M2 tumor-associated macrophages resist to oxidative stress through heme oxygenase-1 in the colorectal cancer tumor microenvironment.

M2 tumor-associated macrophages (M2-TAMs) promote cancer cell proliferation and metastasis in the TME. Our study aimed to elucidate the mechanism of increased frequency of M2-TAMs infiltration in the colorectal cancer (CRC)-TME, focusing on the resistance to oxidative stress through nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In this study, we evaluated the correlation between M2-TAM signature and mRNA expression of antioxidant related genes using public datasets, and the expression level of antioxidants in M2-TAMs by flow cytometry and the prevalence of M2-TAMs expressing antioxidants by immunofluorescence staining using surgically resected specimens of CRC (n = 34). Moreover, we generated M0 and M2 macrophages from peripheral blood monocytes and evaluated their resistance to oxidative stress using the in vitro viability assay. Analysis of GSE33113, GSE39582, and The Cancer Genome Atlas (TCGA) datasets indicated that mRNA expression of HMOX1 (heme oxygenase-1 (HO-1)) was significantly positively correlated with M2-TAM signature (r = 0.5283, r = 0.5826, r = 0.5833, respectively). The expression level of both Nrf2 and HO-1 significantly increased in M2-TAMs compared to M1- and M1/M2-TAMs in the tumor margin, and the number of Nrf2+ or HO-1+M2-TAMs in the tumor stroma significantly increased more than those in the normal mucosa stroma. Finally, generated M2 macrophages expressing HO-1 significantly resisted to oxidative stress induced by H2O2 in comparison with generated M0 macrophages. Taken together, our results suggested that an increased frequency of M2-TAMs infiltration in the CRC-TME is related to Nrf2-HO-1 axis mediated resistance to oxidative stress.

[A Case of MSI-High Sigmoid Colon Cancer in Which Long-Term Survival Was Achieved by Pembrolizumab for Recurrent Lesions Resistant to Conventional Chemotherapy].

The patient underwent sigmoidectomy with D3 lymph node dissection and partial bladder resection for sigmoid colon cancer(cT4bN1M0, cStage Ⅲa), after preoperative chemotherapy with mFOLFOX plus panitumumab, and FOLFOXIRI plus bevacizumab. Postoperative adjuvant chemotherapy was performed by 8 courses of CAPOX. He relapsed hilar lymph nodes and peritoneal dissemination after 13 months after surgery, he underwent resection of the recurrent lesions. Four months after, he developed recurrence in liver and peritoneum. Although he was treated with FOLFIRI plus ramucirumab or aflibercept, resulted in progression of disease, then he received trifluridine tipiracil hydrochloride plus bevacizumab. At this point, the Japanese health insulance had started to cover pembrolizumab, this therapy was started as the fourth chemotherapy after the diagnosis of high frequency microsatellite instability(MSI), and then tumor markers rapidly declined. He underwent 38 courses of pembrolizumab, the recurrent lesions both liver and peritoneum disappeared. He had stoma closure, peritoneal dissemination disappeared not only intraoperatively but also in histologically from the peritoneal scar. He has received pembrolizumab for 4 years without another recurrence. Here, we report a case of MSI-high sigmoid colon cancer in which long-term survival was achieved by pembrolizumab for recurrent lesions resistant to conventional chemotherapy.

SH2D4A downregulation due to loss of chromosome 8p is associated with poor prognosis and low T cell infiltration in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) develops through chromosomal instability (CIN) or microsatellite instability (MSI) due to deficient mismatch-repair (dMMR). We aimed to characterise novel cancer-associated genes that are downregulated upon malignant transformation in microsatellite stable (MSS) CRCs, which typically exhibit CIN with proficient mismatch-repair (pMMR). METHODS: Comprehensive screening was conducted on adenomas, MSI/MSS CRCs and cell lines, followed by copy number analysis, and their genetic and prognostic relevance was confirmed in microarray and RNA-seq cohorts (n = 3262, in total). Immunohistochemistry for SH2D4A was performed in 524 specimens of adenoma, carcinoma in situ and dMMR/pMMR CRC. The functional role of SH2D4A was investigated using CRC cell lines. RESULTS: A set of 11 genes, including SH2D4A, was downregulated during the adenoma-carcinoma sequence in MSS/CIN CRCs, mainly due to chromosome 8p deletions, and their negative prognostic impact was validated in independent cohorts. All adenomas were SH2D4A positive, but a subset of CRCs (5.3%) lacked SH2D4A immunohistochemical staining, correlating with poor prognosis and scarce T cell infiltration. SH2D4A depletion did not affect cell proliferation or IL-6-induced STAT3 phosphorylation. CONCLUSIONS: Our findings suggest that downregulation of multiple genes on chromosome 8p, including SH2D4A, cooperatively contribute to tumorigenesis, resulting in the immune cold tumour microenvironment and poor prognosis.

