[Laparoscopic Surgical Treatment of Differentiated Intramucosal Gastric Cancer with Lymph Node Metastasis-A Case Report].

A 78‒year‒old man was admitted to our hospital with the chief complaint of 5 kg weight loss in 6 months. An esophagogastroduodenoscopy revealed a 0‒Ⅱa lesion in the posterior wall of the antrum, and biopsy findings showed a well‒differentiated adenocarcinoma. Endoscopic ultrasonography did not show an obvious invasion of the submucosal layer. Contrast‒ enhanced abdominal computed tomography(CT)revealed an enlargement of the #11p lymph node to approximately 30 mm, and positron emission tomography(PET)‒CT showed an accumulation in the same lymph node. Since no other apparent distant metastases were observed, laparoscopic distal gastrectomy and D2 dissection were performed. The postoperative pathological diagnosis was L, 7×8 mm, 0‒Ⅱa, tub1, pT1a, ly0, v0, pPM0(73 mm), pDM0(35 mm), N2, and pStage ⅡA. We report this case because the successful laparoscopic resection of a differentiated gastric mucosal cancer with lymph node metastasis has been considered to be extremely rare.

[Breast Cancer with Cancerous Ascites with Good QOL by KM-CART-A Case Report].

Patients with cancerous ascites often manifest with various symptoms, such as abdominal distension and poor appetite. Ascites puncture may offer temporary relief, but there is a consentration loss of important proteins, such as albumin and immunoglobulin. Cell-free and concentrated ascites reinfusion therapy(CART)is helpful to compensate for this loss of proteins. However, the volume of ascites that can be retrieved is small, and patients occasionally have high fever at the time of reinjection. CART modified by Keisuke Matsusaki(KM-CART)is an improved version of CART with respect to these points. We performed KM-CART for a woman with breast cancer with ascites arising from peritoneal dissemination, and she had a good QOL until she died. We hope that more patients will benefit from KM-CART.

[A Case of Hypophysitis Due to Immune Check Point Inhibitor Treatment].

The patient was a man in his 70s with bone metastasis from renal cell carcinoma who had received immune checkpoint inhibitors(ICI)therapy. After 2 courses of chemotherapy, he was admitted to our hospital with diverticulitis. His diverticulitis could be treated with antibiotics, but he presented with severe hyponatremia and consciousness disorder during hospitalization. Brain MRI showed pituitary swelling, and his serum TSH, ACTH, cortisol levels decreased. We therefore diagnosed him with hypopituitarism due to ICIs. Hydrocortisone improved his hyponatremia and consciousness disorder. Endocrine stimulation tests revealed no reaction of ACTH, and low-level reactions of TSH, LH and FSH, ICIs cause many types of immune- related adverse events(irAEs). The indications for ICI therapy are expanding; thus, we can expect to experience more cases of serious irAEs in association with ICI treatment. Further studies should be performed to improve our understanding of irAEs.

[Multidisciplinary Treatment for Metastatic Breast Cancer in Thoracic Vertebrae Improved Patient' S Quality of Life].

A 40's woman complained of back pain and unable to walk. Computed tomography(CT)suggested that the 4th thoracic vertebra was crushed and spinal cord was compressed. Also, CT pointed out the right breast tumor and axillary lymph nodes metastasis. Spinal cord compression was due to the thoracic vertebra metastasis of breast cancer. She was referred to our hospital within 6 hours after the onset of neuroplasia. Then, laminectomy and posterior spinal fusion was performed immediately. After operation, she received 37.5 Gy of radiotherapy. She became ambulatory and her bladder-rectal disorder was improved. Spinal cord compression is oncologic emergency. It is important to corporate with orthopedic surgeon, and make appropriate indications for spinal metastasis in order to avoid irreversible disorders.

Neoadjuvant Chemotherapy With Nab-paclitaxel Plus Trastuzumab Followed by 5-Fluorouracil/Epirubicin/Cyclophosphamide for HER2-positive Operable Breast Cancer: A Multicenter Phase II Trial.

AIM: This study was conducted in order to evaluate the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus trastuzumab followed by 5-fluorouracil/ epirubicin/cyclophosphamide (FEC) in a neoadjuvant chemotherapy (NAC) setting for patients with human epidermal growth factor receptor 2 (HER2)-positive operable breast cancer. PATIENTS AND METHODS: Each patient received four cycles of 260 mg/m2 nab-paclitaxel with 6 mg/kg trastuzumab (8 mg/kg as the loading dose) every 3 weeks (q3w) followed by four cycles of FEC (500/100/500 mg/m2) q3w. The primary endpoint was pathological complete response (pCR) rate. RESULTS: Twenty-nine patients were analyzed for the efficacy and safety of this treatment. All patients completed four cycles of nab-paclitaxel and trastuzumab, and 28 patients completed four cycles of FEC. Twenty-seven patients subsequently underwent surgery. The pCR rate was 74.0%. The most frequent toxicity was sensory neuropathy (96.6%), but grade 3 neuropathy rate was 3.4%. CONCLUSION: Nab-paclitaxel plus trastuzumab followed by FEC in patients with HER2-positive operable breast cancer is considerably effective and well tolerated.

