Hypoalbuminemia for the prediction of venous thromboembolism and treatment of direct oral anticoagulants in metastatic gastric cancer patients.

BACKGROUND: Venous thromboembolism (VTE) is highly associated with advanced gastric cancer (AGC) and is sometimes lethal. Predictors of VTE have not been identified, and the efficacy and safety of direct oral anticoagulants (DOACs) for AGC-associated VTE remain to be clarified. METHODS: A total of 188 AGC patients who started chemotherapy during the period from January 2014 to December 2017 in our institutions were retrospectively examined for the incidence of VTE, risk factors for VTE, and the efficacy and safety of DOAC-based anticoagulant therapy for VTE. RESULTS: Thirty-four patients (18%) were diagnosed with VTE at the start or during the course of chemotherapy (VTE group). More VTE group patients had a history of abdominal surgery and had moderate-severe ascites (32% versus 17%, 32% versus 14%, respectively) than non-VTE group patients (NVTE group). The mean serum albumin concentrations in the VTE group were significantly lower than NVTE group (3.38 mg/dL vs 3.65 mg/dL, respectively). Multivariate analysis showed that hypoalbuminemia was significantly correlated with VTE (P = 0.012). In the VTE group, 29 patients (85%) received anticoagulant therapy, including 24 patients treated with DOACs. No lethal VTE was observed in any patients. Thirteen patients (45%) terminated DOACs because of anemia or bleeding events, of whom eleven developed major bleeding. Median overall survivals of the VTE and NVTE groups were 9.63 months and 11.5 months, respectively (P = 0.262). CONCLUSION: Hypoalbuminemia appears to be a risk factor for AGC-associated VTE. DOACs are effective to AGC-associated VTE, but careful observation of bleeding events is required.

Epithelial-mesenchymal transition is activated in CD44-positive malignant ascites tumor cells of gastrointestinal cancer.

Disseminated cancer cells in malignant ascites possess unique properties that differ from primary tumors. However, the biological features of ascites tumor cells (ATC) have not been fully investigated. By analyzing ascites fluid from 65 gastrointestinal cancer patients, the distinguishing characteristics of ATC were identified. High frequency of CD44+ cells was observed in ATC using flow cytometry (n = 48). Multiplex quantitative PCR (n = 15) showed higher gene expression of epithelial-mesenchymal transition (EMT)-related genes and transforming growth factor beta (TGF-beta)-related genes in ATC than in the primary tissues. Immunohistochemistry (n = 10) showed that ATC also had much higher expression of phosphorylated SMAD2 than that in the corresponding primary tissues. TGF-beta 1 was detected in all cases of malignant ascites by enzyme-linked immunoassay (n = 38), suggesting the possible interaction of ATC and the ascites microenvironment. In vitro experiments revealed that these ATC properties were maintained by TGF-beta 1 in cultured ATC(n = 3). Here, we showed that ATCrevealed high frequencies of CD44 and possessed distinct EMT features from primary tissues that were mainly maintained by TGF-beta 1 in the ascites.

PD-1+ TIM-3+ T cells in malignant ascites predict prognosis of gastrointestinal cancer.

The liquid biopsy of ascites fluid could be an excellent source of tumor and microenvironment for the study of prognostic biomarkers because of its accessibility. Tumor-infiltrating lymphocytes (TILs) can predict prognosis in multiple malignancies, including the response to immune checkpoint inhibitors, a breakthrough cancer therapy. However, TILs' profiles from malignant ascites have not been extensively studied. Using flow cytometric analysis, we quantified the proportion of exhausted T cells and memory/naive/effector T-cell subsets, among the CD4+ and CD8+ T-cell populations of paired TILs and peripheral blood T cell samples (n = 22). The correlation between CD4+ and CD8+ subset profiles suggested that the combined analysis of CD4+ and CD8+ cells in malignant ascites was clinically significant. We found that cells positive for the exhaustion markers programmed cell death-1 (PD-1), and T-cell immunoglobulin and mucin domain 3 (TIM-3), and cells coexpressing PD-1 and TIM-3 abundantly exist among malignant ascites TILs. Furthermore, patients with high frequency of PD-1+ TIM-3+ cells among the CD4+ and CD8+ T-cell population showed worse clinical outcome in multivariate analysis (n = 27). We propose that exhausted ascites TILs represent a clinically significant prognostic biomarker in advanced gastrointestinal cancer and represent an important target for immune checkpoint inhibitors.

