Comparison of one-year outcomes between as-needed brolucizumab and aflibercept for polypoidal choroidal vasculopathy.

PURPOSE: To compare the one-year visual and anatomic outcomes of an as-needed regimen of brolucizumab and aflibercept for polypoidal choroidal vasculopathy (PCV). STUDY DESIGN: A retrospective comparative study. METHODS: A retrospective medical chart review was performed for consecutive 56 eyes from 56 patients with PCV initially treated with thee monthly intravitreal aflibercept (n = 33, 2.0 mg/0.05 ml) or brolucizumab (n = 23, 6.0 mg/0.05 ml) followed by as-needed administration, followed up for at least 12 months. All patients were followed up monthly, and fluorescein and indocyanine green angiography (ICGA) were performed at baseline, 3-month, and 12-month visits. RESULTS: At the 12-month visit, best-corrected visual acuity significantly improved from 0.30 ± 0.31 to 0.21 ± 0.29 (p = 0.042) in the brolucizumab-treated group and from 0.24 ± 0.25 to 0.14 ± 0.25 (p = 7.7×10-3) in the aflibercept-treated group, suggesting comparable visual improvement in both groups. Central retinal thickness and subfoveal choroidal thickness decreased by 38.4% and 14.2%, respectively, in the brolucizumab-treated group and by 34.8% and 13.9%, respectively, in the aflibercept-treated group at the 12-month visit. The mean number of additional injections was significantly higher in the aflibercept-treated group (2.9 ± 2.7) than in the brolucizumab-treated group (1.3 ± 1.2, p = 0.045). The complete resolution of polypoidal lesions on ICGA was higher in the brolucizumab-treated group than in the aflibercept-treated group (3-month visit: 56.5% vs 30.3%, 12-month visit: 56.5% vs 30.3%). CONCLUSIONS: In treatment-naïve eyes with PCV, the as-needed administration regimen of brolucizumab was comparable to aflibercept in terms of visual and anatomical outcomes, with fewer additional injections during the 12-month follow-up.

A Treat-and-Extend Regimen of Intravitreal Brolucizumab for Exudative Age-Related Macular Degeneration Refractory to Aflibercept: A 12-Month Result.

We aimed to investigate whether a treat-and-extend regimen of intravitreal brolucizumab (6.0 mg/0.05 mL) is effective for eyes with exudative age-related macular degeneration (AMD) refractory to aflibercept for 12 months. Sixty eyes from 56 patients receiving brolucizumab for exudative AMD refractory to aflibercept were included. Patients received a mean of 30.1 aflibercept administrations for a mean 67.9-month follow-up. All patients exhibited exudation on optical coherence tomography (OCT) despite regular 4-8 weeks of aflibercept administration. Visit 1 was scheduled at the same interval from the last aflibercept injection to the baseline. The treatment interval was extended or shortened by 1-2 weeks depending on the presence or absence of exudation on OCT. After switching to brolucizumab, the follow-up interval significantly extended at 12 months (before switching: 7.6 ± 3.8 weeks vs. at 12 months: 12.1 ± 6.2 weeks, p = 1.3 × 10-7). Forty-three percent of the eyes achieved a dry macula at 12 months after switching. However, the best-corrected visual acuity did not improve at any visit. Morphologically, the central retinal thickness and subfoveal choroidal thickness significantly decreased from baseline at 12 months (p = 3.6 × 10-3 and 1.0 × 10-3, respectively). Switching to brolucizumab can be considered to extend the treatment interval in eyes with exudative AMD refractory to aflibercept.

Mid-Term Results of Ab Interno Trabeculectomy among Japanese Glaucoma Patients.

