Transcatheter tricuspid valve repair: early experience in the Netherlands.

BACKGROUND: Symptomatic tricuspid regurgitation (TR) is increasingly prevalent and impairs quality of life and survival, despite medical treatment. Transcatheter tricuspid valve repair (TTVR) has recently become available as a treatment option for patients not eligible for tricuspid valve surgery. In this study we describe the early experience with TTVR in the Netherlands. METHODS: All consecutive patients scheduled for TTVR in two tertiary hospitals were included in the current study. Patients were symptomatic and had severe functional TR. TTVR was performed either with the MitraClip (off-label use) or dedicated TriClip delivery system and device. Procedural success was defined as achievement of clip implantation, TR reduction ≥ 1 grade and no need for re-do surgical or transcatheter intervention. Clinical improvement was evaluated after 4 weeks. RESULTS: Twenty-one patients (median age 78 years, 33% male, 95% New York Heart Association class ≥ 3, 100% history of atrial fibrillation) underwent TTVR. Procedural success was achieved in 16 patients, of whom 15 reported symptomatic improvement (New York Heart Association class 1 or 2). There was no in-hospital mortality and no major complications occurred. Baseline glomerular filtration rate and TR coaptation gap size were associated with procedural success. CONCLUSION: The current study showed that TTVR seems a promising treatment option for patients with severe functional TR deemed high risk for surgery. Successful TR reduction is most likely in patients with limited coaptation gap size and strongly determines clinical benefit. Adequate patient selection and timing of treatment seem essential for an optimal patient outcome.

SPARC-positive macrophages are the superior prognostic factor in the microenvironment of diffuse large B-cell lymphoma and independent of MYC rearrangement and double-/triple-hit status.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with respect to outcome. Features of the tumor microenvironment (TME) are associated with prognosis when assessed by gene expression profiling. However, it is uncertain whether assessment of the microenvironment can add prognostic information to the most relevant and clinically well-established molecular subgroups when analyzed by immunohistochemistry (IHC). PATIENTS AND METHODS: We carried out a histopathologic analysis of biomarkers related to TME in a very large cohort (n = 455) of DLBCL treated in prospective trials and correlated with clinicopathologic and molecular data, including chromosomal rearrangements and gene expression profiles for cell-of-origin and TME. RESULTS: The content of PD1+, FoxP3+ and CD8+, as well as vessel density, was not associated with outcome. However, we found a low content of CD68+ macrophages to be associated with inferior progression-free survival (PFS) and overall survival (OS; P = 0.023 and 0.040, respectively) at both univariable and multivariable analyses, adjusted for the factors of the International Prognostic Index (IPI), MYC break and BCL2/MYC and BCL6/MYC double-hit status. The subgroup of PDL1+ macrophages was not associated with survival. Instead, secreted protein acidic and cysteine rich (SPARC)-positive macrophages were identified as the subtype of macrophages most associated with survival. SPARC-positive macrophages and stromal cells directly correlated with favorable PFS and OS (both, P[log rank] <0.001, P[trend] < 0.001). The association of SPARC with prognosis was independent of the factors of the IPI, MYC double-/triple-hit status, Bcl2/c-myc double expression, cell-of-origin subtype and a recently published gene expression signature [lymphoma-associated macrophage interaction signature (LAMIS)]. CONCLUSIONS: SPARC expression in the TME detected by a single IHC staining with fair-to-good interobserver reproducibility is a powerful prognostic parameter. Thus SPARC expression is a strong candidate for risk assessment in DLBCL in daily practice.

A novel approach quantifying the periorbital morphology: A comparison of direct, 2-dimensional, and 3-dimensional technologies.

