Nivolumab in never-smokers with advanced squamous non-small cell lung cancer: Results from the Italian cohort of an expanded access program.

OBJECTIVES:: Never-smokers may be a distinct subgroup among patients with advanced non-small cell lung cancer, appearing to benefit less from immunotherapy than smokers. We report results from never-smokers enrolled in the Italian cohort of the nivolumab expanded access program in pre-treated patients with advanced squamous non-small cell lung cancer. MATERIALS AND METHODS:: Nivolumab (3 mg/kg every 2 weeks for ≤24 months) was available on physician request. Efficacy data included objective tumor response, date of progression, and survival information. Safety was monitored. RESULTS:: Overall, 371 patients received at least one dose of nivolumab, including 31 never-smokers (8%). Objective response rate, disease-control rate, and median overall survival were 23%, 45%, and 12.1 months (95% confidence interval: 3.7-20.4), respectively, in never-smokers, and 18%, 47%, and 7.9 months (95% confidence interval: 6.2-9.6), respectively, in the overall expanded access program population. Any-grade and grade 3-4 treatment-related adverse events were reported in 12 (39%) and 3 (10%) never-smokers, respectively, and in 109 (29%) and 21 (6%) patients, respectively, in the overall expanded access program population. Grade 3-4 treatment-related adverse events in non-smokers were increased transaminases (n = 2; 6%) and diarrhea (n = 1; 3%). Treatment-related adverse events led to treatment discontinuation in 4 non-smokers (17%) and in 26 patients (9%) overall. CONCLUSION:: Pre-treated never-smokers with advanced squamous non-small cell lung cancer in this Italian expanded access program demonstrated efficacy and safety that were consistent with those in the overall expanded access program population and clinical trials. These results suggest that a proportion of never-smoker patients with squamous non-small cell lung cancer may be responsive to immunotherapy. Other factors, such as the tumor mutational load and the status of programmed death-ligand 1, anaplastic lymphoma kinase, and epidermal growth factor receptor, might play a potential key role.

Efficacy and safety of ipilimumab in patients with advanced melanoma and brain metastases.

Patients with melanoma brain metastases have a poor prognosis and historically have been excluded from clinical trials. The Expanded Access Program (EAP) provided an opportunity to evaluate the feasibility of ipilimumab (3 mg/kg every 3 weeks for four doses) in patients with stage 3 (unresectable) or 4 melanoma and asymptomatic brain metastases, who had failed or did not tolerate previous treatments and had no other therapeutic option available. Tumor assessments were conducted at baseline and week 12 using immune-related response criteria and patients were monitored for adverse events (AEs). Of 855 patients participating in the EAP in Italy, 146 had asymptomatic brain metastases. With a median follow-up of 4 months, the global disease control rate was 27%, including 4 patients with a complete response and 13 with a partial response. Median progression-free survival and overall survival were 2.8 and 4.3 months, respectively and approximately one-fifth of patients were alive 1 year after starting ipilimumab. In total, 29% of patients reported a treatment-related AE of any grade, which were grade 3/4 in 6% of patients. AEs were generally reversible with treatment as per protocol-specific guidelines. Ipilimumab shows durable benefits in some patients with advanced melanoma metastatic to the brain, with safety results consistent with those previously reported in clinical trials.

Mucoepidermoid Carcinoma of the Thyroglossal Duct: Two Rare Entities in a Unique Case Report.

BACKGROUND: Mucoepidermoid Carcinoma (MEC) of the thyroid represents less than 0.5% of all thyroid neoplasms. Thyroglossal duct cyst carcinoma is a rare condition with only approximately 300 cases reported. CASE REPORT: A 34-year-old pregnant woman at 37 weeks gestation presented to an endocrinological center for primary autoimmune hypothyroidism. The thyroid ultrasound revealed a pseudonodular pattern. The patient was followed up after two years. She reported a full-term delivery without complications. A new thyroid ultrasound was performed, showing a cystic lesion in the median suprathyroid area, measuring 6 x 9 x 10 mm, not previously reported. After 4 months, the suprathyroid cystic lesion was confirmed by thyroid ultrasound, measuring 6 x 11 x 12 mm. The patient was referred for fine-needle aspiration cytology. Cytological examination showed lymphocytes, red blood cells, and some epithelial aggregates with large cytoplasm and nuclear polymetrism with oxyphilic aspects. The patient underwent the Sistrunk procedure for the suprathyroid lesion. The histological examination revealed lymphocytic thyroiditis in heterotopic thyroid tissue with solid cell nest, epidermoid epithelium, and mucus-secreting cells suggestive of low-grade mucoepidermoid carcinoma. The immunohistochemistry study was positive, exhibiting thyroid transcription factor 1 and cytokeratin-19. No positivity was observed for thyroglobulin, calcitonin, galectin-3, and Hector Battifora mesothelial antigen 1. The recent follow-up examination, 13 months after the surgery, has been found negative for disease recurrence. CONCLUSION: This is the first case of an MEC occurring within a thyroglossal duct. Considering the age of the patient, the histological diagnosis, and the absence of thyroid nodules and metastasis, we decided on the Sistrunk procedure without total thyroidectomy.