BACKGROUND: The evaluation of ab interno trabeculectomy, referred to as trabectome®, among Japanese patients is insufficient. SUBJECTS AND METHODS: Japanese patients who underwent trabectome® at the University of Yamanashi Hospital were included. The investigated parameters were intraocular pressure (IOP), best corrected visual acuity, glaucoma medications, visual field, and corneal endothelial cell density. The success rate and its associated factors were investigated. RESULTS: A total of 250 eyes from 197 patients were enrolled. The trabectome® significantly reduced IOP and glaucoma medications up to 48 months. Concomitant cataract extraction enhanced the reduction in IOP and glaucoma medications up to 42 months. At 36 months postoperatively, 40.8% satisfied IOP of the same or less than 18 mmHg or more than a 20% IOP reduction with the same or less use of glaucoma medications as preoperatively. Preoperative IOP and combined cataract extraction were significantly associated with the success rate. The trabectome® alone did not show a significant reduction in corneal endothelial cells. Eyes with postoperative transient IOP elevation and removal of anterior chamber hemorrhage were 11.2% and 1.2%, respectively. Twenty-four eyes (9.6%) underwent additional glaucoma surgeries. CONCLUSIONS: The trabectome® could be considered an effective and safe surgery. Compared to trabectome® alone, combined cataract surgery was superior in lowering IOP and reducing glaucoma medications.

The combination therapy of subtenon triamcinolone acetonide injection and intravitreal brolucizumab for brolucizumab-related intraocular inflammation.

RATIONALE: Brolucizumab is a novel anti-vascular endothelial growth factor agent with clinical trials demonstrating excellent efficacy for neovascular age-related macular degeneration (AMD) in both visual and anatomic outcomes. However, there is concern of intraocular inflammation (IOI), and we propose concurrent subtenon triamcinolone acetonide (STTA) to prevent IOI. PATIENT CONCERN: A 73-year-old man was treated with aflibercept for neovascular AMD in his right eye. Despite 11 months of monthly intravitreal aflibercept injections, optical coherence tomography demonstrated persistent exudation. Ten days following his second brolucizumab injection, the patient presented with decreased vision due to vitritis in his right eye. DIAGNOSIS: Brolucizumab-related IOI in neovascular AMD refractory to aflibercept. INTERVENTIONS: A combination therapy involving of intravitreal brolucizumab and STTA. OUTCOMES: The anti-vascular endothelial growth factor inhibitor was changed back to aflibercept; however, exudation persisted. Therefore, a combination therapy involving STTA (5 mg/0.5 mL) and intravitreal injection of brolucizumab (6.0 mg/0.05 mL) was performed to treat the exudation and as prophylaxis to recurrent IOI. Combination therapy achieved no recurrent IOI and resolution of exudation with 8-week treatment intervals. LESSONS: This case might indicate that STTA is not only an optimal treatment option for brolucizumab-related IOI but also a preventive agent for this condition.

Comparison of Outcomes between 3 Monthly Brolucizumab and Aflibercept Injections for Polypoidal Choroidal Vasculopathy.

We compared the short-term outcomes between 3-monthly aflibercept and brolucizumab injections for treatment-naïve polypoidal choroidal vasculopathy (PCV). A total of 52 eyes were included. Patients received 3 monthly intravitreal aflibercept (n = 38) or intravitreal brolucizumab (n = 14). Indocyanine green angiography (ICGA) was performed at baseline and at the 3-month visit. Selection of anti-VEGF agents depended on time. In the brolucizumab-treated group, best-corrected visual acuity (BCVA) improved from 0.27 ± 0.34 (log MAR unit) at baseline to 0.20 ± 0.24 at 3-month visit, which is comparable with the aflibercept-treated group (p = 0.87), after adjustment of confounding factors. Central retinal thickness significantly decreased by 43%-44% in both groups. Subfoveal choroidal thickness also significantly decreased by 20.5% during this interval in the brolucizumab-treated group, which was greater than the aflibercept-treated group. The complete resolution rate of polypoidal lesions on ICGA was significantly higher (p = 0.043) in the brolucizumab-treated group (78.6%) than in the aflibercept-treated group (42.1%). Intraocular inflammation was observed in 14.3% (2/14) in the brolucizumab-treated group only. In short-term follow-up, intravitreal injection of 3-monthly brolucizumab was comparable with aflibercept in terms of BCVA and morphological improvement along with higher resolution of polypoidal lesion(s) on ICGA.

