[A Case of Multicentric HER2-Positive Breast Cancer with Alterations of the Intrinsic Subtype].

In cases where there are 2 or more tumors, it is crucial to conduct core needle biopsies on each of them. A 39-year-old woman presented at our hospital with pain in her left breast. Ultrasonography(US)revealed the presence of 2 contiguous tumors: a 35 mm tumor(tumor 1)and a 20 mm tumor(tumor 2)in the AC area of the left breast. US-guided core needle biopsies(CNB)were performed. The histological findings confirmed an invasive ductal carcinoma, characterized by ER(-)/ PR(-)/HER2(3+). Neoadjuvant chemotherapy indicated tumor 1 as PD and tumor 2 as PR, and surgery was subsequently performed(Bt plus SLN). Upon histopathological examination, the findings demonstrated a non-pCR invasive ductal carcinoma, featuring an ER(+)/PR(-)/HER2(-)profile. Depending on the specific subtype identified, post-operative treatment included HER2-targeted therapy or ER/PR-targeting hormone therapy in conjunction with chemotherapy.

[A Case of Splenectomy for Isolated Splenic Metastasis after Surgery for Gastric Cancer].

Splenic metastasis of gastric cancer is rare. Cases of long-term survival after the resection of metachronous solitary splenic metastasis have been reported, and proactive resection should be performed. A 77-year-old man was presented to our hospital with anorexia. Further investigation showed type 2 gastric cancer in the greater curvature of the stomach in the lower body. Subsequently distal gastrectomy was performed on October 2018. The pathological stage was T3N2M0, Stage ⅢA, and the patient was treated with S-1 as adjuvant chemotherapy for 1 year. Two years after surgery, enhanced computed tomography(CT)showed a solitary splenic tumor with a diameter of 10 mm. Six months later, the tumor had grown to 25 mm, and PET-CT revealed no other tumors. Thus we diagnosed the patient as metachronous solitary splenic metastasis of gastric cancer, and splenectomy was performed on June 2021. Histopathological diagnosis was a metastasis of gastric cancer. The patient was treated with S-1 and remains recurrence-free for 1 year after the second operation.

Association between the preoperative neutrophil-to-lymphocyte ratio and tertiary lymphoid structures surrounding tumor in gastric cancer.

The neutrophil-to-lymphocyte ratio (NLR) has been reported to be associated with a poor prognosis in various types of cancer. We previously reported that an antitumor immune response was induced by tertiary lymphoid structures (TLSs) surrounding tumor, and increased TLS was an independent prognostic factor in patients with gastric cancer. The present study examined the stratification based on the correlation between the preoperative NLR and TLS density in gastric cancer. A total of 199 patients who underwent surgery for stage Ib-IV gastric cancer were included in the study. Receiver operating characteristic curve analysis was used to determine the appropriate cut-off values of the preoperative NLR and the TLS density. The prognostic factors were evaluated in a multivariate analysis. The median NLR was 2.18 (mean ± SD, 2.7±2.04). A total of 91 patients with an NLR ≥2.33 was classified into the high NLR group. The overall survival was significantly improved in patients with a low NLR than in those with a high NLR. Additionally, the low NLR group tended to have a high TLS density. The multivariate analysis indicated that the preoperative NLR and TLS density were independent risk factors. When the patients were classified into the high and low NLR and TLS groups and the survival rates were compared, the prognosis was significantly improved in the low NLR and high TLS group than in the other groups. The preoperative NLR may be associated with the presence of TLSs surrounding the tumor, and the combination of NLR and TLS may be useful for the stratification of patient prognosis. The present results suggested that the NLR and TLS density may be surrogate markers for immunotherapy against gastric cancer.

[A Case of Long-Term Survival of Anaplastic Transformation of Thyroid Cancer in Lymph Node Metastasis Due to Radiation Therapy and Lenvatinib].

