LncRNA PVT1 promotes strong stemness and endothelial progenitor cell characteristics in renal carcinoma stem cells.

Renal cancer stem cells (RCSCs) derived from clear cell renal cell carcinoma (ccRCC) tissues with higher microvessel density (MVD) have strong stemness and endothelial progenitor cells-like (EPCs-like) characteristics. A high level of lncRNA PVT1 expression is essential for simultaneously retaining strong RCSC stemness and EPCs-like characteristics. PVT1 binds with TAZ protein and prevents its phosphorylation, which promotes RCSC stemness. Moreover, RCSCs support endothelial differentiation and angiogenesis, which are mediated via the PVT1/miR-15b/KDR axis. This report provides insight into the determinants of RCSC impact on stemness and highlights the critical role of RCSC in angiogenesis. The presented findings suggest that targeting RCSC through PVT1 expression may be a new treatment strategy for ccRCC.

The specific shapes of capillaries are associated with worse prognosis in patients with invasive breast cancer.

Angiogenesis is considered essential for tumor progression; however, whether histological counting of blood vessel numbers, expressed as microvessel density (MVD), can be a prognostic factor in breast cancer remains controversial. It has been suggested that the specific morphology of blood vessels such as glomeruloid microvascular proliferation (GMP) is associated with clinical parameters. Here, we aimed to clarify the significance of MVD with revised immunohistochemistry and to identify new blood vessel shapes that predict prognosis in breast cancer. Four hundred and eleven primary breast cancer specimens were collected, and the sections were immunohistochemically stained with CD31 (single staining) and CD31 and Collagen IV (double staining). The prognosis of patients was examined based on the MVD value, and the presence of GMP and other blood vessels with other specific shapes. As a result, high MVD value and the presence of GMP were not associated with worse prognosis. By contrast, patients with deep-curved capillaries surrounding tumor cell nests (C-shaped) or excessively branched capillaries near tumor cell nests showed a significantly poor prognosis. The presence of these capillaries was also correlated with clinicopathological parameters such as Ki-67 index. Thus, the morphology of capillaries rather than MVD can be a better indicator of tumor aggressiveness.

Diagnostic value of one-stop CT energy spectrum and perfusion for angiogenesis in colon and rectum cancer.

OBJECTIVE: Evaluation of the predictive value of one-stop energy spectrum and perfusion CT parameters for microvessel density (MVD) in colorectal cancer cancer foci. METHODS: Clinical and CT data of 82 patients with colorectal cancer confirmed by preoperative colonoscopy or surgical pathology in our hospital from September 2019 to November 2022 were collected and analyzed retrospectively. Energy spectrum CT images were measured using the Protocols general module of the GSI Viewer software of the GE AW 4.7 post-processing workstation to measure the CT values of the arterial and venous phase lesions and the neighboring normal intestinal wall in a single energy range of 40 kev∼140 kev, and the slopes of the energy spectrum curves (λ) were calculated between 40 kev-90 kev; Iodine concentration (IC), Water concentration (WC), Effective-Z (Eff-Z) and Normalized iodine concentration (NIC) were measured by placing a region of interest (ROI) on the iodine concentration map and water concentration map at the lesion and adjacent to the normal intestinal wall.Perfusion CT images were scanned continuously and dynamically using GSI Perfusion software and analyzed by applying CT Perfusion 4.0 software.Blood volume (BV), blood flow (BF), surface permeability (PS), time to peak (TTP), and mean transit time (MTT) were measured respectively in the lesion and adjacent normal colorectal wall. Based on the pathological findings, the tumors were divided into a low MVD group (MVD < 35/field of view, n = 52 cases) and a high MVD group (MVD ≥ 35/field of view, n = 30 cases) using a median of 35/field of view as the MVD grouping criterion. The collected data were statistically analyzed, the subjects' operating characteristic curve (ROC) was plotted, and the area under curve (AUC), sensitivity, specificity, and Yoden index were calculated for the predicted efficacy of each parameter of the energy spectrum and perfusion CT and the combined parameters. RESULTS: The CT values, IC, NIC, λ, Eff-Z of 40kev∼140kev single energy in the arterial and venous phase of colorectal cancer in the high MVD group were higher than those in the low MVD group, and the differences were all statistically significant (p < 0.05). The AUC of each single-energy CT value in the arterial phase from 40 kev to 120 kev for determining the high or low MVD of colorectal cancer was greater than 0.8, indicating that arterial stage has a good predictive value for high or low MVD in colorectal cancer; AUC for arterial IC, NIC and IC + NIC were all greater than 0.9, indicating that in arterial colorectal cancer, both single and combined parameters of spectral CT are highly effective in predicting the level of MVD. The AUC of 40 kev to 90 kev single-energy CT values in the intravenous phase was greater than 0.9, and its diagnostic efficacy was more representative; The AUC of IC and NIC in venous stage were greater than 0.8, which indicating that the IC and NIC energy spectrum parameters in venous stage colorectal cancer have a very good predictive value for the difference between high and low MVDs, with the greatest diagnostic efficacy in IC.The values of BV and BF in the high MVD group were higher than those in the low MVD group, and the differences were statistically significant (P < 0.05), and the AUC of BF, BV, and BV + BF were 0.991, 0.733, and 0.997, respectively, with the highest diagnostic efficacy for determining the level of MVD in colorectal cancer by BV + BF. CONCLUSION: One-stop CT energy spectrum and perfusion imaging technology can accurately reflect the MVD in living tumor tissues, which in turn reflects the tumor angiogenesis, and to a certain extent helps to determine the malignancy, invasion and metastasis of living colorectal cancer tumor tissues based on CT energy spectrum and perfusion parameters.