Long-term prognosis of polypoidal choroidal vasculopathy with a 5-year remission after an initial combination therapy.

PURPOSE: To investigate the visual prognosis of patients with polypoidal choroidal vasculopathy (PCV) with a 5-year remission after an initial combination therapy involving photodynamic therapy (PDT) and intravitreal ranibizumab (IVR) or aflibercept injection (IVA). METHODS: Medical records of 69 consecutive patients with PCV treated with PDT with IVR/IVA were retrospectively reviewed, and 17 eyes were identified with a 5-year remission after the initial combination therapy. The eyes that did not require additional treatment during the 1st-5th year were assigned to the remission group and the eyes requiring additional treatment during the 1st-5th year were assigned to the recurrence group. RESULTS: During the 7-year follow-up, the mean logarithm of the minimal angle resolution best-corrected visual acuity (logMAR BCVA) significantly improved from 0.39±0.27 to 0.17±0.38 (p=2.9 × 10-4) in the remission group, whereas the mean logMAR BCVA was maintained throughout the follow-up period (0.58±0.27 to 0.60±0.48) in the recurrence group. In the remission group, only two (11.8%) of the 17 eyes experienced recurrence during the 5th-7th year. Comparison of baseline characteristics between the two groups revealed that a higher proportion of female (p=0.012), better baseline BCVA (p=3.1 × 10-3), and lower risk allele frequency in ARMS2 A69S (p=0.029) were observed in the remission group. CONCLUSIONS: The combination therapy showed a favourable outcome for PCV over a 7-year follow-up, especially in the eyes without recurrence during the 1st-5th year. Physicians should be careful of recurrent exudation in the eyes without recurrence during the 1st-5th years, although the recurrence rate was low.

Five-Year Outcome of Aflibercept Monotherapy for Exudative Age-Related Macular Degeneration with Good Baseline Visual Acuity.

We investigated the long-term visual and anatomical outcomes of aflibercept monotherapy for exudative age-related macular degeneration (AMD) with good baseline best-corrected visual acuity (BCVA). A medical chart review was performed for 40 consecutive patients with baseline decimal BCVA ≥ 0.6 secondary to exudative AMD. Three monthly injections were administrated, and thereafter additional injection was performed if needed over 5 years. In total, 13 eyes with neovascular AMD (nAMD) and 27 eyes with polypoidal choroidal vasculopathy (PCV) were enrolled. In both groups, the mean BCVA significantly improved at the 12-month visit (p < 0.05). However, the significant improvement in BCVA disappeared at the 24-month visit, and the final mean BCVA was equivalent to that at baseline (p = 0.17 in the nAMD group and p = 0.15 in the PCV group). The median number of injections required after the loading dose was 15.0 during the 5-year follow-up (nAMD:15.0 vs. PCV:15). During the study period, 37 (92.5%) eyes required retreatment(s). Cox regression analysis demonstrated that the protective allele of ARMS2 A69S was associated with a retreatment-free period from the initial injection (p = 0.041, repeated forward selection method). As-needed aflibercept monotherapy is a preferable treatment option for exudative AMD with good initial visual acuity regardless of nAMD or PCV during the 5-year study period.

Medical Costs of and Changes in Glaucoma Treatment among Patients Newly Starting Glaucoma Care.

Purpose: To use a medical claim database to investigate medical costs and treatment patterns among patients newly starting glaucoma care.Subjects and methods: Subjects registered in the Japan Medical Database Center (JMDC) from January 2005 to March 2016 who were newly diagnosed with glaucoma, started glaucoma treatment, and had treatment records covering more than five years were included in the analysis. All direct medical costs were collected for a period of up to ten years. Factors affecting medical costs were analyzed. Changes in hypotensive eyedrops and choices related to glaucoma surgery were also analyzed.Results: Out of approximately 1.42 million subjects, 2,393 satisfied the inclusion and exclusion criteria. The average total medical cost incurred per patient over a period of ten years was US$9,030, including US$1,214 during the initial year. The proportion of the total cost represented by the cost of hypotensive eyedrops increased from 5.2% to 10.6% over the ten-year period. Medical costs were higher in patients younger than ten years old than in patients of all other age groups. The number of ocular hypotensive eyedrops increased from 0.9 to 1.5 over the ten-year period. Medical costs were higher for subjects with secondary glaucoma than for other subjects. Sixty-three patients underwent trabeculotomy or trabeculectomy, and trabeculectomy was the preferred choice in later years.Conclusions: The total direct medical cost associated with glaucoma was US$9,030 for the first ten years. Drug costs gradually increased with treatment duration and patient age and varied by glaucoma type.

