophage infiltration would be a useful biomarker in predicting the response to NAC and unfavorable survival among a variety of immune cells in EC patients. Our results support the possibility of using immunotherapy, targeting M2 macrophages, alongside conventional neoadjuvant chemotherapy.
CXCL9, an IFN‐γ inducible chemokine, has been reported to play versatile roles in tumor‐host interrelationships. However, little is known about its role in intrahepatic cholangiocarcinoma (iCCA). ...Here, we aimed to elucidate the prognostic and biological implications of CXCL9 in iCCA. Endogenous CXCL9 expression and the number of tumor‐infiltrating lymphocytes were immunohistochemically assessed in resection specimens. These data were validated in mice treated by silencing CXCL9 with short hairpin RNA. In addition, the induction of endogenous CXCL9 and the effects of CXCL9 on tumor biological behaviors were evaluated in human cholangiocarcinoma cell lines. Immunohistochemical analyses revealed that high CXCL9 expression was closely correlated with prolonged postoperative survival and a large number of tumor‐infiltrating natural killer (NK) cells. In fact, due to the trafficking of total and tumor necrosis factor‐related apoptosis‐inducing ligand‐expressing NK cells into tumors, CXCL9‐sufficient cells were less tumorigenic in the liver than CXCL9‐deficient cells in mice. Although CXCL9 involvement in tumor growth and invasion abilities differed across cell lines, it did not exacerbate these abilities in CXCL9‐expressing cell lines. We showed that CXCL9 was useful as a prognostic marker. Our findings also suggested that CXCL9 upregulation might offer a therapeutic strategy for treating CXCL9‐expressing iCCA by augmenting anti–tumor immune surveillance.
CXCL9, an IFN‐γ inducible chemokine, plays versatile roles in the tumor‐host interrelationship. In this study, we demonstrated that elevated intratumoral CXCL9 expression was associated with a large number of tumor‐infiltrating NK cells, leading to favorable postoperative survival in patients with intrahepatic cholangiocarcinoma. Upregulation of CXCL9 might be an immunotherapeutic approach for treating intrahepatic cholangiocarcinoma.
Background
Endoscopic submucosal dissection (ESD) is a challenging procedure for the removal of colorectal tumors, especially tumors located in the right colon. The use of traction could make this ...procedure technically easier and reduce procedure times and complication rates. In this study, we demonstrated the feasibility and utility of a traction technique utilizing an endoscopic snare through an overtube, a double-balloon endolumenal interventional platform (DEIP) in a porcine colorectal model.
Methods
A total of 120 procedures were performed using three different techniques: standard ESD technique (STD), ESD with DEIP (DEIP alone), and ESD with DEIP and a snare (DEIP + Snare). The snare was passed inside the overtube and used as a grasper on the tissue to provide traction. Lesions 3 or 4 cm in diameter were removed with a 5 mm margin from the anterior and posterior walls of the proximal Transverse Colon, the Hepatic Flexure, and the posterior wall of the Cecum. The outcomes measured included procedure times and the number of muscularis propria injuries.
Results
The DEIP + Snare group showed significantly shorter total procedure and submucosal dissection times for lesions in all locations (median 28.1 min (DEIP + Snare,
n
= 32) vs 39.8 (STD,
n
= 32) vs 39.7 (DEIP alone,
n
= 32); 7.5 min vs 25.3 vs 25.1) and had fewer muscularis propria injuries (median 0 range 0–2 vs 2 0–7 vs 1 0–6) than the two other groups. Larger lesions (4 cm) were successfully removed by regrasping the tissue in DEIP + Snare group, which showed significantly shorter total procedure time 31.4 min (DEIP + Snare,
n
= 8) vs 40.1 (STD,
n
= 8) vs 45.6 (DEIP alone,
n
= 8) and submucosal dissection time (12.3 min vs 27.6 vs 29.1) than the two other groups.
Conclusions
ESD traction technique with an endolumenal platform and snare enables faster removal of large polyps in the right colon with fewer injuries than standard methods of ESD.
Endoscopic submucosal dissection (ESD) is challenging in the right colon. Traction devices can make it technically easier. In this study, we evaluated a flexible grasper with articulating tip and ...elbow-like bending (IgE) through a double-balloon surgical platform (DESP), compared with an earlier generation grasper without elbow-like bending (Ig). The reach of Ig/IgE was investigated at eight locations using a synthetic colon within a 3D model. Using a fresh porcine colorectum, 4 cm pseudo-polyps were created at the posterior wall of the ascending colon. Fifty-four ESD procedures were performed using three techniques: standard ESD (STD), ESD using Ig (DESP + Ig), and ESD using IgE (DESP + IgE). IgE was able to reach the full circumference at all the locations, whereas the medial walls proximal to the descending colon were out of Ig's reach. Compared with the STD, both DESP + Ig and DESP + IgE showed significantly shorter procedure time (STD vs. DESP + Ig vs. DESP + IgE = median 48.9 min vs. 38.6 vs. 29.9) and fewer injuries (1.5 vs. 0 vs. 0). Moreover, the DESP + IgE had a shorter procedure time than the DESP + Ig (p = 0.0025). The IgE with DESP increased instrument reach compared to Ig, and likely represented a traction tool for excision of large pseudo-polyps in the right colon.