BACKGROUND: The measurement of anatomical structures is critical in plastic and reconstructive surgery. However, few detailed and standardized measurements have been widely used in the periorbital region. This study aimed to evaluate the feasibility of a novel detailed and standardized protocol with 2D and 3D technologies, and explore the relationship between them and direct measurements. METHODS: Fifty healthy Caucasians (100 eyes) between 20 and 68 years old were recruited and captured for 3D photographs by VECTRA M3 3D Imaging System. Subsequently, 24 landmarks were located on each 3D photographs following a standardized protocol, and then 19 linear and 3 angular periorbital variables were measured. Furthermore, two-dimensional (2D) and direct measurements were conducted on each subject and compared with 3D measurements and one another. RESULTS: The grand r means across all measurements were 0.77, 0.78, and 0.88 for direct vs. 2D values, direct vs. 3D values, and 3D vs. 2D values, respectively. The mean absolute differences were 1 mm (ranging from 0.2 mm to 3.7 mm) between direct and 3D measurements, 1 mm (ranging from 0.04 mm to 2.4 mm) between direct and 2D measurements, and 1 mm and 6.6° (ranging from 0.04 mm or 0.5° to 3 mm or 12.8°) between 2D and 3D measurements. CONCLUSIONS: This study verified the feasibility of this detailed and standardized landmark localization protocol for assessing the periorbital morphology with 2D and 3D technologies. This protocol may work as a bridge communicating with all studies involving any of the three technologies in the future.

First-line treatment with R-CHOP or rituximab-bendamustine in patients with follicular lymphoma grade 3A-results of a retrospective analysis.

Based on centroblast frequency, follicular lymphoma (FL) is subdivided into grades 1-2, 3A, and 3B. Grade FL3A frequently coexists with FL1-2 (FL1-2-3A). Based on clinical trials, FL1-2 is treated with rituximab (R) or obinutuzumab plus bendamustine (B) or CHOP, while FL3B is treated with R-CHOP. In contrast, there are little data guiding therapy in FL3A. We present a retrospective, multicenter analysis of 95 FL3A or FL1-2-3A and 203 FL1-2 patients treated with R-CHOP or R-B first-line. R-CHOP facilitated a higher response rate (95% versus 76%) and longer overall survival (OS) (3-year OS 89% versus 73%, P = 0.008) in FL3A or FL1-2-3A, whereas the difference in progression-free survival (PFS) did not reach statistical significance. While transformation rates into aggressive lymphoma were similar between both groups, there were more additional malignancies after R-B compared with R-CHOP (6 versus 2 cases). In FL1-2, R-B achieved a higher 3-year PFS (79% versus 47%, P < 0.01), while there was no significant difference regarding OS or transformation. With the limitations of a retrospective analysis, these results suggest a benefit for R-CHOP over R-B in FL3A or FL1-2-3A. Confirmatory data from prospective clinical trials are needed.

[Surgical resection with ophthalmoplastic reconstruction : Gold standard in periocular basal cell carcinoma]. / Chirurgische Resektion mit ophthalmoplastischer Rekonstruktion : Goldstandard beim periokulären Basalzellkarzinom.

The gold standard for the treatment of periocular basal cell carcinoma is surgical resection followed by ophthalmoplastic reconstruction. The highest priority in most cases is the complete histopathologically controlled tumor excision. The histopathological preparation can be carried out in two stages by rapid overnight embedding or intraoperatively by a rapid frozen section procedure. A variety of reconstruction methods enable a customized and in most cases also a cosmetically and functionally attractive defect coverage. Postoperatively, a regularly performed tumor aftercare is essential.

[Importance of interdisciplinary collaboration for optimal treatment of orbital tumors]. / Bedeutung der interdisziplinären Zusammenarbeit für eine optimale Behandlung orbitaler Tumoren.

Optimal treatment of tumors with orbital invasion may exceed the competences of an individual medical specialty and require interdisciplinary cooperation. The aim of this article is to present an interdisciplinary treatment concept based on the examples of intraorbital hemangioma and squamous cell carcinoma of the paranasal sinuses infiltrating the orbit. In addition to a detailed medical history and a complete ophthalmological examination, a detailed imaging technique with standardized echography and tomography methods such as orbital thin-slice CT and/or in many cases MRI is essential for the primary classification of an intraorbital pathology. Depending on the type of pathology, a purely surgical procedure involving various disciplines such as ophthalmology, otorhinolaryngology, maxillofacial surgery, neurosurgery, and pathology, or an interdisciplinary treatment regimen including (neo)adjuvant radiotherapy or chemotherapy is necessary. Orbital tumors have a wide range of potential pathologies, requiring complex surgical procedures and multimodal therapies. In case of infiltration of the paranasal sinuses or intracranial structures, an interdisciplinary team including neuroradiologists, oral-maxillofacial surgeons, otorhinolaryngologists, neurosurgeons, radiation therapists, ophthalmologists, pathologists, oncologists, and psycho-oncologists is essential for successful treatment.

