Notch signaling regulates UNC5B to suppress endothelial proliferation, migration, junction activity, and retinal plexus branching.

Notch signaling guides vascular development and function by regulating diverse endothelial cell behaviors, including migration, proliferation, vascular density, endothelial junctions, and polarization in response to flow. Notch proteins form transcriptional activation complexes that regulate endothelial gene expression, but few of the downstream effectors that enable these phenotypic changes have been characterized in endothelial cells, limiting our understanding of vascular Notch activities. Using an unbiased screen of translated mRNA rapidly regulated by Notch signaling, we identified novel in vivo targets of Notch signaling in neonatal mouse brain endothelium, including UNC5B, a member of the netrin family of angiogenic-regulatory receptors. Endothelial Notch signaling rapidly upregulates UNC5B in multiple endothelial cell types. Loss or gain of UNC5B recapitulated specific Notch-regulated phenotypes. UNC5B expression inhibited endothelial migration and proliferation and was required for stabilization of endothelial junctions in response to shear stress. Loss of UNC5B partially or wholly blocked the ability of Notch activation to regulate these endothelial cell behaviors. In the developing mouse retina, endothelial-specific loss of UNC5B led to excessive vascularization, including increased vascular outgrowth, density, and branchpoint count. These data indicate that Notch signaling upregulates UNC5B as an effector protein to control specific endothelial cell behaviors and inhibit angiogenic growth.

Reactive cutaneous capillary endothelial proliferation following camrelizumab monotherapy or combination therapy for multi-cancers: a large-scale pooled analysis of 10 studies in China.

Background: Skin toxicities are the most common adverse events related to immunotherapy, such as reactive cutaneous capillary endothelial proliferation (RCCEP) following treatment with the anti-programmed cell death-1 antibody camrelizumab. Objective: This study aimed to comprehensively analyze the clinical features and prognostic value of RCCEP in patients with malignancies who received camrelizumab alone (Camre) or in combination with the angiogenesis-targeted agent apatinib (Camre-Apa) or chemotherapy (Camre-Chemo). Design: A large-scale pooled analysis. Methods: Individual patient-level data were derived from 10 clinical trials of camrelizumab monotherapy, camrelizumab plus apatinib, or camrelizumab plus chemotherapy (n = 1305). Results: RCCEP occurred in 77.0% (516/670) of patients with Camre, 23.6% (70/296) with Camre-Apa, and 67.8% (230/339) with Camre-Chemo. Most RCCEP lesions were grade 1 or 2 in severity. The median time to onset was 0.8 months [interquartile range (IQR), 0.6-1.2] with Camre, 5.0 months (IQR, 2.7-8.0) with Camre-Apa, and 1.6 months (IQR, 1.0-4.2) with Camre-Chemo; and the median duration was 4.8 months (IQR, 2.6-8.8), 4.4 months (IQR, 1.7-8.9), and 7.2 months (IQR, 4.1-14.3), respectively. In all the three groups, patients with RCCEP showed significantly better clinical outcomes compared with those without [objective response rate: 23.8% versus 1.9% with Camre, 48.6% versus 21.2% with Camre-Apa, and 78.7% versus 54.1% with Camre-Chemo; median progression-free survival: 3.2 versus 1.7 months (hazard ratio (HR) = 0.36), 10.2 versus 4.5 months (HR = 0.39), and 12.7 versus 7.3 months (HR = 0.38); median overall survival: 13.3 versus 3.8 months (HR = 0.34), 29.2 versus 13.5 months (HR = 0.46), and not reached versus 12.8 months (HR = 0.19); all p < 0.0001]. Conclusion: Although RCCEP occurred frequently with camrelizumab, most lesions were mild and self-limiting. The occurrence of RCCEP was strongly associated with the antitumor activity and survival of camrelizumab, both as monotherapy and in combination therapy.

A case report and literature review on reactive cutaneous capillary endothelial proliferation induced by camrelizumab in a nasopharyngeal carcinoma patient.

