Impact of macrophages on tumor growth characteristics in a murine ocular tumor model.

Tumor associated macrophages (TAM), mean vascular density (MVD), PAS positive extravascular matrix patterns, and advanced patients' age are associated with a poor prognosis in uveal melanoma. These correlations may be influenced by M2 macrophages and their cytokine expression pattern. Thus, the effect of TAM and their characteristic cytokines on histologic tumor growth characteristics were studied under the influence of age. Ninety five CX3CR1(+/GFP) mice (young 8-12weeks, old 10-12months) received an intravitreal injection of 1 × 10(5) HCmel12 melanoma cells. Subgroups were either systemically macrophage-depleted by Clodronate liposomes (n = 23) or received melanoma cells, which were pre-incubated with the supernatant of M1- or M2-polarized macrophages (n = 26). Eyes were processed histologically/immunohistochemically (n = 75), or for flow cytometry (n = 20) to analyze tumor size, mean vascular density (MVD), extravascular matrix patterns, extracellular matrix (ECM) and the presence/polarization of TAM. Prognostically significant extravascular matrix patterns (parallels with cross-linkings, loops, networks) were found more frequently in tumors of untreated old compared to tumors of untreated young mice (p = 0.024); as well as in tumors of untreated mice compared to tumors of macrophage-depleted mice (p = 0.014). Independent from age, M2-conditioned tumors showed more TAM (p = 0.001), increased collagen IV levels (p = 0.024) and a higher MVD (p = 0.02) than M1-conditioned tumors. Flow cytometry revealed a larger proportion of M2-macrophages in old than in young mice. The results indicate that TAM and their cytokines appear to be responsible for a more aggressive tumor phenotype. Tumor favoring and pro-angiogenic effects can be directly attributed to a M2-dominated tumor microenvironment rather than to age-dependent factors alone. However, an aged immunoprofile with an increased number of M2-macrophages may provide a tumor-favoring basis. Further, old mice represent a more suitable tumor model instead of young mice since their histologic tumor pattern better resembles human tumors.

Impact of Chemotherapy on Retroperitoneal Lymph Nodes in Ovarian Cancer.

BACKGROUND: Complete cytoreduction is the most important prognostic factor in ovarian cancer. However, there exist conflicting data on whether the removal of microscopic tumor metastasis in macroscopically unsuspicious retroperitoneal lymph nodes is beneficial. PATIENTS AND METHODS: Ovarian cancer tissues and tissues from lymph node metastasis of 30 patients with FIGO IIIC or IV disease undergoing neoadjuvant chemotherapy (NACT) were obtained and assessed using a validated regression score. Histopathological markers, size of largest tumor focus, and overall score were evaluated in lymph node and ovarian tissue. Regression and known prognostic factors were analyzed for influence on survival. RESULTS: No difference in the overall score between lymph nodes and ovarian tissue was shown, however, single parameters such as fibrosis and pattern of tumor infiltration, were significantly different. CONCLUSION: The pattern of tumor regression in lymph nodes and ovarian tissue are of prognostic value. Lymph node dissection even of unsuspicious nodes should, therefore, be performed.

HIPEC ROC I: a phase I study of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion followed by postoperative intravenous platinum-based chemotherapy in patients with platinum-sensitive recurrent epithelial ovarian cancer.

This phase I study tested the safety, feasibility, pharmacokinetics and pharmacodynamics of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion (HIPEC) in patients with platinum-sensitive recurrent epithelial ovarian cancer (EOC) undergoing secondary cytoreductive surgery followed by postoperative platinum-based intravenous chemotherapy. Twelve patients with operable, recurrent platinum-sensitive EOC (recurrence ≥6 months after first-line therapy) were included according to the classical 3+3 dose-escalation design at three dose levels-60, 80 and 100 mg/m(2). After surgical cytoreduction, a single dose of cisplatin was administered via HIPEC for 90 min at 41-43°C. Postoperatively, all patients were treated with standard intravenous platinum-based combination chemotherapy. One of six patients experienced a dose-limiting toxicity (grade 3 renal toxicity) at a dose of 100 mg/m(2). The remaining five patients treated with 100 mg/m(2) tolerated their treatment well. The recommended phase II dose was established at 100 mg/m(2). The mean peritoneal-to-plasma AUC ratio was 19·5 at the highest dose level. Cisplatin-induced DNA adducts were confirmed in tumor samples. Common postoperative grade 1-3 toxicities included fatigue, postoperative pain, nausea, and surgical site infection. The ability to administer standard intravenous platinum-based chemotherapy after HIPEC was uncompromised. Cisplatin administered as HIPEC at a dose of 100 mg/m(2) has an acceptable safety profile in selected patients undergoing secondary cytoreductive surgery for platinum-sensitive recurrent EOC. Favorable pharmacokinetic and pharmacodynamic properties of HIPEC with cisplatin were confirmed at all dose levels, especially at 100 mg/m(2). The results are encouraging to determine the efficacy of HIPEC as a complementary treatment in patients with EOC.

