Computer-Aided Diagnosis of Skin Lesions Using Conventional Digital Photography: A Reliability and Feasibility Study

Background

Computer-aided diagnosis (CADx) software that provides a second opinion has been widely used to assist physicians with various tasks. In dermatology, however, CADx has been mostly limited to melanoma or melanocytic skin cancer diagnosis. The frequency of non-melanocytic skin cancers and the accessibility of regular digital macrographs have raised interest in developing CADx for broader applications.

Objectives

To investigate the feasibility of using CADx to diagnose both melanocytic and non-melanocytic skin lesions based on conventional digital photographic images.

Methods

This study was approved by an institutional review board, and the requirement to obtain informed consent was waived. In total, 769 conventional photographs of melanocytic and non-melanocytic skin lesions were retrospectively reviewed and used to develop a CADx system. Conventional and new color-related image features were developed to classify the lesions as benign or malignant using support vector machines (SVMs). The performance of CADx was compared with that of dermatologists.

Results

The clinicians'' overall sensitivity, specificity, and accuracy were 83.33%, 85.88%, and 85.31%, respectively. New color correlation and principal component analysis (PCA) features improved the classification ability of the baseline CADx (p = 0.001). The estimated area under the receiver operating characteristic (ROC) curve (Az) of the proposed CADx system was 0.949, with a sensitivity and specificity of 85.63% and 87.65%, respectively, and a maximum accuracy of 90.64%.

Conclusions

We have developed an effective CADx system to classify both melanocytic and non-melanocytic skin lesions using conventional digital macrographs. The system''s performance was similar to that of dermatologists at our institute. Through improved feature extraction and SVM analysis, we found that conventional digital macrographs were feasible for providing useful information for CADx applications. The new color-related features significantly improved CADx applications for skin cancer.     

Characterization of the Melanoma miRNAome by Deep Sequencing

Background

MicroRNAs (miRNAs) are 18–23 nucleotide non-coding RNAs that regulate gene expression in a sequence specific manner. Little is known about the repertoire and function of miRNAs in melanoma or the melanocytic lineage. We therefore undertook a comprehensive analysis of the miRNAome in a diverse range of pigment cells including: melanoblasts, melanocytes, congenital nevocytes, acral, mucosal, cutaneous and uveal melanoma cells.

Methodology/Principal Findings

We sequenced 12 small RNA libraries using Illumina''s Genome Analyzer II platform. This massively parallel sequencing approach of a diverse set of melanoma and pigment cell libraries revealed a total of 539 known mature and mature-star sequences, along with the prediction of 279 novel miRNA candidates, of which 109 were common to 2 or more libraries and 3 were present in all libraries.

Conclusions/Significance

Some of the novel candidate miRNAs may be specific to the melanocytic lineage and as such could be used as biomarkers to assist in the early detection of distant metastases by measuring the circulating levels in blood. Follow up studies of the functional roles of these pigment cell miRNAs and the identification of the targets should shed further light on the development and progression of melanoma.     

Vacuum-assisted core-needle biopsy as a diagnostic and therapeutic method in lesions radiologically suspicious of breast fibroadenoma

Background

Treatment of breast fibroadenoma remains a subject of clinical discussion. Recommended methods include clinical observation or surgical excision of the lesion. The procedure involves hospitalisation and anaesthesia, leaving a scar on the breast.

Aim

The aim of this study was to present the Centre''s experience in removing lesions radiologically suspicious of fibroadenoma by means of an ultrasound-guided vacuum-assisted core-needle biopsy as an alternative to a classical surgery.

Materials and methods

Between March 2007 and April 2010, 196 ultrasound-guided vacuum-assisted biopsies were performed in the Mammotome Biopsy Laboratory of the 1st Surgical Oncology and General Surgery Department at the Greater Poland Cancer Centre in Poznań. The procedure was delivered to female patients aged 17–91 years (mean 40.8, median 39). Qualified for removal were ultrasound identified lesions described as fibroadenomas.

Results

The average size of excised lesions according to pre-biopsy ultrasound image was 13.53 ± 8.92 mm (median 11 mm, range 4–60 mm). In 184 cases (93.9%), benign lesions were found in the final histopathologic examination. Pre-cancer lesions were found in 10 cases, and invasive lesions in two cases. Overall, after follow-up ultrasound examination, four patients were qualified for subsequent surgical resection of lesions that had been left behind.

