The analysis of the outcomes and factors related to iliac-obturator involvement in cutaneous melanoma patients after lymph node dissection due to positive sentinel lymph node biopsy or clinically detected inguinal metastases.

BACKGROUND: We assessed clinical-pathological features and outcomes of cutaneous melanoma patients after ilio-inguinal lymph node dissection (LND) in relation to the presence of metastases in iliac-obturator nodes. METHODS: We analyzed 390 consecutive patients who underwent ilio-inguinal therapeutic LND [TLND] (237) due to clinical/cytologically detected metastases or after completion LND [CLND] (153) due to positive SLN biopsy (in one cancer centre 1994-2009). Median follow-up time was 60 months. RESULTS: The 5-year overall survival (OS) rate was 49% and median OS - 52 months in the entire group of patients. According to univariate analysis following factors had significant negative influence on OS: presence of metastases to iliac-obturator nodes (5-year OS for positive versus negative: 54.5% and 32%, respectively), macrometastases, higher Breslow thickness, ulceration, higher Clark level, male gender, number of metastatic lymph nodes, extracapsular extension, and, additionally in the CLND group - micrometastases size ≥ 0.1 mm according to the Rotterdam criteria and non-subcapsular location of micrometastases. Iliac-obturator involvement was also negative factor for OS in multivariate analysis. The presence of iliac-obturator nodal metastases correlated with the following factors: type of LND-CLND versus TLND (15% versus 27.5%) of iliac-obturator involvement, respectively), higher Breslow thickness, extracapsular extension of nodal metastases, male gender. We have not identified any metastases in iliac-obturator nodes in group of patients with micrometastases size ≤1.0 mm and primary tumour Breslow thickness <4.0 mm or no ulcerated primary tumours. CONCLUSIONS: Metastases to iliac-obturator nodes have additional negative prognostic value for melanoma patients with inguinal basin involvement. We are able to identify the subgroup of patients after positive SLN biopsy without metastases to iliac-obturator nodes, probably requiring only inguinal LND.

Validation of the Joensuu risk criteria for primary resectable gastrointestinal stromal tumour - the impact of tumour rupture on patient outcomes.

BACKGROUND: Approval of imatinib for adjuvant treatment of gastrointestinal stromal tumours (GIST) raised discussion about accuracy of prognostic factors in GIST and the clinical significance of the available risk stratification criteria. METHODS: We studied the influence of a new modification of the NIH Consensus Criteria (the Joensuu risk criteria), NCCN-AFIP criteria, and several clinicopathological factors, including tumour rupture, on relapse-free survival (RFS) in a prospectively collected tumour registry series consisting of 640 consecutive patients with primary, resectable, CD117-immunopositive GIST. The median follow-up time after tumour resection was 39 months. None of the patients received adjuvant imatinib. RESULTS: The median RFS time after surgery was 50 months. In univariable analyses, high Joensuu risk group, tumour mitotic count >5/50 HPF, size >5 cm, non-gastric location, tumour rupture (7% of cases; P = 0.0014) and male gender had adverse influence on RFS. In a multivariable analysis mitotic count >5/50HPF, tumour size >5 cm and non-gastric location were independent adverse prognostic factors. Forty, 151, 86 and 348 patients were assigned according to the Joensuu criteria to very low, low, intermediate and high risk groups and had 5-year RFS of 94%, 94%, 86% and 29%, respectively. CONCLUSION: The Joensuu criteria, which include 4 prognostic factors (tumour size, site, mitotic count and rupture) and 3 categories for the mitotic count, were found to be a reliable tool for assessing prognosis of operable GIST. The Joensuu criteria identified particularly well high risk patients, who are likely the proper candidates for adjuvant therapy.

Diagnostic yield and safety of endoscopic ultrasound-guided trucut [corrected] biopsy in patients with gastric submucosal tumors: a prospective study.

BACKGROUND AND STUDY AIMS: Endoscopic-ultrasound-guided trucut needle biopsy (EUS-TCB) has not been adequately evaluated in patients with submucosal tumors (SMTs). PATIENTS AND METHODS: This prospective, uncontrolled study involving 49 consecutive patients with hypoechoic gastric SMTs (> or = 20 mm) evaluated diagnostic yield and 30-day morbidity of EUS-TCB, factors related to the success of EUS-TCB, and agreement between EUS-TCB and the surgical pathology diagnosis. Seventy-three percent of tumors were gastrointestinal stromal tumors (GIST). RESULTS: Tumor tissue adequate for diagnosis was obtained by EUS-TCB in 31 patients (63 %; 95 %CI 49 % to 75 %). In the remaining cases, EUS-TCB provided no tissue (n = 11) or an insufficient amount (n = 7). Logistic regression analysis showed that tumor location on the lesser curvature of the stomach was the only independent predictor of obtaining diagnostic material [odds ratio (OR) 7.4; 95 %CI 1.9 to 28; P = 0.004]. The experience of the endosonographer, the size of the tumor, and the location of the tumor relative to the long axis of the stomach were not related to the success of the biopsy. Agreement between EUS-TCB and surgical pathology specimens in respect of the diagnosis and CD117 status was high (0.9, standard error 0.31; and 0.95, standard error 0.16, respectively); however, there was no correlation between the mitotic index as determined on EUS-TCB and that determined on the surgical pathology specimen (correlation coefficient, 0.08). There were two severe septic complications in 52 procedures (3.9 %; 95 %CI 0.3 % to 14 %). CONCLUSIONS: The diagnostic yield of EUS-TCB in patients with gastric SMTs was moderate. Tissue samples were too small to reliably determine the mitotic index. Antibiotic prophylaxis should be considered because of possible septic complications.