A case of metastatic renal cell carcinoma and bile duct carcinoma treated with a combination of sunitinib and gemcitabine.

BACKGROUND: Metastatic renal cell carcinoma (mRCC) had been a chemo-refractory disease, but recent advances in multiple kinase inhibitors such as sunitinib have dramatically changed the clinical course of mRCC. Sunitinib is used for mRCC chemotherapy based on the favorable results of a recent clinical trial, but specific biomarkers predicting efficacy and safety are not yet available. Locally advanced bile duct carcinoma (BDC) has generally been treated with single agent gemcitabine or as doublet therapy with cisplatin. Concomitant occurrence of mRCC and BDC is extremely rare, and a standard therapeutic strategy has not been established. CASE PRESENTATION: A 65-year-old woman was diagnosed as having multiple mRCC and intercurrent, locally advanced BDC. A single course of combination therapy with sunitinib (25 mg/day, day2-15) and gemcitabine (750 mg/m(2), days 1, 8) was administered, and this showed obvious effects, with partial response for mRCC and stable disease for BDC. However, the patient also experienced severe adverse events, including hematological and various non-hematological toxicities; the combination therapy was then terminated on day 13 after its initiation. She recovered on day 28 and is alive 3.5 years after the diagnosis. The plasma trough levels of sunitinib and its active metabolite SU12662 on day 13 were 91.5 ng/mL and 19.2 ng/mL, respectively, which were relatively higher than in previous reports. Analysis of her single nucleotide polymorphisms (SNPs) detected TC in ABCB1 3435C/T, TC in 1236C/T and TT in 2677G/T, suggesting a possible TTT haplotype. CONCLUSION: A rare case of double cancer of mRCC and BDC was treated by combination chemotherapy. Although unknown synergistic mechanisms of these agents may be involved, severe toxicities might be possibly associated with high sunitinib exposure. Further exploration of combination therapy with sunitinib and gemcitabine is required.

Myocardial metastasis from ZEB1- and TWIST-positive spindle cell carcinoma of the esophagus: A case report.

BACKGROUND: Metastatic cardiac tumors are known to occur more frequently than primary cardiac tumors, however, they often remain asymptomatic and are commonly discovered on autopsy. Malignant tumors with a relatively high frequency of cardiac metastasis include mesothelioma, melanoma, lung cancer, and breast cancer, whereas reports of esophageal cancer with cardiac metastasis are rare. CASE SUMMARY: The case of a 60-year-old man who complained of dysphagia is presented. Upper gastrointestinal endoscopy showed a submucosal tumor-like elevated lesion in the esophagus causing stenosis. Contrast-enhanced computed tomography showed left atrial compression due to the esophageal tumor, multiple liver and lung metastases, and a left pleural effusion. Pathological examination of a biopsy specimen from the esophageal tumor showed spindle-shaped cells, raising suspicion of esophageal sarcoma. The disease progressed rapidly, and systemic chemotherapy was deemed necessary, however, due to his poor general condition, administration of cytotoxic agents was considered difficult. Given his high Combined Positive Score, nivolumab was administered, however, the patient soon died from the disease. The autopsy confirmed spindle cell carcinoma (SCC) of the esophagus and cardiac metastasis with similar histological features. Cancer stem cell markers, ZEB1 and TWIST, were positive in both the primary tumor and the cardiac metastasis. CONCLUSION: To the best of our knowledge, there have been no prior reports of cardiac metastasis of esophageal SCC. This case highlights our experience with a patient with esophageal SCC who progressed rapidly and died from the disease, with the autopsy examination showing cardiac metastasis.

