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HER2, a member of the human epidermal growth factor receptor(HER)family, exhibits gene amplification, protein overexpression, or both in 13-27% of gastric cancer(GC)cases. Through the activation of downstream Akt and ERK pathways, HER2 promotes the survival and proliferation of gastric cancer cells. The impact of HER2 signaling on the tumor microenvironment(TME)in GC remains unclear, and the heterogeneity of HER2 overexpression in GC tissues is considered a contributing factor. In this study, we focused on differences in the TME between HER2-positive and HER2-negative areas in HER2-positive GC and found that HER2 signaling, particularly the HER2-Akt cascade, may suppress stimulator of interferon genes (STING)expression and reduce CD8+ T cell infiltration in tumor cells. Overall, our findings suggest the potential for a novel therapeutic approach to activate the anti-tumor immune response in HER2-positive GC.

Background/aim: Regulatory T cells (Tregs) suppress various anti-tumor immune responses in the tumor microenvironment (TME) and their control is considered essential to enhancing efficacy of cancer immunotherapy. The purpose of the study was to evaluate the strategy to regulate Tregs through the vascular endothelial growth factor (VEGF) pathway., Materials and Methods: We evaluated VEGF receptor (VEGFR) expression in subtypes of Tregs by analysis of public databases and through flow cytometry by investigating surgically resected specimens and peripheral blood mononuclear cells (PBMCs) from 26 patients with advanced colorectal cancer (CRC)., Results: Analysis of The Cancer Genome Atlas colorectal adenocarcinoma dataset (n=592) showed that mRNA expression of both FLT1 (VEGFR1) and KDR (VEGFR2) was positively correlated with mRNA expression of FOXP3 as well as Treg signature. Clinical specimens revealed abundant VEGFR2 expression on Tregs, but very marginal VEGFR1 expression. The frequency of effector Tregs, the most immunosuppressive fraction of Tregs, was significantly higher in the tumor than in the PBMC and normal mucosa, and the majority of effector Tregs expressed VEGFR2. Furthermore, by using in vitro generated Tregs, the proportion of Tregs expressing IL-10 or TGF-β1 was significantly inhibited by a VEGFR2 inhibitor., Conclusion: A therapeutic strategy targeting the VEGFR2 axis may have a potential to control effector Tregs in the CRC-TME., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: An elevated neutrophil-to-lymphocyte ratio (NLR) in peripheral blood is an independent prognostic indicator of various cancers., Aims: In this study, we aimed to investigate the prognostic relevance of the intratumoral immune cell balance in gastric cancer., Methods and Results: The study included 82 patients who underwent curative resection for gastric cancer. The intratumoral cluster of differentiation (CD) 15- and CD8-positive cells were evaluated using immunohistochemical staining. Additionally, clinicopathological factors and prognoses were analyzed. Patients with high intratumoral CD15/CD8 ratios had significantly lower overall survival (OS) and relapse-free survival (RFS) compared to those with low CD15/CD8 ratios (p = .0026 and p < .0001, respectively). Additionally, a high CD15/CD8 ratio was associated with lymph node metastasis (p = .019). Patients with high NLR had a significantly lower RFS than those with low NLR (p = .0050). Multivariate analysis revealed that the intratumoral CD15/CD8 ratio, NLR, and venous invasion were independent prognostic indicators of RFS (CD15/CD8 ratio: p < .001, hazard ratio (HR) = 14.7, 95% confidence interval (CI) = 3.8-56.8; NLR: p = .010, HR = 5.4, 95% CI = 1.5-19.6; venous invasion: p = .005, HR = 7.4, 95% CI = 1.8-29.7)., Conclusion: In summary, we found that the intratumoral CD15/CD8 ratio is an independent prognostic factor following gastric cancer resection and its increase is associated with lymph node metastasis and microscopic lymph vessel invasion. Immunological evaluation with additional aspects of innate immunity may be useful in predicting cancer prognosis., (© 2024 The Author(s). Cancer Reports published by Wiley Periodicals LLC.)

