T-cell bispecific antibodies in node-positive breast cancer: novel therapeutic avenue for MHC class I loss variants.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) represent a prognostic factor for survival in primary breast cancer (BC). Nonetheless, neoepitope load and TILs cytolytic activity are modest in BC, compromising the efficacy of immune-activating antibodies, which do not yet compete against immunogenic chemotherapy. PATIENTS AND METHODS: We analyzed by functional flow cytometry the immune dynamics of primary and metastatic axillary nodes [metastatic lymph nodes (mLN)] in early BC (EBC) after exposure to T-cell bispecific antibodies (TCB) bridging CD3ε and human epidermal growth factor receptor 2 (HER2) or Carcinoembryonic Antigen-Related Cell Adhesion Molecule 5 (CEACAM5), before and after chemotherapy. Human leukocyte antigen (HLA) class I loss was assessed by whole exome sequencing and immunohistochemistry. One hundred primary BC, 64 surrounding 'healthy tissue' and 24 mLN-related parameters were analyzed. RESULTS: HLA loss of heterozygosity was observed in EBC, at a clonal and subclonal level and was associated with regulatory T cells and T-cell immunoglobulin and mucin-domain-3 expression restraining the immuno-stimulatory effects of neoadjuvant chemotherapy. TCB bridging CD3ε and HER2 or CEACAM5 could bypass major histocompatibility complex (MHC) class I loss, partially rescuing T-cell functions in mLN. CONCLUSION: TCB should be developed in BC to circumvent low MHC/peptide complexes.

Development and validation of a nomogram to predict recurrence and melanoma-specific mortality in patients with negative sentinel lymph nodes.

BACKGROUND: Patients with melanoma and negative sentinel nodes (SNs) have varying outcomes, dependent on several prognostic factors. Considering all these factors in a prediction model might aid in identifying patients who could benefit from a personalized treatment strategy. The objective was to construct and validate a nomogram for recurrence and melanoma-specific mortality (MSM) in patients with melanoma and negative SNs. METHODS: A total of 3220 patients with negative SNs were identified from a cohort of 4124 patients from four EORTC Melanoma Group centres who underwent sentinel lymph node biopsy. Prognostic factors for recurrence and MSM were studied with Cox regression analysis. Significant factors were incorporated in the models. Performance was assessed by discrimination (c-index) and calibration in cross-validation across the four centres. A nomogram was developed for graphical presentation. RESULTS: There were 3180 eligible patients. The final prediction model for recurrence and the calibrated model for MSM included three independent prognostic factors: ulceration, anatomical location and Breslow thickness. The c-index was 0·74 for recurrence and 0·76 for the calibrated MSM model. Cross-validation across the four centres showed reasonable model performance. A nomogram was developed based on these models. One-third of the patients had a 5-year recurrence probability of 8·2 per cent or less, and one-third had a recurrence probability of 23·0 per cent or more. CONCLUSION: A nomogram for predicting recurrence and MSM in patients with melanoma and negative SNs was constructed and validated. It could provide personalized estimates useful for tailoring surveillance strategies (reduce or increase intensity), and selection of patients for adjuvant therapy or clinical trials.

Long-term results of ultrasound guided fine needle aspiration cytology in conjunction with sentinel node biopsy support step-wise approach in melanoma.