Role of the cGAS-STING pathway in regulating the tumor-immune microenvironment in dMMR/MSI colorectal cancer.

Deficient mismatch repair (dMMR)/microsatellite instability (MSI) colorectal cancer (CRC) has high immunogenicity and better prognosis compared with proficient MMR (pMMR)/microsatellite stable (MSS) CRC. Although the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been considered to contribute to the high number of CD8+ TILs, its role in dMMR/MSI CRC is largely unknown. In this study, to examine the role of the cGAS-STING pathway on the recruitment of CD8+ TILs in dMMR/MSI CRC, we used public datasets and clinical tissue samples in our cohorts to evaluate the expression of cGAS, STING, and CD8+ TILs in pMMR/MSS and dMMR/MSI CRCs. According to the analysis of public datasets, the expression of cGAS-STING, CD8 effector gene signature, and CXCL10-CCL5, chemoattractants for CD8+ TILs which regulated by the cGAS-STING pathway, was significantly upregulated in dMMR/MSI CRC, and the expression of cGAS-STING was significantly associated with the expression of CD8 effector gene signature. Immunohistochemistry staining of the clinical tissue samples (n = 283) revealed that cGAS-STING was highly expressed in tumor cells of dMMR CRC, and higher expression of cGAS-STING in tumor cells was significantly associated with the increased number of CD8+ TILs. Moreover, we demonstrated that the downregulation of MMR gene in human CRC cell lines enhanced the activation of the cGAS-STING pathway. Taken together, for the first time, we found that dMMR/MSI CRC has maintained a high level of cGAS-STING expression in tumor cells, which might contribute to abundant CD8+ TILs and immune-active TME.

Incidence of upper extremity deep vein thrombosis in the retrosternal reconstruction after esophagectomy.

BACKGROUND: Upper extremity deep vein thrombosis (UEDVT) is relatively rare but cannot be negligible because it can cause fatal complications. Although it is reported that the occurrence rate of UEDVT has increased due to central venous catheter (CVC), cancer, and surgical invasion, there is still limited information for esophagectomy. The aim of this study was to evaluate the clinical factors, including CVC placement and thromboprophylaxis approach, as well as retrosternal space's width as a predictive factor for UEDVT in patients receiving esophagectomy. METHODS: This study included 66 patients who underwent esophagectomy with retrosternal reconstruction using a gastric tube. All patients routinely underwent contrast-enhanced computed tomography (CT) on the 4th postoperative day. Low-molecular-weight-heparin (LMWH) was routinely administered by the 2nd postoperative day. To evaluate retrosternal space's width, (a) The distance from sternum to brachiocephalic artery and (b) the distance from sternum to vertebra were measured by preoperative CT, and the ratio of (a) to (b) was defined as the width of retrosternal space. RESULTS: Among all patients, 11 (16.7%) suffered from UEDVT, and none was preoperatively received CVC placement, while 7 were inserted in non-UEDVT cases. Retrosternal space's width in patients with UEDVT was significantly smaller than that in patients without UEDVT (0.17 vs. 0.26; P < 0.0001). A cutoff value of the width was 0.21, which has high sensitivity (87%) and specificity (82%) for UEDVT prediction, respectively. CONCLUSION: The existence of CVC may not affect the development of UEDVT, but preoperative evaluation of retrosternal ratio may predict the occurrence of UEDVT.

ARID1A deficiency in EBV-positive gastric cancer is partially regulated by EBV-encoded miRNAs, but not by DNA promotor hypermethylation.

