Management of Merkel cell carcinoma of unknown primary origin: the Vienna Medical School experience.

Merkel cell carcinoma is a rare, but highly aggressive skin tumor. We describe our single-institution experience with the diagnosis and treatment of Merkel cell carcinoma of unknown primary (MCCUP). We conducted a retrospective medical chart review of patients treated with MCCUP at the Vienna General Hospital between 2002 and 2011. Clinicopathologic variables and outcomes were analyzed. Of the entire cohort of 57 patients, 8 patients (14%) were diagnosed with MCCUP. Three patients presented with parotid gland involvement, four patients with positive inguinal lymph nodes and one with axillar lymph nodes. CK20 staining was positive in all tumor specimens, whereas MCPyV protein was positive in four out of six patients. The primary surgical modality in five cases was wide local excision. In one patient excisional biopsy was followed by re-resection. In one case only excisional biopsy was performed due to metastatic disease at first diagnosis. Two patients underwent concomitant parotidectomy and neck dissection, and four patients received adjuvant radiation therapy. Median recurrence-free survival was 20 months. Four patients died, three of disease and one of other cause. Recurrent disease was observed in two patients and treated with radiotherapy and chemotherapy. The 1- and 3-year overall survival rates were 87.5 and 37.5%, respectively. The 1- and 3-year disease-specific survival rates were 87.5 and 62.5%, respectively. Our study shows a poor outcome in patients with MCCUP, particularly in patients with node involvement of the trunk. We therefore suggest an aggressive and multimodal treatment approach for patients with MCCUP.

Prognostic significance of lymph node ratio in patients with Merkel cell carcinoma.

Merkel cell carcinoma is a rare and aggressive metastasizing tumor of the skin. Lymph node metastasis is a significant clinical prognostic factor for overall and disease-free survival in patients with Merkel cell carcinoma. A retrospective medical chart review of 12 Merkel cell carcinoma patients was performed. All patients received treatment at the Medical University of Vienna and underwent lymph node dissection between 1994 and 2013. The lymph node ratio was determined by dividing the total number of positive lymph nodes by the entire number of dissected lymph nodes. A positive lymph node ratio was defined as a number >0 and the negative lymph node ratio was defined by zero. The median follow-up was 44 months (range 4-92). A positive lymph node ratio (range 1.00-0.04) was found in 7 (58%) out of 12 patients of whom 5 (71%) died of disease. A negative lymph node ratio was found in 5 (42%) out of 12 patients of whom 2 (40%) patients died of disease. The disease-specific death rate was higher in patients diagnosed with a positive lymph node ratio compared to patients diagnosed with a negative lymph node ratio. Based on these preliminary findings, there might be a prognostic impact of lymph node ratio in patients suffering from Merkel cell carcinoma.

Expression of Merkelcell polyomavirus (MCPyV) large T-antigen in Merkel cell carcinoma lymph node metastases predicts poor outcome.

BACKGROUND: The aim of this study was to determine the prevalence of MCPyV in Merkel cell carcinoma (MCC) primaries versus lymph node metastasis and to evaluate possible prognostic factors. METHODS: Samples of MCC primaries and lymph node metastases were stained immunohistochemically for the MCPyV large T-antigen and expression was compared to patients´ clinical outcome. RESULTS: 41 MCC patients were included. 33 (61%) out of 54 specimens were MCPyV-positive in the immunohistochemistry. 15 (47%) out of 32 primary tumors were positive compared to 18 (82%) out of 22 lymph node metastases. Eleven patients with positive polyomavirus expression died from the carcinoma compared to 4 patients without virus expression. Cox regression analysis showed worse disease-free survival in patients with MCPyV compared to virus-negative lymph nodes (p = 0.002). CONCLUSIONS: To our knowledge this is the first study to describe a negative prognostic effect of the MCPyV expression in lymph node metastasis in MCC patients.

Long-Term Effects of Severe Burn Injury on Bone Turnover and Microarchitecture.

Severe burn injury triggers massive alterations in stress hormone levels with a dose-dependent hypermetabolic status including increased bone resorption. This study evaluated bone microarchitecture measured by noninvasive high-resolution peripheral quantitative computed tomography (HR-pQCT). Changes of serum bone turnover markers (BTM) as well as regulators of bone signaling pathways involved in skeletal health were assessed. Standardized effect sizes as a quantitative measure regarding the impact of serum changes and the prediction of these changes on bone microarchitecture were investigated. In total, 32 male patients with a severe burn injury (median total body surface area [TBSA], 40.5%; median age 40.5 years) and 28 matched male controls (median age 38.3 years) over a period of 24 months were included. In patients who had sustained a thermal injury, trabecular and cortical bone microstructure showed a continuous decline, whereas cortical porosity (Ct.Po) and pore volume increased. Initially, elevated levels of BTM and C-reactive protein (CRP) continuously decreased over time but remained elevated. In contrast, levels of soluble receptor activator of NF-κB ligand (sRANKL) increased over time. Osteocalcin, bone-specific alkaline phosphatase (BALP), intact N-terminal type 1 procollagen propeptide (P1NP), and cross-linked C-telopeptide (CTX) acutely reflected the increase of Ct.Po at the radius (R2 = 0.41), followed by the reduction of trabecular thickness at the tibia (R2 = 0.28). In adult male patients, early and sustained changes of markers of bone resorption, formation and regulators of bone signaling pathways, prolonged inflammatory cytokine activities in conjunction with muscle catabolism, and vitamin D insufficiency were observed. These alterations are directly linked to a prolonged deterioration of bone microstructure. The probably increased risk of fragility fractures should be of clinical concern and subject to future interventional studies with bone-protective agents. © 2017 American Society for Bone and Mineral Research.

