Non-metastatic cholestatic paraneoplastic syndrome associated with soft tissue sarcoma

Paraneoplastic syndromes have been described in association with variety of malignant neoplasms. The non-metastatic cholestatic paraneoplastic syndrome first described as Stauffer's syndrome in association with renal cell carcinomas is also associated with other malignancies. We describe the autopsy findings of a patient with recurrent and metastatic leiomyosarcomas presenting with cholestatic liver dysfunction. The diagnosis requires the exclusion of all other possible causes of hepatitis and, where possible, resolution after the effective treatment of the underlying malignancy.     

A cell culture, chromosomal and quantitative DNA analysis of a metastatic epithelioid sarcoma. Deletion 1p, a possible primary chromosomal abnormality in epithelioid sarcoma

The chromosomal banding pattern and the in vitro growth characteristics of a metastatic epithelioid sarcoma are described. The cultured tumor cells retained growth characteristics as well as ultrastructural and immunohistochemical properties similar to the cells of the primary tumor. Cytogenetic analysis revealed a modal range in the diploid-hypodiploid region, a finding which was corroborated by quantitative DNA determinations of both the primary tumor and a lymph node metastasis. Fourteen different marker chromosomes were identified. The most frequent clonal rearrangement was a 1p-marker resulting from a short arm terminal deletion, i.e., del (1) (p21-22). A similar 1p- marker has previously been observed in an established epithelioid sarcoma cell line. The finding of an apparently identical 1p-marker in two of two analyzed epithelioid sarcomas suggests that this rearrangement may be a primary cytogenetic abnormality in epithelioid sarcoma. An elevated ras p21 expression was demonstrated using immunohistochemical methods. The possible involvement of the N-ras gene and/or a tumor suppressor in the 1p deletion is considered.     

Significance of local treatment in patients with metastatic soft tissue sarcoma

Metastatic soft tissue sarcomas (STS) represent enormous challenges to improve the low survival rate, which is almost the same as past 2 decades ago, although surgery, radiotherapy and radiofrequency ablation has been accepted in the treatment of metastatic STS. Moreover, STS varies between elderly and younger victims in the aspect of diagnoses, prognosis, and treatment strategies. In order to evaluate the role of local treatment in improving prognosis for patients with metastatic STS and select the proper candidates who will benefit from local therapy, a single-institution nearly 50-year experience were collected and reviewed. Finally, we found that local treatments could improve treatment response and survival, but overall survival advantage could not be seen in elderly patients. This conclusion from a single institution could serve as a basis for future prospective multi-institutional large-scale studies.     

Palmar fasciitis and arthritis Syndrome associated with metastatic ovarian cancer: A paraneoplastic syndrome

Palmar fasciitis and polyarthritis syndrome (PFPA) is an uncommon syndrome that affects predominantly elderly women and characterized by symmetrical polyarthritis followed by flexioncontracture of the hands. It is usually associated with a metastatic malignant neoplasm, and therefore implies a poor prognosis. We report a case of a 54-year old woman presented with palmar fasciitis and polyarthritis six months before the diagnosis of a metastatic adenocarcinoma of the ovary. Surgical excision of the tumor and adjuvant chemotherapy caused remission of the polyarthritis. Keywords: Palmar fasciitis and arthritis, paraneoplastic syndrome, polyarthritis ovarian cancer.     

The value of local treatment in patients with primary,disseminated, multifocal Ewing sarcoma (PDMES)

BACKGROUND:

The value of local treatment in patients with primary, disseminated, multifocal Ewing sarcoma (PDMES) was investigated.

METHODS:

We analyzed 120 patients registered into the European Ewing Tumor Working Initiative of National Groups (EURO‐E.W.I.N.G. 99) trial at the trial center of Muenster from 1998 to 2006. Median age was 16.2 years. Local treatment of the primary tumor was surgery in 26 of 120 patients, surgery and radiotherapy in 21 patients, and definitive radiotherapy in 40 patients. For treatment of metastases, 6 of 120 patients received surgery; 9 patients, surgery and radiotherapy; and 33 patients, definitive radiotherapy. Forty‐seven (39%) patients had local treatment of both the primary tumor and metastases, 41 (34%) patients of either the primary tumor or metastases, and 32 (27%) received no local therapy.

