Pharmacokinetic study of the oral fluorouracil antitumor agent S‐1 in patients with impaired renal function

Although dose reduction of S‐1 is recommended for patients with impaired renal function, dose modification for such patients has not been prospectively evaluated. The aim of the present study was to investigate the pharmacokinetic parameters of 5‐fluorouracil, 5‐chloro‐2,4 dihydroxypyridine and oteracil potassium, and to review the recommended dose modification of S‐1 in patients with renal impairment. We classified patients receiving S‐1 into 4 groups according to their renal function, as measured using the Japanese estimated glomerular filtration rate (eGFR) equation. The daily S‐1 dose was adjusted based on the patient's eGFR and body surface area. Blood samples were collected for pharmacokinetic analysis. A total of 33 patients were enrolled and classified into 4 groups as follows: 10 patients in cohort 1 (eGFR ≥ 80 mL/min/1.73 m²), 10 patients in cohort 2 (eGFR = 50‐79 mL/min/1.73 m²), 10 patients in cohort 3 (eGFR = 30‐49 mL/min/1.73 m²), and 3 patients in cohort 4 (eGFR < 30 mL/min/1.73 m²). Those in cohorts 3 and 4 treated with an adjusted dose of S‐1 showed a similar area under the curve for 5‐fluorouracil (941.9 ± 275.6 and 1043.5 ± 224.8 ng/mL, respectively) compared with cohort 2 (1034.9 ± 414.3 ng/mL). Notably, while there was a statistically significant difference between cohort 1 (689.6 ± 208.8 ng/mL) and 2 (P = 0.0474) treated with an equal dose of S‐1, there was no significant difference observed in the toxicity profiles of the cohorts. In conclusion, dose adjustment of S‐1 in patients with impaired renal function using eGFR is appropriate and safe.     

Osimertinib in poor performance status patients with T790M-positive advanced non-small-cell lung cancer after progression of first- and second-generation EGFR-TKI treatments (NEJ032B)

Background

Osimertinib is effective in patients with T790M mutation-positive advanced non-small-cell lung cancer (NSCLC) resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, its effectiveness and safety in patients with poor performance status (PS) are unknown.

Methods

Enrolled patients showed disease progression after treatment with gefitinib, erlotinib, or afatinib; T790M mutation; stage IIIB, IV, or recurrent disease; and PS of 2–4. Osimertinib was orally administered at a dose of 80 mg/day. The primary endpoint of this phase II study (registration, jRCTs061180018) was response rate and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate, and safety.

Results

Thirty-three patients were enrolled, of which 69.7% and 24.2% had PS of 2 and 3, respectively. One patient was excluded due to protocol violation; in the remaining 32 patients, the response rate was 53.1%; disease control rate was 75.0%; PFS was 5.1 months; and OS was 10.0 months. The most frequent adverse event of grade 3 or higher severity was lymphopenia (12.1%). Interstitial lung disease (ILD) was observed at all grades and at grades 3–5 in 15.2% (5/33) and 6.1% (2/33) of patients, respectively. Treatment-related death due to ILD occurred in one patient. Patients negative for activating EGFR mutations after osimertinib administration had longer median PFS than those positive for these mutations.

Conclusion

Osimertinib was sufficiently effective in EGFR-TKI-resistant, poor PS patients with T790M mutation-positive advanced NSCLC. Plasma EGFR mutation clearance after TKI treatment could predict the response to EGFR-TKIs.

     

Common clinicopathological features of the patients with chronic hepatitis B virus infection who developed hepatocellular carcinoma after seroconversion to anti-HBs--a consideration of the pathogenesis of HBV-induced hepatocellular carcinoma and a strategy to inhibit it

BACKGROUND/AIMS: The incidence of hepatocellular carcinoma among patients who have seroconverted to anti-hepatitis B surface antigen (anti-HBs) remains controversial. METHODOLOGY: We report four patients with chronic hepatitis B virus (HBV) infection who had cleared HBsAg and had developed anti-HBs at a later time, but who developed hepatocellular carcinoma (HCC) eventually. RESULTS: The common clinicopathological characteristics of the four patients were: An established diagnosis of precirrhosis or liver cirrhosis more than a decade previously, a long-standing normalization or stabilization at a low level of ALT values due to undetectable HBV DNA by the Amplicore Monitor assay, and a marked reduction of the fibrosis level in the non-tumorous liver obtained at HCC surgery or autopsy compared to the previous histology more than a decade previously. There was no fibrosis in the needle biopsy specimen from one patient. CONCLUSIONS: Our findings suggest that HCC due to HBV can occur in the serologically-cured stage if progression to pre-cirrhosis or cirrhosis already has occurred, where the fibrosis level has improved considerably because of the long-term absence of active HBV viremia and inflammation. Active medical intervention to prevent liver cirrhosis for chronic hepatitis B may have an important role in the inhibition of HCC in patients with chronic hepatitis B.     