Diagnosis and monitoring denosumab therapy of giant cell tumors of bone: radiologic-pathologic correlation.

OBJECTIVE: To determine the value of CT and dynamic contrast-enhanced (DCE-)MRI for monitoring denosumab therapy of giant cell tumors of bone (GCTB) by correlating it to histopathology. MATERIALS AND METHODS: Patients with GCTB under denosumab treatment and monitored with CT and (DCE-)MRI (2012-2021) were retrospectively included. Imaging and (semi-)quantitative measurements were used to assess response/relapse. Tissue samples were analyzed using computerized segmentation for vascularization and number of neoplastic and giant cells. Pearson's correlation/Spearman's rank coefficient and Kruskal-Wallis tests were used to assess correlations between histopathology and radiology. RESULTS: Six patients (28 ± 8years; five men) were evaluated. On CT, good responders showed progressive re-ossification (+7.8HU/month) and cortical remodeling (woven bone). MRI showed an SI decrease relative to muscle on T1-weighted (-0.01 A.U./month) and on fat-saturated T2-weighted sequences (-0.03 A.U./month). Time-intensity-curves evolved from a type IV with high first pass, high amplitude, and steep wash-out to a slow type II. An increase in time-to-peak (+100%) and a decrease in Ktrans (-71%) were observed. This is consistent with microscopic examination, showing a decrease of giant cells (-76%), neoplastic cells (-63%), and blood vessels (-28%). There was a strong statistical significant inverse correlation between time-to-peak and microvessel density (ρ = -0.9, p = 0.01). Significantly less neoplastic (p = 0.03) and giant cells (p = 0.04) were found with a time-intensity curve type II, compared to a type IV. Two patients showed relapse after initial good response when stopping denosumab. Inverse imaging and pathological findings were observed. CONCLUSION: CT and (DCE-)MRI show a good correlation with pathology and allow adequate evaluation of response to denosumab and detection of therapy failure.