Camrelizumab, a monoclonal antibody, blocks programmed cell death protein-1 from binding to T cells and programmed cell death ligand 1 on tumor cells, thereby ensuring sustained T cell activation and blocking immune escape of various types of cancer, including nasopharyngeal carcinoma. Reactive cutaneous capillary endothelial hyperplasia (RCCEP) is the most common immune-related adverse event in patients treated with camrelizumab. We report a case nasopharyngeal carcinoma in a patient with camrelizumab-induced RCCEP. A 68-year-old man diagnosed with nasopharyngeal carcinoma developed RCCEP at multiple locations after 3 months of camrelizumab treatment. RCCEP of the right lower eyelid affected closure of the right eye. In this report, we also reviewed previous literature on camrelizumab-induced RCCEP. In summary, the mechanism underlying camrelizumab-induced RCCEP remains unclear. RCCEP typically gradually subsides after discontinuing camrelizumab treatment. Larger nodules can be treated with lasers, ligation, or surgery. Although surgical excision is effective, RCCEP may recur in patients undergoing camrelizumab treatment. RCCEP management may not be required in the absence of adverse effects on the patient's daily life.

Reactive cutaneous capillary endothelial proliferation predicted the efficacy of camrelizumab in patients with recurrent/metastatic head and neck squamous cell carcinoma

Background: Reactive cutaneous capillary endothelial proliferation (RCCEP), a special adverse event (AE) only observed in patients treated with camrelizumab, was reported to be correlated with the efficacy of camrelizumab in patients with advanced hepatocellular carcinoma. This study to analyze the possible correlation between the occurrence of RCCEP and efficacy of camrelizumab in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Material and Methods: In this study, we retrospectively analyzed the efficacy and RCCEP occurrence of camrelizumab in 58 patients with R/M HNSCC in the Shanghai Ninth People's Hospital affiliated to Shanghai JiaoTong University School of Medicine between January 2019 and June 2022. Kaplan-Meier analysis was used to assess the correlation between the occurrence of RCCEP and the survival of enrolled patients, and COX multifactor analysis was adopted to evaluate associated factors that affected the efficacy of camrelizumab immunotherapy. Results: A significant correlation between the incidence of RCCEP and a higher objective response rate was observed in this study (p=0.008). The occurrence of RCCEP was associated with better median overall survival (17.0 months vs. 8.7 months, p<0.0001, HR=5.944, 95% CI:2.097-16.84) and better median progression-free survival (15.1 months vs. 4.0 months, p<0.0001, HR=4.329,95% CI:1.683-11.13). In COX multifactor analysis, RCCEP occurrence was also an independent prognostic factor affecting OS and PFS in patients with R/M HNSCC. Conclusions: The occurrence of RCCEP can show a better prognosis, it could be used as a clinical biomarker to predict the efficacy of camrelizumab treatment. (AU)

A 67-Year-Old Man with Grade 3 Reactive Cutaneous Capillary Endothelial Proliferation Induced by Camrelizumab First Manifested in the Oral Mucosa - A Case Report.

Reactive cutaneous capillary endothelial proliferation (RCCEP) is the most common immune-related adverse event induced by camrelizumab (SHR-1210). Very rare cases have been reported in oral tissues, especially the oral mucosa. We reported a 67-year-old male with Grade 3 RCCEP. Multiple dome-shaped and bright red papules were first observed in the oral mucosa, which gradually developed on his lip, face, scalp, neck, foot, calf, abdomen and groin. The patient's symptoms gradually improved at 4 weeks after SHR-1210 discontinuation and were mostly relieved at 7 weeks after discontinuation. Our findings revealed that oral examination should be performed regularly during SHR-1210 treatment.

Reactive Cutaneous Capillary Endothelial Proliferation Caused by Camrelizumab: Sixteen Case Reports.