[Hematological neoplasias as differential diagnoses of soft tissue tumors]. / Hämatologische Neoplasien als Differenzialdiagnosen von Weichgewebstumoren.

BACKGROUND: Several hematological malignancies might morphologically present as differential diagnoses of sarcomas. OBJECTIVES: To illustrate entities of hematological malignancies that might cause difficulties in differentiation from sarcomas and to introduce immunohistochemical and molecular tests that facilitate the diagnosis. MATERIAL AND METHODS: Selective literature research ( http://www.ncbi.nlm.nih.gov ) was combined with the clinico-pathological experience of the authors. RESULTS: In particular, hematologic malignancies with small blue round cell cytology, as well as lymphomas with anaplastic or spindle cell morphology, may mimic sarcomas. Identification of the correct diagnosis is usually possible by applying immunohistochemical and molecular analyses. Lymphomas without expression of CD45 and hematological neoplasias with expression of markers characteristic of sarcomas may cause difficulties in differential diagnosis. CONCLUSION: Hematological malignancies should be kept in mind as differential diagnoses of sarcomas and should be excluded by immunohistochemical and molecular analyses according to morphology and the clinical picture.

Cardiology fellows-in-training are exposed to relatively high levels of radiation in the cath lab compared with staff interventional cardiologists-insights from the RECAP trial.

BACKGROUND: Interventional cardiologists are inevitably exposed to low-dose radiation, and consequently are at risk for radiation induced diseases like cataract and left-sided brain tumours. Operator behaviour may possibly be the largest influencer on radiation exposure. We hypothesised that awareness regarding radiation exposure grows as skill and the general experience in the catheterization laboratory increase. OBJECTIVES: In this study we determined the difference in the relative radiation exposure of staff interventional cardiologists compared with cardiology fellows-in-training. METHODS: During this prospective trial the operator's radiation exposure (E in µSv) was measured at chest height during 766 diagnostic catheterisations and percutaneous coronary interventions. Also, the patient exposure (DAP in mGy·cm2), representing the amount of radiation administered by the operator per procedure, was collected. The primary outcome of this study was the difference in relative exposure between staff interventional cardiologists versus cardiology fellows-in-training (E/DAP). RESULTS: From January to May 2017, staff interventional cardiologists performed 637 procedures and cardiology fellows-in-training 129 procedures. The performance of relatively complex procedures by staff interventional cardiologists resulted in a 74% higher use of radiation compared with fellows-in-training. Consequently, staff interventional cardiologists were exposed to 50% higher levels of actual radiation exposure. However, when correcting for the complexity of the procedure, by comparing the relative operator exposure (E/DAP), fellows-in-training were exposed to a 34% higher relative exposure compared with staff interventional cardiologists (p = 0.025). CONCLUSIONS: In the current study, when corrected for complexity, cardiology fellows-in-training were exposed to significantly higher radiation levels than staff interventional cardiologists during catheterisation procedures.

[Clinico-echographic diagnostics of iris tumors]. / Klinisch-echographische Diagnostik bei Iristumoren.

BACKGROUND: The differentiation of iridic space-occupying lesions represents a regularly reoccurring diagnostic challenge. OBJECTIVE: This article presents an overview of the epidemiological data and describes the diagnostic procedure for iris tumors. MATERIAL AND METHODS: The article provides a review of the literature from PubMed and own clinical results. RESULTS: Melanocytic lesions comprise the vast majority of all iris tumors and include nevi and melanomas. Slit lamp biomicroscopy with standardized photography reveals two-dimensional planar tumor growth over time, which is the only recognized clinical surrogate finding for a malignant event. Ultrasound biomicroscopy (UBM) is additionally obligatory because it is the only method which enables documentation of the extent of tumor penetration, ciliary body involvement and internal structure of iris tumors. CONCLUSION: Serial slit lamp and UBM examinations with reproducible pupillary diameters are indispensable for the differentiation of cystic, solid and tumor-simulating lesions and for the detection of malignant transformation in iris tumors.

[Cheek-midface lift for revision following failed excessive lower eyelid blepharoplasty]. / Wangen-Mittelgesichts-Anhebung zur Revision nach unsachgemäß exzessiver Unterlidblepharoplastik.