Histopathological growth pattern and vessel co-option in intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (iCCA) exhibits different blood imaging features and prognosis depending on histology. To clarity histopathological growth patterns (HGPs) and vascularization processes of iCCA, we collected 145 surgical specimens and histologically classified them into large bile duct (LBD) (20 cases), small bile duct (SBD) (54), cholangiolocarcinoma (CLC) (35), combined SBD-CLC (cSBD-CLC) (26), and ductal plate malformation (DPM) (10) (sub)types. According to the invasive pattern at the interface between tumor and adjacent background liver, HGPs were classified into desmoplastic, pushing, and replacing HGPs. Desmoplastic HGP predominated in LBD type (55.5%), while replacing HGP was common in CLC (82.9%) and cSBD-CLC (84.6%) subtypes. Desmoplastic HGP reflected angiogenesis, while replacing HGP showed vessel co-option in addition to angiogenesis. By evaluating microvessel density (MVD) using vascular markers, ELTD1 identified vessel co-option and angiogenesis, and ELTD1-positive MVD at invasive margin in replacing HGP was significantly higher than those in desmoplastic and pushing HGPs. REDD1, an angiogenesis-related marker, demonstrated preferably higher MVD in the tumor center than in other areas. iCCA (sub)types and HGPs were closely related to vessel co-option and immune-related factors (lymphatic vessels, lymphocytes, and neutrophils). In conclusion, HGPs and vascular mechanisms characterize iCCA (sub)types and vessel co-option linked to the immune microenvironment.

Histological findings of thyroid cancer after lenvatinib therapy.

AIMS: Lenvatinib is a multikinase inhibitor used for treating unresectable or metastatic cancers, including thyroid cancer. As total thyroidectomy followed by radioactive iodine therapy is a commonly recommended initial treatment for thyroid cancer, histological findings of the thyroid after lenvatinib therapy remain unclear. Therefore, the aim of this study was to analyse in-vivo changes in patients who underwent thyroidectomy after lenvatinib therapy. METHODS AND RESULTS: We screened 167 patients with thyroid cancer [papillary thyroid cancer (PTC), n = 102; follicular thyroid cancer (FTC), n = 26; anaplastic thyroid cancer (ATC), n = 39] who underwent lenvatinib therapy. Among these patients, six underwent thyroidectomy (lenvatinib-treated group: PTC, n = 3; FTC, n = 1; ATC, n = 2), and the specimens were examined. Five patients with PTC who did not receive lenvatinib therapy were included for comparison (untreated group). Microvessel density (MVD) was evaluated in both groups. The PTC and FTC specimens showed relatively more ischaemic changes than ATC specimens. Coagulative necrosis and ischaemic changes in cancer cells were frequently observed. ATC specimens showed fibrosis and mild cell damage. As hypothyroidism is a common side effect of lenvatinib therapy, non-cancerous thyroid tissues were also examined. Histological findings included mild lymphocytic infiltration, lymphoid follicular formation, histiocytic reaction and follicular epithelial destruction. The MVD in lenvatinib-treated tissues was significantly lower than that in untreated tissues. CONCLUSIONS: Lenvatinib therapy probably induces relatively specific ischaemic changes in thyroid cancer cells. Moreover, inflammatory cell infiltration and decreased MVD occur to varying degrees in non-cancerous thyroid tissue and may be related to hypothyroidism, a side effect of lenvatinib.

PET/MRI of hypoxia and vascular function in ER-positive breast cancer: correlations with immunohistochemistry.

OBJECTIVES: To explore the relationship between indices of hypoxia and vascular function from 18F-fluoromisonidazole ([18F]-FMISO)-PET/MRI with immunohistochemical markers of hypoxia and vascularity in oestrogen receptor-positive (ER +) breast cancer. METHODS: Women aged > 18 years with biopsy-confirmed, treatment-naïve primary ER + breast cancer underwent [18F]-FMISO-PET/MRI prior to surgery. Parameters of vascular function were derived from DCE-MRI using the extended Tofts model, whilst hypoxia was assessed using the [18F]-FMISO influx rate constant, Ki. Histological tumour sections were stained with CD31, hypoxia-inducible factor (HIF)-1α, and carbonic anhydrase IX (CAIX). The number of tumour microvessels, median vessel diameter, and microvessel density (MVD) were obtained from CD31 immunohistochemistry. HIF-1α and CAIX expression were assessed using histoscores obtained by multiplying the percentage of positive cells stained by the staining intensity. Regression analysis was used to study associations between imaging and immunohistochemistry variables. RESULTS: Of the lesions examined, 14/22 (64%) were ductal cancers, grade 2 or 3 (19/22; 86%), with 17/22 (77%) HER2-negative. [18F]-FMISO Ki associated negatively with vessel diameter (p = 0.03), MVD (p = 0.02), and CAIX expression (p = 0.002), whilst no significant relationships were found between DCE-MRI pharmacokinetic parameters and immunohistochemical variables. HIF-1α did not significantly associate with any PET/MR imaging indices. CONCLUSION: Hypoxia measured by [18F]-FMISO-PET was associated with increased CAIX expression, low MVD, and smaller vessel diameters in ER + breast cancer, further corroborating the link between inadequate vascularity and hypoxia in ER + breast cancer. KEY POINTS: • Hypoxia, measured by [18F]-FMISO-PET, was associated with low microvessel density and small vessel diameters, corroborating the link between inadequate vascularity and hypoxia in ER + breast cancer. • Increased CAIX expression was associated with higher levels of hypoxia measured by [18F]-FMISO-PET. • Morphologic and functional abnormalities of the tumour microvasculature are the major determinants of hypoxia in cancers and support the previously reported perfusion-driven character of hypoxia in breast carcinomas.