To investigate the regularity and characteristics of adverse drug reaction (ADR) of reactive cutaneous capillary endothelial proliferation caused by Camrelizumab, so as to provide reference for clinical rational use of drugs. Searching for case reports of Camrelizumab-induced reactive cutaneous capillary endothelial proliferation (RCCEP) in databases such as China Biology Medicine disc, VIP Database, CNKI, Wanfang Medical, PubMed, Wiley online library, Embase with "Carritzumab/Ericab," "SHR-1210," "Reactive cutaneous capillary endothelial proliferation," "Reactive capillary hemangiomas," and "Capillary proliferation" as search terms. The retrieval time is from the establishment of the database to February 2022. After eliminating clinical trials and incomplete literature, information of patients included in the literature was analyzed, which included gender, age, reason for medication, usage and dosage, time of ADR, concomitant medication, clinical manifestations, intervention measures, outcomes of patients, etc. A total of 11 articles involving 16 patients were included, including 11 males and five females, with an average age of 60.5 years. Reasons for medication included nine cases of non-small cell lung cancer (NSCLC), four cases of liver cancer, one case of small cell lung cancer (SCLC), one case of synovial sarcoma, and one case of Hodgkin lymphoma. Thirteen patients recorded in detail that the dosage of Camrelizumab was 200 mg, and the frequency of medication was q2w~q4w. Eight patients were treated with Camrelizumab alone, and eight patients were treated with combined medication. RCCEP occurred in nine patients after the first medication, and in seven patients after two-four cycles of medication, the average medication cycle was two cycles, and the average occurrence time was 12.5 days after the last medication. The main clinical manifestations were that several different sizes of growths such as red nevus-like, pearl-like, and mulberry-like growths appear on the head, face, neck, torso, limbs, and other parts of the body, all of which were grade 1-2. The RCCEP of all patients was controlled after treatment. During the treatment, 11 patients were stable and five patients were local remission. RCCEP is caused by Camrelizumabis a special skin immune response, which will not cause life-threatening to patients. However, clinicians and pharmacists should be familiar with the characteristics and regularities of the adverse reaction, to do a good job in medication monitoring and management, as for ensuring the safety of patients with medication.

Spinal Cord Blood Vessels in Aged Mice Show Greater Levels of Hypoxia-Induced Vascular Disruption and Microglial Activation.

In response to chronic mild hypoxia (CMH, 8% O2), spinal cord blood vessels launch a robust angiogenic response that is associated with transient disruption of the blood-spinal cord barrier (BSCB) which, in turn, triggers a microglial vasculo-protective response. Because hypoxia occurs in many age-related conditions, the goal of this study was to define how aging influences these responses by comparing events in young (8-10 weeks) and aged (20 months) mice. This revealed that aged mice had much greater (3-4-fold) levels of hypoxic-induced BSCB disruption than young mice and that, while the early stage of the angiogenic response in aged mice was no different to young mice, the maturation of newly formed vessels was significantly delayed. Interestingly, microglia in the spinal cords of aged mice were much more activated than young mice, even under normoxic conditions, and this was further enhanced by CMH, though, surprisingly, this resulted in reduced microglial clustering around leaky blood vessels and diminished vasculo-protection. Vascular disruption was associated with loss of myelin in spinal cord white matter (WM) in both young and aged mice. Furthermore, it was notable that the spinal cord of aged mice contained a lower density of Olig2+ oligodendroglial cells even under normoxic conditions and that CMH significantly reduced the density of Olig2+ cells in spinal cord WM of the aged, but not the young, mice. These results demonstrate that spinal cord blood vessels of aged mice are much more vulnerable to the damaging effects of hypoxia than young mice, in part due to the reduced vasculo-protection conferred by chronically activated microglial cells. These observations may have implications for the pathogenesis and/or treatment of spinal cord diseases such as amyotrophic lateral sclerosis (ALS) and suggest that an improvement in microglial function could offer therapeutic potential for treating these age-related conditions.

