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Bempegaldesleukin (BEMPEG: NKTR-214) is an immunostimulatory IL-2 cytokine prodrug engineered to deliver a controlled, sustained and preferential IL-2 pathway signal. Nivolumab (NIVO), a PD-L1 inhibitor, has been shown to prolong survival in patients with advanced melanoma and recurrence-free survival in the adjuvant setting. PIVOT-02 showed that BEMPEG plus NIVO was well-tolerated and demonstrated clinical activity as first-line therapy in metastatic melanoma. PIVOT-12 is a randomized, Phase Ill, global, multicenter, open-label study comparing adjuvant therapy with BEMPEG plus NIVO versus NIVO alone in adult and adolescent patients with completely resected cutaneous stage III/IV melanoma at high risk of recurrence. The primary objective is to compare the efficacy, as measured by recurrence-free survival, of BEMPEG plus NIVO versus NIVO. Lay abstract: Following surgery, patients with advanced melanoma may require further treatment to reduce the likelihood of disease recurrence. Nivolumab (NIVO), a checkpoint inhibitor, reduces the risk of melanoma recurrence by enhancing the ability of the immune system to fight disease. Despite the availability of NIVO and other therapies, many patients with melanoma still experience disease recurrence after surgery. This article presents information on a clinical trial named PIVOT-12, which aims to assess the effectiveness of a new investigational drug called bempegaldesleukin that modifies the immune system and is given with NIVO to patients with stage III/IV melanoma following surgery. The main end point being measured is recurrence-free survival, which measures the time between a patient starting the study and the date of disease recurrence.

Microsatellite instability (MSI) is caused by replication errors due to deficient DNA mismatch repair and has been associated with tumour progression in different types of cancer. Controversial results have been provided about both frequency and significance of MSI in malignant melanoma (MM). In this study, time of onset and relative incidence of MSI were determined during the progression of melanocytic tumours, starting from benign melanocytic nevi. MSI was studied at 13 loci containing single-, di-, or trinucleotide repeat sequences and mapping to five different chromosomal locations. Tumours were classified as low-frequency (L-MSI+) or high-frequency (H-MSI+) MSI, when one or at least two marker loci (respectively) displayed mutant alleles in tumour DNA compared to corresponding normal tissue DNA. None of the 8 melanocytic nevi showed MSI, whereas moderate frequency of H-MSI was detected in dysplastic nevi (1/11; 9%) and primary melanomas (6/56; 11%). The incidence of MSI was increased in melanoma metastases from the same patients (H-MSI: 9/42; 21%). In contrast to previously reported data showing higher rates of MSI in melanoma, genetic instability seems to be present in a minority of MM lesions. However, our findings are consistent with the hypothesis that MSI may be sequentially induced during malignant evolution, contributing to the progression of a subset of melanocytic tumours.

Purpose: Factors that are predictive of prognosis in patients who are diagnosed with malignant melanoma (MM) are widely awaited. Detection of circulating melanoma cells (CMCs) by reverse transcriptase-polymerase chain reaction (RT-PCR) has recently been postulated as a possible negative prognostic factor. Two main questions were addressed: first, whether the presence of CMCs, defined as the patient being positive for any of the three markers, had a prognostic role; and second, what the predictive value of each individual marker was. Patients and Methods: A consecutive series of 200 melanoma patients observed between January 1997 and December 1997, with stage of disease ranging from I to IV, was analyzed by semiquantitative RT-PCR. Tyrosinase, p97, and MelanA/MART1 were used as markers to CMCs on baseline peripheral blood samples. Progression-free survival (PFS) was used as a unique end point and was described by the product limit method. Multivariable analysis was applied to verify whether the auspicated prognostic value of these markers was independent of the stage of disease, and a subgroup analysis was performed that excluded patients with stage IV disease. Results: Overall, 32% (64 of 200) of patients progressed, and a median PFS of 52 months in the whole series was observed. The presence of CMCs and the markers individually or combined was predictive of prognosis in the univariate analysis but did not provide additional prognostic information to the stage of disease in multivariable models. In the subgroup analysis of stage (ie, I–III subgroup), similar results were observed. Conclusion: Detection of CMCs in peripheral blood samples at the time of MM diagnosis by semiquantitative RT-PCR does not add any significant predictive value to the stage of disease. Thus, this approach should not be used in clinical practice, and further studies are required to determine its usefulness.