Molecular and biochemical testing in stage III melanoma: multimarker reverse transcriptase-polymerase chain reaction assay of lymph fluid after lymph node dissection and preoperative serum lactate dehydrogenase level.

BACKGROUND: There is a need for biomarkers to identify patients at risk for disease progression after resection of melanoma regional lymph node metastasis. OBJECTIVES: This study assessed the prognostic value of multimarker reverse transcriptase-polymerase chain reaction (RT-PCR) assay in lymphatic drainage (LY) after lymph node dissection (LND) and of preoperative serum lactate dehydrogenase (LDH) levels in American Joint Committee on Cancer (AJCC) stage III melanoma patients. METHODS: We collected 24-h LY from 255 stage III melanoma patients after radical LND [114, completion LND after positive sentinel node biopsy (CLND); 141, therapeutic LND for clinically/cytologically detected regional nodal metastases (TLND)]. For detection of melanoma cells, RT-PCR assays with primers specific for tyrosinase, MART1 (MelanA) and uMAGE mRNA were conducted. The LY sample was deemed positive if at least one marker was detected. In 244 patients, the preoperative serum LDH level was available. Median follow-up time was 25 months (range 5-60). RESULTS: The LY multimarker RT-PCR assay results were positive in 82 of 255 patients (32%). A significantly higher rate of melanoma recurrence was observed in patients with positive LY multimarker RT-PCR results (P = 0.01). Significant relationships were observed between positive LY multimarker RT-PCR results and shorter 3-year overall survival (OS) and disease-free survival (DFS), both in univariate and multivariate analyses (P = 0.007). Preoperative serum LDH level was increased in 79 of 244 patients (32%) [40.5% in TLND group and 23.0% in CLND group (P = 0.003)]. There were significant differences in OS between patients with normal and high preoperative LDH levels (P = 0.007), and these differences were seen mainly in patients in the TLND group. CONCLUSIONS: The multimarker RT-PCR assay detected melanoma cells in approximately 32% of LY after LND, which correlated significantly with early melanoma recurrence and shorter survival. Increased pre-LND serum LDH level had an additional negative impact on OS of melanoma patients with palpable nodal metastases after TLND.

In transit/local recurrences in melanoma patients after sentinel node biopsy and therapeutic lymph node dissection.

This study has analyzed the incidence of in transit/local recurrences (IT/LR) in melanoma patients after sentinel node (SLN) biopsy; completion lymph node dissection (CLND) that was performed due to positive node; and therapeutic LND (TLND) due to clinically detected node metastases and factors influencing IT/LR. Between May 1995 and May 2004, 1187 consecutive patients underwent SLN biopsy (median Breslow thickness 2.5 mm) and 224 of them had subsequent CLND. During the same time period, 306 patients had TLND (median Breslow 3.9 mm). The excision margin of primaries was > or =1cm. At median follow-up time of 37.5 months, we analyzed the incidence of IT/LR as the first site of relapse and clinicopathological parameters affecting these recurrences. In SLN-negative cases, IT/LR as the site of the first recurrence were rare (46/963; 4.8%) and; in SLN+/-CLND IT/LR were detected in 45/224 cases (20.1%). IT/LR in SLNB group correlated with presence of SLN metastases (P<0.0001), higher Breslow thickness (P<0.001) and lower extremity localization (P=0.03). In TLND group, IT/LR were observed in 52/306 patients (17%), which is similar to all CLND patients (P=0.3), but less common when analyzing only patients who relapsed (TLND: 52/209 (24.9%) vs. CLND: 45/121 (37.2%); P=0.02). Estimated 3-year overall survival (from the date of relapse) in IT/LR only patients was better than in other types of relapses after LND (29% vs. 8%; P<0.0001). IT/LR incidence in the entire group of SLN+/-CLND patients was similar to that observed in TLND patients and it was affected by presence of nodal metastases, Breslow thickness and lower extremity location.

The clinical characteristics and the role of surgery and imatinib treatment in patients with liver metastases from c-Kit positive gastrointestinal stromal tumors (GIST).