Real-time tissue elastography as promising diagnostic tool for diagnosis of lymph node metastases in patients with malignant melanoma: a prospective single-center experience.

BACKGROUND: Real-time tissue elastography is a new, noninvasive method in ultrasonography, differentiating tissues according to their stiffness. Earlier studies have highlighted this technique as a useful diagnostic tool for the detection of noncutaneous malignancies like breast, prostate and thyroid cancer based on the principle that tumor cells present a higher stiffness compared to the adjacent normal tissue. OBJECTIVE: The purpose of our study was to investigate the value of real-time tissue elastography for the differentiation of benign and metastatic peripheral lymph nodes (LN) in patients with cutaneous melanoma by comparing this technique with conventional B-mode sonography combined with power Doppler sonography (PDS). METHODS: In this prospective study, 36 melanoma patients (23 females and 13 males, mean age 62.7 ± 11.1 years) undergoing LN excision at the Department of Dermatology and Allergy, University of Bonn, were included between July 2011 and July 2012. Real-time tissue elastography was planned prior to surgery and histopathological examination. Elasticity images had been qualitatively scored for the proportion of stiff areas from pattern 1-5 (soft to stiff) on the basis of a newly defined system for LNs. RESULTS: A total of 42 LNs have been removed in 36 patients. Of these 42 LNs, 21 carried melanoma cells and 21 were benign LNs. Significant differences in elastographic patterns were found between metastatic and nonmetastatic LNs. In real-time tissue elastography, 19 (90.5%) of 21 metastatic LNs showed a pattern of 3, 4 or 5. Of all benign LNs, 76.2% had a pattern of 1 or 2 in their elastogram. Sensitivity and specificity of B-mode sonography combined with PDS were 80.9 and 76.2%, respectively, 90.5 and 76.2% for elastography and 95.2 and 76.2% for the combined evaluation. CONCLUSION: An elastography pattern ≥3 was identified as an independent significant factor, predicting a metastatic LN involvement. The combination of elastography with conventional B-mode sonography has the potential to further improve the differentiation between benign and metastatic peripheral LNs in melanoma patients.

Role of high-resolution ultrasound and PET/CT imaging for preoperative characterization of sentinel lymph nodes in cutaneous melanoma.

The purpose of our study was the comparison of high-resolution ultrasound (HRUS) and positron emission tomography combined with computerised tomography (PET/CT) in the preoperative characterization and identification of subclinical nodal metastases focusing on sentinel lymph nodes (SLN) in melanoma patients. Patients with cutaneous melanoma (CM) who received sentinel lymph node biopsy at the Department of Dermatology and Allergy, University of Bonn, between January 2009 and January 2011 had been evaluated with a retrospective computer-aided search concerning preoperative staging procedures. A combination of PET/CT and HRUS had been performed preoperatively in 20 of 123 patients. A total of 59 SLNs had been removed in those 20 patients followed by histopathologic examination. HRUS correctly identified two of 17 positive SLNs whereas PET/CT imaging identified none. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of HRUS were 11.8 % (95 % confidence interval [CI] = 3.3-34.3), 100 % (95 % CI = 91.6-100.0), 100.0 % (95 % CI = 34.2-100.0), and 73.7 % (95 % CI = 61.0-83.3), respectively. On the basis of this limited study cohort, HRUS had a better value than PET/CT in preoperative identification of positive SLNs, suggesting a possible diagnostic superiority of HRUS in general characterization of peripheral nodal disease in CM.

Sentinel lymph node status as most important prognostic factor in patients with high-risk cutaneous melanomas (tumour thickness >4.00 mm): outcome analysis from a single institution.

PURPOSE: Sentinel lymph node biopsy (SLNB) is considered the most powerful prognostic indicator of survival in patients with cutaneous melanoma of intermediate thickness (1-4 mm). The use of SLNB in patients with melanoma with a tumour thickness >4.0 mm is still controversial. The purpose of the current study was to determine the prognostic value of SLNB in patients with thick cutaneous melanomas (tumour thickness >4.0 mm) in terms of progression-free survival (PFS) and overall survival (OS). METHODS: A retrospective single-centre study was performed at the Department of Dermatology and Allergy, University of Bonn, and the Department of Nuclear Medicine, University of Bonn, based on data collected between September 2000 and January 2010. A total of 142 patients with cutaneous melanoma of thickness >4.00 mm were identified, and 63 of these patients underwent SLNB. RESULTS: Of the 63 patients in whom SLNB was performed, 25 (39.7 %) had a positive SLN. Ulceration was more frequent in SLN-positive patients (44 %) than in SLN-negative patients (18.4 %). The mean follow-up time for the 63 patients was 50.7 months. Positive SLN status predicted a significantly reduced life expectancy in the analyses of PFS and OS. In SLN-positive patients 5-year OS was 76 % and in SLN-negative patients was 84.2 % (p = 0.048). Patients with a combination of ulcerated tumour and positive SLN had the worst prognosis. CONCLUSION: On the basis of our follow-up data, SLNB has to be recommended in patients with a tumour thickness >4.00 mm after exclusion of lymph node macrometastases or distant metastases. SLN status is the most significant prognostic factor in this group of patients.