Merkel cell carcinoma: Overall survival after open biopsy versus wide local excision.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor of the skin with a dismal prognosis. METHODS: We conducted a retrospective medical chart review of patients with MCC who were initially diagnosed with an open biopsy (n = 30) or wide local excision (n = 24). RESULTS: Stages I, II, and III disease was found in 38%, 20%, and 16%, respectively. The 2-year and 5-year overall and disease-specific survival rates were 64.8% and 38.8% versus 45.2% and 26.4%, respectively. Cox regression multivariate model, including tissue sampling technique, re-resection, therapy modalities, pathological staging, and T and N classifications, showed that patients diagnosed initially with an open biopsy have significant worse overall (p = .014) and disease-free (p = .005) survival rates compared with patients who had a wide local excision. CONCLUSION: This study showed an improved overall survival in patients with MCC after wide local excision compared to open biopsy of the primary site at first diagnosis. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1014-E1018, 2016.

Early and Sustained Changes in Bone Metabolism After Severe Burn Injury.

CONTEXT: Severe burn injury causes a massive stress response, consecutively heightened serum levels of acute phase proteins, cortisol, and catecholamines with accompanying disturbance in calcium metabolism. OBJECTIVE: Evaluation of early and prolonged changes of serum bone turnover markers (BTMs) and regulators of bone metabolism. DESIGN: Longitudinal observational design. SETTING: University clinic. PATIENTS: A total of 32 male patients with a median age of 40.5 years and a median burned total body surface area of 40% (83% patients with full thickness burn injury). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Comparison of changes of BTM/regulators of bone metabolism in the early (d 2­7) and prolonged (d 7­56) phases after trauma. RESULTS: All investigated BTM/regulators significantly changed. During the early phase, pronounced increases were observed for serum type 1 collagen cross-linked C-telopeptide, intact N-terminal propeptide of type I procollagen, sclerostin, Dickkopf-1, bone-specific alkaline phosphatase, fibroblast growth factor 23, and intact parathyroid hormone levels, whereas 25-hydroxyvitamin D, albumin, serum, and ionized calcium levels decreased. Changes of osteoprotegerin, osteocalcin, and phosphate were less pronounced but remained significant. In the prolonged phase, changes of intact N-terminal propeptide of type I procollagen were most pronounced, followed by elevated sclerostin, osteocalcin, bone-specific alkaline phosphatase, and lesser changes for albumin levels. Calcium and ionized calcium levels tardily increased and remained within the limit of normal. In contrast, levels of intact parathyroid hormone, fibroblast growth factor 23, C-reactive protein, and to a lesser extent serum type 1 collagen cross-linked C-telopeptide and phosphate levels declined significantly during this phase of investigation. CONCLUSIONS: Ongoing changes of BTM and regulators of bone metabolism suggest alterations in bone metabolism with a likely adverse influence on bone quality and structure in male patients with severe burn injuries.

Predisposing factors for candidemia in patients with major burns.

BACKGROUND: Despite advances in surgery and critical care, candidemia remains a significant cause of morbidity and mortality in patients with extensive burns. METHODS: A retrospective single-center cohort study was performed on 174 patients admitted to the Burn Intensive Care Unit of the General Hospital of Vienna (2007-2013). An AIC based model selection procedure for logistic regression models was utilized to identify factors associated with the presence of candidemia. RESULTS: Twenty (11%) patients developed candidemia on median day 16 after ICU admission associated with an increased overall mortality (30% versus 10%). Statistical analysis identified the following factors associated with proven candidemia: younger age (years) odds ratio (OR):0.96, 95% confidence interval (95% CI):0.92-1.0, female gender (reference male) OR:5.03, 95% CI:1.25-24.9, gastrointestinal (GI) complications requiring surgery (reference no GI complication) OR:20.37, 95% CI:4.25-125.8, non-gastrointestinal thromboembolic complications (reference no thromboembolic complication) OR:17.3, 95% CI:2.57-170.4 and inhalation trauma (reference no inhalation trauma) OR:7.96, 95% CI:1.4-48.4. CONCLUSIONS: Above-mentioned patient groups are at considerably high risk for candidemia and might benefit from a prophylactic antifungal therapy. Younger age as associated risk factor is likely to be the result of the fact that older patients with a great extent of burn body surface have a lower chance of survival compared to younger patients with a comparable TBSA.

Non-occlusive mesenteric ischaemia: the prevalent cause of gastrointestinal infarction in patients with severe burn injuries.

