Dermatologic complications in transplantation and cellular therapy for acute leukemia.

Adoptive cellular immunotherapy, mainly hematopoietic stem cell transplant and CAR-T cell therapy have revolutionized treatment of patients with acute leukemia. Indications and inclusion criteria for these treatments have expanded in recent years. While these therapies are associated with significant improvements in disease response and overall survival, patients may experience adverse events from associated chemotherapy conditioning, engraftment, cytokine storm, supportive medications, and post-transplant maintenance targeted therapies. Supportive oncodermatology is a growing specialty to manage cutaneous toxicities resulting from the anti-cancer therapies. In this review, we summarize diagnosis and management of the common cutaneous adverse events including drug eruptions, graft-versus-host disease, neoplastic and paraneoplastic complications in patients undergoing cellular therapies.

Leptomeningeal Metastatic Prostate Cancer Imitating a Subdural Hematoma.

Metastases to the dura and adjacent parenchyma occur in 1%-2% of patients with prostate cancer. Dural metastases manifest as subdural fluid collections and present as a chronic subdural hematoma. We present a patient with advanced prostate cancer who experienced a fall and a traumatic brain injury. Computer tomography (CT) of the brain revealed a bilateral subdural hematoma (SDH). During the follow-up examination, the patient's mental status declined, and a follow-up brain CT showed an expansion of the SDH. Brain MRI with contrast demonstrated dural lesions suspicious for metastasis to the dura. Histopathologic examination of the lesions confirmed metastatic prostate adenocarcinoma. While uncommon, leptomeningeal-dural metastatic lesions stemming from prostate adenocarcinoma should be suspected in patients with known prostate cancer who present with subdural collections. This is even more significant if the patient with prostatic adenocarcinoma has sustained a recent head injury and presents with a subdural hematoma on neuroimaging. Brain MRI provides more data towards the differential diagnosis of these lesions and should be an essential part of the diagnostic workup. Biopsy and histopathologic examination of these lesions are indicated in the diagnostic workup of these uncommon lesions.

Dermatophytosis Incognito Mimicking Cutaneous T-Cell Lymphoma.

Dermatophytosis incognito can be missed in diagnosis, given its relatively low prevalence as compared with common cases of dermatophytosis and therefore, is likely under-reported. Cutaneous T-cell lymphoma (CTCL) is also a rare entity with variable clinical manifestations. While successful treatment of dermatophytosis is feasible withmultiple topical and systemic antifungal options, CTCL can present a therapeutic challenge associated with significant emotional distress for the patients. We present a case of tinea incognito initially treated for eczema, later considered biopsy-supported CTCL that was successfully treated with antifungal therapy.

Comparative Analysis of Methods for Detecting Isocitrate Dehydrogenase 1 and 2 Mutations and Their Metabolic Consequence, 2-Hydroxyglutarate, in Different Neoplasms.

Isocitrate dehydrogenase (IDH) mutations have been recognized in a few neoplasms including glioma, acute myeloid leukemia, chondrosarcoma, cholangiocarcinoma, and angioimmunoblastic T-cell lymphoma. The direct methods to detect IDH mutations include DNA sequencing, immunohistochemistry (IHC), or by measuring its byproduct, 2-hydroxyglutarate (2-HG), in the blood or urine. Moreover, conventional magnetic resonance imaging can be modified to magnetic resonance spectroscopy (MRS) to measure 2-HG in tumor. By conducting a search in Medline/PubMed and ISI/Web of Science for the published articles in English related to the methods for detection of IDH mutations and its byproduct 2-HG, we compared different methodologies to detect these mutations and discuss advantages and limitations of each method. Studies in which a methodology of detection was compared with another modality were included. Multiple studies have shown that both DNA sequencing and IHC are reliable methods for detecting IDH mutations in glioma and other solid neoplasms. IHC appeared to be less costly, easier to perform, and may be slightly more accurate than DNA sequencing. 2-HG has also been measured in bone marrow aspirate, serum and urine of patients with mutant IDH acute myeloid leukemia, and correlated very well with sequencing and IHC. Lastly, in some glioma patients, MRS detected IDH mutations noninvasively and reliably with excellent correlations with other modalities such as IHC and sequencing. In conclusion, IHC, MRS, and 2-HG detection all are clinically useful and comparable with DNA sequencing in identifying IDH mutations in different neoplasms. 2-HG and MRS can be utilized for monitoring treatment response in a variety of neoplasms.

RET mutation and expression in small-cell lung cancer.