An 82-year-old woman who underwent total thyroidectomy and left cervical lymph node dissection 21 years ago admitted our hospital because of left cervical pain. Neck CT scan showed a 6 cm tumor on the left clavicle. Pathological diagnosis by needle biopsy revealed poorly differentiated to undifferentiated carcinoma, positive for TTF-1, and diagnosed as thyroid cancer lymph node metastasis anaplastic transformation. Administration of lenvatinib was started after radiation therapy. Since thrombocytopenia was observed, lenvatinib was gradually reduced from 14 mg and the dose was continued at 4 mg. The tumor shrinked and the effect of chemotherapy was partial response. She survived for 3 years while continuing lenvatinib. We reported long-term survival due to radiation therapy and lenvatinib of anaplastic transformation of thyroid cancer in lymph node metastasis due to radiation therapy and lenvatinib.

[Biomarkers for Immunotherapy Based on the Local Microenvironment of Gastric Cancer].

Currently, the immunotherapy approved for gastric cancer is immune checkpoint blockade( ICB) therapy. The effects of ICB depend on the T cell-mediated immune response elicited at the cancer site. Based on the results of previous clinical trials, it is clear that an enhanced immune response to cancer improves prognosis. Thus, the development of biomarkers to predict local immune responses may increase the significance of future immunotherapy for gastric cancer. Biomarker research has clearly progressed with the rapid development of genetic analysis technologies, enabling the analysis of data from clinical trials. Not only the molecular biomarkers known to date for ICB biomarkers, but immune cells that influence ICB therapy are also reviewed in this article.

[A Case of Retroperitoneal Primary Well-Differentiated Liposarcoma Treated by Laparoscopic Surgery].

A 76-year-old woman visited the hospital due to occult blood in her urine. An abdominal CT scan showed a low-density tumor inside the left iliopsoas muscle in the retroperitoneum, and a well-differentiated liposarcoma was suspected. Therefore, laparoscopic tumor resection was performed. The tumor was on the inside of the left iliopsoas muscle, without any invasion around it. The macroscopic appearance of the resected tumor showed a yellow, fat-like, solid mass and it was histopathologically diagnosed as a well-differentiated liposarcoma. We conclude that a retroperitoneal primary well-differentiated liposarcoma can be treated by laparoscopic surgery, as in our case.

Immunological potential of tertiary lymphoid structures surrounding the primary tumor in gastric cancer.

Tertiary lymphoid structures (TLSs), which consist of B cells, T cells, follicular dendritic cells and high endothelial venules, have recently been found to be associated with effective antitumor immune responses in patients with cancer. Tumor­infiltrating T cells and B cells have each been demonstrated to be associated with survival in patients with cancer. We hypothesized that TLSs, an assembly of immune cells, may be important for the initiation and/or maintenance of T cell and B cell responses against tumors. The aim of the present study was to examine the cellular mechanism of B cells in TLSs within gastric cancer and to understand the antitumor immune response of TLSs. Each B cell subset in a tumor was examined using flow cytometry to evaluate B cell differentiation and the functional status of B cells. In addition, B cell clonality was investigated by analyzing the B cell antigen receptor gene using PCR, and the function and formation/maintenance of TLSs were evaluated using reverse transcription­quantitative PCR. Tumor­infiltrating B cells were more differentiated compared with that in distant non­tumor tissues and tumor­draining lymph nodes. The PCR results revealed specific BCR gene expression in tumor­infiltrating B cells. The expression of co­stimulatory factors, CD80 and CD86, was observed, in addition to the constantly expressed major histocompatibility complex molecules (HLA­ABC and HLA­DR). CD70 was expressed in addition to CD27 in both CD20+ B cells and CD8+ T cells, indicating that these factors are activated together through their interaction. The mRNA expression levels of CCL21, CXCL13, PD­L1, perforin and granzyme B in TLSs was significantly higher compared with that in non­TLSs. The majority of tumor­infiltrating B cells in gastric cancer exist in the form of TLSs around the tumor and have been antigen­sensitized and differentiated, and proliferated in TLSs but not in the lymph nodes. In addition, B cells in TLSs might primarily function as antigen­presenting cells and be associated with the induction of cytotoxic T cells.

[A Case of Hepatectomy for Primary Hepatic Neuroendocrine Tumor, Preoperatively Diagnosed with Hepatocellular Carcinoma].

