The association between pesticide use and cutaneous melanoma: a systematic review and meta-analysis.

BACKGROUND: The incidence of cutaneous melanoma (CM), the deadliest form of skin cancer, has gradually increased in the last decades among populations of European origin. Epidemiological studies suggested that farmers and agricultural workers are at an increased risk of CM because they were exposed to pesticides. However, little is known about the relationship between pesticides and CM. OBJECTIVES: To investigate the association between exposure to pesticides and CM by systematically reviewing the literature. Secondary aim was to determine the categories of pesticides mainly involved in CM development. METHODS: A systematic review of the literature was performed up to September 2018 using MEDLINE, Embase and Web of Science. Studies assessing CM risk in licensed pesticide applicators were considered. Strict criteria were established to select independent studies and risk estimates; random effect models, taking into account heterogeneity, were applied. A pooled risk estimate for CM was calculated for the use of each type of pesticide and type of exposure. Between-study and estimate heterogeneity was assessed and publication bias investigated. RESULTS: A total of nine studies (two case-controls and seven cohorts) comprising 184 389 unique subjects were included. The summary relative risks for the categories 'herbicides - ever exposure', 'insecticides - ever exposure', 'any pesticide - ever exposure' and 'any pesticide - high exposure' resulted 1.85 [95% confidence interval (CI): 1.01, 3.36], 1.57 (95% CI: 0.58, 4.25), 1.31 (95% CI: 0.85, 2.04) and 2.17 (95% CI: 0.45, 10.36), respectively. Herbicides and insecticides had no between-study heterogeneity (I2  = 0%), while a significant heterogeneity (I2  > 50%) was detected for the high exposure to any pesticide. No indication for publication bias was found. CONCLUSIONS: Individuals exposed to herbicides are at an increased risk of CM. Future properly designed observational studies are required to confirm this finding.

Apremilast in psoriasis - a prospective real-world study.

BACKGROUND: Apremilast is a novel oral phosphodiesterase-4 inhibitor approved for psoriasis treatment. Randomized trials have documented its efficacy and safety, but data on real-world patients are scarce. OBJECTIVES: We aim to characterize psoriasis patients treated with apremilast in a real-world setting and calculate drug survival as an important measure of efficacy and compliance. METHODS: All patients with psoriasis who received apremilast between 1 April 2015 and 19 January 2017 were evaluated every 4 weeks, and we documented: age, weight, height, smoking status, family history of psoriasis, joint involvement, previous treatments, psoriasis area severity index (PASI) scores, and the onset and duration of adverse events (AE). Efficacy was analysed by PASI50, PASI75 and PASI90, reflecting the improvement of skin lesions compared to the PASI-baseline. Kaplan-Meier statistics were used for drug survival estimates. RESULTS: Forty-eight patients were included. The median apremilast drug survival was 12.5 weeks (range 1-87). Three patients (6.3%) reached PASI90, nine (18.8%) PASI75 and eight patients (16.7%) PASI50. Patient weight inversely correlated with a PASI50 response (P < 0.05, n = 37), and none of the obese patients (BMI > 30.0, n = 6) reached PASI75, compared to 32% of the non-obese patients (BMI < 30.0, n = 31). Thirty-one patients (64.6%) reported at least one AE, most frequently diarrhoea (n = 21, 43.8%), headache (n = 7, 14.6%) and joint pain (n = 5, 10.4%). CONCLUSIONS: Despite differences between real-world and trial patients, apremilast is safe and effective for the treatment of skin psoriasis in the daily practice. Up to 40% of patients will reach PASI50 or higher, but only few patients will reach PASI90. Bodyweight might affect drug efficacy.

Efficacy of electrochemotherapy for eruptive legs keratoacanthomas.

Generalized eruptive keratoacanthoma, is considered a serious condition because the eruptions are diffuse, persistent, and recurrent. Constant pruritus, visceral neoplasms, and unsatisfactory response to treatment are ominous prognostic factors. Even if skin cancers are usually well controlled with surgical and/or radiotherapic approaches, there are some cases in which these two techniques are not effective. With respect to surgery, radiotherapy and other standard treatments, ECT acts rapidly on multiple lesions with limited side effects and no functional impairment; moreover, repeated sessions can be performed to achieve or maintain the clinical response. We report a case of generalized eruptive keratoacanthomas in which electrochemotherapy was effective in inducing local regression of skin lesions. A 72-year-old woman with eruptive and painful keratoacanthomas for 3 months on both the lower limbs in which the conventional treatments could not be cosmetically acceptable. One session of electrochemotherapy with bleomycin sulfate was then performed on all isolated skin lesions. The treatment was well tolerated and led to a rapid clinical regression of the treated lesions. Use of ECT should be considered as an excellent alternative to current therapies in treatment of painful eruptive keratoacanthomas with a significant improvement of quality of life.