"In the last few years, the field of tumor immunology has significantly expanded and its boundaries, never particularly clear, have become less distinct. Although the immune system plays an important role in controlling tumor growth, it has also become clear that tumor growth can be promoted by inflammatory immune responses. A good example that exemplifies the ambiguous role of the immune system in cancer progression is represented by interleukin 18 (IL-18) that was first identified as an interferon-γ-inducing factor (IGIF) involved in T helper type-1 (Th1) immune response. The expression and secretion of IL-18 have been observed in various cell types from immune cells to circulating cancer cells. In this review we highlighted the multiple roles played by IL-18 in immune regulation, cancer progression and angiogenesis and the clinical potential that may result from such understanding"

Background The effect of the addition of fotemustine and/or interferon (IFN) to standard therapy with dacarbazine alone in patients with advanced malignant melanoma was investigated in a multicenter, randomized 2x2 factorial design trial. Methods A total of 260 patients were randomly assigned to one of four treatment groups: (A) fotemustine and dacarbazine repeated on 3-week cycle; (B) same treatment as (A) plus IFN-α2b three times per week; (C) dacarbazine alone repeated on 3-week cycle; (D) same treatment as (C) plus IFN-α2b three times per week. Two comparisons were planned to assess the efficacy of fotemustine (groups A+B vs. C+D) and IFN-α2b (groups A+C vs. B+D). Results Addition of fotemustine did not significantly improve overall survival (OS) (p=0.28) or progression-free survival (PFS) (p=0.55); Hazard ratio (HR) for OS was 0.93 (95% CI 0.71-1.21). Similarly, addition of IFN-α2b did not improve OS (p=0.68) or PFS (p=0.65); HR for OS was 0.92 (95% CI 0.70-1.20). Overall response rate was not improved by the addition of either fotemustine (p=0.87) or IFN-α2b (p=0.57). The combination of all three drugs resulted in the highest occurrence of adverse events. Conclusions No significant improvement in outcomes were observed with the addition of either fotemustine or IFN-α2b to dacarbazine. Trial registration ClinicalTrials.gov: NCT01359956

A functional single nucleotide polymorphism (SNP) 309 T/G within mouse double minute 2 (MDM2) gene has been linked to onset and outcome of disease in tumors. Two published studies have shown discordant results regarding the effect of this SNP on age at diagnosis of cutaneous melanoma (CM) in Caucasian female populations. Here, we examined the age at diagnosis and clinical associations of CM with SNP309 and the related polymorphism, p53 Arg72Pro, in an Italian population (249 CM patients and 291 cancer-free controls) composed of women and men. MDM2 intronic region of 294 bp was directly sequenced, whereas Arg72Pro SNP was analyzed by polymerase chain reaction-restriction fragment length polymorphism. No associations were found among the SNP309, Arg72Pro, risk of CM, age at diagnosis and presence of metastasis in total subjects and when stratified according to the gender. The SNP309 was significantly associated with tumor Breslow thickness. The P-value in the minor allele recessive mode was 0.02, and the odds ratio (OR) adjusted for gender and age was 3.11 (95% confidential interval (CI)=1.21–8.00). The SNP309 is not associated with the risk and age of onset of CM, and the presence of metastasis in an Italian population but the SNP309 GG may be a risk genotype for increasing in tumor Breslow thickness.

Kerion Celsi is a parasitic fungal skin infection that tends to occur mainly on the back of the neck, scalp or beard. It is caused by animal fungi. Sometimes the condition resolves itself in a matter of weeks but hair loss in the affected area may be permanent. We report a case of a young woman with Kerion Celsi favored by the use of a tretinoin+minoxidil+betametasone valerate lotion.