A 70-year-old male patient was diagnosed with advanced gastric cancer with para-aortic lymph node metastasis. After diagnostic laparoscopy, the patient received 2 courses of neoadjuvant chemotherapy. Subsequently, distal gastrectomy, D2 plus para-aortic lymph node dissection, and Roux-en-Y reconstruction were performed. An enlarged lymph node(No. 16b2)was identified during surgery. The histopathological diagnosis revealed ypT4b, ypN3b, cM1(LYM; No. 16), Stage ⅣB. Chemotherapy with ramucirumab plus nab-paclitaxel was administered at 6 weeks postoperatively. However, after 2 courses of chemotherapy, the patient developed an abscess discharge from the wound, which was confirmed by an abdominal CT scan and diagnosed as an intra-abdominal abscess derived from duodenal perforation. The abscess was drained percutaneously. Subsequently, chemotherapy with nab-paclitaxel, nivolumab, and trifluridine/tipiracil hydrochloride was administered. After the appearance of brain metastases, the treatment was shifted to palliative care. The patient died 2 years and 7 months later from the primary disease.

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.

It has been reported that tumor cell-intrinsic cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING) pathway is essential for radiotherapy(RT)-induced activation of anti-tumor immune responses. However, its role in the RT- induced remodeling of the tumor microenvironment(TME)in esophageal squamous cell carcinoma(ESCC), is largely unknown. In this study, we found that the tumor cell-intrinsic cGAS-STING pathway is a critical component for RT-induced activation of immune cells in the TME through the induction of type Ⅰ interferon and C-X-C motif chemokine ligand 10 in tumor cells in ESCC. However, at the same time, the tumor cell-intrinsic cGAS-STING pathway is also involved in RT-triggered infiltration and polarization of immunosuppressive CD163+ tumor-associated macrophages (TAM) through the induction of interleukin 34 (IL-34) in tumor cells in ESCC. Our findings suggest that targeting IL-34 to impede the infiltration and polarization of CD163+ TAM could potentially enhance the efficacy of RT-induced immune cell activation in ESCC TME.

In order to develop a biomarker predicting the efficacy of treatments for patients with esophageal squamous cell carcinoma (ESCC), we evaluated the subpopulation of T cells in ESCC patients treated with chemotherapy (CT), chemoradiotherapy (CRT), and nivolumab therapy (NT). Fifty-five ESCC patients were enrolled in this study, and peripheral blood samples were collected before and after CT or CRT and during NT. Frequencies of memory, differentiated, and exhausted T cells were evaluated using flow cytometry among cStages, treatment strategies, pathological responses of CT/CRT, and during NT. The frequencies of PD-1 + or TIM-3 + CD4 + T cells were significantly higher in patients with cStage IV. PD-1 + CD4 + and TIM-3 + CD8 + T-cell populations were significantly higher in patients treated with CRT but were not associated with treatment response. The frequencies of both CD4 + and CD8 + CD45RA - CD27 + CD127 + central memory T cells (T CM ) were significantly decreased during the course of NT in the progressive disease group. Taken together, the alteration in frequency of CD45RA - CD27 + CD127 + T CM during NT may be a biomarker to predict its therapeutic response in ESCC patients.

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.

The Tn antigen is the most prevalent tumor-associated carbohydrate antigen. It interacts with macrophage galactose-specific lectin(MGL)on dendric cells and macrophages, driving immune inhibitory signals. Colorectal cancer(CRC)exhibiting deficient mismatch repair(dMMR)is characterized by tumor-infiltrating lymphocytes(TILs), the expression of immune checkpoint molecules, and immune evasion. We recently reported that Tn antigen expression was associated with dMMR and that dMMR CRCs with strong Tn antigen expression demonstrated CD8+ T cell exclusion and a lack of PD-L1 expression. Our findings suggest that the immune cold subset of dMMR CRCs with strong Tn antigen may be effectively treated with immune checkpoint blockade therapy or cellular immunotherapy targeting Tn antigens.

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.

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.

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 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.

Neoadjuvant chemotherapy plus surgery is recommended for clinical StageⅡ and Ⅲ esophageal cancer treatment by the JCOG9906. In contrast, definitive chemoradiotherapy(dCRT)is also a curative treatment. We encountered a case of recurrence in the cervical lymph nodes that was confirmed 6 years later, although thoracic esophageal cancer had completely disappeared following dCRT. Since there was no recurrence or metastasis in the primary lesion or other organs, we performed bilateral cervical lymph node dissection. There were 3 lymph node metastases among the dissected cervical lymph nodes pathologically. After the surgery, no relapses have occurred without the adjuvant chemotherapy.