Phenotypical characterization of circulating cell subsets in pyoderma gangrenosum patients: the experience of the Italian immuno-pathology group.

BACKGROUND: No data are available as to the phenotype of circulating lymphocyte subsets in pyoderma gangrenosum (PG). AIM: To analyse the expression of different chemokine receptors associated to T-helper (Th)1 (CCR5), Th2 (CCR4) and Th17 (CCR6), as well as the regulatory T-cell subset (Treg) and dendritic cell polarization in the blood of newly diagnosed untreated PG patients. MATERIALS AND METHODS: Multi-parameter flow cytometry was performed on blood samples from 10 PG patients collected at first diagnosis among centres belonging to the Italian Immuno-pathology Group. Blood samples from 10 age- and sex-matched healthy controls (HC) were used as controls. RESULTS: PG patients are characterized by an over-expression in the blood of the CD4+CCR5+ and CD4+CCR6+ and a down-regulation of CD4+CCR4+ counts with respect to healthy subjects. Moreover, they show increased levels of myeloid derived dendritic cells type1 and reduced levels of the Treg CD4+CD25highFOXP3+ subset. CONCLUSIONS: The pattern of chemokine expression argues in favour of a Th1 (CCR5+) and Th17 (CCR6+) polarization with a down-regulation of Th2 (CCR4+).

Sentinel Lymph Node Biopsy in Thick-Melanoma Patients (N=350): What is Its Prognostic Role?

BACKGROUND: Sentinel lymph node biopsy (SLNB) is currently recommended for patients with intermediate-thickness melanomas (T2-T3). Historically, T4 melanoma patients have not been considered good candidates for SLNB because of the high risk of distant progression. However, some authors suggest that T4 melanoma patients could be considered as a heterogeneous group that could benefit from SLNB. METHODS: We retrospectively analyzed 350 patients with thick (>4 mm) melanomas between 1999 and 2011. Patients were stratified into three groups depending on the results of SLNB: (1) 94 SLNB-negative; (2) 84 SLNB-positive; and (3) 172 SLNB not performed (observation group). The associations of clinical-pathologic features with the result of SLNB, disease-free interval (DFI), and disease-specific survival (DSS) were analyzed. RESULTS: Multivariate analyses confirmed a better prognosis for SLN-negative patients compared with patients in the observation group (DSS hazard ratio [HR] 0.62, p = 0.03; DFI HR 0.47, p < 0.001). The observation group was shown to have the same prognosis as the positive-sentinel lymph node group, when adjusted for principal confounders in the model. CONCLUSIONS: We confirmed that thick-melanoma patients are a heterogeneous group with different prognosis. In our experience, SLNB allowed for an appropriate stratification of patients in different survival groups. On the basis of our results, we strongly recommend the routine execution of SLNB in cases of primary melanoma thicker than 4 mm.

Mycoplasma pneumoniae-associated mucositis--case report and systematic review of literature.

BACKGROUND: Mycoplasma pneumoniae, a bacterium known to be a common cause of pneumonia, has been documented to cause complications such as debilitating mucositis previously described as an atypical Stevens-Johnson syndrome without skin lesions. However, in the spectrum of epidermal dermatopathies, the condition is increasingly recognized as a separate entity, now termed M. pneumoniae-associated mucositis (MPAM). OBJECTIVES: We present a case of MPAM and systemically review the literature to discuss diagnostic and therapeutic options. METHODS: A systematic literature search was performed to find studies reporting MPAM in adults. We extracted and analysed patient demographics, disease symptomatology, diagnostic testing and treatment. RESULTS: Eleven articles, describing 12 patients and our own patient met the predefined criteria and were analysed. Respiratory, ocular and oral symptoms were present in all patients. Therapies predominantly included antibiotics (10 of 13) and immunosuppressive treatment (9 of 13) leading to complete resolution of symptoms in all patients. CONCLUSION: Our findings highlight that MPAM should be recognized as a distinct disease entity within the spectrum of epidermal dermatopathies. We discuss and show in our patient why M. pneumoniae IgA serum levels could prove to be more reliable diagnostic tools in the MPAM diagnosis than the widely used IgG and IgM titre levels.

