Pseudocirrhosis after chemotherapy for gastric cancer with diffuse liver metastases: A case report.

Pseudocirrhosis is a rare but important complication of metastatic cancer. We herein present the case of a patient with pseudocirrhosis occurring after a complete response to chemotherapy for metastatic gastric cancer was achieved. A 72-year-old man was diagnosed with gastric adenocarcinoma with multiple liver metastases. The patient's general condition was good, with an Eastern Cooperative Oncology Group performance status of 1. Chemotherapy with oxaliplatin and S-1 was initiated and, after four cycles, the patient noticed sudden abdominal distension. Despite the marked regression of the liver metastases, massive ascites, segmental atrophy and esophageal varices developed, findings consistent with pseudocirrhosis. The patient achieved complete response for the primary and metastatic lesions. Following endoscopic ligation of the varices, he underwent subsequent chemotherapy with S-1 only and management of his ascites for 6 months. At 12 months after initial chemotherapy, the patient appeared to be disease-free. In conclusion, clinicians should be aware of the possibility of pseudocirrhosis in cases of cancer metastasis to the liver, including metastatic gastric cancer.

Downregulation of ARID1A in gastric cancer cells: a putative protective molecular mechanism against the Harakiri-mediated apoptosis pathway.

This study was designed to unravel the pathobiological role of impaired ARID1A expression in gastric carcinogenesis. We examined ARID1A expression immunohistochemically in 98 gastric cancer tissue specimens with regard to the clinicopathological features. Based on the proportion and intensity of ARID1A immunoreactivity at the cancer invasion front, we subdivided the specimens into low- and high-expression ARID1A groups. Notably, low ARID1A expression was significantly correlated with overall survival of the patients. Subsequently, we determined the molecular signature that distinguished ARID1A low/poor prognosis from ARID1A high/good prognosis gastric cancers. A comprehensive gene profiling analysis followed by immunoblotting revealed that a mitochondrial apoptosis mediator, Harakiri, was less expressed in ARID1A low/poor prognosis than ARID1A high/good prognosis gastric cancers. siRNA-mediated ARID1A downregulation significantly reduced expression of the Harakiri molecule in cultured gastric cancer cells. Interestingly, downregulation of ARID1A conferred resistance to apoptosis induced by the mitochondrial metabolism inhibitor, devimistat. In contrast, enforced Harakiri expression restored sensitivity to devimistat-induced apoptosis in ARID1A downregulated gastric cancer cells. The present findings indicate that impaired ARID1A expression might lead to gastric carcinogenesis, putatively through gaining resistance to the Harakiri-mediated apoptosis pathway.

Efficacy and Safety of Enoxaparin for Prophylaxis of Postoperative Venous Thromboembolism After Esophagectomy: A Single-center Prospective Randomized Controlled Phase II Study.

BACKGROUND/AIM: This study aimed to assess whether low-molecular-weight heparin (LMWH) is effective and safe in preventing postoperative venous thromboembolism (VTE) in patients undergoing esophageal cancer surgery. PATIENTS AND METHODS: In this single-institution, prospective, randomized trial, 73 patients with esophageal cancer undergoing esophagectomy were randomly divided into the enoxaparin group (E group) and intermittent pneumatic compression group (I group). The primary endpoint was efficacy of enoxaparin, and secondary endpoints were evidence of bleeding and serum anti-Xa activity in the E group. RESULTS: The E group comprised 42 patients and the I group comprised 31 patients. Deep vein thrombosis was observed in 0 (0%) patients in the E group and 7 (22.6%) patients in the I group (p=0.002). Soluble fibrin monomer complex was significantly lower in the E versus I group on day 8 (p<0.001). D-dimer was significantly lower in the E versus I group on days 2, 8, and 15 (p=0.008, p<0.001, p<0.001, respectively). CONCLUSION: VTE was significantly reduced by using enoxaparin.

[Therapeutic Effect and Adverse Events of Ramucirumab in Patients with Gastric Cancer in Our Hospital].

