Trabectedin in Cancers: Mechanisms and Clinical Applications.

Trabectedin, a tetrahydroisoquinoline alkaloid, is the first marine antineoplastic agent approved with special anticancer mechanisms involving DNA binding, DNA repair pathways, transcription regulation and regulation of the tumor microenvironment. It has favorable clinical applications, especially for the treatment of patients with advanced soft tissue sarcoma, who failed in anthracyclines and ifosfamide therapy or could not receive these agents. Currently, trabectedin monotherapy regimen and regimens of combined therapy with other agents are both widely used for the treatment of malignancies, including soft tissue sarcomas, ovarian cancer, breast cancer, and non-small-cell lung cancer. In this review, we have summarized the basic information and some updated knowledge on trabectedin, including its molecular structure, metabolism in various cancers, pharmaceutical mechanisms, clinical applications, drug combination, and adverse reactions, along with prospects of its possibly more optimal use in cancer treatment.

Dual source hybrid spectral micro-CT using an energy-integrating and a photon-counting detector.

Preclinical micro-CT provides a hotbed in which to develop new imaging technologies, including spectral CT using photon counting detector (PCD) technology. Spectral imaging using PCDs promises to expand x-ray CT as a functional imaging modality, capable of molecular imaging, while maintaining CT's role as a powerful anatomical imaging modality. However, the utility of PCDs suffers due to distorted spectral measurements, affecting the accuracy of material decomposition. We attempt to improve material decomposition accuracy using our novel hybrid dual-source micro-CT system which combines a PCD and an energy integrating detector. Comparisons are made between PCD-only and hybrid CT results, both reconstructed with our iterative, multi-channel algorithm based on the split Bregman method and regularized with rank-sparse kernel regression. Multi-material decomposition is performed post-reconstruction for separation of iodine (I), gold (Au), gadolinium (Gd), and calcium (Ca). System performance is evaluated first in simulations, then in micro-CT phantoms, and finally in an in vivo experiment with a genetically modified p53fl/fl mouse cancer model with Au, Gd, and I nanoparticle (NP)-based contrasts agents. Our results show that the PCD-only and hybrid CT reconstructions offered very similar spatial resolution at 10% MTF (PCD: 3.50 lp mm-1; hybrid: 3.47 lp mm-1) and noise characteristics given by the noise power spectrum. For material decomposition we note successful separation of the four basis materials. We found that hybrid reconstruction reduces RMSE by an average of 37% across all material maps when compared to PCD-only of similar dose but does not provide much difference in terms of concentration accuracy. The in vivo results show separation of targeted Au and accumulated Gd NPs in the tumor from intravascular iodine NPs and bone. Hybrid spectral micro-CT can benefit nanotechnology and cancer research by providing quantitative imaging to test and optimize various NPs for diagnostic and therapeutic applications.

Plasma levels of polychlorinated biphenyls (PCB) and the risk of soft tissue sarcoma.

BACKGROUND: Soft tissue sarcoma (STS) is a heterogeneous group of rare neoplasms whose aetiology is largely unknown. Dioxin and dioxin-like compounds, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) and polychlorinated biphenyls (PCBs), are potential risk factors for STS. OBJECTIVES: To investigate the relation of 17 PCBs congeners, assessed in human plasma, with STS risk. METHODS: We conducted a case-control study in Italy, including 52 STS cases and 99 hospital-based controls. Selected PCB were extracted by high-performance liquid chromatography (HPLC) and measured with gas chromatography-mass spectrometry (GC-MS). Odds ratios (OR), and the corresponding 95% confidence intervals (CI), were estimated through multivariate logistic regression models. RESULTS: The most frequently detected PCB congeners were 138, 170, 180 and 149 (detected in 40-77% of controls). The OR for the sum of all 17 PCB congeners was 1.20 (95% CI 0.50-2.92). In categorical analysis no consistent association was found for individual congeners and for groups based on Wolff's classification or the degree of chlorination. For continuous estimates, borderline positive associations emerged for Wolff's groups 2A (OR 1.23, 95% CI 0.97-1.55), 2B (OR 1.34, 95% CI 1.00-1.77, and 3 (OR 1.19, 95% CI 0.96-1.49), for moderately (OR 1.20, 95% CI 0.96-1.51) and highly (OR 1.18, 95% CI 0.99-1.41) chlorinated PCBs, and for congeners 170 (OR 1.26, 95% CI 0.98-1.63), 180 (OR 1.26, 95% CI 0.97-1.64) and 138 (OR 1.45, 95% CI 1.02-2.04). DISCUSSION: Most associations between PCBs and STS risk were not significant, but, given the limited sample size, we cannot exclude moderate associations.