A pharmacoeconomic analysis from Italian guidelines for the management of prolactinomas.

Background: Prolactinoma, the most common pituitary adenoma, is usually treated with dopamine agonist (DA) therapy like cabergoline. Surgery is second-line therapy, and radiotherapy is used if surgical treatment fails or in relapsing macroprolactinoma. Objective: This study aimed to provide economic evidence for the management of prolactinoma in Italy, using a cost-of-illness and cost-utility analysis that considered various treatment options, including cabergoline, bromocriptine, temozolomide, radiation therapy, and surgical strategies. Methods: The researchers conducted a systematic literature review for each research question on scientific databases and surveyed a panel of experts for each therapeutic procedure's specific drivers that contributed to its total cost. Results: The average cost of the first year of treatment was €2,558.91 and €3,287.40 for subjects with microprolactinoma and macroprolactinoma, respectively. Follow-up costs from the second to the fifth year after initial treatment were €798.13 and €1,084.59 per year in both groups. Cabergoline had an adequate cost-utility profile, with an incremental cost-effectiveness ratio (ICER) of €3,201.15 compared to bromocriptine, based on a willingness-to-pay of €40,000 per quality-adjusted life year (QALY) in the reference economy. Endoscopic surgery was more cost-effective than cabergoline, with an ICER of €44,846.64. Considering a willingness-to-pay of €40,000/QALY, the baseline findings show cabergoline to have high cost utility and endoscopic surgery just a tad above that. Conclusions: Due to the favorable cost-utility profile and safety of surgical treatment, pituitary surgery should be considered more frequently as the initial therapeutic approach. This management choice could lead to better outcomes and an appropriate allocation of healthcare resources.

Italian Guidelines for the Management of Sporadic Primary Hyperparathyroidism.

AIM: This guideline (GL) is aimed at providing a clinical practice reference for the management of sporadic primary hyperparathyroidism (PHPT) in adults. PHPT management in pregnancy was not considered. METHODS: This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinology (AME) and Società Italiana dell'Osteoporosi, del Metabolismo Minerale e delle Malattie dello Scheletro (SIOMMMS) identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence. Those classified as "critical" were considered for the clinical practice recommendations. RESULTS: The present GL provides recommendations about the roles of pharmacological and surgical treatment for the clinical management of sporadic PHPT. Parathyroidectomy is recommended in comparison to surveillance or pharmacologic treatment in any adult (outside of pregnancy) or elderly subject diagnosed with sporadic PHPT who is symptomatic or meets any of the following criteria: • Serum calcium levels >1 mg/dL above the upper limit of normal range. • Urinary calcium levels >4 mg/kg/day. • Osteoporosis disclosed by DXA examination and/or any fragility fracture. • Renal function impairment (eGFR <60 mL/min). • Clinic or silent nephrolithiasis. • Age ≤50 years. Monitoring and treatment of any comorbidity or complication of PHPT at bone, kidney, or cardiovascular level are suggested for patients who do not meet the criteria for surgery or are not operated on for any reason. Sixteen indications for good clinical practice are provided in addition to the recommendations. CONCLUSION: The present GL is directed to endocrinologists and surgeons - working in hospitals, territorial services or private practice - and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise.

Pituitary Enlargement and Hypopituitarism in Patients Treated with Immune Checkpoint Inhibitors: Two Sides of the Same Coin?

