Glypican-1 Is a Novel Target for Stroma and Tumor Cell Dual-Targeting Antibody-Drug Conjugates in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a stroma-rich cancer. Extracellular matrix proteins produced by cancer-associated fibroblasts (CAFs) found in tumor stroma that impedes effective delivery of chemotherapeutic agents results in poor response in patients with PDAC. Previously, our group reported that glypican-1 (GPC1) was overexpressed in human PDAC and negatively correlated with patient survival. Immunohistochemical analysis of 25 patients with PDAC tumor specimens revealed elevated expression of GPC1 in stromal cells and pancreatic cancer cells in 80% of patients. Interestingly, GPC1 was expressed on CAFs in PDAC. We generated a GPC1 antibody-drug conjugate conjugated with monomethyl auristatin E [GPC1-ADC(MMAE)] and evaluated its preclinical antitumor activity by targeting GPC1-positive CAF and cancer cells in PDAC. GPC1-ADC(MMAE) inhibited the growth of GPC1-positive PDAC cell lines in vitro Furthermore, GPC1-ADC(MMAE) showed a potent antitumor effect in the PDAC patient-derived tumor xenograft (PDX) model against GPC1-positive CAF and heterogeneous GPC1-expressing cancer cells. Notably, GPC1-ADC(MMAE) showed robust preclinical efficacy against GPC1 in a stroma-positive/cancer-negative PDAC PDX model. GPC1-ADC(MMAE) was delivered and internalized to CAFs. Although apoptosis was not observed in CAFs, the released MMAE from CAFs via MDR-1 induced apoptosis of cancer cells neighboring CAFs and efficiently inhibited PDAC tumor growth. GPC1-ADC(MMAE) exhibited potent and unique antitumor activity in GPC1-positive PDAC PDX models, which suggests that GPC1 is a novel therapeutic target in PDAC and other stromal GPC1-positive solid tumors. These findings show that targeting GPC1 on CAF using GPC1-ADC(MMAE) is a useful approach in case of stroma-rich tumors such as PDAC.

A glypican-1-targeted antibody-drug conjugate exhibits potent tumor growth inhibition in glypican-1-positive pancreatic cancer and esophageal squamous cell carcinoma.

An antibody-drug conjugate (ADC) is a promising therapeutic modality because selective and effective delivery of an anti-cancer drug is achieved by drug-conjugated antibody-targeting cancer antigen. Glypican 1 (GPC1) is highly expressed in malignant tumors, including pancreatic ductal adenocarcinoma (PDAC) and esophageal squamous cell carcinoma (ESCC). Herein, we describe the usefulness of GPC1-targeting ADC. Humanized anti-GPC1 antibody (clone T2) was developed and conjugated with monomethyl auristatin E (MMAE) via maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-vc-PABC) linkers (humanized GPC1-ADC[MMAE]). Humanized GPC1-ADC(MMAE) inhibited the growth of GPC1-positive PDAC and ESCC cell lines via inducing cycle arrest in the G2/M phase and apoptosis in vitro. The binding activity of humanized GPC1-ADC(MMAE) with GPC1 was comparable with that of the unconjugated anti-GPC1 antibody. The humanized GPC1-ADC(MMAE) was effective in GPC1-positive BxPC-3 subcutaneously xenografted mice but not in GPC1-negative BxPC-3-GPC1-KO xenografted mice. To assess the bystander killing activity of the humanized GPC1-ADC(MMAE), a mixture of GPC1-positive BxPC-3 and GPC1-negative BxPC-3-GPC1-KO-Luc cells were subcutaneously inoculated, and a heterogenous GPC1-expressing tumor model was developed. The humanized GPC1-ADC(MMAE) inhibited the tumor growth and decreased the luciferase signal, measured with an in vivo imaging system (IVIS), which suggests that the suppression of the BxPC-3-GPC1-KO-Luc population. The humanized GPC1-ADC(MMAE) also inhibited the established liver metastases of BxPC-3 cells and significantly improved the overall survival of the mice. It exhibited a potent antitumor effect on the GPC1-positive PDAC and ESCC patient-derived xenograft (PDX) models. Our preclinical data demonstrate that GPC1 is a promising therapeutic target for ADC.