RESULTS:

Event‐free survival (EFS) at 3 years was 0.24 (95% CI, 0.16‐0.33). Univariate analyses demonstrated the impact of local therapy given to the primary tumor: 3‐year EFS was 0.25 with surgery, 0.47 with surgery and radiotherapy, 0.23 with radiotherapy, and 0.13 when no local therapy was administered (P < .001). Three‐year EFS in PDMES was also influenced by the local treatment: surgery, 0.33; surgery and radiotherapy, 0.56; radiotherapy, 0.35; no local therapy, 0.16 (P = .003). Three‐year EFS was 0.39 in patients who received local treatment of both primary tumor and PDMES, compared with 0.17 in patients with any local treatment of either primary tumor or PDMES and 0.14 in patients with no local therapy (P < .001). Multivariate analysis showed absence of local treatment to be the major risk factor (HR = 2.21; P = .027; n = 20).

CONCLUSIONS:

Local therapy of involved sites is important for patients with PDMES and should complement systemic treatment whenever possible. Cancer 2010. © 2010 American Cancer Society.     

Prognostic factors associated with local recurrence, metastases, and tumor-related death in patients with synovial sarcoma

Prognostic factors associated with local recurrence, metastases, and tumor-related death in synovial sarcoma were studied in 51 patients in the Scottish Bone Tumor Registry from 1955 to 1999. In a multivariate analysis, the presence of poorly differentiated (PD) areas was the strongest prognostic factor associated with local recurrence (Hazard ratio [HR] = 11.3, 95% CI 2.3, 122.5, p = 0.033), metastases (HR = 16.9, 95% CI 2.3,122.5, p = 0.005), and tumor-related death (HR = 6.9, 95% CI 1.1,41.8, p = 0.036). Other significant independent risk factors included bone invasion (HR = 16.6, 95% CI 1.1, 252.5, p = 0.043) and necrosis (HR = 5.1, 95% CI 1.4, 18.99, p = 0.016) for metastases and bone invasion (HR = 17.6, 95% CI 1.2, 253.2, p = 0.035) for tumor-related death. Increasing percentages of PD areas and necrosis were associated with increasing hazard ratios for metastases and death. In the univariate analysis, PD areas, tumor size, and a mitotic count over 10/10 high-power fields were significantly associated with recurrence, whereas necrosis, vascular invasion, and age more than 25 years were additional risk factors for metastases and death. Local recurrence was significantly associated with increased risks for metastases (OR = 6.8, 95% CI 1.6, 28.7, p = 0.006), and death (all cases). Histologic features such as PD areas, necrosis, vascular invasion, and bone invasion should be considered when deciding about adjuvant therapy.     

Ewing's sarcoma of the axial system in patients older than 15 years: dismal prognosis despite intensive multiagent chemotherapy and aggressive local treatment

BACKGROUND: Older age and axial location of Ewing's sarcoma have been reported as unfavorable prognostic factors. METHODS: The records of patients older than 15 years with the Ewing's family of tumors were reviewed retrospectively. After the induction chemotherapy consisting of alternating vincristine, adriablastin, cyclophosphamide (VAC) and etoposide, ifosfamide with mesna protection (IE), a local treatment modality was chosen based on tumor and patient characteristics. RESULTS: Twenty-five patients with a median age of 19 years were evaluated. Median follow-up was 26 months (range 4-58). Seventeen patients (68%) had died. In univariate analysis, factors predictive of shorter survival were the patients presenting with metastatic disease, with the primary tumor located at the pelvis, those who never achieved complete response to chemotherapy and those who had chemotherapy for <12 months. Only a negative link with pelvic location was observed in multivariate analysis [risk ratio 7.5; 95% confidence interval (CI) 1.52-37.06; P = 0.0134]. Median progression-free survival (PFS) and overall survival (OS) were 10 months (95% CI 6.2-13.8) and 14 months (95% CI 9.3-18.7), respectively. Cumulative 2-year PFS and OS were 19.0% (95% CI, SD +/-8.4) and 32.7% (95% CI, SD +/-9.8), respectively. CONCLUSIONS: The prognosis of patients with axial Ewing's sarcoma is dismal despite an intensive, multimodality approach including multiagent, alternating chemotherapy, surgery and/or radiotherapy. A more aggressive approach should be considered for this group of Ewing's sarcoma patients.     