We report 2 cases of superficial non-ampullary duodenal tumor resected using laparoscopic endoscopic cooperative surgery( LECS). A man in his5 0's underwent screening esophagogastroduodenoscopy. Endoscopy revealed a 0-Ⅱc lesion at the anal side of the papilla of Vater that measured 5 mm. We performed LECS, and pathologic examination revealed tubular adenoma with no tumor cellsat the edge of the specimen. A man in his 80's underwent screening esophagogastroduodenoscopy. Endoscopy revealed a 0-Ⅱc lesion at the posterior wall above the papilla of Vater that measured 10 mm. The biopsy showed a well-differentiated adenocarcinoma. We performed LECS, and the pathological examination revealed a tubular adenocarcinoma in the mucosal layer with no carcinoma cells at the edge of the specimen. As the treatment strategy for superficial duodenal tumors has not established yet, further accumulation of cases and investigation are necessary.

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.

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 55-year old man underwent distal gastrectomy with lymphadenectomy for gastric cancer(T1N0M0, Stage I A). Six months after the radical operation, he presented with multiple liver metastases. Based on immunohistochemical examination, he was diagnosed with AFP-producing gastric cancer and metachronous liver metastases. He underwent a surgery to remove the liver metastases. Two months after the surgery, recurrent tumors were found in the lung and remnant liver. He received chemotherapy(S-1/CDDP and CPT-11/CDDP)for the recurrent tumor and lived for 15 months after the surgical intervention.

The patient was a 56-year-old man with advanced esophagogastric junction cancer. He received neoadjuvant chemotherapy with 5-FU plus CDDP followed by lower esophagectomy and total gastrectomy via the left thoracoabdominal approach in October 2011. Pathological examination revealed EGJ adenocarcinoma (ypT4aN1M0, Stage ⅢA, Japanese Classification of Gastric Carcinoma ver.14), and histological analysis indicated Grade 0 (no change). Adjuvant chemotherapy with S-1 was administered. Nevertheless, 6 months after the operation, a solitary hepatic metastasis (f: 32 mm) was detected in S7 of the liver. The patient underwent proton beam irradiation of the liver metastasis, resulting in a complete response, and he was followed up without any chemotherapy. However, 21 months after the irradiation, regrowth of the previous lesion with FDG re-accumulation was noted. Given the absence of any neoplasms other than the liver metastasis, right hepatic lobectomy was performed. Pathological examination revealed a small cluster of viable tumor cells surrounded by extensive fibrotic tissue (Grade 2). At 45 months after the initial operation (10 months after the liver lobectomy), the patient is living without any signs of recurrence. Surgical resection for liver metastasis of EGJ cancer may be feasible after careful selection.

Background: This is a randomized phase II trial to evaluate non-inferiority of progression-free surviva(l PFS) by comparing S-1 and S-1/PSK for advanced or recurrent gastric cancer. Sample size was calculated to be 120. However, the trial was terminated because of slow accrual. This exploratory analysis was done by collecting the minimum data., Results: Only 8 patients were enrolled. Four patients were randomly assigned to S-1 and the others to S-1/PSK. Performance status was 0 in all 8 patients. Median age was 64. Median overall survival was 13.7 months in all 8 patients, 8 . 9 months in S-1 group, and 13 . 7 months in S-1/PSK group., Conclusion: When considering PS 0 in 8 patients enrolled, an overall survival was comparable to that observed in S-1 group of other phase III trials. Standard chemotherapy for advanced gastric cancer was changed to S-1/CDDP by SPIRITS phase III trial which was presented just after this trial was initiated, which would be a major cause of slow accrual. When conducting phase III trial, we should carefully determine design and standard arm by considering on-going phase III trial.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract that are diagnosed by c-kit staining in most cases. A lysosomal cysteine proteinase termed cathepsin L has been commonly associated with malignancy in several cancer types, but this finding has not been reported for GISTs. We analyzed the cathepsin L mRNA and protein expression in GISTs. Real-time reverse transcription polymerase chain reaction (RT-PCR) analysis revealed that cathepsin L levels were higher in GISTs than those in gastric or colorectal tumors; this finding was supported by results of the Western blot analysis. Immunohistochemistry revealed that cathepsin L was localized to the cytoplasm of GIST cells as an intense granular signal, which was not observed in the cells of leiomyoma, a mesenchymal tumor that was analyzed as a control specimen. Double immunofluorescence microscopy revealed that a portion of the granular signal colocalized with lysosome-associated membrane protein-1 (LAMP-1), which is a lysosomal marker. Moreover, immunohistochemical analysis of 43 tumor specimens revealed that 86.0% (n=37) were cathepsin-L positive, and this positivity was significantly correlated with c-kit positivity but not with other clinicopathological factors, including gender, age, region, size, mitosis and risk of recurrence. From these results, we conclude that cathepsin L is highly expressed in GISTs compared to its expression in other cancerous lesions; this identifies cathepsin-L as a new diagnostic marker for GISTs.