Anti-Glypican-1 Antibody-drug Conjugate as Potential Therapy Against Tumor Cells and Tumor Vasculature for Glypican-1-Positive Cholangiocarcinoma.

Cholangiocarcinoma is a highly malignant cancer. Many patients need systemic chemotherapy to prevent tumor development and recurrence; however, their prognosis is poor due to the lack of effective therapy. Therefore, a new treatment option is urgently required. We recently identified glypican-1 (GPC1) as a novel cancer antigen of esophageal squamous cell carcinoma. We also demonstrated the efficacy and safety of GPC1-targeted ADC (GPC1-ADC) conjugating anti-GPC1 mAb possessing high internalization activity with monomethyl auristatin F (MMAF), which is a potent tubulin polymerizing inhibitor. In this study, we confirmed that GPC1 was highly expressed in cholangiocarcinoma cells and tissues. IHC analysis of 49 extrahepatic cholangiocarcinoma patient tumor specimens revealed high expression of GPC1 in 47% of patients. These patients demonstrated significantly poorer prognosis compared with the low-expression group in terms of disease-free survival and overall survival (P < 0.05). GPC1 was also expressed in tumor vessels of cholangiocarcinoma, but not on the vessels of nontumor tissues. MMAF-conjugated GPC1-ADC showed potent tumor growth inhibition against GPC1-positive cholangiocarcinoma cells in vitro and in vivo In a GPC1 knockout xenograft model, GPC1-ADC partially inhibited tumor growth. Vascular endothelial cells in tumor tissues of GPC1-negative xenograft mice expressed GPC1 and were arrested in the G2-M phase of cell cycle by GPC1-ADC. GPC1-ADC exhibits direct as well as indirect antitumor effects via inhibition of tumor angiogenesis. Our preclinical data highlight GPC1-ADC as a promising therapy for GPC1-positive cholangiocarcinoma.

Incidence and risk factors of osteoporotic status in outpatients who underwent gastrectomy for gastric cancer.

BACKGROUND AND AIM: Disorders in bone metabolism have long been recognized as typical sequelae of gastrectomy; however, the pathogenesis has not been fully elucidated, resulting in a variation of reported incidence. This study aimed to evaluate current bone health by measuring bone mineral density (BMD) in patients treated by gastrectomy for gastric cancer, with a focus on incidence and risk factors of osteoporosis. METHODS: The study enrolled 81 patients who underwent gastrectomy for gastric cancer at Kochi Medical School. BMD of the lumbar spine was measured by dual-energy X-ray mineral absorptiometry, with the results expressed as a percentage of the young adult mean (YAM). Clinical data were also obtained to investigate associations with BMD. RESULTS: Of the 81 study patients, 12 (14.8%) were deemed to have osteoporosis, defined by a percentage of YAM <70, with a dominance of females over males (66.7% vs 17.4%; P < 0.001). The median body weight, hemoglobin concentration, and serum alkaline phosphatase (ALP) level of the patients with osteoporosis was significantly lower than in those with a percentage of YAM ≥70 group (39.6 kg vs 53.1 kg, P < 0.001; 10.9 mg/dL vs 12.5 mg/dL, P = 0.010; 210 U/L vs 251 U/L, P = 0.002). Further analyses revealed a significant positive correlation between body weight and percentage of YAM (r = 0.441, P < 0.001). Despite the administration of bisphosphonates in these patients during this study, one acquired a bone fracture. CONCLUSION: Osteoporosis was found in 14.8% of postoperative gastric cancer patients, with female gender, low body weight, and low ALP proposed as risk factors for osteoporosis and thus future bone fracture.

Evaluation of Systemic Inflammatory Response and Nutritional Biomarkers as Predictive Factors in Patients with Recurrent Gastric Cancer.

