Serum Concentration of Thymidine Kinase 1 (TK1) as a Tumor Marker in Soft Tissue Sarcomas.

BACKGROUND/AIM: The aim of this prospective study was to determine whether serum Thymidine kinase -1 (TK1) could serve as a tumor marker in soft tissue sarcomas (STS). PATIENTS AND METHODS: A total of 48 patients diagnosed with localized STS were included. None had received preoperative oncological treatment. Samples were collected before and after surgery and TK1 levels measured with the AroCell TK210 ELISA. RESULTS: Mean preoperative TK1 was 0.32 µg/l, range=0.11-1.47, and 18 cases (38%) had values above the reference limit (0.41 µg/l). Mean postoperative TK1 was 0.35 µg/l (0.06-0.86). In patients with preoperative values above the reference limit, TK1 decreased significantly after surgery (n=13, p=0.001). We found no association between increased preoperative TK1 and age, sex, tumor size, grade, and the presence of vascular invasion or necrosis. CONCLUSION: TK1 has limited use as a tumor marker in localized STS.

Is early change in systemic inflammatory markers associated with treatment response in patients who received pazopanib?

PURPOSE: To demonstrate whether early changes in systemic inflammatory markers are related with pazopanib treatment response in soft tissue sarcoma and renal cell carcinoma. METHODS: Forty-one patients with metastatic clear cell renal carcinoma (mRCC) (n=22) and advanced stage soft tissue sarcoma (STS) (n=19) were assessed. Systemic inflammatory markers such as neutrophils, lymphocytes, c-reactive protein (CRP), mean platelet volume (MPV), lactate dehydrogenase (LDH) and neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) at both baseline and 1-month of pazopanib treatment were obtained and their relation with the first radiological response about 3-months later after pazopanib treatment was evaluated. RESULTS: Disease control rate (DCR) at the first initial radiological evaluation was 58.5 % for all, it was 77.3% for the RCC group and 36.8% in the STS group. Serum neutrophil, NLR and CRP levels were significantly decreased from baseline in RCC patients who had DCR with pazopanib treatment. Also, serum CRP levels after pazopanib treatment was significantly lower in RCC patients who had DCR (+) rather than those who progressed. CONCLUSIONS: Early decline in serum CRP, neutrophil and NLR levels in RCC patients who received pazopanib at the first month was significantly associated with disease control, assuming a predictive role for the first radiological assessment. However, there was no significant association between change in serum inflammatory marker levels and disease control in STS patients.

Liquid Biopsy: A New Translational Diagnostic and Monitoring Tool for Musculoskeletal Tumors.

Soft tissue and bone sarcomas represent a group of aggressive neoplasms often accompanied by dismal patient prognosis, especially when distant metastases are present. Moreover, effective treatment can pose a challenge, as recurrences are frequent and almost half of patients present with advanced disease. Researchers have unveiled the molecular abnormalities implicated in sarcomas' carcinogenesis, paving the way for novel treatment strategies based on each individual tumor's characteristics. Therefore, the development of new techniques aiding in early disease detection and tumor molecular profiling is imperative. Liquid biopsy refers to the sampling and analysis of patients' fluids, such as blood, to identify tumor biomarkers, through a variety of methods, including qRT-PCR, qPCR, droplet digital PCR, magnetic microbeads and digital PCR. Assessment of circulating tumor cells (CTCs), circulating free DNA (ctDNA), micro RNAs (miRs), long non-coding RNAs (lncRNAs), exosomes and exosome-associated proteins can yield a plethora of information on tumor molecular signature, histologic type and disease stage. In addition, the minimal invasiveness of the procedure renders possible its wide application in the clinical setting, and, therefore, the early detection of the presence of tumors. In this review of the literature, we gathered information on biomarkers assessed through liquid biopsy in soft tissue and bone sarcoma patients and we present the information they can yield for each individual tumor type.

Evaluation of Absolute Lymphocyte Count at Diagnosis and Mortality Among Patients With Localized Bone or Soft Tissue Sarcoma.

