Merkel cell carcinoma: Do you know your guidelines?

BACKGROUND: Merkel cell carcinoma (MCC) is a cutaneous neuroendocrine malignancy that exhibits clinically aggressive features and is associated with a poor prognosis. The incidence of MCC seems to be increasing for reasons unknown, and is estimated to be 0.32/100,000 in the United States. METHODS: This article will review the current literature and National Comprehensive Cancer Network practice guidelines in the treatment of MCC. RESULTS: Resection of MCC with negative margins remains the mainstay of therapy. Positive nodal disease should be treated with neck dissection and adjuvant radiotherapy. High-risk patients should undergo adjuvant radiotherapy, which improves oncologic outcomes. The role of chemotherapy is less clear and is currently reserved for advanced-stage MCC and palliative therapy. CONCLUSION: The pathogenesis of MCC has recently been impacted with the discovery of the Merkel cell polyomavirus (MCPyV). Research to establish targeted and immunologic therapeutic options are ongoing.

Pediatric hemorrhagic cystitis.

PURPOSE: To review the current literature as it pertains to hemorrhagic cystitis (HC) in the pediatric bone-marrow transplant (BMT) population. By reviewing the pathophysiology of the disease, preventive methods, and therapeutic options, urologists may be better equipped to manage this challenging clinical scenario. MATERIALS AND METHODS: The HC literature was reviewed using a MEDLINE/PubMed literature search, specifically focusing on the pediatric BMT population as it pertains to the incidence, pathophysiology, prevention, and treatment of HC. RESULTS: Conservative estimates of HC incidence in recent retrospective studies of pediatric BMT populations still approach 10-20%. Several high-volume pediatric BMT centers have reported contemporary data on their experience with HC providing increased insight into incidence and pathophysiology. Accumulating evidence linking BK virus to HC is a significant development warranting further investigation. Other contributing agents/risk factors need identification in the likely multifactorial etiology of HC. Preventive and therapeutic strategies have made modest advances, but certainly need further validation with prospective randomized studies. CONCLUSIONS: Pediatric BMT patients are susceptible for HC development despite preventive measures and improved insight into the pathophysiology. Unfortunately, there are no evidence-based treatment guidelines for this difficult clinical issue that frequently requires prolonged care and multiple treatment modalities necessitating judicious patience in the application of more aggressive interventions.

Hyperbaric oxygen therapy in BKV-associated hemorrhagic cystitis refractory to intravenous and intravesical cidofovir: case report and review of literature.

Hemorrhagic cystitis is a common complication in hematopoietic stem cell transplant recipients. We report here a case of severe BKV-associated hemorrhagic cystitis who did not respond to intravenous cidofovir. Overt hematuria successfully resolved after a few days on hyperbaric oxygen and intravesical instillations of cidofovir, while BK viruria dropped after a few weeks and remained low. We review the literature for therapeutic options in hemorrhagic cystitis and try to explain how hyperbaric oxygen stimulates mucosal repair in the urinary bladder.

Chapter 17: Genital human papillomavirus infections--current and prospective therapies.

Many therapies are available for the treatment of human papillomavirus (HPV)-associated disease, particularly external genital warts. However, at present, these therapies aim to remove the lesion rather than specifically target HPV infection. When disease and infection are local, as in cervical intraepithelial neoplasia (CIN), excisional therapies removing lesion and transformation-susceptible cells are highly effective. However, when infection is regional, as is usually the case for the anogenital warts, vulval intraepithelial neoplasia (VIN), anal intraepithelial neoplasia (AIN), penile intraepithelial neoplasia, and vaginal intraepithelial neoplasia, then current treatments are generally inadequate, with high recurrence rates. Future therapies will be directly or indirectly antiviral, targeting HPV protein functions or enhancing the ability of the immune system to resolve infection or inducing apoptosis indirectly in HPV-infected cells. In the short to the medium term, immunotherapies for low-grade disease are the most likely to be in the clinic. Vaccines targeting the E1 and E2 early proteins combined with immunomodulators or conventional adjuvants that induce a strong cell-mediated HPV antigen-specific response and good immune memory would be the predicted combination. Vaccines designed to target high-grade intraepithelial disease, even when used in combination with immunomodulators, are unlikely to effect lesion clearance in more than a fraction of the cases. However, they may have a role as adjunct therapy after cervical conization to prevent the recurrence of CIN or HPV reinfection. They certainly appear to have a role in multifocal disease, such as VIN and AIN, where partial clearance may be effected and lesion size reduced enough for effective ablative or excisional therapy. It seems unlikely that anti-HPV chemotherapies specifically targeting HPV protein functions will be in the clinic in the medium term. However, agents such as indole-3-carbinol have shown efficacy in small clinical trials, and if these effects are confirmed in larger, randomized, placebo-controlled trials, they could be clinically useful.