Low-dose inhalation of interleukin-2 bio-chemotherapy for the treatment of pulmonary metastases in melanoma patients.

BACKGROUND: Interleukin-2 (IL-2) treatment for patients with metastatic melanoma has shown remarkable durable responses. Systemic administration of IL-2 may cause severe side effects, whereas local administration is considered to be a safe alternative. The lungs are common sites of metastases in melanoma patients causing considerable respiratory problems. We sought to evaluate the potential antitumoral effect of a low-dose inhalative IL-2 (lh-IL-2) regimen for patients with melanoma lung metastases. In addition, we explored the prophylactic potential of Ih-IL-2 after surgical removal of lung metastases in a study carried out in an outpatient setting. METHODS: Twenty patients with American Joint Committee on Cancer stage-IV (M1b and M1c) melanoma were enrolled in this study and treated with 3 × 3 million IU inhalative IL-2 q.d. together with monthly dacarbazine bolus injections. Five patients received lh-IL-2 after surgical resection of lung metastases to prevent recurrence of the disease (prophylaxis group, N=5). All other patients were enrolled in the treatment group (N=15). Clinical evaluations were carried out monthly and radiological follow-up was performed every third month. RESULTS: Nine patients in the treatment group had a clinical benefit with partial regression (27%) or stable disease (33%). Four patients had progression of lung metastases (26.7%) and two patients were not evaluable (13.3%). In the prophylaxis group, none of the patients developed new lung metastases during lh-IL-2 therapy. The median follow-up period was 7.8 months in the treatment group and 25.7 months in the prophylaxis group. In the majority of patients, treatment was well tolerated. CONCLUSIONS: Low-dose IL-2 inhalation might offer an effective and safe treatment option for lung metastases in melanoma patients. In addition, lh-IL-2 may have a prophylactic potential to prevent recurrence in the lungs after pulmonary melanoma metastasectomy. Administration can easily be performed in an outpatient setting, thus offering an attractive treatment option.

Favourable prognostic role of regression of primary melanoma in AJCC stage I-II patients.

BACKGROUND: The prognostic significance of regression in primary melanoma has been debated over the past few years. Once it was considered to be a negative prognostic factor, as it may have prevented proper melanoma thickness measurement, therefore affecting the staging of the tumours. For this reason, it was considered to be an indication for sentinel lymph node biopsy (SLNB) in melanoma < 1 mm. OBJECTIVES: To ascertain the utility of SLNB in thin melanoma and to clarify the role of regression in disease-free survival (DFS) and overall survival (OS) in our series. METHODS: We analysed data collected from 1693 consecutive patients with AJCC (American Joint Committee on Cancer) stage I-II melanoma. RESULTS: Globally, SLNB was performed in 656 out of 1693 patients. Regression was present in 349 patients and 223 of them were characterized by thin lesions. SLNB was performed in 104 cases of thin melanoma with regression. The majority of regional lymph node metastases were observed in patients who did not undergo SLNB (89 out of 132). Among the remaining 43 'false negative' patients only three showed regression in the primary. Using the Cox multivariate model, histological regression maintained a significant protective role [hazard ratio (HR) 0·62, P = 0·012 for DFS; HR 0·43, P = 0·008 for OS] when corrected for the principal histopathological and clinical features, despite SLNB. CONCLUSIONS: We confirmed that regression alone should not be a reason to perform SLNB in thin melanoma and, on the contrary, it can be considered a favourable prognostic factor in patients with AJCC stage I-II melanoma.

Relevance of multiple basin drainage and primary histologic regression in prognosis of trunk melanoma patients with negative sentinel lymph nodes.