BACKGROUND: There is growing interest in defining the somatic mutations associated with small-cell lung cancer (SCLC). Unfortunately, a serious blockade to genomic analyses of this disease is a limited access to tumors because surgery is rarely performed. We used our clinical/pathologic database of SCLC patients to determine the availability of biopsy specimens that could be used for genomic studies and to identify tumors for initial oncogene analysis. METHODS: DNA was extracted from six tumors, three primary and three metastatic, and analyzed by SEQUENOM platform technology. RESULTS: Primary-resected tumor tissue represents less than 3% of all diagnostic specimens in this disease, highlighting the limited access to tissue sufficient for comprehensive genomic analyses. We identified an activating M918T RET somatic mutation in a metastatic SCLC tumor specimen. Bioinformatic search identified RET mutations in other SCLC studies. Stable overexpression of both mutant M918T and wild-type RET in two SCLC cell lines, H1048 and SW1271, activated ERK signaling, MYC expression, and increased cell proliferation, particularly by mutant RET. Stable cells became sensitized to the RET tyrosine kinase inhibitors, vandetanib and ponatinib. Further analysis of RET mRNA expression in SCLC revealed wide variability in both cells and tumors, and SCLC cells demonstrated significantly higher RET expression compared with adenocarcinoma lung cells. CONCLUSIONS: Our data suggest that a subpopulation of SCLC patients may derive benefit from tyrosine kinase inhibitors targeting RET. Coupled with the presence of RET fusion proteins in non-small-cell lung cancer, our data indicate an emerging role for RET in SCLC.

Clinical trial design in small cell lung cancer: surrogate end points and statistical evolution.

BACKGROUND: Small-cell lung cancer (SCLC) is a disease for which few recent therapeutic advances have been achieved. SCLC trial design and reporting may have an impact on the interpretation of studies. Furthermore, the use of surrogate end points in SCLC has not been explored. MATERIAL AND METHODS: Through examining SCLC trials published in the Journal of Clinical Oncology (JCO) (8471 patients from 66 trials between 1983 and 2010), we examined how SCLC trial reporting and design has evolved, determining if the type I error, power, and sample size calculations were provided. We assessed primary end points for all trials and sought to discover surrogate end points for overall survival (OS). RESULTS: There was increased reporting of statistical design in power (16.7% in 1986-1996 to 77.8% in 2006-2010; P = .001) and type I error (22.2% in 1986-1996 to 72.2% in 2006-2010; P = .005). Of trials published in 1986 to 1996, 72.2% failed to report a primary end point, whereas only 5.56% of trials conducted in 2006 to 2010 failed to do so (P = .004). Of phase II trials, primary end points were identified as response rate (RR) in 65%, OS in 25%, and progression-free survival (PFS) in 10%. CONCLUSION: There is a strong correlation between RR and both PFS (P = .013) and OS (P = .012) in extensive disease (ED). RR (P = .029) exhibits a negative trend over time, with a dramatic and significant decrease in RR across all studies starting in 2005. A strong correlation exists between PFS and OS for limited disease (LD) (P = .036) and ED (P = .058). We found no change in OS (P = .383) over time.

Serum calcium concentration and prostate cancer risk: a multicenter study.

This study sought to further evaluate the possible effects of serum calcium level on prostate cancer (PC) risk, with considering the age, body mass index (BMI), and sex steroid hormones. Using data from a prospective multicenter study, serum calcium concentration, as well as thorough demographic and medical characteristics, were determined in 194 cases with newly diagnosed, clinicopathologically confirmed PC and 317 controls, without any malignant disease, admitted to the same network of hospitals. Serum total and ionized calcium levels were categorized into tertiles. Multivariate logistic regression model was used to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI) after adjustment for major potential confounders, including age, BMI, smoking, alcohol, education, occupation, marital status, family history of PC, and sex hormones level. The mean serum calcium level (±SD) in case and control groups was 9.22 (±0.46) mg/dl and 9.48 (±0.51) mg/dl, respectively (P < 0.001). After adjustment for mentioned confounders, a significant trend of decreasing risk was found for serum total calcium concentration (OR = 0.27, 95% CI = 0.12-0.59, comparing the highest with the lowest tertile) and ionized calcium (OR = 0.25, 95% CI = 0.10-0.58). An increase of 1 mg/dl in serum calcium level was associated with a significant decrease in PC risk (OR = 0.52; 95% CI = 0.34-0.76). Our findings reveal the inverse association between serum total and ionized concentrations and PC risk, which supports the hypothesis that calcium may protect against PC. Furthermore, no evidence was found regarding age, BMI, and sex steroid hormones to modify the association between serum calcium and PC risk.

