Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.

BACKGROUND: Pembrolizumab demonstrated robust antitumor activity and safety in the phase Ib KEYNOTE-001 study (NCT01295827) of advanced melanoma. Five-year outcomes in all patients and treatment-naive patients are reported herein. Patients whose disease progressed following initial response and who received a second course of pembrolizumab were also analyzed. PATIENTS AND METHODS: Patients aged ≥18 years with previously treated or treatment-naive advanced/metastatic melanoma received pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks until disease progression, intolerable toxicity, or patient/investigator decision to withdraw. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. Objective response rate and PFS were based on immune-related response criteria by investigator assessment (data cut-off, September 1, 2017). RESULTS: KEYNOTE-001 enrolled 655 patients with melanoma; median follow-up was 55 months. Estimated 5-year OS was 34% in all patients and 41% in treatment-naive patients; median OS was 23.8 months (95% CI, 20.2-30.4) and 38.6 months (95% CI, 27.2-not reached), respectively. Estimated 5-year PFS rates were 21% in all patients and 29% in treatment-naive patients; median PFS was 8.3 months (95% CI, 5.8-11.1) and 16.9 months (95% CI, 9.3-35.5), respectively. Median response duration was not reached; 73% of all responses and 82% of treatment-naive responses were ongoing at data cut-off; the longest response was ongoing at 66 months. Four patients [all with prior response of complete response (CR)] whose disease progressed during observation subsequently received second-course pembrolizumab. One patient each achieved CR and partial response (after data cut-off). Treatment-related AEs (TRAEs) occurred in 86% of patients and resulted in study discontinuation in 7.8%; 17% experienced grade 3/4 TRAE. CONCLUSIONS: This 5-year analysis of KEYNOTE-001 represents the longest follow-up for pembrolizumab to date and confirms the durable antitumor activity and tolerability of pembrolizumab in advanced melanoma. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov, NCT01295827.

Conservation de l'ejaculation au cours de la resection transurethrale de prostate

Objective: To evaluate the role of partial prostatectomy in the management of bladder outlet obstruction due to benign prostatic hyperplasia (BPH) and to illustrate the indications and results with regard to micturition and preservation of antegrade ejaculation. Patients and Methods: Sixty-nine patients with a mean age of 53 years (range: 40 - 85 years) who had undergone partial prostatectomy for BPH were followed up between January 1997 and December 2002. Details on the quality of micturition and ejaculation of each patient were obtained via telephone calls after a period of at least 6 months following surgery. Results: As for micturition; good results were reported by 75;36(52/69) of the patients; while 23;19(16/69) and 1;45(1/69) of the patients reported satisfactory and unsatisfactory results; respectively. Antegrade ejaculation could be achieved in 97;1(67/69) patients. Conclusion: We conclude that partial prostatectomy as suggested by Hermabessiere3 is a technique which allows for the preservation of antegrade ejaculation. It is of special interest in the young patient; but can also be applied in the elder man

NY-ESO-1 encodes DRB1*0401-restricted epitopes recognized by melanoma-reactive CD4+ T cells.

The NY-ESO-1 gene is expressed by a range of human tumors and encodes HLA-A2-restricted melanoma peptides recognized by CD8+ CTLs. Here we report that the NY-ESO-1 gene also encodes two overlapping, but non-cross-reactive, HLA-DRB1*0401-presented peptides that are recognized by CD4+ T cells. The NY-ESO-1(119-143) peptide was able to induce specific CD4+ T cells in vitro from both an HLA-DRB1*0401+ normal donor and an HLA-DRB1*0401+ patient with melanoma. Bulk and cloned CD4+ T cells produced IFN-gamma specifically in response to, and also lysed, T2.DR4 cells pulsed with peptide NY-ESO-1(119-143) and the autologous tumor cell line, but not a DRB1*0401+ melanoma cell line that does not express NY-ESO-1. Interestingly, the NY-ESO119-143 peptide contains two overlapping putative "core" epitopes recognized by non-cross-reactive anti-NY-ESO-1(119-143) CD4+ T-cell clones. Taken together, these data support the use of this novel DR4-restricted tumor peptide, NY-ESO-1(119-143), or its two "sub-epitopes" in immunotherapeutic trials designed to generate or enhance specific CD4+ T-cell responses against tumors expressing NY-ESO-1 in vivo.

Melanoma antigens recognised by CD8+ and CD4+ T cells.