AT-rich interactive domain 1A (ARID1A), which is a tumor suppressor gene, is frequently mutated in Epstein-Barr virus-positive gastric cancer [EBV (+) GC]. While most ARID1A mutations in GC are truncating mutations, leading to loss of ARID1A protein expression, epigenetic modifications appear to contribute to ARID1A deficiency in EBV (+) GC harboring wild-type ARID1A. Based on the significant role of epigenetic modifications in EBV (+) GC that contributes to ARID1A deficiency, the methylation status of ARID1A was evaluated in EBV-infected cells and GC patients using a publicly available microarray and the Cancer Genome Atlas (TCGA) database. EBV-encoded miRNAs that potentially target ARID1A were identified as an additional epigenetic modulator by computational prediction. In vitro experiments were conducted to evaluate how EBV-encoded miRNAs affected ARID1A mRNA and protein levels. In clinical GC samples, the expression of predicted miRNAs and ARID1A and the mutation status of ARID1A was evaluated. As results, ARID1A was not hypermethylated in EBV (+) GC samples or EBV-infected GC cells. EBV infection did not alter ARID1A mRNA levels, suggesting that ARID1A protein deficiency was caused by post-transcriptional gene silencing in ARID1A-WT EBV (+) GC. Overexpression of miR-BART11-3p and miR-BART12, which were identified as miRNAs that potentially bind ARID1A, suppressed ARID1A protein expression in MKN7 and NCI-N87 cells. Highly expressed miR-BART11-3p and miR-BART12 were correlated with decreased ARID1A levels in GC tumors which did not harbor ARID1A mutations. The present findings revealed that ARID1A expression was epigenetically regulated by miR-BART11-3p and miR-BART12 in EBV (+) GC.

Therapeutic potential of anti-VEGF receptor 2 therapy targeting for M2-tumor-associated macrophages in colorectal cancer.

BACKGROUND: Although immunotherapy with immune checkpoint inhibitors (ICIs) has become a standard therapeutic strategy in colorectal cancer (CRC) exhibiting microsatellite instability-high, limited patients benefit from this new approach. To increase the efficacy of ICIs in CRC patients, it is crucial to control the function of immunosuppressive cells in the tumor microenvironment. M2-tumor-associated macrophages (TAMs) are key immunosuppressive cells and promote tumor growth, angiogenesis, and epithelial-mesenchymal transition. In the present study, we focused on the VEGF signaling pathway in M2-TAMs to control their inhibitory function. METHODS: We evaluated the population of M2-TAMs, the VEGF receptor 2 (VEGFR2) expression on M2-TAMs, and the correlation between HIF-1α-positive cells and VEGFR2 expression levels on M2-TAMs in CRC using the analysis of The Cancer Genome Atlas colorectal adenocarcinoma dataset (n = 592), the flow cytometry of freshly resected surgical specimens of CRC (n = 20), and the immunofluorescence staining of formalin-fixed paraffin-embedded whole tissue samples of CRC (n = 20). Furthermore, we performed a functional assay of M2 macrophages through the VEGF/VEGFR2 signaling pathway in vitro. RESULTS: The population of M2-TAMs and their VEGFR2 expression significantly increased in the tumor compared to the normal mucosa in the CRC patients. HIF1-α-positive cells significantly correlated with the VEGFR2 expression level of M2-TAMs. M2 macrophages induced by cytokines in vitro produced TGF-ß1 through the VEGF/VEGFR2 signaling pathway. CONCLUSIONS: Our results suggest that anti-VEGFR2 therapy may have therapeutic potential to control the immune inhibitory functions of M2-TAMs in CRC, resulting in enhanced efficacy of immunotherapy with ICIs.

Selective sensitivity of EZH2 inhibitors based on synthetic lethality in ARID1A-deficient gastric cancer.