A 65-year-old man has pointed out a hepatic tumor when he was rushed to the hospital because of disturbance of consciousness associated with hypoglycemia. Abdominal dynamic CT images showed a tumor, 2.5 cm in diameter, in S2/3 close to the umbilical portion of the portal vein, and it had enhancement in the arterial phase and became washout in the portal phase. We performed left lateral segmentectomy with a diagnosis of hepatocellular carcinoma. The tumor was histopathologically diagnosed as a Grade 1 neuroendocrine tumor(NET). As additional examinations could not detect a primary lesion in any other site, the tumor was considered as a primary hepatic NET(PHNET). PHNETs are rare and because of the possibility that an unknown primary lesion exists, we have to observe for years carefully.

Gastric cancer cells alter the immunosuppressive function of neutrophils.

Tumor­associated neutrophils (TANs) have an immunosuppressive function and play an important role in tumor progression. However, the detailed mechanism is largely unknown. The present study investigated the immunosuppressive ability of TANs in gastric cancer. Tumor tissue culture supernatant (TTCS) and non­tumor tissue culture supernatant (NTCS) were purified and added to neutrophils. Expression of programmed cell death ligand­1 (PDL­1), 7­amino­actinomycin D and human leukocyte antigen­DR (HLA­DR), and the levels of hydrogen peroxide (H2O2) were determined. Levels of programmed cell death­1 (PD­1) and CD25 were assessed in T cells co­cultured with neutrophils. Furthermore, CD4+ T cells were co­cultured with dendritic cells and neutrophils to examine their proliferation. CD15 and PD­1 immunohistochemical staining was also performed to explore the positional relationship. The results revealed that the neutrophils incubated with TTCS showed upregulation of PDL­1 expression, as well as a decreases in the ratio of apoptotic cells, expression of HLA­DR, and levels of H2O2. CD4+ T cells co­cultured with neutrophils conditioned with TTCS showed a decrease in proliferation, upregulation of PD­1 expression, and downregulation of CD25 expression. IHC showed that PD­1+ T cells formed clusters and TANs infiltrated around the clusters. In conclusion, neutrophils in gastric cancer tissue inhibit the proliferation of CD4+ T cells and may form a local immunosuppressive environment through the PD­1/PDL­1 pathway.

[A Case of Curative Resection of Locally Advanced Gastric Cancer after Nutrition Therapy and Chemotherapy with S-1 and Oxaliplatin Using Elemental Diet Tube].

We report a case of advanced gastric cancer with stenosis under severe malnutrition, in which nutritional treatment along with chemotherapy using an elemental diet(ED)tube led to complete resection of the tumor. A 66-year-old man who presented with difficulty in dietary intake came to our hospital. He was emaciated with a body mass index(BMI)score of 13.5 and a prognostic nutritional index(PNI)score of 33.8 and was admitted to the hospital for an emergency. He was diagnosed with advanced gastric cardia cancer invading the distal pancreas, spleen, and left diaphragm(U, type 3, tub2, cT4bN3M0, cStage ⅢC, HER2 score 0). There was obstruction of the passage of food due to the tumor, we performed nutrition therapy and chemotherapy consisting of 3 courses of S-1 and oxaliplatin using an ED tube. After chemotherapy, the primary tumor and lymph nodes were reduced, and we performed total gastrectomy with D2 lymph node, distal pancreas, spleen, and left partial diaphragm dissection. Histopathological diagnosis was ypT4aN1M0, ypStage ⅢA, indicating a pathological partial response(Grade 1). Adjuvant chemotherapy was performed for 6 months, and there has been no relapse for 3 years since the operation.

[A Case Report of Lung Resection for Lung Metastasis from Pancreatic Cancer].

