Circulating Protein Biomarkers to Differentiate Uterine Sarcomas from Leiomyomas.

Uterine sarcomas are rare but very aggressive. Uterine myomas, on the other hand, are the most common benign tumors of the uterus. Currently there is no diagnostic technique available to distinguish them with certainty. This study aimed to summarize the published literature concerning protein-based biomarkers in the peripheral blood that can assist in this difficult differential diagnosis. In total, 48 articles, published between 1990 and 2017, were included. Most studies (n=37) concerned soft tissue sarcomas, while 11 discussed uterine sarcomas specifically. Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), interleukins (IL), cancer antigen 125 (CA 125), lactate dehydrogenase, gangliosides (LDH) and growth differentiation factor 15 (GDF-15) are the most studied proteins in soft tissue sarcomas, including uterine sarcomas. Future research on improving sarcoma diagnosis should include these proteins.

Solitary Muscle Metastasis of Hepatocellular Carcinoma to the Biceps Femoris Muscle with Only Elevated Serum PIVKA-II: A Case Report.

BACKGROUND Hepatocellular carcinoma (HCC) is a common primary hepatic cancer. Regardless of its metastatic potential, metastasis to skeletal muscle is rare, especially to one solitary muscle. The diagnostic efficiency of Protein induced by Vitamin K absence/antagonist-II (PIVKA-II) has been illustrated sufficiently and it has been proven that PIVKA-II is a potent biomarker and independent of alpha-fetoprotein (AFP). The present report describes a case of solitary muscle metastasis with PIVKA-II elevation. CASE REPORT An 81-year-old man noticed a growing mass in the proximal posterior thigh, and it was found to be a solitary tumor in the biceps femoris muscle. He had undergone a medial segmentectomy for primary HCC and transcatheter arterial chemoembolization for an intrahepatic recurrence 7 and 4 years before, respectively. The level of PIVKA-II was elevated to 11 400 mAU/mL, but the alpha-fetoprotein (AFP) level was normal. Elevation of PIVKA-II to over 50 mAU/mL had been observed 7 months before the muscular lesion was first observed. When the solitary metastasis was diagnosed, a wide resection was performed in the same way as for primary sarcoma, and the PIVKA-II value decreased to 71 mAU/mL. No recurrence at the muscle was observed, but multiple lung metastases were seen and the PIVKA-II was elevated to 1410 mAU/mL 4 months after the resection. CONCLUSIONS Resection of the solitary muscle metastasis helped control the local metastatic lesion and helped with ability to perform daily activities, as well as possibly prolonging survival. PIVKA-II is an important biomarker for HCC surveillance in conjunction with alpha-fetoprotein (AFP). PIVKA-II can be independent of AFP. Examination of the whole body is still necessary in cases with elevated PIVKA-II in order to detect extrahepatic metastasis.

Interleukin-6, C/EBP-ß and PPAR-γ expression correlates with intramuscular liposarcoma growth in mice: The impact of voluntary physical activity levels.

IL-6 is an axial cytokine overexpressed in cancer to promote growth and increase resistance to anti-cancer therapies. As the application of IL-6-targeting therapies are still limited, alternative non-aggressive and adjuvant approaches, like physical activity (PA) could be useful to reverse IL-6 effects. To get more insights into liposarcoma (LS) pathophysiology, we investigated potential molecular links between IL-6 and LS growth and we tested the impact of PA on such mechanism in an orthotopic model of intramuscular LS. Initially active nude mice have received an intramuscular injection of either human SW872 cells or vehicle, then were respectively randomized into voluntary-active or inactive mice with open or restricted access to activity-wheels. We found that LS-bearing mice exhibited ∼6 fold increase in circulating IL-6 comparing to controls, with a concomitant decrease in hepatic drug-metabolizing enzymes expression. Circulating IL-6 levels were positively correlated with intra-tumor IL-6 expression (r = 0.85, P < 0.01). Interestingly, intra-tumor IL-6, C/EBP-α/ß and PPAR-γ expression were correlated together and with greater tumor mass and autophagy markers, notably, GABARAPL-1. Intriguingly, we found that maintaining a spontaneous PA after tumor injection did not reduce the levels of IL-6, but even enhanced tumor growth, induced body weight loss and increased the risk of developing lung metastasis. Our findings suggest that (1) IL-6, C/EBP-ß and PPAR-γ exert a potential role in promoting growth of dedifferentiated LS and (2) that PA failed to mechanistically interfere with these factors, but enhanced LS growth via other independent-mechanisms. The preclinical data reported here could be helpful in the sub-molecular classification of LS patients to improve diagnosis and design a low-risk treatment. Circulating IL-6 could serve as an indicator for treatment follow-up and, perhaps, for infra-radiologic LS relapses.