Iatrogenic ectropion with sagging of the lower eyelid after failed excessive lower eyelid blepharoplasty is a severe complication in aesthetic surgery. Traditionally, free skin grafting is the method of choice for correction. This overview presents the cheek-midface lift as a useful and powerful method for the correction of ectropion following excessive lower eyelid blepharoplasty. This technique, which can be performed with the patient under local anesthesia, enables good functional as well as aesthetic outcomes.

[New treatment options for iridociliary tumors]. / Neue therapeutische Möglichkeiten bei iridoziliären Tumoren.

BACKGROUND: Benign iridal tumors rarely necessitate a therapeutic intervention. In contrast, malignant tumors of the iris can threaten the patient's life and eyesight and require early treatment to prevent the development of metastases. OBJECTIVE: Presentation of current treatment options for iridal tumors with special emphasis on iridal melanoma. METHODS: This article gives an overview of the current literature based on a PubMed search as well as own clinical experience. RESULTS: Treatment options for iridal and ciliary body melanomas comprise radiotherapeutic and surgical (eyeball-sparing and non-sparing) approaches. The eyeball-sparing surgical procedure of choice is block excision. While local tumor control rates and metastasis rates of block excision and radiotherapy are comparable, there are distinct differences especially between the spectra of complications. New treatment procedures include immunomodulatory approaches and targeted therapies. Using checkpoint inhibitors, no convincing enhancement of overall survival could be demonstrated for metastatic iridal melanoma, as is the case for cutaneous melanoma. In contrast, tumor vaccination with the help of tumor RNA-laden patient-derived dendritic cells seems to be a promising option for a subgroup of high-risk patients. Targeted therapies aiming to suppress the MAPK and PI3K/Akt pathways could not achieve any improvement in patient survival. CONCLUSION: For the primary treatment of iridal melanoma a surgical, eyeball-sparing approach and also when appropriate, radiotherapy can be recommended. In the future, eligible high-risk patients could profit from a tumor vaccination. To date, there is no effective systemic treatment for metastatic iridal melanoma.

[CyberKnife®: new treatment option for uveal melanoma]. / CyberKnife®: Eine neue Therapieoption bei uvealem Melanom.

BACKGROUND: CyberKnife® stereotactic radiosurgery is a new treatment option for uveal melanoma. OBJECTIVE: This review outlines the technique of robot-assisted CyberKnife® therapy, as well as the pros and cons in the treatment of uveal melanoma. METHODS: The study provides a PubMed literature review and own preliminary clinical experiences. RESULTS: CyberKnife® therapy for choroidal and ciliary body melanomas shows comparable results concerning local tumor control and overall survival matching those of conventional therapies. With only low complication rates, a high level of quality of life can be conserved by possible preservation of visual acuity as well as the ocular globe. CONCLUSION: Stereotactic radiosurgery using CyberKnife® seems to be an efficient and safe therapeutic option for malignant melanomas affecting the choroid and ciliary body. Comparative studies with conventional radiation strategies are now a high priority.

CBF1 is clinically prognostic and serves as a target to block cellular invasion and chemoresistance of EMT-like glioblastoma cells.

BACKGROUND: Glioblastoma is the most common and most lethal primary brain cancer. CBF1 (also known as Recombination signal Binding Protein for immunoglobulin kappa J, RBPJ) is the cardinal transcriptional regulator of the Notch signalling network and has been shown to promote cancer stem-like cells (CSCs) in glioblastoma. Recent studies suggest that some of the malignant properties of CSCs are mediated through the activation of pro-invasive programme of epithelial-to-mesenchymal transition (EMT). Little is known whether CBF1 is involved in the EMT-like phenotype of glioma cells. METHODS: In a collection of GBM neurosphere lines, we genetically inhibited CBF1 and investigated the consequences on EMT-related properties, including in vitro invasiveness by Boyden chambers assay, chemoresistance using a clinical drug library screen and glycolytic metabolism assessing live-cell extracellular acidification rate. We also compared CBF1 expression in cells exposed to low and high oxygen tension. In silico analysis in large-scale Western and Eastern patient cohorts investigated the clinical prognostic value of CBF1 expression in low- and high-grade glioma as well as medulloblastoma. RESULTS: Mean CBF1 expression is significantly increased in isocitrate dehydrogenase 1 (IDH1) R132H mutant glioblastoma and serves as prognostic marker for prolonged overall survival in brain tumours, particularly after therapy with temozolomide. Hypoxic regions of glioblastoma have higher CBF1 activation and exposure to low oxygen can induce its expression in glioma cells in vitro. CBF1 inhibition blocks EMT activators such as zinc finger E-box-binding homeobox 1 (ZEB1) and significantly reduces cellular invasion and resistance to clinically approved anticancer drugs. Moreover, we indicate that CBF1 inhibition can impede cellular glycolysis. CONCLUSIONS: Mean CBF1 activation in bulk tumour samples serves as a clinical predictive biomarker in brain cancers but its intratumoral and intertumoral expression is highly heterogeneous. Microenvironmental changes such as hypoxia can stimulate the activation of CBF1 in glioblastoma. CBF1 blockade can suppress glioblastoma invasion in vitro in particular in cells undergone EMT such as those found in the hypoxic niche. Targeting CBF1 can be an effective anti-EMT therapy to impede invasive properties and chemosensitivity in those cells.

