Multiple plaques on the hands and feet. Mycosis fungoides (MF) palmaris et plantaris (MFPP).
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Aged, 80 and over↗
Biomedical subjects
Victor G Prieto
Publications and source records attributed to Victor G Prieto.
Accuracy of lymphatic mapping and sentinel lymph node biopsy after previous wide local excision in patients with primary melanoma.
BACKGROUND: Sentinel lymph node (SLN) status is the most important prognostic factor with respect to the survival of patients with primary cutaneous melanoma. However, lymphatic mapping and SLN biopsies (LM/SLNBs) performed in patients who have had a wide local excision (WLE) may not accurately reflect the pathologic status of the draining lymph node basins. The purpose of this study was to assess the feasibility and accuracy of LM/SLNB in patients who have had a previous WLE. METHODS: A single-institution database was examined to identify patients who had a WLE before LM/SLNB and patients who had a concomitant LM/SLNB. Primary clinicopathologic features (age, tumor thickness, and ulceration), SLN identification rate, SLN pathologic status, and the incidence and sites of recurrences were compared between patients with and without prior WLE. RESULTS: Of the 1395 patients identified, 104 had WLE before LM/SLNB. The mean preoperative WLE radial margin was 1.4 cm (median, 1.0 cm). LM/SLNB was successful in 103 of 104 (99%) patients. Age, tumor thickness, incidence of ulceration, and incidence of SLN positivity in the group with prior WLE were similar to those of the cohort of patients who had concomitant LM/SLNB and WLE (n = 1291). In 97 (93%) of the 104 prior-WLE patients, the surgical defects were closed by either primary closure or skin graft; 7 patients (7%) had rotational flaps. The median follow-up of these 104 patients was 51 months. Among the prior-WLE group, 19 patients (18%) had a positive SLNB; of these 19 patients, 4 (21%) had recurrences (3 distant failures and 1 local and distant failure). There were no lymph node recurrences-in a mapped or unmapped basin-in these 104 patients with a negative or positive SLNB. CONCLUSIONS: SLNs can be successfully identified and accurately reflect the status of the regional lymph node basin in carefully selected melanoma patients with a previous WLE. Prior WLE does not appear to adversely impact the ability to detect lymphatic metastases, although the utility of LM/SLNB in patients who have undergone extensive reconstruction of the primary excision site remains to be defined. Because more extensive surgery may be required to accomplish accurate lymph node staging in patients who have undergone prior WLE-including the possible removal of SLNs from additional lymph node basins and an additional surgical procedure-to minimize morbidity and cost, concomitant WLE and LM/SLNB is strongly preferred whenever possible.
Adolescent↗
Galectin-3 expression is associated with tumor progression and pattern of sun exposure in melanoma.
PURPOSE: Most studies accept a multistep pathogenic process in melanoma that may include the phases of benign nevi and dysplastic nevi, melanoma, and metastatic melanoma. Dysregulation of cellular proliferation and apoptosis is probably involved in melanoma progression and response to therapy. We have studied the expression of galectin-3, a beta-galactoside-binding protein involved in apoptosis, angiogenesis, and cell proliferation, in a large series of melanocytic lesions, and correlated the expression with clinical and histologic features. EXPERIMENTAL DESIGN: Tissue microarray blocks of 94 melanocytic lesions were semiquantitatively evaluated by immunohistochemistry for the cytoplasmic or nuclear expression of galectin-3. RESULTS: Primary and metastatic melanomas expressed galectin-3 at a significantly higher level than nevi in both cytoplasm and nuclei (P<0.0073). There was a significant association between anatomic source (as indirect indication of level of sun-exposure) and cytoplasmic and nuclear expression. Lymph node and visceral metastases had a higher level of expression than s.c. lesions (P<0.004). Interestingly, there was an almost significant finding of worse survival in those patients with lesions showing higher levels of cytoplasmic than nuclear galectin-3 expression (log-rank test, P=0.06). CONCLUSIONS: Melanocytes accumulate galectin-3 with tumor progression, particularly in the nucleus. The strong association of cytoplasmic and nuclear expression in lesions of sun-exposed areas suggests an involvement of UV light in activation of galectin-3.
Biomarkers, Tumor↗
Genetic variants of the vitamin D receptor gene alter risk of cutaneous melanoma.
