Multiple cutaneous histiocytomas treated with lomustine in a dog.

BACKGROUND: Histiocytoma is a common benign neoplasm of young dogs. Multiple histiocytomas are rare. Surgical or medical treatment of solitary tumours is not required in the majority of cases because the tumour usually undergoes spontaneous regression. Therapy is required when lesions are persistent, recurrent, ulcerated or in uncomfortable locations. HYPOTHESIS/OBJECTIVES: To describe a case of canine multiple cutaneous histiocytomas treated with lomustine. ANIMAL: A 5-year-old miniature Pinscher dog was presented with multiple, disseminated, alopecic cutaneous nodules, with no associated systemic signs on initial presentation. METHODS: Histopathological examination of skin biopsies and immunocytochemistry of biopsy imprints were performed. Inguinal lymph node, liver, spleen and bone marrow cytological examination and abdominal ultrasound examination were also performed. RESULTS: The clinical, histopathological and immunocytochemical findings supported a diagnosis of canine multiple cutaneous histiocytomas. Owing to the increasing number and size of the nodules, medical treatment was initiated. Prednisone and ciclosporin resulted in worsening of lesions. Lomustine orally once monthly led to complete resolution followed by relapse. Metabolic disorders such as increased serum alanine transaminase and alkaline phosphatase activities were recorded, and therapy was stopped. Increase in size of the tumours, severe dullness and anorexia led the owner to elect euthanasia. CONCLUSIONS AND CLINICAL IMPORTANCE: To the best of the authors' knowledge, this is the first case report of canine multiple cutaneous histiocytomas treated with lomustine. Lomustine is effective in histiocytic diseases, but adverse effects must be considered because they can be severe and life threatening.

Scopolamine for cancer-related nausea and vomiting.

Nausea and vomiting is a common and troublesome symptom in advanced cancer. There have been different approaches described for the management of nausea and vomiting, specifically empirical and etiological. Scopolamine is listed in textbooks as a useful medication in management of nausea and vomiting in this setting, although there is no published data to support this recommendation. We present three cases that support the use of scopolamine in an etiologically based approach for management of nausea in advanced cancer.

[Identification of low-molecular inhibitors of proteinase ASK1].

Protein kinase ASK1 (Apoptosis signal-regulating kinase 1) plays a key role in cell differentiation, aging and apoptosis. High activity of the kinase is associated with several pathologies. The ASK1 inhibitors might be therapeutic for patients with neurodegenerative, cardiovascular diseases and fibrous histiocytoma. In this work the identification of ASK1 inhibitors was performed by the methods of computer modeling and biochemical testing in vitro. The virtual screening experiments were carried out targeting the ATP binding site of ASK1 by browsing the database which contained 164 840 compounds of diverse chemical classes. The best-scored 300 ligands have been taken for the kinase assay analysis. In vitro tests revealed that derivatives of 2-thioxo-thiazolidin-4-one exhibited inhibitory activity against ASK1. The most active compound was 5-bromo-3-(4-oxo-2-thioxo-thiazolidin-5-ylidene)-1,3-dihydro-indol-2-one (IC50 = 2 microM). Binding mode for inhibitors of this class with ASK1 ATP-binding site was proposed. Our results can be used for further optimization and developing more potent and selective inhibitors of ASK1.

Generalized eruptive histiocytoma treated with isotretinoin.

BACKGROUND: Generalized eruptive histiocytoma (GEH) is a rare, benign non-Langerhans cell histiocytosis characterized by widespread and symmetric skin-colored to blue-red papules on the trunk and proximal extremities affecting mainly adults. GEH is associated with a self-limiting course lasting from 1 month to over 12 years, and the lesions typically resolve spontaneously; therefore, reports of potential therapies for GEH are lacking. OBJECTIVE: We report for the first time the use of isotretinoin in the treatment of GEH. An otherwise healthy 53-year-old female with a 3-month history of GEH had resolution of lesions without further development of new lesions over 8 months of treatment with isotretinoin, although, eventually, lesions began to recur. CONCLUSION: Although there has been success with isotretinoin in the management of Rosai-Dorfman disease and Langerhans cell histiocytosis, further investigation is needed to delineate the exact mechanism of action and future role of isotretinoin in the management of GEH.

