Over the past decades, thermoablative techniques for the therapy of localized tumors have gained importance in the treatment of patients not eligible for surgical resection Anecdotal reports have described spontaneous distant tumor regression after thermal ablation, indicating a possible involvement of the immune system, hence an induction of antitumor immunity after thermoinduced therapy In recent years, a growing body of evidence for modulation of both adaptive and innate immunity, as well as for the induction of danger signals through thermoablation, has emerged Induced immune responses, however, are mostly weak and not sufficient for the complete eradication of established tumors or durable prevention of disease progression, and combination therapies with immunomodulating drugs are being evaluated with promising results This article aims to summarize published findings on immune modulation through radiofrequency ablation, cryoablation, microwave ablation therapy, high-intensity focused ultrasound, and laser-induced thermotherapy

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More Than Just Tumor Destruction: Immunomodulation by Thermal Ablation of Cancer

To assess the effectiveness of 5% imiquimod cream (IQ) in the treatment of vulvar, penile and anal intraepithelial neoplasias (VIN, PIN and AIN), we searched Medline, Embase, PubMed and Cochrane Library databases. With regard to VIN there were two randomized controlled trials (RCTs), eight uncontrolled/cohort studies, nine case reports and one review article. Use of IQ in PIN and AIN were only supported by cohort studies (two each for PIN and AIN) and case reports (15 for PIN and 3 for AIN). On pooled analysis of RCTs, uncontrolled and cohort studies, the mean complete response (CR) rate for VIN, PIN and AIN were 51%, 70% and 48%, respectively. The mean partial response (PR) rate for VIN, PIN and AIN were 25%, 30% and 34% respectively. The recurrence (RR) rate for VIN, PIN and AIN were 16%, 0% and 36%, respectively. The follow-up period for VIN, PIN and AIN ranged from 2 to 32 months, 10 to 12 months and 11 to 39 months, respectively. Although the results for PIN look the best, the strongest evidence regarding efficacy of IQ in anogenital intraepithelial neoplasia is for VIN supported by RCTs. Evidence for use of IQ in AIN was essentially limited to HIV-positive men who have sex with men. IQ was reasonably well tolerated with side-effects being managed with reduction in frequency of drug usage and/or rest periods. Based on these results, IQ seems to be a safe mode of treatment and is possibly an alternative to currently available methods of treatment. However, there are no comparative studies assessing its efficacy against traditional modes of treatment.

More than a decade on: review of the use of imiquimod in lower anogenital intraepithelial neoplasia:

DNA damage response (DDR) in eukaryotic cells is initiated in the chromatin context. DNA damage and repair depend on or have influence on the chromatin dynamics associated with genome stability. Epigenetic modifiers, such as chromatin remodelers, histone modifiers, DNA (de-)methylation enzymes, and noncoding RNAs regulate DDR signaling and DNA repair by affecting chromatin dynamics. In recent years, significant progress has been made in the understanding of plant DDR and DNA repair. SUPPRESSOR OF GAMMA RESPONSE1, RETINOBLASTOMA RELATED1 (RBR1)/E2FA, and NAC103 have been proven to be key players in the mediation of DDR signaling in plants, while plant-specific chromatin remodelers, such as DECREASED DNA METHYLATION1, contribute to chromatin dynamics for DNA repair. There is accumulating evidence that plant epigenetic modifiers are involved in DDR and DNA repair. In this review, I examine how DDR and DNA repair machineries are concertedly regulated in Arabidopsis thaliana by a variety of epigenetic modifiers directing chromatin remodeling and epigenetic modification. This review will aid in updating our knowledge on DDR and DNA repair in plants.

https://www.mdpi.com/1422-0067/20/17/4093/pdf

Chromatin Remodeling and Epigenetic Regulation in Plant DNA Damage Repair.