Complete remission of reactive cutaneous capillary endothelial proliferation caused by the programmed cell death-1 inhibitor camrelizumab achieved through thalidomide monotherapy: A case report.

Reactive cutaneous capillary endothelial proliferation (RCCEP) is a common adverse effect of the anti-programmed cell death-1 (PD-1) monoclonal antibody camrelizumab and usually occurs on the skin. This condition causes bleeding nodules of varying severity depending on disease grade; these affect a person's appearance and quality of life. The exact mechanism remains elusive and its occurrence in visceral organs has not been previously reported, to the best of our knowledge. Furthermore, there is currently a lack of standard, uniform treatments. The present study reported on a patient who experienced RCCEP during treatment with camrelizumab and benefited greatly from thalidomide, which caused no serious adverse events. An elderly Chinese female initially diagnosed with stage II endometrial cancer had previously undergone surgery, radiotherapy and intravenous chemotherapy but developed multiple metastases in the peritoneum and vaginal remnant. The patient was subsequently prescribed camrelizumab after systemic treatment failed. Soon after commencing treatment with this PD-1 inhibitor, the patient developed RCCEP, whereupon oral low-dose thalidomide monotherapy (100 mg nightly) was prescribed. At two weeks after commencing thalidomide, the RCCEP symptoms were alleviated. Based on this patient's successful treatment, it is suggested that low-dose thalidomide may be an alternative intervention for patients with camrelizumab-induced RCCEP.

A combination of anti-PD-1 therapy and apatinib successfully treated a patient with EGFR mutation-negative advanced lung adenocarcinoma: A case report.

Here, we report the case of a patient with advanced lung adenocarcinoma with negative driver genes, who benefited from treatment with anti-programmed cell death-1 (anti-PD-1) therapy combined with a low dose of apatinib. From February 2020, the patient was treated with camrelizumab combined with pemetrexed disodium. The treatment regimen was adjusted to camrelizumab combined with a low dose of apatinib every 3 weeks because the patient could not tolerate the side effects of the previous chemotherapy, and camrelizumab led to reactive cutaneous capillary endothelial proliferation (RCCEP). After six cycles of camrelizumab plus a low dose of apatinib, the curative effect achieved was complete response (CR), with milder symptoms of RCCEP than before. Until the follow-up time of March 2021, the efficacy evaluation reached CR and the symptoms of RCCEP disappeared. This case report provides a theoretical basis for camrelizumab combined with a low dose of apatinib for the treatment ofcarcinoma patients with advanced lung adenocarcinoma with negative driver genes.

Oscillatory shear stress promotes vein graft intimal hyperplasia via NADPH oxidase-related pathways.

Background: Uncontrolled intimal hyperplasia (IH) after autologous saphenous vein grafting triggers a high restenosis rate; however, its association with the activation of NADPH oxidase (NOX)-related pathways is unclear. Here, we investigated the effects and mechanism of oscillatory shear stress (OSS) on grafted vein IH. Methods: Thirty male New Zealand rabbits were randomly divided into control, high-OSS (HOSS), and low-OSS (LOSS) groups, and the vein grafts were harvested after 4 weeks. Hematoxylin and eosin staining and Masson staining assays were used to observe morphological and structural changes. Immunohistochemical staining was used to detect α-SMA, PCNA, MMP-2, and MMP-9 expression. Immunofluorescence staining was used to observe reactive oxygen species (ROS) production in the tissues. Western blotting was used to determine the expression levels of pathway-related proteins (NOX1, NOX2, AKT, p-AKT, and BIRC5), PCNA, BCL-2, BAX, and caspase-3/cleaved caspase-3 in tissues. Results: Blood flow velocity was lower in the LOSS group than in the HOSS group, while vessel diameter did not change significantly. Shear rate was elevated in both HOSS and LOSS groups but was higher in the HOSS group. Additionally, vessel diameter increased with time in the HOSS and LOSS groups, whereas flow velocity did not. Intimal hyperplasia was significantly lower in the LOSS group than in the HOSS group. IH was dominated by smooth muscle fibers in the grafted veins and collagen fibers in the media. OSS restriction significantly reduced the α-SMA, PCNA, MMP-2, and MMP-9 levels. Moreover, ROS production and the expression of NOX1, NOX2, p-AKT, BIRC5, PCNA, BCL-2, BAX, and cleaved caspase-3 were phase-reduced in LOSS compared to the levels in the HOSS group. Total AKT was not differentially expressed among the three groups. Conclusion: OSS promotes the proliferation, migration, and survival of subendothelial vascular smooth muscle cells in grafted veins, which may be related to the regulation of downstream p-AKT/BIRC5 levels through the increased production of ROS by NOX. Drugs inhibiting this pathway might be used to prolong vein graft survival time.