Pancreatic acinar cell carcinoma presenting with panniculitis, successfully treated with FOLFIRINOX: A case report.

Pancreatic acinar cell carcinoma (PACC) is a rare tumor of the exocrine pancreas, representing only 1% of all pancreatic malignancies. A 50-year-old man presented with edema of the thumb joints bilaterally, followed by an appearance of masses in the bilateral lower extremities and fever (38°C). The masses were diagnosed as panniculitis by skin biopsy, and multiple intraperitoneal masses were incidentally detected on pelvic magnetic resonance imaging performed to investigate the leg abnormalities. The patient was referred to the Kyushu University Hospital for further investigation, and fluorodeoxyglucose-positron emission tomography/computed tomography (CT) revealed high-uptake tumors in the pancreatic tail, in the periphery of the liver, and in the pelvis. Laboratory examinations revealed high serum concentrations of pancreatic exocrine enzymes, such as lipase, trypsin, elastase 1 and pancreatic phospholipase A2. Histological examination of a bioptic specimen obtained from a hepatic lesion revealed proliferation of atypical cells arranged in a tubular or glandular pattern. Immunohistochemical staining revealed that the atypical cells were positive for cytokeratin (CK)7, CK19 and lipase, but negative for CK20 and thyroid transcription factor-1, leading to a final diagnosis of acinar cell carcinoma of the pancreatic tail (T4bN0M1, stage IV according to the 7th edition of the TNM Classification of Malignant Tumors). Combined chemotherapy with oxaliplatin, irinotecan and fluorouracil (FOLFIRINOX) was administered and fever was soon alleviated. The serum levels of lipase also declined and panniculitis completely resolved. As of the start of the 8th course of chemotherapy, the levels of the pancreatic exocrine enzymes were within normal ranges and CT revealed partial response. Therefore, the severe lipase hypersecretion syndrome was well controlled by the FOLFIRINOX regimen and shrinkage of the mass was also achieved. Thus, the FOLFIRINOX regimen may represent an effective treatment option for advanced PACC.

Programmed death-ligand 1 expression is associated with fibrosarcomatous transformation of dermatofibrosarcoma protuberans.

Dermatofibrosarcoma protuberans (DFSP) is a locally invading tumor, characterized by the presence of the collagen type I α 1 (COL1A1)-platelet-derived growth factor (PDGF) ß fusion gene. We herein report the case of a 31-year-old man with a history of resection of an abdominal wall DFSP. The patient presented with chest pain and a computed tomography scan revealed a large mass in the posterior mediastinum and another mass in the right lung. The mediastinal mass was a sarcomatous lesion expressing the COL1A1-PDGFß fusion gene, suggesting that it represented a metastasis of the DFSP following fibrosarcomatous (FS) transformation. Following resection of the mediastinal metastasis and subsequent radiotherapy, the mass in the right lung was also resected. Due to the emergence of pleural and pancreatic tail metastases, the patient was treated with a combination therapy of adriamycin and ifosfamide. After five courses, the disease progressed and the patient was subsequently treated with pazopanib for ~2 months until further progression. Three years after the diagnosis of the mediastinal metastasis of DFSP, the patient was referred to another hospital for palliative care. The expression of programmed cell death 1 ligand (PD-L1) in the primary and metastatic tumors was investigated: PD-L1 expression was detected in the metastasis but not in the primary tumor. Given that the metastatic tumor exhibited FS transformation (DFSP-FS), PD-L1 expression may be induced by FS transformation, contributing to the metastasis through escape from immune surveillance. Further investigation of the PD-L1 pathway in DFSP and DFSP-FS in primary as well as metastatic sites is required to evaluate the clinical efficacy of therapies targeting the PD-L1 signaling cascade.