BACKGROUND: Immune checkpoint inhibitor hypophysitis (IIHs) is an emerging problem in cancer patients treated with immune checkpoint inhibitors (ICIs). We aimed to describe the clinical and molecular features of a multicenter series of IIHs. METHODS: Demographic and clinical features were retrospectively collected for all cases. Anti-pituitary and anti-hypothalamus autoantibodies were also measured. RESULTS: Nine patients were included. Six patients were treated with nivolumab and three with ipilimumab. Secondary hypoadrenalism was diagnosed in all patients. Pituitary MRI showed pituitary enlargement in two cases and no abnormalities in the other seven. Anti-pituitary antibodies were positive in 57.1% of cases and anti-hypothalamus antibodies in 85.7% of cases. Multidisciplinary treatments were established by a neuroendocrinologist and oncologists: all patients were treated with hydrocortisone replacement; ICI was withdrawn in two cases. At follow-up, hypoadrenalism persisted in all cases. Pituitary enlargement on MRI spontaneously recovered in the two affected patients. We found that the typical features of hypophysitis involved more frequently females and patients treated with ipilimumab. CONCLUSIONS: Although this study did not clarify if autoimmune secondary hypoadrenalism and ICI hypophysitis on brain imaging are two sides of the same disease, our preliminary data underline the need for molecular studies of IIHs and of autoimmune ICIs-related hypopituitarism.

Italian Guidelines for the Management of Prolactinomas.

INTRODUCTION: This guideline (GL) is aimed at providing a reference for the management of prolactin (PRL)-secreting pituitary adenoma in adults. However, pregnancy is not considered. METHODS: This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinologi (AME) has identified potentially relevant outcomes, which have then been rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" have been considered in the systematic review of evidence and only those classified as "critical" have been considered in the formulation of recommendations. RESULTS: The present GL provides recommendations regarding the role of pharmacological and neurosurgical treatment in the management of prolactinomas. We recommend cabergoline (Cab) vs. bromocriptine (Br) as the firstchoice pharmacological treatment to be employed at the minimal effective dose capable of achieving the regression of the clinical picture. We suggest that medication and surgery are offered as suitable alternative first-line treatments to patients with non-invasive PRL-secreting adenoma, regardless of size. We suggest Br as an alternative drug in patients who are intolerant to Cab and are not candidates for surgery. We recommend pituitary tumor resection in patients 1) without any significant neuro-ophthalmologic improvement within two weeks from the start of Cab, 2) who are resistant or do not tolerate Cab or other dopamine-agonist drugs (DA), 3) who escape from previous efficacy of DA, and 4) who are unwilling to undergo a chronic DA treatment. We recommend that patients with progressive disease notwithstanding previous tumor resection and ongoing DA should be managed by a multidisciplinary team with specific expertise in pituitary diseases using a multimodal approach that includes repeated surgery, radiotherapy, DA, and possibly, the use of temozolomide. CONCLUSION: The present GL is directed to endocrinologists, neurosurgeons, and gynecologists working in hospitals, in territorial services or private practice, and to general practitioners and patients.

Italian Guidelines for the Management of Non-Functioning Benign and Locally Symptomatic Thyroid Nodules.

AIM: This guideline (GL) is aimed at providing a reference for the management of non-functioning, benign thyroid nodules causing local symptoms in adults outside of pregnancy. METHODS: This GL has been developed following the methods described in the Manual of the National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinology (AME) identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence and only those classified as "critical" were considered in the formulation of recommendations. RESULTS: The present GL contains recommendations about the respective roles of surgery and minimally invasive treatments for the management of benign symptomatic thyroid nodules. We suggest hemithyroidectomy plus isthmectomy as the first-choice surgical treatment, provided that clinically significant disease is not present in the contralateral thyroid lobe. Total thyroidectomy should be considered for patients with clinically significant disease in the contralateral thyroid lobe. We suggest considering thermo-ablation as an alternative option to surgery for patients with a symptomatic, solid, benign, single, or dominant thyroid nodule. These recommendations apply to outpatients, either in primary care or when referred to specialists. CONCLUSION: The present GL is directed to endocrinologists, surgeons, and interventional radiologists working in hospitals, in territorial services, or private practice, general practitioners, and patients. The available data suggest that the implementation of this GL recommendations will result in the progressive reduction of surgical procedures for benign thyroid nodular disease, with a decreased number of admissions to surgical departments for non-malignant conditions and more rapid access to patients with thyroid cancer. Importantly, a reduction of indirect costs due to long-term replacement therapy and the management of surgical complications may also be speculated.