Conclusion

Vacuum core-needle biopsy is an effective tool enabling removal of breast fibroadenomas. It combines features of a lesion resection and histopathologic material collection providing an access with minimum invasiveness.     

Cranialization of the Frontal Sinus for Secondary Mucocele Prevention following Open Surgery for Benign Frontal Lesions

Objective

To compare frontal sinus cranialization to obliteration for future prevention of secondary mucocele formation following open surgery for benign lesions of the frontal sinus.

Study Design

Retrospective case series.

Setting

Tertiary academic medical center.

Patients

Sixty-nine patients operated for benign frontal sinus pathology between 1994 and 2011.

Interventions

Open excision of benign frontal sinus pathology followed by either frontal obliteration (n = 41, 59%) or frontal cranialization (n = 28, 41%).

Main Outcome Measures

The prevalence of post-surgical complications and secondary mucocele formation were compiled.

Results

Pathologies included osteoma (n = 34, 49%), mucocele (n = 27, 39%), fibrous dysplasia (n = 6, 9%), and encephalocele (n = 2, 3%). Complications included skin infections (n = 6), postoperative cutaneous fistula (n = 1), telecanthus (n = 4), diplopia (n = 3), nasal deformity (n = 2) and epiphora (n = 1). None of the patients suffered from postoperative CSF leak, meningitis or pneumocephalus. Six patients, all of whom had previously undergone frontal sinus obliteration, required revision surgery due to secondary mucocele formation. Statistical analysis using non-inferiority test reveal that cranialization of the frontal sinus is non-inferior to obliteration for preventing secondary mucocele formation (P<0.0001).

Conclusion

Cranialization of the frontal sinus appears to be a good option for prevention of secondary mucocele development after open excision of benign frontal sinus lesions.     

Mutational Profile of GNAQ Q209 in Human Tumors

Background

Frequent somatic mutations have recently been identified in the ras-like domain of the heterotrimeric G protein α-subunit (GNAQ) in blue naevi 83%, malignant blue naevi (50%) and ocular melanoma of the uvea (46%). The mutations exclusively affect codon 209 and result in GNAQ constitutive activation which, in turn, acts as a dominant oncogene.

Methodology

To assess if the mutations are present in other tumor types we performed a systematic mutational profile of the GNAQ exon 5 in a panel of 922 neoplasms, including glioblastoma, gastrointestinal stromal tumors (GIST), acute myeloid leukemia (AML), blue naevi, skin melanoma, bladder, breast, colorectal, lung, ovarian, pancreas, and thyroid carcinomas.

Principal Findings

We detected the previously reported mutations in 6/13 (46%) blue naevi. Changes affecting Q209 were not found in any of the other tumors. Our data indicate that the occurrence of GNAQ mutations display a unique pattern being present in a subset of melanocytic tumors but not in malignancies of glial, epithelial and stromal origin analyzed in this study.     

RASopathic Skin Eruptions during Vemurafenib Therapy

Purpose

Vemurafenib is a potent inhibitor of V600 mutant BRAF with significant impact on progression-free and overall survival in advanced melanoma. Cutaneous side effects are frequent. This single-center observational study investigates clinical and histological features of these class-specific cutaneous adverse reactions.

Patients and Methods

Patients were all treated with Vemurafenib 960 mg b.i.d. within local ethic committees approved clinical trials. All skin reactions were collected and documented prospectively. Cutaneous reactions were classified by reaction pattern as phototoxic and inflammatory, hair and nail changes, keratinocytic proliferations and melanocytic disorders.

Results

Vemurafenib was well tolerated, only in two patients the dose had to be reduced to 720 mg due to arthralgia. 26/28 patients (93%) experienced cutaneous side effects. Observed side effects included UVA dependent photosensitivity (n = 16), maculopapular exanthema (n = 14), pruritus (n = 8), folliculitis (n = 5), burning feet (n = 3), hair thinning (mild alopecia) (n = 8), curly hair (n = 2) and nail changes (n = 2). Keratosis pilaris and acanthopapilloma were common skin reactions (n = 12/n = 13), as well as plantar hyperkeratosis (n = 4), keratoacanthoma (n = 5) and invasive squamous cell carcinoma (n = 4). One patient developed a second primary melanoma after more than 4 months of therapy (BRAF and RAS wild type).