Sunlight causes DNA damage but also induces production of vitamin D whose metabolite 1,25-(OH)2D3 has antiproliferative and pro-differentiative effects in both melanocytes and cutaneous melanoma (CM) cells mediated through the vitamin D receptor (VDR). We hypothesized that genetic polymorphisms of VDR are associated with risk of CM. In a hospital-based case-control study of 602 non-Hispanic white CM patients and 603 cancer-free control subjects frequency matched by age and sex, we genotyped two VDR polymorphisms (TaqI and FokI) and assessed their association with CM risk. We found that a significantly decreased risk was associated with VDR-TaqI Tt (adjusted odds ratio (OR), 0.70; 95% confidence interval (CI), 0.54-0.90) and Tt+tt (OR=0.70; 95% CI, 0.55-0.89) genotypes, compared with the VDR-TaqI TT genotype, whereas an increased risk was associated with VDR-FokI Ff genotype (OR=1.32; 95% CI, 1.03-1.68), and a borderline significantly increased risk was associated with Ff+ff (OR=1.26; 95% CI, 1.00-1.59) genotypes, compared with the VDR-FokI FF genotype. In conclusion, genetic variants (i.e., TaqI t protective allele and FokI f risk allele) in VDR may alter risk of CM.
Alleles↗
Quantitative analysis of melanocytic tissue array reveals inverse correlation between activator protein-2alpha and protease-activated receptor-1 expression during melanoma progression.
The identification of molecular markers of melanoma progression is needed to more accurately stage and identify treatments for patients with malignant melanoma. Previously, we demonstrated that loss of the activator protein-2alpha (AP-2alpha) expression results in overexpression of the protease-activated receptor-1 (PAR-1) in human melanoma cell lines. Here, we used a tissue microarray platform that consisted of 64 melanocytic lesions, including dysplastic nevi (N=21), primary melanoma (N=20), and metastatic melanoma (N=23). We analyzed the expression of AP-2 and PAR-1 simultaneously by immunofluorescent microscopy with an automated quantification laser scanning cytometer. AP-2 was highly expressed in normal cutaneous melanocytes and dysplastic nevi but not in melanoma metastases. We observed a significantly higher number of AP-2-positive cells in the dysplastic nevi (P=0.0013) and primary melanoma (P=0.0023) compared to the metastatic melanoma. In contrast, we observed a significantly higher percentage of PAR-1-positive cells in the metastatic melanoma compared to dysplastic nevi (P=0.0072) and primary melanoma (P=0.0138). Increased expression of PAR-1 in metastatic melanomas contributes to tumor progression by modulating expression of genes, such as IL-8, matrix metalloproteinase-2, vascular endothelial growth factor, platelet-derived growth factor, and integrins. These findings support our hypothesis that loss of AP-2 is a crucial event in the progression of human melanoma and contributes to the acquisition of the metastatic phenotype via upregulation of PAR-1.
Disease Progression↗
Tumor iNOS predicts poor survival for stage III melanoma patients.
Inducible nitric oxide synthase (iNOS) produces nitric oxide, which has growth promoting activity in melanoma. A preliminary study of tumors from patients with Stage III melanoma who had received neo-adjuvant therapy revealed an association of tumor iNOS expression with shortened survival. The objective of the present study was to determine whether iNOS expression in tumors of newly diagnosed, untreated Stage III patients is predictive of survival. iNOS expression was examined by immunohistochemistry in tumors from 132 patients. The staining was evaluated for percentage of positive cells (Number score) and the intensity of staining (Intensity score). The association of iNOS expression with overall and disease-specific survival was tested in univariate and multivariate Cox proportional hazards regression models that included other known prognostic factors. Results of the univariate analysis demonstrated that the presence of iNOS in a patient's tumor, whether graded on the basis of Number or Intensity score, was associated with a significant increase in the hazard ratio of death from melanoma. These findings were corroborated by median survival data estimated from Kaplan Meier analysis. In the multivariate model including iNOS number or intensity, gender, age, number of lymph nodes, macroscopic disease and in-transit disease, only iNOS expression predicted survival. We conclude that a significant association exists between tumor iNOS expression and shortened survival in untreated Stage III melanoma patients. The ability of iNOS to predict outcomes for these patients may be independent of other known prognostic factors, providing a new molecular marker with significant potential for clinical utility.
Adolescent↗
Genetic variants of the ADPRT, XRCC1 and APE1 genes and risk of cutaneous melanoma.