Treatment-related side effects and quality of life in cancer patients.

BACKGROUND: Cancer leads to a complicated pattern of change in quality of life (QoL). OBJECTIVE: The aims of this study were to assess the impact of treatment-related side effects on QoL in cancer patients and to explore which other factors, and to what extent, contribute to explain low QoL scores. METHODS: One hundred twenty-three cancer patients receiving chemotherapy completed the self-administered questionnaires (Medical Outcomes Short-Form-36 (SF-36) and 12-item General Health Questionnaire). Multiple regression analyses were conducted with the SF-36 physical component summary (PCS) and SF-36 mental component summary (MCS) scores as the dependent variables and demographic and clinical factors as independent variables. RESULTS: Seventy-two percent of patients experienced treatment-related side effects, and 32% resulted positive for psychiatric diseases. Two multivariate analyses showed that worse PCS scores, like worse MCS scores, were significantly and independently predicted by treatment-related side effects (odds ratio (OR) = 5.00, 95%CI 1.29-19.45; OR = 8.08, 95%CI 2.03-32.22, respectively) and changes in health over the last 12 months (OR =2.34, 95%CI 1.47-3.76; OR = 3.21, 95%CI 1.90-5.41, respectively), after adjustment for age, gender, years of school, time from cancer diagnosis, and psychiatric disease. CONCLUSIONS: Given the new emphasis on QoL, we suggest that physicians have a responsibility to openly discuss therapy efficacy, prognosis as well as the potential for adverse events with their patients. Changes in health, as perceived by patient, should also be monitored at follow-up.

Endocrine Toxicities of Antineoplastic Therapy: The Adrenal Topic.

Immune checkpoint inhibitors (ICIs) have improved survival in patients affected by several solid tumours at the cost of new autoimmune adverse events. Endocrine toxicity is frequently reported in patients treated with these agents, mainly as thyroid dysfunction and hypophysitis. Primary adrenal insufficiency is reported in 1-2% of patients receiving a single ICI, but its rate is approximately 5% in patients treated with a combination of two ICIs. The clinical presentation of adrenal insufficiency may be insidious due to symptoms that are not specific. The same symptoms in cancer patients are frequently multifactorial, rendering the early diagnosis of adrenal insufficiency challenging in this group of patients. As adrenal insufficiency can be fatal if not rapidly diagnosed and treated, oncologists should be aware of its clinical presentations to timely involve endocrinologists to offer patients the appropriate management. In parallel, it is essential to educate patients, their caregivers, and relatives, providing them with detailed information about the risk of adrenal insufficiency and how to manage alarming symptoms at their onset. Finally, large collaborative trials are needed to develop appropriate tests to assess better the personal risk of drug-induced adrenal insufficiency and its early diagnosis and treatment, not only in cancer patients.

Obesity management: Attitudes and practice of Italian endocrinologists.

Introduction: Obesity is a global pandemic and is cause of serious concern in all regions of the world. It is important to raise the attention of health care professionals in order to provide early treatment of patients with obesity. Obesity management, however, varies greatly amongst endocrinologists with respect to attitudes to diagnosis and treatment. Aim of this study was to identify practices and needs of Italian endocrinologists with respect to people with obesity. Methods: In this study, all members of the Italian Association of Clinical Endocrinologists (AME) were invited to participate in a web-based survey concerning the management of obesity. Results: The response rate was 24.1% (542/2248). Nutritional and obesity problems were reported as major areas of interest by 29.4% of the participants. A large proportion of patients seeking an endocrine consultation for other reasons are affected by obesity, but one in five respondents addressed the issue in 25% or less of the cases, while one in three always dealt with the problem. Obesity was managed personally/within a dedicated team by 42.6% of participants, while the remainders referred the patient to a dietician/nutritionist or a 2nd level center for obesity therapy. Metformin was used in a median of 30% of the patients (Interquartile range: 10-50) and liraglutide in 10% of the cases (IQR 0-30), while orlistat (median 0%; IQR 0-10) and naltrexone/bupropion (median 0%; IQR 0-5) were seldom prescribed. Cost of therapy was considered as the major limitation to the use of anti-obesity drugs, affecting adherence to long-term treatment. According to 41.9% of respondents, psychological support should be offered to all patients with obesity. Finally, 56% of participants believe that the availability of new drugs will increase the number of patients candidate to drug therapy. Discussion: In conclusion, it is of primary importance to raise the awareness of endocrinologists towards the problem of obesity and increase their confidence in managing this pathological condition.