An epulis-like camrelizumab related reactive cutaneous capillary endothelial proliferation (RCCEP) in the oral cavity: A case report.

BACKGROUND: Immunotherapy, especially anti-PD-1 and anti-PD-L1 antibodies, have observably improved the overall survival of patients with advanced solid tumors following the unavoidable immune-related adverse events (irAEs). Camrelizumab is a novel anti-PD-1 agent with the reported most common irAEs of reactive cutaneous capillary endothelial proliferation (RCCEP). Despite it is widely occurred in the skin, oral RCCEP is rarely reported. CASE SUMMARY: A 59-year-old man complained about a painless nodule on left mandibular gingiva for two weeks. He started to inject Camrelizumab because of the recurrence of esophageal squamous cell carcinoma two month ago. An 8 mm lesion was observed on his mucosa. Several disseminated bright purple red papules were then found on his skins. The oral lesion and one lesion on his face was removed by surgery. After the final diagnosis of reactive cutaneous capillary endothelial proliferation was confirmed by histological examination. Other operable lesions on his face were removed by ligation. All the removed lesions had a good prognosis without recurrence within the follow-up visit. CONCLUSION: With the widespread use of Camrelizumab in other solid tumors, the occurrence of oral RCCEP will increase. Surgery and ligation are both effective treatment for RCCEP with a good prognosis.

Risk of reactive cutaneous capillary endothelial proliferation induced by camrelizumab in patients with non-small cell lung cancer: a retrospective study.

Background: Reactive cutaneous capillary endothelial proliferation (RCCEP) is a common immune-related adverse event (irAE) related to camrelizumab. This study aimed to investigate the risk factors of RCCEP and its association with patients' survival. Methods: This retrospective study collected the data of consecutive patients with non-small cell lung cancer (NSCLC) who received camrelizumab between January 2019 and December 2021. Baseline characteristics and peripheral blood biomarkers were collected. The outcomes were the occurrence of RCCEP and progression-free survival (PFS). The factors associated with RCCEP were analyzed using univariable and multivariable logistic regression. The association between PFS and RCCEP occurrence was analyzed by the log-rank test. Results: Among the 80 patients included, 24 (30.0%) developed RCCEP, and 56 did not. Among the patients with RCCEP, only four reported the occurrence of grade 3-4 RCCEP. The multivariable analysis revealed that a percentage of eosinophil (EOS%) >1.75% was significantly associated with a higher risk of RCCEP [odds ratio (OR) =4.484; 95% confidence interval (CI): 1.139-17.651] and camrelizumab combined with an anti-angiogenic agent was significantly associated with a lower risk of RCCEP (OR =0.188; 95% CI: 0.055-0.639). The median PFS was numerically longer in patients with RCCEP than in those who did not (17 vs. 9 months, P=0.069). Patients who had baseline EOS% >1.75% and received camrelizumab without an anti-angiogenic agent had a longer median PFS than those who did not (17 vs. 9 months, P=0.011). Conclusions: Baseline EOS% >1.75% and camrelizumab without an anti-angiogenic agent were risk factors of RCCEP and might be associated with better survival in patients with NSCLC.