Conclusion

Vemurafenib has a broad and peculiar cutaneous side effect profile involving epidermis and adnexa overlapping with the cutaneous manifestations of genetic diseases characterized by activating germ line mutations of RAS (RASopathy). They must be distinguished from allergic drug reaction. Regular skin examination and management by experienced dermatologists as well as continuous prophylactic photo protection including an UVA optimized sun screen is mandatory.     

Primary mucosal sinonasal melanoma—Case report and review of the literature. The role of complex treatment-surgery and adjuvant radiotherapy

Aim

The place of adjuvant radiotherapy in the treatment of sinonasal melanoma.

Background

Sinonasal mucosal melanoma is a rare disease with poor prognosis and requires a complex treatment. Elective neck dissection in patients with N0 and adjuvant radiotherapy has been a source of controversy. High late regional recurrence rates rise questions about elective irradiation of the neck nodes in patients with N0 stage disease.

Methods

We present our two years’ follow up in a case of locally advanced sinonasal melanoma and literature review of the treatment options for mucosal melanoma.

Results

In locally advanced sinonasal melanoma treated with surgical resection, postoperative radiotherapy and chemotherapy we had local tumor control. Two years later, a regional contralateral recurrence without distant metastasis occurred.

Conclusions

Literature data for frequent neck lymph nodes recurrences justify elective neck dissection. Postoperative elective neck radiotherapy for patients with locally advanced sinonasal melanoma and clinically N0 appears to decrease the rate of late regional recurrences.     

Cost-Minimization Analysis Favours Intravenous Ferric Carboxymaltose over Ferric Sucrose for the Ambulatory Treatment of Severe Iron Deficiency

Objective

Intravenous iron is widely used to treat iron deficiency in day-care units. Ferric carboxymaltose (FCM) allows administration of larger iron doses than iron sucrose (IS) in each infusion (1000 mg vs. 200 mg). As FCM reduces the number of infusions required but is more expensive, we performed a cost-minimization analysis to compare the cost impact of the two drugs.

Materials and Methods

The number of infusions and the iron dose of 111 consecutive patients who received intravenous iron at a gastrointestinal diseases day-care unit from 8/2007 to 7/2008 were retrospectively obtained. Costs of intravenous iron drugs were obtained from the Spanish regulatory agencies. The accounting department of the Hospital determined hospital direct and indirect costs for outpatient iron infusion. Non-hospital direct costs were calculated on the basis of patient interviews. In the pharmacoeconomic model, base case mean costs per patient were calculated for administering 1000 mg of iron per infusion using FCM or 200 mg using IS. Sensitivity analysis and Monte Carlo simulation were performed.

Results

Under baseline assumptions, the estimated cost of iron infusion per patient and year was €304 for IS and €274 for FCM, a difference of €30 in favour of FCM. Adding non-hospital direct costs to the model increased the difference to €67 (€354 for IS vs. €287 for FCM). A Monte Carlo simulation taking into account non-hospital direct costs favoured the use of FCM in 97% of simulations.

Conclusion

In this pharmacoeconomic analysis, FCM infusion reduced the costs of iron infusion at a gastrointestinal day-care unit.     

Experimental Differentiation of Intraocular Masses Using Ultrahigh-Field Magnetic Resonance Imaging – A Case Series

Purpose

The case reports presented here were compiled to demonstrate the potential for improved diagnosis and monitoring of disease progress of intraocular lesions using ultrahigh-field magnetic resonance microscopy (MRM) at 7.1 Tesla.

Methods

High-resolution ex vivo ocular magnetic resonance (MR) images were acquired on an ultrahigh-field MR system (7.1 Tesla, ClinScan, Bruker BioScan, Germany) using a 2-channel coil with 4 coil elements and T2-weighted turbo spin echo (TSE) sequences of human eyes enucleated because of different intraocular lesions. Imaging parameters were: 40×40 mm field of view, 512×512 matrix, and 700 µm slice thickness. The results were correlated with in vivo ultrasound and histology of the enucleated eyes.