Importance: Host-related immune factors have been implicated in the development and progression of diverse malignant neoplasms. Identifying associations between immunologic laboratory parameters and overall survival may inform novel prognostic biomarkers and mechanisms of antitumor immunity in localized bone and soft tissue sarcoma. Objective: To assess whether lymphopenia at diagnosis is associated with overall survival among patients with localized bone and soft tissue sarcoma. Design, Setting, and Participants: This retrospective cohort study analyzed patients from the Stanford Cancer Institute with localized bone and soft tissue sarcoma between September 1, 1998, and November 1, 2018. Patients were included if laboratory values were available within 60 days of diagnosis and, if applicable, prior to the initiation of chemotherapy and/or radiotherapy. Statistical analysis was performed from January 1, 2019, to November 1, 2020. Exposures: Absolute lymphocyte count within 60 days of diagnosis and antimicrobial exposure, defined by the number of antimicrobial agent prescriptions and the cumulative duration of antimicrobial administration within 60 days of diagnosis. Main Outcomes and Measures: The association between minimum absolute lymphocyte count at diagnosis and 5-year overall survival probability was characterized with the Kaplan-Meier method and multivariate Cox proportional hazards regression models. Multivariable logistic regressions were fitted to evaluate whether patients with lymphopenia were at greater risk of increased antimicrobial exposure. Results: Among 634 patients, the median age at diagnosis was 53.7 years (interquartile range, 37.5-66.8 years), and 290 patients (45.7%) were women, with a 5-year survival probability of 67.9%. There was a significant inverse association between lymphopenia at diagnosis and overall survival (hazard ratio [HR], 1.82; 95% CI, 1.39-1.40), resulting in a 13.5% 5-year survival probability difference compared with patients who did not have lymphopenia at diagnosis (60.2% vs 73.7% for those who never had lymphopenia). In addition, poorer survival was observed with higher-grade lymphopenia (grades 3 and 4: HR, 2.44; 95% CI, 1.68-3.55; grades 1 and 2: HR, 1.60; 95% CI, 1.18-2.18). In an exploratory analysis, patients with increased antibiotic exposure were more likely to have lymphopenia (odds ratio, 1.96; 95% CI, 1.26-3.07 for total number of antimicrobial agents; odds ratio, 1.70; 95% CI, 1.10-2.57 for antimicrobial duration) than antimicrobial-naive patients. Conclusions and Relevance: This study suggests that an abnormally low absolute lymphocyte count at diagnosis is associated with higher mortality among patients with localized bone and soft tissue sarcoma; therefore, lymphopenia may serve as a reliable prognostic biomarker. Potential mechanisms associated with host immunity and overall survival include a suppressed antitumor response and increased infectious complications, which merit future investigation.

Survival and prognostic analysis of preoperative indicators in patients undergoing surgical resections with rhabdomyosarcoma.

Several preoperative blood and biochemical parameters are associated with postoperative survival in many kinds of tumors. The aim of this study is to study the predictive value of several routine preoperative blood and biochemical parameters on the prognosis patients with rhabdomyosarcoma (RMS).We retrospectively recruited 55 patients diagnosed with RMS and had surgery at West China Hospital, Sichuan University between January 2010 and December 2018. Baseline characteristics of the patients, tumor features, surgery details, and values of several examinations were extracted. A long-term follow-up was conducted by phone call. A novel statistical analysis was subsequently carried out to look for the relationship of preoperative parameters and patients' prognosis.The ROC analysis showed an area under curve (AUC) of 0.608, 0.620, 0.626, 0.591, and 0.518 for neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), monocyte to lymphocyte ratio (MLR), lactic dehydrogenase (LDH), and alkaline phosphatase (ALP) respectively, and the cut-off value of 2.843, 162.961, and 0.239 for NLR, PLR, and MLR respectively. The survival analysis showed that certain blood and biochemical parameters could cause differences in overall survival (OS) (P = .005 for NLR, P = .005 for PLR, and P = .007 for MLR) and progression free survival (PFS) (P = .029 for NLR, P = .008 for PLR, and P = .013 for MLR).Several preoperative blood and biochemical parameters are novel prognostic factors in RMS patients. Specifically, a higher NLR, PLR, and MLR value will predict a statistically shorter OS and PFS.In the future, surgeons should care more about NLR, PLR, and MLR values and several other parameters in patients' preoperative normal blood and biochemical tests to predict the postoperative conditions.

