Kyoko Inadomi

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.

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) β 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-PDGFβ 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.

Efficacy analysis of the aprepitant-combined antiemetic prophylaxis for non-round cell soft-tissue sarcoma patients received adriamycin and ifosfamide therapy.

Abstract Appropriate antiemetic prophylaxis for moderately emetogenic chemotherapy in patients with non-round cell soft-tissue sarcomas (NRC-STS) remains unclear. We retrospectively investigated efficacy and safety of aprepitant-combined antiemetic prophylaxis in patients with NRC-STS receiving adriamycin plus ifosfamide (AI) therapy. Forty NRC-STS patients were enrolled, their median age was 50 years (range 18–74), and 13 (32.5%) were female. Median cycle number of AI therapy was 4. Twenty patients received the doublet antiemetic prophylaxis (5-hydroxytryptamine-3 receptor antagonist and dexamethasone), and 20 received triplet (5-hydroxytryptamine-3 receptor antagonist, dexamethasone, and aprepitant). In the overall period, complete response rate for nausea and emesis in the triplet group was significantly higher than that in the doublet group (70% vs 35%; P = 0.027). Patients with no-emesis in the overall period were more frequently observed in the triplet group than in the doublet group (90% vs 65%; P = 0.058). All toxicities other than emesis were almost equivalent in both the groups. These results suggest that a triplet antiemetic prophylaxis may be optimal in the treatment with AI therapy for NRC-STS.

A phase 2 study of fosaprepitant combined with high-dose dexamethasone for Japanese cancer patients receiving highly emetogenic chemotherapy

Purpose: Combination therapy of fosaprepitant, dexamethasone (DEX) and a serotonin (5-HT3) receptor antagonist is a standard antiemetic prophylaxis for patients receiving highly emetogenic chemotherapy (HEC). However, the appropriate dose of DEX has not been established in Japan. This study determined the efficacy and safety of triplet antiemetic prophylaxis in Japanese patients receiving HEC when administered the same doses of DEX as those given in a previous international phase 3 study on this drug. Methods: To assess the efficacy and safety of a sufficient dose of DEX (12 mg on day 1, 8 mg on day 2, 16 mg on days 3 and 4) in combination with intravenous fosaprepitant and granisetron, we prospectively examined patients receiving HEC including cisplatin (≥50 mg/m2). The primary endpoint was to determine the percentage of patients who had achieved a complete response (CR), which was defined as no vomiting and no rescue therapy during the entire treatment course. Results: Between February 2013 and January 2015, 44 patients were enrolled with a median age of 65 years (range, 30–75). There were 34 males (77.3%) in the study. Most of the patients had upper gastrointestinal cancers. The CR rate during the treatment course was 70% (95% confidence interval [CI]: 55%–83%) in the overall phase and 91% (95% CI: 78%–97%) in the acute phase and 70% (95% CI: 55%–83%) in the delayed phase. Appreciable severe toxicities related to the antiemetic therapy were not observed. Conclusions: These results suggest that a sufficient dose of DEX in combination with fosaprepitant and granisetron is optimal as an antiemetic prophylaxis for Japanese patients receiving HEC.

Successful treatment of Ph ALL with hematopoietic stem cell transplantation from the same HLA-haploidentical related donor of previous liver transplantation