BACKGROUND: US-FNAC is a common diagnostic tool in the work-up of many cancers. Results in melanoma were initially poor (sensitivity 20-40%). Introduction of the Berlin Morphology criteria has shown potential improvement up to 65-80% in selected patients. AIM: This cohort study evaluates the long-term survival outcome of melanoma patients undergoing Ultrasound (US) guided Fine Needle Aspiration Cytology (FNAC) prior to sentinel node biopsy (SNB) or direct lymphadenectomy. METHODS: Between 2001 and 2010 over 1000 consecutive melanoma patients prospectively underwent targeted US-FNAC prior to SNB. The Berlin US morphology criteria: peripheral perfusion (PP), loss of central echoes (LCE) and balloon shape (BS) were registered. FNAC was performed if any factor was present. All patients underwent SNB or lymphadenectomy in case of positive FNAC. RESULTS: Median follow-up was 61 months (IQR 40-95). SN positivity rate was 21%. Survival analyses demonstrated that patients with positive US-FNAC had poor survival. After adjustment for SN status and other known prognostic features, patients with positive US-FNAC (hazard ratio (HR) 1.80, 95% CI 1.10-2.96) had worse survival than patients with normal US (reference). Patients with suspicious US and negative FNAC (HR 1.13, 95% CI 0.71-1.78) had survival comparable to patients with normal US. CONCLUSIONS: The long-term US-FNAC results support this step-wise approach to melanoma patients. Patients with positive US-FNAC have a poor survival and can be spared a SNB. Patients with suspicious US and negative FNAC should undergo SNB to detect microscopic occult disease. Completely US-FNAC negative patients might only require follow-up and no SN staging at all.

Timing of completion lymphadenectomy after positive sentinel node biopsy in patients with melanoma.

BACKGROUND: Nodal staging with sentinel node biopsy (SNB) and completion lymph node dissection (CLND) provides prognostic information to patients with melanoma and their physicians. It is not known whether the timing of CLND is associated with survival outcome and/or CLND tumour load. This study investigated whether CLND timing is associated with CLND tumour load, disease-free survival (DFS) and/or melanoma-specific survival (MSS). METHODS: A retrospective cohort of patients with SNB-positive melanoma from nine European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group centres undergoing surgery between 1993 and 2009 were examined. Patients were selected based on availability of CLND and follow-up data. The CLND interval was defined as the number of days between diagnosis and CLND. Patient and tumour characteristics were collected. Five-year DFS and MSS rates were calculated. Cox and logistic regression analysis were performed, adjusting for known prognostic/predictive indicators. RESULTS: A total of 784 patients were included in the study. Their median age was 51 (i.q.r. 40-62) years, and 418 patients (53·3 per cent) were men. Median Breslow thickness was 3·0 (i.q.r. 2·0-5·0) mm, and 148 patients (18·9 per cent) had a residual tumour load. Median CLND interval was 84 (i.q.r. 65-105) days. Five-year DFS and MSS rates were not significantly different for patients operated on with a median CLND interval of less than 84 days and those with an interval of at least 84 days (DFS: 54·2 versus 53·3 per cent respectively; MSS: 66·9 versus 65·1 per cent). In a multivariable Cox model, CLND interval was not a significant prognostic indicator. CLND interval was negatively correlated with identification of positive non-sentinel nodes, but following adjustment for known risk factors this effect was no longer found. CONCLUSION: The time interval between diagnosis of melanoma and CLND did not influence CLND tumour load, DFS or MSS.

The interval between primary melanoma excision and sentinel node biopsy is not associated with survival in sentinel node positive patients - An EORTC Melanoma Group study.

BACKGROUND: Worldwide, sentinel node biopsy (SNB) is the recommended staging procedure for stage I/II melanoma. Most melanoma guidelines recommend re-excision plus SNB as soon as possible after primary excision. To date, there is no evidence to support this timeframe. AIM: To determine melanoma specific survival (MSS) for time intervals between excisional biopsy and SNB in SNB positive patients. METHODS: Between 1993 and 2008, 1080 patients were diagnosed with a positive SNB in nine Melanoma Group centers. We selected 1015 patients (94%) with known excisional biopsy date. Time interval was calculated from primary excision until SNB. Kaplan-Meier estimated MSS was calculated for different cutoff values. Multivariable analysis was performed to correct for known prognostic factors. RESULTS: Median age was 51 years (Inter Quartile Range (IQR) 40-62 years), 535 (53%) were men, 603 (59%) primary tumors were located on extremities. Median Breslow thickness was 3.00 mm (IQR 1.90-4.80 mm), 442 (44%) were ulcerated. Median follow-up was 36 months (IQR 20-62 months). Median time interval was 47 days (IQR 32-63 days). Median Breslow thickness was equal for both <47 days and ≥47 days interval: 3.00 mm (1.90-5.00 mm) vs 3.00 mm (1.90-4.43 mm) (p = 0.402). Sentinel node tumor burden was significantly higher in patients operated ≥47 days (p = 0.005). Univariate survival was not significantly different for median time interval. Multivariable analysis confirmed that time interval was no independent prognostic factor for MSS. CONCLUSIONS: Time interval from primary melanoma excision until SNB was no prognostic factor for MSS in this SNB positive cohort. This information can be used to counsel patients.