Systemic chemotherapy with pronounced efficacy and neutropenia in a granulocyte-colony stimulating factor-producing advanced gastric neuroendocrine carcinoma.

An advanced granulocyte-colony stimulating factor (G-CSF)-producing tumor is rare, and it exhibits leukocytosis in association with high serum G-CSF levels. A 67-year-old male with a 1-month history of bloody emesis and black stools was revealed to exhibit leukocytosis, anemia and a high serum concentration of G-CSF. During a gastrointestinal endoscopy, an ulcerating tumor was identified in the stomach. Computed tomography and a fluorodeoxyglucose-positron emission tomography scan demonstrated direct invasion of the gastric tumor into the transverse colon, regional lymphadenopathy, lung nodules and diffuse high uptake of FDG in bone marrow. The histological diagnosis was a G-CSF-producing neuroendocrine carcinoma (NEC) (tumor 4b, node 2, metastasis 1, pulmonary, clinical stage IV). Systemic chemotherapy consisting of cisplatin and irinotecan was started. Common terminology criteria of adverse events grade 3 tumor lysis syndrome and gastric penetration appeared. Grade 4 neutropenia lasted for 10 days despite intensive G-CSF administration. Prominent shrinkage of the primary and the metastatic tumors was observed subsequent to 3 cycles of chemotherapy. Total gastrectomy and resection of the transverse colon were subsequently performed. Systemic chemotherapy was effective for a G-CSF-producing advanced gastric NEC with careful monitoring and appropriate supportive care for severe adverse events.

Bi-cytopenia possibly induced by anti-PD-1 antibody for primary malignant melanoma of the esophagus: A case report.

BACKGROUND: Anti-programmed cell death 1 antibody nivolumab is a promising agent for various cancers. Immune-related adverse events are recognized; however, bi-cytopenia with nivolumab has not been reported. CASE PRESENTATION: A 73-year-old man was diagnosed with advanced primary malignant melanoma of the esophagus with liver, lung, and lymph node metastases. Previous therapies including dacarbazine and radiation of 39 Gy to the esophageal region were performed, but the liver metastases deteriorated. The patient was then administered nivolumab (2 mg/kg, every 3 weeks). After 3 cycles, the esophageal tumor and lymph nodes showed marked reductions in size, the lung metastases disappeared, and the liver metastases shrank partially. The treatment continued with 7 cycles for 4 months. However, severe anemia and thrombocytopenia appeared in the 6th cycle, and intermittent blood transfusions were required. The patient received high-dose intravenous methylprednisolone therapy for bi-cytopenia, but it was ineffective. Seven months after the initiation of nivolumab, the patient died of tumor. Although the mechanisms of bi-cytopenia were unclear, it could have been induced by nivolumab. CONCLUSION: The present case shows a rare but serious life-threatening bi-cytopenia possibly associated with nivolumab and suggests the importance of awareness of hematological adverse events during nivolumab therapy.

Intraluminal superior vena cava metastasis from adenosquamous carcinoma of the duodenum: A case report.