Systemic Inflammation Is Associated with Oncological Outcome in Patients with High-Grade Myxofibrosarcoma of the Extremities: A Retrospective Analysis.

BACKGROUND: The aim of this retrospective study is to verify whether preoperative systemic inflammatory markers (serum C-reactive protein [CRP] and neutrophil-lymphocyte ratio [NLR]) can help in predicting the disease-specific survival (DSS) and local recurrence (LR) rate in adult patients affected by localized myxofibrosarcoma (MFS) of the extremities. METHODS: We reviewed 126 adult patients with primary, localized MFS of the limbs. We analyzed DSS and LR. RESULTS: Median age at the time of surgery was 68 years (range 19-92). Median CRP was 0.4 mg/dL and median NLR was 2.8. A worse DSS was found in patients who had preoperative CRP >0.5 mg/dL (p = 0.002) and in those with NLR >3.5 (p < 0.001). In multivariate analysis, tumor size and grade as well as preoperative CRP values and NLR were confirmed to be prognostic factors in terms of DSS. An increased risk of LR was found in multivariate analysis in patients with a tail sign and with high gadolinium enhancement at preoperative MRI. CONCLUSIONS: Patients with high preoperative CRP and NLR levels, as well as large and high-grade tumors, might be considered as candidates for additional, more aggressive treatment approaches or more stringent follow-up schedules.

Clinical and genetic analysis of idiopathic normophosphatemic tumoral calcinosis in 19 patients.

PURPOSE: Tumoral calcinosis is a rare clinicopathological entity characterized by ectopic soft-tissue calcification, typically periarticular. Normophosphatemic tumoral calcinosis is seldom reported in East Asian populations, and the preoperative diagnosis is often elusive. This study was performed to characterize the clinical profile of normophosphatemic tumoral calcinosis and investigate the presence of the SAMD9 gene mutation. METHODS: The clinical features, pathological examination findings, and outcomes of 19 subjects were retrospectively reviewed. All patients were analyzed for SAMD9 gene mutation using paraffin-embedded tumoral calcinosis specimens. RESULTS: Nineteen subjects were analyzed (7 males, 12 females). Their mean age at surgery, mean age at symptom onset, and median disease duration was 51.9 ± 17.3 (range 7-75) years, 49.1 ± 17.2 (range 7-74) years, and 1.3 (interquartile range 0.5-3.0) years, respectively. Lesions were located in the hand in 8 (42.1%) subjects; wrist in 5 (26.3%); shoulder in 2 (10.5%); and hip, knee, buttock, and scrotum in 1 (5.3%) subject each. The lesions in 17 (89.5%) subjects were located around the joints [small joints (hand and wrist) in 13 (68.4%) and large joints (shoulder, hip, and knee) in 4 (21.1%)]. Lesions occurred in the upper limbs in 15 (78.9%) subjects and in the lower limbs in 2 (10.5%). Multiple-lesion involvement (distal right index finger and middle finger) occurred in one (5.3%) subject. Symptoms included pain in 15 (78.9%) subjects, impaired mobility in 5 (26.3%), swelling in 5 (26.3%), numbness in 2 (10.5%), and an asymptomatic mass in 2 (10.5%). The serum inorganic phosphorus concentration was normal in all 19 subjects (mean 1.17 ± 0.15 mmol/L). The serum calcium concentration was normal in 18 subjects and low in 1. The serum alkaline phosphatase concentration was normal in all 19 subjects. Pathological examination indicated multiple nodules of calcified materials that manifested an amorphous or granular blue-purple crystal and were surrounded by proliferation of mononuclear or multinuclear macrophages, osteoclastic-like giant cells, fibroblasts, and chronic inflammatory cells. Notably, different phases of pathological manifestations were observed in the same microscopic field. During follow-up (0.5-65.0 months), no recurrence of tumoral calcinosis was observed in 18 (94.7%) subjects, but 1 subject developed in situ recurrence of an asymptomatic subcutaneous mass after 6 months postoperatively. Genetic analysis in all 19 subjects revealed no SAMD9 gene mutations. CONCLUSIONS: Most subjects were females and developed calcinosis in adulthood. Small joints (hand and wrist) and the upper limbs were frequently involved. The presence of different phases of pathological features in the same subject suggests that about half of the study participants had been misdiagnosed with another condition (such as gout, osteoarthritis, etc.). Complete surgical excision led to cure without recurrence during follow-up in majority of the study participants.