BACKGROUND: AT-rich interactive domain 1A (ARID1A) is a tumor suppressor gene that is frequently mutated in gastric cancer (GC). Although ARID1A mutations are not a druggable target for conventional treatments, novel therapeutic strategies based on a synthetic lethal approach are effective for ARID1A-deficient cancers. The histone methyltransferase EZH2 acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer, although its role in GC remains unknown. METHODS: The selective sensitivity of the EZH2 inhibitors for ARID1A-deficient GC cells was evaluated using cell viability and colony formation assays. The expression of PI3K/AKT signaling genes were investigated using TCGA's cBioPortal database to determine whether the homeostasis between ARID1A and EZH2 is related to cell proliferation and survival via the PI3K/AKT signaling pathway. We also evaluated the phosphorylation of PI3K/AKT signaling proteins in ARID1A knock downed ARID1A-WT GC cells. RESULTS: EZH2 inhibitors decreased the viability of ARID1A-deficient cells in a dose-dependent manner and demonstrated the selective sensitivity to ARID1A-deficient cells in vitro experiment system. Bioinformatics approach revealed that the PI3K/AKT signaling was tended to be activated in ARID1A-deficient GC enhancing cell viability and, furthermore, down-regulation of EZH2 in ARID1A-deficient GC was related to normalization of PI3K/AKT signaling pathway. The cell experiment revealed that phosphorylated AKT was upregulated in ARID1A-deficent GC cells. CONCLUSIONS: The present findings provide a rationale for the selective sensitivity of EZH2 inhibitors against ARID1A-deficient GC and suggest the potential efficacy of targeted therapy using EZH2 inhibitors in this patient population.

[Significance and Treatment Strategy of Glasgow Prognostic Score in High Risk Stage â ¡ Colorectal Cancer].

In this study, we investigated the usefulness of Glasgow prognostic score(GPS)as a prognostic factor for Stage Ⅱ colorectal cancer, and the treatment strategy by individualizing adjuvant chemotherapy. We enrolled 86 patients with Stage Ⅱ primary colorectal cancer who underwent curative resection. This study examines the prognostic significance of clinicopathological factors and GPS, NLR, LMR, PLR. Multivariate analyses was performed to evaluate the factors affecting recurrence free survival. The 5-year OS was 92.5%, and the RFS was 86% in Stage Ⅱ colorectal cancer. The recurrence rate was 12.8%. In multivariate analysis, GPS(HR: 13.66, p=0.005)was extracted as an independent poor prognosis factor. In comparison of survival rates, RFS of GPS 0, 1 was 95.2% and that of GPS 2 43.8%, and GPS 2 had a significantly poor prognosis(p< 0.01). GPS 2 is an independent high risk factor for recurrence of Stage Ⅱ colorectal cancer. In order to improve the prognosis of Stage Ⅱ colorectal cancer, individualized adjuvant chemotherapy is important.

[A Case of Laparoscopic Surgery for Preoperatively Diagnosed Gastric Metastasis of Lung Cancer].

The patient was a 66-year-old male who had undergone an operation for lung cancer and solitary brain metastases. Follow- up PET-CT after 1 year detected FDG accumulation in the stomach. We performed esophagogastroscopy and found an approximately 20 mm-sized Type 2 tumor on the greater curvature of the upper stomach. A pathological diagnosis of lung adenocarcinoma metastasis in the stomach was made. Laparoscopic surgery was performed on the metastatic lesion to prevent bleeding and perforation, and resection was achieved with minimal invasion. The current development of chemotherapy, including immunotherapy, has contributed to the improved prognosis of cancer patients, including those with lung metastasis in the stomach. Considering these backgrounds, preventive surgical resection under laparoscopy may be an effective approach for improving prognosis and preventing acute life-threatening adverse events. We report this case along with a literature review.

Circulating tumor cells after neoadjuvant chemotherapy are related with recurrence in esophageal squamous cell carcinoma.

BACKGROUND: Circulating tumor cells (CTCs) are known to be a systemic process of malignant progression of cancer cells and there is a possibility that analysis for CTCs as a liquid biopsy become predictive or prognostic tools for cancer patients. METHODS: In the present study with the novel CTCs detection system (Celsee system®), we performed quantitative and qualitative analysis of CTCs in patients with esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant chemotherapy (NAC) with 5FU + CDDP regimen. CTCs are defined as having both DAPI positive and CD45 negative. Vimentin-positive CTCs were defined as mesenchymal-type CTCs (M-CTCs), while epithelial-type CTCs (E-CTCs) were only positive for pan-cytokeratin. RESULTS: At the baseline, there are detectable amounts of CTCs in all patients (n = 30) at all stages, and there were no significant differences of total CTCs, E-CTCs, or M-CTCs numbers between stages. Of importance, among total CTCs, M-CTCs are more dominant than E-CTCs in number. Also, there was no significant change of detectable amounts and phenotype of CTCs before and after NAC (n = 24). Of note, early recurrent group indicated that there was an elevated total CTCs number before NAC and an increased M-CTCs after NAC in comparison to those in non-recurrent group. CONCLUSIONS: Quantitative and qualitative analysis of CTCs may provide useful complementary predictive and prognostic information in ESCC.