Results

Imaging was performed in enucleated eyes with choroidal melanoma, malignant melanoma of iris and ciliary body with scleral perforation, ciliary body melanoma, intraocular metastasis of esophageal cancer, subretinal bleeding in the presence of perforated corneal ulcer, hemorrhagic choroidal detachment, and premature retinopathy with phthisis and ossification of bulbar structures. MR imaging allowed differentiation between solid and cystic tumor components. In case of hemorrhage, fluid-fluid levels were identified. Melanin and calcifications caused significant hypointensity. Microstructural features of eye lesions identified by MRM were confirmed by histology.

Conclusion

This study demonstrates the potential of MRM for the visualization and differential diagnosis of intraocular lesions. At present, the narrow bore of the magnet still limits the use of this technology in humans in vivo. Further advances in ultrahigh-field MR imaging will permit visualization of tumor extent and evaluation of nonclassified intraocular structures in the near future.     

Treatment Results in the Different Surgery of Intradural Extramedullary Tumor of 122 Cases

Study Design

A retrospective study of intradural extramedullary tumor.

Objective

To compare the treatment results in the different surgeries of spinal intradural extramedullary tumor.

Methods

The study retrospectively reviewed 122 patients. The minimally invasive surgery (MIS) group was divided into Group A (hemilaminectomy + tumor microscopic excision) and Group B (laminectomy + tumor microscopic excision + pedicle screw fixation). Meanwhile, the non-MIS group was divided into Group C (hemilaminectomy + tumor excision), Group D (laminectomy + tumor excision), and Group E (laminectomy + tumor excision + pedicle screw fixation). In order to study postoperative spinal stability, we simultaneously divided all of the subjects into three categories, namely Group HE: hemilaminectomy + tumor excision; Group LE: laminectomy + tumor excision; and Group LEPSF: laminectomy + tumor excision + pedicle screw fixation.

Results

The MIS group exhibited fewer postoperative complications (p<0.05), better short-term clinical efficacy (p<0.05) and less non-surgical cost (p<0.05) than in non-MIS group. The rate of postoperative spinal instability in hemilaminectomy was lower than in laminectomy in a single spinal segment (p<0.05). The rate of postoperative spinal instability in laminectomy + pedicle screw fixation was lower than in hemilaminectomy and laminectomy in two or more spinal segments (p<0.05).

Conclusion

In the case of appropriate surgical indications, minimally invasive surgery for intradural extramedullary tumor is a useful method that can successfully produce good clinical results and reduce non-surgical cost. In addition, pedicle screw fixation helps avoid spinal postoperative instability.     

Gender Differences in Survival and the Use of Primary Care Prior to Diagnosis of Three Cancers: An Analysis of Routinely Collected UK General Practice Data

Objective

To explore whether there are gender differences in the number of GP recorded cases, the probability of survival and consulting pattern prior to diagnosis amongst patients with three non-sex-specific cancers.

Design

Cross sectional study.

Setting

UK primary care.

Subjects

12,189 patients aged 16 years or over diagnosed with colorectal cancer (CRC), 11,081 patients with lung cancer and 4,352 patients with malignant melanoma, with first record of cancer diagnosis during 1997–2006.

Main outcome measures

Cancer cases recorded in primary care; probability of survival following diagnosis; and number of GP contacts within the 24 months preceding diagnosis.

Results

From 1997–2006, overall rates of GP recorded CRC and lung cancer cases recorded were higher in men than in women, but rates of malignant melanoma were higher in women than in men. Gender differences in survival were small; 49% of men and 53% of women survived at least 5 years following CRC diagnosis; 9% of men and 12% of women with lung cancer, and 77% of men and 86% of women with malignant melanoma. The adjusted male to female relative hazard ratio of death in all patients was 1.20 (95%CI 1.13–1.30), 1.24 (95%CI 1.16–1.33) and 1.73 (95%CI 1.51–2.00) for CRC, lung cancer and malignant melanoma respectively. However, gender differences in the relative risk were much smaller amongst those who died during follow-up. For each cancer, there was little evidence of gender difference in the percentage who consulted and the number of GP contacts made within 24 months prior to diagnosis.

Conclusions

This study found that patterns of consulting prior to cancer diagnosis differed little between two genders, providing no support for the hypothesis that gender differences in survival are explained by gender differences in consultation for more serious illness, and suggests the need for a more critical view of gender and consultation.     

