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.

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.

[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.

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.

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.

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.

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.

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.

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.

Advances in systemic treatment of melanoma.

After decades of phase III trials failing to demonstrate an impact on survival of various drugs in metastatic melanoma there are finally significant advances in systemic therapies for melanoma emerging. Novel ways to modulate the immune system by monoclonal antibodies as well as various signalling pathway inhibitors are responsible for creating a whole new therapeutic landscape. For the first time it is likely that a number of new drugs with completely different mechanisms of action will be approved in the near future. The imminent candidates are the anti-CTLA-4 antibody ipilimumab, and the highly selective BRAF inhibitor PLX4032. But in each class other molecules are under development with good perspectives. Various new combinations will have to be explored and it is reasonable to expect synergies between the different classes of drugs as well as between novel molecules within the same class of drugs. Here, an overview of current developments and the most important new drugs under consideration is provided.

'Staged' liver resection in synchronous and metachronous colorectal hepatic metastases: differences in clinicopathological features and outcome.

AIM: Approximately 25% of the patients with colorectal cancer already have liver metastases at diagnosis and another 30% will develop them subsequently. The features and prognosis of patients with synchronous and metachronus colorectal liver metastases, treated with primary resection first followed by partial liver resection were analysed. METHOD: Curative staged resection of liver metastases was performed in 272 consecutive patients. Demographics, characteristics of the primary tumour and metastatic tumours, surgery-related data and outcome were analysed. RESULTS: Synchronous metastases were present in 105 (39%) patients and metachronous metastases in 167 (61%). More patients in the synchronous group had an advanced primary tumour (T3/T4 and/or node positivity), more than three liver metastases and bilobar distribution. A significantly higher percentage of patients in the synchronous group received neoadjuvant chemotherapy. The 5-year survival rate in the group of 272 patients was 38%. Patients with more than three metastases had a significantly worse survival rate. There were no differences in disease-free and overall survival rates between the synchronous and metachronous group. CONCLUSION: Although patients with synchronous colorectal liver metastases may have poorer biological features, there was no difference in 5-year disease-free and overall survival compared with patients with metachronous metastases. This may be explained by the observation that patients in the synchronous group received significantly more neoadjuvant chemotherapy.

Epidemiology of invasive cutaneous melanoma.

Data are presented on the current incidence of melanoma with recent and predicted future trends illustrating a likely continuing increase in incidence. Risk factors for developing melanoma are discussed, including current known melanoma susceptibility genes. Phenotypic markers of high-risk subjects include high counts of benign melanocytic naevi. Other risk factors considered include exposure to natural and artificial ultraviolet radiation, the effect of female sex hormones, socioeconomic status, occupation, exposure to pesticides and ingestion of therapeutic drugs including immunosuppressives and non-steroidal anti-inflammatory drugs. Aids to earlier diagnosis are considered, including public education, screening and use of equipment such as the dermatoscope. Finally, the current pattern of survival and mortality is described.

Staging of cutaneous melanoma.

The American Joint Committee on Cancer (AJCC) staging of cutaneous melanoma is a continuously evolving system. The identification of increasingly more accurate prognostic factors has led to major changes in melanoma staging over the years, and the current system described in this review will likely be modified in the near future. Likewise, application of new imaging techniques has also changed the staging work-up of patients with cutaneous melanoma. Chest and abdominal computed tomography (CT) scanning is most commonly used for evaluation of potential metastatic sites in the lungs, lymph nodes and liver, and is indicated in patients with new symptoms, anaemia, elevated lactate dehydrogenase or a chest X-ray abnormality. CT scans should be restricted to patients with high-risk melanoma (stage IIC, IIIB, IIIC and stage IIIA with a macroscopic sentinel lymph node). Magnetic resonance imaging (MRI) of the brain is a mandatory test in patients with stage IV, optional in stage III and not used in patients with stage I and II disease. Positron emission tomography (PET)/CT is more accurate than CT or MRI alone in the diagnosis of metastases and should complement conventional CT/MRI imaging in the staging work-up of patients who have solitary or oligometastatic disease where surgical resection is most relevant.

Surgery and radiotherapy in the treatment of cutaneous melanoma.

Adequate surgical management of primary melanoma and regional lymph node metastasis, and rarely distant metastasis, is the only established curative treatment. Surgical management of primary melanomas consists of excisions with 1-2 cm margins and primary closure. The recommended method of biopsy is excisional biopsy with a 2 mm margin and a small amount of subcutaneous fat. In specific situations (very large lesions or certain anatomical areas), full-thickness incisional or punch biopsy may be acceptable. Sentinel lymph node biopsy provides accurate staging information for patients with clinically unaffected regional nodes and without distant metastases, although survival benefit has not been proved. In cases of positive sentinel node biopsy or clinically detected regional nodal metastases (palpable, positive cytology or histopathology), radical removal of lymph nodes of the involved basin is indicated. For resectable local/in-transit recurrences, excision with a clear margin is recommended. For numerous or unresectable in-transit metastases of the extremities, isolated limb perfusion or infusion with melphalan should be considered. Decisions about surgery of distant metastases should be based on individual circumstances. Radiotherapy is indicated as a treatment option in select patients with lentigo maligna melanoma and as an adjuvant in select patients with regional metastatic disease. Radiotherapy is also indicated for palliation, especially in bone and brain metastases.

Biomarkers in melanoma.

Biomarkers are tumour- or host-related factors that correlate with tumour biological behaviour and patient prognosis. High-throughput analytical techniques--DNA and RNA microarrays--have identified numerous possible biomarkers, but their relevance to melanoma progression, clinical outcome and the selection of optimal treatment strategies still needs to be established. The review discusses a possible molecular basis for predictive tissue biomarkers such as melanoma thickness, ulceration and mitotic activity, and provides a list of promising new biomarkers identified from tissue microarrays that needs confirmation by independent, prospectively collected clinical data sets. In addition, common predictive serum biomarkers--lactate dehydrogenase, S100B and melanoma-inhibiting activity--as well as selected investigational serum biomarkers such as TA90IC and YKL-40 are also reviewed. A more accurate, therapeutically predictive classification of human melanomas and selection of patient populations that would profit from therapeutic interventions are among the major challenges expected to be addressed in the future.