Adjuvant chemotherapy for advanced gastric cancer has not yet been established. We report a patient with advanced gastric cancer responding remarkably to neo-adjuvant combination chemotherapy consisting of CPT-11 and S-1. The patient was a 69-year-old woman diagnosed with large type 3 advanced gastric cancer with esophageal invasion and having No.3 lymph node metastasis (cT3, cN1, cM0, cStage IIIA), treated with 2 courses of CPT-11 plus S-1 as neo-adjuvant chemotherapy. Computed tomography after neo-adjuvant chemotherapy showed improvement of gastric wall thickness and reduction of lymph node metastasis. Subsequently, she underwent an operation. There was no lymph node swelling,so we performed curative surgery consisting of total gastrectomy, splenectomy, cholecystectomy, and D 2 lymph node dissection. Histological diagnosis was pT2 (MP), pN1, pStage II, and estimation of the histological change by chemotherapy was Grade 2. The course after surgery was good, and she was treated by S-1 after discharge. To date, 8 months after surgery, there is no evidence of recurrence. Combination chemotherapy consisting of CPT-11 plus S-1 can be performed safely as a neo-adjuvant treatment, and may be an effective treatment modality for advanced gastric cancer.

Present status and problems in diagnostic procedure combination (DPC) for treatment of gastric cancer are reviewed in this article. DPC for gastric malignancies are subgrouped by the presence or absence of operation, operative procedures and adjuvant treatment such as intensive care, radiotherapy and chemotherapy. In a comparison between prospective payment and medical cost invested, most investments can be recovered by DPC in patients who underwent mucosal resection or gastrectomy without major complications. However, in patients with postoperative complications who required intensive treatment,considerable investments can not be recovered by DPC. In patients given chemotherapy, most of the investments in conventional chemotherapy can be recovered by current DPC. The clinical pathway appears to be a useful tool to control homogeneously well-qualified investments in DPC.

Dihydropyrimidine dehydrogenase (DPD) is a reducing enzyme for fluoropyrimidine which is a widely-used anti-cancer agent, and its deficiency leads to serious toxicities. We report a rare patient with a DPD deficiency. A 39-year-old man was suspected to have a gastric cancer recurrence from the elevation of CEA. Although TS-1 was administered for five days, it was stopped due to the development of grade 2 anorexia and nausea. Although we administered UFT at his request after a one-month drug rest, grade 1 stomatorrhagia besides the former adverse events developed after five days. Therefore he discontinued it and was admitted to our hospital. After 19 days, he died from multiple brain hemorrhage despite the intensive therapies. We considered that the congenital DPD deficiency caused the development of these adverse events because the DPD value was less than 5 pmol/mg/min in mononuclear cells of peripheral blood.

As the frequency of chemotherapy was increasing at an out-patient clinic, chemotherapy centers for an outpatient clinic have been established. When chemotherapy was carried out for 25 patients in a day at an outpatient clinic, the mean time was 27.6 minutes from ordering the drugs to the drugs' arrival. When the line was crowded, the drug arrival time was more than one hour, and at least 90 minutes was necessary to begin the chemotherapy. As the number of patients increases, it is necessary to have the effective use of a chemotherapy room and the patients have to be divided according to the duration of time required for chemotherapy. It appears that a continuation of infusion chemotherapy will be frequently carried out and the chemotherapy with an IVH port and a portable pump system will be popular in the future. It is necessary to make the system which supports a continuous infusion like this.