Influence of sporting activity and smoking on peripheral lymph nodes in patients with melanoma analyzed by high-resolution ultrasound.

BACKGROUND: The sonographic examination of peripheral lymph nodes (LNs) plays an important role in the preoperative treatment and in the follow-up of patients with melanoma. OBJECTIVE: A prospective study including 200 consecutive patients with a history of invasive cutaneous melanoma was performed at the Department of Dermatology and Allergy, University of Bonn, Germany, to examine the influence of sporting activity, physical workload, interferon alfa therapy, smoking habits, and infections of the upper respiratory tract on morphology and number of LNs analyzed by high-resolution ultrasound. METHODS: Between May 2010 and June 2011, 106 men and 94 women (mean age 51.1 ± 12.8 years) were included in this study. During their follow-up visits for cutaneous melanoma, high-resolution ultrasound examination of cervical, axillary, and inguinal LN regions were performed. LN diameters and volumes were measured and correlated with the above given factors. RESULTS: Sports-active patients had more LNs in inguinal regions, a higher volume and a larger LN diameter, and a higher maximum width of the hypoechoic LN margin in comparison with the nonactive patients. Patients with a hard physical workload in their occupations had a significantly higher volume of the biggest LN. Compared with nonsmoking patients smokers presented higher values in the total quantity of the LNs, in the greatest volume of LN, and in the greatest diameter of LN in the cervical regions. The other factors had no significant influence on the LN parameters. LIMITATIONS: Our study population was too small to comment on influencing factors in more detail especially the influences of different sporting activities or smoking habits. CONCLUSION: Sporting activity, physical workload, and smoking habits as associated cofactors influencing sonomorphologic aspects in patients with cutaneous melanoma should always be considered.

Assessment of tumor thickness in melanocytic skin lesions: comparison of optical coherence tomography, 20-MHz ultrasound and histopathology.

BACKGROUND: Accurate assessment of vertical tumor size is important for surgical treatment planning of melanocytic skin lesions. High-frequency ultrasound (HFUS) is frequently used for this purpose, but overestimation of tumor thickness is known as a problem especially in thin melanocytic lesions. Optical coherence tomography (OCT) as a new imaging technique might be a promising alternative. OBJECTIVE: To evaluate the ability of OCT to accurately determine the vertical tumor thickness of melanocytic skin lesions and to compare it with HFUS and histopathology in order to improve surgical planning. METHODS: In this single-center study, 26 melanocytic lesions were imaged by OCT and HFUS. Vertical lesion dimensions of both methods were compared with histopathological measurements. RESULTS: Bland-Altman plots for OCT and histopathology as well as for HFUS and histopathology revealed better agreement for OCT and histopathology concerning tumor thickness measurements. Tumor thickness values for the melanocytic lesions measured by OCT presented a median tumor thickness of 0.31 mm (range 0.10-0.77) compared to a median tumor thickness of 0.25 mm (range 0.06-1.5) measured by histopathology. The median tumor thickness of HFUS was 0.44 mm (range 0.23-1.1). A Spearman correlation procedure including the correlation coefficient (r) showed a stronger relationship between OCT and histopathology (r = 0.734) compared to HFUS and histopathology (r = 0.390). CONCLUSIONS: On the basis of this smaller study cohort, OCT seems to be more exact than HFUS as far as thickness determination of thin melanocytic skin lesions is concerned.

Perioperative management and outcome of general and abdominal surgery in hemophiliacs.

BACKGROUND: The aim of the current study was to investigate perioperative management and outcome of surgery in hemophiliacs. METHODS: Fifty-five hemophiliacs underwent surgery (appendectomy, cholecystectomy, inguinal hernia repair, hemorrhoidectomy). Surgical procedures in hemophiliacs and matched pairs were analyzed for duration of surgery, drainages, hospital stay, factor use (VIII, IX), and complications. Factor substitution was analyzed. Mann-Whitney U and Kruskal-Wallis tests were used (P < .05). RESULTS: No significant differences were found for duration of drains and operation time in hemophiliacs versus matched pairs. Significance for duration of hospital stay compared with controls was found in hemophiliacs for appendectomy, inguinal hernia repair, and hemorrhoidectomy but not for cholecystectomy. In both groups, complications were low without significant differences. CONCLUSIONS: This study found no significant differences in perioperative data and postoperative outcome in hemophiliacs compared with nonhemophiliacs due to the excellent perioperative interdisciplinary management at our Hemophilia Center with prolonged hospital stay in hemophiliacs.