Ilkka Koskivuo

Serum matrix metalloproteinase-8 is associated with ulceration and vascular invasion of malignant melanoma.

Serological markers of malignant melanoma have failed to provide prognostic significance in patients who are tumour-free after surgery. Immune response regulation is important regarding progression and therapeutic interventions of malignant melanoma. Matrix metalloproteinase (MMP)-8 is one of the collagenases involved in the regulation of tissue remodelling and immune response, being incompletely studied in melanoma as yet. We assessed whether serum MMP-8 is of prognostic value in malignant melanoma. We studied serum samples of 117 patients, of which 63 were stage I, 13 stage II, 12 stage III and 29 stage IV. The mean serum MMP-8 levels (47.5 ng/ml) did not significantly correlate with patient or tumour characteristics, that is, patient sex, age, tumour Clarks or Breslows classification, sentinel lymph node status or to survival. Importantly, high serum MMP-8 levels were significantly related to presence of vascular invasion (P=0.001) in primary tumour, tumour ulceration (P=0.003) and tumour bleeding (P=0.033). Tendency to increased serum MMP-8 levels in patients with coronary heart disease or type II diabetes mellitus was detected. These data imply that high serum MMP-8 level is associated with earlier recognized histopathology markers of melanoma progression. Results also suggest that elevated serum MMP-8 might be related to haematogenous spreading of melanoma through vascular invasion.

Whole body positron emission tomography in follow-up of high risk melanoma

The aim of this study was to determine the clinical impact of whole body positron emission tomography (FDG PET) to detect clinically silent metastases in the follow-up of patients with high risk melanoma. FDG PET was performed to 30 asymptomatic melanoma patients (AJCC stage IIB–IIIC) 7–24 months after the primary surgery and sentinel node biopsy. FDG PET was able to detect six of seven recurrences, constituting 20% of all study patients. One patient presented with a negative FDG PET finding at the very first scanning, but was positive later in a repeated scan after manifestation of palpable mass in the axilla. The positive PET finding had an impact on treatment decisions in every case: three patients underwent surgical resection and four patients received chemotherapy or interferon. The mean follow-up time was 27 months (range, 12–48 months) and during that time the other 23 patients with true negative FDG PET were disease-free. One of the seven recurrences was in remission after surgical metastasectomy. In conclusion, whole body FDG PET is a valuable follow-up tool in high risk melanoma to diagnose recurrences and to select the patients, who are suitable for surgical metastasectomy.

Physical discomfort due to redundant skin in post-bariatric surgery patients

Massive weight loss after bariatric surgery leads to excess skin with functional and aesthetic impairments. The aim of this study was to evaluate the prevalence of excess skin after bariatric surgery and identify any relationship with pre- and postoperative characteristics. A total of 360 patients who had undergone bariatric surgery procedures were asked to complete a questionnaire designed by the surgical team at least 1 year after surgery. This questionnaire was planned to estimate any impairment due to redundant skin, which was graded according to a visual analogue scale (VAS, 0--0). Mean (standard deviation, SD) age of 110 males and 250 females was 51.2 (10.8) years. Mean preoperative body mass index (BMI) was 45.7 (6.4) kg m(-2) and mean postoperative BMI at follow-up was 33.6 (6.0) kg m(-2). After a mean follow-up of 56.1 (43.6) months, the mean weight loss was 35.2 (18.8) kg. Most patients (92.8%) reported problems with redundant skin, especially on the abdomen, upper arms and rear/buttocks, which impaired daily physical activity in half of them. Excess skin was associated with female gender (β=-13.56, 95% confidence interval (CI) -16.81 to -10.32, p<0.0001), weight loss (β=0.21, 95% CI 0.12-0.29, p<0.0001) and ΔBMI (β=0.21, 95% CI 0.12-0.29, p<0.0001) at multivariate analysis. Patients with a ΔBMI>20 kg m(-2) showed a significantly surplus skin discomfort compared to ΔBMI≤5 and 550 kg showed a significantly redundant skin discomfort compared to weight loss<20 kg (p<0.001). Weight loss after bariatric surgery reduces the medical risks of obesity but psychosocial and functional problems often remain due to the surplus skin. Our data suggest that a ΔBMI≤10 kg m(-2) and weight loss>20 kg, not BMI alone, might be taken into consideration as cut-off values for developing score systems with the intention to apply evidence-based indications for the surgical management of post-bariatric impairments.

Effectiveness of local anaesthetic pain catheters for abdominal donor site analgesia in patients undergoing free lower abdominal flap breast reconstruction: A meta-analysis of comparative studies.

