BACKGROUND: To identify genotypes associated with neovascular age-related macular degeneration (nAMD) and investigate the associations between genotype variations and anti-vascular endothelial growth factor (VEGF) treatment response.
METHODS: This observational, retrospective, case series study enrolled patients diagnosed with nAMD who received anti-VEGF treatment in National Taiwan University Hospital with at least one-year follow-up between 2012 and 2020. A genome-wide association study (GWAS) was conducted on enrolled patients and controls. Correlations between the genotypes identified from GWAS and the treatment response of functional/anatomical biomarkers, including visual acuity (VA), presence of intraretinal or subretinal fluid (SRF), serous or fibrovascular pigmented epithelium detachment (PED), and disruption of the ellipsoid zone (EZ), were analysed.
RESULTS: In total, 182 patients with nAMD and 1748 controls were enrolled. GWAS revealed 16 single nucleotide polymorphisms (SNPs) as risk loci for nAMD, including seven loci in CFH and ARMS2/HTRA1 and nine novel loci, including rs117517872 and rs79835234(COPB2-DT), rs7525578(RAP1A), rs2123738(LOC105376755), rs1374879(CNTN3), rs3812692(SAR1A), rs117501587(PRKCA), rs9965945(CNDP1), and rs189769231(MATK). Our study revealed rs800292(CFH), rs11200638(HTRA1), and rs2123738(LOC105376755) correlated with poor treatment response in VA (P = 0.005), SRF (P = 0.044), and fibrovascular PED (P = 0.007), respectively. Rs9965945(CNDP1) was correlated with poor response in disruption of EZ (P = 0.046) and serous PED (P = 0.049).
CONCLUSIONS: Among the 16 SNPs found in the GWAS, four loci-CFH, ARMS2/HTRA1, and two novel loci-were correlated with the susceptibility of nAMD and anatomical/functional responses after anti-VEGF treatment.

UNASSIGNED: Hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, used in the treatment of renal anemia, hold the potential to increase the production of vascular endothelial growth factors. Therefore, HIF-PH inhibitors may exacerbate retinal hemorrhage in diseases such as diabetic retinopathy. Here, we present a case involving the administration of an HIF-PH inhibitor, resulting in the exacerbation of retinal hemorrhage in a patient with diabetic retinopathy.
UNASSIGNED: A 32-year-old man with diabetes mellitus and renal anemia caused by diabetic nephropathy was referred to our department for ophthalmic examination, revealing diabetic retinopathy with scattered retinal hemorrhages, exudates, and diabetic maculopathy in both eyes. Darbepoetin alfa was initially administered and switched to the HIF-PH inhibitor roxadustat on day 74. By day 88, fresh retinal hemorrhage was observed in the right eye. On day 132, the retinal hemorrhage had further worsened, with new preretinal hemorrhage in both eyes. Roxadustat was discontinued, replaced with darbepoetin alfa, resulting in retinal hemorrhage improvement by day 181 (49 days post-roxadustat cessation). On day 201, fundus hemorrhage further improved, optical coherence tomography showed no macular edema or subretinal fluid, and the retina was thinning. Fluorescein angiography showed neovascular vessels, active fluorescein leakage, and extensive avascular areas in both eyes, prompting pan-retinal photocoagulation. Visual acuity remained stable throughout treatment.
UNASSIGNED: Patients with advanced diabetic retinopathy taking HIF-PH inhibitors should be aware of retinal hemorrhage exacerbations. If observed, the treatment plan, including discontinuation of the HIF-PH inhibitor or switching to another agent, should be discussed with a diabetologist, nephrologist, and ophthalmologist.

A 75-year-old woman with colon cancer and distant metastases was treated with fluorouracil, levofolinate, and irinotecan (FOLFIRI) plus bevacizumab postoperatively. During the 32nd course, the patient developed massive proteinuria, and only bevacizumab was discontinued; the proteinuria improved rapidly over time. However, more than six months later, the patient developed massive proteinuria again, and her renal function declined. Renal biopsy revealed glomerular microangiopathy with prominent foam cell infiltration into the glomerulus, which was thought to be caused by chronic endothelial cell damage to the glomerular capillaries. Endothelial cell damage is thought to be caused not only by the inhibition of vascular endothelial growth factor action of bevacizumab in the glomerular capillary but also by the cytotoxicity of the concomitant anticancer drugs and coexisting clinical conditions such as dyslipidemia and hypertension. After discontinuing anticancer agents and intensifying diet and antihypertensive therapy, proteinuria and dyslipidemia slowly improved; however, it became difficult to continue adequate chemotherapy, and the tumor marker levels worsened. Combination therapies, including molecular targeted agents, have become common, and the side effects of anticancer agents are expected to continue to be complicated. To prevent the onset and severity of renal complications, management of blood pressure, lipid level, and glucose metabolism, as well as multidisciplinary medical management, including dietary therapy, is required.