BACKGROUND: The present study sought to evaluate host-related factors as predictors in patients receiving chemotherapy for recurrent advanced gastric cancer. METHODS: Sixty-three patients were enrolled in the study and received chemotherapy for recurrent gastric cancer at the Kochi Medical School from 2008 to 2015. Clinicopathological information and systemic inflammatory response data were obtained retrospectively to investigate associations between baseline cancer-related prognostic variables and survival outcomes. RESULTS: The median survival time was significantly higher for patients with a Glasgow prognostic score (GPS) of 0 compared to a GPS of 1 or 2 (18.2 vs. 7.1 months; p = 0.006), and for patients in the normal range for carbohydrate antigen-125 (CA125) compared to higher levels (17.9 vs. 4.1 months; p = 0.003). There was no significant influence on overall survival by age, gender, disease status, metastatic site, time to recurrence, carcinoembryonic antigen level, CA19-9 level, prognostic nutrition index, or neutrophil to lymphocyte ratio according to the results of the univariate log-rank tests. Multivariate survival analysis identified a GPS of 1 or 2 (hazard ratio, 3.520; 95% confidence interval, 1.343-9.227; p = 0.010) and a high CA125 level (hazard ratio, 3.135; 95% confidence interval, 1.276-7.697; p = 0.013) as significant independent predictors associated with a poorer prognosis in the studied group of cancer patients. CONCLUSIONS: A GPS of 1 or 2 and a high level of CA125 are independent predictors of a poorer prognosis in patients receiving chemotherapy for recurrent gastric cancer.

Anti-glypican-1 antibody-drug conjugate is a potential therapy against pancreatic cancer.

BACKGROUND: Pancreatic cancer (PDAC) is the most lethal malignancy. New treatment options for it are urgently required. The aim was to develop an antibody-drug conjugate (ADC) targeting glypican-1 (GPC-1) as a new therapy for PDAC. METHODS: We evaluated GPC-1 expression in resected PDAC specimens and PDAC cell lines. We then measured the antitumour effect of anti-GPC-1 monoclonal antibody conjugated with the cytotoxic agent monomethyl auristatin F (MMAF) in vitro and in vivo. RESULTS: GPC-1 was overexpressed in most primary PDAC cells and tissues. The PDAC cell lines BxPC-3 and T3M-4 strongly expressed GPC-1 relative to SUIT-2 cells. Compared with control ADC, GPC-1-ADC showed a potent antitumour effect against BxPC-3 and T3M-4, but little activity against SUIT-2 cells. In the xenograft and patient-derived tumour models, GPC-1-ADC significantly and potently inhibited tumour growth in a dose-dependent manner. GPC-1-ADC-mediated G2/M-phase cell cycle arrest was detected in the tumour tissues of GPC-1-ADC-treated mice relative to those of control-ADC-treated mice. CONCLUSIONS: GPC-1-ADC showed significant tumour growth inhibition against GPC-1-positive pancreatic cell lines and patient-derived, GPC-1-positive pancreatic cancer tissues. Our preclinical data demonstrated that targeting GPC-1 with ADC is a promising therapy for patients with GPC-1-positive pancreatic cancer.

Intrahepatic bile duct adenoma in a patient with gastric cancer.

We report a case of intrahepatic bile duct adenoma (BDA) detected during laparoscopic distal gastrectomy for gastric cancer. A 70-year-old man was referred to our hospital for the treatment of gastric cancer. Esophagogastroduodenoscopy revealed an irregular, nodular, and elevated lesion on the greater curvature side of the middle third of the stomach. Abdominal contrast-enhanced computed tomography showed wall thickening with homogeneous enhancement in the middle part of the stomach, and no lesions in the liver. The patient underwent laparoscopic distal gastrectomy with regional lymphadenectomy, and during the operation a small whitish nodule was observed on the lateral segment of the liver surface. The lesion was excised by partial resection of the liver for the purpose of both histological diagnosis and treatment. Pathological examination of the liver lesion revealed no structural or cellular atypia, no stromal invasion, and immunohistochemical positivity for CK7 and CK19, but negativity for p53. The final diagnosis was well-differentiated adenocarcinoma invading the gastric serosal layer without lymph node metastasis, and intrahepatic BDA measuring 0.4 × 0.3 cm. Following surgery, the patient remained symptom-free without evidence of recurrence for 5 months. To the best of our knowledge, this is the first case of BDA with gastric cancer. Because it is difficult to distinguish BDA from other liver tumors including metastatic cancer due to its characteristically small size and lack of specific morphological features on standard imaging, surgical resection should be considered as the most suitable approach for both accurate diagnosis and treatment.