[Sonographic criteria for diagnosing sentinel node metastases in melanoma patients]. / Sonografische Kriterien zur Diagnostik von Metastasen im Sentinel-Lymphknoten bei Patienten mit malignem Melanom.

PURPOSE: Ultrasound-guided fine needle aspiration cytology (US-FNAC) prior to surgical excision of a sentinel lymph node (SLN) is a new microinvasive approach for detecting micrometastases in melanoma patients. The aim of the current prospective study was to determine the sensitivity and specificity of the method and to define new diagnostic generally applicable ultrasound criteria. MATERIALS AND METHODS: In 800 consecutive patients suffering from malignant melanoma of stage I/II, the SNs were examined sonographically after lymphoscintigraphy. US-FNAC was performed in all suspicious lesions in 302 patients. All patients underwent surgical removal of the SLN. The final histopathology and sonographic findings were correlated. RESULTS: After a follow-up of 37 months and a given median tumor thickness of 1.6 mm in our cohort, 21 % of the patients had a positive SLN in the histologic examination. We calculated a sensitivity and specificity of US-FNAC of 56 % and 99 %, respectively. The positive and negative predictive values were 92 % and 89 %, respectively. The highest positive predictive values were achieved using the ultrasound criterion of peripheral perfusion in power mode. The sensitivity of US-FNAC increased in parallel with an increasing pT stage of the primary tumor and increasing size of the largest diameter of the involved SN nest. CONCLUSION: Our prospective study shows the impact of ultrasound-guided FNAC in the staging of the SN prior to a planned SLNB. It proved to be an additional, cost-effective diagnostic tool that enhances the discriminatory power for the indication to perform SLNB and spares both the patient and the surgeon a second surgical procedure. Among the tested ultrasound criteria, peripheral perfusion (PP) showed the highest sensitivity for detecting early SN.

Isolated limb perfusion using tumour necrosis factor α and melphalan in patients with advanced aggressive fibromatosis.

BACKGROUND: Aggressive fibromatoses (desmoid tumours) may be locally aggressive, but do not metastasize. Although a conservative approach is advocated for most patients, pain and functional impairment are indications for active treatment. Tumour necrosis factor (TNF) α and melphalan-based isolated limb perfusion (TM-ILP) is a limb-saving treatment modality for soft tissue tumours. This study reports the results of TM-ILP treatment in patients with aggressive fibromatosis. METHODS: Institutional databases of three European centres were searched. All patients who received TM-ILP treatment for aggressive fibromatosis between 1990 and 2012 were included. Before therapy, the patients were discussed at multidisciplinary tumour board meetings. RESULTS: Twenty-five patients received 28 TM-ILP treatments. The median age of patients was 28 (i.q.r. 19-34) years and median hospital stay was 8 (7-12) days. Median follow-up was 84 (34-114) months. A complete response was achieved after two TM-ILP treatments, and a partial response after 17 treatments in 16 patients. Stable disease was reported after eight treatments in seven patients, including a patient with stable disease after the first treatment and progression after the second TM-ILP. Toxicity was modest after most treatments; Wieberdink grade IV (extensive epidermolysis, and threatening or manifest compartment syndrome) was seen after two TM-ILP treatments. Systemic leakage was reported after one treatment, but did not lead to systemic toxicity. Functional outcome was good; 16 patients had no physical limitations, and six patients had some limitations but did not need medical aids. Amputation was prevented in all but three patients. CONCLUSION: TNF-α-based ILP is effective in patients with aggressive fibromatosis.