C-Terminal Tensin-Like Protein Is a Novel Prognostic Marker for Primary Melanoma Patients

Background

C-terminal tensin-like protein (Cten) is a focal adhesion protein originally identified as a tumor suppressor in prostate cancer. It has since been found to be overexpressed and function as an oncogene in numerous other cancers, but the expression status of Cten in melanoma is still unknown.

Methods

Using tissue microarrays containing 562 melanocytic lesions, we evaluated Cten protein expression by immunohistochemistry. The association between Cten expression and patient survival was examined using Kaplan-Meier survival analysis, and univariate and multivariate Cox regression analyses were used to estimate the crude and adjusted hazard ratios.

Results

Strong Cten expression was detected in 7%, 24%, 41%, and 46% of normal nevi, dysplastic nevi, primary melanoma, and metastatic melanoma samples, respectively, and Cten expression was found to be significantly higher in dysplastic nevi compared to normal nevi (P = 0.046), and in primary melanoma compared to dysplastic nevi (P = 0.003), but no difference was observed between metastatic and primary melanoma. Cten staining also correlated with AJCC stages (P = 0.015) and primary tumor thickness (P = 0.002), with Cten expression being induced in the transition from thin (<1mm) to thick (≥1mm) melanomas. Strong Cten expression was significantly associated with a worse 5-year overall (P = 0.008) and disease-specific survival (P = 0.004) for primary melanoma patients, and multivariate Cox regression analysis revealed that Cten expression was an independent prognostic marker for these patients (P = 0.038 for overall survival; P = 0.021 for disease-specific survival).

Conclusion

Our findings indicate that induction of Cten protein expression is a relatively early event in melanoma progression, and that Cten has the potential to serve as a prognostic marker for primary melanoma patients.     

Cytoplasmic Skp2 expression is increased in human melanoma and correlated with patient survival

Background

S-phase kinase protein 2 (Skp2), an F-box protein, targets cell cycle regulators via ubiquitin-mediated degradation. Skp2 is frequently overexpressed in a variety of cancers and associated with patient survival. In melanoma, however, the prognostic significance of subcellular Skp2 expression remains controversial.

Methods

To investigate the role of Skp2 in melanoma development, we constructed tissue microarrays and examined Skp2 expression in melanocytic lesions at different stages, including 30 normal nevi, 61 dysplastic nevi, 290 primary melanomas and 146 metastatic melanomas. The TMA was assessed for cytoplasmic and nuclear Skp2 expression by immunohistochemistry. The Kaplan-Meier method was used to evaluate the patient survival. The univariate and multivariate Cox regression models were performed to estimate the harzard ratios (HR) at five-year follow-up.

Results

Cytoplasmic but not nuclear Skp2 expression was gradually increased from normal nevi, dysplastic nevi, primary melanomas to metastatic melanomas. Cytoplasmic Skp2 expression correlated with AJCC stages (I vs II–IV, P<0.001), tumor thickness (≤2.00 vs >2.00 mm, P<0.001) and ulceration (P = 0.005). Increased cytoplasmic Skp2 expression was associated with a poor five-year disease-specific survival of patients with primary melanoma (P = 0.018) but not metastatic melanoma (P>0.05).

Conclusion

This study demonstrates that cytoplasmic Skp2 plays an important role in melanoma pathogenesis and its expression correlates with patient survival. Our data indicate that cytoplasmic Skp2 may serve as a potential biomarker for melanoma progression and a therapeutic target for this disease.     

Serum Antibodies against CD28– A New Potential Marker of Dismal Prognosis in Melanoma Patients

Background

Autoantibodies against CD28 have been found in patients with autoimmune and atopic diseases. These antibodies may act as superagonists and activate T cells but may also be antagonistic or induce immunosuppressive effects by activating regulatory T cells. Autoimmunity in melanoma patients has been discussed controversially.

Objective

We investigated 230 melanoma patients for the occurrence of CD28 antibodies and the effect of the latter on overall and progress-free survival.

Methods

We constructed an ELISA assay to measure CD28 serum antibodies. 230 patients with melanoma and a control-group of 625 patients consistent of 212 patients with virus hepatitis b or c, 149 patients with allergies, 78 patients with psoriasis, 46 patients with plasmocytoma and 140 healthy blood donors were investigated for the occurrence of CD28 antibodies.