Microvascular density analysis and histological parameters of oral cancer progression.

OBJECTIVES: This study aimed to investigate the role of blood and lymphatic microvascular density in the progression of oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: The sample was composed of 54 cases of OSCC. The immunoexpression to anti-alpha-smooth muscle actin (α-SMA) and to anti-endoglin (CD105) was used to determine the microvessel density (MVD); anti-podoplanin (D2-40) was used to assess the lymphatic vessel density (LVD); vascular endothelial growth factor (VEGF) was evaluated in malignant cells. The histological differentiation, the worst pattern of invasion (WPOI), tumour thickness and tumour budding (TB) intensity were assessed using haematoxylin-eosin and anti-pan-cytokeratin (AE1/AE3). Patients' age and sex, TNM classification and follow-up time were collected from the medical records. RESULTS: MVD markers presented a similar pattern of expression in blood vessels. However, only α-SMA + MVD was significantly higher among women and in tumours ≤4 cm. LVD was lower in tumours with lymph node metastasis. Regarding the histological parameters, high TB intensity was associated with histological differentiation, advanced clinical stage, greater tumour thickness and reduced disease-free survival. No difference was found in VEGF. CONCLUSIONS: The decrease in OSCC LVD could be related to pathological node involvement, whereas high TB intensity could indicate OSCC progression and worse patient outcomes.

Contrast-enhanced Ultrasound Combined With Elastography for the Evaluation of Muscle-invasive Bladder Cancer in Rats.

OBJECTIVES: By comparing with the control group, we evaluated the usefulness of contrast-enhanced ultrasound (CEUS) combined with elastography for the assessment of muscle invasion by bladder cancer (MIBC) in a Sprague-Dawley (SD) rat model. METHODS: In the experimental group, 40 SD rats developed in situ bladder cancer (BLCA) in response to N-methyl-N-nitrosourea treatment, whereas 40 SD rats were included in the control group for comparison. We compared PI, Emean , microvessel density (MVD), and collagen fiber content (CFC) between the two groups. In the experimental group, Bland-Altman test was used to assess the relationships between various parameters. The largest Youden value was used as the cut-off point, and binomial logistic regression analysis was performed to analyze the PI and Emean . Receiver operating characteristic (ROC) curve analysis was performed to determine the diagnostic power of parameters, individually and in combination. RESULTS: The PI, Emean , MVD, and CFC were significantly lower in the control group than in the experimental group (P < .05). The PI, Emean , MVD, and CFC were significantly higher for MIBC than for non-muscle-invasive bladder cancer (P < .05). There were significant correlations between PI and MVD, and between Emean and CFC. The diagnostic efficiency analysis showed PI had the highest sensitivity, CFC had the highest specificity, and PI + Emean had the highest diagnostic efficacy. CONCLUSION: CEUS and elastography can distinguish lesions from normal tissue. PI, MVD, Emean , and CFC were useful for the detection of BLCA myometrial invasion. The comprehensive utilization of PI and Emean improved diagnostic accuracy and have clinical application.

Research on the correlation between the renal resistive index, renal microvessel density, and fibrosis.

