Delayed immune-related adverse events in long-responders of immunotherapy: a single-center experience.

BACKGROUND: Immune-checkpoint inhibitors (ICIs) often cause immune-related adverse events (irAEs). The spectrum of irAEs and their managements has been partially clarified, however the knowledge on time-course of irAEs is not well understood. METHODS: A retrospective study based on the medical record was performed. The study subjects were consisting of patients with various types of solid tumors for whom ICIs (nivolumab, pembrolizumab, durvalumab, atezolizumab, nivolumab plus ipilimumab) were used between April 2016 and October 2021. We focused on irAEs developed more than 1-year after commencement ICIs (delayed irAE group) and compared with irAEs developed within 1-year (non-delayed irAE group) in terms of types and severity of irAEs. RESULTS: A total of 336 patients were enrolled in the study. Eighty-eight patients (26.2%) developed irAEs and 248 did not. Most of the patients developing irAEs were treated using PD-L1/PD-1 inhibitors. Eighty-one patients (24.1%) in non-delayed irAE group and 7 patients (2.1%) in delayed irAE group developed irAEs. The median onset of irAEs in the delayed irAE group was 18.6 months (range: 13.5-24.3). The types of irAEs observed in delayed irAE group were dermatitis (2 cases), pneumonitis (2 cases), nephritis (1 case), arthritis (1 case), and gastritis (1 case). The severity of irAEs was almost mild (≤G2), but one patient (.3%) developed G3 nephritis. CONCLUSION: PD-L1/PD-1 inhibitors frequently caused various irAEs but their severities were mostly tolerable. Few patients developed delayed irAE with mild toxities.

Development of a simple high-performance liquid chromatography-ultraviolet method for sotorasib quantification in human plasma: Implications for therapeutic drug monitoring.

Sotorasib, an oral small-molecule inhibitor, reportedly exerts promising activity against Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant tumors. However, the currently administered dose may fail to represent the optimal dose based on the therapeutic efficacy. Herein, we developed a simple and sensitive method using high-performance liquid chromatography with ultraviolet (HPLC-UV) to measure the sotorasib concentration in human plasma. The sotorasib calibration curve exhibited linearity across the concentration range of 0.10-20.0 µg/mL (r2 = 0.9999). The coefficients of intra- and inter-day validation ranged between 0.79-9.75% and 3.01-6.13%, respectively. The assay accuracy ranged between -3.14 and 5.18%, with > 98.5% recovery. Subsequently, we applied the developed method to estimate sotorasib concentrations in a patient with KRAS G12C-mutated non-small cell lung cancer. We anticipate that our HPLC-UV method will be valuable for assessing the safety and efficacy of sotorasib in larger patient cohorts.

[Evaluation of Usefulness of the Tools for Collaboration between Hospital and Community Pharmacists in the Provision of Outpatient Cancer Chemotherapy].

Outpatient cancer chemotherapy is becoming increasingly widely adopted. It is, therefore, essential to strengthen the collaboration between hospital and community pharmacists. Although there have been several reports on the collaboration between these two health care providers in the provision of outpatient cancer chemotherapy, there have been no reports on the usefulness of the tools provided by hospital pharmacists to their community counterparts. Hence, this study examined the usefulness of the Adverse Drug Reaction Information Form, which was provided to insurance pharmacies. The response rate of community pharmacists to the information provided was 80%. The most common content of the information provided was related to supportive care(55.9%). Telephone consultations between community pharmacists and patients were conducted in 20 cases(34.8%)to confirm the symptoms of adverse drug reactions. The telephone follow-up rate for each grade of adverse drug reaction was 34.8% for grade 1 and 45.5% for Grade 2, with the number of Grade 2 adverse drug reaction cases being the highest. These findings demonstrate that collaboration between hospital and community pharmacists using the Adverse Drug Reaction Information Form can help provide high-quality outpatient cancer care.

Effects of inorganic and organic arsenic compounds on growth and apoptosis of human T-lymphoblastoid leukemia cells.

BACKGROUND/AIM: To investigate the effects of inorganic and organic arsenic compounds on human T-lymphoblastoid leukemia cells. MATERIALS AND METHODS: Cell proliferation was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5¬diphenyltetrazolium bromide (MTT) assay. Apoptotic cell morphology was examined by cell staining with Hoechst 33342. Cellular caspase-3/7 activities were measured after arsenic treatment. RESULTS: The inhibitory concentration by 50% (IC(50)) values of As(2)O(3) towards MOLT-4 and daunorubicin- resistant MOLT-4/DNR cell proliferation were 0.87 and 0.92 µM, while the values for arsenic acid were 69.1 and 116.6 µM, respectively. These arsenic compounds also inhibited mitogen-induced proliferation of human peripheral blood mononuclear cells. Six organic arsenic compounds did not inhibit leukemia cell proliferation. As(2)O(3) and arsenic acid induced apoptotic cell morphology and increased caspase-3/7 activity in the leukemia cells. Ascorbic acid and buthionine sulfoxide enhanced, while N-acetyl-L-cysteine abated, the suppressive effects of inorganic arsenic compounds on leukemia cell proliferation. CONCLUSION: As(2)O(3) and arsenic acid inhibit proliferation and induce apoptosis in MOLT-4 and daunorubicine-resistant MOLT-4/DNR cells via glutathione-depletion and subsequent caspase-3/7 activation. Organic arsenic compounds have no inhibitory activity on the leukemia cell proliferation. Inorganic arsenic compounds are suggested as useful agents for treatment of T-lymphoblastoid leukemia.

Methoxy- and fluoro-chalcone derivatives arrest cell cycle progression and induce apoptosis in human melanoma cell A375.

Because of the lack of efficacious treatments for advanced melanoma, new approaches are necessary. Chalcones are contained in fruits and vegetables, and have been suggested to be cancer-preventive. In this study, effects of synthetic chalcone derivatives were investigated especially on the proliferation of human melanoma cells and peripheral blood mononuclear cells (PBMCs). Four out of the 12 synthetic chalcones: 4-trifluoromethyl-4'-methoxychalcone (CH-1), 4-trifluoromethyl-2'-methoxychalcone (CH-3), 3-trifluoromethyl-2',4'-dimethoxychalcone (CH-4) and 3-trifluoromethyl-4'-methoxychalcone (CH-7) exhibited significant antiproliferative efficacies against the cultured cells of the human melanoma cell line A375. CH-1, CH-3, CH-4, and CH-7 induced cell cycle arrest at the S-G(2)/M phase within 24 h after the treatment. CH-3, CH-4, and CH-7 significantly activated caspase-3 at 12 h, subsequently induced apoptosis at 72 h. All chalcones inhibited concanavalin A-induced proliferation of PBMCs dose-dependently. Our results suggest that some methoxy- and/or fluoro-chalcones have antitumor efficacy by inducing apoptosis and the cell-cycle arrest.