Neutrophils Driving Unconventional T Cells Mediate Resistance against Murine Sarcomas and Selected Human Tumors.

Neutrophils are a component of the tumor microenvironment and have been predominantly associated with cancer progression. Using a genetic approach complemented by adoptive transfer, we found that neutrophils are essential for resistance against primary 3-methylcholantrene-induced carcinogenesis. Neutrophils were essential for the activation of an interferon-γ-dependent pathway of immune resistance, associated with polarization of a subset of CD4- CD8- unconventional αß T cells (UTCαß). Bulk and single-cell RNA sequencing (scRNA-seq) analyses unveiled the innate-like features and diversity of UTCαß associated with neutrophil-dependent anti-sarcoma immunity. In selected human tumors, including undifferentiated pleomorphic sarcoma, CSF3R expression, a neutrophil signature and neutrophil infiltration were associated with a type 1 immune response and better clinical outcome. Thus, neutrophils driving UTCαß polarization and type 1 immunity are essential for resistance against murine sarcomas and selected human tumors.

Mutational landscape in genetically engineered, carcinogen-induced, and radiation-induced mouse sarcoma.

Cancer development is influenced by hereditary mutations, somatic mutations due to random errors in DNA replication, or external factors. It remains unclear how distinct cell-intrinsic and -extrinsic factors impact oncogenesis within the same tissue type. We investigated murine soft tissue sarcomas generated by oncogenic alterations (KrasG12D activation and p53 deletion), carcinogens (3-methylcholanthrene [MCA] or ionizing radiation), and in a novel model combining both factors (MCA plus p53 deletion). Whole-exome sequencing demonstrated distinct mutational signatures in individual sarcoma cohorts. MCA-induced sarcomas exhibited high mutational burden and predominantly G-to-T transversions, while radiation-induced sarcomas exhibited low mutational burden and a distinct genetic signature characterized by C-to-T transitions. The indel to substitution ratio and amount of gene copy number variations were high for radiation-induced sarcomas. MCA-induced tumors generated on a p53-deficient background showed the highest genomic instability. MCA-induced sarcomas harbored mutations in putative cancer-driver genes that regulate MAPK signaling (Kras and Nf1) and the Hippo pathway (Fat1 and Fat4). In contrast, radiation-induced sarcomas and KrasG12Dp53-/- sarcomas did not harbor recurrent oncogenic mutations, rather they exhibited amplifications of specific oncogenes: Kras and Myc in KrasG12Dp53-/- sarcomas, and Met and Yap1 for radiation-induced sarcomas. These results reveal that different initiating events drive oncogenesis through distinct mechanisms.

Preventative effect of celecoxib in dimethylbenz[a]anthracene-induced ovarian cancer in rats.

PURPOSE: The present study investigated the preventive effect of the cyclooxygenase (COX)-2 inhibitor, celecoxib, in 7,12-dimethylbenz[a]anthracene (DMBA)-induced ovarian cancer in a rat model. METHODS: A diet containing celecoxib (1500 ppm) was started 2 weeks before the introduction of DMBA. DMBA-soaked cotton threads were surgically applied to induce ovarian cancer in female Wistar rats. Tumor growth and survival were observed for 24 weeks. RESULTS: During the study period, an overall tumor incidence of 97.5% was observed and 65% of tumors were ovarian adenocarcinoma. The celecoxib diet significantly reduced the incidence and size of DMBA-induced ovarian cancers and significantly improved survival of tumor-bearing rats. The preventive effect of celecoxib was associated with increased apoptosis. CONCLUSION: DMBA-induced ovarian cancer in rats recapitulates many pathophysiological features of the human counterpart. Our results provide supportive evidence that celecoxib has a preventive effect on development of ovarian cancer in a rat model.