Glomus tumor of the stomach treated by laparoscopic distal gastrectomy: A case report.

Glomus tumor of the stomach is a rare submucosal mesenchymal tumor. The present study reports a patient with gastric glomus tumor treated by laparoscopic distal gastrectomy. A 39-year-old male was referred to Kochi Medical School Hospital for examination of a gastric submucosal tumor (SMT) initially diagnosed following a medical check-up. Esophagogastroduodenoscopy revealed a solitary, well-defined, submucosal lesion in the antrum of the stomach. Endoscopic ultrasonography (EUS) revealed a hypoechoic solid mass primarily connected to the gastric muscular layer. Abdominal contrast-enhanced computed tomography confirmed a 1.5 cm, well-defined mass lesion demonstrating homogeneous strong enhancement in the gastric antrum. Subsequent EUS-guided fine-needle aspiration produced a clinical diagnosis of neuroendocrine neoplasm and the patient underwent laparoscopic distal gastrectomy with regional lymph node dissection. Histopathology revealed solid proliferation of round, α-smooth muscle actin-immunopositive tumor cells with dilated vessels lined by endothelial cells without atypia, prompting a diagnosis of gastric glomus tumor. To the best of our knowledge, this is the seventh case of gastric glomus tumor treated by laparoscopy reported in English literature. The present case suggested that glomus tumor should be considered in the differential diagnosis for SMT of the stomach.

Prognostic significance of serum alkaline phosphatase and lactate dehydrogenase levels in patients with unresectable advanced gastric cancer.

BACKGROUND: This study evaluated the prognostic value of alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) together with host-related factors in patients with unresectable advanced gastric cancer. METHODS: The study enrolled 262 patients who received chemotherapy for unresectable advanced gastric cancer at Kochi Medical School from 2007 to 2015. Clinicopathological information and systemic inflammatory response data were analyzed for associations between baseline cancer-related prognostic variables and survival outcomes. RESULTS: The median survival time was significantly lower for patients with high ALP, high LDH, high total bilirubin, high aspartate aminotransferase, high alanine transaminase, high gamma-glutamyltransferase, high creatinine, a Glasgow prognostic score (GPS) of 1 or 2 score compared to GPS 0, higher compared to lower neutrophil to lymphocyte ratio (NLR) 3.9, lower compared to higher prognostic nutrition index 36.1, T3-4 compared to T1-2 tumor and diffuse-type compared to intestinal-type histology. Multivariate survival analysis identified high ALP 322 (HR 1.808; 95% CI 1.015-3.220; P = 0.044), T2-3 (HR 2.622; 95% CI 1.224-5.618; P = 0.013), and diffuse-type gastric cancer (HR 2.325; 95% CI 1.341-4.032; P = 0.003) as significant independent predictors of worse prognosis in the studied group of cancer patients. CONCLUSIONS: High level of ALP is an independent, worse prognosis factor for patients receiving chemotherapy for unresectable and recurrent gastric cancer.

Pathological Complete Response by S-1 Chemotherapy in Advanced Gastric Cancer.