Successful treatment of generalized eruptive histiocytoma with PUVA.

Generalized eruptive histiocytoma (GEH) is a rare benign skin disease mainly affecting adults which belongs to the family of non-Langerhans-cell histiocytoses. A 32-year-old Caucasian woman developed disseminated, monomorphic papules of the trunk after a common cold with sinusitis. Mucous membranes, palms and soles were spared. She also suffered from arthralgia without fever or night sweats. After one month, the patient noticed progression of the reddish papules involving the trunk, extremities and face. Clinical as well as histological examination and immunohistochemistry led to the diagnosis of GEH. The clinical examination and laboratory testing were normal, except for eosinophilia in the peripheral blood and bone marrow. No neoplastic diseases were found during thorough examinations. Systemic PUVA therapy produced rapid regression of the skin lesions. After 10 treatments the lesions began to regress leaving slight papules and multiple brown hyperpigmentations. The lesions resolved completely after 20 PUVA treatments. No relapses occurred. Systemic PUVA therapy represents a promising option for the treatment of GEH.

Retroperitoneal and truncal sarcomas: prognosis depends upon type not location.

BACKGROUND: Prognostication of truncal and retroperitoneal soft tissue sarcomas has traditionally been predicated on tumor location and grade. OBJECTIVE: To compare outcomes for patients with retroperitoneal or truncal sarcomas. METHODS: Retrospective analysis of a prospective cancer data registry from 1977 to 2004 was performed and outcomes were determined. RESULTS: The study group numbered 312 patients (median age 58 years, 54% male, 56% Caucasian, 14% black, 29% Hispanic). The most common tumor types were liposarcoma (35.9%), leiomyosarcoma (30.1%), and malignant fibrous histiocytoma (MFH) (19.5%). Tumor distributions were retroperitoneal (38.9%), pelvic (24.7%), abdominal (18.6%) and thoracic (17.9%). Median overall survival was 74 months. Operative resection was undertaken in 89.4% of cases and multiple surgeries (range 2-5) in 42.2%. Negative resection margins were obtained in 72.7% of patients. Univariate analysis comparing retroperitoneal versus truncal location demonstrated no significant differences in survival. Survival was improved in lower grade tumors (P < 0.02). Liposarcoma and fibrosarcoma were associated with improved survival (P < 0.0001). Multivariate analysis of pre-treatment variables showed increasing age, grade, histopathology (leiomyosarcoma and MFH) and metastasis to be associated with worse outcomes. Multivariate analysis of the treatment variables showed that surgery and negative resection margins were associated with improved survival (P < 0.001). No advantage for chemoradiotherapy could be demonstrated. CONCLUSIONS: Successful operative resection can confer prolonged disease-free survival and cure for truncal and retroperitoneal sarcomas. Histological subtype, not location, is predictive of long-term survival. Future studies should focus on histological subtype rather than tumor location for truncal and retroperitoneal sarcomas.

Complications of mitomycin C therapy in 100 eyes with ocular surface neoplasia.

AIM: To determine the complications associated with mitomycin C (MMC) in the treatment of ocular surface neoplasia. METHODS: A retrospective and consecutive study of 100 eyes in 91 patients with ocular surface neoplasia treated with MMC in a single centre between November 1998 and January 2005. Outcome measures included complications of MMC and the treatment required for these complications. RESULTS: One to three 7 day cycles of topical MMC 0.04% four times a day were given to 59 eyes with localised corneal-conjunctival intraepithelial neoplasia (CIN), 19 eyes with diffuse CIN, six eyes with recurrent CIN, one eye with ocular surface squamous cell carcinoma, three eyes with primary acquired melanosis (PAM) with atypia, nine eyes with conjunctival malignant melanoma (MM), two eyes with sebaceous carcinoma with pagetoid spread, and one eye with recurrent atypical fibroxanthoma. Nine patients had bilateral CIN. 31 (34%) cases developed an allergic reaction to MMC and 14 (14%) eyes had epiphora secondary to punctal stenosis at a mean follow up period of 26.5 months. CONCLUSION: In the largest study looking at complications of topical MMC in the treatment of ocular surface neoplasia, allergic reaction and punctal stenosis are relatively common. Serious complications were not observed suggesting the safe use of MMC in mid-term follow up.

