Adoptive immunotherapy using autologous lymphocytes activated ex vivo with antigen stimulation for patients with incurable cancer

Adoptive immunotherapy (AIT) using autologous lymphocytes activated ex vivo with antigen stimulation, including zoledronate-activated killer (ZAK) cells, were conducted in the treatment of patients with incurable cancer. Efficacy, safety and treatment feasibility were all evaluated, retrospectively. Two-hundred and twenty-eight patients were enrolled and 198 were treated with AIT every 3 weeks. Success of effector cell generation was evident in 94.0% of the culture. A mean number of the administration was 6.8 times with a total number of 5.8 x 10^9 cells. Survival analysis implied marginal benefit of AIT in addition to chemotherapy in lung, colorectal, pancreatic cancers, especially in biliary cancer, showing the median survival time of 11.9 months. Objective tumor response of 3 CR and 6 PR was observed in colorectal, pancreatic, breast and biliary cancers, showing a response rate of 13.2%. Improvement of QOL was replied in 33% patients and FACT-BRM analysis demonstrated significant improvements in physical, social, emotional and functional well-beings. Together, it is suggested that AIT using autologous lymphocytes activated ex vivo with antigen stimulation, including ZAK cells, is safe and feasible, and may be effective in prolonging survival and improving QOL for patients with incurable cancer

Severe thrombocytopenia and maculopapular erythema-induced by regorafenib in a patient with advanced gastrointestinal stromal tumor

　A 28-year-old Japanese male was diagnosed with a gastrointestinal stromal tumor and multiple liver metastases at 23 years of age underwent gastrectomy and partial hepatectomy. At 27 year of age, multiple liver metastases and peritoneal dissemination were observed and the patient was switched to sunitinib. Approximately, one year later, the liver metastases worsened, and the patient was switched to regorafenib. Fatigue and palmar-plantar erythrodysesthesia syndrome occurred seven days after starting regorafenib, and thrombocytopenia occurred nine days later. Eleven days later, small erythema with fever and erythematous papules appeared throughout the body; therefore regorafenib was discontinued, and oral administration of steroids was initiated accordingly. After 17 days, platelets count decreased to 14,000/μL, prompting platelet transfusion. Maculopapular erythema was diagnosed based on the skin findings and histopathological examination. Oral and topical steroids were initiated and the maculopapular eruption gradually improved. A drug hypersensitivity reaction to regorafenib was diagnosed and treatment was discontinued, after which the patient entered a clinical trial for a new drug. We encountered a case of marked thrombocytopenia and maculopapular erythema during the early stages of regorafenib treatment. Regorafenib occasionally causes serious adverse events; therefore, careful observation and prompt treatment are necessary

Advanced gastrointestinal stromal tumor with intracerebral hemorrhage during sunitinib treatment\n

　Herein, a 70-year-old female was initially treated with sunitinib 50 mg/day to treat an imatinib-resistant gastrointestinal stromal tumor. After sunitinib initiation, nausea, hypertension, hepatic dysfunction, anorexia, fatigue, thrombocytopenia, epistaxis, and palmoplantar erythrodysesthesia syndrome developed; the dose was reduced to 25 mg/day.　Subsequently, adverse events improved, and from the fifth course onward, sunitinib 37.5 mg/day was continued. Approximately 11 months after initiating sunitinib therapy, the patient developed disturbance of consciousness, aphasia, and left hemiplegia. Computed tomography of the head revealed intracerebral hemorrhage, and the patient was hospitalized. No brain metastases, cerebral aneurysms, or cerebral arteriovenous malformations were observed. Sunitinib-induced hypertensive cerebral hemorrhage was suspected as the cause of intracerebral hemorrhage. Conservative treatments, such as antihypertensive drugs, were administered without surgical treatment. The symptoms and intracerebral hemorrhage gradually improved, and the patient was discharged from the hospital. Intracerebral hemorrhage with sunitinib is extremely rare, but has a high mortality rate. During sunitinib treatment, controlling blood pressure and thrombocytopenia is important to prevent bleeding

Concordance of acquired mutations between metastatic lesions and liquid biopsy in metastatic colorectal cancer

Aim: To evaluate whether PCR-reverse sequence-specific oligonucleotide can examine the concordance between liquid biopsy and metastatic lesions with acquired resistance. Materials & methods: We examined acquired mutations in chemoresistant lesions and blood obtained from four patients with RAS wildtype metastatic colorectal cancer who underwent treatment with anti-epidermal growth factor receptor antibodies. Results: In one patient, metastatic lesions harbored diverse acquired mutations in KRAS in all seven metastases; the two acquired mutations were detectable in blood collected after the patient acquired resistance. None of the other patients exhibited liquid biopsy mutations, except one, with a BRAF mutation confirmed in primary tumor and peritoneal dissemination. Conclusion: Liquid biopsy based on PCR-reverse sequence-specific oligonucleotide is a successful procedure for capturing acquired mutations with precise information on the RAS mutational spectrum