KRT17 as a prognostic biomarker for stage II colorectal cancer.

Adjuvant chemotherapy is considered for patients with stage II colorectal cancer (CRC) characterized by poor prognostic clinicopathological features; however, current stratification algorithms remain inadequate for identifying high-risk patients. To develop prognostic assays, we conducted a step-wise screening and validation strategy using nine cohorts of stage II patients based on multiple platforms, including microarray, RNA-sequencing (RNA-seq) and immunohistochemistry (IHC) on formalin-fixed paraffin-embedded (FFPE) tissues. Four microarray datasets (total n = 458) were used as the discovery set to screen for single genes associated with postoperative recurrence. Prognostic values of candidate genes were evaluated in three independent microarray/RNA-seq validation cohorts (n = 89, n = 93 and n = 183, respectively), and then IHC for KRT17 was conducted in two independent FFPE series (n = 110 and n = 44, respectively). We found that high levels of KRT17 transcript expression were significantly associated with poor relapse-free survival (RFS) not only in the discovery set, but also in three validation cohorts, and its prognostic impact was independent of conventional factors by multivariate analyses. Positive staining of KRT17 protein was significantly associated with poor RFS in two independent FFPE cohorts. KRT17 protein expression had independent prognostic impact on RFS in a multivariate model adjusted for conventional variables, including high-risk clinicopathological features. In conclusion, using nine independent cohorts consisting of 997 stage II patients, we identified and validated the expression of KRT17 transcript and KRT17 protein as a robust prognostic biomarker that can discriminate postoperative stage II patients who are at high probability of disease recurrence, providing additional prognostic stratification beyond the currently available high-risk factors.

Characterization of tumor-infiltrating immune cells in relation to microbiota in colorectal cancers.

BACKGROUND: Several articles have recently reported that certain colon microbiota can improve the efficacy of cancer immunotherapy. To develop new treatment strategies, including immunotherapy for colorectal cancer (CRC), we evaluated the correlations between subpopulations of tumor-infiltrating immune cells (TIICs) and intestinal microbiota in CRC. METHODS: Fresh surgically resected specimens, formalin-fixed paraffin-embedded whole tissue samples, and stool samples were collected. TIICs including Tregs, Th17 cells and tumor-associated macrophages (TAMs) in the surgically resected specimens were analyzed using flow cytometry. FOXp3, CD8, CD163, and phosphorylated-STAT1-positive TIICs in the whole tissue samples were analyzed using IHC, and intestinal microbiota in the stool samples was analyzed using 16S metagenome sequencing. TIICs subpopulations in the normal mucosa and tumor samples were evaluated, and the correlations between the TIIC subpopulations and intestinal microbiota were analyzed. RESULTS: FOXp3lowCD45RA+ Tregs were significantly reduced (p = 0.02), FOXp3lowCD45RA- Tregs were significantly increased (p = 0.006), and M1 TAMs were significantly reduced in the tumor samples (p = 0.03). Bacteroides (phylum Bacteroidetes) and Faecalibacterium (phylum Firmicutes) were increased in the patients with high numbers of Tregs and clearly high distribution of FOXp3highCD45RA- Tregs, which are the effector Tregs. Faecalibacterium, Ruminococcaceae, Eubacterium (phylum Firmicutes), and Bacteroides were increased in patients with a high distribution of M1 TAMs. CONCLUSIONS: The findings of the present study indicate that immune responses to tumors are suppressed in the tumor microenvironment of CRC depending on the increment of Tregs and the reduction of M1 TAMs and that intestinal microbiota might be involved in immunosuppression.