Experience in daily practice with ipilimumab for the treatment of patients with metastatic melanoma: an early increase in lymphocyte and eosinophil counts is associated with improved survival.

BACKGROUND: Ipilimumab is a recently approved immunotherapy that has demonstrated an improvement in the overall survival (OS) of patients with metastatic melanoma. We report a single-institution experience in patients treated in a compassionate-use program. PATIENTS AND METHODS: In this prospective study, patients were treated between June 2010 and September 2011. Inclusion criteria were a diagnosis of unresectable stage III or IV melanoma, at least one previous line of chemotherapy, and survival 12 weeks after the first perfusion. Four courses of ipilimumab were administered at a dose of 3 mg/kg every 3 weeks. RESULTS: Seventy-three patients were included. Median OS was 9.1 months (95% CI 6.4-11.3) from the start of ipilimumab. Immune-related adverse events were observed in 45 patients (62%), including 19 grade 3-4 events (26%). No drug-related death occurred. A lymphocyte count >1000/mm(3) at the start of the second course and an increase in the eosinophil count >100/mm(3) between the first and second infusions were correlated with an improved OS. CONCLUSION: Ipilimumab toxic effect is manageable in real life. Biological data such as lymphocyte and eosinophil counts at the time of the second ipilimumab infusion appear to be early markers associated with better OS.

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.

Prognosis in patients with sentinel node-positive melanoma without immediate completion lymph node dissection.

BACKGROUND: The therapeutic value of immediate completion lymph node dissection (CLND) for sentinel node (SN)-positive melanoma is unknown. The aim of this study was to evaluate the impact of immediate CLND on the outcome of patients with SN-positive melanoma. METHODS: Patients with SN metastases treated between 1993 and 2008 at ten cancer centres from the European Organization for Research and Treatment of Cancer Melanoma Group were included in this retrospective study. Maximum tumour size, intranodal location and penetrative depth of SN metastases were measured. Outcome in those who had CLND was compared with that in patients who did not undergo completion lymphadenectomy. RESULTS: Of 1174 patients with SN-positive melanoma, 1113 (94.8 per cent) underwent CLND and 61 (5.2 per cent) did not. Median follow-up for the two groups was 34 and 48 months respectively. In univariable survival analysis, CLND did not significantly influence disease-specific survival (hazard ratio (HR) 0.89, 95 per cent confidence interval 0.58 to 1.37; P = 0.600). However, patients who did not undergo CLND had more favourable prognostic factors. Matched-pair analysis, with matching for age, Breslow thickness, tumour ulceration and SN tumour burden, showed that CLND had no influence on survival (HR 0.86, 0.46 to 1.61; P = 0.640). After adjusting for prognostic factors in multivariable survival analyses, no difference in survival was found. CONCLUSION: In these two cohorts of patients with SN-positive melanoma and prognostic heterogeneity, outcome was not influenced by CLND.

Can immuno-oncology offer a truly pan-tumour approach to therapy?