A pathological complete response (pCR) to treatment for gastric cancer is a rare event, even when powerful treatment regimens are used. Herein, a case of 61-year-old male referred to our hospital with advanced gastric cancer who achieved a pCR following chemotherapy using S-1, and subsequently underwent total gastrectomy is reported. His initial esophagogastroduodenoscopy (EGD) revealed an irregular, nodular, ulcerated lesion in the upper third of the stomach that was analyzed by biopsy to be a moderately differentiated adenocarcinoma. Abdominal contrast-enhanced computed tomography (CT) showed gastric wall thickening and lymph node swelling in the perigastric area. The patient was clinically diagnosed with cT3N1M0, stage IIB advanced gastric cancer. The patient decided against curative surgery due to his work circumstances and was started on S-1 (80 mg/m2) chemotherapy administered orally twice a day for 4 weeks, followed by 2 weeks of no chemotherapy. After four such courses of systemic S-1 chemotherapy, EGD showed a small, reddened lesion with aggregated, whitish lines. The gastric wall thickening and lymphadenopathy in the perigastric area were also reduced remarkably. The patient subsequently agreed to surgery, undergoing total gastrectomy with D2 lymphadenectomy. Gross examination of the surgically resected specimen showed a slightly erythrogenic, flat lesion measuring 1.5×1.0 cm. Pathological examination of the resected specimen and harvested lymph nodes detected no malignant cells. The postoperative course was uneventful. The patient has continued to receive S-1 chemotherapy, with no evidence of recurrence at 4 months post-surgery. To the best of our knowledge, this is only the second case of a gastric cancer patient achieving a pCR by S-1 monotherapy reported in the English literature and indicates the potential adoption of curative resection after S-1 chemotherapy as a treatment strategy for advanced gastric cancer.

Successful treatment of liver metastases arising from early gastric cancer achieved clinical complete response by nivolumab.

BACKGROUND: Although a recent randomized clinical trial has demonstrated that the objective response rate to nivolumab for metastatic gastric cancer was 11.2%, there was no patients confirmed complete response. Herein, we report on a case of liver metastasis arising from early gastric cancer in which a complete clinical response was achieved to nivolumab as third-line therapy. CASE PRESENTATION: A 77-year-old man was referred to Kochi Medical School Hospital for the treatment of liver metastases from gastric cancer. The patient had undergone laparoscopic total gastrectomy with regional lymph node dissection 30 months prior for early gastric cancer, with a final diagnosis of T1N0M0, stage IA. The patient developed solitary splenic metastasis measuring 42 mm 28 months later and underwent splenectomy because there was no evidence of further metastatic lesions in any other organ. The patient was treated with S-1 plus oxaliplatin based on negative immunohistochemical staining of the resected specimens for human epidermal growth factor receptor 2 (HER2). Four months after the splenectomy, the patient developed multiple liver metastases and was treated with ramucirumab plus paclitaxel. Because of disease progression, the patient was administered 3 mg/kg, i.v., nivolumab every 2 weeks. After 4 cycles of systemic treatment using nivolumab, abdominal computed tomography revealed marked shrinkage of the liver metastases. After 12 cycles of nivolumab, the liver metastases had disappeared completely. The patient did not develop any adverse reactions, including immune-reactive adverse events, during treatment. The patient continues to receive nivolumab, and there is no evidence of disease recurrence in the 8-month period since starting nivolumab. CONCLUSIONS: To the best of our knowledge, this is the first case report in the English literature of a gastric cancer patient achieving a complete clinical response to nivolumab, and highlights the potential for successful treatment of metastatic gastric cancer using nivolumab.

Clinical application of photodynamic medicine technology using light-emitting fluorescence imaging based on a specialized luminous source.

