Fertility preservation and management of pregnancy in melanoma patients requiring systemic therapy.

Melanoma is one of the most common cancers in adolescents and adults at fertile age, especially in women. With novel and more effective systemic therapies that began to profoundly change the dismal outcome of melanoma by prolonging overall survival, the wish for fertility preservation or even parenthood has to be considered for a growing portion of melanoma patients-from the patients' as well as from the physicians' perspective. The dual blockade of the mitogen-activated protein kinase pathway by B-Raf proto-oncogene serine/threonine kinase and mitogen-activated protein kinase inhibitors and the immune checkpoint inhibition by anti-programmed cell death protein 1 and anti-cytotoxic T-lymphocyte-associated protein-4 monoclonal antibodies constitute the current standard systemic approaches to combat locally advanced or metastatic melanoma. Here, the preclinical data and clinical evidence of these systemic therapies are reviewed in terms of their potential gonadotoxicity, teratogenicity, embryotoxicity and fetotoxicity. Recommendations for routine fertility and contraception counseling of melanoma patients at fertile age are provided in line with interdisciplinary recommendations for the diagnostic work-up of these patients and for fertility-protective measures. Differentiated recommendations for the systemic therapy in both the adjuvant and the advanced, metastatic treatment situation are given. In addition, the challenges of pregnancy during systemic melanoma therapy are discussed.

[Decision criteria and patient characteristics for patient-oriented treatment of field cancerization : Standardized algorithm for personalized treatment concepts]. / Entscheidungskriterien und Patientencharakteristika zur patientenorientierten Therapie der Feldkanzerisierung : Ein standardisierter Bewertungsalgorithmus für individuelle Behandlungskonzepte.

BACKGROUND: Actinic keratosis (AK), which frequently affects larger skin areas (field cancerization), is characterized by chronic course. Weighing therapy-specific advantages and disadvantages of field-oriented therapy for individual patients is challenging. OBJECTIVES: The main objective was the development of patient-oriented decision criteria for the pragmatic classification of field-directed AK treatment options in patients with a predisposition for field cancerization (patient types 1-3). MATERIALS AND METHODS: The development of the decision criteria and patient typology was based on a nominal respectively structured multilevel group process. The developed algorithm was then subsequently applied for the systematic evaluation of field-directed AK therapies. RESULTS: Patient-relevant criteria for the treatment decision included (among others): effectiveness, selectivity, safety, duration of therapy, cosmesis, patient preference and comorbidities. With regard to the decision criteria and patient types in which field therapy was the treatment of choice, daylight photodynamic therapy notably met the requirement profile. CONCLUSION: The definition of patient-relevant and therapy-related decision criteria in AK field therapy allows a systematic yet practice-oriented approach to classify specific treatment options and to derive individual treatment decisions.

The volume of postoperative drainage fluid as a potential early predictor of lymphedema after lymph node excision for metastatic melanoma.

Lymphedema (LE) following lymph node dissection is a major problem for cancer patients, and radiation therapy, extended surgery, groin dissection, obesity, and older age are well-established risk factors of LE. We studied whether these risk factors are further associated with high volumes of postoperative drainage fluid after complete lymph node dissection (CLND) for melanoma metastases. Moreover, we examined whether a high amount of drainage fluid after sentinel lymph node biopsy (SLNB) can predict a high amount of drainage fluid after subsequent CLND. Using descriptive statistics and regression analyses, we analyzed the cumulative volumes of postoperative drainage fluid for 836 melanoma patients with lymph node excision in the axilla or groin. In multiple regression analyses, the well-established risk factors of LE, i.e., increased body mass index, older age, and ilioinguinal versus inguinal versus axillary dissection predicted a high drainage volume after CLND. Of note, a high drainage fluid volume after SLNB also predicted a high drainage volume after subsequent CLND. In patients with groin dissections, who are particularly susceptible to swelling, extended iliac dissection, age above 60, and a cumulative drainage volume of more than 100 ml in the preceding SLNB were predictors of the cumulative drainage volume. We find that common risk factors predict the volume of postoperative drainage fluid after CLND and postoperative LE. Further, high postoperative drainage volume may therefore function as a potential early predictor of LE following CLND.

Nd:YAG and pulsed dye laser therapy in infantile haemangiomas: a retrospective analysis of 271 treated haemangiomas in 149 children.

BACKGROUND: Infantile haemangiomas (IH) are common benign tumours in infancy. Most IH resolve spontaneously, but some require treatment due to ulceration, functional impairment or cosmetic disfiguration. While systemic propranolol is effective in many cases, laser therapy may be a safe topical alternative. OBJECTIVE: To assess the efficacy of combined Nd:YAG/pulsed dye laser (PDL) or PDL alone for therapy of IH. PATIENTS AND METHODS: A total of 271 IH in 149 infants were treated with combined Nd:YAG/PDL or PDL alone. Based on photographs before and 4-6 weeks after the last treatment, the results were evaluated independently by three physicians. Remissions were categorized as 0-25% (I), 26-50% (II), 51-75% (III) and 76-100% (IV). RESULTS: In total, 472 laser treatments were performed. In 137 of 149 infants (91.9%) laser therapy was performed during a short sevoflurane mask anaesthesia, while 12 of 149 infants (8.1%) received topical anaesthetic gel. Combined Nd:YAG/PDL was applied in 187 of 271 IH (69.0%), while PDL alone in 84 of 271 IH (31.0%). On average, 1.74 treatments per IH were necessary (Nd:YAG/PDL: 1.95, PDL: 1.26). Moderate or strong (III/IV) improvement was observed in 92.4% of all IH treated. No serious adverse effects were observed. CONCLUSION: Combined Nd:YAG/PDL therapy is an effective and well-tolerated local treatment option for IH of any classification, in any phase of development and at any age. With regard to the systemic use of propranolol, combined Nd:YAG/PDL therapy seems a safe and promising alternative in many cases.