同種造血幹細胞移植患者への緩和ケアチーム介入の試み

　血液がんの治療の一つである同種造血幹細胞移植治療（以下，移植）は，患者にとって唯一の治癒を目指した治療であるが，想像以上の副作用に苦しむ可能性の高い治療でもある．成功率20～30% 程度と説明された不安，前処置の副作用，生着前・後の感染症状，GVHD 症状，退院に向けての社会的負担などの苦痛が測り知れなく出現する．主治医は患者の生命維持に精一杯であり，看護師は大量の点滴や身体ケアに精一杯であり，移植患者の苦痛への対応が困難な状況に陥りやすい．そこで，2018年10月から緩和ケアチームが移植患者全例に介入することとした．移植治療のインフォームドコンセント時に緩和ケアチームの専従看護師が立ち会い，主治医から移植治療中の苦痛に対して緩和ケアチームが介入していくことを説明し開始した．これまでに，４症例の移植患者に介入できており，主に心理的対応と栄養士の早期対応が実現できた．しかし，主治医との連携は，良好なものから連携不良とさまざまであり，今後も検討していく必要性があると考えられた．移植患者の苦痛への早期対応が，患者，家族そして主治医と看護師を含めた医療者との三位一体の緩和ケアが可能となり，成果が期待される．　Allogeneic hematopoietic stem-cell transplantation (hereinafter referred to as transplantation) is one of the treatments for blood cancer. Although it is the only treatment that may cure cancer, it is highly likely to cause excruciating side effects. Patients undergoing transplantation face difficulties beyond their imagination such as anxiety upon learning that the success rate is approximately 20-30%, side effects from preliminary treatment, infection symptoms before and after engraftment, GVHD symptoms, and social burden while preparing for discharge. Such patients’ doctors and nurses find it difficult to deal with their and distress. While the doctors are fully engaged in maintaining patients’ lives, nurses are similarly engaged in performing a large amount of drip infusions and maintaining their personal hygiene. Owing to this situation, in October 2018, a palliative care team began interventions for all patients who undergo transplantation. At the beginning of the intervention, a dedicated nurse from the palliative care team attends an informed consent session for transplantation treatment. The doctor explains to the patient that the palliative care team will perform an intervention for him or her in order to alleviate pain and distress during the transplantation treatment. To date, the team has performed interventions for four patients who underwent transplantation. The main achievements were psychological support and early-stage interventions by a dietitian. However, collaborating with the doctors of patients is not always successful. Thus, this practice requires further research in the future. Dealing with the pain and distress of a patient who undergoes transplantation at an early stage makes it possible for the patient, his or her family, and healthcare providers-including doctors and nurses-to collaborate with each other in palliative care. It is believed that such collaborative practices will lead to favorable outcomes

Dose-Finding Study of Anti-CD25 Antibody for Targeting Regulatory T Cells in Locoregional Immunotherapy of Malignant Effusion

Effects of low-dose anti-CD25 antibody on targeting regulatory T (Treg) cells in vitro and in vivo were investigated. Human-mouse chimeric anti-CD25 monoclonal antibody basiliximab was administered into the effusion cavity, followed by locoregional immunotherapy using OK-432 on day 7. Peripheral blood mononuclear cells and effusion lymphocytes (ELs) were collected before and after the basiliximab administration and subjected to further investigations. Surface phenotypes, IFN-y production, cytotoxic activity and foxp3 expression of ELs were assessed by flow cytometry, ELISA, 51Cr-releasing assay, and RT-PCR analysis, respectively. We observed that a low concentration of 0.01 μg/ml basiliximab effectively targeted CD4+CD25bri Treg cells while preserving CD4+CD25tlim activated T cells in vitro. This concentration of basiliximab significantly augmented interferon (IFN)- y production of ELs when interleukin (IL)-2 was added on day 0 or on day 1 after basiliximab. In the clinical study, intracavitary administration of basiliximab on day 0 followed by OK-432 on day 7 was as safe, well-tolerated, and effective as using OK-432 alone, and a low-dose of 0.002-0.005 mg/kg basiliximab could target CD4+CD25bri cells for at least 3 days while relatively preserving CD4 +CD25tlim cells. Foxp3 expression of ELs was not changed definitely by the intracavitary basiliximab. These results suggest that low-dose basiliximab can target Treg cells in vitro and in vivo, and subsequently augment the activation of ELs. Locoregional immunotherapy of malignant effusion using the Treg cell-conditioning regimen with low-dose basiliximab followed by OK-432 administration on day 0 or on day 1 should be evaluated for clinical efficacy in the next phase II trial

Severe thrombocytopenia and maculopapular erythema-induced by regorafenib in a patient with advanced gastrointestinal stromal tumor

Case Reportjournal articl

Advanced gastrointestinal stromal tumor with intracerebral hemorrhage during sunitinib treatment\n

Case Reportjournal articl