BACKGROUND: This study was designed to investigate the relationship between the renal resistive index (RRI), renal microvessel density (RMD), and fibrosis in patients with chronic kidney disease (CKD). METHODS: A total of 73 CKD patients were included in the study. Prior to kidney biopsy, we recorded the RRI of the interlobar artery and the estimated glomerular filtration rate (eGFR). Immunohistochemical analysis was performed to assess CD34 expression, and Masson staining was used to evaluate histopathological specimens for RMD and the degree of fibrosis. The percentage of the positive area (PPA) was recorded. Subsequently, we investigated the correlation between RRI, RMD, and kidney fibrosis. RESULTS: RMD (CD34 PPA-total and CD34 PPA-peritubular capillary) showed a slight increase in early CKD stages (1-2) and gradually declined from CKD stages 2 to 5. No correlation was observed between the RRI and RMD or between the RRI and fibrosis across CKD stages 1 to 5. However, across CKD stages 2 to 5, RRI negatively correlated with CD34 PPA-glomerulus (r = -0.353, p = 0.022), but no correlation was found with CD34 PPA-total, CD34 PPA-peritubular capillary, or kidney fibrosis. eGFR showed a positive correlation with RMD (CD34 PPA-total, CD34 PPA-peritubular capillary, and CD34 PPA-glomerulus) across CKD stages 2 to 5, while no correlation was found from CKD stages 1 to 5. CONCLUSION: There was no correlation between RRI and RMD or between RRI and fibrosis across CKD stages 1 to 5 (RRI ≤ 0.7).

Microvessel Density: Integrating Sex-Based Differences and Elevated Cardiovascular Risks in Metabolic Syndrome.

Metabolic syndrome (MetS) is a complex pathological state consisting of metabolic risk factors such as hypertension, insulin resistance, and obesity. The interconnectivity of cellular pathways within various biological systems suggests that each individual component of MetS may share common pathological sources. Additionally, MetS is closely associated with vasculopathy, including a reduction in microvessel density (MVD) (rarefaction) and elevated risk for various cardiovascular diseases. Microvascular impairments may contribute to perfusion-demand mismatch, where local metabolic needs are insufficiently met due to the lack of nutrient and oxygen supply, thus creating pathological positive-feedback loops and furthering the progression of disease. Sexual dimorphism is evident in these underlying cellular mechanisms, which places males and females at different levels of risk for cardiovascular disease and acute ischemic events. Estrogen exhibits protective effects on the endothelium of pre-menopausal women, while androgens may be antagonistic to cardiovascular health. This review examines MetS and its influences on MVD, as well as sex differences relating to the components of MetS and cardiovascular risk profiles. Finally, translational relevance and interventions are discussed in the context of these sex-based differences.

Monitoring Bevacizumab-Induced Tumor Vascular Normalization by Intravoxel Incoherent Motion Diffusion-Weighted MRI.

BACKGROUND: Accurate monitoring of tumor blood vessel normalization progression is beneficial to accurate treatment of patients. At present, there is a lack of safe and noninvasive monitoring methods. PURPOSE: To serial monitor the vascular normalization time window of tumor antiangiogenesis treatment through intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) and histopathological methods. STUDY TYPE: Exploratory animal study. POPULATION: Sixty rat C6 glioma models were randomly and equally divided into the control groups (N = 30) and bevacizumab treatment groups (N = 30). Twenty-five for magnetic resonance imaging (MRI) and five for electron microscope testing in each group. FIELD STRENGTH/SEQUENCE: T1-weighted imaging (T1WI), T2WI with a fast spin echo sequence and IVIM-DWI with a spin-echo echo-planar imaging sequence at 3 T. ASSESSMENT: IVIM-DWI quantitative parameters (f, D, D*, and fD*) were obtained on days 0, 2, 4, 6, and 8 after bevacizumab treatment. After MRI, the microvessel density (MVD), pericyte coverage, and hypoxia-inducible factor-1α (HIF-1α) were assessed. Electron microscope observation was performed at each time point. STATISTICAL TESTS: One-way analysis of variance and Student's t-tests were used to compare differences within and between groups. Spearman's correlation coefficient (r) assess the correlation between IVIM and pathological parameters. The intragroup correlation coefficient was determined to assess the repeatability of each IVIM parameter. RESULTS: The IVIM-DWI perfusion parameters (f and fD*) of the treated group were higher than the control group on days 2 and 4. Compared to the control group, MVD decreased on days 2 and pericyte coverage increased on days 4 in the treatment group. Electron microscopy showed that the tight junctions of the treatment group were prolonged on days 2-4. In the control group, f had the highest correlation with MVD (r = 0.689). In the treated group, f had a good correlation with pericyte coverage (r = 0.557), HIF-1α had a moderately positive correlation with f (r = 0.480) and fD*(r = 0.447). DATA CONCLUSION: The vascular normalization time window of bevacizumab treatment of glioma was days 2-4 after antiangiogenesis treatment, which could be monitored noninvasively by IVIM-DWI. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