Allergic contact dermatitis to metal allergens in Iran.

BACKGROUND: Metallic allergens such as nickel are among the most common causes of allergic contact dermatitis (ACD), but frequencies of contact dermatitis to these allergens may vary in different areas. OBJECTIVES: This study aimed to determine the frequencies of ACD caused by three common metallic allergens: nickel sulfate; potassium dichromate; and cobalt chloride. METHODS: Data for 1137 patients with clinical diagnoses of contact dermatitis and/or atopic dermatitis evaluated by patch testing in Iran during a 5-year period were retrospectively studied to establish the frequencies of hypersensitivity to these metallic allergens. RESULTS: A total of 313 patients (27.5%) gave positive patch test results for at least one metallic allergen. Allergy to nickel (229 cases, 20.0%) was the most commonly observed, followed by allergy to cobalt (90 cases, 8.0%) and allergy to chromium (70 cases, 6.2%). Nickel allergy was significantly more frequent in females and in subjects aged <40 years, whereas chromium hypersensitivity was more common in males and in subjects aged >40 years. Sensitivity to nickel or chromium was a risk factor for cobalt allergy. CONCLUSIONS: Nickel was most commonly identified as a metallic allergen in Iran and tended to affect women aged <40 years. Regulations pertaining to nickel release may decrease the frequency of nickel hypersensitivity in Iran.

Immunohistochemical study of p53, Ki-67, MMP-2 and MMP-9 expression at invasive front of squamous cell and verrucous carcinoma in oral cavity.

Squamous cell carcinoma (SCC) is the most common malignancy in the oral cavity. Verrucous carcinoma (VC) is a lower grade subtype of SCC with pathological similarities but different management. Tumor invasive front (TIF) is a dynamic location in the differentiation of malignancies. p53 is a tumor suppressor and Ki-67 a proliferation marker. Matrix metalloproteinases 2 and 9 are involved in the tumor invasiveness. We assessed these markers in TIF of oral SCC and VC to find more precise grading scales. We studied the expression of markers in the invasive front of 42 cases of SCC (21 high and 21 low grade), 20 cases of VC and 8 cases of normal oral mucosa using immunohistochemistry. There were significant differences among the study groups regarding the number of cells expressing p53, MMP-2 and 9. Except for Ki-67, other studied markers can be used for the histological grading of SCC and its differentiation from VC. MMP-9 is the most reliable one for invasive SCC grading. The extent of the expression of these markers is related to the infiltration pattern of SCC at the invasive front. The less invasive nature of VC can be associated with the expression pattern of these markers.

Combined SCLC clinical and pathologic characteristics.

INTRODUCTION: Despite the well characterized clinical course of 'pure' SCLC, there have not been many data on combined SCLC, ie, tumors, which contain both small-cell and non-small-cell components. MATERIALS AND METHODS: We analyzed 1628 consecutive cases of lung cancer (1200 NSCLC, 428 SCLC) at our institution over the past decade. We identified 22 patients with C-SCLC. The pathologic and clinical characteristics of these patients were reviewed. Survival analysis was performed and prognostic factors were assessed. These data were compared with the results obtained from our 406 pure SCLC patients who presented during the same time period. RESULTS: The most common pathology was combined small-cell and large-cell with 16 cases followed by combined small- and squamous-cell carcinoma (3 cases), 2 cases of small-cell and nonspecified NSCLC, and 1 case of small cell and adenocarcinoma. Overall survival was significantly higher in C-SCLC patients compared with pure SCLC (median 15 vs. 10.8 months; P = .035). Surgery was significantly more common in this group of patients (45% vs. 3% in the pure small cell group; P < .0001). No difference in overall survival was observed in patients with C-SCLC and patients with pure SCLC, that did not receive surgery (P = .64). CONCLUSION: Patients with combined SCLC carry a better prognosis than those with pure small-cell variety and are more likely to undergo surgery.

Treatment of female pattern hair loss.

Female pattern hair loss (FPHL) as a distinctive entity was first described about 30 years ago. The objective of this study was to perform a systematic review of all randomized controlled trials for treatment of FPHL. A preliminary search was carried out in several databases up to August 2008 to identify all randomized controlled trials on nonsurgical interventions for treatment of FPHL. Studies reporting fewer than 10 patients and non-English articles were excluded. Additionally, references of relevant articles and reviews were checked manually in search for additional sources. Among 238 citations found in the preliminary search, 12 fulfilled all criteria to be included in the systematic review. Topical minoxidil 1% to 5% for 24 to 48 weeks was shown to be effective in FPHL and its effect was not related to age or androgen level of patients. In addition, it may be effective in women with FPHL, both with and without hyperandrogenism, and in young and old premenopausal or postmenopausal. In patients with increased serum androgens, oral flutamide but not finasteride or cyproterone acetate was more effective than no treatment. Topical minoxidil is effective in patients with FPHL, with or without hyperandrogenism, but there is limited evidence for the efficacy of antiandrogens.

