Identification of novel chemotherapeutic strategies for metastatic uveal melanoma.

Melanoma of the uveal tract accounts for approximately 5% of all melanomas and represents the most common primary intraocular malignancy. Despite improvements in diagnosis and more effective local therapies for primary cancer, the rate of metastatic death has not changed in the past forty years. In the present study, we made use of bioinformatics to analyze the data obtained from three public available microarray datasets on uveal melanoma in an attempt to identify novel putative chemotherapeutic options for the liver metastatic disease. We have first carried out a meta-analysis of publicly available whole-genome datasets, that included data from 132 patients, comparing metastatic vs. non metastatic uveal melanomas, in order to identify the most relevant genes characterizing the spreading of tumor to the liver. Subsequently, the L1000CDS2 web-based utility was used to predict small molecules and drugs targeting the metastatic uveal melanoma gene signature. The most promising drugs were found to be Cinnarizine, an anti-histaminic drug used for motion sickness, Digitoxigenin, a precursor of cardiac glycosides, and Clofazimine, a fat-soluble iminophenazine used in leprosy. In vitro and in vivo validation studies will be needed to confirm the efficacy of these molecules for the prevention and treatment of metastatic uveal melanoma.

Cutaneous metastases of internal malignancies: a clinicopathologic study.

BACKGROUND: Secondary tumor deposits in the skin represent advanced malignancy and are of uncommon occurrence. The clinical presentation of these lesions is variable, and the clinical impression is rarely correct, except in cases of known primary malignancies. AIM: To summarize the clinical and histopathological findings in biopsy-proven cutaneous metastases. METHODS: The present study has analyzed 14 cases of cutaneous metastases from internal malignant neoplasms, excluding hematolymphoid neoplasms. The clinical parameters analyzed include presentation of deposits and their relation to the primary tumor. The histological features of cutaneous metastases were compared with the primary tumors and the frequency of common features in them were evaluated. RESULTS: Cutaneous metastases from internal organ malignancies showed a prevalence rate of approximately 2%. Eight cases (56%) presented as primary manifestations of the tumor; biopsy evaluation in these cases suggested the possible primary tumor site and triggered further evaluation and imaging studies. Four patients, undergoing treatment for a known malignant tumor, had recurrence of the tumor in the form of cutaneous metastatic deposits. In the remaining two patients, cutaneous metastases of the tumor appeared simultaneously with the primary neoplasm and represented a higher stage of malignancy. CONCLUSIONS: Skin biopsy findings were significant in all cases. The morphological patterns of cutaneous metastases corresponded with the primary tumors and their evaluation helped localize unknown primary malignancies. In cases with known primaries, cutaneous metastases upstaged the malignancy and affected the prognosis.

Identificaçao de metastases nos linfonodos sentinelas e nao sentinelas em câncer de mama / Metastases identification in the linfonodos sentries and no sentries in breast cancer

Realizou-se estudo prospectivo em 36 pacientes com carcinoma de mama. Em todas, fez-se exérese do tumor primلrio associado à identificaçمo do linfonodo sentinela (LS) com corante azul V® e posterior esvaziamento axilar. Buscou-se avaliar se o exame intra-operatَrio de LS, através de cortes de congelaçمo e de esfregaços ("imprint") corados por hematoxilina-eosina (H-E), é procedimento confiلvel na detecçمo de metلstase, e se o emprego de imunoistoquيmica (IQ) com anticorpos anticitoceratina aumenta a detecçمo de metلstase em relaçمo aos cortes corados por H-E. Os linfonodos sentinelas foram cortados em fatias transversais de 2-3 mm de espessura, sendo que de cada fatia obtiveram-se um esfregaço e um corte de congelaçمo. Posteriormente, todas as fatias foram fixadas em formalina 10 por cento, incluيdas em parafina e cortadas de forma seriada e completa em intervalos de 100μm, sendo que de cada nيvel foram obtidos dois cortes de 4μm de espessura, sendo um para E-H e outro para IQ. Os linfonodos nمo sentinelas foram processados de forma semelhante. Dessa forma, obtiveram-se 4.076 cortes de linfonodos sentinelas, 32.012 dos nمo sentinelas, num total de 36.088 cortes, metade corados po EH e metade por IQ. Os يndices para detecçمo de metلstases através de cortes de congelaçمo e "imprint" citolَgico, respectivamente, foram : sensibilidade de 82 por cento e de 88 por cento, especificidade e valor preditivo positivo (VPP) de 100 por cento para ambos; valor preditivo negativo (VPN) de 81 por cento e 87 por cento; e acurلcia de 90 por cento e 93 por cento. Os mesmos يndices, quando comparamos o nْmero total de cortes (36.088) entre HE e IQ, resultaram: sensibilidade de 94 por cento, especificidade de VPP de 100 por cento para ambos, VPN de 99 por cento e acurلcia de 99 por cento. Os resultados demonstraram que o exame intra-operatَrio do LS por "imprint" é superior aos cortes por congelçمo e que a valiaçمo de matلstases em todos os linfonodos por cortes seriados...