Association between Polygenic Risk Score and One-Year Outcomes Following As-Needed Aflibercept Therapy for Exudative Age-Related Macular Degeneration.

We investigated whether polygenic risk score (PRS) was associated with one-year outcome of as-needed aflibercept therapy for exudative age-related macular degeneration (AMD), including AMD (n = 129) and polypoidal choroidal vasculopathy (n = 132). A total of 261 patients were treated with as-needed intravitreal aflibercept injection (IAI) after three monthly IAIs and the completion of a one-year follow-up. One hundred and seventy-two healthy volunteers served as controls. Genotyping of ARMS2 A69S (rs10490924), CFH I62V (rs800292), SKIV2L-C2-CFB (rs429608), C3 (rs2241394), ADAMTS-9 (rs6795735) and CETP (rs3764261) was performed for all participants. A total of 63 PRSs were quantified. There was a positive association between the PRS involving ARMS2, CFH, C3, and ADAMTS-9 and best-corrected visual acuity at twelve months (p = 0.046, multiple regression analysis). When comparing PRSs of patients requiring retreatment and of patients without retreatment, 35 PRSs were significantly greater in patients requiring retreatment than in patients without requiring retreatment, with the PRS involving ARMS2 and CFH being most significantly associated (p = 1.6 × 10-4). The number of additional injections was significantly associated with 40 PRSs and the PRS involving ARMS2 and CFH showed a most significant p-value (p = 2.42 × 10-6). Constructing a PRS using a combination with high-risk variants might be informative for predicting the response to IAI for exudative AMD.

Response to photodynamic therapy combined with intravitreal aflibercept for polypoidal choroidal vasculopathy depending on fellow-eye condition:2-year results.

We investigated whether response to photodynamic therapy (PDT) with intravitreal aflibercept injection (IAI) for polypoidal choroidal vasculopathy (PCV) differs depending on fellow eye condition. A retrospective review was conducted for consecutive 60 eyes with PCV treated with PDT combined with IAI as well as 2-years of follow-up data. Fellow eyes were divided into 4 groups; Group 0: no drusen, Group 1; pachydrusen, Group 2; soft drusen, Group 3: PCV/fibrovascular scarring. Best-corrected visual acuity improved at 24-months irrespective of groups and there were no significant differences in visual improvement among treated eyes among the 4 groups. Within 2-years, 35 (58.3%) required the retreatment. The need for retreatment including additional injection and the combination therapy was significantly less in Group 1(12.5%) compared to the others (P = 0.0038) and mean number of additional IAI was also less in Group 1 compared to the others (P = 0.017). The retreatment-free period from the initial combination therapy was longest in Group 1 (23.6±1.1 months) (P = 0.0055, Group 0: 19.1±6.9, Group 2: 12.8±7.9, Group 3: 11.5±9.9). The need for retreatment was significantly different according to fellow-eye condition. Among PCV patients, pachydrusen in fellow eyes appear to be a predictive characteristic for a decreased treatment burden at 2 years.

Title: Pachydrusen in Fellow Eyes Predict Response to Aflibercept Monotherapy in Patients with Polypoidal Choroidal Vasculopathy.