Detection of circulating sarcoma tumor cells using a microfluidic chip-type cell sorter.

Analyses of circulating tumor cells have been shown to be effective for the detection of cancer relapse and prognosis prediction. However, research regarding its utility in sarcoma remains scarce. In this study, the microfluidic chip-type cell sorter On-chip Sort was used to construct a system for detecting circulating sarcoma cells (CSCs). A pilot study using normal fibroblast or sarcoma cell lines was designed to establish a reliable protocol to separate CSCs by On-chip Sort. A single CSC was separated and recovered from 10 ml of whole blood from a patient with locally advanced myxofibrosarcoma. The nonsynonymous mutation for KMT2B p.Ile2602Val identified in the formalin-fixed paraffin-embedded tumor sample was also confirmed in the CSC. Use of the developed protocol may allow CSCs to become an early predictor for metastasis and recurrence of sarcoma. Further, it may aid in optimizing post-operative therapies for patients without metastasis.

Serum thrombomodulin as a metastatic and prognostic marker in soft tissue sarcomas.

BACKGROUND: Thrombomodulin (TM) has multiple biological functions and modulates not only anti-coagulation, but also cell proliferation, adhesion, and anti-inflammation activities. The main function of TM is to activate the anticoagulant pathway of protein C. Soluble TM is related to metastasis by its inactivation of thrombin. OBJECTIVES: To clarify the correlation between serum TM levels and clinicopathological parameters. METHODS: The plasma TM levels (FU/ml) of 135 primary soft tissue tumors (benign, 67; soft tissue sarcoma (STS), 68) were measured before biopsy or treatment. TM levels were analyzed and compared to various clinicopathological parameters. Log-rank test and Cox proportional analysis were used to evaluate recurrence-free survival, metastasis-free survival, and overall survival. RESULTS: STS tumors had significantly higher TM values (15.9) than benign tumors (13.7) (p= 0.0138). 5-year MFS was 81.1% in low TM and 40.0% in high TM (p= 0.00671), and 5-year OS was 85.5% in low and 52.5% in high TM in grades 1-3 (p= 0.0673). In multivariate COX proportional analysis, high-TM showed a significant difference (MFS: HR 4.37, p= 0.0147; OS: HR 3.60, p= 0.0557) in grades 1-3. CONCLUSIONS: We demonstrated that a high level of soluble TM has the potential to be a significant predictor of metastasis and poor prognosis in STS patients. TM is a candidate molecular marker for high metastatic potential and can be clinically useful for guiding therapeutic strategy.

A serum microRNA classifier for the diagnosis of sarcomas of various histological subtypes.

Due to their rarity and diversity, sarcomas are difficult to diagnose. Consequently, there is an urgent demand for a novel diagnostic test for these cancers. In this study, we investigated serum miRNA profiles from 1002 patients with bone and soft tissue tumors representing more than 43 histological subtypes, including sarcomas, intermediate tumors, and benign tumors, to determine whether serum miRNA profiles could be used to specifically detect sarcomas. Circulating serum miRNA profiles in sarcoma patients were clearly distinct from those in patients with other types of tumors. Using the serum levels of seven miRNAs, we developed a molecular detector, Index VI, that could distinguish sarcoma patients from benign and healthy controls with remarkably high sensitivity (90%) and specificity (95%), regardless of histological subtype. Index VI provides an approach to the early and precise detection of sarcomas, potentially leading to curative treatment and longer survival.

Harnessing soft tissue sarcoma with low-dose pazopanib - a matter of blood levels.