[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 3mm Gastric Neuroendocrine Tumor That Metastasized to a Lymph Node].

A 46-year-old man underwent a medical check-up and gastrointestinal endoscopy, which revealed a brown lesion at the greater curvature of the gastric body. Biopsy was performed, and a gastric neuroendocrine tumor(NET)was diagnosed. The serum levels of gastrin and other tumor markers were not elevated. The preoperative diagnosis was Rindi type Ⅲ gastric NET, and laparoscopic distal gastrectomy with D1 plus lymph node dissection was performed. Histological examination showed that the resected specimen was positive for chromogranin A, CD56, and synaptophysin, which was consistent with the findings of NET. Even though the tumor diameter was only 3 mm, a metastatic #4d lymph node was found. This case suggests that Rindi type Ⅲ gastric NET has high malignant potential, and gastrectomy with lymph node dissection is necessary, regardless of tumor size.

A case of Adrenocoricotrophic hormone -independent bilateral adrenocortical macronodular hyperplasia concomitant with primary aldosteronism.

BACKGROUND: Adrenocoricotrophic hormone (ACTH) - independent bilateral adrenocortical macronodular hyperplasia (AIMAH) is a rare cause of Cushing's syndrome, and is characterized by bilateral adrenal hyperplasia. However, Primary aldosteronism (PA) is a relatively common adrenal disease. CASE PRESENTATION: A 56-year-old man who has been treated hypertension and diabetes mellitus was detected low plasma potassium level with an elevated level of plasma aldosterone concentration and bilateral adrenal swelling. Endocrinological examinations showed autonomous secretion of cortisol and aldosterone, with suppression of plasma ACTH level and renin activity. A selective adrenal venous sampling demonstrated that left adrenal gland was responsible for aldosterone hypersecretion. He was diagnosed preclinical Cushing's syndrome due to ACTH - independent bilateral adrenocortical macronodular hyperplasia (AIMAH) associated with aldosterone producing adenoma of the left adrenal gland. A laparoscopic left adrenalectomy was performed. CONCLUSION: The resected adrenal specimen histologically consisted with a diagnosis of AIMAH. Moreover, tiny cell clusters positive immunostaining for aldosterone synthase was revealed. This is a rare case of AIMAH accompanied by preclinical Cushing's syndrome and primary aldosteronism.

Immunoregulatory Function of Lymphatic Endothelial Cells in Tumor-draining Lymph Nodes of Human Gastric Cancer.

BACKGROUND/AIM: Lymph node metastasis is the most important prognostic factor for patients with gastric cancer. Increasing evidence suggests that lymphatic endothelial cells (LECs) regulate immune responses. The aim of this study was to examine the effect of LECs on the activation of CD4+ T cells. MATERIALS AND METHODS: We examined the impact of cancer cells on the phenotype and production of cytokines of LECs derived from tumor-draining lymph nodes. RESULTS: We showed that LECs inhibited CD4+ T cell production of cytokines, such as IL-2, IL-10, and INF-γ. The mRNA expression of programmed death-ligand 1 (PD-L1) and indoleamine 2, 3-dioxygenase (IDO) by LECs were significantly up-regulated when the LECs and CD4+ T cells were co-cultured with cells of the gastric cancer cell line, OCUM12. CONCLUSION: Intranodal LECs may be a key player in the induction of immune tolerance against cancer and in facilitating metastasis through lymphatic vessels in 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.

Predictive factors for the occurrence of four or more axillary lymph node metastases in ER-positive and HER2-negative breast cancer patients with positive sentinel node: A retrospective cohort study.

