Successful continuance of CDK4/6 inhibitor treatment with palbociclib after abemaciclib-induced hepatotoxicity in breast cancer: a case report.

Abemaciclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, causes severe hepatotoxicity, a severe adverse event associated with the loss of treatment opportunities. We report a case of liver injury (grade 4) during treatment with abemaciclib, in which the patient was switched to palbociclib and successfully treated with this CDK4/6 inhibitor. A 73-year-old woman with bone metastatic breast cancer (hormone-positive, HER2-negative) was treated with abemaciclib, fulvestrant, denosumab, and precipitated calcium carbonate with cholecalciferol and magnesium carbonate (pCCCM). On day 17, the patient developed skin rashes on her trunk and arms. On day 22, abemaciclib and pCCCM were discontinued due to drug eruption. Grade 3 aspartate aminotransferase (AST) and grade 4 alanine aminotransferase (ALT) levels increased on day 29. Therefore, fulvestrant and denosumab were suspended as the causes of severe hepatotoxicity, in addition to the two drugs suspected of causing the skin eruption. On day 43, AST and ALT levels did not improve, and the patient was referred to a hepatologist. The hepatologist diagnosed hepatotoxicity as a drug-induced liver injury through additional tests and interviews. Fulvestrant treatment was resumed on day 78, and palbociclib on day 92, and denosumab and pCCCM on day 134. On day 287, treatment with the CDK4/6 inhibitor was continued without evidence of liver dysfunction. This case suggests that rechallenge with palbociclib after severe liver injury with abemaciclib may allow for continued treatment with CDK4/6 inhibitors.

Absolute configuration of tetrandrine and isotetrandrine influences their anti-proliferation effects in human T cells via different regulation of NF-κB.

Natural compound tetrandrine was reported to inhibit the proliferation of T cells by inhibiting activation of NF-κB. Chemically, isotetrandrine differs from tetrandrine only in the stereochemistry at the chiral centers. The present study aimed to compare their anti-proliferation effects on human T cells with a focus on NF-κB. The IC50 values of tetrandrine against MOLT-4 cells, MOLT-4/DNR cells, and concanavalin A-activated peripheral blood mononuclear cells of healthy subjects and dialysis patients were 4.43 ± 0.22, 3.62 ± 0.22, 1.91 ± 0.22 and 3.03 ± 0.28 µM, respectively. Whereas, the IC50 values of isotetrandrine against the above immune cells were 2.19 ± 0.27, 2.28 ± 0.33, 1.29 ± 0.14 and 1.55 ± 0.26 µM, respectively. The inhibitory effect of isotetrandrine against the proliferation of T cells was stronger than that of tetrandrine significantly (p < 0.05). Molecular mechanism investigation showed that 10 µM of isotetrandrine largely decreased the expression of p-NF-κB and NF-κB in both MOLT-4 and MOLT-4/DNR T cells (p < 0.05), whereas 10 µM of tetrandrine slightly inhibited the phosphorylation of p-NF-κB with little influence on the expression of NF-κB. Taken together, absolute configurations of tetrandrine and isotetrandrine are suggested to influence on their anti-proliferation effects in human T cells via different regulation of NF-κB.

[A Case of Adult T-Cell Leukemia/Lymphoma with Severe Hand-Foot Syndrome during Administration of Modified LSG15 Regimen].

The patient was a 56-year-old woman. A modified LSG15(VCAP-AMP-VECP)regimen was initiated as the first-line treatment for acute adult T-cell leukemia/lymphoma. On day 13 from the initiation of the second course of chemotherapy, the onset of hand-foot syndrome(HFS)(hands: Grade 2; feet: Grade 1)occurred. Therefore, the administration of a heparin analog cream and betamethasone butyrate propionate ointment was initiated. On day 20 from the start of the second course of chemotherapy, the foot symptoms improved; however, hand symptoms deteriorated to Grade 3. Frequent use of alcohol-based hand hygiene products is associated with infection prevention during neutropenia, but was likely an exacerbating factor. The symptoms gradually improved after this was taken into consideration, and the usage was discontinued. At the start of the third course, the symptoms had improved to Grade 1, and chemotherapy was continued. On day 11, symptoms worsened(Grade 2). HFS management was performed similar to that in the second course, and symptoms improved again.