Yap Expression Is Closely Related to Tumor Angiogenesis and Poor Prognosis in Hepatoblastoma.

Background: Hepatoblastoma (HB) is malignant embryonal tumor typically arising in infants and young children. Yes-associated protein (YAP) is aberrantly activated in various tumors; however, the role of YAP in hepatoblastoma is still unexplored. Methods: We assessed YAP expression in hepatoblastoma using immunohistochemistry. The relationships to clinicopathology and survival were analyzed. Results: Positive rate of YAP expression was higher in hepatoblastoma than in adjacent tissues. YAP overexpression was significantly correlated with lymph node metastasis and vascular invasion. Both epithelial and mixed histological types expressed YAP, but high expression was more frequent in MT. YAP expression correlated with VEGF expression, high microvascular density and low overall survival. Multivariable Cox regression analysis revealed that YAP was an independent prognostic factor for survival in children with hepatoblastoma. Conclusion: In hepatoblastoma, YAP may promote VEGF induced angiogenesis and metastases, with resulting poorer prognosis, representing a potential adverse prognostic marker.

Do extraglomerular microvasculature and mesenchymal interstitial cell proliferation indicate a stable course of lupus nephritis?

Background: Lupus Nephritis (LN) is a major and frequent manifestation of Systemic Lupus Erythematosus (SLE), an autoimmune disease. Renal biopsy has a pivotal role in the diagnosis, prognosis, and management of the LN. The aim of this study was to count the mesenchymal interstitial cells utilizing CD34 immunohistochemistry (IHC) and morphometric analysis, correlate them with clinical parameters, class, activity, and chronicity indices and see if it can predict the course of the disease. Methods: A total of 32 renal biopsy blocks were analyzed by H&E stain, special stains, and CD34 IHC. Microvasculature density and interstitial stem cells were highlighted by CD34. These were then counted using a previously standardized computerized digital photomicrograph system (Dewinter Optical Inc) and manual count, respectively. Results: Out of the 32 cases, Lupus class 3 comprised of 11 (34.38%) cases, class 4 comprised of 16 (50%) cases, and mixed class 4 + 5 had 5 (15.62%) cases. It was found that CD34 expression in the microvasculature (for both microvascular density and mean vascular lumen diameter) decreased in patients of Lupus Nephritis with higher disease activity (p < 0.05). Although not statistically significant, the number of interstitial stem cells increased with lower disease activity. A statistical significance was found between serum total protein, serum albumin, and serum creatinine among the three groups of LN. Conclusion: Immunohistochemical staining of renal biopsy with CD34 may be used as a surrogate marker of disease activity in Lupus Nephritis patients.

Noninvasive, in vivo assessment of the cervical microcirculation using incident dark field imaging.