Epithelioid sarcoma and unclassified sarcoma with epithelioid features: clinicopathological variables, molecular markers, and a new experimental model

Background.

Epithelioid sarcoma (ES) and unclassified sarcoma with epithelioid features (USEF) are clinically and therapeutically unresolved. We compared ES and USEF patients'' clinical behavior, treatment, outcome, and molecular marker expression. Furthermore, preclinical ES study models were developed to enable comprehensive benchside investigations.

Patients and Methods.

A database of ES and USEF patients (n = 116) treated since 1992 was created. A clinically annotated ES–USEF tissue microarray (TMA) was assayed for tumor-related markers. Newly established human and commercially available ES cell lines were characterized and tested in vivo.

Results.

ES and USEF patients presenting with localized disease exhibited 22% and 25% local recurrence rates, 35% and 19% nodal metastasis rates, and 41% and 53% distant metastasis rates (median follow-up, 54 months and 39 months, respectively). The 5- and 10-year disease-specific survival rates were 88% and 43% and 52% and 42% (ES and USEF, respectively). TMA immunohistochemistry identified integrase interactor (INI)-1 loss, cancer antigen 125, and p53 nuclear expression as significantly more common in ES than USEF cases. Both cell lines preserved ES morphological and biochemical characteristics in vitro and in vivo; loss of INI-1 was shown to occur in both lines.

Conclusions.

Enhanced knowledge of ES and USEF clinical behavior, marker expression, and molecular determinants, extended via experimental models, will hopefully accelerate development of urgently needed effective targeted therapies for ES and USEF.     

上皮样肉瘤的临床诊疗及预后因素分析

目的 分析上皮样肉瘤(Epithelioid sarcoma,ES)的临床特点、诊疗与预后的影响因素,为临床的诊疗提供依据。方法 对我院2010年1月—2015年12月间收治并获得随访31例上皮样肉瘤临床资料进行回顾性分析和生存分析,总结其临床特点,术前诊断及术后复发的相关数据,以性别、年龄、肿瘤类型、肿瘤大小、有无放化疗为因素,进行复发因素的相关性分析。结果 本组6例患者死亡,5年总生存率78.8%。31例均获随访,随访时间为3~56个月,中位时间为27个月。5年复发率为70.9%,在单因素分析中,影响5年复发率的因素为肿瘤的类型及肿瘤大小,其中肿瘤＞5 cm与≤5 cm相比,肿瘤近端型与远端型相比,前者的5年复发率均高于后者(P＜0.05)。全组中CD34阳性表达占90.3%,INI1表达缺失占83.9%。对于肿瘤与周围血管神经界限不清的患者,给予术前放疗后可手术治疗,避免截肢。结论 ES的复发与肿瘤大小、肿瘤分型具有相关性,CD34、INI1等免疫组化检测以帮助鉴别诊断,术前放疗在一定情况下可避免截肢,提高患者生活质量。     

Analysis of growth factor-dependent signalling in human epithelioid sarcoma cell lines. clues To the role of autocrine, juxtacrine and paracrine interactions in epithelioid sarcoma