BACKGROUND: Lymphatic drainage to multiple basins (MLBD) is frequently observed in patients with primary melanoma located in the trunk. Conflicting data regarding the prognostic impact of MLBD are reported. OBJECTIVE AND METHODS: We reviewed our case series of 352 patients with trunk melanoma to evaluate the pattern of basin drainage and to analyse whether different basin drainages may have different significance in negative sentinel lymph node (SLN) patients. The presence of single/multiple basin drainage, the status of SLN, the presence of melanoma regression, Breslow thickness, ulceration and type of melanoma were recorded for each patients and correlated to Disease Free Survival (DFS) and Overall Survival (OS). RESULTS: MLBD occurred in 77 patients (21.9%) and single basin lymphatic drainage (SLBD) occurred in 275 patients (79.1%). The presence of metastases in SLN was not significantly different in patients with MLBD compared to those with SLBD (26% vs. 19.6%). No differences in OS and DFS were found in SLBD/MLBD independently from SLN status. However DFS was higher in patients with MLBD and negative SLN (P = 0.0001), in addition, in patients with negative SLN and SLBD disease recurrence was 19% while was only 7% in patients with negative SLN obtained from MLBD (P = 0.03). Multivariate analysis showed that Breslow thickness <2 mm, MLBD pattern and regression of melanoma were favourable variables for DFS of patients with negative SLN. CONCLUSIONS: An accurate study of the drainage basin and of all the SLNs obtained from MLBD is recommended because of the impact in prognosis of melanoma of the trunk.

Melanoma in patients younger than 20 years.

AIM: Melanoma is rare in children and uncommon in adolescents. Clinical and prognostic factors can differ from adult population. There is often a delay in diagnosis and the therapeutic management is not unequivocally established. The aim of this study was to review our monocentric case series to establish the characteristics of the population and the possible different behaviour of the malignancy compared to adults. METHODS: From 1975 to 2011 we selected 36 out of 43 patients with a diagnosis of melanoma before the age of 20. We reported a female predominance, the most common site of primary lesions for both sexes were the lower extremities and according to adulthood population the most common histotype was Superficial Spreading Melanoma. RESULTS: None of our patients presented distant metastasis at diagnosis, but 29.4% showed a progression, and the 17.6% died during the follow-up. A significant difference based on gender was found at the multivariate analysis on Disease free survival as well as Breslow thickness, but only Breslow thickness was the only parameter that maintained a role on survival at multivariate analysis when corrected for gender and age. We performed the sentinel lymph node biopsy in 3 patients and they all resulted negative. CONCLUSION: Despite our small case series we observed some important differences of melanoma in children compared to adults. It remains difficult to establish the prognostic factors in younger melanoma patients. Similar to adults, the detection of melanoma in an early phase of development, with a low Breslow thickness, is the most important prognostic factor.

Oncogenic KIT mutations in different exons lead to specific changes in melanocyte phospho-proteome.

UNLABELLED: Mutations in the proto-oncogene c-KIT (KIT) are found in several cancers, and the site of these mutations differs markedly between cancer types. We used site directed mutagenesis to induce KIT(559), KIT(642) and KIT(816) mutations in primary human melanocytes (PHM) and we investigated the impact of each mutation on KIT function. We studied canonical KIT-signaling pathways by immunoblotting, and we used stable isotope labeling by amino acids in cell culture (SILAC) and kinase prediction models to identify kinases differently activated in respective mutants. We validated our results with the analysis of phosphorylation levels of selected substrates for each kinase. We concluded that CK1 ε and δ are more active in cell clones harboring KIT(559) and KIT(642) mutations, whereas PAK4 is more active in clones with KIT(816) mutation. Our findings might help to develop further therapeutic options for tumors with specific KIT mutations in different domains. BIOLOGICAL SIGNIFICANCE: Different types of cancers harbor mutations in the oncogene KIT. The use of small molecules inhibitors directly targeting KIT had a limited success in the treatment of patients with KIT mutant cancers. Our study describes specific phospho-proteome changes due to different KIT mutations, and provides targets of further therapeutic options.

Combined Inhibition of MEK and Plk1 Has Synergistic Antitumor Activity in NRAS Mutant Melanoma.