Characterizing the Blood Oxygen Level-Dependent Fluctuations in Musculoskeletal Tumours Using Functional Magnetic Resonance Imaging.

This study characterized the blood oxygen level-dependent (BOLD) fluctuations in benign and malignant musculoskeletal tumours via power spectrum analyses in pre-established low-frequency bands. BOLD MRI and T1-weighted imaging (T1WI) were collected for 52 patients with musculoskeletal tumours. Three ROIs were drawn on the T1WI image in the tumours' central regions, peripheral regions and neighbouring tissue. The power spectrum of the BOLD within each ROI was calculated and divided into the following four frequency bands: 0.01-0.027 Hz, 0.027-0.073 Hz, 0.073-0.198 Hz, and 0.198-0.25 Hz. ANOVA was conducted for each frequency band with the following two factors: the location of the region of interest (LoR, three levels: tumour "centre", "peripheral" and "healthy tissue") and tumour characteristic (TC, two levels: "malignant" and "benign"). There was a significant main effect of LoR in the frequencies of 0.073-0.198 Hz and 0.198-0.25 Hz. These data were further processed with post-hoc pair-wise comparisons. BOLD fluctuations at 0.073-0.198 Hz were stronger in the peripheral than central regions of the malignant tumours; however, no such difference was observed for the benign tumours. Our findings provide evidence that the BOLD signal fluctuates with spatial heterogeneity in malignant musculoskeletal tumours at the frequency band of 0.073-0.198 Hz.

Serum periplakin as a potential biomarker for urothelial carcinoma of the urinary bladder.

The objectives of this study were to examine serum periplakin expression in patients with urothelial carcinoma of the urinary bladder and in normal controls, and to examine relationships with clinicopathological findings. Detection of serum periplakin was performed in 50 patients and 30 normal controls with anti-periplakin antibodies using the automatic dot blot system, and a micro-dot blot array with a 256 solid-pin system. Levels in patients with urothelial carcinoma of the urinary bladder were significantly lower than those in normal controls (0.31 and 5.68, respectively; p<0.0001). The area under the receiver-operator curve level for urothelial carcinoma of the urinary bladder was 0.845. The sensitivity and specificity, using a cut-off point of 4.045, were 83.7% and 73.3%, respectively. In addition, serum periplakin levels were significantly higher in patients with muscle-invasive cancer than in those with nonmuscle-invasive cancer (P=0.03). In multivariate Cox proportional hazards regression analysis, none of the clinicopathological factors was associated with an increased risk for progression and cancer-specific survival. Examination of the serum periplakin level may play a role as a non- invasive diagnostic modality to aid urine cytology and cystoscopy.

Venous thromboembolism in the management of patients with musculoskeletal tumor.