Increased understanding of cellular and molecular tumour immunology over the past two decades has enabled the identification of new and innovative ways to manipulate the immune response to cancer, with recent phase III trials in patients with metastatic melanoma and hormone-resistant prostate cancer providing proof-of-principle that immunotherapies can improve survival. Based on these successes, many new immunotherapies are being developed, including vaccines and other agents that prime or boost the immune system, T-cell modulatory agents, agents that enhance innate immunity and agents designed to inhibit immunosuppression within the tumour microenvironment. Current experience suggests that immunotherapies are a promising foundation to build treatment regimens for a variety of tumour types. Because many approaches target the immune system and not the cancer, immunotherapies are being evaluated in almost every tumour type, including those that were not previously considered likely to respond to immune manipulation. Immunotherapies also have potential for durable and adaptable cancer control at different stages of disease, including those with early-stage disease and low tumour burdens. To maximise benefits, however, it is likely that combination regimens with conventional cancer treatments or other immunotherapies will be necessary. In addition, the identification of biomarkers will allow further optimisation from a mechanistic and a patient selection perspective. Further advances in research will necessitate multidisciplinary collaboration among physicians, basic and translational researchers and the pharmaceutical industry to ensure that immuno-oncology becomes a cornerstone element in the development of cancer therapy.

Tumour basement membrane laminin expression predicts outcome following curative resection of pancreatic head cancer.

BACKGROUND: Although widely fragmented BMs have been associated with adverse outcome in several cancer types, comparatively little is known with respect to its effect on the prognosis of pancreatic cancer. The aim of the current study was therefore to determine the prognostic value of tumour basement membrane (BM) continuity in two anatomically closely related, however, prognostically different tumours, pancreatic head- and periampullary cancer. METHODS: Tumour BM continuity was determined by immunohistochemical staining of its two major components, laminin and collagen type IV. Associations were made with recurrence free survival (RFS), cancer-specific survival (CSS), overall survival (OS) and conventional prognostic factors. RESULTS: Fifty-nine and 61% of pancreatic head and periampullary tumours, respectively, showed limited BM laminin expression. Whereas 43% and 41% of pancreatic head and periampullary cancers, respectively, showed limited BM collagen type IV expression. Limited BM laminin was associated with poor outcome following curative resection of pancreatic head cancer (P=0.034, 0.013 and 0.017 for RFS, CSS and OS, respectively). Two and a half times as many patients with ≥ 25% BM laminin were recurrence free and alive 5 years following resection compared with those with limited BM laminin. Although staining patterns of both BM components were weakly correlated with each other, BM collagen type IV expression was not significantly associated with outcome in either tumour type. CONCLUSION: Discontinuous BMs, determined by laminin expression, are associated with poor outcome following curative resection of pancreatic head cancer.

Expression and prognostic significance of thymidylate synthase (TS) in pancreatic head and periampullary cancer.

BACKGROUND: Pancreatic cancer has a dismal prognosis. Attempts have been made to improve outcome by several 5-FU based adjuvant treatment regimens. However, the results are conflicting. There seems to be a continental divide with respect to the use of 5-FU based chemoradiotherapy (CRT). Furthermore, evidence has been presented showing a different response of pancreatic head and periampullary cancer to 5-FU based CRT. Expression of thymidylate synthase (TS) has been associated with improved outcome following 5-FU based adjuvant treatment in gastrointestinal cancer. This prompted us to determine the differential expression and prognostic value of TS in pancreatic head and periampullary cancer. PATIENTS AND METHODS: TS protein expression was studied by immunohistochemistry on original paraffin embedded tissue from 212 patients following microscopic radical resection (R0) of pancreatic head (n = 98) or periampullary cancer (n = 114). Expression was investigated for associations with recurrence free (RFS), cancer specific (CSS) and overall survival (OS), and conventional prognostic factors. RESULTS: High cytosolic TS expression was present in 26% of pancreatic head tumours and 37% of periampullary tumours (p = .11). Furthermore, TS was an independent factor predicting favourable outcome following curative resection of pancreatic head cancer (p = .003, .001 and .001 for RFS, CSS and OS, respectively). In contrast, in periampullary cancer, TS was not associated with outcome (all p > .10). CONCLUSION: TS, was found to be poorly expressed in both pancreatic head and periampullary cancer and identified as an independent prognostic factor following curative resection of pancreatic head cancer.

Trends in incidence, treatment and survival of patients with stage IV colorectal cancer: a population-based series.

