Kai-Martin Thoms

Postoperative morbidity of lymph node excision for cutaneous melanoma-sentinel lymphonodectomy versus complete regional lymph node dissection.

For patients with melanoma metastasis to a sentinel lymph node, subsequent complete regional lymph node dissection (CLND) is currently regarded to be the surgical standard. This approach, however, has not been confirmed by controlled studies, so that surgical morbidity is of primary importance. Using clinical examination and a questionnaire, we determined morbidity in 315 patients with axillary or inguinal lymph node excision on whom 275 sentinel lymphonodectomies (SLNEs) and 90 CLNDs were performed. The overall incidence of at least one complication following SLNE was 13.8%. The short-term complication rate was 11.3% (allergic reaction to blue dye 0%, wound breakdown 0%, haematoma 2.5%, wound infection 3.6%, seroma 6.9%). The incidence of long-term complications was 4.1% (persistent tattoo 0.4%, functional deficit 0.4%, nerve dysfunction/pain 0.7% or swelling 2.5%). All complications were mild. Significantly, the complication rate was not higher for patients aged 70 years or older. After CLND, the overall complication rate was significantly higher (65.5%, P<0.000001). The incidence of short-term complications was 50% (haematoma 0%, wound breakdown 6.7%, wound infection 24.7% or seroma 34.8%). The incidence of long-term complications was also 50% (nerve dysfunction/pain 8.9%, functional deficit 16.8%, swelling 37.1%). Overall, inguinal lymph node excision was burdened by a higher complication rate (P=0.015). Age and sex did not influence postoperative morbidity. No deaths linked to either procedure were noted. Complication rates after SLNE are low and most complications are minor and short-lasting. In contrast, CLND has been demonstrated to be a major and potentially morbid surgical procedure. This highlights the importance of testing the therapeutic value that CLND adds to the sentinel lymph node procedure.

Sentinel lymph node status is the most important prognostic factor for thick (≥ 4 mm) melanomas

Background: The value of the status of the sentinel lymph node (SLN) in patients with thick melanomas (Breslow thickness ≥ 4 mm) is controversial.

Lessons learned from DNA repair defective syndromes

Abstract:  Genomic instability is the driving force behind cancer development. Human syndromes with DNA repair deficiencies comprise unique opportunities to study the clinical consequences of faulty genome maintenance leading to premature aging and premature cancer development. These syndromes include chromosomal breakage syndromes with defects in DNA damage signal transduction and double‐strand break repair, mismatch repair defective syndromes as well as nucleotide excision repair defective syndromes. The same genes that are severely affected in these model diseases may harbour more subtle variations in the ‘healthy’ normal population leading to genomic instability, cancer development, and accelerated aging at later stages of life. Thus, studying those syndromes and the molecular mechanisms behind can significantly contribute to our understanding of (skin) cancerogenesis as well as to the development of novel individualized preventive and therapeutic anticancer strategies. The establishment of centers of excellence for studying rare genetic model diseases may be helpful in this direction.

Skin cancer in organ transplant recipients: effects of immunosuppressive medications on DNA repair

Abstract:  UV‐induced skin cancers comprise a major problem in organ transplant recipients (OTRs). Cyclosporin A, a calcineurin inhibitor, is used as a standard immunosuppressant and clearly increases the skin cancer risk. Azathioprine does not appear to result in such an increase in skin cancer risk, and mTOR inhibitors are associated with an even lesser skin cancer risk. The underlying molecular mechanisms of these clinically important differences among immunosuppressants are still unclear and may relate to other than immunological effects. Insights may be gained by the multistep skin cancer theory and xeroderma pigmentosum, where defective nucleotide excision repair (NER) results in a cellular mutator phenotype and cutaneous carcinogenesis. This viewpoint assay summarizes current knowledge about the influence of the most commonly used immunosuppressive drugs in OTRs on DNA repair. Calcineurin inhibition results in a 200‐fold increased skin cancer risk compared with the normal population and inhibits NER. The skin cancer risk under azathioprine is threefold less compared with calcineurin inhibitors, which may relate to inhibition of only the last step of NER, i.e. gap filling. mTOR inhibitors do not reduce NER in the global genome and can inhibit the growth of already initiated tumors, which may account for the markedly reduced skin cancer risk compared with calcineurin inhibitors. We conclude that OTRs may benefit from treatment regimens other than calcineurin inhibitors and speculate that a targeted modulation of calcineurin‐dependent signalling may prevent UV‐induced tumor formation by enhancing NER not only in OTRs but also in the general population, at least in part.