A cross-sectional survey of methods for controling hand-foot syndrome in patients receiving capecitabine treatment.

Medical personnel actively provide patients taking capecitabine with information on the items to prevent and treat hand-foot syndrome (HFS). However, they are typically unable to ascertain the extent of patient compliance with the recommended items. Thus, the aim of the present study was to ascertain the association between patient compliance with preventative measures for HFS and the development of HFS. Subjects included 90 patients who were treated with a drug regimen that included capecitabine. Patients were treated at one of four facilities between July 2015 and January 2017. The main parameters studied were the extent to which items to prevent and treat HFS were (or were not) followed, and the associaiton between this extent and the development of HFS symptoms. A manual prepared by a pharmaceutical company that manufactures capecitabine describes 15 routine items to follow in order to prevent and treat HFS. The two activities patients most often performed were 'applying a moisturizer' (74.1%) and 'keeping one's skin clean (e.g., washing one's hands and feet)' (64.7%). The two activities patients least often performed were 'using sunscreen on exposed areas' (14.1%) and 'using soft insoles' (11.8%). Patients who performed more items to prevent and treat HFS were significantly less likely to develop symptoms of HFS (P=0.022). Based on these findings, it is recommended that medical personnel provide instructions to the patients regarding the specific items necessary to prevent and treat HFS, and to follow-up with the patients regarding their compliance, with an emphasis on the items they are less likely to take and on the instructions to avoid external irritants. Following these guidelines should lead to qualitative improvement in HFS management.

Vitamin K1 and Vitamin K2 immunopharmacological effects on the peripheral lymphocytes of healthy subjects and dialysis patients, as estimated by the lymphocyte immunosuppressant sensitivity test.

WHAT IS KNOWN AND OBJECTIVE: Renal transplant recipients receive immunosuppressive therapy to prevent acute rejection. We evaluated the immunopharmacological efficacy of vitamin K1 (VK1) and vitamin K2 (VK2) on T-cell mitogen-activated-peripheral lymphocytes of dialysis patients and healthy subjects. METHODS: The effects of VK1 and VK2 on the T-cell mitogen-stimulated proliferation of peripheral blood mononuclear cells (PBMCs) obtained from 12 healthy subjects and 12 dialysis patients were estimated. Seven cytokines produced from the activated PBMCs were measured by a BD Cytometric Beads Array kit. Regulatory T cells (Tregs) in PBMCs were analysed as CD4 + CD25 + FoxP3 +  lymphocytes by flow cytometry. RESULTS: VK2 dose-dependently suppressed the concanavalin A-stimulated proliferation of PBMCs from healthy subjects and dialysis patients, whereas VK1 had no significant effect on the PBMC proliferation. VK1 and VK2 did not influence the production of most of the Th1/Th2/Th17 cytokines from the activated PBMCs of these subjects, although VK2 increased the IL-4 production from PBMCs of healthy subjects. The Treg percentages in the PBMCs of dialysis patients were markedly decreased compared to healthy PBMCs after the treatment with relatively low concentrations of VK2. WHAT IS NEW AND CONCLUSION: The present data suggest that VK2 has immunosuppressive efficacy. VK2 may enhance the immunosuppressive efficacies of glucocorticoids while preventing osteoporosis caused by glucocorticoids.

Immunosuppressive efficacy of tetrandrine combined with methylprednisolone against mitogen-activated peripheral blood mononuclear cells of haemodialysis patients.

