First‐in‐human phase I study of E7090, a novel selective fibroblast growth factor receptor inhibitor,in patients with advanced solid tumors

Fibroblast growth factor receptors (FGFR) are a family of transmembrane receptor tyrosine kinases involved in regulating cellular processes. FGFR mutations are implicated in oncogenesis, representing therapeutic potential in the form of FGFR inhibitors. This phase I, first‐in‐human study in Japan evaluated safety and tolerability of E7090, a potent selective FGFR1‐3 inhibitor, in patients with advanced solid tumors. Dose escalation (daily oral dose of 1‐180 mg) was carried out to assess dose‐limiting toxicity (DLT), maximum tolerated dose, and pharmacokinetics. Pharmacodynamic markers (serum phosphate, fibroblast growth factor 23, and 1,25‐(OH)₂‐vitamin D) were also evaluated. A total of 24 patients refractory to standard therapy or for whom no appropriate treatment was available were enrolled. No DLT were observed up to the 140‐mg dose; one patient in the 180‐mg cohort experienced a DLT (increased aspartate aminotransferase/alanine aminotransferase, grade 3). The maximum tolerated dose was not reached. Dose‐dependent increases in the maximum concentration and area under the curve from time 0 to the last measurable concentration were observed up to 180 mg. Dose‐dependent increases were observed in all pharmacodynamic markers and plateaued at 100‐140 mg, indicating sufficient FGFR pathway inhibition at doses ≥100 mg. In conclusion, E7090 showed a manageable safety profile with no DLT at doses ≤140 mg. Maximum tolerated dose was not determined. The recommended dose for the follow‐up expansion part, restricted to patients with tumors harboring FGFR alterations, was determined as 140 mg, once daily.     

Wound,pressure ulcer and burn guidelines – 4: Guidelines for the management of connective tissue disease/vasculitis-associated skin ulcers

The Japanese Dermatological Association prepared guidelines focused on the treatment of skin ulcers associated with connective tissue disease/vasculitis practical in clinical settings of dermatological care. Skin ulcers associated with connective tissue diseases or vasculitis occur on the background of a wide variety of diseases including, typically, systemic sclerosis but also systemic lupus erythematosus (SLE), dermatomyositis, rheumatoid arthritis (RA), various vasculitides and antiphospholipid antibody syndrome (APS). Therefore, in preparing the present guidelines, we considered diagnostic/therapeutic approaches appropriate for each of these disorders to be necessary and developed algorithms and clinical questions for systemic sclerosis, SLE, dermatomyositis, RA, vasculitis and APS.     

Encephalopathy related to status epilepticus during slow sleep (ESES) as atypical evolution of Panayiotopoulos syndrome: an EEG and neuropsychological study

Aim: We report two patients with Panayiotopoulos syndrome (PS) who developed encephalopathy related to status epilepticus during slow sleep (ESES) at the peak of their clinical course. Methods: Clinical charts and EEG data were reviewed. Results: The patients exhibited nocturnal autonomic seizures and occipital EEG foci, the latter of which later evolved into multifocal EEG foci with synchronous frontopolar and occipital spikes (Fp‐O EEG foci), and finally into continuous spikes‐waves during sleep (CSWS; spike‐wave index >85% based on whole‐night sleep recording) at eight years and seven years of age, respectively. The occipital spikes always preceded frontopolar spikes by 30～50 mseconds based on the analysis of CSWS. Neuropsychological ability, including IQ, deteriorated during the CSWS period in both patients. The autonomic seizures and focal to bilateral tonic‐clonic seizures were initially resistant to antiepileptic drugs (AEDs), and occurred more than 10 times in both patients. However, the seizures and EEG findings gradually resolved, and AEDs were successfully terminated in both patients. Conclusion: PS can progress to ESES if the clinical course exhibits atypical evolution. The initial autonomic symptom of the seizures and interictal Fp‐O EEG foci should be carefully monitored in patients with CSWS or ESES.     

Recurrent infarctions due to a dome-shaped pannus above the mitral valve prosthesis

This report describes a unique case of a 56-year-old female who suffered from recurrent stroke after double mechanical valve replacement. During the four years after the surgery, she remained in normal sinus rhythm, received adequate anticoagulation therapy, and no apparent left atrial thrombus was detected. She underwent redo surgery to prevent further stroke after fourth instance of cerebral infarction. Intraoperative findings revealed a ‘dome-shaped’ pannus formation covering the sewing ring of the mitral prosthesis circumferentially, probably leading to clot formation and repeated infarctions. She has been stroke free for three years after pannus resection.