Preeclampsia (PE) is a systemic vascular disorder, is caused by an imbalance of pro- and anti-angiogenic factors that directly affect endothelial function. Vascular endothelial growth factor A (called VGF), a pro-angiogenic factor associated with endothelial dysfunction, plays an important role in the pathophysiology of PE. Therefore, we investigated the relationship between -2549 insertion/deletion (I/D) variant in the VEGF promoter region and PE in pregnant women in Turkey. A total of 100 patients diagnosed with PE and 118 healthy pregnants were recruited. To genotype the VEGF I/D variant, the PCR method was used. The results of analyses were evaluated for statistical significance. The weight of the PE group was found to be higher before and after pregnancy than the control group (p = 0.009, p = 0.012, respectively). The birth weight, and Apgar score (1 min and 5 min) of the PE group was lower than that of the control group (p= <0.001, p= <0.001, p= <0.001, respectively). The mean 24-h urine protein, ALT and AST levels in the PE group were higher than the control group (p= <0.001, p= <0.001, p= <0.001, respectively). There was no significant difference between the patients and the controls in terms of VEGF I/D genotype and allele distribution. There was no deviation from HWA for VEGF I/D variant in patient and control groups. In the patients carrying D/D genotype and the D allele had low gestational week and birth weight. Knowing the risk factors for PE is very important for its prevention and treatment. In conclusion, for the first time, our results supported that the VEGF I/D variant is not a risk factor for the development of PE in a group of Turkish populations. But VEGF I/D variant D/D genotype associated with low gestational week and birth weight while I/D genotype seems to be protective from high systolic blood pressure.

The number of patients with diabetic nephropathy is increasing worldwide and it is important to understand the underlying pathological mechanisms of the disease. In early stage diabetic nephropathy, the hyperglycemic environment leads to vascular endothelial cell damage, resulting in overexpression of vascular endothelial growth factor (VEGF) in podocytes and renal pathology of glomerular hypertrophy, glomerular basement membrane thickening, and mesangial hyperplasia. In diabetic nephropathy, renal thrombotic microangiopathy (TMA) develops and the nephropathy progressively worsens in some cases of severe glomerular podocyte damage. Further, receptor tyrosine kinase inhibitors (RTKIs) may suppress VEGF secretion via VEGF receptor-2 tyrosine kinase inhibition in podocytes, which results in renal TMA and rapid deterioration of diabetic nephropathy. Osimertinib, a third-generation irreversible epidermal growth factor receptor (EGFR)-TKI, is approved as a first-line treatment agent for metastatic or locally advanced EGFR mutation-positive non-small cell lung cancer. We encountered a case of a patient with diabetic nephropathy with lung adenocarcinoma treated with osimertinib, whose condition deteriorated from early nephropathy to end-stage renal disease in approximately 4 months. The patient had early diabetic nephropathy, but the use of a RTKI suppressed VEGF expression in podocytes, resulting in the induction of renal TMA and the development of rapidly progressive diabetic nephropathy.

Vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) serve key roles in the regulation of vascular development, revascularization and vasopermeability in the endometrium, decidua and trophoblasts. Furthermore, both VEGF and PlGF are modulators of embryonic vascular development. Thus, the present study aimed to investigate the serum levels of VEGF and PlGF in female patients with early threatened abortion (TA) who experienced preterm delivery. The present case-control study included 130 pregnant patients with or without TA that were admitted to The Maternal and Childcare Hospital of Nantong University from January 2019 to January 2022. Patients were divided into two groups: i) Group A, which included 55 patients diagnosed with TA with slight vaginal bleeding and closed cervical internal os within the first 6-12 weeks of pregnancy; and ii) group B, which included 75 patients with healthy asymptomatic pregnancy. Blood samples were obtained from all patients and VEGF and PlGF levels were examined prior to treatment, and the chi-squared, Student\'s t-test and two-way ANOVA followed by Bonferroni\'s post hoc analysis were used to analyze statistical differences between the two patient groups. Results of the present study demonstrated that patients with TA had significantly lower levels of VEGF and PlGF, compared with the controls. In patients with or without TA, the levels of serum PlGF in the preterm delivery group were significantly decreased compared with patients that did not experience preterm delivery. However, there was no significant difference in the levels of VEGF between patients with or without preterm delivery. In addition, lower levels of PlGF, compared with those in patients without TA, may be associated with an increased risk of preterm delivery in patients without early TA.