We investigated whether responses to as-needed intravitreal aflibercept injections (IAIs) for polypoidal choroidal vasculopathy (PCV) differed among patients based upon drusen characteristics in fellow eyes. 110 eyes from 110 patients with PCV received 3 monthly IAI and thereafter Pro re nata (PRN) IAI over 12 months. Patients were classified into 4 groups depending on fellow eye findings. Group 1 (n = 16): pachydrusen; Group 2 (n = 45): no drusen; Group 3 (n = 35): soft drusen; Group4 (n = 14) PCV/scarring. Best-corrected visual acuity improved at 12 months in all groups, but not significantly in Group 1 and Group 4; however, visual improvement was similar among the groups after adjusting baseline confounders. Group 1 had a significantly lower percentage of eyes needing retreatment (all p < 0.001; Group 1: 16.7%; Group 2: 50.8%; Group 3: 80%; Group 4: 85.7%). The mean number of retreatments was least in Group 1 among the groups (all p-value < 0.003; Group 1: 0.50 ± 1.32; Group 2: 1.73 ± 2.08; Group 3:2.71 ± 1.99; Group 3: 2.71 ± 2.16). Patients with pachydrusen in fellow eyes were less likely to require additional IAI following the loading dose and may be ideal candidates for aflibercept monotherapy in their first year.

Association of CRP levels with ARMS2 and CFH variants in age-related macular degeneration.

PURPOSE: To investigate whether plasma high sensitivity C-reactive protein (hs-CRP) level is associated with exudative age-related macular degeneration (AMD) as well as variants of ARMS2 A69S and CFH I62V in patients with exudative AMD. METHODS: A case-control study was done comparing CRP among patients with exudative AMD including those with polypoidal choroidal vasculopathy, typical AMD and retinal angiomatous proliferation, and CRP were also compared between cases and controls. Plasma CRP was measured from peripheral blood using latex nepherometry for all participants. Genotyping of ARMS2 A69S and CFH I62V was performed for all patients with exudative AMD using TaqMan technology. RESULTS: Among 125 patients with exudative AMD, including 31 with typical neovascular AMD, 73 with PCV and 21 with RAP lesions and 150 controls, CRP levels were higher in exudative AMD than in controls. (P = 2.7 × 10-5) There was not a significant difference in hs-CRP levels among AMD subtypes. Neither variants of ARMS2 nor CFH was associated with hs-CRP level in patients with exudative AMD. A multiple regression analysis revealed that gender male, presence of exudative AMD and presence of cardiovascular diseases were associated with increased plasma hs-CRP. CONCLUSIONS: Plasma hs-CRP was elevated independent of variants of ARMS2 A69S and CFH I62V in patients with exudative AMD.

Genetic factors associated with response to as-needed aflibercept therapy for typical neovascular age-related macular degeneration and polypoidal choroidal vasculopathy.

In the present study, we investigated the association between susceptible genetic variants to age-related macular degeneration (AMD) and response to as-needed intravitreal aflibercept injection (IAI) therapy for exudative AMD including both typical neovascular AMD and polypoidal choroidal vasculopathy (PCV) over 12-months. A total of 234 patients with exudative AMD were initially treated with 3 monthly IAI and thereafter as-needed IAI over 12 months. Seven variants of 6 genes including ARMS2 A69S (rs10490924), CFH (I62V:rs800292 and rs1329428), C2-CFB-SKIV2L(rs429608), C3 (rs2241394), CETP (rs3764261) and ADAMTS-9 (rs6795735) were genotyped for all participants using TaqMan technology. After adjusting for age, gender, baseline BCVA and AMD subtype, A (protective) allele of C2-CFB-SKIV2L rs429608 was associated with visual improvement at 12-month (P = 0.003). Retreatment was associated with T(risk) allele of ARMS2 A69S (P = 2.0 × 10-4; hazard ratio: 2.18:95%CI: 1.47-3.24) and C(risk) allele of CFH rs1329428 (P = 2.0 × 10-3; hazard ratio: 1.74:95%CI: 1.16-2.59) after adjusting for the baseline confounders. The need for additional injections was also associated with T allele of ARMS2 A69S (P = 1.0 × 10-5) and C allele of CFH rs1329428 (P = 3.0 × 10-3) after adjusting for the baseline confounders. The variants of ARMS2 and CFH are informative for both physicians and patients to predict recurrence and to quantify the need for additional injections.

