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

Quantitative activation-induced manganese-enhanced MRI reveals severity of Parkinson’s disease in mice

We demonstrate that activation-induced manganese-enhanced magnetic resonance imaging with quantitative determination of the longitudinal relaxation time (qAIM-MRI) reveals the severity of Parkinson’s disease (PD) in mice. We first show that manganese ion-accumulation depends on neuronal activity. A highly active region was then observed by qAIM-MRI in the caudate-putamen in PD-model mice that was significantly correlated to the severity of PD, suggesting its involvement in the expression of PD symptoms

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

Dog erythrocyte rosette-forming lymphocyte: blockage by OKT11 monoclonal antibody.

Human peripheral blood mononuclear cells (PBM) were separated into sheep erythrocyte rosette-forming (Es+) and non Es+ cells by the Ficoll-Hypaque gradient sedimentation method. Thirty-eight percent of the Es+ cells formed rosettes with dog erythrocytes and were designated as Es+Ed+ cells. The remaining Es+ cells were designated as Es+Ed- cells. Only a few non Es+ cells formed rosettes with dog erythrocytes. Among Es+Ed+ cells, T4 antigen-positive cells were observed approximately 1.7 times as often as T8 antigen-positive cells, when measured by staining with OKT4 or OKT8 monoclonal antibody. Among Es+Ed- cells, however, T4 and T8 antigen-positive cells were observed in almost equal proportion. Preincubation of PBM with OKT11 monoclonal antibody, but not with OKT4 monoclonal antibody, inhibited the rosette formation with dog as well as sheep erythrocytes. These results indicated that Es+Ed+ cells were a subpopulation of T-cells in which a majority of the cells were T4 antigen-positive, and that the binding sites of dog erythrocytes on human T-cells was closely linked with that of sheep erythrocytes.</p

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

Reduction of 223Ra retention in the Large Intestine During Targeted Alpha Therapy with 223RaCl2 by Oral BaSO4 Administration in Mice

Background: Targeted alpha therapy with 223RaCl2 is used to treat skeletal metastases of hormone-refractory prostate cancer. The intravenous injection of 223RaCl2 causes gastrointestinal disorders such as nausea, abdominal discomfort, and diarrhea as frequent clinical adverse events caused by radiation. BaSO4 is known to display Ra2+ ion uptake in its structure and is clinically used as a contrast agent for X-ray imaging following oral administration. Here, we investigated the feasibility of a method to reduce 223Ra retention in the large intestine with BaSO4 by biodistribution studies in mice. Methods: 223RaCl2 biodistribution was examined in ddY mice after intravenous administration (10 kBq/mouse).BaSO4 (100 mg/mouse) was orally administered 1 h before 223RaCl2 injection. We also investigated the effect of laxative treatment on BaSO4 activity, since laxatives are clinically used with BaSO4 to avoid impaction in the large intestine. Results: BaSO4 significantly reduced 223Ra retention in the large intestine after 223RaCl2 injection in mice when compared with the control without BaSO4 administration (P &lt; 0.05). Excretion of 223Ra into the feces was significantly increased by BaSO4 administration (P &lt; 0.05). Laxative treatment did not affect BaSO4 activity in reducing 223Ra retention, although no additional effect of laxative treatment to 223Ra excretion was observed in mice. Conclusions. BaSO4 administration was effective in reducing 223Ra retention in the large intestine during 223RaCl2 therapy, and laxative treatment did not attenuate BaSO4 activity. This method could be useful in reducing adverse events caused by radiation exposure to the large intestine during 223RaCl2 therapy

Intracrine activity involving NAD-dependent circadian steroidogenic activity governs age-associated meibomian gland dysfunction

新たなイントラクライン機構を用いた加齢性眼疾患治療へ --眼局所のホルモンの加齢変化とサーカディアンリズムが鍵--. 京都大学プレスリリース. 2022-02-14.Canonically, hormones are produced in the endocrine organs and delivered to target tissues. However, for steroids, the concept of tissue intracrinology, whereby hormones are produced in the tissues where they exert their effect without release into circulation, has been proposed, but its role in physiology/disease remains unclear. The meibomian glands in the eyelids produce oil to prevent tear evaporation, which reduces with aging. Here, we demonstrate that (re)activation of local intracrine activity through nicotinamide adenine dinucleotide (NAD+)-dependent circadian 3β-hydroxyl-steroid dehydrogenase (3β-HSD) activity ameliorates age-associated meibomian gland dysfunction and accompanying evaporative dry eye disease. Genetic ablation of 3β-HSD nullified local steroidogenesis and led to atrophy of the meibomian gland. Conversely, reactivation of 3β-HSD activity by boosting its coenzyme NAD+ availability improved glandular cell proliferation and alleviated the dry eye disease phenotype. Both women and men express 3β-HSD in the meibomian gland. Enhancing local steroidogenesis may help combat age-associated meibomian gland dysfunction