Factors Predicting the Risk of In-Transit Recurrence After Sentinel Lymphonodectomy in Patients With Cutaneous Malignant Melanoma

BackgroundIn-transit metastasis is an important morbidity factor after sentinel lymphonodectomy (SLNE). So far, factors posing an increased risk after SLNE have not been adequately analyzed.MethodsUsing Kaplan-Meier estimations and the Cox proportional hazards model, we analyzed the risk of developing in-transit metastases after SLNE for 328 consecutive patients (median tumor thickness, 2.0 mm; median follow-up period, 40 months).ResultsThe 5-year probability of developing in-transit metastases as a first recurrence was 11.2%. After negative and positive SLNE, the probabilities were 6.3% and 24%, respectively. Patients in whom satellite metastases were excised concurrently with the primary tumor had a probability of recurrence with in-transit metastases of 41%. In sentinel lymph node (SLN)-negative patients with primary tumors having a thickness of more than 4 mm, the probability was 22.1%. Among the group of SLN-positive patients, significantly increased in-transit probabilities were observed in those with primary tumors that were thicker than 4 mm (41.8%), with tumors located on the distal extremities (42.1%), and with penetration of the nodal metastasis of >1 mm into the SLN (36%) and in patients with capsular breakthrough (63.3%). By using multifactorial analysis, the SLN status (P = .005), Breslow thickness (P = .0009), and extremity location of the primary melanoma (P = .005) significantly predicted the risk of in-transit recurrence. Satellite metastasis (P < .089), Clark level, and ulceration did not reach significance.ConclusionsSubgroups of patients can be identified who seem to have an increased risk of developing in-transit metastases as a first recurrence after SLNE. Individualized therapeutic strategies should be developed for these patients.

Cyclosporin A, but not everolimus, inhibits DNA repair mediated by calcineurin: implications for tumorigenesis under immunosuppression

Abstract:  Unlike other immunosuppressive drugs including everolimus, cyclosporin A causes a dramatic increase of UV‐induced skin cancer, a feature that is reminiscent of xeroderma pigmentosum (XP), where defective nucleotide excision repair (NER) of UV‐induced DNA damage results in cutaneous carcinogenesis. The molecular basis of the clinically important differential activities of cyclosporin A and everolimus is still unclear. We measured post‐UV cell survival of cyclosporin A‐ and everolimus‐treated human fibroblasts and lymphoblasts using a cell proliferation assay (MTT). The cellular NER capacity was assessed by host cell reactivation. Using an ELISA and specific antibodies, cyclobutane pyrimidine and pyrimidine‐6,4‐pyrimidone photoproduct removal from the cellular genome was measured. The effect of calcineurin on NER was investigated using a calcineurin A expression vector and specific RNAi. Cyclosporin A led to a dose dependent decrease in post‐UV cell survival, inhibited NER and blocked photoproduct removal. In contrast, none of these effects where seen in everolimus‐treated cells. Overexpression of calcineurin A resulted in increased NER and complemented the Cyclosporin A‐induced reduction of NER. Downregulation of calcineurin using RNAi inhibited NER comparable to cyclosporin A‐treatment. We conclude that cyclosporin A, but not everolimus, leads to an increased skin cancer risk via a calcineurin signalling‐dependent impairment of NER.

No association between three xeroderma pigmentosum group C and one group G gene polymorphisms and risk of cutaneous melanoma

Xeroderma pigmentosum (XP) patients exhibit a 1000-fold increased risk for developing skin cancers including malignant melanoma. We investigated the role of three variant alleles of the DNA repair gene XPC and one variant allele of the XPG gene in a hospital-based case–control study of 294 Caucasian patients from Germany with malignant melanoma and 375 healthy control individuals from the same area matched by sex. The polymorphisms G1580A (XPC exon 8; Arg492His), T1601C (XPC exon 8; Val499Ala), G2166A (XPC exon 10; Arg687Arg), and C3507G (XPG exon 15; Asp1104His) were not in linkage disequilibrium. The allele frequencies (cases: controls) were for 1580A 6.29%: 5.63%, for 1601C 79.08%: 78.28%, for 2166A 26.19%: 28.13%, and for 3507G 79.86%: 78.61%. We found no association of the homozygous 1580A, 1601C, 2166A, and 3507G genotypes with increased risks of melanoma: OR 1.254 (95% CI: 0.486–3.217), OR 1.108 (95% CI: 0.629–1.960), OR 0.817 (95% CI: 0.490–1.358), and OR 1.168 (95% CI: 0.670–2.044), respectively. Exploratory analyses of subgroups of melanoma patients compared to all controls indicated no association of these genotypes with increased risks for development of multiple primary melanomas (n=28), a negative family history for melanoma (n=277), melanomas in individuals with a low number of nevi (n=273), melanomas in individuals older than 55 years (n=142), and melanomas thicker than 1 mm (n=126).

Age as a key factor influencing metastasizing patterns and disease-specific survival after sentinel lymph node biopsy for cutaneous melanoma.