Cutaneous adverse events associated with PD-1 inhibitor-based therapy in patients with non-small-cell lung cancer.

Aim: To analyze the incidence and characteristics of cutaneous adverse events (CAEs) in non-small-cell lung cancer patients treated with PD-1 inhibitor-based therapy. Methods: A total of 150 non-small-cell lung cancer patients under PD-1 inhibitor-based therapy from February 2018 to September 2021 were included and were followed up with regularly. Results: Over one-half of patients (88/150; 58.7%) had CAEs. Reactive cutaneous capillary endothelial proliferation, maculopapular rash and pruritus were the most common CAEs. The incidences of CAEs were 50.0 (18/36), 67.0 (50/75) and 51.3% (20/39) with PD-1 inhibitor monotherapy, PD-1 inhibitor in combination with chemotherapy and PD-1 inhibitor in combination with antivascular/targeted therapy, respectively. Conclusion: CAEs occur frequently in PD-1 inhibitor-based therapy but are generally tolerable.

Recall of reactive cutaneous capillary endothelial proliferation (RCCEP) induced by stereotactic body radiation therapy (SBRT) in a patient with lung squamous cell carcinoma.

Camrelizumab (SHR-1210) is a humanized IgG4 monoclonal anti-programmed cell death protein 1 (PD-1) antibody that has been shown to inhibit the binding of PD-1 to PD-L1, thereby blocking the immune escape of various types of cancer, including lung squamous cell carcinoma (LSCC). Reactive cutaneous capillary endothelial proliferation (RCCEP) is the most common adverse event in camrelizumab-treated patients. Here, we introduce a case of LSCC with recall RCCEP induced by stereotactic body radiation therapy (SBRT). A 76-year-old LSCC patient developed RCCEP when he received camrelizumab and chemotherapy. After discontinuing camrelizumab treatment, the RCCEP lesions spontaneously regressed and fell off. However, when the patient received subsequent SBRT, the RCCEP occurred again at the same sites. This case may provide clues for additional study of the immune reactivation effect of SBRT or the underlying mechanism of RCCEP.

Exaggerated hypoxic vascular breakdown in aged brain due to reduced microglial vasculo-protection.

In a recent study of young mice, we showed that chronic mild hypoxia (CMH, 8% O2 ) triggers transient blood-brain barrier (BBB) disruption, and that microglia play an important vasculo-protective function in maintaining BBB integrity. As hypoxia is a common component of many age-related diseases, here we extended these studies to aged mice and found that hypoxia-induced vascular leak was greatly amplified (5-fold to 10-fold) in aged mice, being particularly high in the olfactory bulb and midbrain. While aged mice showed no obvious difference in the early stages of hypoxic angiogenic remodeling, the compensatory increase in vascularity and vessel maturation was significantly delayed. Compared with young brain, microglia in the normoxic aged brain were markedly activated, and this was further increased under hypoxic conditions, but paradoxically, this correlated with reduced vasculo-protection. Microglial depletion studies showed that microglial still play an important vasculo-protective role in aged brain, but interestingly, partial attenuation of microglial activation with minocycline resulted in fewer vascular leaks and reduced loss of endothelial tight junction proteins. Taken together, these findings suggest that increased BBB disruption in hypoxic aged mice can be explained both by a delayed vascular remodeling response and reduced microglial vasculo-protection. Importantly, they show that overly activated microglia in the aged brain are less effective at maintaining vascular integrity, though this can be improved by reducing microglial activation with minocycline, suggesting therapeutic potential for enhancing BBB integrity in the hypoxia-predisposed elderly population.

Anlotinib improved the reactive cutaneous capillary endothelial proliferation induced by camrelizumab: a case report.