[Minimally invasive bypass surgery for nasolacrimal duct obstruction : Transcanalicular laser-assisted dacryocystorhinostomy]. / Minimalinvasive Bypasschirurgie bei infrasakkalen Tränenwegsstenosen : Transkanalikuläre Laserdakryozystorhinostomie.

BACKGROUND: In recent years, the minimally invasive surgical procedure of transcanalicular laser-assisted dacryocystorhinostomy (TKL-DCR) has gained importance in the treatment of primary acquired nasolacrimal duct obstructions (PANDO). OBJECTIVES: Surgical indications, functional success rates, potential advantages, and complications of TKL-DCR are presented and compared with the standard procedures external (EXT-DCR) and endonasal DCR (EN-DCR). METHODS: The study comprises a PubMed literature review and our own clinical results. RESULTS: Using TKL-DCR either as the primary surgical treatment for PANDO, or as a secondary procedure following failure (reobstruction of the surgical ostium) of previous EXT-DCR resulted in good functional success rates (60-90%). The duration of surgery (10-15 min) and the period of recovery are significantly shorter than in EXT-DCR. Visible cutaneous scars and significant postoperative nose bleeding are not among the complications of TKL-DCR, due to the lack of a skin incision and the coagulative ability of the diode laser. The smaller sized surgical ostium has been considered the main disadvantage of TKL-DCR, since it might be prone to earlier reobstruction. On the other hand, TKL-DCR spares the anatomical structures that form the physiological tear pump, which should favor tear drainage. In very few cases, thermal damage to the canaliculus has been observed as a complication. CONCLUSIONS: Given the satisfying functional results, TKL-DCR is a valid alternative to the "gold standard" procedure EXT-DCR, especially in patients who particularly request speedy recovery and who do not want to take the risk of visible skin scaring. Future studies will have to investigate whether the smaller surgical ostia of TKL-DCR remain patent and whether functional success rates decrease during a longer follow-up period of >2 years.

Diabetic and idiopathic gastroparesis is associated with loss of CD206-positive macrophages in the gastric antrum.

BACKGROUND: Animal studies have increasingly highlighted the role of macrophages in the development of delayed gastric emptying. However, their role in the pathophysiology of human gastroparesis is unclear. Our aim was to determine changes in macrophages and other cell types in the gastric antrum muscularis propria of patients with diabetic and idiopathic gastroparesis. METHODS: Full thickness gastric antrum biopsies were obtained from patients enrolled in the Gastroparesis Clinical Research Consortium (11 diabetic, 6 idiopathic) and 5 controls. Immunolabeling and quantitative assessment was done for interstitial cells of Cajal (ICC) (Kit), enteric nerves protein gene product 9.5, neuronal nitric oxide synthase, vasoactive intestinal peptide, substance P, tyrosine hydroxylase), overall immune cells (CD45) and anti-inflammatory macrophages (CD206). Gastric emptying was assessed using nuclear medicine scintigraphy and symptom severity using the Gastroparesis Cardinal Symptom Index. RESULTS: Both diabetic and idiopathic gastroparesis patients showed loss of ICC as compared to controls (Mean [standard error of mean]/hpf: diabetic, 2.28 [0.16]; idiopathic, 2.53 [0.47]; controls, 6.05 [0.62]; P=.004). Overall immune cell population (CD45) was unchanged but there was a loss of anti-inflammatory macrophages (CD206) in circular muscle (diabetic, 3.87 [0.32]; idiopathic, 4.16 [0.52]; controls, 6.59 [1.09]; P=.04) and myenteric plexus (diabetic, 3.83 [0.27]; idiopathic, 3.59 [0.68]; controls, 7.46 [0.51]; P=.004). There was correlation between the number of ICC and CD206-positive cells (r=.55, P=.008). Enteric nerves (PGP9.5) were unchanged: diabetic, 33.64 (3.45); idiopathic, 41.26 (6.40); controls, 46.80 (6.04). CONCLUSION: Loss of antral CD206-positive anti-inflammatory macrophages is a key feature in human gastroparesis and it is associates with ICC loss.