About one-third of cancers harbor activating mutations in rat sarcoma viral oncogene homolog (RAS) oncogenes. In melanoma, aberrant neuroblastoma-RAS (NRAS) signaling fuels tumor progression in about 20% of patients. Current therapeutics for NRAS-driven malignancies barely affect overall survival. To date, pathway interference downstream of mutant NRAS seems to be the most promising approach. In this study, data revealed that mutant NRAS induced Polo-like kinase 1 (Plk1) expression, and pharmacologic inhibition of Plk1 stabilized the size of NRAS mutant melanoma xenografts. The combination of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) and Plk1 inhibitors resulted in a significant growth reduction of NRAS mutant melanoma cells in vitro, and regression of xenografted NRAS mutant melanoma in vivo. Independent cell cycle arrest and increased induction of apoptosis underlies the synergistic effect of this combination. Data further suggest that the p53 signaling pathway is of key importance to the observed therapeutic efficacy. This study provides in vitro, in vivo, and first mechanistic data that an MEK/Plk1 inhibitor combination might be a promising treatment approach for patients with NRAS-driven melanoma. As mutant NRAS signaling is similar across different malignancies, this inhibitor combination could also offer a previously unreported treatment modality for NRAS mutant tumors of other cell origins.

Surgical strategy management following lymph nodal positivity at the three levels (a retrospective and perspective study).

The purpose of this study is to evaluate the type of distribution, regular or irregular, of metastases in lymph nodes of I, II and III level. We inted also to establish if the levels of lymph nodal areas represent an evaluation index of prognostic risk more effective than other ones. The results evidenced that in 19.2% of all the classes N+ metastases were not increasing regularly from the level I to the level III. The influence of seven factors on disease free survival has been evaluated: pT, pN, number of metastatic nodes, ER+ or ER-, PgR+ or PgR-, grading, metastatic level at axillary lymph nodes. The present report points out that only the extent of tumor and lymph nodal level have a statistically significant influence on disease free survival. Comparison among disease free survival curves stage N0 with N+ at I level and with N+ at II level revealed that there is no significant difference of survival among these classes, while the comparison between the first 3 classes and N+ at III level is statistically significant.

[Preoperative determination of CEA and GICA in gastric neoplasms]. / Il dosaggio preoperatorio del CEA e del GICA nelle neoplasie gastriche.

Data are presented on a series of 39 stomach cancer patients subjected to preoperative assays of blood CEA and GICA. High levels of both markers were found in the advanced (stage III and IV) cases. The use of both markers together improved the sensitivity of the test but only to 30%. Nevertheless preoperative CEA and GICA assays are recommended because of the information they provide about tumor stage.

[Primary neoplasms of the gallbladder. Remarks on a case series]. / Le neoplasie primitive della colecisti. Considerazioni su una casistica.

Data relating to a series of 22 patients suffering from primary gallbladder cancer are reported. In 8 cases the condition was benign, in 14 malignant. In 21 cases, concomitant presence of gallbladder calculosis was encountered. Survival in patients with gallbladder carcinoma was poor and significant in only 2 cases in which the tumour was observed at a non-advanced stage.

[Enteral nutrition in the pre- and postoperative therapy of gastric neoplasms. Comments on 21 cases]. / La nutrizione enterale nella terapia pre-postoperatoria delle neoplasie gastriche. Considerazioni su 21 casi.

Results of personal experience of the application of enteral nutrition in a group of patients (21) submitted to surgery for gastric cancer are reported. Enteral nutrition proved easy to perform, provided a significant improvement in some of the parameters considered in the study, was without significant complications and presented acceptable management costs.

[A case of hydrosalpinx permagna]. / A proposito di un caso di idrosalpinge permagna.

A case of hydrosalpinx permagna with liquid content of fully 22 litres is reported. Historical and objective data are illustrated together with the operation performed, the postoperative course, follow-up and discussion of the case.

[Benign lesions of the salivary glands of the lip. Apropos of 3 cases]. / Lesioni benigne delle ghiandole salivari delle labbra. A proposito di tre casi.

The paper reports data concerning three cases of benign salivary gland lesion of the lip in order to contribute to the number of case studies given the reduced frequency of this pathology. Patients underwent surgical exeresis of the lesions and no relapse was observed during follow-up.

[Several cases of benign neoplasms of the parotid gland (excluding pleiomorphic adenomas)]. / Considerazioni su alcuni casi di neoplasie benigne della parotide (esclusi gli adenomi pleiomorfi).

A series of 7 patients (4 males, 3 females) suffering from benign, non-pleiomorphous neoplasia of the parotid observed in the period 1963-1983 is reported. The most commonly adopted surgery was extracapsular enucleo-resection. No post-operative complications were observed. No recurrences were encountered during follow-up.