Distal and proximal interleukin (IL)-10 promoter polymorphisms associated with risk of cutaneous melanoma development: a case--control study.

Inherited promoter polymorphisms of the interleukin (IL)-10 gene resulting in altered IL-10 production may contribute to a genetic susceptibility for melanoma. We investigated the role of a haplotype from distal as well as proximal polymorphic sites [-7400InDel, -6752AT (rs6676671), -3538AT (rs1800890), -1087AG (rs1800896), -597AC (rs1800872)] of the IL-10 5'-flanking region in a hospital-based case-control study of 165 Caucasian patients with cutaneous melanoma from Germany in comparison with 162 healthy cancer-free Caucasian control participants from the same area matched by age. Using multivariate analysis for the number of nevi and skin type, the IL-10 'higher producing' haplotype ITAGC was found to be significantly associated with a reduced risk of developing melanoma (adjusted P=0.02). Although our findings need to be confirmed by independent and larger multicenter studies, we have described for the first time the association of distal gene variants of the IL-10 gene as an independent risk factor for melanoma.

Large speckled lentiginous naevus superimposed with Spitz naevi: sequential digital dermoscopy may lead to unnecessary excisions triggered by dynamic changes.

We report a 14-year-old girl with a large speckled lentiginous naevus (SLN) on her left arm and shoulder. As the occurrence of melanoma within SLN has been described previously, long-term follow-up of atypical lesions by digital dermoscopy was started at the age of 4 years. To date, nine Spitz naevi and four dysplastic compound naevi have been excised due to dynamic changes over time. No melanoma has so far been detected. We critically discuss the possibility of an 'overtreatment' because of a high rate of physiological changes within SLN of children. In conclusion, we would like to encourage a close follow-up of large SLN whenever complete excision is not an option. In order to avoid unnecessary excisions triggered by subtle dynamic changes, a standard approach with overview images, conventional dermoscopy and early excision of lesions that are rated as suspicious for melanoma by established algorithms may be recommended.

Functional DNA repair system analysis in haematopoietic progenitor cells using host cell reactivation.

Deficiencies in individual DNA repair systems are involved in both de novo and therapy-related acute myeloid leukaemia (t-AML), as indicated by genetic markers involving nucleotide excision repair (NER gene polymorphisms), double-strand-break (DSB) or mismatch repair (microsatellite instability (MSI)). We modified a host cell reactivation (HCR) assay for functional DNA repair system analysis of living primary haematopoietic cells; 2 x 10(5) normal peripheral blood lymphocytes (PBLs) and cord blood CD34+ progenitor cells were cryopreserved, thawed and transfected with 75-250 ng luciferase reporter plasmid (pCMVLuc) using DEAE-dextran (0.1 mg/mL) in a transfection volume of 250 microL. We obtained luciferase activities of approximately 300-fold above background in CD34+ progenitor cells and approximately 2000-fold in PBLs, thus rendering these cells applicable for DNA repair analysis. We then evaluated the NER (UV-irradiated pCMVLuc) and DSB repair capacity (linearized pCMVLuc) of normal lymphocytes and several leukaemic cell lineages. Kasumi-1 and HL-60 AML cells exhibited a reduced NER capacity compared to normal GM03715 lymphocytes, PBLs and CD34+ progenitor cells (6.2 +/- 0.9%, 6.5 +/- 0.9% vs. 12.3 +/- 1.8%, 13.5 +/- 0.7% and 13.5 +/- 2.0%, respectively). Kasumi-1 AML tells exhibited a reduced DSB repair capacity compared to AG10107 and GM03715 normal lymphocytes as well as CEM acute T-cell lymphoblastic leukaemia cells (6.4 +/- 0.8% vs. 10.8 +/- 0.7%, 27.3 +/- 1.1% and 20.5 +/- 1.6%, respectively). The modified HCR assay can be used for functional DNA repair analysis in living cells of patients with pre- and post-leukaemic conditions as well as in leukaemic blasts to elucidate the role of DNA repair in de novo and t-AML leukaemogenesis and to determine the individual susceptibility to t-AML prior to chemotherapy.

Sentinel lymphonodectomy does not increase the risk of loco-regional cutaneous metastases of malignant melanomas.

With regard to malignant melanoma, the impact of lymph node surgery on the development of loco-regional cutaneous metastases (LCM) has not yet been adequately addressed. However, this aspect is of interest, since sentinel lymphonodectomy (SLNE) has been suspected of causing LCM by inducing entrapment of melanoma cells. We analysed 244 patients with SLNE and compared the data with 199 patients treated with delayed lymph node dissection (DLND) for clinically palpable metastases. Analysis of both groups commenced at the time of excision of the primary tumour, using the Kaplan-Meier method. LCM that appeared as a first recurrence, as well as the overall probability of developing LCM, were recorded. For sentinel-negative patients with a primary melanoma >1mm thick, the 5-year probability of developing LCM as a first recurrence was 6.9 +/- 0.02% (+/-standard error of the mean (SEM)). The probability was 17.6 +/- 0.03% in the DLND group. Comparing the two node-positive subgroups, the probability of developing LCM as a first recurrence was significantly higher in patients with positive SLNE (27.3 +/- 0.05%, P = 0.03). However, the 5-year overall probability of developing LCM did not differ significantly in the node-positive groups (33.3% in the DLND group vs. 33.7% in patients with positive sentinel lymph nodes (SLNs)). Since early excision of lymphatic metastases by SLNE avoids nodal recurrences, thereby prolonging the recurrence-free interval, the chance of LCM to manifest as a first recurrence should inevitably increase. However, the overall in-transit probability is not increased after SLNE.