Effect of <Emphasis Type="Italic">Kaempferia parviflora</Emphasis> extract on knee osteoarthritis

Knee osteoarthritis (OA) is becoming more prevalent worldwide due to increases in the numbers of elderly and obese patients. Currently, pharmaceutical medicines used for the treatment of OA are for symptomatic therapy and therefore new therapeutic agents are needed. Kaempferia parviflora (KP) is a plant growing naturally in Southeast Asia and has various pharmacological effects including an anti-inflammatory effect, but no effect on OA has yet been reported. We therefore conducted a search for the effects KP and the active components of KP extract (KPE) exert on OA as well as its mechanism of action. Results from a study of KPE using the monoiodoacetic acid rat OA model revealed that KPE reduced the pain threshold and severity of osteoarthritic cartilage lesions. The mechanism of action and active components were then investigated using IL-1β-treated human knee-derived chondrocytes. KPE, as well as 5,7-dimethoxyflavone and 5,7,4′-trimethoxyflavone, which are key constituents of KPE and highly absorbable into the body, reduced the expression of matrix metalloproteinases (MMPs), which are the main extracellular matrix enzymes that degrade collagen within cartilage. As mentioned above, KPE acted to suppress OA and 5,7-dimethoxyflavone and 5,7,4′-trimethoxyflavone were shown to be involved as part of KPE’s mechanism that inhibits MMPs.     

Characterization of bullous pemphigoid antibodies by use of recombinant bullous pemphigoid antigen proteins

The seroreactivity of patients with bullous pemphigoid (BP) to recombinant proteins representing sequences in the carboxyl domain of the murine 230-kD BP antigen (BPA) was determined. Sera from 133 patients with BP, 20 patients with pemphigus, and 21 normal subjects were examined by Western blotting by using two recombinant proteins: RP120 (MW = 120 kD), representing the C-terminal half of the 230-kD BPA, and RP60 (MW = 60 kD), representing the C-terminal quarter. These RP120 and RP60 were recognized by 84% and 61%, respectively, of the BP sera that reacted with the 230-kD BPA in epidermal extract, and not by any of pemphigus or normal sera. Furthermore, these RP120 and RP60 were not recognized by any BP sera that reacted only with the 170-kD BPA, which is known to be another major BPA. These findings indicate that one or more of the major antigenic regions localizes in the carboxyl-half domain of the 230-kD BPA, and also suggest that the 230-kD BPA may be distinct from the 170-kD BPA.     

A case of dermatomyositis complicated with pneumomediastinum that was successfully treated with cyclosporin A]

We reported the case of a 39-year-old man with dermatomyositis (DM) complicated with subcutaneous emphysema and pneumomediastinum during steroid therapy. The patient had complained of muscle weakness, dyspnea and skin eruption on his anterior chest wall 6 months prior to admission. He was diagnosed as having DM on the basis of an elevation in myogenic enzymes, myogenic changes in electromyography, a skin biopsy and a muscle biopsy. Chest roentgenogram revealed interstitial pneumonia (IP) in the lower lobes of the lungs. The administration of prednisolone (60 mg/day) was initiated, which resulted in improvement of DM. Fifteen days after the initiation of the steroid therapy, the patient developed subcutaneous emphysema and pneumomediastinum. Additional administration of cyclosporin A (CsA) enabled us to rapidly taper the dose of prednisolone without aggravating the diseases. Several reports have shown that vasculitis might be involved in the pathogenesis of pneumomediastinum in DM patients. Infection and tissue fragility due to steroid therapy worsen the outcome of those patients. CsA therapy may improve the outcome through the anti-vasculitic- and steroid sparing-effects.     

Antigen Receptor Cross-Linking by Anti-Immunoglobulin Antibodies Coupled to Cell Surface Membrane Induces Rapid Apoptosis of Normal Spleen B cells

Cross-linking of surface immunoglobulin (sIg) has been shown to induce either activation or apoptosis of mature B cells presumably depending on the nature of antigens. However, the nature of antigens for induction of mature B-cell apoptosis is not yet fully understood. We cross-linked sIg of mature B cells with various amounts of either anti-Ig antibodies in the soluble form or anti-Ig coupled to erythrocytes or myeloma cells as surrogate membrane-bound antigens. Anti-Ig antibodies coupled to cell surface membrane induced rapid and extensive apoptosis of normal spleen B cells even in the absence of signalling via the Fc receptor. In contrast, soluble anti-Ig induced proliferation or apoptosis of mature B cells depending on the concentration of anti-Ig. The extent of apoptosis induced by soluble anti-Ig was limited compared to that induced by membrane-bound anti-Ig. These results suggest that mature B cells undergo apoptosis or proliferation depending on whether antigens are soluble or membrane-bound and on antigen doses.     

Antigen receptor-mediated B cell death is blacked by signaling via CD72 or treatment with dextran sukfate and is defective in autoimmunity-prone mice

Mature B cells undergo programmed cell death when surface(s)IGis extensively multimerized. A signal that blocks death of Bcells is thus required for activation of B cells in responseto antigen stimulation.Here we show that only a few diversetransmembranesignals capable of Inducing activation and proliferation ofB cell blocked sig-mediated death of normal mature B cells,fromdeath.The results suggest that a specific signal is requiredfor abrogating B cell death induced by sigcross-linking.Signalingvia IL-4 receptor and CD40, both of which are derived from activatedT cells, blocked sig-mediated death,as decribed previously.Signalingthrough a B cell antigen CD72,a counter-receptor of the pan-Tantigen CD4,also blocked death of anti-Ig-treated mouse spleenB cells.CD72 signalmay play a role in survival of B cells atthe initial step of T B interaction, where resting T cells recongnizeantigens such as llpopolyasccharide and dextran sulfate,andspleen B cells from New Zealand mice, which are prone to autoantibody-dependentautoimmune diseases,were resistant to required in antibody responseto freigin antigens regardless of T independence or T dependenceand in autoantibody production.