BACKGROUND: Although patients with musculoskeletal tumors are at risk of venous thromboembolism (VTE), few detailed studies on the incidence, clinical course, and risk factors of this condition have been reported. METHODS: A total of 299 patients with musculoskeletal tumors during the preceding 3 years were enrolled. D-dimer (DD) levels on admission and on postoperative days 1, 7, and 14 were routinely assessed. For patients who were receiving chemotherapy, an examination was performed every 2-3 days for the survey. Multidetector-row computed tomography (MDCT) was used for the detection of VTE in patients with DD levels > 10 µg/ml. The incidence of clinically detected VTE and the clinical courses of the patients with VTE were reviewed. The risk factors for VTE were analyzed. For statistical analysis, Fisher's exact test, the Mann-Whitney U-test, and logistic regression were used. RESULTS: VTE was detected in eight cases (2.7%). Six cases were detected postoperatively, and the remaining two cases were detected during chemotherapy. Pulmonary embolism was evident in four cases. No VTE-related lethal events were detected during the study period. In the univariate analysis, malignancy (P = 0.003), chemotherapy (P = 0.004), plastic surgery (P = 0.006), tumor size (P = 0.008), and elevated DD levels at admission (P = 0.03) were found to be significant risk factors for VTE. Among these factors, the multivariate analysis indicated that tumor size (P = 0.00 006), plastic surgery (P 0. 01), and chemotherapy (P = 0.02) were independent risk factors. CONCLUSIONS: The incidence and risk factors for VTE in the management of musculoskeletal tumor patients by screening DD levels combined with MDCT were analyzed. For patients at risk, prospective surveys for VTE should be considered in the future.

Serum levels of angiogenic factors and their prognostic relevance in bladder cancer.

Angiogenesis plays a critical role in tumor growth. VEGF, angiopoietins (Ang-1, Ang-2) and their tyrosine kinase receptor Tie2 are major regulators of angiogenesis. The aim of this study was to evaluate the prognostic value of the serum levels of these factors in bladder cancer. We analyzed the serum samples of 117 bladder cancer patients and 64 healthy volunteers by enzyme linked immunosorbent assay (ELISA) for Ang-1, Ang-2, VEGF and the extracellular domain of Tie2. The statistical evaluation of the obtained data was performed via Kaplan-Meier log-rank test, univariate Cox analyses as well as Cox proportional hazards regression model. Serum Ang-1 levels of bladder cancer patients were significantly higher (p < 0.001), while soluble Ang-2 and Tie2 levels were significantly lower (p = 0.016 and p = 0.001 respectively) in patients than those in controls. Cox univariate analysis revealed high sTie2 serum level as a risk factor for metastasis and as a borderline significant risk factor for disease related death (p = 0.022 and p = 0.081 respectively). These correlations were independent from tumor stage and grade in a Cox multivariate model (p = 0.016 and p = 0.069). These data indicate that the serum levels of analyzed angiogenic factors do change characteristically in bladder cancer. The soluble extracellular serum level of Tie2 may provide a stage and grade independent diagnostic tool to select a high risk group of bladder cancer patients.

[A case of metastasis to the diaphragm from ascending colon cancer].

We reported a case of metastatic tumor to the diaphragm discovered by rising CEA after operation of ascending colon cancer. A 72-year-old female underwent right hemicolectomy on January 2005. After discharge, she received adjuvant chemotherapy by S-1, but a rise of CEA was shown. Based on exploratory findings, laparotomy was done with the diagnosis of metastasis to the liver(S7). A tumor was present in the right diaphragm, and contacted the liver(S7). Partial resection of the right diaphragm was performed. The removed specimen revealed the same histological findings of the last operated ascending colon. Metastasis to the diaphragm is very rare, especially a solitary one as in this case. Etiologically speaking, the tumor cells might be absorbed or have strayed into peritoneal stomata of the diaphragm.

Value of measuring subpopulations of T and B lymphocytes in patients with musculoskeletal tumours.