The field of melanoma immunobiology has made tremendous strides in the past decade, resulting in the molecular identification of a vast array of tumour-expressed antigens that contain determinants that are recognised by patient T cells or immunoglobulins. The integration of these antigens, their derivative peptides or improved analogues in vaccine trials allows for the augmentation of melanoma-specific CD4+ and CD8+ T cells in situ that may prove clinically efficacious in the adjuvant or therapeutic setting. Indeed, melanoma peptide-based immunotherapies targeting the activation of anti-tumour CD8+ cytotoxic T lymphocytes have proven successful (i.e. yielding objective clinical responses), particularly when combined with T cell growth factors or potent antigen-presenting cells, such as dendritic cells. Vaccine approaches implementing poly-epitope and/or melanoma peptides recognised by CD4+ T cells are anticipated to yield still better clinical outcomes due to the in vivo promotion and maintenance of a diversified, poly-specific effector T cell repertoire directed against resident tumours.

Mature dendritic cells pulsed with freeze-thaw cell lysates define an effective in vitro vaccine designed to elicit EBV-specific CD4(+) and CD8(+) T lymphocyte responses.

Immunotherapy trials targeting the induction of tumor-reactive T-cell responses in cancer patients appear to hold significant promise. Because nonmutated lineage-specific antigens and mutated idiotypic antigens may be coexpressed by tumor cells, the use of autologous tumor material to promote the broadest range of antitumor T-cell specificities has significant clinical potential in cancer vaccination trials. As a model for vaccination in the cancer setting, we chose to analyze the promotion of T-cell responses against Epstein-Barr virus (EBV)-transformed B-lymphoblastoid cell line (B-LCL)-derived antigens in vitro. A series of bulk antigenic formats (freeze-thaw lysate, trifluoroacetic acid lysate, extracted membranes, affinity-purified MHC class I- and class II-presented peptides, acid-eluted peptides) prepared from EBV B-LCLs were tested for their ability to stimulate EBV B-LCL-reactive CD4(+) and CD8(+) T lymphocytes in vitro when pulsed onto autologous dendritic cells (DCs). DC presentation of freeze-thaw lysate material derived from (either autologous or allogeneic) EBV B-LCLs with an Mr of 10 kd or larger stimulated optimal anti-EBV B-LCL responsiveness from freshly isolated CD4(+) and CD8(+) peripheral blood T cells. These in vivo "memory" T-cell responses were observed only in EBV-seropositive donors. CD4(+) T-cell responses to lysate-pulsed DCs were Th1 type (ie, strong interferon-gamma and weak interleukin-5 responses). While CD8(+) T-cell responses were also observed in interferon-gamma Elispot assays and in cytotoxicity assays, these responses were of low frequency unless the DC stimulators were induced to "mature" after being fed with tumor lysates. Optimal-length, naturally processed, and MHC class I- or class II-presented tumor peptides were comparatively poorly immunogenic in this model system. (Blood. 2000;96:1857-1864)

Melan-A/MART-1(51-73) represents an immunogenic HLA-DR4-restricted epitope recognized by melanoma-reactive CD4(+) T cells.

The human Melan-A/MART-1 gene encodes an HLA-A2-restricted peptide epitope recognized by melanoma-reactive CD8(+) cytotoxic T lymphocytes. Here we report that this gene also encodes at least one HLA-DR4-presented peptide recognized by CD4(+) T cells. The Melan-A/MART-1(51-73) peptide was able to induce the in vitro expansion of specific CD4(+) T cells derived from normal DR4(+) donors or from DR4(+) patients with melanoma when pulsed onto autologous dendritic cells. CD4(+) responder T cells specifically produced IFN-gamma in response to, and also lysed, T2.DR4 cells pulsed with the Melan-A/MART-1(51-73) peptide and DR4(+) melanoma target cells naturally expressing the Melan-A/MART-1 gene product. Interestingly, CD4(+) T cell immunoreactivity against the Melan-A/MART-1(51-73) peptide typically coexisted with a high frequency of anti-Melan-A/MART-1(27-35) reactive CD8(+) T cells in freshly isolated blood harvested from HLA-A2(+)/DR4(+) patients with melanoma. Taken together, these data support the use of this Melan-A/MART-1 DR4-restricted melanoma epitope in future immunotherapeutic trials designed to generate, augment, and quantitate specific CD4(+) T cell responses against melanoma in vivo.

Genes coding for melanoma antigens recognised by cytolytic T lymphocytes.