Local anesthesia of genital mucosa with a lidocaine/prilocaine combination cream before laser therapy of human papillomavirus lesions.

The objective was to assess the efficacy of the lidocaine 2. 5%/prilocaine 2.5% combination cream during CO2 laser vaporisation treatment of human papillomavirus-related anogenital lesions. The cream was applied 1 to 30 min beforehand. Patients assessed pain using a visual analogue scale. Regardless of the site and lesion surface area, anaesthesia was greatest when the cream was applied 5 to 15 min before treatment. Extra-cervical lesions (vagina, vulva, perineum, anus) were globally less painful than cervical lesions. Lesion surface area is a decisive factor in pre-operative anaesthesia. Small surface-area lesions (< 1 cm2) had significantly greater anaesthesia than larger surface area-lesions (> 5 cm2) (p<0.00001). The study cream proved particularly useful for complete anaesthesia in ambulatory treatment of anal (70%) and urethral (60%) mucosa lesions compared to the uterine cervix (p = 0.03). In terms of anaesthetic efficacy and cost-related benefits, the lidocaine/prilocaine cream is an effective and interesting alternative to locoregional intra-lesional anaesthesia or even to general anaesthesia, for excision and destruction of human papillomavirus-related anogenital lesions.

[A comparative evaluation of treatment methods for a genital papillomavirus infection in women with different viral genotypes]. / Sravnitel'naia otsenka nekotorykh sposobov lecheniia genital'noi papillomavirusnoi infektsii u zhenshchin s razlichnymi genotipami virusa.

Such genotypes of human papilloma virus (HPV) as "malignant" (180), "benign" (49) and indeterminate (127) were identified in 356 females by PCR and cytological procedures. The following therapeutic techniques were compared: cryodestruction of the uterine cervix (60), antiviral medication (AVM) (19), combination of AVM and cryodestruction (224), and combination of AVM and laser destruction (54). In the "malignant" HPV group, AVM in conjunction with cryo- or laser destruction was significantly more effective than cryodestruction or AVM alone. Both cryodestruction alone and in combination with AVM were more effective in treating "benign" genotypes. Repeat courses showed the same tendency.

Immunomodulatory treatment with low-dose interferon-alpha and oral retinoic acid in lymphangioma-like Kaposi's sarcoma.

BACKGROUND: The presence of lymphangiectasis without the characteristic spindle cell proliferation may lead to diagnostic difficulties in Kaposi's sarcoma. Although the literary data mention that the lymphangioma-like tumors may occur in Kaposi's sarcoma, there have been few specific reports and case presentations published. OBSERVATIONS: A case of lymphangioma-like Kaposi's sarcoma in association with IgG/lambda type paraproteinaemia is reported in a 60-year-old man. The HSV8 DNA sequence could be detected by PCR analysis from lesional skin. CONCLUSION: The beneficial effect of alpha-2 interferon (4.5 million units per week) combined with retinoic treatment (0.5 mg/body weight of isotretinoin) caused the regression of the skin rashes while improving the values of immunological tests (T cell function, quantity of paraproteins). The patient's improved general condition and the ameliorating immunological parameters were due to the combination of two regimens applied in a low-dose the alpha-2 interferon (tumor regression) and the oral isotretinoid (antitumor activity, reduction of IL-6 receptor display) treatment.

Resolution of recalcitrant hand warts in an HIV-infected patient treated with potent antiretroviral therapy.