Results

CD28 abs occur at a higher percentage in patients with melanoma and in patients with viral hepatitis than in other groups investigated (p<0.001). Occurrence of CD28 abs is significantly higher in patients receiving interferons independent from the underlying disease (p<0.001). In vitro CD28 serum antibodies have an inhibitory effect on the CD28 receptor as they lead to reduced stimulation of Jurkat cells. Presence of CD28 was correlated with a higher risk of dying from melanoma (p = 0.043), but not with a significantly shortened overall survival or progression-free survival.

Conclusion

Interferon therapy appears to induce the production of CD28 abs. In light of reports that these CD28 abs induce immunosuppressive Tregs and – as our data show – that they are inhibitors of CD28 receptor mediated stimulation, the continuation of therapies with interferons in melanoma patients developing CD28 antibodies should be critically reconsidered, since our data indicate a worse outcome of patients with CD28 abs.     

Prognostic Factors of Melanoma Patients with Satellite or In-Transit Metastasis at the Time of Stage III Diagnosis

Background

Prognosis of patients with loco-regional skin metastases has not been analyzed in detail and the presence or absence of concurrent lymph node metastasis represents the only established prognostic factor thus far. Most studies were limited to patients already presenting with skin lesions at the time of initial diagnosis. We aimed to analyze the impact of a broad penal of prognostic factors in patients with skin metastases at the time of first metastatic spread, including patients with synchronous lesions already present at the time of initial diagnosis, stage I/II patients with loco-regional recurrence and patients initially presenting with skin metastasis but unknown primary melanoma.

Patients and Methods

We investigated disease-specific survival of 380 patients treated at our department between 1996 and 2010 using Kaplan Meier survival probabilities and Cox-proportional hazard analysis.

Results

Five-year survival probability was 60.1% for patients with skin metastases only and 36.3% for those with synchronous nodal metastases. The number of involved nodes and a tumor thickness of at least 3 mm had independent negative impact on prognosis. A strong relationship was identified between the risk of death and the number of involved nodes. Neither ulceration nor the timing of the first occurrence of metastases as either in stage I/II patients, at the time of excision of the primary melanoma or initially in patients with unknown primary tumor, had additional effects on survival.

Conclusion

Lymph node involvement was confirmed as the most important prognostic factor for melanoma patients with loco-regional skin metastasis including those with unknown primary tumor and stage I/II patients with skin recurrence. Consideration of the tumor thickness and of the number of involved lymph nodes instead of the exclusive differentiation into presence vs. absence of nodal disease may allow a more accurate prediction of prognosis for patients with satellite or in-transit metastases.     

Melanoma Patients with Unknown Primary Site or Nodal Recurrence after Initial Diagnosis Have a Favourable Survival Compared to Those with Synchronous Lymph Node Metastasis and Primary Tumour

Background

A direct comparison of prognosis between patients with regional lymph node metastases (LNM) detected synchronously with the primary melanoma (primary LNM), patients who developed their first LNM subsequently (secondary LNM) and those with initial LNM in melanoma with unknown primary site (MUP) is missing thus far.

Patients and Methods

Survival of 498 patients was calculated from the time point of the first macroscopic LNM using Kaplan Meier and multivariate Cox hazard regression analysis.

Results

Patients with secondary LNM (HR = 0.67; p = 0.009) and those with initial LNM in MUP (HR = 0.45; p = 0.008) had a better prognosis compared to patients with primary LNM (median survival time 52 and 65 vs. 24 months, respectively). A high number of involved nodes, the presence of in-transit/satellite metastases and male gender had an additional independent unfavourable effect.

Conclusions

Survival of patients with LNM in MUP and with secondary LNM is similar and considerably more favourable compared to those with primary LNM. This difference needs to be considered during patient counselling and for stratification purposes in clinical trials. The assumption of an immune privilege of patients with MUP which is responsible for rejection of the primary melanoma, and results in a favourable prognosis is not supported by our data.     

Risk of Melanoma in People with HIV/AIDS in the Pre- and Post-HAART Eras: A Systematic Review and Meta-Analysis of Cohort Studies

Objective

Following the introduction of highly active antiretroviral therapy (HAART) the risk of AIDS-defining cancers decreased but incidence of many non-AIDS-defining cancers has reportedly increased in those with HIV/AIDS. Whether melanoma risk has also changed in HIV/AIDS patients post-HAART is unknown and therefore we evaluated this in comparison with the risk before HAART.