First case of sternum replacement with a bioceramic prosthesis after radio-induced sarcoma.

Objectives: To date, no "gold standard" technique has been developed for sternum replacement in cases of radioinduced sarcoma, which is a rare and aggressive disease. Current techniques rely on metallic prostheses, meshes, or bone grafts-procedures that that are associated with several complications. We therefore tried a new solution that might simplify and optimize this surgery. Methods: We used a porous alumina ceramic prosthesis (Ceramil: i.ceram, Limoges, France) that has several interesting characteristics, such as osseointegration, biocompatibility, radiolucency, and high mechanical strength. Results: We report the first case of sternal replacement surgery involving the implantation of a ceramic prosthesis after radio-induced sternal sarcoma. In 2005, a 54-year-old woman was diagnosed with local breast cancer for which she underwent all appropriate treatment. Ten years later, she developed radio-induced sarcoma of the sternum. A complete sternal replacement was performed on 24 April 2015, with no postoperative complications. Imaging by 18F-flurodeoxyglucose positron-emission tomography-computed tomography performed 26 months after the surgery showed no local recurrence. The patient seems to have fully recovered and has resumed normal activity. Conclusions: This new technique is promising. For the first time, we highlight the feasibility, safety, and efficacy of sternal replacement using a porous alumina ceramic prosthesis.

Prevention of Feline Injection-Site Sarcomas: Is There a Scientific Foundation for Vaccine Recommendations at This Time?

Recently published guidelines have made specific vaccine recommendations purported to potentially reduce the incidence of feline injection-site sarcomas (FISS). These recommendations have largely been based on experimental models of inflammation under different vaccine formulations. In none of these studies did sarcomas occur. It is scientifically untenable to address FISS risk based on propensity of vaccines to elicit differential inflammatory responses if none of those responses led to sarcoma development. Although the recommendations may ultimately be found to be prescient and valid, it will take considerable additional research before this can happen. Until then, such guidelines must be regarded with skepticism.

Feline vaccine-associated sarcomagenesis: Is there an inflammation-independent role for aluminium?

Aluminium has been found in feline vaccine-associated sarcomas. In this study, we investigated the potential for aluminium to contribute directly to tumourigenesis. Our results indicated that an aluminium hydroxide adjuvant preparation was cytotoxic and mutagenic in human-Chinese hamster ovary (CHO) hybrid cells in vitro. Moreover, CHO cells deficient in DNA double strand break (DSB), but not single-strand break (SSB), repair, were particularly sensitive to aluminium exposure compared with repair proficient cells, suggesting that aluminium is associated with DSBs. In contrast to CHO cells, primary feline skin fibroblasts were resistant to the cytotoxic effects of aluminium compounds and exposure to an aluminium chloride salt promoted cell growth and cell cycle progression at concentrations much less than those measured in particular feline rabies vaccines. These findings suggest that aluminium exposure may contribute, theoretically, to both initiation and promotion of tumours in the absence of an inflammatory response.

Comparison of questionnaire data and analyzed dioxin concentrations as a measure of exposure in soft-tissue sarcoma studies.

Soft-tissue sarcoma is one of the few specific tumors thought to be caused by polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and specifically TCDD. Evidence is, however, based on questionnaire-based case-control studies, and on very few cancer cases in cohort studies at high occupational exposures to chlorophenols or chlorophenoxy acid herbicides with dioxin impurities. Recall bias has been suspected to influence the reporting of exposure, but this possibility has never been adequately put to test. In the present study 87 cancer patients and 308 controls answered a questionnaire asking their exposure to wood preservatives, fungicides and herbicides, and insecticides, and their PCDD/F concentrations were also measured. After matching for age and area 67-69 sarcoma patients and 153-156 controls were available for the study depending on the chemical group, 1-3 controls for each sarcoma patient. Sarcoma patients reported exposure to these chemicals significantly more often than controls did, odds ratios were 6.7 for wood preservatives (p=0.02), 16 for fungicides and herbicides (p=0.01), and 4.9 for insecticides (p=0.06). There was no association, when the analysis was based on measured PCDD/F concentrations (odds ratios close to 1). Although it is not possible to exclude the role of the main chemical as the cause with certainty, the results indicate that recall bias is very likely in previous studies. Thus the causality between contaminant PCDD/Fs and soft tissue sarcoma cannot be considered proven.