From January 2016 through December 2017, 18 patients received paclitaxel plus ramucirumab combination therapy and 1 patient received ramucirumab monotherapy. Thus, a total of 19 patients were analyzed in terms of both therapeutic effect and adverse events. The response evaluation of the targeted lesion was as follows; CR: 0, PR: 1, SD: 16, PD: 2. The median of overall survival and progression-free survival of the combination therapy was 9.9 months and 4.2 months, respectively. Although more than half of the patients were enforced after tertiary therapy in our department, the therapeutic effect of paclitaxel plus ramucirumab combination therapy was considerably satisfactory. Neutropenia as an adverse event was observed in 13(68.4%)out of 19 patients, and 8 patients(42.1%)had neutropenia greater than Grade 3. Non -hematologic toxicity was observed in 17 cases(89.5%), and anorexia, nausea, diarrhea, dysgeusia, peripheral neuropathy, hair loss, and fatigue were determined to be either Grade 1 or 2. Alternatively, 1 patient developed Grade 3 interstitial pneumonia, and 3 patients(15.8%)had complicated Grade 3 high blood pressure. Only 2 patients who had severe adverse events, one was interstitial pneumonia and the other was high blood pressure, discontinued paclitaxel plus ramucirumab combination therapy.

[A Case of Stage IV Gastric Cancer Curative Resection by Conversion Therapy].

We experienced a case of curative resection as a multidisciplinary treatment for unresectable gastric cancer that attributed to peritoneal disseminations and direct invasion to other organs.Two courses of triplet chemotherapy(DCS therapy)were performed under enteral stent placement and nasoenteral nutrition for direct infiltration into the transverse colon with entire circumference stenosis.Distal gastrectomy and right hemicolectomy were performed as conversion therapy, and R0 resection was achieved.After the operation, S-1 as adjuvant chemotherapy was performed and there has been no relapse survival for 13 months since the operation.From this case, it seems that conversion therapy plays an important role in prognosis extension as a treatment strategy for Stage IV gastric cancer.

Effective Timing of Surgical Resection of Colorectal Cancer Liver Metastases During Chemotherapy.

BACKGROUND/AIM: The aim of the present study was to further develop our previous study on c-Met expression in colorectal cancer and epithelial-mesenchymal transition (EMT) induced by hepatocyte growth factor (HGF), to investigate EMT in the process of liver metastases, and evaluate the effects of chemotherapy on EMT cells as a therapeutic strategy for colorectal liver metastasis. MATERIALS AND METHODS: CT26 colon cancer cells were treated with 5-FU and oxaliplatin with or without HGF. The signaling pathway was evaluated by western blotting analysis, and drug resistance was evaluated by the MTT (3-(4,5-dimethyl-2-tetrazolyl)-2,5-diphenyl-2H tetrazolium bromide) assay. RESULTS: Under pretreatment with HGF for 96 h, 5 µM and 10 µM of 5-FU mediated significant growth inhibition by 72.5±3.9% and 76.2±2.4%, respectively, compared to HGF alone, and by 105.1±2.8% and 103.5±2.9%, respectively, without HGF. The expression of E2F1 was decreased significantly to 50.5±3.8% after 24 hours by HGF with a reduction of both cyclin D1 to 52.1±7.0% and E to 73.7±3.8%. Thymidylate synthase was also decreased in a time-dependent manner to 80.6±2.0% after 24 h and to 52.7±1.5% after 96 h. CONCLUSION: The presence of HGF was found to increase the 5-FU-induced death signal, JNK pathway, and inhibition of cell growth. As its mechanism, HGF was shown to decrease E2F-1 by reducing cyclin D or E by cell-cycle activation, resulting in inactivation of thymidylate synthase. The chemotherapeutic effect of 5-FU was increased in HGF- but not TGF-ß-induced EMT.

Downregulation of ARID1A, a component of the SWI/SNF chromatin remodeling complex, in breast cancer.