Successful sequential hematopoietic stem cell transplantation (HSCT) following liver transplantation (LT) has been reported in some cases, most often in children, in whom severe aplastic anemia (SAA) after fulminant hepatitis is the main reason for HSCT requirement [1–5]. We describe a case of ALL after LT that was successfully treated with allogeneic HSCT from the same haploidentical sibling donor. A 50-year-old man with fatigue and fever was referred to our hospital. Tacrolimus (Tac) was administered to induce tolerance to liver allograft, which had been performed for primary biliary liver cirrhosis 14 years ago. On admission, physical examination revealed anemic and icteric conjunctiva. Ultrasonography revealed splenomegaly with an enlarged splenic vein. Complete blood count revealed anemia (hemoglobin, 8.0 g/dL), thrombocytopenia (platelets, 52 10/L), and leukocytosis with 70.5% blasts that were negative for myeloperoxidase (MPO) stain. Coagulation (PT-INR, 1.22) and serum chemistry (total bilirubin [TB], 2.5mg/dL; AST, 75 IU/L; ALT, 36 IU/L; NH3, 112 lg/dL) indicated impaired liver function and/or invasion of leukemic blasts. Bone marrow aspiration revealed accumulation of MPO-negative lymphoblasts with a CD10þCD13dimCD19þCD33dimCD34dimCD66cþHLADRþCD79aþTdTþ phenotype. Cytogenetic and molecular analyses revealed t(9;22)(q34;q11) and 1.7 10 copies/lg RNA of minor-bcr/abl chimeric gene, respectively. Based on these findings, a diagnosis of Ph ALL was confirmed, although we did not test whether these blasts were donorderived or not [6]. The patient achieved complete molecular remission (mCR) after induction therapy with dasatinib and prednisolone (PSL) and thereafter remained in mCR during consolidation chemotherapy with high-dose cytarabine or high-dose methotrexate (MTX) combined with dasatinib. Residual MTX in blood was noted with time, suggesting his impaired drug metabolic potential. Allogeneic HSCT from the same HLA-haploidentical sibling (donor: HLA-A1101/2402, -B4601/5201, -C0102/ 1202, -DR0803/1502; recipient: HLA-A0207/2402, -B4601/ 4601, -C0102/0102, -DR0803/0803) was scheduled to cure the Ph ALL. As summarized in Table 1, the patient received a reduced-intensity conditioning regimen consisting of fludarabine (30mg/sqm on days 8 to 4), melphalan (70mg/sqm on days 6 and 5), and rabbit anti-thymocyte globulin (rATG; 1.25mg/kg on days 4 to 3) followed by G-CSF mobilized peripheral blood stem cell (PBSC) transplantation. The numbers of infused CD34 positive cells was 6.98 10/kg. Intravenous Tac and 0.5mg/kg of methylprednisolone (mPSL) were used as additional GvHD/liver rejection prophylaxis. We excluded busulfan (BU) and MTX from the conditioning and GvHD prophylaxis to reduce liver damage. Prompt engraftment was obtained; a neutrophil count of >0.5 10/L and a platelet count of >20 10/L were achieved on days 10 and 13, respectively. Complete donor chimerism was observed in a bone marrow sample on day 24. Regimenrelated toxicities (oral mucositis and diarrhea) were mild and tolerable for the patient. With hematopoietic recovery, he developed fever, skin eruption, and water diarrhea, resulting in grade III acute GvHD (skin, stage 3; gut, stage 2; liver, none) on day 13. Gut GvHD was resistant to an increased dose of mPSL, flared up to stage 4, and required second-line treatment. We administered an additional 6.5mg/kg of rATG (by five doses), along with 16 subcutaneous doses of etanercept and topically active beclomethasone dipropionate [7], which ameliorated his symptoms. On the other hand, liver toxicity was less observed in the peritransplant period: TB was transiently elevated (maximum 4.5mg/dL on day 18), and sinusoidal obstruction syndrome did not occur. Profound immune suppression caused some infectious complications. Recurrent cytomegarovirus

Systemic chemotherapy with pronounced efficacy and neutropenia in a granulocyte-colony stimulating factor-producingadvanced 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.

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 patients 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.

Abstract 714: Macrophage-to-fibroblast transition promotes cancer progression in peritoneal carcinomatosis of gastrointestinal cancer patient

[Background] Cancer stromal cell plays an important role in cancer progression. Fibroblasts localized in tumor are especially called cancer-associated fibroblasts (CAFs). CAFs and inflammatory cells form tumor microenvironment and promote cancer growth through the direct or indirect interaction between cancer cells and stromal cells. However, the origin of CAF is not fully understood. Malignant ascites contains not only cancer cells but inflammatory cells including macrophage. Accumulation of macrophages and fibrosis has close relationship. In the research field of fibrotic diseases such as renal fibrosis, some reports indicated macrophages were able to change to fibroblasts phenotypically. Peritoneal carcinomatosis also develops peritoneal fibrosis. We demonstrate that malignant ascites are abundant in macrophages and these macrophages changed to CAFs which promote cancer progression in vivo. [Material and method] Ascitic samples from 44 peritoneal carcinomatosis patients due to gastrointestinal cancer were collected at 5 institutions. This study was approved by each institutional review board. Ascites was separated into cell fraction and supernatant by centrifugation. Supernatant was stored at -20°C. Cells were sorted by FACS using anti-CD45, anti-CD14, anti-CD163 and anti-CD90 antibodies. CD45+CD14+ macrophages were cultured in RPMI medium containing fetal bovine serum (FBS) or supernatant of ascites. Human colorectal cancer cell line DLD-1 cells in combination with the cultured cells from ascites were inoculated to immunodeficient mice subcutaneously. All experiments were conducted following the guidelines of the institutional animal committee of Kyushu University. [Result] CD45+CD14+ macrophage was most frequently observed in CD45+ leukocyte fraction from ascites. Most of macrophages expressed M2 marker (CD163). Some of these macrophages changed to CD45-CD90+ fibroblast-like cells which form spindle shape after 2-3 weeks culture. These fibroblast-like cells expressed fibroblast specific genes such as COL3A1, ACTA2 and FAP. These changes were enhanced by ascites supernatant-containing medium compared with FBS-containing medium. DLD-1 cells with the fibroblast-like cells formed larger tumors in immunodeficient mice, compared with DLD-1 cells alone. [Conclusion] In peritoneal carcinomatosis, macrophage is a potential source of CAF. This macrophage-to-CAF transition is enhanced by malignant ascitic environment. As CAF induced from macrophage enhances tumor progression, inhibition of this transition could be possible therapeutic strategy. Citation Format: Mamoru Tanaka, Michitaka Nakano, Hiroshi Ariyama, Kyoko Inadomi, Risa Tanaka, Shigeo Takaishi, Hitoshi Kusaba, Eishi Baba, Koichi Akashi. Macrophage-to-fibroblast transition promotes cancer progression in peritoneal carcinomatosis of gastrointestinal cancer patient. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 714.