Wartime toxin exposure: recognising the silent killer.

Wartime toxin exposures have been implicated in the genesis of malignancy in war veterans. Agent Orange, one toxin among many, has been linked to malignancy and the subcomponent phenoxyacetic acid has been associated with soft tissue sarcomas (STSs). This case demonstrates the association between a wartime toxin exposure (Agent Orange) and subsequent cancer development. Ultimately, we aim to highlight the importance of simple, specific questions in the patient history to account for previous wartime toxin exposures.

Nrf2 Induces IL-17D to Mediate Tumor and Virus Surveillance.

Cells undergoing xenobiotic or oxidative stress activate the transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2), which initiates an intrinsic "stress surveillance" pathway. We recently found that the cytokine IL-17D effects a form of extrinsic stress surveillance by inducing antitumor immunity, but how IL-17D is regulated remains unknown. Here, we show that Nrf2 induced IL-17D in cancer cell lines. Moreover, both Nrf2 and IL-17D were induced in primary tumors as well as during viral infection in vivo. Expression of IL-17D in tumors and virally infected cells is essential for optimal protection of the host as il17d(-/-) mice experienced a higher incidence of tumors and exacerbated viral infections compared to wild-type (WT) animals. Moreover, activating Nrf2 to induce IL-17D in established tumors led to natural killer cell-dependent tumor regression. These data demonstrate that Nrf2 can initiate both intrinsic and extrinsic stress surveillance pathways and highlight the use of Nrf2 agonists as immune therapies for cancer and infection.

Aortic Endograft and Epithelioid Sarcoma: A Random Association or Causality?

BACKGROUND: Angiosarcoma is an uncommon, malignant neoplasm often found in skin and soft tissue. Epithelioid angiosarcoma (EA) is a rarer, more aggressive form of angiosarcoma most common in men in their seventh decade. Dacron®, a polymer comprised of polyethylene terephthalate used in endografts for abdominal aortic aneurysm repairs, has been a suspected carcinogen associated with EA. Currently, three case reports exist in the literature purporting Dacron®-associated epithelioid angiosarcoma. Herein we report a case of Dacron®-associated EA.
CASE: A 64-year-old male with a recent history of a repaired type 2 endoleak and Dacron® endograft for his AAA presented with a painful skin eruption, fever, and weight loss. On exam, erythematous and violaceous papules and nodules were present on the patient's lower back. Biopsy revealed atypical, epithelioid cells forming vascular channels in a sheet-like and infiltrative pattern. These results and subsequent immunostaining were consistent with the diagnosis of EA. A bone marrow biopsy confirmed metastatic angiosarcoma.
CONCLUSION: This case further highlights Dacron® as a rare, but, potential carcinogen associated with EA.

J Drugs Dermatol. 2016;15(7):897-899.

Phenoxy herbicides, soft-tissue sarcoma and non-Hodgkin lymphoma: a systematic review of evidence from cohort and case-control studies.

BACKGROUND: Phenoxy herbicides have been used widely in agriculture, forestry, parks and domestic gardens. Early studies linked them with soft-tissue sarcoma (STS) and non-Hodgkin lymphoma (NHL), but when last reviewed by the International Agency for Research on Cancer in 1986, the evidence for human carcinogenicity was limited. SOURCES OF DATA: We searched Medline and Embase, looking for cohort or case-control studies that provided data on risk of STS and/or NHL in relation to phenoxy herbicides, and checked the reference lists of relevant publications for papers that had been missed. AREAS OF AGREEMENT, AREAS OF CONTROVERSY: The extensive evidence is not entirely consistent, and a hazard of STS or NHL cannot firmly be ruled out. However, if there is a hazard, then absolute risks must be small. GROWING POINTS, AREAS TIMELY FOR DEVELOPING RESEARCH: Extended follow-up of previously assembled cohorts may be the most efficient way of further reducing uncertainties.