BACKGROUND: Pazopanib is a tyrosine kinase inhibitor indicated for the treatment of renal cell carcinoma and soft tissue sarcoma. Despite the high inter-patient variability in pharmacokinetic exposure, pazopanib is administered at a fixed dose of 800 mg once daily (QD). Pharmacokinetic exposure is linked to both efficacy and toxicity. In this case report, we illustrate the value of therapeutic drug monitoring by describing two patients with adequate pazopanib trough concentrations (Cmin) at an eight times lower than standard dose. CASE PRESENTATION: Patient A is a 69-year-old woman with metastatic leiomyosarcoma who had significant toxicities and a high Cmin on the standard dose. While dose reductions to 200 mg QD and later 200 mg every other day were made, pazopanib Cmin remained above the efficacy threshold. Patient B is a 50-year-old male with metastatic angiosarcoma and a history of Gilbert syndrome. Pazopanib treatment was initiated at the standard dose of 800 mg QD, but was reduced to 200 mg QD 1-week-on - 1-week-off due to total bilirubin elevation. Pazopanib Cmin was adequate in this patient as well. CONCLUSION: It could be valuable to measure pazopanib levels in case of dose reductions due to toxicity, as exposure could still be adequate at considerably lower than standard doses.

Phosphaturic mesenchymal tumor and related wound problem.

INTRODUCTION: Phosphaturic mesenchymal tumor mixed connective tissue type (PMT/MCT) is the most common type (up to 90%) of phosphaturic mesenchymal tumor (PMT), a rare clinicopathologic entity. Besides overproduction of fibroblast growth factor 23 (FGF23), there is a big variation of immunohistochemical characteristic across types of PMT, which makes it difficult to obtain an early diagnosis of PMT/MCT. As a benign tumor, PMT/MCT usually happens in subcutaneous tissues and leads to nonhealing of wound. A complete excision of PMT/MCT facilitates wound healing. CONCLUSIONS: Review of the existing evidence indicates that early diagnosis of PMT/MCT is critically important when treating PMT/MCT wound. Hence standardization of early diagnosis for PMT/MCT is mandated.

[Clinical and immunohistopathologic study of phosphaturic mesenchymal tumor].

Objective: To study the clinicopathological characteristics and immunohistochemical phenotype of phosphaturic mesenchymal tumor (PMT) . Methods: The clinicopathological data and immunohistochemical profiles were obtained retrospectively from 206 patients diagnosed with PMT at Peking Union Medical College Hospital (PUMCH) during July 2008 to September 2017, with a review of literature. Results: The mean age of PMT patients was 42 years (range 13 to 70 years), with a male to female ratio of 1.1∶1.0. All patients presented with different degree of bone pain, muscle weakness, shorten of stature, thoracic deformity and pathological fractures, with hypophosphatemia and high serum ALP. Phosphatemia returned to normal within 1 week after operation in all cases underwent complete tumor resection. The duration of osteomalacia before resection (documented in 197 cases) ranged from 20 days to 40 years (average 5.7 years). The average blood phosphorus concentration raised from 0.49 mmol/L to 0.92 mmol/L before and after tumor resection (P<0.01), with 147 cases (84.0%, 147/175) returned to normal range within 2 weeks. The rate or blood phosphorus concentration recovery in 15 days after operation was 79.6% in average, displayed significant differences between patients with complete resection and those with partial resection (85.4% vs. 21.1%, P<0.01). PMT lesions mainly involved lower extremities (55.8%), followed by head and neck (29.1%). In immunohistochemical study, all cases were positive for vimentin (100.0%), while most cases were positive for NSE (96.3%), CD56 (94.2%), FGF23(88.4%), CD68 (88.3%), D2-40 (70.9%), CD34 (23.1%), SMA (55.5%), bcl-2 (59.8%) and CD99 (47.1%). The Ki-67 positive index of tumor varied from less than 2% (51.4%), 3% to 10% (41.3%) to >10% (7.2%). Conclusions: PMT mainly occurs in lower limbs or head and neck, with unique clinical characteristics and blood biochemical indexes. The tumor expresses a variety of immunohistochemical markers, indicating the potential of multi-directional differentiation. Clinical profile, blood biochemistry testing and immunohistochemical phenotype is helpful for diagnosis of PMT.

Postoperative Day 1 Glucose May Be Associated With Wound Complications in Sarcomas Treated With Preoperative Radiation.