Design

Systematic review and meta-analysis.

Methods

We searched Medline, Embase and ISI science citation index databases to April 2013. All cohort studies of patients diagnosed with HIV/AIDS that permitted quantitative assessment of the association with melanoma were eligible. Detailed quality assessment of eligible studies was conducted, focussing particularly on adjustment for ethnicity, a priori considered essential for an unbiased assessment of melanoma risk. Data were pooled using a random effects model.

Results

From 288 articles, we identified 21 that met the inclusion criteria, 13 presenting data for the post-HAART era and 8 for the pre-HAART era. Post-HAART the pooled relative risk (pRR) for the association between HIV/AIDS and melanoma was 1.26 (95% CI, 0.97–1.64) and 1.50 (95% CI 1.12–2.01) among studies that accounted for ethnicity, with evidence of significant heterogeneity (P = 0.004, I² = 55.5). Pre-HAART pRRs were 1.26 (95% CI 1.11–1.43; P_het = 0.82) and 1.28 (95% CI 1.10–1.49) among studies adjusted for ethnicity.

Conclusions

People with HIV/AIDS remain at a significantly increased risk of developing melanoma in the post-HAART era. White skinned people with HIV/AIDS should be screened regularly and counselled against excessive sun exposure.     

Low-Dose Formaldehyde Delays DNA Damage Recognition and DNA Excision Repair in Human Cells

Objective

Formaldehyde is still widely employed as a universal crosslinking agent, preservative and disinfectant, despite its proven carcinogenicity in occupationally exposed workers. Therefore, it is of paramount importance to understand the possible impact of low-dose formaldehyde exposures in the general population. Due to the concomitant occurrence of multiple indoor and outdoor toxicants, we tested how formaldehyde, at micromolar concentrations, interferes with general DNA damage recognition and excision processes that remove some of the most frequently inflicted DNA lesions.

Methodology/Principal Findings

The overall mobility of the DNA damage sensors UV-DDB (ultraviolet-damaged DNA-binding) and XPC (xeroderma pigmentosum group C) was analyzed by assessing real-time protein dynamics in the nucleus of cultured human cells exposed to non-cytotoxic (<100 μM) formaldehyde concentrations. The DNA lesion-specific recruitment of these damage sensors was tested by monitoring their accumulation at local irradiation spots. DNA repair activity was determined in host-cell reactivation assays and, more directly, by measuring the excision of DNA lesions from chromosomes. Taken together, these assays demonstrated that formaldehyde obstructs the rapid nuclear trafficking of DNA damage sensors and, consequently, slows down their relocation to DNA damage sites thus delaying the excision repair of target lesions. A concentration-dependent effect relationship established a threshold concentration of as low as 25 micromolar for the inhibition of DNA excision repair.

Conclusions/Significance

A main implication of the retarded repair activity is that low-dose formaldehyde may exert an adjuvant role in carcinogenesis by impeding the excision of multiple mutagenic base lesions. In view of this generally disruptive effect on DNA repair, we propose that formaldehyde exposures in the general population should be further decreased to help reducing cancer risks.     

Gastrointestinal Hyperplasia with Altered Expression of DNA Polymerase β

Background

Altered expression of DNA polymerase β (Pol β) has been documented in a large percentage of human tumors. However, tumor prevalence or predisposition resulting from Pol β over-expression has not yet been evaluated in a mouse model.

Methodology/Principal Findings

We have recently developed a novel transgenic mouse model that over-expresses Pol β. These mice present with an elevated incidence of spontaneous histologic lesions, including cataracts, hyperplasia of Brunner''s gland and mucosal hyperplasia in the duodenum. In addition, osteogenic tumors in mice tails, such as osteoma and osteosarcoma were detected. This is the first report of elevated tumor incidence in a mouse model of Pol β over-expression. These findings prompted an evaluation of human gastrointestinal tumors with regard to Pol β expression. We observed elevated expression of Pol β in stomach adenomas and thyroid follicular carcinomas, but reduced Pol β expression in esophageal adenocarcinomas and squamous carcinomas.

Conclusions/Significance

These data support the hypothesis that balanced and proficient base excision repair protein expression and base excision repair capacity is required for genome stability and protection from hyperplasia and tumor formation.