Enhanced photodynamic destruction of a transplantable fibrosarcoma using photochemical internalisation of gelonin.

Photochemical internalisation (PCI) is a technique for releasing biologically active macromolecules from endocytic vesicles by light activation of a photosensitiser localised in the same vesicles of targeted cells. This study investigated the PCI of the toxin gelonin as a way of enhancing the effect of photodynamic therapy (PDT) on a human malignant fibrous histiocytoma transplanted into nude mice using the photosensitiser disulphonated aluminium phthalocyanine (AlPcS(2a)). Pharmacokinetic studies after intraperitoneal administration showed that the serum level of AlPcS(2a) fitted a biexponential model (half-lives of 1.8 and 26.7 h). The tumour concentration was roughly constant up to 48 h, although fluorescence microscopy showed that the drug location was initially mainly vascular, but became intracellular by 48 h. To compare PDT with PCI, 48 h after intraperitoneal injection of 10 mg kg(-1) AlPcS(2a), and 6 h after direct intratumour injection of 50 microg gelonin (PCI) or a similar volume of phosphate-buffered saline (PDT controls), tumour-bearing animals were exposed to red light (150 J cm(-2)). Complete response was observed for more than 100 days in 50% of the PCI tumours but only 10% of the PDT tumours (P<0.01). In tumours examined histologically 4 days after light delivery, the depth of necrosis was 3-4 mm after PDT, but 7 mm after PCI. The deeper effect after PCI demonstrates that the light fluence needed to kill tumour is less than with PDT. We conclude that PCI with gelonin can markedly enhance the effect of PDT on this type of tumour and may have a role clinically as an adjunct to surgery to control localised disease.

Inhibitory effect of STI571 on cell proliferation of human malignant fibrous histiocytoma cell lines.

BACKGROUND: Malignant fibrous histiocytoma (MFH) is one of the most common high-grade sarcomas in bone and soft tissue and, due to its chemo-resistance, the prognosis of the disease is poor. ST1571 is a tyrosine kinase inhibitor that was initially developed as a BCR/ABL inhibitor for chronic myeloid leukemia patients. STI571 also selectively inhibits platelet-derived growth factor receptors (PDGFRs) and c-kit. We examined the expression of PDGFRs and c-kit in human MFH cell lines, and the effect of STI571 on cell proliferation. MATERIALS AND METHODS: Four human MFH cell lines (TNMY1, GBS-1, Nara-F and Nara-H) were used. mRNA expression of the receptor tyrosine kinases (PDGFRs and c-kit) was analyzed using reverse transcription-polymerase chain reaction, and the inhibitory effect of STI571 on cell proliferation was analyzed using the MTS assay technique. RESULTS: PDGFRalpha mRNA was expressed in TNMY1 and GBS-1, and PDGFRbeta and c-kit mRNAs were expressed in TNMY1, GBS-1 and Nara-F. All three of these mRNAs were absent in Nara-H. STI571 inhibited cell proliferation of TNMY1, GBS-1 and Nara-F in a dose- and time-dependent manner, but cell proliferation of Nara-H was not inhibited by ST1571 at concentrations of 10 microM or less. CONCLUSION: STI571 significantly inhibited proliferation of the three human MFH cell lines that expressed mRNAs of target receptor tyrosine kinases. The inhibitory effect of ST1571 on cell proliferation in these three cell lines might be due to decreased tyrosine kinase activity. STI571 might be a potent chemotherapeutic agent for human MFHs.