BACKGROUND: Uncontrolled blood glucose impacts key phases of the wound healing process. Various factors have been associated with postoperative wound complications in soft tissue sarcomas; however, the association of postoperative early morning blood glucose with wound complications, if any, remains to be determined. Because blood glucose levels may be modified, understanding whether glucose levels are associated with wound complications has potential therapeutic importance. QUESTIONS/PURPOSES: The purposes of this study were (1) to evaluate if postoperative early morning blood glucose is associated with the development of wound complications in soft tissue sarcomas; (2) to determine a blood glucose cutoff that may be associated with an increased risk of wound complications; and (3) to evaluate if patients with diabetes have higher postoperative blood glucose and an associated increased risk of wound complications. METHODS: From 2000 to 2015, 298 patients with Stage I to III soft tissue sarcomas of the extremity or chest wall were treated with preoperative radiation ± chemotherapy followed by limb-sparing resection. Of those, 191 (64%) patients had demographic, treatment, and postoperative variables and wound outcomes available; these patients' results were retrospectively evaluated. None of the 191 patients were lost to followup. Early morning blood glucose levels on postoperative day (POD) 1 were available in all patients. Wound complications were defined as those resulting in an operative procedure or prolonged wound care for 6 months postresection. Variables that may be associated with wound complications were evaluated using logistic regression for multivariate analysis. Receiver operative curve (ROC) analysis was used to assess the early morning blood glucose level that best was associated postoperative wound complications. RESULTS: After controlling for potentially relevant confounding variables such as patient comorbidities, tumor size, and location, lower extremity soft tissue sarcomas (p = 0.002, odds ratio [OR], 6.4; 95% confidence interval [CI], 1.97-20.84) and elevated POD 1 early morning blood sugars (p < 0.001; OR, 1.1; 95% CI, 1.04-1.11) were associated with increased wound complications postoperatively. ROC analysis revealed that early morning POD 1 blood glucose of > 127 mg/dL was associated with postoperative wound complications with a sensitivity of 89% (area under the curve 0.898, p < 0.001). Median POD 1 early morning blood glucose in patients without diabetes was 118 mg/dL and 153 mg/dL in patients with diabetes (p = 0.023). However, with the numbers available, there was no increase in wound complications in patients with diabetes compared with those without it. CONCLUSIONS: Our study provides preliminary information suggesting that POD 1 early morning blood glucose in patients with soft tissue sarcomas may be associated with a slightly increased risk of postoperative wound complications. An early morning blood glucose of > 127 mg/dL may be a threshold associated with this outcome. Although patients with diabetes had higher POD 1 early morning blood glucose levels, diabetes itself was not associated with the development of wound complications. We cannot conclude that better glycemic control will reduce wound complications in patients who receive preoperative radiation, but our data suggest this should be further studied in a larger, prospective study. LEVEL OF EVIDENCE: Level III, therapeutic study.

The evaluation of circulating endothelial progenitor cells and related angiogenic markers as prognostic factors in soft-tissue tumors.

INTRODUCTION: Neovascularisation is a critical step in the progression of malignant tumors. Circulating endothelial progenitor cells (cEPC) have been proposed as surrogate markers of vasculogenesis in malignancies. In this project, we studied the impact of tumor-specific therapy on cEPC and associated angiogenic factors in patients with soft tissue tumors. MATERIALS AND METHODS: Fifty-three patients with soft tissue tumors (25 soft tissue sarcomas, 19 GIST, 9 desmoids) and 15 healthy controls were included. Blood samples were obtained at two time points, before and 8 weeks after start of tumor-specific therapy. Peripheral blood mononuclear cells (PBMCs) were isolated. cEPCs were characterised as CD34+, CD133+, CD45dim, CD31+ and vascular endothelial growth factor 2 (VEGFR-2) positive cells. Serum concentrations of VEGF-A and angiopoetin-2 were determined by enzyme-linked immunosorbent assay. RESULTS: VEGF-A and Ang-2 concentrations were significantly higher in tumor patients than in healthy controls in both samples (p < .01). Sarcoma patients with progressive disease developed a significant increase in cEPC levels between the two blood samples compared to those with stable disease (p = .002). GIST patients with progressive tumor or metastatic disease showed significant increase in VEGF-A values (p = .01). DISCUSSION: The pre-treatment values of the angiogenic markers did not correlate with the clinical course of the disease. However, cEPCs levels were significantly higher in sarcoma patients with progressive disease compared to those with stable disease and should be further evaluated as early markers of disease progression in sarcoma patients. VEGF-A and angiopoetin-2 clearly play a role as mediators of the vasculogenesis contributing to tumor progression.