Human epithelioid sarcoma (ES) is an extremely aggressive soft tissue tumour of unknown histogenesis. Although growth factor-dependent signalling cascades significantly affect the biological behaviour of malignant tumours, little is known so far about their role in human ES. The present investigation, therefore, analyses the coexpression and function of different growth factors and their receptors in the human ES cell line GRU-1 and its clonal subpopulations (GRU-1A, GRU-1B and GRU-1C). As shown by Northern blot, flow cytometry, immunocytochemistry and MTT assay, all ES cell lines expressed transforming growth factor (TGF)-alpha and the epidermal growth factor receptor (EGF-R). Although no response to exogenous TGF-alpha was observed, antagonistic anti-EGF-R antibodies (at 20 microg/ml) induced significant (P<0.05) growth inhibition in all cell lines. All cell lines showed coexpression of platelet-derived growth factor (PDGF)-A and the corresponding receptors. Neutralisation of ES-derived PDGF by anti-hPDGF antibodies resulted in significant (P<0.05) growth inhibition of all clonal subpopulations. Although all cell lines expressed TGF-beta(1) as well as TGF-beta type I and type II receptors (TGF-BI-R and TGF-BII-R), growth inhibition (P<0.05) by exogenous TGF-beta(1) was achieved in the clonal subpopulations only and not in the parental cell line. No ES cell line expressed acidic fibroblast growth factor (FGF) but stimulation of FGF type 3 and type 4 receptors (FGF-3R and FGF-4R) by exogenous acidic FGF (aFGF) resulted in a marked (P<0.05) acceleration of proliferation in all cell lines. In conclusion, our investigation suggests an intricate network of autocrine, juxtacrine and paracrine signalling between ES tumour cells and adjacent non-neoplastic stromal cells.     

Definitive local therapy is associated with improved overall survival in metastatic cervical cancer

Purpose

Definitive local therapy is often used in metastatic cervical cancer to reduce morbidity associated with local tumor progression. However, the potential benefit of this therapeutic approach has not been rigorously investigated. We hypothesized that definitive local therapy is associated with improved overall survival (OS) in metastatic cervical cancer.

Combined vascular endothelial growth factor receptor/epidermal growth factor receptor blockade with chemotherapy for treatment of local, uterine, and metastatic soft tissue sarcoma

PURPOSE: Soft tissue sarcoma (STS) is a rare heterogeneous malignancy. Overall survival has been stagnant for decades, primarily because systemic therapies are ineffective versus metastases, the leading cause of STS lethality. Consequently, we examined whether tyrosine kinase receptors active in STS growth signaling might be blockable and whether multireceptor blockade might synergize with low-dose STS chemotherapy by therapeutically affecting STS cells and their associated microenvironment. EXPERIMENTAL DESIGN: Vandetanib (AstraZenca), a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor, was evaluated alone and with chemotherapy in vitro and in vivo in three human STS nude mouse xenograft models of different STS locations (muscle, uterus, lung), stages (primary, metastatic), and subtypes (leiomyosarcoma, fibrosarcoma, uterine sarcoma: luciferase-expressing MES-SA human uterine sarcoma cells surgically implanted into uterine muscularis with bioluminescence tumor growth assessment; developed by us). RESULTS: In vitro, human STS cells were sensitive to vandetanib. Vandetanib alone and with chemotherapy statistically significantly inhibited leiomyosarcoma local growth and fibrosarcoma lung metastasis. Direct injection of MES-SA into nude mice uterine muscularis resulted in high tumor take (88%), whereas s.c. injection resulted in no growth, suggesting microenvironmental tumor growth modulation. Vandetanib alone and with chemotherapy statistically significantly inhibited uterine sarcoma growth. In all models, vandetanib induced increased apoptosis, decreased tumor cell proliferation, and decreased angiogenesis. CONCLUSIONS: Vandetanib has antitumor effects against human STS subtypes in vitro and in vivo, where it also affects the tumor-associated microenvironment. Given the urgent need for better systemic approaches to STS, clinical trials evaluating vandetanib, perhaps with low-dose chemotherapy, seem warranted.     