Abstract The use of an infusion pain pump with local wound catheters has increased among different surgical specialities. Autologous breast reconstruction with deep inferior epigastric perforator (DIEP) and transverse rectus abdominis myocutaneous (TRAM) flaps may cause severe abdominal donor site morbidity, and infusion devices delivering local anaesthetic are suggested to improve postoperative analgesia. This study performed a meta-analysis comparing pain pump use vs control to evaluate this issue. A systematic literature search was performed. Primary outcome was the amount of opioid use. Secondary outcomes were the amount of antiemetic drugs and the length of hospital stay. Five studies involving 248 patients were retrieved and included in the present analysis. A significantly decreased use of opioids was observed after using pain pump vs control (MD = −15.13, 95% CI = −24.20, −6.06, p = 0.001). Although not statistically significant, the pooled results showed a trend toward reduction of antiemetic medicament use (MD = −0.71, 95% CI = −2.14, 0.72, p = 0.33) and hospital stay time (MD = −0.53, 95% CI = −1.18, 0.11, p = 0.10). The use of local anaesthetic pain catheters for abdominal donor sites in microsurgical breast reconstruction might be associated with a decreased use of narcotics and antiemetic medicaments and shorter hospital stay. Further studies are needed to validate this promising treatment modality.

Head and neck cutaneous melanoma: A retrospective observational study on 146 patients

Background. Sentinel node biopsy (SNB) is a novel staging technique in cutaneous melanoma, but it is more challenging in the head and neck (H&N) than in the trunk and extremities. The aim of this study was to investigate the utility of SNB in patients with clinical stage I-II H&N cutaneous melanoma, with emphasis on disease outcome. Patients and methods. Twenty five patients with H&N melanoma of >1.0 mm in Breslow depth underwent SNB and were compared to 121 historic H&N melanoma patients, who had either undergone routine prophylactic neck dissection or had been observed without any invasive nodal staging. Results. Sixteen percent of the SNB patients were sentinel-positive and there have been no false-negative cases. In the Kaplan-Meier analysis, there were no significant differences between the study groups in melanoma-specific overall survival. Among the entire cohort, melanoma-specific overall survival rate was 67.1% at 5 years and 61.9% at 10 years. Predictive factors for worsen survival were nodal micrometastases, male sex, scalp location, thick primary lesion and ulceration. Discussion. SNB is a reliable and mini-invasive approach for the nodal staging of H&N cutaneous melanoma. Traditional neck dissection is recommended only for therapeutic purposes in clinically node-positive or sentinel-positive patients.

Previous pregnancy is a favourable prognostic factor in women with localised cutaneous melanoma

Abstract Background. The influence of pregnancy on survival in melanoma has been a controversial issue. Objective. In this retrospective study we investigated whether pregnancy (overall or temporally melanoma-related) has any effect on melanoma progression or patient outcome. Methods. Patient data were collected from Turku University Hospital records concerning all women in fertile age (15–45 years) and diagnosed with melanoma between January 1, 1990 and December 31, 2009. We collected data on melanoma characteristics, treatment, pregnancies and patient outcomes. Results. Of the 334 patients, 248 (74%) had been pregnant in some point during their life while 55 (17%) were nulliparous. The history of pregnancies could not be verified in 31 women (9%). Progression of melanoma to advanced stage was found in 58 (17%) of these women. Altogether, 35 women (14%) with at least one pregnancy had disease progression in contrast to 14 women (26%) with no pregnancies (p =0.049). Women with at least one pregnancy had a 94% probability to survive from melanoma compared to nulliparous women of whom only 83% survived (p =0.041). In Multivariate (COX) analysis pregnancy was a favourable factor for disease-specific survival (DSS) (HR 3.75; 95% CI 1.24–11.34; p =0.019) when adjusted for age (HR 1.064; 95% CI 1.00–1.13; p =0.50), localisation and stage (p =0.040), and Breslow (HR 1.32; 95% CI 1.10–1.58; p =0.002). However, when ulceration of the primary tumour was included in the multivariate model, Breslow remained as the only independent predictor of DSS (HR 1.58; 95% CI 1.34–1.86; p =0.0001) and pregnancy was dropped from the stepwise backward model in the step preceding the last one (p =0.081). Conclusion. Pregnancy is not a risk factor for disease recurrence or progression in melanoma patients, but instead can exert some favourable influence on prognosis.

FMNL2/FMNL3 formins are linked with oncogenic pathways and predict melanoma outcome