BACKGROUND: Aims of our study were to assess the clinical value of measuring subpopulations of T and B lymphocytes in patients with musculoskeletal tumours as an immunodiagnostic procedure in the primary diagnosis of tumours. METHODS: In this prospective study, blood samples were obtained from 145 patients aged 04-98 years with musculoskeletal tumours. CD3, CD4, CD8, Helper/Suppressor ratio and CD19 subpopulations of lymphocytes were measured in specimens of whole blood in EDTA, upon the principle of Ortho Cytoron Absolute flow cytometry. Histological tumour diagnosis was obtained by the histopathology investigation of biopsy sample and lymphocytes values allocated accordingly. RESULTS: Out of 145 patients, osteomyelitis was diagnosed in 15 (10.34%). Median values of subpopulations of lymphocytes were: CD3 2456, CD4 1479, CD8 929, Helper/Suppressor ratio 1.8 and CD19 560 and all were raised above normal values in patients with osteomyelitis. Results were also calculated for osteosarcomas, Ewing sarcomas, giant cell tumours, chondrosarcomas and other tumours. These causes had median values within normal reference levels. To confidently out rule or confirm diagnosis of osteomyelitis, we measured the cut off point values and they were: CD3 2420, CD4 1400, CD8 873 and CD19 550. CONCLUSIONS: The main clinical use of measuring subpopulations of lymphocytes is in establishing the correct diagnosis between suspected osteomyelitis and other musculoskeletal tumours. Levels of measured subpopulations of lymphocytes above the presented cut off values are important and accurate confirming factor for the clinical diagnosis of suspected osteomyelitis. LEVEL OF EVIDENCE: II.

Late relapse of adrenocortical carcinoma in Beckwith-Wiedemann syndrome. Clinical, endocrinological and genetic aspects.

UNLABELLED: We report on a girl with an unusual Beckwith-Wiedemann syndrome (BWS) and hemihypertrophy, who developed an adrenocortical carcinoma with atypical clinical behaviour. At 4 y of age the girls was admitted to hospital with cushingoid features, virilization, increased excretion of steroids and low serum ACTH. A right-sided adrenocortical carcinoma was removed. At age 12.5 y the cushingoid features reappeared together with a tumour in the left thigh. A CT scan of the thorax and abdomen revealed pulmonary metastasis only. Corticosteroid excretion was increased and serum ACTH level suppressed. The femoral and the pulmonary metastases were removed and histology showed adrenocortical carcinoma. Excretion of corticosteroids subsequently normalized. Meningeal and pulmonary metastases with similar histologies appeared one year later with normal hormone values. Twenty-two months after the recurrence the girl died of an intracranial metastasis. Southern blot analysis of the LITI transcript in the KvLQT1 gene in the BWS region on chromosome 11p15 revealed hypomethylation of the maternal allele. CONCLUSION: Adrenocortical carcinoma in childhood may recur years after onset and at rare sites and hormonal levels may be an insufficient indicator of small metastases.

Carbon dioxide reactivity of computed tomography functional parameters in rabbit VX2 soft tissue tumour.

Tumour blood flow is one of the important factors limiting the efficacy of radiation therapy (hypoxic radioresistance), chemotherapy (drug delivery) and thermal therapy (heat dissipation) in treating cancer. The modification of tumour blood flow has been an area of intense investigation. In the current study, the arterial carbon dioxide tension (PaCO2) was changed in order to investigate the tumour vascular response to carbon dioxide. Functional maps of blood flow, blood volume and mean transit time were generated at four PaCO2 levels in VX2 tumour in the rabbit thigh and normal soft tissue. The PaCO2 levels investigated were normocapnia (PaCO2 = 40.9 +/- 1.2 mmHg), hypocapnia (27.2 +/- 2.3 and 33.5 +/- 2.3 mmHg) and hypercapnia (54.9 +/- 4.4 mmHg). The carbon dioxide reactivity of the global tumour blood flow and mean transit time showed significant differences between normocapnia and the two levels of hypocapnia, but not between normocapnia and hypercapnia. The average fractional change of blood flow from normocapnia for the two levels of hypocapnia was -0.41 +/- 0.06 and -0.29 +/- 0.08, respectively (P < 0.05). In the case of mean transit time the fractional change was +0.39 +/- 0.30 and +0.23 +/- 0.24, respectively (P < 0.05). The fractional change of blood volume from normocapnia, however, was not significantly different at any capnic level, as was the case with respect to each of the functional parameters in normal tissue. The ability to reduce blood flow and increase mean transit time through hypocapnia has significant implications in thermal therapy, since heat dissipation is a major factor in limiting the effectiveness of treatment.