Combination of pegylated liposomal doxorubicin (PLD) and paclitaxel in patients with advanced soft tissue sarcoma: a phase II study of the Hellenic Cooperative Oncology Group.

Patients with soft tissue sarcoma (STS), even after complete local disease control, often relapse locally or with distant metastases. This multicenter phase II study was conducted to evaluate the safety and efficacy of the combination of pegylated liposomal doxorubicin (PLD) and paclitaxel, as first-line treatment in patients with advanced STS. In all, 42 patients with locally advanced or metastatic STS, median age 54 years and median Eastern Cooperative Oncology Group performance status (PS) 1 were treated with PLD 45 mg m(-2) and paclitaxel 150 mg m(-2), every 28 days for a total of six cycles. Histological types included mainly leiomyosarcomas (43%), malignant fibrous histiocytomas (14%) and liposarcomas (12%). At study entry, 69% of patients had distant metastases. Overall response rate was 16%, including one complete (CR 2%) and six partial responses (PRs 14%), while an additional 14 patients had disease stabilization (SD 33%). At median follow-up 41.5 months, median time to progression (TTP) was 5.7 months with median overall survival (OS) 13.2 months. Grade 3-4 toxicities included neutropenia (17%), anaemia (15%), neurotoxicity (5%) and palmar-plantar erythrodysesthesia (9%). There were no treatment-related deaths. The combination of PLD and paclitaxel is a safe and well-tolerated regimen demonstrating modest efficacy as first-line treatment in patients with advanced STS.

Salvage surgical resection after high-dose ifosfamide (HDIF) based regimens in advanced soft tissue sarcoma (ASTS): a potential positive selection bias--a study of the Spanish group for research on sarcomas (GEIS).

PURPOSE: To assess the impact of different factors on response rate (RR), time to tumor progression (TTP), and overall survival time (OS) in patients with locally advanced or metastatic soft tissue sarcoma (ASTS), included in three protocols with high-dose ifosfamide (HDIF). PATIENTS AND METHODS: One hundred fifty six ASTS patients included in three consecutive phase II trials with HDIF (>10 g/m(2)), alone or in combination with doxorubicin (DX), were analyzed. Cofactors were institution, trial, gender, age, performance status, histologic type, grade of malignancy, prior radiotherapy, presence of locoregional disease, metastatic site, salvage surgery, number of organs involved, and disease-free interval. RESULTS: By multivariate analysis performance status >0 and lack of salvage surgery correlated with a poorer survival. A good-risk and a poor-risk group were identified, with median survival time (OS) of 29, 5, and 10 months, respectively (P = 0.00001). The 1-, 2-, and 3-year OS for 83 good-risk patients (either with PS = 0 or receiving salvage surgery) was 83, 44, and 29%, respectively, those figures being 37, 7, and 3% for 73 poor-risk patients. CONCLUSION: The design of randomized trials in ASTS including HDIF should consider those prognostic factors as stratification variables.

Primary sarcoma of the breast.

BACKGROUND AND OBJECTIVES: Primary sarcoma occurring in breast is rare and comprises 0.5-1% of all breast neoplasm. Majority of the series include both stromal and cystosarcoma phyllodes, only a few hundred cases of sarcomas other then cystosarcoma are reported. PATIENTS AND METHODS: We carried out a retrospective analysis of 19 patients with primary sarcoma of the breast treated between 1982 and 2002. RESULTS: Mean age of the patients was 38.6 years (12-70 years). Gradually progressive swelling was the commonest presenting feature. There were eight cases of angiosarcoma, four cases of spindle cell sarcoma, two each of pleomorphic sarcoma and stromal sarcoma, and one each of malignant fibrous histiocytoma, embryonal rhabdomyosarcoma, and sarcoma (NOS). Eight of these were high-grade (42%). Eight patients underwent either radical or modified mastectomy, three underwent wide excisions, and one underwent quadrantectomy. Ten (52.6%) patients received postoperative adjuvant radiation. Two patients received chemotherapy. After a mean follow-up time of 34.5 months (median 25 months), eight patients failed. Failure was local in five, opposite breast in one, and both local and distant in two. The disease free survival at 3-year was 39%. In univariate analysis only the margin of first surgery was found to be a significant predictor of survival (P = 0.05). CONCLUSIONS: Primary sarcomas of the breast are aggressive tumors. Surgical treatment should consist of at least simple mastectomy. All attempts should be made to achieve a negative margin as this appears to be the only factor influencing survival in these patients.