Penile intraepithelial neoplasia (PIN), or penile squamous cell carcinoma in situ, is a rare disease and may be associated with high morbidity and mortality. In an attempt to avoid surgical intervention, which may result in poor cosmetic and functional outcomes for patients, many non-invasive treatments have been trialled with variable success rates. This review summarises the available literature describing the use of topical imiquimod for PIN. While the results of our review are limited by the heterogeneity of the methods and follow ups of the included case series and case reports, they highlight the fact that patients with PIN have variable responses to imiquimod which seem less effective than previously reported. Therefore, if imiquimod treatment is instituted in PIN, clinicians should counsel their patients about the effects associated with treatment, the potential for a partial or no response to treatment, and the risk of recurrence. A strict follow-up plan is also necessary to monitor both patient adherence and PIN recurrence after treatment completion, in case surgical options need to be considered.

Imiquimod in the treatment of penile intraepithelial neoplasia: An update.

https://www.cidjournal.com/article/S0738-081X(13)00004-7/pdf

Anogenital malignancies and premalignancies: Facts and controversies

Introduction. So far there have been no papers analyzing the incidence of ‘non-pathological’ lesions or normal variants on the male external genitalia. Subsequently, the number of patients consulted due to the presence of such lesions remains unknown. The aim of the study was to estimate the incidence of normal variants in patients who were consulted due to lesions on the skin or mucosa of the male external genitalia. Material and methods. The study group consisted of 400 males, aged 3-91, who were consulted due to lesions on the genitalia in the Department of Dermatology, Venereology and Allergology of the Medical University of Gdansk. results. The most common lesions were hyperpigmentation of the median raphe of the penis and scrotum (85.6%), pearly penile papules (24%), and prominent veins (24%). Sebaceous hyperplasia or ectopic sebaceous glands were revealed in 9% of patients, respectively. Melanocytic nevi were diagnosed with similar frequency (9.5%), whereas skin tags more rarely (7%). Other ‘nonpathological’ lesions were diagnosed in a considerably lower number of patients. In 32 patients (8% of all patients) the reason of admission to the Clinic was just the presence of some ‘non-pathological’ lesions. Pearly penile papules were found to be the most common condition, occurring in 78.1% patients. Conclusions. Normal variants represent a substantial percentage of generally asymptomatic lesions and the only indication for their removal is cosmetic discomfort or venerophobia.

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Normal variants in patients consulted in the Dermatology Clinic for lesions of the male external genitalia

Background/Aims: This study investigated the gene expression and DNA methylation of selected DNA repair genes (MBD4, TDG, MLH1, MLH3) and DNMT1 in human bladder cancer in the context of pathophysiological and prognostic significance. Methods: To determine the relationship between the gene expression pattern, global methylation and promoter methylation status, we performed real-time PCR to quantify the mRNA of selected genes in 50 samples of bladder cancer and adjacent non-cancerous tissue. The methylation status was analyzed by methylation-specific polymerase chain reaction (MSP) or digestion of genomic DNA with a methylation-sensitive restriction enzyme and PCR with gene-specific primers (MSRE-PCR). The global DNA methylation level was measured using the antibody-based 5-mC detection method. Results: The relative levels of mRNA for MBD4, MLH3, and MLH1 were decreased in 28% (14/50), 34% (17/50) and 36% (18/50) of tumor samples, respectively. The MBD4 mRNA expression was decreased in 46% of non-muscle invasive tumors (Ta/T1) compared with 11% found in muscle invasive tumors (T2-T4) (P<0.003). Analysis of mRNA expression for TDG did not show any significant differences between Ta/T1 and T2-T4 tumors. The frequency of increased DNMT1 mRNA expression was higher in T2-T4 (52%) comparing to Ta/T1 (16%). The overall methylation rates in tumor tissue were 18% for MBD4, 25% for MLH1 and there was no evidence of MLH3 promoter methylation. High grade tumors had significantly lower levels of global DNA methylation (P=0.04). There was a significant association between shorter survival and increased expression of DNMT1 mRNA (P=0.002), decreased expression of MLH1 mRNA (P=0.032) and the presence of MLH1 promoter methylation (P=0.006). Conclusion: This study highlights the importance of DNA repair pathways and provides the first evidence of the role of MBD4 and MLH3 in bladder cancer. In addition, our findings suggest that DNMT1 mRNA and MLH1 mRNA expression, as well as the status of MLH1 promoter methylation, are attractive prognostic markers in this pathology.