A High-grade Sarcoma Arising in a Patient With Recurrent Benign Giant Cell Tumor of the Proximal Tibia While Receiving Treatment With Denosumab.

BACKGROUND: A giant cell tumor of bone is a primary benign but locally aggressive neoplasm. Malignant transformation in a histologically typical giant cell tumor of bone, without radiotherapy exposure, is an uncommon event, occurring in less than 1% of giant cell tumors of bone. Although surgery is the standard initial treatment, denosumab, a monoclonal antibody drug that inhibits receptor activator of nuclear factor-κB ligand (RANKL), has shown considerable activity regarding disease and control of symptoms in patients with recurrence, unresectable, and metastatic giant cell tumors of bone. CASE DESCRIPTION: We report the case of a 20-year-old woman with a recurrent benign, giant cell tumor of bone, who had a bone sarcoma develop while receiving denosumab treatment. LITERATURE REVIEW: To our knowledge, there have been no reports of infection or malignancy with low-dose denosumab administration for osteoporosis. However, while there are relatively few reported side effects, the safety of denosumab and adverse events seen with higher doses, as used in treatment of giant cell tumors of bone are not well defined. CLINICAL RELEVANCE: Denosumab has become a valuable adjunct for treatment of recurrent or unresectable giant cell tumor of bone. It is not clear if our patient's malignant transformation of a giant cell tumor of bone while receiving denosumab treatment was caused by denosumab, but it is important to be aware of the possibility if more cases occur. Future studies should focus on the safety of high-dose denosumab administration in patients with a benign unresectable giant cell tumor of bone.

Soft tissue sarcoma, non-Hodgkin's lymphoma and chronic lymphocytic leukaemia in workers exposed to phenoxy herbicides: extended follow-up of a UK cohort.

OBJECTIVES: To provide further information on the possible carcinogenicity of phenoxy herbicides, and in particular their relationship to soft tissue sarcoma (STS), non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukaemia (CLL). METHODS: We extended follow-up to December 2012 for 8036 men employed at five factories in the UK which had manufactured phenoxy herbicides, or in a contract spraying business. Mortality was compared with that for England and Wales by the person-years method. Nested case-control analyses compared men with incident or fatal STS (n=15) or NHL/CLL (n=74) and matched controls (up to 10 per case). RESULTS: 4093 men had died, including 2303 since the last follow-up. Mortality from all causes and all cancers was close to expectation, but an excess of deaths from NHL was observed among men who had worked for ≥1 year in jobs with more than background exposure to phenoxy herbicides (19 deaths, SMR 1.85, 95% CI 1.12 to 2.89). Four deaths from STS occurred among men potentially exposed above background (3.3 expected). In the nested case-control analyses, there were no significantly elevated risks or consistent trends across categories of potential exposure for either STS or NHL/CLL. Among men who had worked for ≥1 year in potentially exposed jobs, the highest OR (for STS) was only 1.30 (95% CI 0.30 to 5.62). CONCLUSIONS: Our findings are consistent with the current balance of epidemiological evidence. If phenoxy herbicides pose a hazard of either STS or NHL, then any absolute increase in risk is likely to be small.

Tumor fusocelular hialinizante con rosetas gigantes: caso clínico y revisión de la literatura / Hyalinizing spindle cell tumor with giant rossetes

