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Daniel E Speiser,
Katrin Schwarz,
Petra Baumgaertner,
Vania Manolova,
Estelle Devevre,
Wolfram Sterry,
Peter Walden,
Alfred Zippelius,
Katrin Baumann Conzett,
Gabriela Senti, [......], Jean-Philippe Cerottini,
David Guggisberg,
Jörg Willers,
Christine Geldhof,
Pedro Romero,
Thomas Kündig,
Alexander Knuth,
Reinhard Dummer,
Uwe Trefzer,
Martin F Bachmann
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ABSTRACT: Induction of cytotoxic CD8 T-cell responses is enhanced by the exclusive presentation of antigen through dendritic cells, and by innate stimuli, such as toll-like receptor ligands. On the basis of these 2 principles, we designed a vaccine against melanoma. Specifically, we linked the melanoma-specific Melan-A/Mart-1 peptide to virus-like nanoparticles loaded with A-type CpG, a ligand for toll-like receptor 9. Melan-A/Mart-1 peptide was cross-presented, as shown in vitro with human dendritic cells and in HLA-A2 transgenic mice. A phase I/II study in stage II-IV melanoma patients showed that the vaccine was well tolerated, and that 14/22 patients generated ex vivo detectable T-cell responses, with in part multifunctional T cells capable to degranulate and produce IFN-γ, TNF-α, and IL-2. No significant influence of the route of immunization (subcutaneous versus intradermal) nor dosing regimen (weekly versus daily clusters) could be observed. It is interesting to note that, relatively large fractions of responding specific T cells exhibited a central memory phenotype, more than what is achieved by other nonlive vaccines. We conclude that vaccination with CpG loaded virus-like nanoparticles is associated with a human CD8 T-cell response with properties of a potential long-term immune protection from the disease.
Journal of immunotherapy (Hagerstown, Md.: 1997) 10/2010; 33(8):848-58. · 3.20 Impact Factor
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ABSTRACT: In sentinel node (SN) biopsy, an interval SN is defined as a lymph node or group of lymph nodes located between the primary melanoma and an anatomically well-defined lymph node group directly draining the skin. As shown in previous reports, these interval SNs seem to be at the same metastatic risk as are SNs in the usual, classic areas. This study aimed to review the incidence, lymphatic anatomy, and metastatic risk of interval SNs.
SN biopsy was performed at a tertiary center by a single surgical team on a cohort of 402 consecutive patients with primary melanoma. The triple technique of localization was used-that is, lymphoscintigraphy, blue dye, and gamma-probe. Otolaryngologic melanoma and mucosal melanoma were excluded from this analysis. SNs were examined by serial sectioning and immunohistochemistry. All patients with metastatic SNs were recommended to undergo a radical selective lymph node dissection.
The primary locations of the melanomas included the trunk (188), an upper limb (67), or a lower limb (147). Overall, 97 (24.1%) of the 402 SNs were metastatic. Interval SNs were observed in 18 patients, in all but 2 of whom classic SNs were also found. The location of the primary was truncal in 11 (61%) of the 18, upper limb in 5, and lower limb in 2. One patient with a dorsal melanoma had drainage exclusively in a cervicoscapular area that was shown on removal to contain not lymph node tissue but only a blue lymph channel without tumor cells. Apart from the interval SN, 13 patients had 1 classic SN area and 3 patients 2 classic SN areas. Of the 18 patients, 2 had at least 1 metastatic interval SN and 2 had a classic SN that was metastatic; overall, 4 (22.2%) of 18 patients were node-positive.
We found that 2 of 18 interval SNs were metastatic: This study showed that preoperative lymphoscintigraphy must review all known lymphatic areas in order to exclude an interval SN.
Journal of Nuclear Medicine 11/2007; 48(10):1607-13. · 6.38 Impact Factor
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ABSTRACT: Objective:To assess whether Jass staging enhances prognostic prediction in Dukes' B colorectal carcinoma.Design:A historical cohort observational study.Setting:A university tertiary care centre, Switzerland.Subjects:108 consecutive patients.Interventions:Curative resection of Dukes' B colorectal carcinoma between January 1985 and December 1988, Patients with familial adenomatous polyposis; hereditary non-polyposis colorectal cancer; Crohns' disease; ulcerative colitis and synchronous and recurrent tumours were excluded. A comparable group of 155 consecutive patients with Dukes' C carcinoma were included for reference purposes.Main outcome measures:Disease free and overall survival for Dukes' B and overall survival for Dukes' C tumours.Results:Dukes' B tumours in Jass group III or with an infiltrated margin had a significantly worse disease-free survival (p = 0.001 and 0.0001, respectively) and those with infiltrated margins had a significantly worse overall survival (p = 0.002). Overall survival among those with Dukes' B Jass III and Dukes' B with infiltrated margins was no better than overall survival among all patients with Dukes' C tumours.Conclusion:Jass staging and the nature of the margin of invasion allow patients undergoing curative surgery for Dukes' B colorectal carcinoma to be separated into prognostic groups. A group of patients with Dukes' B tumours whose prognosis is inseparable from those with Dukes' C tumours can be identified, the nature of the margin of invasion being used to classify a larger number of patients. Copyright © 1999 Taylor and Francis Ltd.