A 66-year-old man had an elevated CEA level. Further examinations showed a pancreatic head tumor. A pancreaticoduodenectomy was then performed. The histopathological examination showed a mixed tumor of papillary adenocarcinoma and neuroendocrine cancer. In addition, a tumor in the upper lobe of the right lung was found 18 months after the initial pancreatic resection, and the bronchoscope indicated lung metastasis. The patient underwent partial pneumonectomy. After the pneumonectomy, he received S-1 chemotherapy. Thirty -nine months after the pneumonectomy, CEA was slightly elevated. We changed the chemotherapy to gemcitabine and nab-paclitaxel without further examinations to confirm the recurrence. The patient discontinued chemotherapy after CEA fell within the normal range. He has been alive without tumor relapse for 64 months since the second operation for the lung metastasis. We report a successful case of lung resection for lung metasta- sis from pancreatic cancer.

Neutrophils in primary gastric tumors are correlated with neutrophil infiltration in tumor-draining lymph nodes and the systemic inflammatory response.

BACKGROUND: Tumor-Associated Neutrophils (TANs) may be able to induce lymphangiogenesis and angiogenesis, although the detailed roles of TANs remain unclear. The Neutrophil-Lymphocyte Ratio (NLR) is an inflammation-based prognostic factor for gastric cancer. This study aimed to investigate the distribution of CD15+neutrophils in the primary tumor and Tumor-Draining Lymph Nodes (TDLNs), and to examine the association of TANs with the clinicopathological features (including NLR) of patients with gastric cancer. RESULTS: Immunohistochemical staining showed that the median number of CD15+TANs was 18 and 24 per high-power field (HPF) in primary tumors and TDLNs, respectively. Patients were divided into high and low infiltration groups based on the median number. A high number of infiltrating CD15+TANs in the primary tumors and in the TDLNs were associated with depth of invasion and lymph node metastasis. Kaplan-Meier analysis revealed that a poor overall survival was associated with high numbers of CD15+TANs, and the multivariate analyses revealed that a high number of CD15+TANs in the TDLNs was an independent prognostic factor. The numbers of CD15+TANs in the primary tumors and TDLNs showed weak positive correlation. The number of CD15+TANs in the primary tumors was positively correlated with the preoperative NLR, (P = 0.001, R = 0.327) and immunohistochemical staining revealed that C-X-C motif chemokine receptor 2 (CXCR2) +neutrophils might be the origin of the CD15+TANs. Flow cytometry analysis indicated that infiltrating neutrophils increased in the tumor and TDLN compared to non-cancerous tissue. Neutrophils treated with cancer supernatant upregulated TWIST and IL-6 genes in vitro. CONCLUSION: Our findings suggested that local infiltration of CD15+TANs may be correlated with inflammation in TDLNs and systemic response to cause metastasis in gastric carcinoma.

[Significance of Immune-Cell Infiltration in Gastric].

There are many reports on the association between infiltrating immune cells andcancer prognosis. It is generally thought that cancer cells escape from the immune surveillance system in vivo. Cells associatedwith tumor immunosuppressive mechanisms include macrophages, regulatory T cells, bone marrow-derived immunosuppressive cells(MDSC), andneutrophils. These immunosuppressive cells enhance the production of TGF-b andIL -10 andthe expression of PDL-1 by cytokines producedby stromal cells such as cancer cells andfibroblasts, thereby inducing cytotoxic T cells lymphocytes(CTL). On the other hand, it has been proved that CD8+ T cells react in an antigen-specific manner even in advanced gastric cancer, suggesting the possibility that memory T cells, NK cells andNKT cells in gastric cancer tissues correlate with goodprognosis. Recently, it has been reportedthat the presence of follicular lymphoidstructure calledtertiary lymphoidstructure(TLS)in gastric cancer tissue is associatedwith favorable prognosis. Although immune responses are suppressedin gastric cancer tissues, the effectiveness of an immune checkpoint inhibitor(anti-PD-1 antibody)has been provedin 2017. The tumor-infiltrating immune cells is known as a predictive effect biomarker. As cancer genome research progresses, which type of immune response is induced is gradually being elucidated in near future. Thus, assessing the invasive morphology and function of various tumorinfiltrating immune cells is considered to be extremely important in Precision Medicine for gastric cancer.

[A Case of Rectal Gastrointestinal Stromal Tumor(GIST)with Long-Term Survival Treated with Multidisciplinary Therapy].