Immunosuppressive therapy for prevention of acute rejection episode occasionally causes serious adverse effects, and thus it is important to develop new therapeutic approach for renal transplant recipients. This study evaluated the immunosuppressive pharmacodynamics of tetrandrine (TET) and/or methylprednisolone (MP) in haemodialysis patients in vitro by using the peripheral blood mononuclear cells (PBMCs) isolated from whole blood of haemodialysis patients. The median (range) of MP IC50 values against the proliferation of patients PBMCs was 7.04 (2.30-500.00) ng/mL. In contrast, the median (range) of MP IC50 values against the proliferation of healthy PBMCs was 4.44 (3.19-5.08) ng/mL. The median (range) of TET IC50 values against the proliferation of patients PBMCs was 1.61 (1.04-4.79) µmol/L. Lower concentrations of TET (0.3-300 nmol/L) were able to decrease the IC50 values of MP and thus potentiate the MP immunosuppressive effect on patient PBMCs. The median (range) of MP IC50 values in combination with 0.3, 3, 30, and 300 nmol/L TET were 0.92 (0.49-8.39), 2.10 (0.45-20.00), 0.35 (0.092-1.05), and 0.14 (0.05-6.78) ng/mL, respectively. TET potentiates the MP immunosuppressive pharmacodynamics and thus, it was possible to use the combination of MP and TET to attenuate MP side effects. There were significant correlations between the IC50 values of TET and stimulation indices (P=0.04, r=.58), the IC50 values of TET and the haemodialysis periods (P=0.04, r=.57), or the IC50 values of MP combined with 0.3 nmol/L TET and C-reactive protein concentrations (P=0.04, r=.64), respectively.

Evaluation of the Infection Risk in Dialysis and Chronic Kidney Disease Patients Using an ATP Monitoring Assay.

The ATP monitoring assay is a useful biomarker for risk monitoring to detect infection and rejection episodes in transplant recipients. Hemodialysis patients have a higher rate of infectious mortality. Infections in hemodialysis patients are mainly caused by venous catheters, uremia, malnutrition and inflammation. However, the risk of infection episodes has not been evaluated using a lymphocyte ATP monitoring assay in hemodialysis and chronic kidney disease (CKD) patients. We measured the ATP amounts in the peripheral CD4+ cells of CKD (N = 85) and dialysis patients (N = 17) using an "Immuknow" assay kit. These CKD patients were divided, according to kidney disease stage, into G3a, G3b, G4, and G5 groups. The ATP amounts in CD4+ cells of the dialysis patients and each of the CKD groups were compared with healthy subjects. In both the dialysis and CKD patients, the ATP amounts in CD4+ cells were lower than in healthy subjects. Furthermore, there were significant differences in the ATP amounts between healthy subjects and each of the CKD-G3a, CKD-G3b, and CKD-G4 groups (P < 0.05). Patients with CKD-G3a, CKD-G3b and CKD-G4 were evaluated as being at high risk for infection according to the lymphocyte ATP monitoring assay. However, the ATP amounts in the dialysis and CKD-G5 patients did not differ from those in healthy subjects to a statistically significant extent. These results suggest that the ATP amount in the CD4+ cells of these patients with serve renal failure are influenced by dialysis treatment, uremia and/or oxidative stress.

Isolation, structure determination, and synthesis of allo-RA-V and neo-RA-V, RA-series bicyclic peptides from Rubia cordifolia L.

Two bicyclic hexapeptides, allo-RA-V (4) and neo-RA-V (5), and one cyclic hexapeptide, O-seco-RA-V (6), were isolated from the roots of Rubia cordifolia L. Their gross structures were elucidated on the basis of spectroscopic analysis and X-ray crystallography of compound 5. The absolute stereochemistry of compounds 4 and 5 were established by their total syntheses, and the absolute stereochemistry of compound 6 by chemical correlation with deoxybouvardin (3). Comparison of the 3D structures of highly active RA-VII (1) with less-active compounds 4 and 5 suggests that the orientation of the Tyr-5 and/or Tyr-6 phenyl rings plays a significant role in their biological activity. The isolation of peptides 4-6, along with compound 3, and the comparison of their structures seem to indicate that peptide 6 may be the common precursor to bicyclic peptides 3-5 in the plant.