[Merkel cell carcinoma of the eyelid. An often unrecognized tumor entity : Clinical aspects and treatment strategies]. / Merkel-Zell-Karzinom des Augenlids ­ eine häufig verkannte Diagnose : Klinische Aspekte und Behandlungsmethoden.

Merkel cell carcinoma of the eyelid is an aggressive, highly malignant tumor of the skin. Totaling approximately 0.5 % of all tumors of the eyelid, it constitutes a relatively small group of lid tumors. Nevertheless Merkel cell carcinoma is of significance to the ophthalmologist. Because of its clinical presentation it can be easily confused as a chalazion, a hordeolum or the lesser aggressive basal cell carcinoma. This often leads to delayed treatment. In this article we describe clinical aspects, which aim to help the ophthalmologist suspect Merkel cell carcinoma earlier. Additionally we outline a diagnostic and therapeutic workup taking into consideration the special anatomy of the eyelid.

[Current diagnostics and therapy recommendations for ocular basal cell carcinoma]. / Aktuelle Diagnostik und Therapieempfehlungen beim Basalzellkarzinom am Auge.

The treatment options for basal cell carcinoma (BCC) have recently been augmented with the introduction of novel chemotherapeutic drugs. New S2 guidelines on the disease have also been published. The aim of this article is to present a comprehensive state of the art description of the features of ocular BCC and an overview of the various therapeutic options. Particular emphasis is placed on the clinical signs, the diagnostic tools to identify periocular BCC and interpretation of the different histopathological subtypes. Tumor staging, TNM classification, interdisciplinary tumor conference reviews as well as psycho-oncological services play an important role in patients with pronounced periocular BCC. Surgical removal with a histological R0 resection is an important component of therapy options in this disease and includes the microsurgical excision into healthy tissue and the subsequent covering of the defect. A special focus of this article is the treatment of locally extensive and metastasized BCC.

[Tumors of the lacrimal drainage system]. / Tumoren der ableitenden Tränenwege.

BACKGROUND: The prevalence of tumors affecting the lacrimal drainage system is low, thus generating a risk of late diagnosis and treatment in clinical routine. However, these tumors can be potentially life-threatening, which emphasizes the relevance of early diagnosis and treatment. OBJECTIVE: This review focuses on the symptoms, incidence, management, and prognosis of the different tumor entities affecting the lacrimal drainage system. METHODS: The study provides a PubMed-based literature review and presents own clinical results. RESULTS: Alongside detailed medical history taking and comprehensive clinical examination, precise inspection during external dacryocystography is important for diagnosis of tumors affecting the lacrimal drainage system. There is a wide spectrum of tumor entities located in the lacrimal drainage system. The tumors are classified into three groups: primary epithelial, primary nonepithelial, and inflammatory lesions. The most common primary epithelial tumors include papilloma, squamous cell carcinoma, and transitional cell carcinoma. The most common nonepithelial tumors include fibrous histiocytoma, malignant lymphoma, and malignant melanoma; while the most common inflammatory lesions comprise sarcoidosis, Wegener granulomatosis, and pyogenic granuloma. Treatment depends on the entity and stage of the tumor. In the case of malignancy, a multimodal and interdisciplinary approach is usually indicated. CONCLUSION: Differential diagnostic signs in favor of a malignancy include a long medical history, predisposing conditions in the patient's history, a mass above the medial canthal ligament, teleangiectasis above the mass, and serosanguinous secretion.