暂无摘要。

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare multisystem disease characterized by plasma cell dyscrasia and overproduction of vascular endothelial growth factor, which is related to disease activity. Recent treatment strategies have improved survival of patients suffering from this disorder; however, ischemic stroke remains a poor prognostic factor. POEMS patients with ischemic stroke frequently develop cerebral large artery stenosis/occlusion, followed by progressive stroke. Post literature review, we present an ischemic stroke case of quasi-moyamoya disease linked with this syndrome that was successfully treated with surgical revascularization. A 41-year-old woman diagnosed with POEMS syndrome developed progressive ischemic stroke due to quasi-moyamoya disease, despite decreased vascular endothelial growth factor level with lenalidomide and dexamethasone treatment. She underwent superficial temporal artery to middle cerebral artery bypass with encephalo-duro-myo-synangiosis bilaterally. The postoperative course was uneventful. Two years and five months after the stroke, neuroimaging demonstrated bypass patency, neovascularization after encephalo-duro-myo-synangiosis, and no recurrence of stroke. Our case is the first to report successful surgical revascularization for a POEMS patient. Surgical revascularization may be a useful treatment option for patients with quasi-moyamoya disease associated with POEMS syndrome, especially for those who develop refractory ischemic stroke despite reduced vascular endothelial growth factor level.

BACKGROUND: Polyneuropathy organomegaly endocrinopathy M-protein and skin changes (POEMS) syndrome is a rare paraneoplastic syndrome caused by a potential plasma cell tumor. The clinical manifestations of POEMS syndrome are diverse. Due to the insidious onset and lack of specific early-stage manifestations, POEMS syndrome is easily misdiagnosed or never diagnosed, leading to delayed treatment. Neurological symptoms are usually the first clinical manifestation, while ascites is a rare symptom in patients with POEMS syndrome.
METHODS: A female patient presented with unexplained ascites as an initial symptom, which is a rare early-stage manifestation of the condition. After 1 year, the patient gradually developed progressive renal impairment, anemia, polyserosal effusion, edema, swollen lymph nodes on the neck, armpits, and groin, and decreased muscle strength of the lower extremities. The patient was eventually diagnosed with POEMS syndrome after multidisciplinary team discussion. Treatment comprised bortezomib + dexamethasone, continuous renal replacement therapy, chest and abdominal closed drainage, transfusions of erythrocytes and platelets, and other symptomatic and supportive treatments. The patient\'s condition initially improved after treatment. However, then her symptoms worsened, and she succumbed to the illness and died.
CONCLUSIONS: Ascites is a potential early manifestation of POEMS syndrome, and this diagnosis should be considered for patients with unexplained ascites. Furthermore, multidisciplinary team discussion is helpful in diagnosing POEMS syndrome.

We report a rare case of ovarian hyperstimulation syndrome (OHSS) in a 28-year-old woman with breast cancer and with a history of polycystic ovary syndrome (PCOS) despite treatment with letrozole and gonadotropin-releasing hormone agonist (GnRH-a) triggering in a GnRH antagonist (GnRH-ant) protocol without the administration of any human chorionic gonadotropin (hCG) for luteal-phase support. The patient, who underwent controlled ovarian syndrome (COS)-oocyte cryopreservation before chemotherapy, required hospitalization. Complete recovery was achieved after treatment with volume expanders, human albumin, and cabergoline. Based on our case and literature review, it is possible to establish that estradiol (E2) modulation with letrozole and GnRH-a triggering does not eliminate the risk of OHSS. Furthermore, it is advisable to postpone GnRH-a depot to minimize the risk of OHSS after the suspension of letrozole, following menstruation or at least 7-8 days after triggering. It would be desirable to identify high-risk patients, also on a genetic basis, in order to avoid delays in oncologic treatments that could strongly impact life expectancy.