Background/Aim
We previously demonstrated that inflammatory cytokine interleukin-6 (IL-6) was produced during cancer progression, worked together with transforming growth factor-beta 1 (TGF-β1), and ...induced the epithelial–mesenchymal transition (EMT) with chemo-resistance against gemcitabine (GR) at the invasion front of biliary tract cancers (BTCs). However, the significance of cytokine-induced T cell accumulation at the tumor microenvironment in biliary tract cancer (BTC) is not well understood. Because these cytokines (IL-6 and TGF-β1) are able to differentiate naïve T cells into Foxp3-expressing T cells (Tregs) and/or IL-17–producing T helper 17 (Th17) cells, we investigated the relationship between heterogeneous, cancer-producing cytokines and T cell differentiation.
Methods
In total, 127 curative resected specimens from patients with BTCs at Osaka University Hospital between 2000 and 2012 were evaluated for IL-6, TGF-β1, Tregs, and Th17 cells by immunohistochemistry. The ability of BTC–GR cells to undergo T cell differentiation was investigated in vitro.
Results
Tregs accumulated at the tumor center and Th17 cells accumulated at the invasion front during cancer progression and/or metastasis; each signaled poor prognosis. Treg accumulation was related to TGF-β1 expression by cancer cells, and Th17 cell accumulation was related to IL-6 expression by cancer cells, in resected specimens; this was confirmed in vitro. Compared with parent cells, GR cells produced IL-6 but not TGF-β1 in a time-dependent manner, had EMT features, and induced T cell differentiation to Th17 cells but not Tregs.
Conclusion
Cytokines produced by cancer cells (IL-6 and TGF-β1) induced heterogeneity of Tregs and Th17 cells in the tumor microenvironment, supporting progression of BTC.
The optimal number of neoadjuvant chemotherapy (NAC) cycles remains to be established for treating oesophageal squamous cell carcinoma (ESCC). We compared two versus three courses of NAC for treating ...locally advanced ESCC in a multi-institutional, randomised, Phase II trial.
We randomly assigned 180 patients with locally advanced ESCC at 6 institutions to either two (N = 91) or three (N = 89) courses of DCF (docetaxel 70 mg/m
, cisplatin 70 mg/m
i.v. on day 1, fluorouracil 700 mg/m
continuous infusion for 5 days) every 3 weeks, prior to surgery. The primary endpoint was 2-year progression-free survival (PFS) with an intention-to-treat analysis.
Patient background parameters were well-balanced. The R0 resection rates were 98.9 and 96.5% in the two- and three-course groups, respectively (P = 0.830). In resected cases, the two- and three-course groups had comparable pN0 rates (P = 0.225) and histological responses (P = 0.898). The 2-year PFS rate was also comparable between the two groups (71.4 vs. 71.1%, P = 0.669). Among subgroups based on baseline characteristics, only patients aged under 65 years old showed a tendency for better survival with the three-course treatment (hazard ratio = 2.612, 95% confidence interval: 1.012-7.517).
Two courses of a DCF regimen showed potential as an optional NAC treatment for locally advanced ESCC.
University Hospital Medical Information Network Clinical Trials Registry of Japan (identification number UMIN 000015788).
To assess the potential clinical utility of cell-free DNA (cfDNA)-based biomarkers for identifying gastric cancer (GC) patients who benefit from nivolumab. From 31 GC patients treated with nivolumab ...monotherapy (240 mg/body, Bi-weekly) in 3rd or later line setting, we prospectively collected blood samples at baseline and before the 3rd dose. We compared cfDNA-based molecular findings, including microsatellite instability (MSI) status, to tissue-based biomarkers. We assessed the clinical value of blood tumor mutation burden (bTMB) and copy number alterations (CNA) as well as the cfDNA dynamics. The concordance between deficient-MMR and cfDNA-based MSI-high was 100% (3/3). Patients with bTMB ≥ 6 mut/Mb had significantly better progression-free survival (PFS) and overall survival (OS); however, such significance disappeared when excluding MSI-High cases. The combination of bTMB and CNA positivity identified patients with survival benefit regardless of MSI status (both PFS and OS, P < 0.001), with the best survival in those with bTMB
and CNA
. Moreover, patients with decreased bTMB during treatment had a better disease control rate (P = 0.04) and longer PFS (P = 0.04). Our results suggest that a combination of bTMB and CNA may predict nivolumab efficacy for GC patients regardless of MSI status. bTMB dynamics have a potential utility as an on-treatment biomarker.