Background: Programmed cell death protein-1 (PD-1) or its ligand PD-L1 monoclonal antibodies, opening a new era of tumor immunotherapy, and they have significantly improved the overall survival of many patients with advanced solid tumors. However, in addition to its effectiveness, we should also pay attention to its adverse effects. The instructions of the PD-1 inhibitor camrelizumab clearly indicate that reactive cutaneous capillary endothelial proliferation (RCCEP) is the most common adverse reaction; it is common for many immune checkpoint inhibitors (ICIs). Here we describe a case that anlotinib improved RCCEP induced by anti-PD-1 blockade camrelizumab with some focus on further management of this symptoms. Case Description: A 57-year-old man with squamous cell carcinoma of the upper lobe of the left lung, and with mediastinal lymphocyte and liver metastasis, received the fifth cycle of chemotherapy and immunotherapy with camrelizumab (200 mg, every 3 weeks). Four days after treatment with camrelizumab, the patient's face, head, neck, and chest skin had multiple scattered bright red round papules, which were diagnosed as RCCEP. The patient was treated with oral anlotinib (8 mg, once a day). After 5 days of treatment, the symptoms of RCCEP gradually eased, and the patient was discharged. Conclusions: In conclusion, we have reported a case of RCCEP induced by anti-PD-1 blockade camrelizumab. The patient was given oral anlotinib to relieve the symptoms of RCCEP. Suggesting that anlotinib could be a potential management to reduce the adverse reactions who are treated with camrelizumab. The risk for RCCEP should always be kept in mind during camrelizumab treatment.

Thalidomide for prevention of camrelizumab-induced reactive cutaneous capillary endothelial proliferation.

OBJECTIVES: The study evaluated the efficacy of thalidomide in prevention of camrelizumab-induced reactive cutaneous capillary endothelial proliferation (RCCEP). METHODS: In this study, patients treated with camrelizumab plus thalidomide or camrelizumab alone were included. The occurrences, onset time, severity of RCCEP and the adverse effect of thalidomide were analysed. RESULTS: A total of 19 patients were enrolled. The incidence of RCCEP in thalidomide group (2/9, 22.2%) was significantly lower than that in camrelizumab group (8/10, 80%). The median onset time of RCCEP was 5 weeks and 4 weeks respectively. The adverse events of thalidomide were mild, and no treatment-associated interruption was observed. CONCLUSIONS: Thalidomide showed a promising in prevention of the RCCEP in patients receiving camrelizumab therapy with an acceptable safety profile.

Mild hypoxia triggers transient blood-brain barrier disruption: a fundamental protective role for microglia.

We recently demonstrated that when mice are exposed to chronic mild hypoxia (CMH, 8% O2), blood vessels in the spinal cord show transient vascular leak that is associated with clustering and activation of microglia around disrupted vessels. Importantly, microglial depletion profoundly increased hypoxia-induced vascular leak, implying that microglia play a critical role maintaining vascular integrity in the hypoxic spinal cord. The goal of the current study was to examine if microglia play a similar vasculo-protective function in the brain. Employing extravascular fibrinogen leak as an index of blood-brain barrier (BBB) disruption, we found that CMH provoked transient vascular leak in cerebral blood vessels that was associated with activation and aggregation of Mac-1-positive microglia around leaky vessels. Interestingly, CMH-induced vascular leak showed regional selectivity, being much more prevalent in the brainstem and olfactory bulb than the cerebral cortex and cerebellum. Pharmacological depletion of microglia with the colony stimulating factor-1 receptor inhibitor PLX5622, had no effect under normoxic conditions, but markedly increased hypoxia-induced cerebrovascular leak in all regions examined. As in the spinal cord, this was associated with endothelial induction of MECA-32, a marker of leaky CNS endothelium, and greater loss of endothelial tight junction proteins. Brain regions displaying the highest levels of hypoxic-induced vascular leak also showed the greatest levels of angiogenic remodeling, suggesting that transient BBB disruption may be an unwanted side-effect of hypoxic-induced angiogenic remodeling. As hypoxia is common to a multitude of human diseases including obstructive sleep apnea, lung disease, and age-related pulmonary, cardiac and cerebrovascular dysfunction, our findings have important translational implications. First, they point to a potential pathogenic role of chronic hypoxia in triggering BBB disruption and subsequent neurological dysfunction, and second, they demonstrate an important protective role for microglia in maintaining vascular integrity in the hypoxic brain.