AIM: This study evaluates the feasibility of handheld vital microscopy for noninvasive, objective assessment of the microcirculation of the human uterine cervix. We qualitatively and quantitatively describe the microcirculation in healthy subjects in order to provide a basis for its application in cervical pathology. METHODS: Incident dark field imaging was used to image the microcirculation in four quadrants of the uterine ectocervix in ten healthy participants. If the squamocolumnar junction was visible, measurements were repeated on the endocervical columnar epithelium as well. Image acquisition time was recorded and participants scored the experienced level of discomfort. Angioarchitecture was classified according to Weber's classification. Quantitative parameters included capillary density (CD), total and perfused vessel density (TVD, PVD), proportion of perfused vessels (PPV) and microvascular flow index (MFI). RESULTS: Image acquisition was easy, fast and well tolerated. Angioarchitecture was characterized by two distinctive and organized patterns; capillary loops underneath the squamous epithelium of the ectocervix and vascular networks underneath the columnar epithelium. In the image sequences containing capillary loops, mean CD was 33.2 cpll/mm2 (95% CI 28.2-38.2 cpll/mm2). In the image sequences with vascular networks, mean TVD was 12.5 mm/mm2 (95% CI 11.2-13.77 mm/mm2), mean PVD was 12.2 (95% CI 11.0-13.5 mm/mm2), MFI was 3 and PPV was 100%. CONCLUSIONS: Incident dark field imaging allows for noninvasive, real time visualization and objective evaluation and quantification of the microcirculation of the uterine cervix. The organized vascular patterns and optimal perfusion observed in healthy subjects allow for comparison with cervical pathology, for example in patients with cervical dysplasia or cervical cancer.

Effects of lenalidomide on the bone marrow microenvironment in acute myeloid leukemia: Translational analysis of the HOVON103 AML/SAKK30/10 Swiss trial cohort.

This translational study aimed at gaining insight into the effects of lenalidomide in acute myeloid leukemia (AML). Forty-one AML patients aged 66 or older of the Swiss cohort of the HOVON-103 AML/SAKK30/10 study were included. After randomization, they received standard induction chemotherapy with or without lenalidomide. Bone marrow biopsies at diagnosis and before the 2nd induction cycle were obtained to assess the therapeutic impact on leukemic blasts and microenvironment. Increased bone marrow angiogenesis, as assessed by microvessel density (MVD), was found at AML diagnosis and differed significantly between the WHO categories. Morphological analysis revealed a higher initial MVD in AML with myelodysplasia-related changes (AML-MRC) and a more substantial decrease of microvascularization after lenalidomide exposure. A slight increase of T-bet-positive TH1-equivalents was identifiable under lenalidomide. In the subgroup of patients with AML-MRC, the progression-free survival differed between the two treatment regimens, showing a potential but not significant benefit of lenalidomide. We found no correlation between the cereblon genotype (the target of lenalidomide) and treatment response or prognosis. In conclusion, addition of lenalidomide may be beneficial to elderly patients suffering from AML-MRC, where it leads to a reduction of microvascularization and, probably, to an intensified specific T cell-driven anti-leukemic response.

Melanoma brain metastases have lower T-cell content and microvessel density compared to matched extracranial metastases.

BACKGROUND: Although melanoma brain metastases (MBM) tend to respond to systemic therapy concordantly with extracranial metastases, little is known about differences in immune cell and vascular content between the brain and other metastatic sites. Here we studied infiltrating immune cell subsets and microvessel density (MVD) in paired intracerebral and extracerebral melanoma metastases. METHODS: Paired intracerebral and extracerebral tumor tissue was obtained from 37 patients with metastatic melanoma who underwent craniotomy between 1997 and 2014. A tissue microarray was constructed to quantify subsets of tumor-infiltrating T-cell, B-cell, and macrophage content, PD-L1 expression, and MVD using quantitative immunofluorescence. RESULTS: MBM had lower CD3+ (p = 0.01) and CD4+ (p = 0.003) T-cell content, lower MVD (p = 0.006), and a trend for lower CD8+ (p = 0.17) T-cell content compared to matched extracerebral metastases. There were no significant differences in CD20+ B-cell or CD68+ macrophage content, or tumor or stroma PD-L1 expression. Low MVD (p = 0.008) and high CD68+ macrophage density (p = 0.04) in intracerebral metastases were associated with improved 1-year survival from time of first MBM diagnosis. CONCLUSIONS: Although responses to immune-modulating drugs in the body and the brain tend to be concordant, differences were found in MVD and T-cell content between these sites. Studies of these markers should be incorporated into prospective therapeutic clinical trials to determine their prognostic and predictive value.

Prognostic Value of Microvessel Density in Non-Hodgkin Lymphoma: A Meta-Analysis.

