Evaluation of the Immunological Response of Childhood Cancer Patients Treated with a Personalized Peptide Vaccine for Refractory Soft Tissue Tumor: A Four-Case Series.

This case series aimed to evaluate the peptide-specific immunoglobulin G (IgG) response, clinical effectiveness, and the safety of a personalized peptide vaccine (PPV) in four children with refractory solid cancer. Although the pre-vaccination IgG responses were suppressed, IgG levels against the vaccinated peptides after 12 vaccinations were increased in all three cases who received at least 12 vaccinations. Vaccination-related adverse effects were grade 1 injection-site local skin lesions. One patient, whose diagnosis was relapsed rhabdomyosarcoma, remains in sustained remission after 37 months. Although the pre-vaccination immune response in this patient was low, IgG levels against 2 of the 4 peptide vaccines were increased after the sixth vaccination, followed by a strong increase at the eighteenth vaccination against all 4 peptides, with a >100-fold increase vs. 2 peptides. The remaining three patients exhibited progressive disease and eventually died of their original cancer. The results of the current case series suggest that in cases of childhood solid tumors, when the tumor is controlled at the time of entry PPV may have some consolidation effect. Therefore, PPV could be a new immunotherapy modality for refractory childhood solid tumors.

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.

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.

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.

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.

Congenital fibrosarcoma and history of prenatal exposure to petroleum derivatives.

Congenital fibrosarcoma (CFS) is a rare fibrous tissue malignancy that usually presents in the first few years of life. It is unique among human sarcomas in that it has an excellent prognosis. We describe a temporal clustering of a number of cases of CFS and investigate the possible associated prenatal risk factors. The Pediatric Environmental History, a questionnaire developed in our clinic that is instrumental in determining environmental risk factors for tumor-related disease, was essential in documenting the presence or absence of risk factors considered as human carcinogens. We found a history of exposure to petroleum products in four cases of CFS that occurred at a greater than expected rate in a short time frame-an apparent cancer cluster. We call attention to the possibility that exposure to petroleum products raises the risk of developing CFS. While future studies should focus on systematic investigation of CFS and its underlying mechanisms, this report suggests the need for proactive measures to avoid exposure to solvents and petroleum products during pregnancy.

Granular cell tumour in a patient with Crohn's disease treated with infliximab: coincidence or causal relationship?

Granular cell tumour (or Abrikossoff's tumour) was first described by Abrikossoff in 1926. This is a rare benign neoplasm of unclear histogenesis that is generally believed to be of nerve sheath origin. Usually, it presents as a solitary lesion, located mainly in the subcutaneous tissue of the head, or the neck, or in the oral cavity, such as a tongue lesion, although it may develop anywhere in the body. Approximately 1-2% of granular cell tumours are malignant. Granular cell tumours are extremely rare in patients with inflammatory bowel disease. To the best of our knowledge, granular cell tumours have never been reported in association either with Crohn's disease or scheduled infliximab treatment. Herein, we report a case of a granular cell tumour that presented as a subcutaneous skin nodule of the right lumbar area without any associated local or systemic symptoms in a 41-year-old woman with Crohn's disease who was receiving scheduled treatment with infliximab (5 mg/kg every 8 weeks) for 7 years.

Therapy-related acute leukemia with mixed phenotype and t(9;22)(q32;q11.2): a case report and review of the literature.

Therapy-related acute leukemia showing mixed phenotype is extremely rare. We report a 49-year-old woman who presented with palpable masses in her neck and back. She had received systemic chemotherapy (adriamycin and cisplatin) and radiotherapy for endometrial adenocarcinoma 7 years before. Her peripheral blood and bone marrow showed increased blasts, which coexpressed myeloid (CD13, CD33, and myeloperoxidase) and B-lymphoid antigens (CD19 and CD79a). Cytogenetic analysis showed a karyotype of 46,XX,dup(1)(q21q32),add(5)(q33),t(9;22)(q34;q11.2)[12]/47,idem,+der(22)t(9;22)[8], and BCR/ABL1 rearrangement was detected. Leukemic infiltration was also confirmed in her back mass. After induction chemotherapy with idarubicin, cytarabine, and imatinib, she achieved complete remission. Only 2 cases of therapy-related acute leukemia with mixed phenotype have been reported so far: one with hyperploidy and the other with t(1;21)(p36;q22). To the best of our knowledge, this is the first case of therapy-related acute leukemia with mixed phenotype and t(9;22) as well as extramedullary leukemic infiltrations.

Myofibroblastic fibrosarcoma with multifocal osseous metaplasia at the site of equine influenza vaccination.