AIM: The incidence, patterns of care and survival were determined in patients with stage IV colorectal cancer (CRC) in a population-based series. METHOD: Computer records for patients diagnosed with stage IV CRC diagnosed from 1 January 1995 to 31 December 2007 were retrieved from the Rotterdam Cancer Registry. Surgical resection of the primary tumour, chemotherapy use, hepatic surgery and survival were evaluated according to year of diagnosis, age, gender and primary tumour site. RESULTS: In the southwestern part of the Netherlands, 19 014 new patients with CRC were diagnosed and synchronous metastatic disease was found in 3482 (18%). This proportion increased during the study period, from 16% to 21%. Surgical resection of the primary tumour was performed in approximately 50% of the patients and did not change over time. Postoperative 30-day mortality was 8%. Chemotherapy use increased from 18% in the first period to 56% in the latest period. Liver surgery increased from 4% in the first period to 10% in the latest period. Median survival increased from 7 months to 12 months and 2-year survival increased from 14% to 28%. Two-year survival declined with increasing age and was significantly worse for right-sided tumours (14%). CONCLUSION: Survival of patients with stage IV CRC has improved over time and this is probably a result of the increased use of chemotherapy and the increased numbers of patients who underwent hepatic surgery.

Long-term outcome of isolated limb perfusion with tumour necrosis factor-α for patients with melanoma in-transit metastases.

BACKGROUND: The use of tumour necrosis factor (TNF) α in isolated limb perfusion (ILP) for in-transit melanoma metastasis is not uniformly accepted. This article reports the long-term results of adding TNF-α to standard melphalan-based ILP (TM-ILP) for treatment of melanoma in-transit metastases. METHODS: Data for patients treated between 1991 and 2005 were retrieved from a prospectively maintained database. Hyperthermic ILP was performed with 1-4 mg TNF-α. With a median potential follow-up of 13 years, response rates, time to local progression and disease-specific survival were analysed in relation to standard baseline factors. RESULTS: Some 118 TM-ILPs were analysed in 105 patients, 54 for stage IIIA, 50 for stage IIIAB and 14 for stage IV disease. The overall response rate was 93·2 per cent; the response was complete in 67·8 per cent and partial in 25·4 per cent. The response rate was significantly influenced by stage of disease (IIIA versus IIIAB; P = 0·006). The complete response was maintained until the end of follow-up in 35 patients (33·3 per cent), and local control was achieved with one additional intervention in 12 others (11·4 per cent). Local progression occurred after 66 ILPs (55·9 per cent). Number of in-transit metastases (P = 0·008) and complete response after ILP (P < 0·001) were strong prognostic factors for time to local progression. The 5-year disease-specific survival rate was 27·3 per cent; survival was positively influenced by age, stage of disease, previous ILP and complete response after ILP. CONCLUSION: ILP with TNF-α may obtain long-term local control in selected patients with in-transit metastases from melanoma.

Therapeutic surgical management of palpable melanoma groin metastases: superficial or combined superficial and deep groin lymph node dissection.

BACKGROUND: Management of patients with clinically detectable lymph node metastasis to the groin is by ilioinguinal or combined superficial and deep groin dissection (CGD) according to most literature, but in practice superficial groin dissection (SGD) only is still performed in some centers. The aim of this study is to evaluate the experience in CGD versus SGD patients in our center. METHODS: Between 1991 and 2009, 121 therapeutic CGD and 48 SGD were performed in 169 melanoma patients with palpable groin metastases at our institute. Median follow-up was 20 and, for survivors, 45 months. RESULTS: In this heterogeneous group of patients, overall (OS) and disease-free survival, local control rates, and morbidity rates were not significantly different between CGD and SGD patients. However, CGD patients had a trend towards more chronic lymphedema. Superficial lymph node ratio, the number of positive superficial lymph nodes, and the presence of deep nodes were prognostic factors for survival. CGD patients with involved deep lymph nodes (24.8%) had estimated 5-year OS of 12% compared with 40% with no involved deep lymph nodes (p=0.001). Preoperative computed tomography (CT) scan had high negative predictive value of 91% for detection of pelvic nodal involvement. CONCLUSIONS: This study demonstrated that survival and local control do not differ for patients with palpable groin metastases treated by CGD or SGD. Patients without pathological iliac nodes on CT might safely undergo SGD, while CGD might be reserved for patients with multiple positive nodes on SGD and/or positive deep nodes on CT scan.