Correction: Five-year outcomes of photodynamic therapy combined with intravitreal injection of ranibizumab or aflibercept for polypoidal choroidal vasculopathy.

[This corrects the article DOI: 10.1371/journal.pone.0229231.].

Five-year outcomes of photodynamic therapy combined with intravitreal injection of ranibizumab or aflibercept for polypoidal choroidal vasculopathy.

We report 5-year visual and anatomical outcomes after combination therapy of photodynamic therapy (PDT) and intravitreal injection of ranibizumab or aflibercept for polypoidal choroidal vasculopathy (PCV) and predictive factors for visual outcomes at 5-year and time to recurrence. Medical charts were retrospectively reviewed for 43 consecutive eyes with PCV treated with combination therapy of PDT and intravitreal injection of ranibizumab(n = 13) or aflibercept(n = 30) and completed 5-year follow-up. The variants of ARMS2 A69S and CFH I62V were genotyped using TaqMan assay. Best corrected visual acuity (BCVA) significantly improved at 5-year (P = 0.01) with 20% reduction of subfoveal choroidal thickness irrespective of presence or absence of recurrence. Visual improvement was associated with baseline shorter greatest linear dimension (GLD) (P = 1.0×10-4). Mean time to recurrence was 28.6±23.1 months (95% CI: 21.5-35.7, Median:18.0) and time to recurrence was associated with G allele (protective allele) of ARMS2 A69S and GLD (P = 4.0×10-4 and 1.0×10-2, respectively). Multiple regression analysis revealed that time to recurrence extended by 15.5 months when the G allele of ARMS2 A69S increased by one allele (TT: 15.7±17.0, TG: 30.8±23.5, GG: 41.1±22.6 months). The combination therapy resulted in a favorable visual outcome for PCV during 5-year follow-up.

Clinical and genetic characteristics of pachydrusen in patients with exudative age-related macular degeneration.

We investigated the clinical and genetic characteristics of patients with unilateral exudative age-related macular degeneration (AMD), including typical AMD, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation, in whom pachydrusen was seen. Patients with unilateral exudative AMD with at least a 12-month follow-up period were included. According to the fellow eye condition, 327 consecutive patients were classified into 4 groups: Group 0: no drusen (42.8%), Group 1: pachydrusen (12.2%), Group 2: soft drusen (30.3%), Group 3: pseudodrusen with or without soft drusen (14.7%). Development of exudative AMD in the fellow eye was retrospectively studied for a 60-month period and this inter-group comparisons were performed. Genotyping was performed for ARMS2 A69S and CFH I62V. The thickness of the choroid in the fellow eyes increased significantly in Group 1 than in other groups (all P < 1.0 × 10-7). The development of exudative AMD in the fellow eye was significantly less frequent in Group 1 than in Groups 2 or 3 (P = 0.022 and 0.0015, respectively). Risk allele frequency of ARMS2 A69S was significantly lower in Group 1 than in Group 2 and 3 (all P < 1.0 × 10-4). Patients with pachydrusen have genetic and clinical characteristics distinct from those of soft drusen and pseudodrusen.

The Novel Arylamidine T-2307 Selectively Disrupts Yeast Mitochondrial Function by Inhibiting Respiratory Chain Complexes.

The novel arylamidine T-2307 exhibits broad-spectrum in vitro and in vivo antifungal activities against clinically significant pathogens. Previous studies have shown that T-2307 accumulates in yeast cells via a specific polyamine transporter and disrupts yeast mitochondrial membrane potential. Further, it has little effect on rat liver mitochondrial function. The mechanism by which T-2307 disrupts yeast mitochondrial function is poorly understood, and its elucidation may provide important information for developing novel antifungal agents. This study aimed to determine how T-2307 promotes yeast mitochondrial dysfunction and to investigate the selectivity of this mechanism between fungi and mammals. T-2307 inhibited the respiration of yeast whole cells and isolated yeast mitochondria in a dose-dependent manner. The similarity of the effects of T-2307 and respiratory chain inhibitors on mitochondrial respiration prompted us to investigate the effect of T-2307 on mitochondrial respiratory chain complexes. T-2307 particularly inhibited respiratory chain complexes III and IV not only in Saccharomyces cerevisiae but also in Candida albicans, indicating that T-2307 acts against pathogenic fungi in a manner similar to that of yeast. Conversely, T-2307 showed little effect on bovine respiratory chain complexes. Additionally, we demonstrated that the inhibition of respiratory chain complexes by T-2307 resulted in a decrease in the intracellular ATP levels in yeast cells. These results indicate that inhibition of respiratory chain complexes III and IV is a key factor for selective disruption of yeast mitochondrial function and antifungal activity.