In our study, we investigated the impact of the constitutional factor age on the clinical courses of melanoma patients with sentinel lymph node (SLN) biopsy. Descriptive statistics, Kaplan‐Meier estimates, logistic regression analysis and the Cox proportional hazards model were used to study a population of 2,268 consecutive patients from three German melanoma centers. Younger age was significantly related to less advanced primary tumors. Nevertheless, patients younger than 40 years of age had a twofold risk of being SLN‐positive (p < 0.000001). Of the young patients with primary melanomas with a thickness of 0.76 mm to 1.0 mm, 19.7% were SLN‐positive. Using multivariate analysis, younger age, increasing Breslow thickness, ulceration and male sex were significantly related to a higher probability of SLN‐metastasis. During follow‐up, older patients displayed a significantly increased risk of in‐transit recurrences (p = 0.000002) and lymph node recurrences (p = 0.0004). With respect to melanoma specific overall survival the patients age was highly significant in the multivariate analysis. The unfavorable effect of being older was significant in the subgroups with positive and negative SLNs. Age remained also significant for the survival after the onset of distant metastases (p = 0.002). In conclusion, the patients age is a strong and independent predictor of melanoma‐specific survival in patients with localized melanomas, in patients with positive SLNs and after the onset of distant metastases. Younger patients have a better prognosis despite their higher probability of SLN metastasis. Older patients are less frequently SLN‐positive but have a higher risk of loco‐regional recurrence.

The immunosuppressive drugs cyclosporin A and tacrolimus inhibit membrane depolarization-induced CREB transcriptional activity at the coactivator level

1 Cyclosporin A and tacrolimus are clinically important immunosuppressive drugs directly targeting the transcription factor nuclear factor of activated T cells (NFAT). Through inhibition of calcineurin phosphatase activity they block the dephosphorylation and thus activation of NFAT. Cyclosporin A and tacrolimus also inhibit other calcineurin‐dependent transcription factors including the ubiquitously expressed cAMP response element‐binding protein (CREB). Membrane depolarization by phosphorylating CREB on Ser119 leads to the recruitment of its coactivator CREB‐binding protein (CBP) that stimulates initiation of transcription. 2 It was unknown at what step in CREB‐mediated transcription cyclosporin A and tacrolimus interfere. 3 In transient transfection experiments, using GAL4‐CREB fusion proteins and a pancreatic islet β‐cell line, cyclosporin A inhibited depolarization‐induced activation of CREB proteins which carried various deletions or mutations throughout their sequence providing no evidence for the existence of a distinct CREB domain conferring cyclosporin A sensitivity. In a mammalian two‐hybrid assay, cyclosporin A did not inhibit Ser119‐dependent interaction of CREB with its coactivator CBP. 4 Using GAL4‐CBP fusion proteins, cyclosporin A inhibited depolarization‐induced CBP activity, with cyclosporin A‐sensitive domains mapped to both the N‐ (aa 1–451) and C‐terminal (aa 2040–2305) ends of CBP. The depolarization‐induced transcriptional activity of the CBP C‐terminus was enhanced by overexpression of calcineurin and was inhibited by cyclosporin A and tacrolimus in a concentration‐dependent manner with IC50 values (10 and 1 nM, respectively) consistent with their known IC50 values for inhibition of calcineurin. 5 These data suggest that, in contrast to NFAT, cyclosporin A and tacrolimus inhibit CREB transcriptional activity at the coactivator level.

Lymph node ultrasound during melanoma follow-up significantly improves metastasis detection compared with clinical examination alone: a study on 433 patients.

Early detection of melanoma metastases is essential for effective treatment and may be crucial for the prevention of systemic metastases and patient survival. However, data demonstrating the reliability and accuracy of ultrasound examination for the detection of lymph node metastases, in addition to clinical examination, are rare. We have examined 433 melanoma patients with stage-dependent follow-up intervals of 3 to 12 months. One thousand three hundred and thirty-two paired clinical and nonblinded sonographic tests of the locoregional lymph node areas were performed. Lesions suspicious of melanoma metastases were examined histopathologically. Of note, sensitivity [0.9394 (95% confidence interval: 0.7977–0.9926)] and specificity [0.9808 (95% confidence interval: 0.9717–0.9875)] of combined clinical and sonographic investigations were significantly (P<0.0001) higher than clinical results alone. Significant differences between clinical follow-up and sonographically assisted follow-up were found for American Joint Committee on Cancer 2002 melanoma stages I (P=0.0389), III (P=0.0101), and IV (P=0.0016). For stage II melanoma, a trend was detected (P=0.0821). Lymph node metastases were detected sonographically in 1.73% of clinically metastasis-free investigations (n=22). Our data suggest that high-frequency sonography should be part of all melanoma follow-up investigations, independent of melanoma type, melanoma stage, or lymph node biopsy status.