We report a case of gastrointestinal stromal tumor(GIST)with long-term survival treated by multidisciplinary therapy, including surgery and imatinib to prevent repeated recurrence. A 76-year-old woman visited our hospital with difficulty in defecation and bloody bowel discharge. She was diagnosed with rectal GIST and underwent transanal partial resection of the rectum. Local recurrence occurred 1 year after the operation, and the tumor was resected transanally. Hepatic metastasis occurred 8 months after the second operation. The patient was administered imatinib for 2 months, which caused the tumor to shrink, and extended left lobectomy was performed. Imatinib was administered for 2 years after hepatectomy. After another 2 years, metastasis to the liver and thoracic and lumbar vertebrae occurred. The recurrent tumors reverted to cystic lesions after 6 months of imatinib treatment. She has been alive without tumor progression during re-treatment with imatinib for 7 years(13 years after the first surgery).

B cells in tertiary lymphoid structures are associated with favorable prognosis in gastric cancer.

BACKGROUND: The role of tumor-infiltrating B cells in the tumor microenvironment is still unclear. Recent studies have reported that B cells and tertiary lymphoid structures (TLSs) that contain B cell follicles correlate with the favorable prognosis of cancer patients. The aim of this study was to investigate the association between tumor-infiltrating B cells and clinicopathological features in gastric cancer. METHODS: Tumor blocks were obtained from 226 patients with stage Ib to stage IV gastric cancer. The density of CD20+ B cells within the tumor and in the invasive margin area was assessed using immunohistochemistry. We also evaluated CD3+ T cells, CD21+ follicular dendritic cells, Bcl6+ germinal center B cells, and PNAd+ high endothelial venules to show the presence of TLSs. RESULTS: Tumor-infiltrating B cells were mostly organized as clusters that were surrounded by CD3+ T cells. The B cell area contained follicular dendritic cells and some clusters contained Bcl6+ B cells. High endothelial venules were present around follicles. We identified these follicles as TLSs. A high number of CD20+ B cells were associated with significantly better overall survival, and multivariate analysis also showed that CD20 high was one of the independent predictors of prognosis. In addition, there was a significant correlation between CD20+ B cell and CD8+ T cell infiltration. CONCLUSIONS: B cells mostly infiltrated tumors as TLSs and were associated with better prognosis in patients with gastric cancer.

Tumor-associated macrophages induce capillary morphogenesis of lymphatic endothelial cells derived from human gastric cancer.

Tumor lymphangiogenesis is a major prognostic indicator of gastric cancer. Tumor-induced inflammation has been shown to attract tumor-associated macrophages that affect lymphangiogenesis. However, detailed mechanisms of macrophage-induced lymphangiogenesis have not been elucidated. Here, we evaluated the interaction between tumor-associated macrophages and lymphatic endothelial cells (LECs) derived from lymph nodes (LNs) of human gastric cancer. Lymphatic endothelial cells were directly or indirectly cocultured with macrophages from healthy human blood, with or without the supernatant of the gastric cancer cell line, OCUM-12. We analyzed the effect of cancer pretreated macrophages and of macrophages from metastatic LNs of gastric cancer on LECs. We observed morphological changes of LECs in coculture and assessed the gene expression of possible lymphangiogenic molecules of macrophages and LECs after contact coculture, and of cancer pretreated macrophages, by quantitative RT-PCR. Specimens of metastatic LN of gastric cancer were immunofluorescently stained. We found that tubulogenesis of LECs was observed only in the contact coculture model. OCUM-12 cells promoted macrophage-induced tubulogenesis of LECs. Relative gene expression of MMP and adhesion molecules was significantly upregulated in both capillary-forming LECs and cocultured macrophages. Cancer pretreated macrophages upregulated lymphangiogenic factors including inflammatory cytokines, MMPs, adhesion molecules, and vascular endothelial growth factor-C. Blocking of intercellular adhesion molecule-1 and macrophage activation suppressed tubulogenesis of LECs. Immunohistochemistry showed macrophages localized around lymphatic vessels. Our results suggested that interaction between LECs and macrophages may be an important initial step of tumor lymphangiogenesis developing LN metastasis. Understanding of its mechanisms could be useful for future therapeutics of gastric cancer.