Treatment and outcomes of tumor-induced osteomalacia associated with phosphaturic mesenchymal tumors: retrospective review of 12 patients.

BACKGROUND: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by severe hypophosphatemia and osteomalacia. Nonspecific symptoms make the diagnosis elusive. In addition, locating the responsible tumor(s) is challenging. The aim of this study was to investigate the clinical management and outcomes of TIO. METHODS: The clinical features, diagnostic procedures, treatment, and outcomes of 12 patients were reviewed retrospectively. RESULTS: The cohort comprised six men and six women (mean age 45.5 ± 9.9 years, range 23-61 years). The mean duration of disease was 3.7 ± 2.6 years. All patients manifested progressive bone pain, muscle weakness, and/or difficulty walking. Serum phosphorus concentrations were low in all patients (mean 0.42 ± 0.12 mmol/L). Technetium-99m octreotide scintigraphy was performed in 11 patients and showed lesions in the right distal femur, left femoral head, and right tibial plateau, respectively, in three patients. Magnetic resonance imaging (MRI) was negative for lesions in one patient. Two patients underwent biopsies that showed negative histopathology. Two patients, at 2 years and 8 months, respectively, after having negative technetium-99m octreotide studies, underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (CT), which revealed lesions in the sacrum and soft tissue of the left palm, respectively. One tumor was detected by CT and MRI. Overall, lesion sites were the head (two patients, 16.7%), thoracic and lumbar region (two, 16.7%), pelvis (three, 25%), lower limbs (four, 33.3%), and upper limbs (one, 8.3%). All patients underwent surgery, and histopathology showed phosphaturic mesenchymal tumors in each. Postoperatively, serum phosphorus concentrations normalized within 2-7 days in 11 patients. With follow-ups of 1-41 months, surgery was effective in 10 patients. One patient developed local recurrence and another had metastases. CONCLUSIONS: Locating tumors responsible for tumor-induced osteomalacia is often challenging. Although complete tumor resection confers a good prognosis in most patients, surveillance for recurrence and metastasis is necessary. Before surgery or when surgery is not indicated, oral phosphate can alleviate symptoms and metabolic imbalance.

A distinct plasma lipid signature associated with poor prognosis in castration-resistant prostate cancer.

Lipids are known to influence tumour growth, inflammation and chemoresistance. However, the association of circulating lipids with the clinical outcome of metastatic castration-resistant prostate cancer (CRPC) is unknown. We investigated associations between the plasma lipidome and clinical outcome in CRPC. Lipidomic profiling by liquid chromatography-tandem mass spectrometry was performed on plasma samples from a Phase 1 discovery cohort of 96 CRPC patients. Results were validated in an independent Phase 2 cohort of 63 CRPC patients. Unsupervised analysis of lipidomic profiles (323 lipid species) classified the Phase 1 cohort into two patient subgroups with significant survival differences (HR 2.31, 95% CI 1.44-3.68, p = 0.0005). The levels of 46 lipids were individually prognostic and were predominantly sphingolipids with higher levels associated with poor prognosis. A prognostic three-lipid signature was derived (ceramide d18:1/24:1, sphingomyelin d18:2/16:0, phosphatidylcholine 16:0/16:0) and was also associated with shorter survival in the Phase 2 cohort (HR 4.8, 95% CI 2.06-11.1, p = 0.0003). The signature was an independent prognostic factor when modelled with clinicopathological factors or metabolic characteristics. The association of plasma lipids with CRPC prognosis suggests a possible role of these lipids in disease progression. Further research is required to determine if therapeutic modulation of the levels of these lipids by targeting their metabolic pathways may improve patient outcome.

Analysis of Factors for Predicting Survival in Soft-tissue Sarcoma with Metastatic Disease at Initial Presentation.