The aim of the present study was to assess the prognostic value of soluble interleukin-2 receptor (sIL-2R) serum levels in stage I-III melanoma patients. The levels of sIL-2R were determined using an enzyme immunometric test kit in 329 patients affected by malignant melanoma (MM) from 1995 to 2004. Correlations between sIL-2R values, baseline patients and tumour features were studied by contingency tables and the chi-square test. The Kaplan-Meier product limit method was applied to plot disease-free survival (DFS) curves. Univariate analysis was performed with the Log-rank test. Cox proportional-hazards regression was used to analyse the effect of several risk factors on DFS. In total, 2330 blood samples were collected during follow-up of 329 MM patients. Forty-five (13.7%) patients had Breslow tumour thicknessor=1.00, 83 (25.2%) patients1.00 andor=2.00 mm, 72 (21.9%) patients2.00 andor=4.00 mm, and 47 (14.3%) patients4.00 mm. Ulceration was present in 64 cases (19.4%). Thirty-nine sentinel lymph nodes (SLNs) (11.8%) were infiltrated by MM. Soluble IL-2R values ranged from 130 to 1420 U/ml; median value was 500 U/ml. One hundred twenty-one (36.8%) patients presented with sIL-2R600 U/ml at first measure (FM), 194 patients (58.9%) with values increasing up to or more than 600 U/ml [increasing values (IV) pattern]. A correlation was found between Breslow's tumour values and the IV sIL-2R pattern group (P=0.0304 with chi2 test). Gender, presence of ulceration, Breslow tumour thickness, FM and IV sIL-2R pattern groups had a significant prognostic value for DFS. At multivariate analysis, presence of ulceration, gender, FM and IV sIL-2R pattern groups emerged as independent prognostic factors for DFS. The 5-year DFS rate was 88% for patients with FM600 U/ml and 76.9% for patients with FM600 U/ml. In IV pattern, the 5-year DFS rate was 69.5% compared to 87% for patients with no sIL-2R values600 U/ml during follow-up. sIL-2R values are associated with progression of MM. Further studies are needed to address the role of the IL-2/IL-2R/sIL-2R axis in melanoma biology.

BACKGROUND: CXCR4, the chemokine receptor for CXCL12, has recently been involved in the metastatic process of several neoplasms. MATERIALS AND METHODS: The expression of CXCR4 was evaluated by immunohistochemistry of colorectal tissue samples and by flow cytometry on Caco2, GEO, SW480, SW48, Lovo and SW620 human colon carcinoma cell lines. Correlations with pathological characteristics of the specimens were analysed with chi-square test. To verify the functional status of CXCR4, cell lines were tested in adhesion, migration, and proliferation assays. RESULTS: We studied the expression of CXCR4 in 88 human colorectal tissues and we found that CXCR4 was expressed in > 10% of epithelial cells in 50% of normal mucosae (7/14), in 55% of polyps (29/53), in all of carcinomas (16/16) and hepatic metastasis (5/5). Notably, CXCR4 was significantly over-expressed in cancerous lesions (carcinomas and metastasis) compared to non-cancerous lesions (normal mucosa and polyps) (P = 0.003) and in adenomatous polyps versus hyperplastic polyps (P = 0.009). The diameter of a polyp was also significantly associated with CXCR4 expression (P = 0.031). SW480, SW48 and SW620 cell lines showed the highest levels of CXCR4 (60-80% of positive cells). Adhesion, migration, and proliferation increased in response to the CXCL12 chemokine. These effects were abrogated by the addition of anti-CXCR4 antibodies. Further, CXCL12 activated ERK1/2 in SW480 cells. CONCLUSIONS: These data suggest that CXCR4 might play a role in colon cancer cell properties and that anti-CXCR4 antibodies could have therapeutic effects against colorectal cancer.

Purpose: The purpose is to evaluate the expression of CD40, a membrane protein predominantly expressed on B cells, dendritic cells, and macrophages, in a series of adult soft tissue sarcomas and to test its possible prognostic value. Experimental Design: CD40 expression was studied by immunohistochemistry. Correlations with other baseline characteristics of patients and tumors were analyzed with χ2 test. The prognostic value was studied with univariable and multivariable analysis adjusted by age, sex, tumor size, grade, location, and distant metastases. Results: Eighty-two patients, between January 1994 and May 2001, were analyzed. Membrane or cytoplasmic staining for CD40 protein was absent in 30% of the tumors but present in 50% of cells in 12 (15%) tumors. There was no correlation between CD40 expression and age, sex, size, grade, and location of the primary tumor and distant metastases. With 61 patients (74.4%) progressed and 31 (37.8%) dead, CD40 expression was a significant prognostic factor for disease-free and overall survival at univariable and multivariable analysis. Patients with tumors expressing CD40 in >50% of cells had a dramatically unfavorable prognosis with median disease-free and overall survival of 7 and 17 months, respectively, and hazard ratios of relapse and death as compared with patients with CD40-negative tumors of 2.89 (95% confidence interval: 1.26–6.60) and 6.92 (95% confidence interval: 2.18–22.0), respectively. Conclusions: These data suggest that expression of CD40 protein in >50% of cells might indicate an unfavorable prognosis in adult soft tissue sarcomas.

The authors report a case of congenital rubella in a 7-month-old female infant presenting a Blueberry Muffin Rash. Blueberry Muffin Syndrome is a cutaneous manifestation characterized by widespread maculo papular lesions of a reddish-blue or magenta colour, due to persistent dermal erythropoiesis in patients with congenital viral infections.