We describe a fibrosarcoma in a 12-year-old Quarterhorse x Arabian gelding as a sequela to equine influenza vaccination. Shortly after the second vaccination, swelling at the site was noticed by the owner and it continued to increase in size over the following 6 months. Biopsy of the mass indicated a fibrosarcoma had developed at the vaccination site. It was approximately 20 cm in diameter and elevated well above the level of the skin. There was no clinical evidence of metastases to the lungs or local lymph nodes. Surgical resection of the mass was performed and the wound healed by first and second intention. Histopathological examination and immunohistochemical staining confirmed a myofibroblastic fibrosarcoma with multifocal osseous metaplasia. To the authors' knowledge, this is the first equine case of a vaccine-associated fibrosarcoma.

Factitial soft tissue pseudotumor due to injection of anabolic steroids: a report of 3 cases in 2 patients.

Traumatically induced inflammation or reactive processes are a relatively well-known phenomenon in both skin and soft tissue. These include panniculitides, fat necrosis, nodular fasciitis, and nonspecific fibrosis. Occasionally, traumatic reactions can be associated with factitial injury due to self-induced blunt trauma or injection of chemical agents. Factitial pseudotumors of soft tissue mimicking neoplasms and occurring in deep-seated locations are rare and not well recognized. We have had the opportunity to review a handful of cases over the years of soft tissue pseudotumors caused by self injection of steroids for the purposes of bodybuilding. Three of these cases in 2 patients are presented here. One patient developed a deep lateral thigh mass that was radiologically suspicious for sarcoma but upon core biopsy was found to be a lipogranulomatous reaction. The second patient had 2 masses occurring in the upper and lower extremity with an interval of 1 year between the two. This patient had both masses resected. The first had the appearance of a giant cell tumor with no immediately discernible foreign material. The second mass was initially presumed to be a metastasis from the upper extremity tumor and showed similar areas to the first specimen; however, it also had areas of obvious reactive features with foreign material. These features were found in the first tumor as well upon retrospective review. Both patients admitted to self injection of anabolic steroids after further history was sought by the clinicians. Deep soft tissue pseudosarcomas caused by injection of steroids are not well documented, and patient's reluctance to provide this information leads to difficulty in arriving at a correct diagnosis. Recognition of this possibility is important in avoiding incorrect diagnoses and unnecessary treatments.

Bilateral subcutaneous fibrosarcomas in a cat following feline parvo-, herpes- and calicivirus vaccination.

A crossbred cat developed a subcutaneous fibrosarcoma on the left side of the thorax at the site of previous administration of a feline parvo-, herpes- and calicivirus vaccine. A few months later the cat developed a second mass on the right side of the thorax after a booster vaccine had been administered at this site. This unique case of bilateral fibrosarcomas in a cat shortly after vaccination with parvo-, herpes- and caliciviruses suggests an individual disposition for the development of vaccine-associated sarcomas and a possible triggering of this type of pathological response which could have precipitated the development of the second tumour. To the authors' knowledge, this is the first case of vaccine-induced fibrosarcomas occurring bilaterally after injection of a feline parvo-, herpes- and calicivirus containing vaccine at different sides of the thorax.

[Dioxin emissions and soft-tissue sarcoma: results of a population-based case-control study]. / Emission de dioxines et sarcomes des tissus mous: étude cas-témoins en population.

BACKGROUND: In 1998, the French Ministry of Environment revealed that of 71 French municipal solid waste incinerators processing more than 6 metric tons of material per hour, dioxin emission from 15 of them was above the 10 ng international toxic equivalency factor/m3 (including Besançon, emitting 16.3 ng international toxic equivalency factor/m3) which is substantially higher than the 0.1 international toxic equivalency factor/m3 prescribed by a European directive of 1994. In 2000, a macrospatial epidemiological study undertaken in the administrative district of Doubs, identified two significant clusters of soft-tissue sarcoma and non Hodgkin lymphoma in the vicinity of the municipal solid waste incinerator of Besançon. This microspatial study (at the Besançon city scale), was designed to test the association between the exposure to dioxins emitted by the municipal solid waste incinerator of Besançon and the risk of soft-tissue sarcoma. METHODS: Ground-level concentrations of dioxin were modeled with a dispersion model (Air Pollution Control 3 software). Four increasing zones of exposure were defined. For each case of soft tissue sarcoma, ten controls were randomly selected from the 1990 census database and matched for gender and age. A geographic information system allowed the attribution of a dioxin concentration category to cases and controls, according to their place of residence. RESULTS: Thirty-seven cases of soft tissue sarcoma were identified by the Doubs cancer registry between 1980 and 1995, corresponding to a standardized incidence (French population) of 2.44 per 100,000 inhabitants. Compared with the least exposed zone, the risk of developing a soft tissue sarcoma was not significantly increased for people living in the more exposed zones. CONCLUSION: Before definitely concluding that there is no relationship between the exposure to dioxin released by a solid waste incinerator and soft tissue sarcoma, a nationwide investigation based on other registries should be conducted.