BACKGROUND/AIM: We aimed to confirm predictors of survival in soft-tissue sarcoma (STS) patients with metastatic disease at initial presentation in 9 Institutions under the Tokai Musculoskeletal Oncology Consortium. PATIENTS AND METHODS: Between 2008 and 2013, 47 STS patients with metastatic disease at initial presentation were referred for treatment. The mean follow-up duration was 24 months. RESULTS: The mean C-reactive protein (CRP) levels were 2.47 mg/dl. The mean hemoglobin and albumin levels were 13.1 g/dl and 4.1 g/dl, respectively. Hemoglobin and albumin levels were significantly correlated with CRP levels. In the multivariate analysis, age, CRP levels, and albumin levels were confirmed as independent prognostic factors for disease-specific survival (DSS). CONCLUSION: We suggest that the measurements of CRP and albumin levels are a useful method of identifying STS patients with metastasis at initial presentation that have poor prognosis.

Phase 1/2 study of immunotherapy with dendritic cells pulsed with autologous tumor lysate in patients with refractory bone and soft tissue sarcoma.

BACKGROUND: There are limited options for the curative treatment of refractory bone and soft tissue sarcomas. The purpose of this phase 1/2 study was to assess the immunological and clinical effects of dendritic cells (DCs) pulsed with autologous tumor lysate (TL) in patients with advanced bone and soft tissue sarcomas. METHODS: Thirty-seven patients with metastatic or recurrent sarcomas were enrolled in this study. Peripheral blood mononuclear cells obtained from the patients were suspended in media containing interleukin 4 (IL-4) and granulocyte-macrophage colony-stimulating factor. Subsequently, these cells were treated with TL, tumor necrosis factor α, and OK-432. The DCs were injected into the inguinal or axillary region. One treatment course comprised 6 weekly DC injections. The toxicity, clinical response (tumor volume, serum interferon-γ [IFN-γ], and serum IL-12), and oncological outcomes were observed. RESULTS: In total, 47 courses of DC therapy were performed in 37 patients. No severe adverse events or deaths associated with the DC injections were observed in the study patients. Increased serum IFN-γ and IL-12 levels were observed 1 month after the DC injection. Among the 37 patients, 35 patients were assessed for clinical responses: 28 patients showed tumor progression, 6 patients had stable disease, and 1 patient showed a partial response 8 weeks after the DC injection. The 3-year overall and progression-free survival rates of the patients were 42.3% and 2.9%, respectively. CONCLUSIONS: Although DC therapy appears safe and resulted in an immunological response in patients with refractory sarcoma, it resulted in an improvement of the clinical outcome in only a small number of patients. Cancer 2017;123:1576-1584. © 2017 American Cancer Society.

Detection of a second malignancy in prostate cancer patients by using [(18)F]Choline PET/CT: a case series.

BACKGROUND: The role of radiolabeled choline (Cho) in patients with biochemical recurrence after radical treatment for prostate cancer (PCa) is well established. Its widespread clinical use has prompted the depiction of incidentalomas, unusual sites of metastatic lesions, as well as false positive and negative cases. We reported a series of patients affected by biochemical recurrence of PCa imaged by [(18)F]Cho positron emission tomography/computed tomography (PET/CT) which resulted suspected for a second malignancy. CASE PRESENTATION: [(18)F]Cho PET/CT was performed in patients with biochemical PCa recurrence. From an internal clinical database we identified patients in which PET/CT resulted suspected for a second malignancy. A second malignancy was suspected in presence of "unusual" site of [(18)F]Cho uptake not consistent with clinical-instrumental history. Histology was used as reference standard for final diagnosis. Seven PCa patients (76 years, 71-84 years) with the suspicion of a second tumor based on [(18)F]Cho PET/CT findings were identified. Mean value of PSA at the time of [(18)F]Cho PET/CT was 2,37 ng/mL. The median time between PCa diagnosis and PET/CT was 6 years (range 0-14 years). In two cases history of a second malignancy (lung cancer and cutaneous basocellular carcinoma) was known (diagnosed 12 and 6 years after PCa, respectively). PET/CT identified 13 sites of [(18)F]Cho uptake (lung = 5, lymph node = 7, bone = 1). Final diagnosis was consistent with lung cancer in 5/7 cases (first diagnosis = 4/5, recurrence = 1/5), colorectal cancer and nodal metastases from melanoma in 1 case each. CONCLUSIONS: Although the clinical usefulness of Cho PET/CT for detecting cancer lesions other than prostate origin is known, for those patients who undergo this examination according to indication, the diagnosis of a second tumor has a significant impact on their therapeutic management.