INTRODUCTION: Patients with four or more axillary lymph node metastases have benefited from postmastectomy radiotherapy to the supraclavicular region. However, when metastatic sentinel nodes (SNs) are present, information regarding the total number of node metastases cannot be obtained if axillary lymph node dissection (ALND) is omitted from the treatment protocol. It is important to determine the indication for additional chemotherapy in ER-positive and HER2-negative breast cancer patients. We investigated the predictive factors for the occurrence of four or more metastases in patients with ER-positive and HER2-negative breast cancer in the presence of macrometastasis in the SNs. METHODS: We reviewed 83 patients with ER-positive and HER2-negative breast cancer, who had macrometastasis in the SN and had undergone ALND. The clinicopathological findings and prognosis between patients with pN1 disease and those with pN2 disease were also compared. RESULTS: Nineteen percent of patients had pN2-3 disease. The predictive factor for poor prognosis in these patients was the presence of pN2-3 disease. The independent predictive factors for pN2-3 disease were the T stage and the ratio of the number positive SNs to the number of removed SNs (SN ratio). Patients with both T2 tumors and a high SN ratio had a 50% risk of having pN2-3 disease. CONCLUSION: The presence of four or more metastases was found to be the strongest prognostic factor in ER-positive and HER2-negative breast cancer patients with macrometastasis in the SN. The T stage and SN ratio determined before surgery or during surgery were useful in predicting pN2-3 disease in these patients.

Tumor-Associated Macrophages Extend Along Lymphatic Flow in the Pre-metastatic Lymph Nodes of Human Gastric Cancer.

BACKGROUND: Tumor-associated macrophages (TAMs) correlate with lymphangiogenesis in primary lesions and with lymph node (LN) metastasis of several cancers. However, the association of TAMs in regional LNs with lymphatic spread of cancer remains unclear. The purpose of this study was to evaluate the distribution of TAMs in draining LNs and the impact of TAMs on the establishment of LN metastasis of gastric cancer. METHODS: The number and distribution of TAMs in regional LNs that were obtained from 49 patients who underwent radical surgery for gastric cancer at Osaka City University Hospital in 2011 were assessed. TAMs were defined as immunohistochemically CD163 positive cells. The association of the TAM density with lymph node metastasis and the lymphatic drainage route of the stomach were investigated. RESULTS: A high density of TAMs was significantly associated with pathologically positive lymph nodes and pathological TNM stage. The density of TAMs was increased in LNs with micro metastasis compared with those without metastasis. There was a significant, positive correlation between TAM number and lymphatic vessel density in LNs. In nonmetastatic LNs, TAMs were likely to accumulate in the neighborhood of the primary lesion. In addition, the density of TAMs in distant LNs was significantly increased in patients in whom LN metastasis was observed in perigastric LNs. CONCLUSIONS: Accumulated TAMs may induce lymphangiogenesis and prepare an environment that facilitates cancer proliferation in LNs. Our findings might provide a conceptual framework for understanding the lymphatic spreading of cancer and for designing future therapeutic strategies for gastric cancer.

Identification of tumour-reactive lymphatic endothelial cells capable of inducing progression of gastric cancer.

BACKGROUND: Tumour cells and stromal cells interact in the tumour microenvironment; moreover, stromal cells can acquire abnormalities that contribute to tumour progression. However, interactions between lymphatic endothelial cells (LECs) and tumour cells are largely unexamined. In this study, we aimed to determine whether tumour-specific LECs inhabit the tumour microenvironment and examine their influence on this microenvironment. METHODS: We isolated normal LECs (NLECs) from a non-metastatic lymph node and tumour-associated LECs (TLECs) from cancerous lymph nodes. We examined proliferative and migratory potency, growth factor production, and gene expression of each type of LEC. Moreover, we developed a co-culture system to investigate the interactions between gastric cancer cells and LECs. RESULTS: When compared with NLEC, TLECs had an abnormal shape, high proliferative and migratory abilities, and elevated expression of genes associated with inflammation, cell growth, and cell migration. NLECs co-cultured with gastric cancer cells from the OCUM12 cell line acquired TLEC-like phenotypes. Also, OCUM12 cells co-cultured with TLECs expressed high levels of genes responsible for metastasis. CONCLUSIONS: Our results demonstrated that LECs interacted with tumour cells and obtained abnormal phenotypes that could have important roles in tumour progression.

Alteration of CD4 T cell subsets in metastatic lymph nodes of human gastric cancer.

Studies of tumor-infiltrating immune cells have revealed that immune escape plays an important role in tumor growth. The aim of the present study was to investigate the impact of metastasis affecting CD4+ T cell subsets in human clinical samples. Single-cell suspensions derived from tumor-draining lymph node (TDLN) and primary cancer specimens were assessed by flow cytometry, qRT-PCR and immunohistochemistry. In the CD4+ T cell subsets detected in TDLN, effector T cells (TE) in metastatic TDLN (mTDLN) was significantly lower than that in metastatic-free TDLN (mfTDLN). TE in mfTDLN were increased compared with normal controls. Similarly, effector memory T cells (TEM) in mTDLN was significantly lower than in control and mfTDLN. There was a significantly positive correlation between the proportion of TEM in TDLN and number of tumor-infiltrating CD4+ and CD8+ T cells. Th1 to Th2 ratio was lower in mTDLN, and Treg in mTDLN was significantly higher than in mfTDLN. CD4+ T cell and TE subsets in TDLN were significantly affected by metastasis. Immunosuppressive cells exhibit increased migration to TDLN, in which a subset of CD4+ TE is skewed towards immune tolerance in the tumor microenvironment.

