Microvessel Density and Clinicopathologic Characteristics in Hepatocellular Carcinoma With and Without Cirrhosis

Angiogenesis is essential to the survival, growth, invasion, and metastasis of various human solid tumors. We compared the microvessel density (MVD) and clinicopathologic features of two different groups of hepatocellular carcinoma (HCC), namely HCC with cirrhosis (HCC-C) and without cirrhosis (HCC-NC). A tissue microarray composed of 20 normal livers, 20 cirrhotic livers, tumor and adjacent background non-neoplastic liver tissues from 20 HCC-C and 20 HCC-NC were constructed and stained immunohistochemically with antibodies against the antigen CD34. The MVD was determined by the measurement of the area and density of CD34 positive sinusoidal endothelial cells using the Image Pro Plus software. There was a trend of increased MVD in cirrhotic liver compared to normal liver and in cirrhotic background non-neoplastic liver adjacent to the tumor compared to the non-cirrhotic background non-neoplastic liver. Tumor tissue of HCC-C and HCC-NC both showed significantly higher MVD than their adjacent background non-neoplastic liver tissue. There was no statistical difference in MVD between HCC-C and HCC-NC. A higher value of MVD was seen in tumors of intermediate size (5–10 cm), high histologic grade, the presence of lymphvascular space invasion, and the underlying etiology of hepatitis C and alcoholic steatohepatitis. This data indicates that MVD may play an important role in liver carcinogenesis and neoplastic progression. The difference in clinical behavior between HCC-C and HCC-NC does not seem to be associated with differences in tumor MVD. Objective measurement of MVD using standardized computer software could potentially be used as a clinical marker to predict patients’ prognosis

Prognostic Factors in Dedifferentiated Chondrosarcoma: A Retrospective Analysis of a Large Series Treated at a Single Institution.

Background:Dedifferentiated chondrosarcomas (DDCSs) are highly malignant tumors with a dismal prognosis and present a significant challenge in clinical management. Methods:In an IRB approved retrospective protocol, we identified 72 patients with DDCS treated at our institution between 1993 and 2017 and reviewed clinicopathological characteristics, treatment modalities, and outcomes to analyze prognostic factors. Results:Femur (44.4%), pelvis (22.2%), and humerus (12.5%) were most commonly involved sites. Twenty-three patients (31.9%) presented with distant metastasis, and 3 (4.2%) of them also had regional lymph node involvement. The median overall survival (OS) was 13.9 months. On multivariate analysis, pathological fracture, larger tumor size, lymph node involvement, metastasis at diagnosis, extraosseous extension, and undifferentiated pleomorphic sarcoma component correlated with worse OS, whereas surgical resection and chemotherapy were associated with improved OS. For progression-free survival (PFS), pathological fracture and metastasis at diagnosis showed increased risk, while chemotherapy was associated with decreased risk. Among patients who received chemotherapy, doxorubicin and cisplatin were significantly associated with improved PFS but not OS. Among patients without metastasis at diagnosis, 17 (34.7%) developed local recurrence. Thirty-one (63.3%) developed distant metastases at a median interval of 18.1 months. On multivariate analysis, R1/R2 resection was related with local recurrence, while macroscopic dedifferentiated component was associated with distant metastasis. Conclusions:The prognosis of DDCS is poor. Complete resection remains a significant prognostic factor for local control. Chemotherapy with doxorubicin and cisplatin seems to have better PFS. More prognostic, multicenter trials are warranted to further explore the effectiveness of chemotherapy in selected DDCS patients

LIN28B Underlies the Pathogenesis of a Subclass of Ewing Sarcoma

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Histologic variants of chondrosarcoma

The histologic subtypes of chondrosarcoma are uncommon. Despite their rarity, they present with characteristic clinical and histopathologic features distinguishing them from conventional type of chondrosarcoma. The histologic variants, clear cell and mesenchymal chondrosarcoma, are reviewed herein. Dedifferentiated chondrosarcoma, although typically arising from conventional chondrosarcoma, is also reviewed due to its distinct histomorphology. Finally, so-called extraskeletal myxoid chondrosarcoma, which may rarely arise primary in bone, is also discussed despite its uncertain histogenesis

Coadministered cannabidiol and clobazam : preclinical evidence for both pharmacodynamic and pharmacokinetic interactions