The natural amino acid 5-aminolevulinic acid (ALA) is a protoporphyrin IX (PpIX) precursor and a new-generation photosensitive substance that accumulates specifically in cancer cells. When indocyanine green (ICG) is irradiated with near-infrared (NIR) light, it shifts to a higher energy state and emits infrared light with a longer wavelength than the irradiated NIR light. Photodynamic diagnosis (PDD) using ALA and ICG-based NIR fluorescence imaging has emerged as a new diagnostic technique. Specifically, in laparoscopic examinations for serosa-invading advanced gastric cancer, peritoneal metastases could be detected by ALA-PDD, but not by conventional visible-light imaging. The HyperEye Medical System (HEMS) can visualize ICG fluorescence as color images simultaneously projected with visible light in real time. This ICG fluorescence method is widely applicable, including for intraoperative identification of sentinel lymph nodes, visualization of blood vessels in organ resection, and blood flow evaluation during surgery. Fluorescence navigation by ALA-PDD and NIR using ICG imaging provides good visualization and detection of the target lesions that is not possible with the naked eye. We propose that this technique should be used in fundamental research on the relationship among cellular dynamics, metabolic enzymes, and tumor tissues, and to evaluate clinical efficacy and safety in multicenter cooperative clinical trials.

Superficial Spreading-type Gastric Cancer with Situs Inversus Totalis.

Situs inversus totalis (SIT) is a congenital anomaly characterized by a complete mirror-image transposition of the thoracic and abdominal viscera. We report on a rare case of superficial spreading gastric cancer associated with SIT in a 66-year-old woman referred to our hospital for examination of gastric cancer initially diagnosed by medical check-up. Esophagogastroduodenoscopy showed a slightly depressed lesion in the lesser curvature side of the stomach. Abdominal contrast-enhanced computed tomography showed complete transposition of the abdominal viscera, confirming SIT. The patient underwent total gastrectomy with regional lymph node dissection and Roux-en-Y reconstruction. Gross examination of the surgically resected specimen showed a slightly depressed lesion measuring 12×8 cm in diameter, and histopathology confirmed the diagnosis of signet-ring cell carcinoma, confined to the gastric mucosal layer without lymph node metastasis. The postoperative course was favorable, and the patient has been well without evidence of recurrence for 11 years following the operation. To the best of our knowledge, this is only the second case of a superficial spreading-type gastric cancer in a patient with SIT reported in the English literature.

Conversion surgery after S-1 plus oxaliplatin combination chemotherapy for advanced gastric cancer with multiple liver metastases.

Conversion therapy for gastric cancer is a new therapeutic concept. We report a case of a patient with advanced gastric cancer who underwent conversion surgery due to a remarkable regression of multiple liver metastases following chemotherapy. A 71-year-old man was referred to our hospital with gastric cancer. Esophagogastroduodenoscopy (EGD) revealed an irregular, nodular, ulcerated lesion in the lower third of the stomach. Analysis of biopsy specimens revealed a poorly differentiated adenocarcinoma. Abdominal contrast-enhanced computed tomography (CT) showed multiple liver mass lesions. The patient was clinically diagnosed with advanced gastric cancer with liver metastases and received S-1 plus oxaliplatin chemotherapy. After 6 cycles of chemotherapy, CT and magnetic resonance imaging showed complete resolution of the liver metastases, and EGD detected mucosal irregularities only. Since there was no evidence of further metastatic lesions in other organs, the patient underwent distal gastrectomy with D2 lymphadenectomy. The gross appearance of the surgically resected specimen showed a slightly elevated tumor measuring 4.5 × 3.5 cm. Pathological examination confirmed the diagnosis of a moderately differentiated gastric adenocarcinoma invading the muscularis propria with no lymph node metastases. The postoperative course was uneventful. The patient has continued to receive S-1 and oxaliplatin chemotherapy, and there has been no evidence of recurrence for 3 months following the operation. We propose that conversion therapy might be an effective treatment for patients with advanced gastric cancer; however, further studies and assessments are needed to confirm and establish this treatment strategy.

[A Case of Long-Term Survival in a Patient with Lung Metastasis of Gastric Cancer Treated Using Curative Surgery].