El tumor fusocelular hialinizante con rosetas gigantes (TFHRG) pertenece al grupo de los sarcomas fibromixoides de bajo grado (SFBG), representando un 10-25% de estos. Se trata de un tumor de tejidos blandos de estirpe fibroblástica muy poco frecuente y del que hay pocas referencias en la literatura. Es un tumor de lento crecimiento y que raramente produce dolor. Su aparición más frecuente es en tronco y extremidades y suelen localizarse proximales y profundos. Se presenta el caso clí- nico de una mujer de 65 años con una tumoración a nivel de raíz de miembro superior derecho, se realiza exéresis y el resultado anátomo-patológico es compatible con TFHRG. En el estudio de extensión no se evidencian lesiones a distancia. Tras 5 años de seguimiento no presenta datos de recidiva ni metástasis. Dada la rareza del TFHRG, no existen guías diagnóstico-terapéuticas para su manejo, por lo que es interesante señalar cuál es la evidencia clínica actual. El estadiaje inicial está basado en la realización de biopsia y TAC (Tomografía Axial Computarizada) o RMN (Resonancia Magnética Nuclear). El tratamiento de elección es quirúrgico mediante exéresis, tanto en las lesiones primarias como en las metastásicas. En cuanto al pronóstico, inicialmente se creía que era favorable, con bajo índice de recidivas y metástasis, pero en los últimos estudios con períodos de seguimiento a más largo plazo se ha visto que son más frecuentes de lo que se pensaba. Las metástasis son principalmente a pulmón y pleura. Esto hace que nos replanteemos si el término sarcoma fibromixoide de bajo grado es el adecuado

Hyalinizing spindle cell tumor with giant rosettes is a low-grade fibromixoid sarcoma, representing 10-25% of these. It is a fibroblastic soft tissue tumor and only a few cases have been described in literature. The tumors occur principally as a painless, slowly growing, deeply situated mass of the proximal extremities. We describe a 65 year-old man who appeared to have an axillary tumor, which we subsequently removed. The anathomopathologic results revealed hyalinizing spindle cell tumor with giant rosettes. The extension exam did not reveal any metastatic lesions. The first five years after surgery, we didn´t find recurrence or metastatic lesions. This kind of tumor therefore, is very uncommon and protocols for the diagnosis, treatment and following are thus scarce. Having access at the time to a clinical guide to help decipher the complexities surrounding the diagnosis would have been hugely beneficial. Initial treatment should be the same as all other soft-tissue tumors as this treatment is based in image studies and biopsy. Choice treatment is to surgically remove the tumor, both the primary and metastatic lesions. In terms of prognosis, it was initially believed to be consistent with a low rate of recurrence and metastasis. However, actual studies with longer follow-up periods do show recurrence and metastasis to be more common than previously thought. Metastases mainly occur in the lung and pleura. With the actual state we rethink if low-grade fibromixoid sarcoma is a correct term to wedge it

Risk of second bone sarcoma following childhood cancer: role of radiation therapy treatment.

Bone sarcoma as a second malignancy is rare but highly fatal. The present knowledge about radiation-absorbed organ dose-response is insufficient to predict the risks induced by radiation therapy techniques. The objective of the present study was to assess the treatment-induced risk for bone sarcoma following a childhood cancer and particularly the related risk of radiotherapy. Therefore, a retrospective cohort of 4,171 survivors of a solid childhood cancer treated between 1942 and 1986 in France and Britain has been followed prospectively. We collected detailed information on treatments received during childhood cancer. Additionally, an innovative methodology has been developed to evaluate the dose-response relationship between bone sarcoma and radiation dose throughout this cohort. The median follow-up was 26 years, and 39 patients had developed bone sarcoma. It was found that the overall incidence was 45-fold higher [standardized incidence ratio 44.8, 95 % confidence interval (CI) 31.0-59.8] than expected from the general population, and the absolute excess risk was 35.1 per 100,000 person-years (95 % CI 24.0-47.1). The risk of bone sarcoma increased slowly up to a cumulative radiation organ absorbed dose of 15 Gy [hazard ratio (HR) = 8.2, 95 % CI 1.6-42.9] and then strongly increased for higher radiation doses (HR for 30 Gy or more 117.9, 95 % CI 36.5-380.6), compared with patients not treated with radiotherapy. A linear model with an excess relative risk per Gy of 1.77 (95 % CI 0.6213-5.935) provided a close fit to the data. These findings have important therapeutic implications: Lowering the radiation dose to the bones should reduce the incidence of secondary bone sarcomas. Other therapeutic solutions should be preferred to radiotherapy in bone sarcoma-sensitive areas.