Heterogeneity in DCE-MRI parametric maps: a biomarker for treatment response?

This study aims to quantify the heterogeneity of tumour enhancement in dynamic contrast-enhanced MRI (DCE-MRI) using texture analysis methods. The suitability of the coherence and the fractal dimension to monitor tumour response was evaluated in 18 patients with limb sarcomas imaged by DCE-MRI pre- and post-treatment. According to the histopathology, tumours were classified into responders and non-responders. Pharmacokinetic (K(trans)) and heuristic model-based parametric maps (slope, max enhancement, AUC) were computed from the DCE-MRI data. A substantial correlation was found between the pharmacokinetic and heuristic model-based parametric maps: ρ = 0.56 for the slope, ρ = 0.44 for maximum enhancement, and ρ = 0.61 for AUC. From all four parametric maps, the enhancing fraction, and the heterogeneity features (i.e. coherence and fractal dimension) were determined. In terms of monitoring tumour response, using both pre- and post-treatment DCE-MRI, the enhancing fraction and the coherence showed significant differences between the response group and the non-response group (i.e. the highest sensitivity (91%) for K(trans), and the highest specificity (83%) for max enhancement). In terms of treatment prediction, using solely the pre-treatment DCE-MRI, the enhancing fraction and coherence discriminated between responders and non-responders. For prediction, the highest sensitivity (91%) was shared by K(trans), slope and max enhancement, and the highest specificity (71%) was achieved by K(trans). On average, tumours that responded showed a high enhancing fraction and high coherence on the pre-treatment scan. These results suggest that specific heterogeneity features, computed from both pharmacokinetic and heuristic model-based parametric maps, show potential as a biomarker for monitoring tumour response.

Prognostic value of serial blood S100B determinations in stage IIB-III melanoma patients: a corollary study to EORTC trial 18952.

S100B is a prognostic factor for melanoma as elevated levels correlate with disease progression and poor outcome. We determined its prognostic value based on updated information using serial determinations in stage IIb/III melanoma patients. 211 Patients who participated in the EORTC 18952 trial, evaluating efficacy of adjuvant intermediate doses of interferon α2b (IFN) versus observation, entered a corollary study. Over a period of 36 months, 918 serum samples were collected. The Cox time-dependent model was used to assess prognostic value of the latest (most recent) S100B determination. At first measurement, 178 patients had S100B values <0.2 µg/l and 33 ≥ 0.2 µg/l. Within the first group, 61 patients had, later on, an increased value of S100B (≥ 0.2 µg/l). An initial increased value of S100B, or during follow-up, was associated with worse distant metastasis-free survival (DMFS); hazard ratio (HR) of S100B ≥ 0.2 versus S100B < 0.2 was 5.57 (95% confidence interval (CI) 3.81-8.16), P < 0.0001, after adjustment for stage, number of lymph nodes and sex. In stage IIb patients, the HR adjusted for sex was 2.14 (95% CI 0.71, 6.42), whereas in stage III, the HR adjusted for stage, number of lymph nodes and sex was 6.76 (95% CI 4.50-10.16). Similar results were observed regarding overall survival (OS). Serial determination of S100B in stage IIb-III melanoma is a strong independent prognostic marker, even stronger compared to stage and number of positive lymph nodes. The prognostic impact of S100B ≥ 0.2 µg/l is more pronounced in stage III disease compared with stage IIb.