A 50-year-old man was referred to our hospital with gastric cancer. Esophagogastroduodenoscopy(EGD)revealed an irregular nodular lesion with an ulcer in the esophagogastric junction, the biopsy specimens of which showed moderately differentiated adenocarcinoma. Abdominal computed tomography(CT)showed a lymph node measuring 1.2 cm in the perigastric area. A clinical diagnosis of advanced gastric cancer was made, and the patient underwent total gastrectomy with D2 lymphadenectomy followed by Roux-en-Y reconstruction. Microscopic examination confirmed that the moderately differentiated adenocarcinoma invaded the muscularis propria with 1 lymph node metastasis and lymphovascular invasion. The final diagnosis according to the Japanese classification of gastric carcinoma was UE, Less, Type 2, 3.8×1.7 cm, T2(MP), M0, H0, P0, N1(1/15), tub2, ly1, v2, StageⅡ. The postoperative course was uneventful, and he received postoperative adjuvant chemotherapy with S-1. The patient underwent periodic follow-up physical examinations, and 1 year after the surgery, CT showed a well-defined mass measuring 1.0 cm in diameter located in the middle lobe of the right lung. Because there was no evidence of further metastatic lesions in any other organs, he underwent surgical resection of the solitary pulmonary lesion by video-assisted thoracic surgery. Pathological examination confirmed the presence of moderately differentiated adenocarcinoma, and the proliferating tumor cells were positive for cytokeratin(CK)7 and CK20, and negative for thyroid transcription factor 1, which confirmed metastasis from gastric cancer. After the surgery, the patient received combination chemotherapy with S-1 plus cisplatin, followed by S-1 monotherapy. Five years after pulmonary metastasectomy, we discontinued chemotherapy because of no evidence of recurrence and the patient's wishes. The patient has remained in good health without evidence of recurrence for 7 years following the second surgery. Resection of the metastatic lesion might be a promising treatment for solitary pulmonary metastasis of gastric cancer; however, further investigations involving the accumulation of a large number of cases and prospective cohort studies are required to verify the above issue, and future development of multidisciplinary therapy is expected.

[Long-term survival of a breast cancer patient with carcinomatous pleuritis and carcinomatous cardiac tamponade successfully treated by multimodality therapy].

A 69-year old woman was admitted to our hospital because of dyspnea and pain in her left breast. Computed tomography revealed a massive quantity of left pleural effusion, a tumor in the left breast(5 cm in diameter), left cervical and supraclavicular lymph node metastasis, and a large left axillary metastatic mass. Based on a core needle biopsy, her breast tumor was diagnosed pathologically as scirrhous carcinoma, which was positive for estrogen receptor/progesterone receptor and negative for HER2 using the FISH assay, and left pleural metastasis was diagnosed cytologically. The carcinomatous pleural effusion was successfully controlled using pleural instillations of pirarubicin HCl and OK-432 after pleural drainage. A near clinical complete response was achieved by EC systemic chemotherapy(6 months)followed by endocrine therapy(letrozole), but 3 months later she was diagnosed cytologically with carcinomatous cardiac tamponade. After operative pericardial drainage, intrapericardial instillations of cisplatin and OK-432 successfully prevented re-accumulation of pericardial effusion. Systemic chemotherapy(weekly paclitaxel)for 11 months and endocrine therapy(letrozole)resulted in a clinical complete response. One year and 10 months after pericardial drainage, she underwent surgery(mastectomy and axillary lymph node dissection level II)because of two small tumors in the left breast which were found to be malignant using PET-CT. One tumor(diameter 1.6 cm)was found pathologically to consist of degenerated cancer cells, and another tumor(diameter 2 cm)was diagnosed as recurrent cancer. There was no lymph node metastasis in the axilla except for a single mass(1.4×0.7×0.3 cm), which was composed of extremely degenerative and necrotic non-lymphoid cancerous tissue. Since having the surgery, she has not experienced recurrence on hormone therapy with fulvestrant, and to date she is still alive, 3 years and 5 months since the left pleural metastasis episode.

The effect of the neutrophil elastase inhibitor sivelestat on early injury after liver resection.