Soft-tissue sarcoma and dioxin: A case-control study.

Soft-tissue sarcoma has been proposed to be a candidate for a dioxin-induced cancer. However, previous epidemiologic studies have suffered from poor exposure data and mixed exposures. We studied the association between sarcoma risk and individually estimated dioxin exposure in a general population exposed to relatively low levels of dioxin via food. A multicenter prospective case-control study was conducted in 4 university hospitals and 12 other hospitals in southern Finland. Participants included 110 patients with soft-tissue sarcoma (cases) and 227 area- and age-matched controls. Controls were patients operated for appendicitis. Individual dioxin concentrations were analyzed from subcutaneous fat samples by gas chromatography-mass spectrometry. The average (range) dioxin concentration was 33.4 (4.4-145.5) ng/kg (toxic equivalencies in fat according to WHO). No increased risk associated with increased dioxin concentration was observed. In contrast, the highest risk of sarcoma was found at low levels of dioxin. Odds ratios for different quintiles as compared with the lowest quintile of dioxins (median, 11.5 ng/kg) varied from 0.43 (95% CI = 0.18-1.05) to 0.65 (95% CI = 0.22-1.95). The result was little affected by studied confounders and the findings were similar for different sarcoma subtypes, age groups and study areas. The results imply that dioxin does not increase the risk of soft-tissue sarcoma at the present population levels.

[Soft tissue sarcomas in Mantua: epidemiological evidence and perspectives for environmental remediation]. / I sarcomi dei tessuti molli a Mantova: revisione delle evidenze epidemiologiche e prospettive di risanamento ambientale.

Subsequently to the report by a general practitioner of an apparent cluster of soft tissue sarcomas (STS) in thepopulation resident in the neighbourhood of Mantua chemical industries, two independent epidemiological studies (an incidence study and a case-control study) confirmed the original observation and extended the findings in a wider time-span. The two studies are reviewed in the present paper in order to analyze concordant and diverging findings. In the light of the available evidence, recommendations for further studies are presented and perspectives of environmental remediation are discussed.

Principles of treatment for vaccine-associated sarcomas.

In the last decade, there has been a great deal of information surrounding the etiology, diagnosis, and treatment of feline vaccine-associated sarcomas. The presence of a mass in areas used for subcutaneous or intramuscular injections should alert the clinician to the possibility of a vaccine-associated sarcoma. Early detection and subsequent treatment is paramount to limit local invasion and distant metastasis. The current data are suggesting that a team approach with multi-modality therapy is the appropriate way to address this disease. In the following article, we will discuss the history/incidence, pathology, diagnosis, and current treatment options, which include a combination of surgery, radiation, and chemotherapy for vaccine-associated sarcomas.

Extraosseous cement granuloma associated with total hip replacement in 6 dogs.

OBJECTIVE: To report the clinical, radiographic, and pathologic features of extraosseous cement granuloma (ECG), a low occurrence, long-term complication of total hip replacement (THR). STUDY DESIGN: Retrospective clinical study. Sample Population-Six client-owned dogs. METHODS: Medical records for 6 dogs that had a cemented modular THR and developed ECG were reviewed for the clinical, radiologic, and histopathologic findings of ECG. Morphologic and elemental analyses of retrieved particles were conducted in 2 dogs using scanning electron microscopy (SEM) and energy-dispersive x-ray spectroscopy (EDS). RESULTS: Three golden retrievers and 3 Labrador retrievers had progressive lameness in the operated limb 4 to 7 years after THR and developed ECG. Other clinical features included an acute deterioration to non-weight bearing associated with pathologic fracture of the proximal femur in 2 dogs, and obstipation in 1 dog. In 5 dogs, there was a large caseous mass surrounding the proximal femur. Obstipation in 1 dog was caused by a similar mass adjacent to bone cement used for fixation of the acetabular cup. Radiographic changes included a multilobular soft tissue mass, containing irregular mineral densities, in the gluteal mass surrounding the proximal femur, THR interface deterioration, osteolysis, new bone formation, and implant subsidence were consistent with chronic aseptic loosening. The histopathologic diagnosis was sterile granuloma associated with a massive heterogeneous particulate burden, which was assumed to have resulted from severe wear of all prosthesis components. CONCLUSIONS: ECG is a manifestation of severe aseptic loosening of cemented total hip replacement, with the generation of wear debris probably responsible for granuloma formation. CLINICAL RELEVANCE: Because revision can offer a good prognosis in early aseptic femoral loosening, yearly radiographic monitoring of the recipients is recommended.