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Gene Expression, DNA Methylation and Prognostic Significance of DNA Repair Genes in Human Bladder Cancer.

© 2009 The Authors JEADV 2009, 23, 954–982 Journal compilation © 2009 European Academy of Dermatology and Venereology dermatomyositis. The mechanism of calcinosis in dermatomyositis is unclear, but it may be caused by the release of calcium from the cytosol in damaged muscle cells. However, a high intracellular calcium concentration is more essential than is muscle damage for calcinosis in dermatomyositis, since calcinosis can develop prior to myositis.4 Dysfunctional transport of calcium would therefore contribute to the pathogenesis of both dermatomyositis and keratosis follicularis. In summary, we describe here a patient with both keratosis follicularis and dermatomyositis. Our findings suggest that disordered intracellular transport of calcium may have a role in the development of both conditions. To clarify their association, studies characterizing the nature of the abnormality underlying impaired calcium transport by the SR/ER in dermatomyositis are needed.

Topical treatment of bowenoid papulosis of the penis with imiquimod

Cystitis glandularis (CG) is defined as glandular metaplasia of bladder urothelium. In most cases the course of CG is asymptomatic. However, some patients complain of hematuria and lower urinary tract symptoms (LUTS) of varying degrees. We present a case of 45-year-old man with an extensive CG causing acute urinary retention. Although it was initially treated as an infection, prompt ultrasound and cystoscopy helped to establish the diagnosis. Transurethral resection of the cyst with biopsy of the bladder mucosa was then performed. Immediately after surgery the patient noticed significant improvement in urine passing. During the 2-month follow-up there was no relapse.

Acute urinary retention in a patient with extended cystitis glandularis

Purpose With the development of diagnostic techniques, renal cell carcinoma (RCC) is currently diagnosed in earlier stages, allowing the introduction of less invasive techniques in its management. One of the most promising new treatment methods is based on the utilization of high temperature created by radiofrequency current circulating around the needle probe introduced into the tumor. Besides the direct destruction of the cancer tissue, the treatment may induce immunologic reaction to tumor antigens released from destroyed tumor cell. This paper describes changes observed in the peripheral blood lymphocyte population after radiofrequency ablation (RFA) of RCC. Methods Blood was tested before, and 2, 4, and 6 weeks after the RFA in 6 patients with RCC for the proportions and numbers of CD3+, CD3+HLA-DR+, CD3+CD4+, CD3+CD8+, and CD56+CD16+ cells. The blood was stained with fluorochrome-conjugated monoclonal antibodies and percentages of cells expressing various markers were determined by flow cytometry. Results In all patients, the changes were most pronounced 2 weeks after the procedure. The proportion of CD4+ and CD8+ lymphocytes were changed. In 1 patient, an increase in both CD4+ and CD8+ cells was observed. In 5 out of 6 patients, the proportion of activated (DR+) cells was increased over the whole follow-up period with the highest values in the second week after RFA. The percentage of the CD56+CD16+ was decreased in most of the patients. Conclusions Our study confirms that in the majority of patients, RFA of the renal tumors causes significant changes in the proportion of the peripheral immune cells. We suggest that the results presented in this article shows the necessity for further studies.

Jerzy Michajłowski

Papers

Normal variants in patients consulted in the Dermatology Clinic for lesions of the male external genitalia

Gene Expression, DNA Methylation and Prognostic Significance of DNA Repair Genes in Human Bladder Cancer.

Topical treatment of bowenoid papulosis of the penis with imiquimod

Acute urinary retention in a patient with extended cystitis glandularis

Impact of radiofrequency ablation on PBMC subpopulation in patients with renal cell carcinoma