European Journal of Surgery. 11/2003; 165(6):588 - 592.
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Donata Rimoldi,
Robert Lemoine,
Anne-Marie Kurt,
Suzanne Salvi,
Magali Berset,
Maurice Matter,
Bruno Roche, Jean-Philippe Cerottini,
David Guggisberg,
Joachim Krischer,
Ralph Braun,
Jean-Pierre Willi,
Christian Antonescu,
Daniel Slosman,
Ferdy J Lejeune,
Danielle Liénard
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ABSTRACT: The technique of sentinel lymph node (SLN) dissection is a reliable predictor of metastatic disease in the lymphatic basin draining the primary melanoma. Reverse transcription-polymerase chain reaction (RT-PCR) is emerging as a highly sensitive technique to detect micrometastases in SLNs, but its specificity has been questioned. A prospective SLN study in melanoma patients was undertaken to compare in detail immunopathological versus molecular detection methods. Sentinel lymphadenectomy was performed on 57 patients, with a total of 71 SLNs analysed. SLNs were cut in slices, which were alternatively subjected to parallel multimarker analysis by microscopy (haematoxylin and eosin and immunohistochemistry for HMB-45, S100, tyrosinase and Melan-A/MART-1) and RT-PCR (for tyrosinase and Melan-A/MART-1). Metastases were detected by both methods in 23% of the SLNs (28% of the patients). The combined use of Melan-A/MART-1 and tyrosinase amplification increased the sensitivity of PCR detection of microscopically proven micrometastases. Of the 55 immunopathologically negative SLNs, 25 were found to be positive on RT-PCR. Notably, eight of these SLNs contained naevi, all of which were positive for tyrosinase and/or Melan-A/MART-1, as detected at both mRNA and protein level. The remaining 41% of the SLNs were negative on both immunohistochemistry and RT-PCR. Analysis of a series of adjacent non-SLNs by RT-PCR confirmed the concept of orderly progression of metastasis. Clinical follow-up showed disease recurrence in 12% of the RT-PCR-positive immunopathology-negative SLNs, indicating that even an extensive immunohistochemical analysis may underestimate the presence of micrometastases. However, molecular analyses, albeit more sensitive, need to be further improved in order to attain acceptable specificity before they can be applied diagnostically.
Melanoma Research 11/2003; 13(5):511-20. · 2.19 Impact Factor
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Donata Rimoldi,
Robert Lemoine,
Anne-Marie Kurt,
Suzanne Salvi,
Magali Berset,
Maurice Matter,
Bruno Roche, Jean-Philippe Cerottini,
David Guggisberg,
Joachim Krischer,
Ralph Braun,
Jean-Pierre Willi,
Christian Antonescu,
Daniel Slosman,
Ferdy J Lejeune,
Danielle Liénard,
for the Groupe Mélanome Lémanique
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ABSTRACT: The technique of sentinel lymph node (SLN) dissection is a reliable predictor of metastatic disease in the lymphatic basin draining the primary melanoma. Reverse transcription-polymerase chain reaction (RT-PCR) is emerging as a highly sensitive technique to detect micrometastases in SLNs, but its specificity has been questioned. A prospective SLN study in melanoma patients was undertaken to compare in detail immunopathological versus molecular detection methods. Sentinel lymphadenectomy was performed on 57 patients, with a total of 71 SLNs analysed. SLNs were cut in slices, which were alternatively subjected to parallel multimarker analysis by microscopy (haematoxylin and eosin and immunohistochemistry for HMB-45, S100, tyrosinase and Melan-A/MART-1) and RT-PCR (for tyrosinase and Melan-A/MART-1). Metastases were detected by both methods in 23% of the SLNs (28% of the patients). The combined use of Melan-A/MART-1 and tyrosinase amplification increased the sensitivity of PCR detection of microscopically proven micrometastases. Of the 55 immunopathologically negative SLNs, 25 were found to be positive on RT-PCR. Notably, eight of these SLNs contained naevi, all of which were positive for tyrosinase and/or Melan-A/MART-1, as detected at both mRNA and protein level. The remaining 41% of the SLNs were negative on both immunohistochemistry and RT-PCR. Analysis of a series of adjacent non-SLNs by RT-PCR confirmed the concept of orderly progression of metastasis. Clinical follow-up showed disease recurrence in 12% of the RT-PCR-positive immunopathology-negative SLNs, indicating that even an extensive immunohistochemical analysis may underestimate the presence of micrometastases. However, molecular analyses, albeit more sensitive, need to be further improved in order to attain acceptable specificity before they can be applied diagnostically.
Melanoma Research 09/2003; 13(5):511-520. · 2.19 Impact Factor
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ABSTRACT: This study aims at evaluating two automatic contour detection techniques especially developed for dermoscopic images.
Twenty-five images of lesions with a fuzzy boundary have been randomly selected. Five dermatologists experienced in dermoscopy have manually drawn the border of all the lesions and repeated the procedure after two and four weeks. The ability of a dermatologist to reproduce its own results was evaluated by measuring the non-overlapping area enclosed by its three successive contours. The interobserver variability evaluated the contour accuracy when using automatic or manual drawings. The mean probability that a pixel has been misclassified was computed for every observer and automatic technique.