Recent studies unraveled that AT-rich interactive domain-containing protein 1A (ARID1A), a subunit of the mammary SWI/SNF chromatin remodeling complex, acts as a tumor suppressor in various cancers. In this study, we first evaluated ARID1A expression by immunohistochemistry in invasive breast cancer tissue specimens and assessed the correlation with the prognosis of patients with breast cancer. Non-tumorous mammary duct epithelial cells exhibited strong nuclear ARID1A staining, whereas different degrees of loss in ARID1A immunoreactivity were observed in many invasive breast cancer cells. We scored ARID1A immunoreactivity based on the sum of the percentage score in invasive cancer cells (on a scale of 0 to 5) and the intensity score (on a scale of 0 to 3), for a possible total score of 0 to 8. Interestingly, partial loss of ARID1A expression, score 2 to 3, was significantly correlated with poor disease free survival of the patients. Subsequently, we performed siRNA-mediated ARID1A knockdown in cultured breast cancer cells followed by comprehensive gene profiling and quantitative RT-PCR. Interestingly, many genes were downregulated by partial loss of ARID1A, whereas RAB11FIP1 gene expression was significantly upregulated by partial loss of ARID1A expression in breast cancer cells. In contrast, a more than 50% reduction in ARID1A mRNA decreased RAB11FIP1gene expression. Immunoblotting also demonstrated that partial downregulation of ARID1A mRNA at approximately 20% reduction significantly increased the expression of RAB11FIP1 protein in MCF-7 cells, whereas, over 50% reduction of ARID1A mRNA resulted in reduction of RAB11FIP1 protein in cultured breast cancer cells. Recent studies reveal that RAB11FIP1 overexpression leads to breast cancer progression. Altogether, the present findings indicated that partial loss of ARID1A expression is linked to unfavorable outcome for patients with breast cancer, possibly due to increased RAB11FIP1 expression.

[A Case Report of Neuroendocrine Carcinoma of the Esophagus Treated with Multidisciplinary Therapy].

A 72-year-old man was referred to our department because of esophageal tumor. Immunohistochemical findings were CD56-positive, synaptophysin-positive, chromogranin A-positive, Ki-67(labeling index)≥90%. The diagnosis was esophageal neuroendocrine carcinoma, categorized as cT4b(106recR-main bronchus), cN1(106recR), cM0, cStage III C. We had initiated irinotecan plus cisplatin(IP)as neoadjuvant chemotherapy(NAC). Biopsy specimens of primary lesion after 1 course chemotherapy showed a change to squamous cell carcinoma(SCC). The target lesion exhibited partial response(PR)after 2 courses of chemotherapy, and the primary lesion was reduced, but was still present. We performed subtotal esophagectomy and subtotal stomach reconstruction with lymphadenectomy(R0, Cur A). The histopathological findings showed the primary lesion was SCC, metastatic lymph nodes(106recR)was NEC. The final diagnosis was SCC plus NEC, categorized as CT-pT1a (MM), pN1(106recR), M0, fStage II B. After that, we selected treatment regimen considering tissue type, and performed surgery and chemotherapy for 2 times of recurrences. At a follow-up examination 1 year and 2 months after the start of first chemotherapy, the patient is alive without recurrence. Esophageal neuroendocrine carcinoma is relatively rare and the prognosis is poor, but there is as yet no standard therapy. We experienced a case of neuroendocrine carcinoma of the esophagus treated with multidisciplinary therapy.

Expression of TMEM207 in Colorectal Cancer: Relation between TMEM207 and Intelectin-1.

Recent research advances highlighted an intestinal goblet cell-produced lectin, intelectin-1 (also known as omentin-1), as a tumor suppressor. One study indicated that downregulation of intelectin-1 may be related to the unfavorable prognosis among patients with colorectal carcinoma at an advanced stage. The present study was aimed at analyzing the expression of a hitherto uncharacterized transmembrane protein TMEM207 in colorectal carcinoma, and we found that the TMEM207 function is linked to intelectin-1 processing. With specific antibodies, TMEM207 immunoreactivity was detected in 38 of 216 colorectal cancer tissue samples. TMEM207 immunoreactivity correlated inversely with lymph node metastatic status (p < 0.01). TMEM207 expression significantly correlated with the mucinous phenotype of colorectal carcinoma. A coimmunoprecipitation assay revealed an interaction between intelectin-1 and TMEM207 in colorectal cancer cells. A proximal ligation assay indicated that intelectin-1 and TMEM207 were colocalized to the cytoplasm of the colorectal cancer cells. A small-interfering-RNA-mediated knockdown of TMEM207 increased polyubiquitination and proteasome degradation of intelectin-1 in cultured colorectal cancer cells and decreased intelectin-1 secretion. These findings indicate that a loss of TMEM207 expression leads to insufficient intelectin-1 production thus promoting colorectal carcinogenesis.