BACKGROUND: Angiogenesis in non-Hodgkin lymphoma (NHL) has been investigated by a variety of studies. However, the correlation between angiogenesis and the occurrence or prognosis of NHL patients remains controversial. METHODS: We performed a systematic and comprehensive retrieval of relevant literatures from PubMed, EMBASE, and Web of Science databases. The quality of the eligible studies was assessed using the Newcastle-Ottawa Scale (NOS). RESULTS: Fifteen eligible studies containing a total of 1373 NHL patients were included in this study. All the eligible studies were high-quality studies scoring ≥6 points. MVD was not different between NHL and control (SMD = 0.281, 95% CI: -1.410 to 1.972, p = 0.745). High MVD was associated with advanced disease stage (OR = 1.580, 95% CI: 1.080-2.311, p = 0.018) and unfavorable OS (HR = 1.656, 95% CI: 1.366-2.009, p = 0.000) but not with PFS (HR = 1.349, 95% CI: 0.852-2.136, p = 0.201). CONCLUSION: This meta-analysis demonstrated that high MVD was related to advanced disease stage and associated with unfavorable OS of NHL patients.

Perfusion-based functional magnetic resonance imaging for differentiating serous borderline ovarian tumors from early serous ovarian cancers in a rat model.

BACKGROUND: Differentiation of borderline tumors from early ovarian cancer has recently received increasing attention, since borderline tumors often affect young women of childbearing age who desire to preserve fertility. However, previous studies have demonstrated that non-enhanced magnetic resonance imaging (MRI) sequences cannot sufficiently differentiate these tumors. PURPOSE: To investigate the value of dynamic contrast-enhanced MRI (DCE-MRI) and intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) in differentiating serous borderline ovarian tumors (SBOT) from early serous ovarian cancers (eSOCA). MATERIAL AND METHODS: Twenty SBOT and 20 eSOCA rat models were performed with DCE-MRI and IVIM-DWI at 3.0-T MR scanner. Qualitative and quantitative parameters of DCE-MRI were acquired and compared between two groups and correlated with the microvessel density (MVD). The receiver operating characteristic (ROC) curve analyses were conducted to determine their differentiating performances. RESULTS: SBOTs presented significantly lower values of the initial area under the enhancement curve (iAUC), volume transfer constant (Ktrans), and extracellular extravascular volume fraction (ve) (P < 0.05) and a significantly higher value of true diffusion (D) (P = 0.001) compared with eSOCAs. The diagnostic effectiveness of ve combined with D was significantly better than that of ve or Ktrans alone (P ≤ 0.039). CONCLUSION: DCE-MRI may represent a promising tool for differentiating SBOTs from eSOCAs and may not be replaced by IVIM-DWI. Combining DCE-MRI with DWI may improve the diagnostic performance of ovarian tumors.

Intratumoral Canine Distemper Virus Infection Inhibits Tumor Growth by Modulation of the Tumor Microenvironment in a Murine Xenograft Model of Canine Histiocytic Sarcoma.

Histiocytic sarcomas refer to highly aggressive tumors with a poor prognosis that respond poorly to conventional treatment approaches. Oncolytic viruses, which have gained significant traction as a cancer therapy in recent decades, represent a promising option for treating histiocytic sarcomas through their replication and/or by modulating the tumor microenvironment. The live attenuated canine distemper virus (CDV) vaccine strain Onderstepoort represents an attractive candidate for oncolytic viral therapy. In the present study, oncolytic virotherapy with CDV was used to investigate the impact of this virus infection on tumor cell growth through direct oncolytic effects or by virus-mediated modulation of the tumor microenvironment with special emphasis on angiogenesis, expression of selected MMPs and TIMP-1 and tumor-associated macrophages in a murine xenograft model of canine histiocytic sarcoma. Treatment of mice with xenotransplanted canine histiocytic sarcomas using CDV induced overt retardation in tumor progression accompanied by necrosis of neoplastic cells, increased numbers of intratumoral macrophages, reduced angiogenesis and modulation of the expression of MMPs and TIMP-1. The present data suggest that CDV inhibits tumor growth in a multifactorial way, including direct cell lysis and reduction of angiogenesis and modulation of MMPs and their inhibitor TIMP-1, providing further support for the concept of its role in oncolytic therapies.