Variation of biophysical parameters of the skin with age, gender, and body region.

BACKGROUND: Understanding the physiological, chemical, and biophysical characteristics of the skin helps us to arrange a proper approach to the management of skin diseases. OBJECTIVE: The aim of this study was to measure 6 biophysical characteristics of normal skin (sebum content, hydration, transepidermal water loss (TEWL), erythema index, melanin index, and elasticity) in a normal population and assess the effect of sex, age, and body location on them. METHODS: Fifty healthy volunteers in 5 age groups (5 males and females in each) were enrolled in this study. A multifunctional skin physiology monitor (Courage & Khazaka electronic GmbH, Germany) was used to measure skin sebum content, hydration, TEWL, erythema index, melanin index, and elasticity in 8 different locations of the body. RESULTS: There were significant differences between the hydration, melanin index, and elasticity of different age groups. Regarding the locations, forehead had the highest melanin index, where as palm had the lowest value. The mean values of erythema index and melanin index and TEWL were significantly higher in males and anatomic location was a significant independent factor for all of 6 measured parameters. CONCLUSION: Several biophysical properties of the skin vary among different gender, age groups, and body locations.

Immunohistochemical comparison of the expression of p53 and MDM2 proteins in ameloblastomas and keratocystic odontogenic tumors.

OBJECTIVE: Ameloblastoma and keratocystic odontogenic tumor (KOT) is characterized by a benign but locally invasive behavior with a high risk of recurrence. MDM2 (murine double minute 2), an amplifier of cell proliferation, and p53, a tumor suppressor gene, are overexpressed in some odontogenic lesions. The aim of this study was to compare the expression of MDM2 and p53 in ameloblastoma and KOT as 2 lesions with similar biologic behavior, by immunohistochemistry. METHODS: The expressions of MDM2 and p53 proteins were determined in 39 ameloblastomas (15 follicular types, 15 plexiform types, and 9 unicystic types) and 15 KOTs. RESULTS: P53 protein was expressed in 100% of KOTs and 77.8% of ameloblastomas, and MDM2 was detected in 74.8% of ameloblastomas and 80% of KOTs. There was no statistical difference between MDM2 and p53 expressions in different subtypes of ameloblastomas and also when KOTs were compared with them (P > 0.05). There was a significant difference between immunohistochemical reactivity of MDM2 among subtypes of ameloblastomas (P < 0.05). MDM2 and p53 expressions were positively correlated. CONCLUSIONS: Overexpression of p53 and MDM2 is associated with the pathogenesis and oncogenesis of ameloblastomas and KOT. Overexpression of these markers can contribute to similar biologic behavior of these lesions.

The expression of heat shock proteins 27 and 105 in squamous cell carcinomaof the tongue and relationship with clinicopathological index

Introduction: In oral cavity, the tongue is the most common site prone to development of squamous cell carcinoma(SCC). Considering malignant transformation as a cellular stress, the expression of heat shock proteins (HSPs)may be affected in this process. In this study we assessed the expression of HSP105 and HSP27 as two of the mostinterested stress proteins and investigated their relationship with grade and stage of the tongue SCC.Material and Methods: Fifty-six specimens including 31 early and 25 advanced tongue SCC were gathered. Allspecimens were graded histologically from I to III. Sixteen sections of normal oral mucosa were used as controlgroup. The cellularity and intensity of HSP105 and HSP27 expression were studied immunohistochemically inboth case and control groups. Results were expressed by histochemical score (HSCORE).Results: Significant differences were observed between expression of HSPs and stage of the disease. From earlyto advanced stage, the expression of HSP105 and HSP27 increased and decreased, respectively. There was norelationship between histological grade of lesion and HSCORE of HSP105 expression (P=0.5), although, HSP27expression had reverse relationship with the SCC histological grade.Conclusion: HSP27 and HSP105 may be indicated for prognostic purposes in evaluation of tongue SCC. HSP 27may be used for more accurate microscopic grading of tongue SCC. Increased expression of HSP105 in advancedstage may lead to using this protein for immunotherapy of tongue SCC (AU)

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