Tn Antigen Expression Defines an Immune Cold Subset of Mismatch-Repair Deficient Colorectal Cancer.

Colorectal cancer (CRC) cells often express Tn antigen, a tumor-associated truncated immature O-glycan (GalNAcα-O-Ser/Thr) that can promote tumor progression. Immunotherapies against Tn antigen have been developed and are being evaluated in clinical trials. Tn antigen can also be considered a novel immune checkpoint that induces immunosuppressive signaling through glycan-biding lectins to lead effector T cell apoptosis. We evaluated the correlation of Tn antigen expression by immunohistochemistry with mismatch-repair (MMR) status, tumor-infiltrating lymphocytes, tumor cell PD-L1 expression, and clinicopathological characteristics in 507 CRC patients. Although 91.9% of CRCs showed negative or weak Tn antigen staining (Tn-negative/weak), we identified a small subset of CRCs (8.1%) that displayed particularly intense and diffuse distribution of Tn antigen immunoreactivity (Tn-strong) that closely related to deficient MMR (dMMR). Moreover, 40 dMMR CRCs were stratified into 24 Tn-negative/weak dMMR tumors (60.0%) exhibiting dense CD8+ lymphocyte infiltrate concomitant with a high rate of PD-L1 positivity, and 16 Tn-strong dMMR tumors (40.0%) that demonstrated CD8+ T cell exclusion and a lack of PD-L1 expression, which was comparable to those of proficient MMR. Our finding suggests that the immune cold subset of patients with Tn-strong dMMR CRC may be effectively treated with immune checkpoint blockade therapy or cellular immunotherapy targeting Tn antigen.

[A Case of Pelvic Liposarcoma Resected by Hybrid Approach].

Surgical resection is the most effective treatment for liposarcoma, a retroperitoneal malignant soft tissue tumor, and a reliable negative margin is required because of the high risk of local recurrence. We reported a case of pelvic liposarcoma that could be resected by laparoscopic and transsacral hybrid approach. A 60's-man had a mixed liposarcoma occupying the right rear of the pelvis in the rectum. The operation was preceded by a laparoscopic operation, and the right internal iliac artery and vein and the superior rectal artery were dissected. The tumor was separated along the right pelvic wall. The oral rectum was transected and the colon was elevated by the extraperitoneal route. After conversion to the Jackknife position, the anterior sacrum was exfoliated with the right transsacral approach, the coccyx was resected, and the rectal anus, tumor, and surrounding fatty tissue were removed as an en bloc fasion. Histopathological examination showed mixed type of liposarcoma and negative margin of the stump. The patient is alive without recurrence 8 months after the surgery.

MLH1 germline mutation associated with Lynch syndrome in a family followed for more than 45 years.

BACKGROUND: Lynch syndrome, is an autosomal dominantly inherited disease that predisposes individuals to a high risk of colorectal cancers, and some mismatch-repair genes have been identified as causative genes. The purpose of this study was to investigate the genomic rearrangement of the gene in a family with Lynch syndrome followed for more than 45 years. CASE PRESENTATION: The family with Lynch syndrome is family N, who received colorectal cancer treatment for 45 years. The proband of family N had multiple colorectal and uterine cancers. Because the proband met the diagnostic Amsterdam criteria and was Microsatellite instability (MSI) - positive, we performed genetic testing several times. However, germline mutations in MLH1 and MSH2 genes were not found by long-distance PCR or RT-PCR/direct sequencing analysis within the 45-year follow-up. MLPA analysis showed that the genomes of the proband and proband's daughter contained a deletion from exon 4 through exon 19 in the MLH1 gene. Her son's son and her daughter's son were found to be carriers of the mutation. CONCLUSIONS: For carriers of mismatch-repair gene mutation among families with Lynch syndrome, the onset risk of associated cancers such as uterine cancer is particularly high, including colorectal cancer. The diagnosis of carriers among non-onset relatives is important for disease surveillance.

[A Case of Rectovaginal Fistula after Rectal Cancer Surgery Cured with Estriol Vaginal Tablet and Vaginal Lavage].