BACKGROUND: The effects of sivelestat on endotoxin-induced lung injury, postperfusion lung injury, and ischemia-reperfusion are known, yet the benefits of sivelestat during liver surgery have yet to be elucidated. The aim of the present study was to assess the effects of sivelestat, with a focus on postoperative chemical data, in hepatectomized patients. PATIENTS AND METHODS: A prospective clinical study was conducted in 50 patients undergoing hepatic resection. Patients were randomly assigned to receive Elaspol, sivelestat (ELP group, n = 25) or placebo (control group, n = 25). Perioperative blood chemistry values in both groups, including high-mobility group box 1 (HMGB1) and interleukin (IL)-6, were monitored. RESULTS: The HMGB1 levels increased immediately after the operation (from the intraoperative period to the second postoperative day [POD]) in the control group. Compared to the control group, the levels of HMGB1 in the ELP group were significantly suppressed by the perioperative administration of sivelestat. At POD 1, the levels of IL-6 in the ELP group decreased more rapidly than those before the operation compared to the control group. CONCLUSIONS: A human clinical study demonstrated the effect of polymorphonuclear leukocyte elastase inhibitor on the earliest markers of liver injury. The present study showed that patients who received sivelestat had reduced release of HMGB1, and that IL-6 levels decreased more rapidly in patients treated with sivelestat than in those who received the placebo. The most appropriate dose, timing, and duration of sivelestat in humans remain unclear; however, it may have therapeutic potential for various liver injuries.

[A case of liver metastasis of pancreatic acinar cell carcinoma treated with S-1 and intra-arterial CDDP combination therapy].

A 55-year-old man underwent a pylorus-preserving pancreatoduodenectomy in August 2006 because of acinar cell carcinoma of the head of the pancreas. Since abdominal CT revealed multiple liver metastases, we started systemic chemotherapy with gemcitabine (1,400 mg/body, day 1, 8, 15/q4w) in October 2006. At the beginning of this treatment, it seemed to be a stable disease, but CT revealed tumor progression in January 2007. Despite the change to oral chemotherapy with S-1 (100 mg/body, day 1-14/q3w), tumors were markedly enlarged in March 2007. Therefore, we selected combination chemotherapy with oral S-1 and hepatic arterial infusion of CDDP (50 mg/body) as third-line. After 6 months of treatment, abdominal CT revealed marked shrinkage of tumors, accompanied by a decrease in AFP level. Though the patient died of hepatic failure in July 2009 (33 months after recurrence), he spent most of his time at home and worked as usual. We suggest that combination chemotherapy with oral S-1 and intra-arterial CDDP can be effective treatments for pancreatic acinar cell carcinoma.

Clinicopathologic features of adenocarcinoma at the gastric cardia: is it different from distal cancer of the stomach?

BACKGROUND: Although the incidence of gastric cardia cancer is considerably less than more distal gastric cancer, the rate of occurrence is now increasing. The objective of this study was to evaluate and compare the clinicopathologic findings of gastric cardia and more distal stomach adenocarcinoma. STUDY DESIGN: Patients included in our study were those who underwent operations for gastric adenocarcinoma in our institute from 1981 to 2006, and who had undergone complete medical history, including history of daily alcohol consumption; smoking; body mass index; and pathologic examinations. A total of 843 patients were included in our study, and were divided into cardia and noncardia cancer groups. RESULTS: Among the 843 patients, 23 (2.8%) had gastric cardia cancer. There were no substantial differences in age, gender, body mass index, smoking, or alcohol consumption between the two groups. Mean size of cardia tumors was larger than noncardia tumors. Although noncardia cancer was often detected at an early stage, gastric cardia cancer was most often diagnosed at an advanced stage. Pathologically, cardia cancer was more invasive and had more lymphatic permeation and lymph node metastasis than noncardia cancer. CONCLUSIONS: Gastric cardia cancer occurs at a low incidence of only 2.8% of resected gastric cancers. Unlike cases of gastric cardia cancer in Western populations, body mass index is not associated with occurrence of gastric cardia cancer in our study. Because gastric cardia cancer appears more aggressive than noncardia gastric cancer, early diagnosis and intervention are important.