In 2013, a 76-year-old male with a cardiac pacemaker was diagnosed with adenosquamous carcinoma of the duodenum. Subsequently, a pancreatoduodenectomy and lymph node dissection were performed, and 12 cycles of adjuvant chemotherapy (modified FOLFOX6 regimen), which consisted of fluorouracil, leucovorin and oxaliplatin, were administered via a central venous catheter. At 5 months after the completion of adjuvant chemotherapy, the patient experienced the sudden onset of severe pain at the back right of the ear, edema of the right side of the face and right jugular vein dilatation. Computed tomography (CT) revealed filling defects in the superior vena cava (SVC) and right brachiocephalic vein, indicating catheter-induced venous thrombosis. Although the catheter was removed and anti-coagulation therapy, aspiration of the thrombosis and ballooning dilatation were performed immediately, the patient's symptoms were not ameliorated. Notably, histological examination following thrombus aspiration revealed metastatic cancer cells, and fluorodeoxyglucose-positron emission tomography/CT identified metabolically active nodules in the SVC at locations consistent with the initial duodenal tumors detected by CT and in the first thoracic vertebrae. The tumor thrombus rapidly increased in size and resulted in worsening dyspnea. Subsequently, radiotherapy was performed, followed by chemotherapy, which relieved the systemic symptoms and suppressed the tumor growth. Adenosquamous carcinoma of the duodenum is extremely rare, and to the best of our knowledge, intraluminal SVC metastasis as a result of adenosquamous carcinoma of the duodenum has not been reported previously. The placement of a cardiac pacemaker, central venous catheter and tumor cells possessing high metastatic potential are hypothesized to have contributed to this rare case of metastasis.

Successful combination chemotherapy for metastatic inflammatory myofibroblastic tumor: A case report.

A 64-year-old male presented with increased abdo-minal fullness and fever. Radiological examination revealed moderate ascites, a tumor with a diameter of 12.5 cm in the mesenteric region, as well as multiple tumors in the thoracic and abdominal para-aortic regions and in the left supraclavicular regions. Pathohistological findings of the biopsy specimen revealed atypical spindle cells accompanied by infiltration of lymphocytes. The plasmacytes were positive for CD68, murine double minute 2 and S-100, while they were negative for α-smooth muscle actin, cyclin-dependent kinase 4 and anaplastic lymphoma kinase. Clinically, the patient presented systemic symptoms and laboratory results indicated an elevation in the inflammatory response, while the CT and MRI findings were consistent with an inflammatory myofibroblastic tumor (IMT). Based on the clinical and histological findings, the patient was diagnosed with IMT. In total, 4 cycles of combination chemotherapy with doxorubicin and ifosfamide were administered. Tumor size reduction by 50% was achieved subsequent to the 4th chemotherapy cycle. In conclusion, successful control of this rare metastatic IMT was achieved by systemic chemotherapy.

Favorable control of rapidly progressive retroperitoneal pleomorphic leiomyosarcoma with multimodality therapy: a case report.

BACKGROUND: Retroperitoneal sarcomas (RPS), such as pleomorphic leiomyosarcoma, often invade or displace vital organs in the abdominal cavity and exhibit an aggressive clinical course. Complete surgical resection of the tumor and preoperative radiotherapy and chemotherapies can be used for non-metastatic RPS. However, in case of huge retroperitoneal sarcoma fully occupying the abdominal cavity, surgical resection tends to be insufficient, resulting in poor outcomes. This report describes a case of rapidly progressive retroperitoneal pleomorphic leiomyosarcoma that was favorably controlled by debulking surgery followed by combination chemotherapy and radiotherapy. CASE PRESENTATION: A 65-year-old Japanese woman developed abdominal discomfort due to a huge retroperitoneal tumor fully occupying the abdominal cavity. The immunohistochemical diagnosis was pleomorphic leiomyosarcoma with high-grade malignancy and aggressive proliferative features. Debulking surgery could be performed, but the small residual tumor had rapidly grown to an approximately 22 cm in length on the major axis within 38 days after the operation. The patient's general condition progressively declined. Combination chemotherapy, consisting of doxorubicin and ifosfamide, was successfully administered for six cycles while maintaining dose intensity. The best objective response was a partial response, and the chemotherapy was well tolerated. Approximately 50 Gy of radiotherapy was delivered to the remaining tumor. This multimodal strategy resulted in progression-free survival for more than 17 months and achieved sustained symptomatic relief. CONCLUSIONS: Multimodal therapy with debulking surgery, combination chemotherapy and radiotherapy controlled a rapidly progressive retroperitoneal pleomorphic leiomyosarcoma. Maintaining dose intensity of the chemotherapy and radiotherapy might contribute to overall tumor control.