Sunlight causes various kinds of DNA damage, including oxidative lesions that are removed effectively by the base excision repair (BER) pathway, in which ADPRT, XRCC1 and APE1 play a key role. However, genetic variation in these genes may alter their functions. We hypothesized that ADPRT, XRCC1 and APE1 polymorphisms are associated with risk of cutaneous melanoma (CM). In a hospital-based case-control study of 602 CM patients and 603 cancer-free control subjects frequency matched on age, sex and ethnicity, we genotyped for three non-synonymous single nucleotide polymorphisms (SNPs) (i.e. the ADPRT Val762Ala, XRCC1 Arg399Gln and APE1Asp148Glu) and assessed their associations with risk of CM. We found no significant difference in the allele frequencies between cases and controls for any of these three SNPs. However, we found that, compared with the APE1 Asp/Asp genotype, a significantly decreased risk of CM was associated with the APE1 Asp/Glu [adjusted odds ratio (OR), 0.60; 95% confidence interval (CI), 0.41-0.86], Glu/Glu (OR, 0.58; 95% CI, 0.38-0.88) and combined APE1 Asp/Glu+Glu/Glu (OR, 0.59; 95% CI, 0.42-0.83) genotypes, but not for other XRCC1 variant genotypes. Moreover, there was evidence for a possible gene-gene interaction between XRCC1 and APE1 variants in the association with risk of CM (P=0.030). We conclude that the APE1 Glu variant may have an effect or interact with XRCC1 in the etiology of CM or in linkage disequilibrium with other untyped protective alleles. Larger studies with more SNPs in the BER genes are needed to verify these findings.
Adult↗
Nuclear expression of the antiapoptotic protein survivin in malignant melanoma.
BACKGROUND: Expression of the antiapoptotic protein survivin has been demonstrated in some melanocytic lesions and is believed to be required for melanoma cell viability. However, its diagnostic value in differentiating melanomas from nevi has not yet been examined. METHODS: Tissue microarray blocks were constructed with paraffin-fixed tissue of 19 nevi, 18 dysplastic nevi, 24 malignant melanomas, and 31 metastatic melanomas. Sections were then reacted with three antisurvivin antibodies (two monoclonal and one polyclonal) assessing labeling intensity (absent or weak, and moderate to strong) as well as the percentage of cells labeled (< 25%, > or = 25%). RESULTS: Of the antibodies evaluated, the polyclonal one was found to be the most sensitive. Nuclear immunoreactivity for survivin (i.e., > or = 25% of cells exhibiting and/or at least moderately intense staining) was seen in a subset of melanomas but not in nevi or dysplastic nevi (P < 0.05). CONCLUSIONS: Survivin is variably expressed in the cytoplasm in the entire spectrum of melanocytic lesions, with nuclear expression detectable only in melanomas. These data may underscore the importance of nuclear survivin in progression to melanoma and may prove useful in the differential diagnosis of melanoma versus nevus.
Cell Nucleus↗
Assessment of the role of sentinel lymph node biopsy for primary cutaneous desmoplastic melanoma.
BACKGROUND: The role of sentinel lymph node biopsy (SLNB) in the treatment of desmoplastic melanoma (DM) remains undefined. The purpose of this study was to evaluate the use of SLNB for DM. METHODS: In all, 1850 patients with cutaneous melanoma underwent wide local excision and SLNB. Patients with DM were identified and stratified as 'pure' DM or 'mixed' DM (i.e., DM associated with at least one other common histologic subtype). RESULTS: Of the 1850 patients, 65 (3.5%) had DM. Of these, 46 (70.8%) had pure DM and 19 (29.2%) had mixed DM. Patients with pure DM had a median tumor thickness of 3.5 mm and 6.5% were ulcerated. Compared with patients with pure DM, patients with either mixed DM or non-DM (n = 1785) had thinner primary tumors (median, 1.7 mm and 1.5 mm, respectively, each P < 0.001 vs. pure DM) that were more likely to be ulcerated (27.7% and 21.3%, respectively, each P < 0.05 vs. pure DM). Although the incidence of a positive SLN was similar in patients with mixed DM (15.8%) and non-DM (17.5%), patients with pure DM were less likely to have a positive SLN (2.2%) (each P < 0.01 vs. non-DM and mixed DM). At a median follow-up of 2.9 years, no patient with pure DM had recurred. CONCLUSIONS: Despite having thicker primary tumors, patients with pure DM have a lower incidence of positive SLNs compared with patients with non-DM. Whereas the treatment approach for patients with mixed DM should be similar to that of other melanoma patients, patients with pure DM are unlikely to have metastatic disease in regional lymph nodes and SLNB may not be warranted.
