Mutation or loss of Wilms' tumor gene 1 (WT1) are not major reasons for immune escape in patients with AML receiving WT1 peptide vaccination

<p>Abstract</p> <p>Background</p> <p>Efficacy of cancer vaccines may be limited due to immune escape mechanisms like loss or mutation of target antigens. Here, we analyzed 10 HLA-A2 positive patients with acute myeloid leukemia (AML) for loss or mutations of the WT1 epitope or epitope flanking sequences that may abolish proper T cell recognition or epitope presentation.</p> <p>Methods</p> <p>All patients had been enrolled in a WT1 peptide phase II vaccination trial (NCT00153582) and ultimately progressed despite induction of a WT1 specific T cell response. Blood and bone marrow samples prior to vaccination and during progression were analyzed for mRNA expression level of WT1. Base exchanges within the epitope sequence or flanking regions (10 amino acids N- and C-terminal of the epitope) were assessed with melting point analysis and sequencing. HLA class I expression and WT1 protein expression was analyzed by flow cytometry.</p> <p>Results</p> <p>Only in one patient, downregulation of WT1 mRNA by 1 log and loss of WT1 detection on protein level at time of disease progression was observed. No mutation leading to a base exchange within the epitope sequence or epitope flanking sequences could be detected in any patient. Further, no loss of HLA class I expression on leukemic blasts was observed.</p> <p>Conclusion</p> <p>Defects in antigen presentation caused by loss or mutation of WT1 or downregulation of HLA molecules are not the major basis for escape from the immune response induced by WT1 peptide vaccination.</p

Influence of migrant background on patient preference and expectations in breast and gynecological malignancies (NOGGO-expression V study): results of a prospective multicentre study in 606 patients in Germany

Background: An effective cross-cultural doctor-patient communication is vital for health literacy and patient compliance. Building a good relationship with medical staff is also relevant for the treatment decision-making process for cancer patients. Studies about the role of a specific migrant background regarding patient preferences and expectations are lacking. We therefore conducted a multicentre prospective survey to explore the needs and preferences of patients with a migrant background (PMB) suffering from gynecological malignancies and breast cancer to evaluate the quality of doctor-patient communication and cancer management compared to non-migrants (NM). Methods: This multicentre survey recruited patients with primary or recurrence of breast, ovarian, peritoneal, or fallopian tube cancer. The patients either filled out a paper form, participated via an online survey, or were interviewed by trained staff. A 58-item questionnaire was primarily developed in German and then translated into three different languages to reach non-German-speaking patients. Results: A total of 606 patients were included in the study: 54.1% (328) were interviewed directly, 9.1% (55) participated via an online survey, and 36.8% (223) used the paper print version. More than one quarter, 27.4% (166) of the participants, had a migrant background. The majority of migrants and NM were highly satisfied with the communication with their doctors. First-generation migrants (FGM) and patients with breast cancer were less often informed about participation in clinical trials (p < 0.05) and 24.5% of them suggested the help of an interpreter to improve the medical consultation. Second and third-generation migrants (SGM and TGM) experienced more fatigue and nausea than expected. Conclusions: Our results allow the hypothesis that training medical staff in intercultural competence and using disease-related patient information in different languages can improve best supportive care management and quality of life in cancer patients with migrant status

The EORTC-DeCOG nomogram adequately predicts outcomes of patients with sentinel node–positive melanoma without the need for completion lymph node dissection

Purpose: Based on recent advances in the management of patients with sentinel node (SN)–positive melanoma, we aimed to develop prediction models for recurrence, distant metastasis (DM) and overall mortality (OM). Methods: The derivation cohort consisted of 1080 patients with SN-positive melanoma from nine European Organization for Research and Treatment of Cancer (EORTC) centres. Prognostic factors for recurrence, DM and OM 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 centres. The models were externally validated using a prospective cohort consisting of 705 German patients with SN-positive: 473 trial participants of the German Dermatologic Cooperative Oncology Group study (DeCOG-SLT) and 232 screened patients. A nomogram was developed for graphical presentation. Results: The final model for recurrence and the calibrated models for DM and OM included ulceration, age, SN tumour burden and Breslow thickness. The models showed reasonable calibration. The c-index for the recurrence, DM and OM model was 0.68, 0.70 and 0.70, respectively, and 0.70, 0.72 and 0.74, respectively, in external validation. The EORTC-DeCOG model identified a robust low-risk group, with all identified low-risk patients (approximately 4% of the entire population) having a 5-year recurrence probability of <25% and an overall 5-year recurrence rate of 13%. A model including information on completion lymph node dissection (CLND) showed only marginal improvement in model performance. Conclusions: The EORTC-DeCOG nomogram provides an adequate prognostic tool for patients with SN-positive melanoma, without the need for CLND. It showed consistent results across validation. The nomogram could be used for patient counselling and might aid in adjuvant therapy decision-making

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 in

Clinically misinterpreted melanoma metastases can correctly be diagnosed by ultrasound-guided fine needle aspiration cytology

Ultrasound-guided fine needle aspiration cytology (US-guided FNAC) of regional nodal basins is increasingly incorporated into the national follow-up schemes of high risk melanoma patients. In this paper we describe an additional added value of US-guided FNAC in the detection and verification of subcutaneous/in-transit metastases. A patient presented with a long lasting, smooth, movable node, close to the scar of the primary melanoma, mimicking a lipoma in every clinical follow-up. Ultrasound at once suspected a metastasis. FNAC was performed within one day of sampling in an outpatient setting, without side effects. A hypothesis of an auto-vaccination in this case could not be proven by examining the T-cell response. Despite the clinically benign aspect of this metastasis, US-guided FNAC can provide diagnosis within 1 day. FNAC is a rapid, cost-effective method, free of complications, of great value in the diagnosis of putative metastases

Clinical and immunological responses in metastatic melanoma patients vaccinated with a high-dose poly-epitope vaccine

BACKGROUND: Safety and cellular immunogenicity of rising doses and varying regimens of a poly-epitope vaccine were evaluated in advanced metastatic melanoma. The vaccine comprised plasmid DNA and recombinant modified vaccinia virus Ankara (MVA) both expressing a string (Mel3) of seven HLA.A2/A1 epitopes from five melanoma antigens. METHODS: Forty-one HLA-A2 positive patients with stage III/IV melanoma were enrolled. Patient groups received one or two doses of DNA.Mel3 followed by escalating doses of MVA.Mel3. Immunisations then continued eight weekly in the absence of disease progression. Epitope-specific CD8+ T cell responses were evaluated using ex-vivo tetramer and IFN-gamma ELISPOT assays. Safety and clinical responses were monitored. RESULTS: Prime-boost DNA/MVA induced Melan-A-specific CD8+ T cell responses in 22/31 (71%) patients detected by tetramer assay. ELISPOT detected a response to at least one epitope in 10/31 (32%) patients. T cell responder rates were &lt;50% with low-dose DNA/MVA, or MVA alone, rising to 91% with high-dose DNA/MVA. Among eight patients showing evidence of clinical benefit-one PR (24 months+), five SD (5 months+) and two mixed responses-seven had associated immune responses. Melan-A-tetramer+ immunity was associated with a median 8-week increase in time-to-progression (P = 0.037) and 71 week increase in survival (P = 0.0002) compared to non-immunity. High-dose vaccine was well tolerated. The only significant toxicities were flu-like symptoms and injection-site reactions. CONCLUSIONS: DNA.Mel3 and MVA.Mel3 in a prime-boost protocol generated high rates of immune response to melanoma antigen epitopes. The treatment was well tolerated and the correlation of immune responses with patient outcomes encourages further investigation