Objective: Cannabidiol (CBD) has been approved by the US Food and Drug Administration (FDA) to treat intractable childhood epilepsies, such as Dravet syn-drome and Lennox‐Gastaut syndrome. However, the intrinsic anticonvulsant activity of CBD has been questioned due to a pharmacokinetic interaction between CBD and a first‐line medication, clobazam. This recognized interaction has led to speculation that the anticonvulsant efficacy of CBD may simply reflect CBD augmenting clobazam exposure. The present study aimed to address the nature of the interaction between CBD and clobazam. Methods: We examined whether CBD inhibits human CYP3A4 and CYP2C19 mediated metabolism of clobazam and N‐desmethylclobazam (N‐CLB), respectively, and performed studies assessing the effects of CBD on brain and plasma pharma-cokinetics of clobazam in mice. We then used the Scn1a+/− mouse model of Dravet syndrome to examine how CBD and clobazam interact. We compared anticonvulsant effects of CBD‐clobazam combination therapy to monotherapy against thermally‐in-duced seizures, spontaneous seizures and mortality in Scn1a+/− mice. In addition, we used Xenopus oocytes expressing γ‐aminobutyric acid (GABA)A receptors to investigate the activity of GABAA receptors when treated with CBD and clobazam together. Results: CBD potently inhibited CYP3A4 mediated metabolism of clobazam and CYP2C19 mediated metabolism of N‐CLB. Combination CBD‐clobazam treatment resulted in greater anticonvulsant efficacy in Scn1a+/− mice, but only when an anticonvulsant dose of CBD was used. It is important to note that a sub‐anticonvulsant dose of CBD did not promote greater anticonvulsant effects despite increasing plasma clobazam concentrations. In addition, we delineated a novel pharmacodynamic mechanism where CBD and clobazam together enhanced inhibitory GABAA receptor activation

Expression of programmed cell death ligand 1 (PD-L1) and prevalence of tumor-infiltrating lymphocytes (TILs) in chordoma

Chordomas are primary malignant tumors of the notochord that are resistant to conventional chemotherapy. Expression of programmed cell death ligand 1 (PD-L1), prevalence of tumor-infiltrating lymphocytes (TILs), and their clinical relevance in chordoma remain unknown. We evaluated PD-L1 expression in three chordoma cell lines and nine chordoma tissue samples by western blot. Immunohistochemical staining was performed on a chordoma tissue microarray (TMA) that contained 78 tissue specimens. We also correlated the expression of PD-L1 and TILs with clinical outcomes. PD-L1 protein expression was demonstrated to be induced by IFN-γ in both UCH1 and UCH2 cell lines. Across nine human chordoma tissue samples, PD-L1 protein was differentially expressed. 94.9% of chordoma samples showed positive PD-L1 expression in the TMA. The expression score of PD-L1 for metastatic chordoma tumors was significant higher as compared with non-metastatic chordoma tumors. Expression of PD-L1 protein significantly correlates with the presence of elevated TILs, which correlates with metastasis. In summary, our study showed high levels of PD-L1 are expressed in chordoma, which is correlated with the prevalence of TILs. The current study suggests targeting PD-L1 may be a novel immunotherapeutic strategy for chordoma clinical trials

Myxoid Liposarcoma: Treatment Outcomes from Chemotherapy and Radiation Therapy

Introduction. Myxoid liposarcoma (MLS) is a subtype of liposarcoma characterized morphologically by lipomatous differentiation with a myxoid stroma. The purpose of this study was to review clinical and pathological information for patients treated for MLS at our institution to better understand neoadjuvant and adjuvant therapy. Materials and Methods. An institutional database of sarcomas was queried for patients who were treated for MLS at our institution between 1992 and 2013. Survival curves were constructed using Kaplan–Meier analysis, and univariate and multivariate statistics were performed using the Cox-proportional hazards model and using linear regression. Results. A total of 85 patients with myxoid liposarcoma were identified. The mean and median histologic response rate to treatment for patients who received preoperative radiation therapy was 77.6%. Five-year disease-free survival, distant metastasis-free survival, local recurrence-free survival, and overall survival were 78.6% (95% CI: 67.8–86.1), 84.7% (95% CI: 74.5–91.0), 95.6% (95% CI: 86.9–98.6), and 87.5% (95% CI: 77.2–93.3) respectively. On univariate analysis, there was a trend towards higher necrosis or treatment response rates in patients who received concurrent chemotherapy, 84.7% (95% CI: 75.9–93.4) and 69.5% (95% CI: 55.1–83.8), p=0.061. Tumor size was associated with inferior disease-free and overall survival. Hazard ratio for disease-free survival is 1.08 (per cm) (95% CI: 1.01–1.16), p=0.019. Conclusions. Myxoid liposarcoma exhibits histological response to chemotherapy and radiation therapy. Tumor size appears to be greatest predictor of long-term disease control and overall survival. We were not able to show that chemotherapy provides a clinical benefit with regard to local control, disease-free survival, or overall survival. However, it is important to note that the selected usage of chemotherapy in the highest risk patients confounds this analysis. Further investigation is needed to help better determine the optimal use of chemotherapy in this group of patients