BACKGROUND: Gastrointestinal complications occur frequently in intensive care patients with severe burns. Intestinal infarction and its deleterious consequences result in high mortality despite rapid surgical intervention. Our objective was to evaluate the aetiology of gastrointestinal infarction in intensive care patients with severe burns. STUDY DESIGN: We retrospectively evaluated all of the severe-burn victims at the burn unit of the Medical University of Vienna from 01/2002 to 06/2012 for whom a gastrointestinal infarction was diagnosed during their inpatient stay on computed-tomography, in the context of acute laparotomy, or upon autopsy by aetiology. RESULTS: After a severe thermal injury, 17 patients suffered a gastrointestinal infarction during their stay. In 82% of those patients, non-occlusive mesenteric ischaemia (NOMI) was identified as the cause of the gastrointestinal infarction. Patients with an embolic infarction tended to be older (78.0years embolism vs. 53.4 NOMI, mean, p<0.01), with a lower abbreviated burn severity index (8.7 embolism vs. 10.4 NOMI, mean, p<0.02) and a smaller total body surface area burned (20% embolism vs. 48% NOMI, mean, p<0.01) than those with a non-occlusive mesenterial ischaemia. No patients with an embolic infarction or any of the females in the entire gastrointestinal infarction group survived this event, resulting in a mortality rate of 100% for the embolic infarction group and female group. The decisive factor for surviving a NOMI was age (median age: male survivors 28years vs. nonsurvivors 66years (of this median, males=72years and females=60years), p<0.02). CONCLUSION: The results of our study clearly demonstrate that in severe-burn intensive care patients, non-occlusive mesenteric ischaemia is the most frequent cause of gastrointestinal infarction and that the decisive factor for survival is the patient's age.

Potential prognostic factors predicting secondary amputation in third-degree open lower limb fractures.

BACKGROUND: With regard to the improved surgical possibilities and the rising tendency of attempted limb salvage, the topic of secondary amputation becomes increasingly important. The aim of this study was to identify potential prognostic factors predicting secondary amputation in third-degree open lower limb fractures. METHODS: All patients experienced third-degree open fractures of the lower limb without primary amputation (1994-2012). Prognostic factors were investigated to explain the final outcome of these patients (limb salvage vs. secondary amputation). RESULTS: From a total of 408 open diaphyseal tibia fractures, 93 consecutive fractures were identified (Gustilo-Anderson [G/A] type IIIA, n = 38; G/A type IIIB, n = 41; G/A type IIIC, n = 14) including seven patients with primary amputation. Definite limb salvage was achieved in 72 patients (88%), whereas in 10 patients (12%), secondary amputation was necessary. The median time to secondary amputation was 12 days (range, 2-1,573 days). The median Injury Severity Score (ISS) was 11 (range, 9-41), and the median Mangled Extremity Severity Score (MESS) was 4 (range, 2-9). The MESS was significantly higher in the amputation group compared with the limb salvage group (p = 0.0001). Furthermore, statistical testing revealed that the amount of complex fractures (p = 0.0132), the soft tissue damage (p = 0.0050), the vascular injury rate (p = 0.0110) and the fasciotomy rate (p = 0.0468) were significantly higher in the amputation group. In 60%, the limitations for limb salvage were infectious complications and/or, in 40%, was irreversible vessel occlusion after initial vessel reconstruction. CONCLUSION: The current study findings indicate that MESS is highly prognostic, but considering the significant advances in reconstructive techniques, decision making in patients with an MESS of 7 or greater should be reevaluated for the everyday clinical use. LEVEL OF EVIDENCE: Prognostic study, level III. Therapeutic study, level IV.

Surgical treatment of GIST--an institutional experience of a high-volume center.

BACKGROUND: Discovery of the molecular pathogenesis of Gastrointestinal stromal tumors led to the development of targeted therapies, revolutionizing their treatment. However, surgery is still the mainstay of GIST therapy and the only chance for cure. AIM: Here we present a single institutional consecutive case series of 159 GIST-patients. METHODS AND PATIENTS: A total of 159 GIST-patients who underwent resection between 1994 and 2011 were reviewed for clinicopathohistological data, informations on surgical and medical therapy and further follow-up, outcome and survival data. RESULTS: Laparoscopic (25.2%) and open (71.1%) GIST surgery achieved complete resection rates of 97.5% and 85.2%, whereas 44.4% of incomplete and 6.6% of complete resected patients died from GIST. Compared to open surgery laparoscopy significantly reduced duration of operation (183.4 vs. 130.6 min), length of hospitalization (16.1 vs. 8.3 d) and morbidity (23% vs. 7.5%). Mean survival time was 3.7 ± 2.7 years (R0: 5.1 a and R1: 2.6 a) and the mean overall survival was 4.5 ± 3.8 years. CONCLUSION: Complete surgical resection is the primary goal and laparoscopy can be performed safely in a subset of GIST-patients with potential perioperative advantages. Although not proven by the present study the authors assume that multimodal GIST-treatment, as performed in reference-centers, is required for advanced or high risk disease. Our data suggest the potential for minimally invasive GIST resection to achieving comparable oncological outcomes as after open surgery while providing low morbidity rates.