A familial case of alveolar capillary dysplasia with misalignment of the pulmonary veins: the clinicopathological features and unusual glomeruloid endothelial proliferation.

BACKGROUND: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare disorder of pulmonary vascular abnormality with persistent pulmonary hypertension of the newborn. The symptom usually presents within hours after birth, leading to an early demise. Heterozygous de novo point mutations and genomic deletions of the FOXF1 (forkhead box F1) gene or its upstream enhancer have been identified in most patients with ACD/MPV. Most cases of ACD/MPV are sporadic; however, familial cases are also reported in 10% of patients. CASE PRESENTATION: We herein report a case of familial ACD/MPV that showed unusual glomeruloid proliferation of endothelial cells. In this family, three of the four siblings died within two to 3 days after birth because of persistent pulmonary hypertension and respiratory failure. Only the second child remains alive and healthy. An autopsy was performed for the third and fourth children, resulting in a diagnosis of ACD/MPV based on the characteristic features, including misalignment of smaller pulmonary veins and lymphangiectasis. In both of these children, glomeruloid endothelial proliferation of vessels was noted in the interlobular septa. The vessels were immunohistochemically positive for D2-40, CD31, Factor VIII, and ERG, suggestive of differentiation for both lymphatic and blood vessels. CONCLUSIONS: Unusual glomeruloid endothelial proliferation was observed in a familial ACD/MPV case. This histologic feature has not been described previously in ACD/MPV or any other pulmonary disease. Although the histogenesis of this histologic feature is unclear, this finding may suggest that ACD/MPV is a compound vascular and lymphovascular system disorder that exhibits various histologic features.

Reactive cutaneous capillary endothelial proliferation in advanced hepatocellular carcinoma patients treated with camrelizumab: data derived from a multicenter phase 2 trial.

BACKGROUND: Association of immune-related adverse events with tumor response has been reported. Reactive cutaneous capillary endothelial proliferation (RCCEP) is the most common adverse event related to camrelizumab, an immune checkpoint inhibitor, but lack of comprehensive analyses. In this study, we conducted comprehensive analyses on RCCEP in advanced hepatocellular carcinoma (HCC) patients treated with camrelizumab monotherapy. METHODS: Data were derived from a Chinese nationwide, multicenter phase 2 trial of camrelizumab in pre-treated advanced HCC. The occurrence, clinicopathological characteristics, and prognostic value of RCCEP were analyzed. RESULTS: With a median follow-up of 12.5 months, 145 of the 217 camrelizumab-treated patients (66.8%) experienced RCCEP (all grade 1 or 2). RCCEP occurred on the skin surface, mainly on the skin surface of head, face, and trunk. RCCEP could be divided into 5 types including "red-nevus-like," "pearl-like," "mulberry-like," "patch-like," and "tumor-like," according to the morphological features. RCCEP biopsy and pathology showed capillary endothelial hyperplasia and capillary hyperplasia in dermis. Significant association between RCCEP occurrence with higher objective response rate was observed (19.3% vs. 5.6%; one-sided p = 0.0044). Compared with those without RCCEP, patients with RCCEP had prolonged progression-free survival (median PFS; 3.2 months vs. 1.9 months; one-sided p < 0.0001) and overall survival (median OS; 17.0 months vs. 5.8 months; one-sided p < 0.0001). In multivariable analyses, the development of RCCEP was significantly associated with prolonged PFS and OS after adjusting for baseline covariates. In addition, the landmark analyses of PFS and OS were consistent with the unadjusted analysis. CONCLUSIONS: RCCEP occurred on the skin surface and was an immune response of skin capillary endothelial cells. RCCEP occurrence positively associated with outcomes of camrelizumab in advanced HCC.