Human papilloma virus (HPV)-related cutaneous manifestations occur with increased frequency and severity among HIV-infected persons. In this report, we describe an HIV-infected man with persistent, severe cutaneous hand warts that did not respond to multiple therapies, including liquid nitrogen cryotherapy, topical dinitrochlorobenzene, topical podophyllin, and intralesional interferon-alfa injections. Approximately 1 year after starting a potent protease inhibitor-containing antiretroviral regimen, the patient's recalcitrant cutaneous warts markedly diminished in size, even though the patient did not receive any specific therapy for the warts after starting aggressive antiretroviral therapy. The patient continued on a potent protease inhibitor-containing antiretroviral regimen and, approximately 2 years later, the warts completely resolved. Our patient's dramatic clinical improvement of cutaneous HPV infection that followed protease inhibitor-containing antiretroviral therapy provides a clear-cut example that protease inhibitor-containing combination antiretroviral therapy can produce significant clinical benefit.

Therapeutic approaches to genital warts.

Although many treatments are available for genital warts caused by human papillomavirus (HPV), none are uniformly successful in the treatment of this disease. Most current treatment options work by destroying affected tissue, either by a cytotoxic or a physically ablative mode of action. Interferons have antiviral, antiproliferative, and immunomodulatory activities, but these have not translated into a high level of cure rates against warts. With all current treatments, recurrent warts are common. Therapies currently being investigated include a 5-fluorouracil/epinephrine collagen gel that achieves high concentrations of 5-fluorouracil at the site of injection. Other new treatment modalities focus on activating the host's immune system or improving the delivery of therapeutic compounds to the affected site. Imiquimod, a novel immune-response modifier, induces interferon and a number of other endogenous cytokines. A cream formulation containing 5% imiquimod resulted in good total clearance rates and generally tolerable side effects in controlled clinical trials of patients with external genital warts. Perhaps the most effective means for managing HPV disease would be a vaccine that prevents the occurrence of genital warts. Although it is unlikely that such a vaccine will be introduced in the near future, preliminary studies indicate that it may be possible to develop suitable prophylactic and therapeutic vaccines.

Interferon as an adjuvant treatment for genital condyloma acuminatum.

OBJECTIVE: To evaluate the effect of alpha-interferon as an adjuvant to laser or fluorouracil treatment in patients with recurrent genital human papillomavirus (HPV) infection. METHODS: Sixty-two females and 21 males were treated for recurrent HPV infection, with either fluorouracil (Efudex 5%) cream or laser ablation of the lesions. Half of the patients were then randomly treated with adjuvant alpha-interferon, to the lesions for patients treated with fluorouracil, or beneath areas previously treated by laser, once a week, for 8 weeks. The other half of the patients did not receive interferon adjuvant. Evaluation of both groups was done using colposcopy and acetic acid, to assess recurrence rates up to 1 year after treatment. RESULTS: Of the 83 patients followed for 1 year, colposcopy revealed recurrent anogenital lesions in 3 of 45 receiving interferon, compared with 9 of 38 patients treated without adjuvant interferon. CONCLUSION: Interferon is effective as adjuvant treatment in controlling the recurrence of genital HPV.

Human papillomavirus infection and genital warts: update on epidemiology and treatment.

The treatment of genital warts remains frustrating since it is often painful, expensive, and unsuccessful. Moreover, little is known about the infectivity and natural history of exophytic genital warts or subclinical genital infection with human papillomavirus. The traditional goals of therapy for sexually transmitted diseases--eradication of infection, elimination of symptoms, prevention of long-term sequelae, and interruption of transmission--are currently not attainable for or applicable to genital warts. The medical literature from January 1988 to August 1993 was reviewed for recent studies on the treatment of exophytic warts. The following treatments were included in the reviewed studies: podofilox (which was recently approved by the Food and Drug Administration), podophyllin, cryotherapy, topical 5-fluorouracil, intralesional interferon, systemic interferon, and laser surgery. No single treatment modality was superior to another, and recurrence rates associated with all modalities were high. Treatment of genital warts should be guided by preferences of the patient, and a specific therapeutic regimen should be chosen with consideration of expense, efficacy, convenience, and potential for adverse effects.

Ribozyme-mediated in vitro cleavage of transcripts arising from the major transforming genes of human papillomavirus type 16.