Although rectovaginal fistula is a rare complication of rectal cancer surgery, it is usually difficult to cure with conservative treatment, and patients generally need surgical intervention. A woman in her 70s underwent laparoscopic low anterior resection with right lateral lymph node dissection for rectal cancer. On postoperative day(POD)6, she had an anastomotic leakage and received conservative treatment. On POD 9, she underwent emergent laparotomy for urinary peritonitis as well as ileostomy and ureteral stenting. On POD 21, the rectovaginal fistula was confirmed with lower gastrointestinal tract fluoroscopic examination. The patient received conservative therapy for the rectovaginal fistula with estriol vaginal tablets and vaginal lavage for 2 weeks. Subsequently, the fistula was completely cured. After continuation of the estriol vaginal tablets for 4 weeks, the rectovaginal fistula has not recurred at the most recent follow-up.

[A Case Receiving Gastric Tube Resection for the Recurrence after a Proton Beam Irradiation in a Patient with Gastric Tube Cancer after Esophagectomy].

A 74-year-oldman underwent transthoracic esophagectomy andgastric tube reconstruction for esophageal cancer 15 years ago. Eleven years after the esophagectomy, he was diagnosedwith gastric tube cancer. He receivedproton beam irradiation therapy. Macroscopic clinical effect revealed complete response at that time. Four years later, due to his discomfort symptom, he was diagnosedwith recurrent gastric tube cancer. Total resection of the gastric tube was performedat our hospital. In pathology findings, poorly differentiated adenocarcinoma was found at the proton beam irradiated part with multiple lymph node metastases in the omentum. He died 8 months postoperatively because of carcinomatous pleurisy. Periodic screening of the gastric tube and early detection of gastric tube cancer at early stage are important.

[A Case of Recurrent Colon Cancer with Peritoneal Dissemination Treated with Aflibercept Showing Partial Response for One Year].

We report a case of recurrent colon cancer that achieved partial response with chemotherapy of combined 5-fluorouracil (5-FU), irinotecan, Leucovorin(FOLFIRI), and aflibercept. A 65-year-old man was diagnosed with colon cancer with lymph node metastasis. He underwent surgery, but after 1 year, he had a recurrence of peritoneal dissemination, nodal enlargement, and liver metastases. He received chemotherapy(mFOLFOX plus bevacizumab), but suffered progressive disease. Thereafter, FOLFIRI plus aflibercept was administered, and CT revealed a decrease in peritoneal dissemination after 2 cycles of chemotherapy. After 23 cycles, a PET-CT showed no evidence of the disease. We also examined 9 recent cases treated with aflibercept in terms of Grade 3 and 4 adverse effects, leukopenia, neutropenia, thrombocytopenia, hypertension, and sweating. Placentalderived growth factor(PIGF)has been reported to stimulate macrophages and induce production of IL-6, and thus it promotes inflammation and growth of extant cancer. Among the responses to chemotherapy based on the RECIST criteria, a partial response was significantly higher in patients with a low neutrophil-to-lymphocyte ratio(NLR)(p≤0.05)compared to those with high NLR. As regards the relationship between NLR and OS in patients treated with FOLFIRI plus aflibercept, OS was significantly worse in patients with high NLR than those with low NLR(p≤0.05). NLR may be a useful marker in conjunction with aflibercept treatment.

[A Case of Rectal Colon Cancer with Paraneoplastic Cerebellar Degeneration].

A case complicated with colorectal and prostate cancers in paraneoplastic(subacute)cerebellar degeneration(PCD)is extremely rare. We report a retrospective case of rectal carcinoma with paraneoplastic cerebellar degeneration. A 79-year-old man with Parkinson's disease was unable to walk because of paralysis. Brain MRI showed cerebellar atrophy. He was admitted to our hospital for anal bleeding and was diagnosed with colon cancer. An associated diagnosis of PCD was made. After resection, his paralysis and dysarthria were resolved to the extent of beingable to walk and speak fluently. Brain MP-RAGE showed no findings suggestive of metastasis or atrophy. He was treated surgically, which resulted in a transient improvement in PCD symptoms. Per blood testing, cytokines IL-6 and IL-10 were lower postoperatively. Immunosuppressive levels of myeloid- derived suppressor cells(MDSCs)were lower compared with the preoperative values. Thus, innate immunocompetence and resolution of paralysis followed the surgical intervention.