The purpose of this study was to analyze the clinical features of the group of c-KIT positive GIST patients with liver metastases evaluated and treated in two referral institutions as well as to attempt to define the role of surgery in the management of GIST given the emergence to imatinib as an important part of treatment strategy in GIST patients. Between August 2001 and December 2002, 90 patients with c-KIT positive GIST were referred to our institutions. In 50 patients metastatic disease were disclosed. Of these, 35 patients (35/50; 70%) were rendered to have liver metastases and therefore offered imatinib or surgical therapy depend on CT assessment. The median follow-up of these 35 patients calculated from the time of first operation was 23 months (range 3-246 months). Male patients comprised the majority of patients (70%) with liver metastases. In 14 patients (40%) the metastases were confined only to the liver, in the others 21 patients (60%) the liver metastases were accompanied by intraperitoneal dissemination (17; 48.6%) or local recurrences (4; 11.4%). The period of time between the diagnosis of primary lesion and occurring liver metastases ranged from 0 to 164 months (median time of liver metastases presentation was 16 months for patients undergone primary curative surgery). The liver metastases were estimated as resectable in 3 cases (8.6%) and hepatic resection of all gross lesions was possible. Group of 32 patients with unresectable liver involvement was considered to treatment with imatinib. The median time of imatinib treatment for survivors is 7.5 months (range: 3.5-18.5 months). Twelve patients (37.5%) demonstrated partial response (PR) and 16 patients (50%) stable disease (SD) according to RECIST criteria. We did not observe any complete response (CR). At median follow-up 7 months, 32 of 35 patients (91.4%) were alive, 3 patients (8.6%)remained free of disease and 28 patients (87.5%) remained on imatinib treatment and have maintained disease although with partial response or stabilization only. Radical surgical resection remains the only possibility of cure for GIST patients because the complete response after imatinib therapy is restricted to a few patients only. However, despite the advanced metastatic disease, approximately 90% of patients are alive and continue imatinib treatment with median follow-up time more than 7 months. Surgery in combination with adjuvant imatinib treatment may result in improved survival with patients with advanced GIST.

Lymph node status and survival in cutaneous malignant melanoma--sentinel lymph node biopsy impact.

AIM: The survival benefit of sentinel lymph node biopsy (SLB) with lymphadenectomy for microscopic melanoma metastases to regional lymph nodes (SLND) is uncertain. The aim of the study was to analyse the factors influencing clinical outcome (overall survival (OS) and disease free survival (DFS)) of patients undergone lymph node dissection (LND) as result of positive sentinel lymph node disease (SLND) or as consequence of clinically detected metastases (CLND). PATIENTS AND METHODS: This was a single-institution retrospective analysis of survival data of 350 consecutive, prospectively collected, melanoma patients who underwent radical LND in 1995-2001. One hundred and forty-five patients underwent SLND and 205 underwent CLND. RESULTS: The median OS and DFS times of the entire group of melanoma patients, computed from the date of primary lesion excision, were 46.3 months and 26.5 months (5-year OS ratio 41.8% and 5-year DFS ratio 31.5%). The factors which correlated with poor OS by multivariate analysis were: primary tumour Breslow thickness >4 mm (p=0.001), extracapsular extension of lymph node metastases (p=0.004), male sex (p=0.001) and metastases to more than one regional lymph node (p=0.04). The negative factors for DFS were: nodal extracapsular invasion (p=0.00002) and primary tumour Breslow thickness >4 mm (p=0.004). There were no significant differences in OS and DFS between SLND and CLND groups, when calculated from the date of primary tumour excision. However, if OS and DFS were estimated from the date of LND, the SLND group demonstrated significantly better survival in comparison with CLND. CONCLUSION: The study demonstrates no survival benefit from SLB with subsequent radical regional LND in malignant melanoma patients with lymph node metastases.

Detection of circulating melanoma cells in peripheral blood by a two-marker RT-PCR assay.

The aim of this study was to develop a highly sensitive two-marker assay for the detection of circulating melanoma cells in patients' blood using a reverse transcriptase-polymerase chain reaction (RT-PCR). We analysed the usefulness of two different sets of markers: tyrosinase and MUC-18 (TYR/MUC-18), and tyrosinase and MART 1 (TYR/MART 1). Total cellular RNA was isolated from 337 blood samples from 80 melanoma patients at different stages of the disease. All patients had undergone primary surgery. Assay sensitivity and specificity were confirmed using three different melanoma cell lines and two different fibroblast lines. In addition, blood from 47 healthy subjects and 10 patients with non-melanoma cancer was used as a negative control. We found that two-marker analysis is more accurate than the single tyrosinase assay. The frequency of melanoma cell detection in patients' blood was about 10% higher when the TYR/MART 1 two-marker assay was used. Using this assay we did not find any statistical correlation between the molecular markers and the UICC stage of disease or the Breslow thickness or Clark level of the primary melanoma. The frequency of melanoma cell detection with the TYR/MUC-18 two-marker assay was even higher than the TYR/MART 1 assay, but unfortunately the MUC-18 transcript was also present in about 20% of healthy subjects. Therefore we do not recommend the use of MUC-18 as a standard value marker.