Human papillomaviruses (HPV) have been strongly implicated as important cofactors in the development of several human malignancies, particularly anogenital carcinomas. Products arising from the E6 and E7 open reading frames (ORFs) from HPV-16, a type commonly associated with human cervical carcinoma, are essential for viral transformation. Unfortunately, a highly effective treatment for this infection is not available. To develop a novel treatment for this disease, ribozymes were designed to cleave all transcripts encoding HPV-16 E6 and E7 ORFs in proximity to their translational start sites ("AUG"). Cleavage sites for Rz110 and Rz558 occur immediately 3' to nucleotides 110 and 558 of the viral genomic DNA, respectively. Oligonucleotides corresponding to these ribozymes were synthesized and inserted into a eucaryotic viral vector derived from the nonpathogenic parvovirus, adeno-associated virus. Ribozyme transcription from this vector, termed CWRT7:SVN, is under control of both the highly active Rous sarcoma virus long terminal repeat and bacteriophage T7 promoters. T7 transcripts of the E6 and E7 ribozymes efficiently cleaved their cognate targets in vitro under a variety of conditions, including physiological temperature. These results may provide the basis for the development of a ribozyme-based, gene therapeutic treatment for HPV-associated diseases.

[Human papillomavirus infections in pregnancy]. / Infezioni da Human Papilloma Virus in gravidanza.

After an overview on the diffusion and transmission of the Human Papilloma Virus infection, the authors' attention is focused on clinical and therapeutic aspects of the disease. Following the most recent findings on congenital transmission, problems related to prophylaxis and therapy are discussed.

[Genital bacterial infections associated with papillomavirus: value of screening and basis for treatment]. / Infections bactériennes génitales associées aux papillomavirus: intérêt du dépistage et base du traitement.

Genital bacterial and viral infections may be responsible of couple infertility and may be potentially oncogenic for genital lesions. Genital bacterial infection is associated with human papillomavirus infection in as much as 48% for men and 64% for women. The bacterias most frequently found are intracellular species (29%) and Gram-negative bacilli (14%). Treatment with specific antibiotics can reduce the frequency of infertility in both men and women. This treatment can also prevent therapeutic complications during treatment for papillomavirus infection.

[Immunochemical therapy of warts and growths due to papillomavirus]. / La thérapie immuno-chimique des verrues et végétations dues au virus papillomateux.

A complex immuno-chemical treatment (immuno-stimulation, blockage of virus replication, interferon induction) was applied to 23 patients with warts and vegetations with various localisations. Results confirmed the treatment efficiency.

Genital warts--therapy.

The main goal of the therapy of human papillomavirus (HPV) infection is the management of the virus. There is no cure for HPV infections. The treatment goal for the female patient is to destroy lesions that are malignant or premalignant. The male patient is treated because he is a carrier of HPV who can infect previously uninfected women and possibly reinfect an already treated partner with a potentially oncogenic virus. Various treatment modalities are discussed.

Superficial laser vulvectomy. V. Surgical debulking is enhanced by adjuvant systemic interferon.

Skillful laser ablation can remove any volume of human papillomavirus-associated vulvar disease but cannot prevent reactivation of the surrounding latent viral reservoir during postoperative healing. Conversely, interferon and 5-fluorouracil are relatively ineffective as primary therapies in clearing bulky lesions. In this study of 71 assessable patients, topical 5-fluorouracil and systemic interferon injections were used postoperatively. Success rates within the adjuvant 5-fluorouracil and laser alone arms were essentially the same (9 of 18 vs 8 of 20). In contrast, outcome in the interferon group was significantly better than that for the other two arms combined (27 of 33 [82%] vs 17 of 38 [45%]; chi 2 10.31; p less than 0.002). Moreover, 18 of 21 failures (86%) in the first two arms and 3 of 6 failures (50%) in the interferon arm were "rescued" from the need for a second laser surgical procedure by crossover to either the 1 or 3 MIU interferon regimen. Results from this open-label, randomized clinical trial suggest that even a relatively low dose of recombinant interferon, used in combination with effective surgical debulking, can markedly reduce the risk of postoperative recurrence.

Office therapy for human papillomavirus infection in nongenital sites.

The many different treatment possibilities for the eradication of warts provide evidence that no single method that is completely effective has been found. Although the various methods described herein are usually successful therapies for warts, they are all associated with treatment failures and side effects. Until the perfect cure for warts is discovered, the physician must evaluate every wart carefully before deciding on a course of action.