Experts in dermoscopy are not able to reproduce measurements precisely and the two automatic techniques had a lower misclassification probability than those obtained by each dermatologist.
This study demonstrates that a single dermatologist should not be used as a reference, and subjective validation of lesion contour is inaccurate outside an experts's group. It is argued that image processing techniques for computer-aided diagnosis must show the best compromise within such a group.
Skin Research and Technology 12/2002; 8(4):240-9. · 1.71 Impact Factor
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Jean-Philippe Cerottini
Revue medicale de la Suisse romande 02/2002; 122(1):9-11.
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Revue medicale de la Suisse romande 02/2002; 122(1):5-8.
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ABSTRACT: At least 2 apparently independent mechanisms, microsatellite instability (MSI) and chromosomal instability, are implicated in colorectal tumorigenesis. Their respective roles in predicting clinical outcomes of patients with T3N0 colorectal cancer remain unknown.
Eighty-eight patients with a sporadic T3N0 colon or rectal adenocarcinoma were followed up for a median of 67 months. For chromosomal instability analysis, Ki-ras mutations were determined by single-strand polymerase chain reaction, and p53 protein staining was studied by immunohistochemistry. For MSI analysis, DNA was amplified by polymerase chain reaction at 7 microsatellite targets (BAT25, BAT26, D17S250, D2S123, D5S346, transforming growth factor receptor II, and BAX).
Overall 5-year survival rate was 72%. p53 protein nuclear staining was detected in 39 patients (44%), and MSI was detected in 21 patients (24%). MSI correlated with proximal location (P <.001) and mucinous content (P <.001). In a multivariate analysis, p53 protein expression carried a significant risk of death (relative risk = 4.0, 95% CI = 1.6 to 10.1, P =.004). By comparison, MSI was not a statistically significant prognostic factor for survival in this group (relative risk = 2.2, 95% CI = 0.6 to 7.3, P =.21).
p53 protein overexpression provides better prognostic discrimination than MSI in predicting survival of patients with T3N0 colorectal cancer. Although MSI is associated with specific clinicopathologic parameters, it did not predict overall survival in this group. Assessment of p53 protein expression by immunocytochemistry provides a simple means to identify a subset of T3N0 patients with a 4-times increased risk for death.
Surgery 02/2002; 131(2):190-7. · 3.10 Impact Factor
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ABSTRACT: PURPOSE: The aim of this study was to determine whether tumor location proximal or distal to the splenic flexure is associated with distinct molecular patterns and can predict clinical outcome in a homogeneous group of patients with Dukes B (T3–T4, N0, M0) colorectal cancer. It has been hypothesized that proximal and distal colorectal cancer may arise through different pathogenetic mechanisms. Althoughp53 and Ki-ras gene mutations occur frequently in distal tumors, another form of genomic instability associated with defective DNA mismatch repair has been predominantly identified in the proximal colon. To date, however, the clinical usefulness of these molecular characteristics remains unproven. METHODS: A total of 126 patients with a lymph node-negative sporadic colon or rectum adenocarcinoma were prospectively assessed with the endpoint of death by cancer. No patient received either radiotherapy or chemotherapy. p53 protein was studied by immunohistochemistry using DO-7 monoclonal antibody, andp53 and Ki-ras gene mutations were detected by single strand conformation polymorphism assay. RESULTS: During a mean follow-up of 67 months, the overall five-year survival was 70 percent. Nuclearp53 staining was found in 57 tumors (47 percent), and was more frequent in distal than in proximal tumors (55vs. 21 percent; chi-squared test,P<0.001). For the whole group, p53 protein expression correlated with poor survival in univariate and multivariate analysis (log-rank test,P=0.01; hazard ratio=2.16; 95 percent confidence interval=1.12–4.11,P=0.02). Distal colon tumors and rectal tumors exhibited similar molecular patterns and showed no difference in clinical outcome. In comparison with distal colorectal cancer, proximal tumors were found to be statistically significantly different on the following factors: mucinous content (P=0.008), degree of histologic differentiation (P=0.012), p53 protein expression, and gene mutation (P=0.001 and 0.01 respectively). Finally, patients with proximal tumors had a marginally better survival than those with distal colon or rectal cancers (log-rank test,P=0.045). CONCLUSION: In this series of Dukes B colorectal cancers, p53 protein expression was an independent factor for survival, which also correlated with tumor location. Eighty-six percent ofp53-positive tumors were located in the distal colon and rectum. Distal colon and rectum tumors had similar molecular and clinical characteristics. In contrast, proximal neoplasms seem to represent a distinct entity, with specific histopathologic characteristics, molecular patterns, and clinical outcome. Location of the neoplasm in reference to the splenic flexure should be considered before group stratification in future trials of adjuvant chemotherapy in patients with Dukes B tumors.
Diseases of the Colon & Rectum 01/2001; 44(3):364-372. · 3.13 Impact Factor