Expression of beclin-1 in the microenvironment of invasive ductal carcinoma of the breast: correlation with prognosis and the cancer-stromal interaction.

We examined the pathobiological properties of beclin-1, which is a key regulator of autophagosome formation in invasive ductal carcinoma of the breast, with a particular focus on the cancer microenvironment. Immunohistochemistry demonstrated that cancer cells and stromal mesenchymal cells expressed beclin-1 in 68 and 38 of 115 invasive ductal cancers, respectively. Expression of beclin-1 in cancer or stromal cells alone did not correlate with patient prognosis. In contrast, loss of beclin-1 in cancer cells and overexpression in stromal mesenchymal cells was associated with local cancer recurrence, postoperative lymph node metastasis, and a poor disease-free survival rate. A comprehensive gene expression analysis was performed on a co-culture of breast cancer cells and mesenchymal stromal cells, that latter of which either expressed beclin-1 or was depleted of beclin-1 by siRNA. Notably, siRNA-mediated downregulation of beclin-1 in mesenchymal cells co-cultured with breast cancer cells decreased the levels of various pro-inflammatory cytokines, their receptors, and collagen receptors. Quantitative reverse transcription polymerase chain reaction analysis confirmed that reduction of stromal beclin-1 expression decreased the expression of IL-1ß and collagen receptor discoidin domain receptor 2 (DDR2). Microenvironmental IL-1ß is believed to play an important role in tumor invasion. Recent work has also indicated that overexpression of DDR2 contributes to breast cancer invasion and lymph node metastasis. Taken together, these findings indicate beclin-1 expression in the stroma might be important for shaping the breast cancer microenvironment and thus could be a potent molecular target in patients with invasive ductal carcinoma of the breast.

[A case of advanced colon cancer with metastases to both supraclavicular and para-aortic lymph nodes effectively treated by radiation and S-1 therapy].

We report the case of a 60-year-old woman with multiple lymph node metastases after ascending colon cancer who received radiation therapy and then chemotherapy with S-1. She was diagnosed with lymph node metastasis of the para aorta and left upper clavicle 10 months after surgery. We performed radiation therapy for the left upper clavicle (64 Gy)and para aorta (40 Gy). Consequently, we administered S-1(100mg/day)orally. After three months, the upper clavicle lymph nodes had disappeared and the para-aortic lymph nodes reduced. All metastatic lesions disappeared after 10 months. She survived for 32 months after the radiation therapy.

[Three cases of gastric cancer with para-aortic lymph node metastases succesfully treated by S-1/CDDP combination therapy followed by curative resection].

Due to advanced gastric cancer with abdominal para-aortic lymph node metastases, we performed a curative operation in three cases in which S-1/CDDP combination therapy proved effective. In case 1, after only one course of this chemotherapy, the reduction of the primary lesion was slight, but para-aortic metastatic lymph nodes were remarkably reduced. We performed a curative operation with complete D3 lymph node dissection. In case 2, after two courses the reduction of the primary lesion was remarkable, and para-aortic metastatic lymph nodes almost disappeared. Therefore, we performed a curative operation with D2 lymph node dissection. In case 3, after two courses the reduction of the primary lesion was cicatrized. Although para-aortic metastatic lymph nodes were gradually reduced, one of them increased after the third period of treatment. Therefore, we performed a curative operation with complete D2 lymph node dissection and 16b1 lateral lymph node dissection. All underwent postoperative adjuvant chemotherapy, and have been surviving for 58 months, 42 months, and 18 months, respectively. In advanced gastric cancer with para-aortic lymph node metastases without other non-curative factors, long-term survival can be expected by combining a curative operation with S-1/CDDP combined therapy.