It is now well established that human melanoma cells express antigens that are recognised by cytolytic T lymphocytes derived from the tumour-bearing patient. The molecular definition of these antigens is progressing at an accelerated pace. The currently characterised melanoma antigens can be classified into three categories: differentiation antigens, antigens encoded by genes that are specifically expressed in tumours, and antigens encoded by mutated genes. Several of these antigens are sufficiently tumour-specific to qualify them as candidate anti-cancer vaccines in melanoma patients.

The majority of autologous cytolytic T-lymphocyte clones derived from peripheral blood lymphocytes of a melanoma patient recognize an antigenic peptide derived from gene Pmel17/gp100.

Anti-melanoma cytolytic T-lymphocyte (CTL) clones were derived from peripheral blood lymphocytes of HLA-A2 melanoma patient LB265 after stimulation with the autologous tumor cell line LB265-MEL, which showed high expression of melanocyte-lineage specific genes. Of 55 CTL clones, 46 recognized HLA-A2-restricted antigens. These 46 CTL clones were studied for their ability to specifically release tumor necrosis factor in the presence of COS cells cotransfected with the HLA-A2 gene and the cDNA of either tyrosinase, Melan-A/MART1, Pmel17/gpl00, gp75/TRP1, or MSH receptor. Six CTL clones recognized the Melan-A/MART1 antigen, whereas the remaining 40 CTL clones recognized a Pmel17/gp100 antigen. These 40 anti-PmelI7/gpl00 CTL clones were all able to lyse T2 cells pulsed with the antigenic peptide YLEPGPVTA, as previously reported. The T-cell receptor beta chain hypervariable region was sequenced and found to be identical in the 15 CTL clones analyzed. Taken together, these data show a high frequency of Pmell7/gp100-specific T cells in autologous antitumor CTL clones derived from peripheral blood of a melanoma patient.

Polymerase chain reaction detection of circulating melanocytes as a prognostic marker in patients with melanoma.

BACKGROUND AND DESIGN: Polymerase chain reaction (PCR) detection of circulating tumor cells from malignant melanoma (MM) was recently described, but the prognostic value of this method in the treatment of patients with MM remained unclear. In the present prospective study, blood samples (n = 193) were collected from 93 patients with MM: 10 stage I patients after primary tumor resection, 18 patients with regional lymph node metastases before node resection, 33 disease-free but high-risk patients (previously treated for node metastases), and 32 patients with distant metastases. Circulating melanocytes were detected using a reverse transcriptase PCR method that analyzes tyrosinase gene expression. All patients were kept under regular surveillance. RESULTS: The PCR assay was always negative in normal individuals and in subjects with non-MM metastatic cancer, while it was positive in 16 of 32 patients with disseminated MM. Five of eight patients who were PCR-positive before node dissection vs one of 10 who were PCR-negative relapsed within 6 months after surgery. In high-risk but apparently disease-free patients, the risk of relapse within the next 6 months was 3.8 times higher after a positive test result. In patients with distant metastases, a positive PCR predicted rapid disease progression. CONCLUSIONS: These data suggest that PCR detection of circulating melanocytes can be considered as a marker for rapid postoperative relapse after node dissection in patients with MM with regional node metastases, for short-term relapse in high-risk disease-free patients, and for rapid and severe progression in patients with distant metastases. This test may have a crucial interest in the treatment of patients with MM.

Cost-effectiveness of surveillance of stage I melanoma. A retrospective appraisal based on a 10-year experience in a dermatology department in France.

BACKGROUND: There is no agreement about surveillance after resection of a stage I melanoma. OBJECTIVE: We assessed the cost-effectiveness of this surveillance. METHODS: Out of 912 patients with stage I (and Clark's level > or = II) melanoma examined from 1981 to 1991, only 528 were regularly followed in our department. RESULTS: 115 out of 528 relapsed; 33% were detected by the patient himself, 16% by the referring physician and 39% were detected in our department. Chest X-ray or abdomen ultrasonography revealed only 10% of relapses; CT scans were useless. There was a huge gap between the cost-effectiveness of clinical examinations and radiology. The time between relapse and the last check-up in our department was less than 4 months in one third of the metastases. CONCLUSIONS: In stage I melanoma, only clinical examination is really cost-effective in the detection of metastases. However, many metastases are likely to become prominent between two examinations if patients are examined less than 3 times a year. A progressive decrease in frequency is thus not advisable, until the risk is considered low enough to stop follow-up.