Female↗
Phase I studies of imatinib mesylate combined with cisplatin and irinotecan in patients with small cell lung carcinoma.
BACKGROUND: Small cell lung carcinoma (SCLC) cell lines commonly express KIT and its ligand, stem cell factor, suggesting an autocrine loop promoting cell growth. Imatinib inhibits KIT kinase activity. SCLC cells treated with imatinib in vitro undergo cell cycle arrest. Imatinib reduces resistance to irinotecan in vitro. Common metabolic pathways suggest there may be drug interactions between imatinib and irinotecan or cisplatin. In the current study, the authors investigated the feasibility of combining these drugs in the treatment of patients with SCLC. METHODS: Two Phase I studies were conducted independently at two institutions. Patients with extensive-disease SCLC underwent therapy with cisplatin, irinotecan, and imatinib using two similar regimens. In one study, immunohistochemical analysis of the expression of potential imatinib targets was performed on pretreatment biopsy specimens, and blood specimens were collected and analyzed for imatinib, irinotecan, and cisplatin pharmacokinetic parameters. RESULTS: Nine patients were enrolled and were evaluable for toxicity. A high incidence of neutropenia, diarrhea, and thrombosis was observed that precluded dose escalation. Six patients were evaluable for response after four cycles; five patients experienced a partial response and the other patient had developed progressive disease. Four of six tumor specimens tested expressed platelet-derived growth factor receptor-alpha and two expressed KIT. Irinotecan clearance was found to be significantly decreased by imatinib (P < 0.04). No significant alteration in the disposition of cisplatin was observed. CONCLUSIONS: The maximum tolerated dose for this combination with granulocyte-colony-stimulating factor support was identified as imatinib at a dose of 300 mg/day with irinotecan (at a dose of 65 mg/m(2)) and cisplatin (at a dose of 30 mg/m(2)) given on Days 1 and 8, every 21 days. The decreased irinotecan clearance may explain the high incidence of diarrhea and neutropenia noted in the current study.
Adult↗
Histopathologic diagnosis of chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: II. Pathology Working Group Report.
This consensus document provides an update for pathologists and clinicians about the interpretation of biopsy results and use of this information in the management of hematopoietic cell transplantation patients. Optimal sampling and tissue preparation are discussed. Minimal criteria for the diagnosis of graft-versus-host disease (GVHD) are proposed, together with specific requirements for the diagnosis of chronic GVHD. Four final diagnostic categories (no GVHD, possible GVHD, consistent with GVHD, and definite GVHD) reflect the integration of histopathology with clinical, laboratory, and radiographic information. Finally, the Working Group developed a set of worksheets to facilitate communication of clinical information to the interpreting pathologist and to aid in clinicopathologic correlation studies. Forms are available at . The recommendations of the Working Group represent a consensus opinion supplemented by evaluation of available peer-reviewed literature. Consensus recommendations and suggested data-capture forms should be validated in prospective clinicopathologic studies.
Biopsy↗
Atypical lymphocytic reaction with epidermotropism and lymphocytic vasculopathic reaction (lymphocytic vasculitis) after treatment with imiquimod.
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Adjuvants, Immunologic↗
Cutaneous leukocytoclastic vasculitis in a patient with myelodysplastic syndrome after therapy with the rapamycin analogue everolimus: case report and review of the literature.
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Aged↗
High flotillin-2 expression is associated with lymph node metastasis and Breslow depth in melanoma.
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Gene Expression Regulation, Neoplastic↗
Polymorphisms of the FAS and FAS ligand genes associated with risk of cutaneous malignant melanoma.