Agminated histiocytomas in a 23-year-old patient.

A 23-year-old patient presented with a group of 17 reddish-brown papules and nodules on the left shoulder lasting for 4 years. The histopathologic examination after a punch biopsy was repetitively consistent with the diagnosis of fibrous histiocytoma (FH). We use the term agminate histiocytomas for the first time to stress the presence of grouped lesions in one skin segment. Intralesional corticosteroids and cryotherapy were partially successful in this patient.

Growth inhibition and induction of apoptosis by flavopiridol in rat lung adenocarcinoma, osteosarcoma and malignant fibrous histiocytoma cell lines.

Flavopiridol is the potent inhibitor of cdks sharing its function with endogenous cdk inhibitors, and causes arrest at both the G1 and G2 phases of the cell cycle resulting in apoptosis in various tumor cell lines. Cyclin-dependent kinase inhibitor p16INK4a induces cell cycle arrest in G1 or G2 or both, and is inactivated in many malignant tumors. In this study, we focused on the effects of flavopiridol on chemically-induced rat lung adenocarcinoma, osteosarcoma and malignant fibrous histiocytoma (MFH) cell lines showing different pattern of p16INK4a status. The data demonstrated that flavopiridol inhibited cellular growth in a dose- and time-dependent manner, inducing apoptosis within 24 h in all cell lines at a concentration of 300 nM. The growth inhibition rate was the greatest for lung adenocarcinoma cells, lacking p16INK4a expression associated with methylation-mediated gene silencing; 83% at a concentration of 300 nM for 72-h treatment; while the growth of osteosarcoma and MFH cells, both expressing p16INK4a, were inhibited at similar levels; 54-61% for osteosarcoma and 61-64% for MFH cell lines. Then, we further investigated the influence of p16INK4a induction upon the effect of flavopiridol in p16INK4a-deficient lung adenocarcinoma cells. 5-aza 2'-deoxycytidine (5-Aza-CdR) induced p16INK4a expression and inhibited cellular growth in lung adenocarcinoma at a similar level to that with flavopiridol treatment. After the induction of p16INK4a expression by 5-Aza-CdR, the growth inhibition rates of flavopiridol in the p16INK4a-induced lung adenocarcinoma cells could not achieve comparable inhibition to that in the p16INK4a-deficient cells; the efficacy was reduced compared to original p16INK4a-deficient cells at each concentration of 50, 100 and 500 nM for 72-h treatment. These data indicate that flavopiridol shows cell type specific inhibition and possibly acts in a more compensatory manner for endogenous p16INK4a function in tumor cells having the aberrations of p16INK4a gene.

ASK1 (MAP3K5) as a potential therapeutic target in malignant fibrous histiocytomas with 12q14-q15 and 6q23 amplifications.

Malignant fibrous histiocytomas (MFHs) are aggressive tumors without any definable line of differentiation. We recently demonstrated that about 20% of them are characterized by high-level amplifications of the 12q14-q15 chromosome region, associated with either 1p32 or 6q23 band amplification. This genetic finding, very similar to that in well-differentiated liposarcomas, strongly suggests that these tumors actually correspond to undifferentiated liposarcomas. It also suggests that the lack of differentiation could be the consequence of amplification of target genes localized in the 1p32 or 6q23 bands. We report here the characterization by array CGH of the 6q23 minimal region of amplification. Our findings demonstrate that amplification and overexpression of ASK1 (MAP3K5), a gene localized in the 6q23 band and encoding a mitogen-activated protein kinase kinase kinase of the JNK-MAPK signaling pathway, could inhibit the adipocytic differentiation process of the tumor cells. Treatment of a cell line with specific inhibitors of ASK1 protein resulted in the bypass of the differentiation block and induction of a strong adipocytic differentiation. These observations indicate that ASK1 is a target for new therapeutic management of these aggressive tumors.