Development of tumor-induced osteomalacia in a subcutaneous tumor, defined by venous blood sampling of fibroblast growth factor-23.

A 25-year-old man with severe lumbago was referred to our department for further evaluation. Serum phosphate and TmP/GFR levels were decreased. Physical examination revealed an elastic tumor in the instep of the right foot, which the patient reported having since the age of 10 years. He had no symptoms of osteomalacia at that time. Within the recent years, the tumor had grown in size and the patient developed lumbago. To examine the existence of a fibroblast growth factor-23 (FGF-23)-producing tumor, venous blood was collected from four main veins. FGF-23 levels were significantly increased in the right femoral vein, compared with other veins. After the resection of the tumor, the histopathology was consistent with a phosphaturic mesenchymal tumor (mixed connective tissue variant). Taken together, these results indicated that the development of osteomalacia in this patient was associated with the production of FGF-23 in the subcutaneous tumor.

Effects of corticotropin-releasing hormone (CRH) on the synthesis and secretion of proopiomelanocortin-related peptides in the anterior pituitary: a study using CRH-deficient mice.

Corticotropin-releasing hormone (CRH) mainly regulates the synthesis and secretion of adrenocorticotropin (ACTH) in the anterior pituitary (AP). By using CRH-deficient mice (CRH KO), we investigated the role of CRH in the processing of proopiomelanocortin (POMC), a precursor of ACTH, beta-lipotropic hormone, and beta-endorphin (EP). In the basal condition, the plasma ACTH level was similar in CRH KO and wild-type mice (WT), while its response to pain stress in CRH KO was smaller than that in WT. Immunoreactive (ir) beta-EP contents in the AP of CRH KO were not significantly different from those of WT. In order to determine the different molecule profile of POMC-related peptides between WT and CRH KO, ir beta-EP contents extracted from AP of WT and CRH KO were assayed by gel filtration chromatography. The gel filtration analyses revealed that a higher molecular weight form of ir beta-EP, putative POMC, was increased in CRH KO, but the beta-EP peak level was small and similar between two groups. These results suggest that CRH has little influence on the basal release of ACTH and prohormone convertase-2 processing enzyme. On the other hand, it is essential for ACTH secretion under stress conditions, and CRH would affect on the prohormone convertase-1/3 processing enzyme in AP.

A report of 7 cases of adrenal tumors secreting both cortisol and aldosterone.

We report 7 cases of adrenal tumors with concurrent increases in cortisol and aldosterone secretion, which we have examined over the last 2 years. We also present the pathology of excised specimens based on immunohistochemical staining, as well as endocrinological findings. Four patients were male and 3 female; 6 were first diagnosed as suffering from primary aldosteronism (PA) and one as adrenal preclinical Cushing's syndrome (PCS). Plasma cortisol concentrations at midnight were greater than 2 microg/dl in 6 patients and more than 1 microg/dl in the dexamethasone suppression test with an 8 mg dose in all patients. This indicates that dexamethasone did not inhibit the secretion of cortisol. No increase in renin activity was seen in the renin-producing irritable test in any of the patients. Immunohistochemical staining showed not only the presence of aldosteronoma, but also the expression of P-450c17, which is involved in the biosynthesis of cortisol, indicating that both cortisol and aldosterone were concurrently synthesized. With regard to the function of adrenal tumors, we suggest that concurrent secretion of cortisol and aldosterone are not rare and that immunohistochemical examination of the surgically-extirpated specimen is important for diagnosis.