Thalidomide: new indications?

Thalidomide, which was developed as a nonbarbiturate sedative agent, was taken off the market in 1961 after it was linked to a spate of major birth defects. Gradually, thalidomide was reintroduced for the treatment of a few skin diseases including leprous erythema nodosum, severe mucosal ulcers (e.g., associated with HIV infection or Behçet's disease), lymphocytic skin infiltrations, cutaneous lupus erythematosus, and chronic graft-versus-host disease. Recent reports of original pharmacological properties including modulation of cytokine production (mainly reduced TNF-alpha production) and inhibition of angiogenesis have led to the suggestion that thalidomide may be useful in some inflammatory and neoplastic conditions. Several open-label studies and case reports have described the effects of thalidomide in Crohn's disease, rheumatoid arthritis, ankylosing spondylarthritis, systemic sclerosis, and a few other systemic disorders. In these indications, minor but dose-limiting side effects were apparently common. Thalidomide analogs with better acceptability profiles are under evaluation. The anti-angiogenic effects of thalidomide may make this compound valuable as single-drug therapy or as an adjunct to chemotherapy in patients with cancer, particularly those with metastases or multiple myeloma. This possibility requires further evaluation.

Autoapheresis and intraoperative blood salvage in oncologic surgery.

Transfusion of predeposit or salvaged autologous blood has continued to grow since the 1980s. Issues such as the indications for use and cost effectiveness as well as the safety of autologous blood salvaged during cancer surgery have emerged and should be addressed. The concern for possible contamination of autologous RBC with cancer cells responsible for metastasis has limited the use of autologous salvaged blood in cancer patients. Nevertheless, clinical experience has been gained on the use of salvaged blood in patients with colorectal, gastric, renal, hepatic, breast, bladder and lung cancer. No evidence has been reported showing an increase in metastasis or a decrease in patient survival, in spite of the obvious demonstration that salvaged blood is contaminated with viable tumor cells which are not washed out of the RBC layer during intraoperative blood salvage (IOBS). However, a number of limitations have hampered the widespread use of IOBS in these patients and the technique is not well established. Increasing knowledge of the deleterious effects of allogeneic blood transfusion both in terms of the increased number of viral or bacterial infections and the down-regulation of the patient's immune system have recalled attention to IOBS and to the techniques such as filtration, which might reduce the risk of reinfusion of cancer cells, or totally eliminate the risks such as irradiation has been proposed by Hansen's group. This paper reviews the topic with some emphasis on our personal experience with gamma and X-ray irradiation of salvaged blood in a large reference hospital, where IOBS and filtration of salvaged blood were established for use in cancer patients in 1993 and 1996.

CEA as a monitor of gastrointestinal malignancy.

Ninety-four patients with carcinoma of the colon have been followed with serial determinations of plasma CEA (carcinoembryonic antigen) levels over a 3-year period using the Hansen assay. Nine hundred twelve CEA determinations have been made in these patients. Plasma CEA levels rose in 90% of the instances of clinical progression documented in these patients. In 30% of patients, this rise indicated progression 6 months or more before it was detected by standard clinical methods. Unfortunately, a few patients never developed elevated CEA levels even though disease clearly progressed. False positive results have also been encountered, with significant elevations occurring in patients who have since remained without evidence of disease for several months. Our data indicate that at least two sequential elevated CEA values, the second being higher, must be a minimal criterion for consideration of possible progression of disease. Even with this standard, we have encountered false positive results in 10% of our patients, indicating recurrence or progression where none has occurred clinically. CEA measurement is of limited usefulness for 30 days after curative surgery, because the elevation of CEA levels due to the original amount of tumor present as well as due to surgery per se may persist for this length of time in a significant number of patients. On the other hand, CEA levels have responded to chemotherapy in close correlation with observed clinical course in those patients with metastatic disease treated in this series. Initial pretherapy CEA values have so far proved to be good prognostic indicators of disease course following complete resection. With an initial CEA value of less than 2.5 ng/ml of plasma, recurrent has been rare (1/20). If the pretreatment CEA was greater than 7.0 ng/ml, it has been the rule (7/9).