Role of sun exposure on nevus. First study in age-sex phenotype-controlled populations.

BACKGROUND: These studies were designed to assess the influence of sun exposure on nevi in white people. To eliminate the confounding effect of age, sex, and phenotype, two parallel studies were conducted on people of the same age (17 to 24 years; median, 20 years old), sex (male), and phenotype: one in people with "red" phenotype (red or red-blond hair, white complexion on the inner part of the arm, and inability to tan) and one in people with "dark" phenotype (brown or black hair, dark complexion on the inner part of the arm, absence of freckles, and easy tanning without burning). RESULTS: In both groups, comparison of nevus counts on the inner and outer side of the upper extremities and comparison of mean density of nevi (number per square meter) in always-exposed and never-exposed skin show that the number of nevi is higher in sun-exposed areas. The density of large and atypical nevi was maximal on intermittently sun-exposed skin while the density of small nevi was maximal on always-exposed skin. The number of large nevi on intermittently exposed skin correlated with cumulative intensive exposure during beach recreation in the red phenotype group. The number of large nevi was significantly higher in red phenotypes who repeatedly experienced severe sunburns in their first 20 years of life. CONCLUSIONS: The number of nevi at the end of the second decade is influenced by cumulative sun exposure from birth. "Traumatizing" sun exposure, which is more frequent in the red phenotype than in the dark phenotype, has an influence on the number of large nevi and is therefore likely to make small nevi grow.

Large keratoacanthomas treated with intralesional interferon alfa-2a.

BACKGROUND: Spontaneous involution of giant keratoacanthomas (KAs) can leave large scars or cause mutilation. Human papillomaviruses have recently been demonstrated in KAs. Intralesional interferon alfa-2a (IFN alfa-2a) has been shown to have activity against different epithelial tumors and to have an antiviral effect. OBJECTIVE: This study was conducted to determine whether it was possible to stop extension of large KAs, to accelerate healing, and to obtain good cosmetic results with intralesional IFN alfa-2a. METHODS: Six large KAs were treated with intralesional IFN alfa-2a. RESULTS: Regression was obtained in five cases in 3 to 7 weeks with excellent cosmetic results. The main side effect was pain during injection. CONCLUSION: Our results suggest that this treatment hastens healing and limits scarring.

Study of sunbathing habits in children and adolescents: application to the prevention of melanoma.

Excessive sun exposure in the first 15 years of life has been shown to be a determinant risk factor for melanoma. This study was conducted on a randomly selected sample of 200 adolescents (13-14 years old) and 150 children (3 years old) in Marseille (South of France). Children and adolescents were examined and interviewed (mothers answered for young children). Our results show that a large number of highly sensitive children were not identified as such by their parents and most adolescents do not realize or at least admit being highly sun sensitive. Adequate sun protection measures were used in only 63% of 3-year-olds and 38% of adolescents. With reference to their constitutional skin sensitivity and taking into account their possible use of effective sun protection measures, 33% of the children and 62% of the adolescents were highly overexposed. Only good sun protection habits of the mother were predictive of acceptable sun exposure in children. In the adolescents the predictive variables were sun protection habits of the father and sunbathing only to obtain a tan. The main reason why adolescents sunbathed was embellishment. Conversely, most mothers said that they exposed their young children to the sun for health. Many adolescents and mothers were reasonably well informed but considered the risk of sun exposure to be exaggerated by the media. These results may be important to determine the targets of future melanoma prevention campaigns.

Palmoplantar orthokeratotic filiform hyperkeratosis in a patient with associated Darier's disease. Classification of filiform hyperkeratosis.

We present here the third published case of palmoplantar orthokeratotic filiform hyperkeratosis of particular clinical interest because of associated Darier's disease. We propose a classification of filiform hyperkeratosis in three groups on the basis of the topography (i.e. palmar and plantar, disseminated with palmoplantar sparing and linear) and the histology (i.e. porokeratosis or orthokeratosis) of the lesions. This keratinization disorder does not seem to be a specific disease entity but rather a syndrome secondary to various disorders.

Extra-anogenital HPV16-related bowenoid papulosis.

In this report we describe a case of bowenoid papulosis (BP) on the face of a 44 year old Algerian man. To our knowledge this is the first reported case of isolated extragenital BP. The presence of type 16 human papilloma virus was demonstrated by in situ hybridisation. This case underscores that multiple HPV-induced severe intraepithelial neoplasia, the so-called BP, is not restricted to the anogenital area.