Gastric cancer (GC) is the most common malignant tumor in digestive organs, and the prognosis of GC patients who have undergone surgery remains poor because of frequent recurrence. Therefore, the ...identification of new markers to predict the outcome of these patients is needed. Monocyte count is a negative prognostic factor associated with inflammation. We investigated the relationship between peripheral monocytes in the peri-operative period and prognosis in GC patients. A high pre-operative monocyte count was identified as a prognostic factor in a retrospective analysis of 278 stage II and III GC patients who underwent curative gastrectomy. In contrast, an increased post-operative monocyte count compared to the pre-operative monocyte count was a marker of poor prognosis, particularly for early relapse. In a prospective analysis of 75 GC patients, a subset of the increased post-operative monocytes was similar to CD14
+
HLA-DR
−
CD11b
+
CD33
+
cells by flow cytometry, and these monocytes produced IDO and arginase and suppressed T cell functions; therefore, we classified these cells as monocytic myeloid-derived suppressive cells (M-MDSCs). Peri-operative neutrophils and C-reactive protein (CRP), which are also related to inflammation, did not affect the prognosis of GC patients, and a neutrophil immunosuppressive function was not observed. These results suggest that peripheral monocytes in the peri-operative period in GC patients are a useful marker for the prognosis of GC patients, and a subset of increased post-operative monocytes may be characterized as M-MDSCs.
It remains unclear whether
Helicobacter pylori
(
H. pylori
), a major cause of gastric cancer (GC), is involved in other intestinal cancers. In our previous study, ICOS
+
Foxp3
+
CD4
+
T cells (ICOS
...+
Tregs) in GC tumors were identified as effector Tregs and associated with
H. pylori
. In the present study, the impact of ICOS
+
Tregs on not only GC, but also colorectal cancer (CRC) and their prognosis was investigated in association with
H. pylori
. Tissue-infiltrating lymphocytes (TILs) purified from fresh tumor and sera were obtained from GC and CRC patients prospectively. % ICOS
+
Tregs were analyzed by flow cytometry and their production of anti-
H. pylori
antibody (Hp-Ab) in sera was detected by ELISA. % ICOS
+
Tregs were higher in GC and CRC patients with Hp-Ab than in those without Hp-Ab, including eradicated patients. ICOS
+
Tregs purified had higher potential to produce IL-10 than ICOS
−
Tregs. For prognostic analysis, immunohistochemical analysis and ELISA were performed using archival fixed specimens and frozen sera, respectively, obtained from GC and CRC patients. Overall survival was longer in patients with low % ICOS
+
Tregs than in those with high % ICOS
+
Tregs, and patients with Hp-Ab showed shorter recurrence-free survival than those without Hp-Ab. These results suggested that ICOS
+
Tregs in GC and CRC patients were closely associated with
H. pylori
in gastric epithelium and their prognosis, and that pre-operative
H. pylori
eradication has potential as a novel immunotherapy for GC and CRC patients.
ObjectiveTo avoid the need for extensive adhesiolysis in patients with small bowel obstruction (SBO). We evaluated the feasibility of using advanced imaging, percutaneous access, and endoscopy as ...alternative therapies for SBO.DesignRetrospective case series (IDEAL Idea, Development, Exploration, Assessment, and Long-term Study Collaborative stages 1 and 2a).SettingSingle tertiary referral center.ParticipantsTwelve adults with chronic SBO resulting from inflammatory bowel disease, disseminated cancer, radiation, and/or adhesive disease. Participants were included if they underwent one of three novel access procedures. There were no exclusion criteria. The median age of participants was 67.5 years (range 42–81); two-thirds were women; and median American Society of Anesthesiology class was 3.InterventionsAll participants underwent one of three novel access methods, followed by wire-guided balloon dilation of a narrowed area of small bowel. These methods combined endoscopic, fluoroscopic, and surgical techniques. The techniques were (1) a purely endoscopic approach aided by an over-the-scope double-balloon device, (2) a combined endoscopic and percutaneous approach, and (3) a cut-down approach.Main outcome measuresProcedural success (defined as successful access to the small bowel and successful balloon dilation of the stenotic area). Secondary outcomes included major complications, recurrence, length of stay, and procedure time.ResultsProcedural success was achieved in 10 of 12 patients (83%). At the time of median follow-up of 10 months, recurrence of SBO was observed in two patients. In only one patient, the novel method did not change the treatment plan. No major complications occurred. Conventional operative intervention was avoided in all patients who achieved technical success with one of the novel approaches. The median postprocedure length of hospital stay was 4 days. Median procedure time was 135 min.ConclusionsNovel minimally invasive approaches to SBO represent feasible alternatives to surgical procedures in select patients. Further study should compare these approaches to standard ones as new methods are refined.
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