While most early (stage I‐II) melanomas are cured by surgery, recurrence is not uncommon. Prognostication by current clinicopathological parameters does not provide sufficient means for identifying patients who are at risk of developing metastases and in need of adjuvant therapy. Actin‐regulating formins may account for invasive properties of cancer cells, including melanoma. Here, we studied formin‐like protein 2 and 3 (FMNL2 and FMNL3) in melanoma by analysing their role in the invasive properties of melanoma cells and by evaluating whether FMNL2 expression is associated with melanoma outcome. Immunohistochemical characterization of FMNL2 in a cohort of 175 primary cutaneous stage I‐II melanomas indicated that high FMNL2 reactivity correlates with poor outcome as evaluated by recurrence free survival (p < 0.0001) or disease specific survival (p < 0.0001). In multivariate analysis, Breslows thickness (p < 0.05) and FMNL2 expression (p < 0.001) remained as independent prognostic factors. Cellular studies revealed that FMNL2 is a component of filopodia in many melanoma cell lines. Inhibition of either FMNL2 or the closely related FMNL3 affected the maintenance of melanoma cell morphology and reduced migration. Finally, inhibition of the BRAF, PI3K and MAPK oncogenic pathways markedly reduced expression of both FMNL2 and FMNL3 in melanoma cells. The results suggest a major role for FMNL2/FMNL3 formins in melanoma biology and raise the possibility that the novel targeted melanoma drugs may interfere with the cellular properties regulated by these formins.

Circulating levels of VEGFR-1 and VEGFR-2 in patients with metastatic melanoma treated with chemoimmunotherapy alone or combined with bevacizumab.

There are no identified biomarkers that could predict response to antiangiogenic or traditional chemoimmunotherapy in metastatic melanoma. We hypothesized that soluble angiogenic factor receptors might help us to identify patients responsive to treatment. A series of 48 patients with stage IV melanoma participating in two phase II clinical trials were included. The trials included treatment with carboplatin, vinorelbine, and subcutaneous interleukin-2 (n=22) or treatment with bevacizumab, dacarbazine, and low-dose interferon-&agr;2a (n=26).Serum samples were prospectively collected and soluble vascular endothelial growth factor receptor 1 (s-VEGFR-1) and 2 (s-VEGFR-2) were measured before starting the trial treatment and during response evaluation.There was a trend toward longer overall survival among patients with higher-than-median serum VEGFR-1 levels (21.3 months) compared with 12.3 months in patients with low pretreatment s-VEGFR-1 levels (P=0.146). Pretreatment s-VEGFR-2 levels did not correlate to survival. Serum VEGFR-2 levels decreased during therapy in 44% of the patients and increased in 56% of the patients. VEGFR-2 increased in 78% (14 of 18) of the patients who progressed during therapy (P=0.017). VEGFR-2 decrease was associated with clinical benefit in 65% of the patients (11 of 17) and with progression in only four patients (P=0.016).High pretreatment levels of s-VEGFR-1 are associated with improved prognosis among patients with metastatic melanoma independently on therapy, whereas increased VEGFR-2 levels during therapy are associated with disease progression. These markers might be useful in selecting patients responsive to antiangiogenic therapy.

Human Metaplastic Breast Carcinoma and Decorin

Metaplastic breast carcinoma (MBC) is a rare subtype of invasive breast cancer and has poor prognosis. In general, cancers are heterogeneous cellular masses comprised of different cell types and their extracellular matrix (ECM). However, little is known about the composition of the ECM and its constituents in MBC. Decorin is a ubiquitous ECM macromolecule known of its oncosuppressive activity. As such, it provides an intriguing molecule in the development of novel therapeutics for different malignancies such as MBC. In this study, decorin immunoreactivity and the effect of adenoviral decorin cDNA (Ad-DCN) transduction were examined in MBC. Multiple immunohistochemical stainings were used to characterize a massive breast tumour derived from an old woman. Furthermore, three-dimensional (3D) explant cultures derived from the tumour were transduced with Ad-DCN to study the effect of the transduction on the explants. The MBC tumour was shown to be completely negative for decorin immunoreactivity demonstrating that the malignant cells were not able to synthesize decorin. Ad-DCN transduction resulted in a markedly altered cytological phenotype of MBC explants by decreasing the amount of atypical cells and by inhibiting cell proliferation. The results of this study support approaches to develop new, decorin-based adjuvant therapies for MBC.

The Efficiency of Sclerotherapy in the Treatment of Vascular Malformations: A Retrospective Study of 63 Patients

Background and Aims. Vascular malformations are a vast group of congenital malformations that are present at birth. These malformations can cause pain, pressure, and cosmetic annoyance as well as downturn growth and development in a child in the case of high flow. Sclerotherapy has become an important tool in the treatment of vascular malformations. However, little is known about the success rate of sclerotherapy. Material and Methods. In this study, the efficiency of sclerotherapy in the treatment of vascular anomalies was investigated retrospectively in 63 patients treated in Turku University Hospital between 2003 and 2013. Results. Out of the 63 patients investigated, 83% (53) had venous malformations (VMs) and 9% (5) were defined as having arteriovenous malformations (AVMs). Patients with a VM were operated on, in 14% (8) out of all VM cases. Hence 86% (45) of patients with a VM received adequate help to their symptoms solely from sclerotherapy. The duration of treatment for the 14% of the VM patients that needed a surgical procedure was prolonged by 7–9 months, that is, by 41%. Conclusions. Sclerotherapy is an effective method in the treatment of VMs with a satisfactory clinical response in patients symptoms in 84% of cases.