Gemcitabine and docetaxel in metastatic sarcoma: past, present, and future

Objective. In the era of oral molecular kinase inhibitors, cytotoxic chemotherapy agents are somewhat overlooked, but remain the backbone of treatment for most cancers. Patients with non-gastrointestinal stromal tumor sarcomas, such as leiomyosarcoma, liposarcoma, and undifferentiated high-grade pleomorphic sarcoma (formerly called malignant fibrous histiocytoma), have received doxorubicin and ifosfamide as the backbone of their treatment for over 15 years or more. The goal of this article is to review the data that have led to the use of gemcitabine and docetaxel as a useful combination for patients with metastatic sarcomas, and to comment on possible synergy of the combination. Methods and results. The literature regarding the use of gemcitabine, docetaxel, or both, is reviewed, with emphasis on patients with metastatic sarcoma. Results. Activity of gemcitabine and docetaxel is observed in leiomyosarcoma and undifferentiated high-grade pleomorphic sarcoma. There is apparent schedule dependence of the combination in other cancers; it is unclear if schedule matters in patients with sarcomas. The dose and schedule of gemcitabine and docetaxel examined in phase II studies are probably too high for routine practice. Conclusions. The combination of gemcitabine and docetaxel is an effective option for patients with metastatic sarcoma, increasing the armamentarium for the practicing oncologist in treating this heterogeneous group of diseases. Given the low response rate to docetaxel as a single agent, it is likely that there is true clinical synergy of the combination. Disclosure of potential conflicts of interest is found at the end of this article.     

Association between survival time with metastatic breast cancer and aggressive end-of-life care

Purpose

For women with stage IV breast cancer (BC), the association between survival time (ST) and use of aggressive end-of-life (EOL) care is unknown.

Methods

We used the SEER-Medicare database to identify women with stage IV BC diagnosed 2002–2011 who died by 12/31/2012. Aggressive EOL care was defined as receipt in the last month of life: >1 ED visit, >1 hospitalization, ICU admission, life-extending procedures, hospice admission within 3 days of death, IV chemotherapy within 14 days of death, and/or ≥10 unique physician encounters in the last 6 months of life. Receipt of aggressive EOL care and hospice in the last month of life were determined using claims, and multivariable analysis was used to identify factors associated with receipt. Costs of care were also evaluated.

Results

We identified 4521 eligible patients. Of these, 2748 (60.8%) received aggressive EOL care. Factors associated with aggressive EOL care were race (OR 1.45, 95% CI 1.19–1.81 for blacks compared to whites) and more frequent oncology office visits (OR 1.56, 95% CI 1.28–1.90). Patients who lived >12 months after diagnosis were less likely to receive aggressive EOL care (OR 0.44, 95% CI 0.38–0.52), and more likely to utilize hospice (OR 1.43, 95% CI 1.21–1.69) compared to patients who lived ≤6 months. Patients with a shorter ST had significantly higher costs of care per-month-alive compared to patients with longer ST.

Conclusion

Patients with a shorter ST were more likely to receive aggressive EOL care and had higher costs of care compared to patients who lived longer.

     

Clinical and biomarker correlates of androgen-independent, locally aggressive prostate cancer with limited metastatic potential.

PURPOSE: We have identified a subset of patients exhibiting extended survival with metastases from androgenindependent prostate cancer of which the principal site of progression was the tumor primary. The purpose of this study was to evaluate the expression of selected biomarkers to characterize this subset of prostate cancer patients. EXPERIMENTAL DESIGN: A 105 core tissue microarray was constructed from primary tumor samples from 16 patients, with matched lymph node metastases in 5 cases. Immunohistochemistry was used to evaluate selected biomarkers associated with prostate cancer progression. Standard statistical methodologies were used to compute the distribution of time to progression and overall survival associations between pairs of biomarkers. Hierarchical clustering was done between groups of biomarkers, and we devised new methods to assess homogeneity of biomarker expression. RESULTS: The median interval from diagnosis to salvage surgery was 65 months. The profile of biomarker expression was notable for virtual absence of neuroendocrine features, high CD10, low matrix metalloproteinase (MMP)-9, high E-cadherin expression, and high membranous beta-catenin. The mean proliferative index was 12.1 +/- 10.1%, and the mean apoptotic index was 3.48 +/- 2.22%, and there was a significant correlation between these indices. Expression of the epidermal growth factor receptor was associated with phospho-AKT and proliferative index but inversely associated with phospho-STAT3. CONCLUSIONS: The cohort of prostate cancer patients, characterized by locally aggressive disease rather than lethal metastatic progression, was associated with a distinctive biomarker signature. The biomarker profile was, in general, more consistent with low-grade prostate cancer exhibiting local growth rather than metastatic progression. Ongoing studies will establish whether this unique subset of patients can be identified prospectively.