The FAS/FAS ligand (FASLG) system has a key role in regulating cell growth and thus tumorigenesis. Functional promoter polymorphisms of the FAS and FASLG genes alter the transcriptional activities, but no published study has investigated the role of these polymorphisms in the etiology of cutaneous malignant melanoma (CMM). In a hospital-based, case-control study of 602 non-Hispanic white CMM patients and 603 cancer-free age- and sex-matched control subjects, we genotyped FAS-1377G>A, FAS-670A>G, FASLG-844T>C and FASLG-IVS2nt-124G>A polymorphisms and assessed their respective associations with CMM risk. We found that an increased risk of CMM was associated with the FAS-1377GG [adjusted odds ratio (OR)=1.32; 95% confidence interval (CI)=1.00-1.75 for -1377GG] and -670AA (adjusted OR=1.28; 95% CI=1.00-1.65 for -670AA) genotypes compared to the -1377AA/AG and -670AG/GG genotypes, respectively; an increased risk of CMM was associated with the FASLG-IVS2nt-124AG+GG (OR=1.54; 95% CI=1.18-2.01) genotype compared to the AA genotype, but no evident risk was associated with any of the FAS-844T>C genotypes. In the combined analysis of these four variant alleles, we found that, compared to those having 0-3 variants, those having 4-8 variant alleles had a significantly increased risk for CMM (OR=1.38; 95% CI=1.10-1.73), and this risk was more pronounced in subgroups of old (>50 years) males, and those who were at low risk of sunlight-induced CMM, except for having fair skin colour, moles, dysplastic nevi and a family history of cancer. In conclusion, genetic variants in the FAS and FASLG genes may contribute to the etiology of CMM in the general population, particularly in those with a low risk of sunlight-induced CMM.
Alleles↗
Expression of retinoid receptors in sebaceous cell carcinoma.
PURPOSE: The aim of this study is to investigate whether there are any abnormalities in the in vivo expression of retinoid acid receptors (RAR-alpha, RAR-beta and RAR-gamma) and retinoid X receptors (RXR-alpha, RXR-beta and RXR-gamma) in sebaceous cell carcinoma. METHODS: Expression of retinoid receptors in paired specimens of cancerous tissues (n = 10) and adjacent normal tissues (n = 10) from 10 patients with sebaceous cell carcinoma was studied immunohistochemically by using anti-retinoid receptor antibodies. RESULTS: In eight of the 10 normal tissue samples, all six receptors were expressed. In the other two samples, all receptors were expressed except RAR-gamma (one sample) or RXR-gamma (two samples). Five tumours (50%) lacked RAR-alpha; RAR-alpha expression was lower in tumours than in normal tissues in eight of 10 cases. RAR-beta was expressed in the cytoplasm of nine of 10 tumours; RAR-beta expression was at least as high in tumours as in normal tissue in eight of 10 cases. Two tumours lacked RAR-gamma; three tumours had lower RAR-gamma expression than paired normal epithelium; four had the same RAR-gamma expression, and one had higher RAR-gamma expression. RXR-alpha expression was strong in all normal tissues and tumour samples. Ten tumours lacked RXR-beta and all 10 tumours lacked RXR-gamma expression. CONCLUSIONS: Diminished RXR-beta and RXR-gamma expression might be related to the development of sebaceous cell carcinoma. Additional studies are required to establish whether the defects in RAR expression in sebaceous cell carcinoma might affect the potential response of this tumour to treatment with retinoids.
Adenocarcinoma, Sebaceous↗
Analysis of protein tyrosine kinases expression in the melanoma metastases of patients treated with Imatinib Mesylate (STI571, Gleevec).
BACKGROUND: Protein tyrosine kinase (PTK) inhibition has been identified as a promising strategy in the development of new selective therapies, targeting the signaling pathways in melanoma progression. Gleevec, a novel class of anti-tumor drugs, may have a potential therapeutic benefit in melanoma, which involves abnormal activation of abl, c-kit, and platelet-derived growth factor (PDGF) tyrosine kinases. METHODS: Tumor biopsies from 13 patients with metastatic melanoma were screened by immunohistochemistry for PTK [c-kit, C-abl, Abl-related gene (ARG), PDGF receptor-alpha (PDGFR-alpha) and PDGFR-beta] expression before and after being treated with Gleevec @ 400 mg bid for 2 weeks. Both, percentage of positive cells and staining intensity were evaluated. RESULTS: We found a statistically significant (p < 0.01) selective loss of PTK expression in the follow-up biopsy, both in intensity and number of positive cells. PDGFR-alpha and -beta had the highest level of expression reduction. One patient had a durable clinical response, and the follow-up biopsy showed negative expression for four of the PTKs, namely c-abl, ARG, PDGFR-alpha, and beta. CONCLUSIONS: Our study reports for the first time the in vivo effect of Gleevec in the induction of apparently selective reduction of PTKs expression under anti-tyrosine kinases treatment, suggesting its potential role in melanoma treatment.
Adult↗