A positive correlation between neutrophils in regional lymph nodes and progression of gastric cancer.

UNLABELLED: BACKGROND/AIM: Recent evidence indicates that inflammation is a hallmark of cancer. Tumor-associated neutrophils (TANs) contribute to tumor invasion. However, whether TANs and lymph node metastasis are related is unknown. Intranodal lymphatic vessel density (LVD) is significantly correlated with tumor progression, lymph node metastasis in gastric cancer. Herein, we investigated the effects of TANs in regional lymph nodes. MATERIALS AND METHODS: We investigated the association of the density of TANs in regional lymph nodes with clinicopathological features by immunohistochemistry. Furthermore, we examined the prognostic value of TANs in lymph nodes. RESULTS: The number of TANs in regional lymph nodes was positively correlated with intranodal LVD and micrometastases. Patients with higher cluster of differentiation 15(+) TAN counts had significantly poorer prognosis than those with lower counts. CONCLUSION: Our results suggest that TANs in regional lymph nodes promote the invasion of lymph nodes by cancer cells via augmentation of lymphangiogenesis and thereby contribute to tumor progression.

[A case of desmoid tumor and advanced sigmoid colon cancer with liver metastasis in familial adenomatous polyposis (FAP)].

We report on a 30-year-old man with familial adenomatous polyposis (FAP ) who developed advanced sigmoid colon cancer with desmoid tumors. The patient initially presented with melena. FAP advanced sigmoid colon cancer was diagnosed following a laparoscopy-assisted proctocolectomy in 2007. A computed tomography (CT) scan, conducted 7 months later, revealed a tumor around the branch of the common iliac artery. We diagnosed sigmoid colon cancer recurrence and attempted treatment by surgical removal. However, there were many smooth tumors within the patient's abdomen, which were diagnosed as desmoid tumors using rapid intraoperative pathological diagnosis. Although the patient was administered a COX-2 inhibitor and tamoxifen after surgery, the tumor grew. Dacarbazine (DTIC) and doxorubicin (DOX) were subsequently administered to the patient, and after 4 courses, the tumor was reduced by 60% and stable disease (SD) was achieved. In 2009, a CT scan indicated sigmoid colon cancer recurrence in the liver. The patient underwent a left hepatic lobectomy by laparoscopy-assisted surgery. To date, 4 years and 6 months after surgery, we have been unable to find new disease or desmoid tumor growth.

[A case of squamous cell lung carcinoma that was difficult to distinguish from squamous cell carcinoma of the breast].

A 74 -year-old man was hospitalized for chest pain. Chest computed tomography showed a 4 × 8 cm-sized tumor pressing on the left pectoralis major muscle. Subsequent imaging showed progression of the tumor along with rib erosion and intrapleural invasion. The patient was admitted to our hospital for a follow-up examination of the tumor. Bronchoscopy results were normal. Ultrasound-guided percutaneous needle biopsy was performed. Histopathology indicated squamous cell carcinoma on the basis of the presence of keratin pearls. We therefore diagnosed the patient with squamous cell lung carcinoma fStage IIb (T3N0M0) and subsequently administered chemoradiotherapy owing to the inoperable status of the lesion. We report a case of squamous cell lung carcinoma that was difficult to differentiate from squamous cell carcinoma of the breast, along with a review of the literature.

[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.

[Eribulin chemotherapy after taxane treatment in advanced metastatic breast cancer].

Clinical outcomes, including adverse events, in 52 advanced breast cancer patients treated with eribulin chemotherapy after taxane treatment (TX) were analyzed to confirm the effectiveness and safety of this treatment.The objective response rate (ORR) in patients was 34.6% (TX group 31.6%, non-TX group 36.4%). There were no significant differences in overall survival, time to treatment failure, or progression-free between three TX and non-TX groups. Further, adverse events did not differ between groups expression of neutropenia of Grade 3 or more. On the other hand, the number of patients with sensory peripheral neuropathy of Grade 1 or more was significantly more in the TX group than in the non-TX group. Eribulin chemotherapy was effective for the treatment of advanced breast cancer regardless of a history of taxane treatment.In addition, sensory peripheral neuropathy is a possible complication that can occur in advanced breast cancer patients treated with eribulin chemotherapy with taxane treatment history.