Chemotherapeutic potential of plant alkaloids and multidrug resistance mechanisms in malignant fibrous histiocytoma of the heart.

Primary malignant fibrous histiocytoma (MFH) of the heart is a rare and highly malignant soft tissue tumor, which is largely resistant to conventional chemotherapy and radiotherapy. Therefore, we analyzed growth inhibitory effects of different chemotherapeutic agents and mechanisms of drug resistance in the recently established cell line MFH-H derived from a human primary cardiac MFH. The growth inhibitory effects of etoposide, vincristine, and paclitaxel were tested using the MTT assay. The expression and function of multidrug resistance-related proteins, i.e. the P-glycoprotein, the multidrug resistance-associated protein (MRP) and the lung resistance-related protein (LRP) were determined by FACScan and functional assays of cellular drug efflux. The concentration required for a 50% inhibition of growth (IC50) was 0.001 microM for etoposide and 0.035 microM for vincristine. Paclitaxel dissolved in Cremophor EL/ethanol inhibited the cell growth of MFH-H cells more intensively (IC50: 0.27 microM) than paclitaxel dissolved in DMSO (IC50: 11.09 microM) suggesting that Cremophor EL is contributing to the inhibitory effects of paclitaxel. The response of MFH-H to etoposide, vincristine and paclitaxel/Taxol could not be predicted by the expression and function of P-glycoprotein, MRP and LRP. This study demonstrates that etoposide and to a lesser extent vincristine can effectively inhibit the growth of MFH-H cells, irrespective of the multidrug resistance phenotype. MFH-H cells are relatively insensitive to paclitaxel dissolved in DMSO, in contrast to paclitaxel dissolved in Cremophor EL/ethanol indicating that the diluent Cremophor contributes to the antiproliferative effects of the taxane paclitaxel.

Outcome of flat bone sarcomas (other than Ewing's) in children and adolescents: a study of 25 cases.

We analysed the clinical features and outcome of young patients with non-Ewing's flat bone sarcoma treated during the era of contemporary chemotherapy. The characteristics and outcome of 25 patients (15 males and 10 females) with primary or radiation-related flat bone sarcoma treated in the Pediatrics Department at the Institut Gustave Roussy from 1981 to 1999 were reviewed. In all, 20 patients had osteosarcoma, four chondrosarcoma and one malignant fibrous histiocytoma. The age at diagnosis ranged from 2 to 23 years (median, 15 years). Nine tumours were located in the craniofacial bones, 11 in the pelvis and five in flat bones at other sites. Four patients had metastatic disease at diagnosis. Radiation-associated flat bone osteosarcoma was diagnosed in 10 out of 25 cases. The projected overall survival and event-free survival (EFS) rates at 5 years were 45.1 and 34.3% for all the 25 patients. The EFS rate of patients with second bone sarcoma was similar to that of patients with de novo flat bone sarcoma (P=0.1). The aim of treatment was curative for 24 patients, 23 of whom were treated with intensive chemotherapy regimens and 19 with surgery. Significant adverse prognostic factors on survival included incomplete surgical resection (P=0.001) and use of regimens without pre- and postoperative chemotherapy (P=0.007). Nine of the 25 patients were treated with pre- and postoperative chemotherapy and complete surgical resection. Among them, eight are alive with no disease. Radical surgical resection is the overriding prognostic factor for flat bone sarcomas in young patients. Nevertheless, our results suggest a more favourable outcome since the advent of intensive chemotherapy.