[The usefulness of intraoperative Doppler echo and laparoscopic echo in laparoscopic colectomy].

Laparoscopic surgery has been increasingly performed in colon cancer patients; it has also been adapted for cases of advanced colorectal cancer. While performing an operation for rectosigmoid colon cancer, preservation of the left colic artery and prompt and accurate detection of the branch of the left colic artery from the inferior mesenteric artery is important. Detecting the left colon arterial bifurcation takes time, especially because of the presence of mesenteric fat, which is observed in many cases. In addition, in cases in which preoperative enhanced computed tomography (CT) cannot be performed, the surgery is sometimes performed without knowing the traveling vessel. As palpation is impossible, it is impossible to tactile running of the arteries as laparotomy in laparoscopic surgery. With endoscopic echo or Doppler echo, real-time identification of the blood vessels during surgery is possible without being invasive. It would be in laparoscopic surgery impossible palpation, and the combined use of intraoperative echo in ensuring the safety to be useful.

[A case of palliative resection resulting in improvement in quality of life in a patient with colon cancer and simultaneous ovarian metastasis].

A 72-year-old woman was admitted for investigation of lower abdominal bloating and melena. She was diagnosed with rectal cancer with ascites, multiple liver metastases, and large bilateral ovarian metastases. The patient underwent bilateral oophorectomy for the ovarian tumors and a Hartmann procedure for rectal cancer. The ovarian lesions were diagnosed as ovarian metastasis of colorectal cancer by histological analysis. Ascites and lower abdominal bloating resolved after the intervention. At 11 months after surgery, the patient is alive and well. Ovarian metastasis from colorectal cancer is relatively rare and associated with poor prognosis. Radical intervention is generally not possible in the presence of metastases, but in the present case, the ovarian tumors were large. It is often difficult to determine the optimal type of invasive surgery, although excision of the lesion may provide palliative relief. In this case, the patient's quality of life improved following palliative resection of the primary colon cancer and ovarian metastases.

[Clinical experience with a handheld vacuum-assisted biopsy system (VACORA® )for mammary lesions].

We evaluated the usefulness and safety of a handheld vacuum-assisted biopsy system (VACORA®) in 253 lesions suspected to be malignant. Biopsy samples were successfully obtained from 252 lesions, and no complications occurred that required other treatments during or after the biopsy. The definitive diagnosis rate using VACORA / ®was 89.3% (226/253). For 27 lesions, biopsy using Mammotome®or open biopsy was performed because a diagnosis could not be made with the VACORA® system, despite a category 4 result on ultrasonography. The lesions that were diagnosed as benign using the VACORA® system did not manifest malignant features during the observation period (1-36 months). We considered the VACORA® biopsy system as an effective technique that has both convenience and high diagnostic accuracy.

[Clinical experience of nab-Paclitaxel treatment in 31 patients with breast cancer].

Nanoparticle albumin-bound paclitaxel (nab-PTX, Abraxane®) does not require premedication, and it can be used for patients with alcohol intolerance. We administered nab-PTX to 31 patients with breast cancer between October 2010 and April 2013. Eighteen patients had progressive, recurring breast cancers and 13 patients had locally advanced operable breast cancers. The treatment schedules were 175 or 260 mg/m² every 3 weeks (q3w). No patient experienced an allergic reaction. Grade 1-3 sensory neuropathies were observed in 20 patients; however, no patient experienced grade 4 neuropathy. In patients with locally advanced, operable breast cancer, 1 patient treated with 175 mg/m² q3w had a partial response (PR), while of the patients treated with 260 mg/m² q3w, 10 patients showed a PR, and 1 patient had stable disease (SD). Of the patients with progressive, recurring breast cancer, 2 patients showed a PR and 4 patients had SD when treated with 175 mg/m² q3w, whereas 1 patient displayed a PR and 1 patient had SD when treated with 260 mg/m² q3w. Our investigation suggests that nab-PTX is well tolerated, even by patients with advanced breast cancer.