Predictors of existential and religious well-being among cancer patients.

Well-being and mental health are not only direct functions of amount of stress, but also depend on how people appraise and face critical situations. Spiritual well-being seems to be a central component of psychological health in physically healthy individuals and it offers some protection against end-of-life despair in those with chronic diseases. In this study, 250 out and in-patients with a cancer diagnosis were interviewed with standardised instruments to measure two aspects of spirituality, existential and religious well-being, coping strategies, psychological state, and quality of life (QoL). Using multivariate logistic regression models we found that coping strategies characterized by acceptance and positive reinterpretation of the stressor, and the absence of anxiety disorder, independently increased the likelihood of the existential well-being (Odds Ratio, OR, 7.7, and OR, 4.5, respectively), whereas religious well-being was not significantly associated with these variables. Our findings show that existential and religious well-being may be very different. A spirituality-based intervention could be differently utilized by patients with different beliefs, cognitive and behaviour characteristics. Measure of coping strategies and psychological state should be part of routine management of cancer patients.

Insulin Resistance as a Risk Factor for Cutaneous Melanoma. A Case Control Study and Risk-Assessment Nomograms.

Insulin resistance and obesity are suggested to have a key role in the molecular pathogenesis of various disorders, including several malignancies. Moreover, insulin resistance has recently been found to be associated with cutaneous and uveal melanoma, while a variable positive correlation between obesity and the risk of cutaneous melanoma was also found at least in men. The present trial aims at confirming whether insulin resistance, assessed with the homeostasis model assessment of insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI), is a risk factor for cutaneous melanoma. One hundred and thirty patients diagnosed with cutaneous melanoma and 130 age-, sex-, and skin phototype-matched controls were evaluated. At the univariate and multivariate analysis, the diagnosis of cutaneous melanoma was inversely related with insulin resistance (HOMA-IR) and positively with BMI (p = 0.0014 and p = 0.008, respectively). Consistently, insulin sensitivity (QUICKI) and BMI resulted positively associated with the diagnosis of cutaneous melanoma (p = 0.0001 and p = 0.0026, respectively). The results obtained are partially in agreement with those reported in the literature. By comparing our data with those generated by other studies, inconsistencies in key features among subgroups of different trials have emerged, possibly affecting final correlations. Based on insulin resistance/sensitivity, fasting insulinemia/glycemia, and BMI values collected from patients who participated in the present trial, two nomograms potentially assessing the risk of cutaneous melanoma have been generated. Molecular aspects sustain a role for insulin resistance in the carcinogenesis of cutaneous melanoma, but clinical data remain uncertain. Larger, well-balanced, correlative trials are still needed to define the potential role of insulin resistance in the carcinogenesis of cutaneous melanoma.

Real-life results from the overall population and key subgroups within the Italian cohort of nivolumab expanded access program in non-squamous non-small cell lung cancer.

BACKGROUND: Nivolumab was the first immune checkpoint inhibitor approved for previously treated advanced non-small cell lung cancer (NSCLC). Before its introduction in the market, nivolumab was made available to NSCLC patients through an expanded access program (EAP). Here we present the Italian cohort of patients with non-squamous NSCLC enrolled in a worldwide nivolumab EAP, with subgroup analyses involving elderly patients, patients with central nervous system (CNS) metastases and patients receiving nivolumab beyond progression. METHODS: Pretreated patients with advanced non-squamous NSCLC received nivolumab at 3 mg/kg every 2 weeks up to 24 months. Efficacy data (investigator-assessed tumour response, progression date and survival) and safety data were collected. FINDINGS: 1588 patients were treated across 153 Italian centres. Overall response rate and disease control rate were 18% and 44%, respectively; median overall survival (OS) was 11.3 months (95% CI: 10.2-12.4). Elderly patients (≥70 n = 522; ≥75 n = 232) achieved outcomes similar to the global study population; patients with CNS metastases (n = 409) had an OS of 8.6 months (95% CI: 6.4-10.8), and a 1-year OS rate of 43%. Nivolumab was administered beyond progression to 276 patients (26%), 57 of whom achieved subsequent disease control; the median OS of patients receiving nivolumab beyond progression was 16.2 months (95% CI: 14.0-18.4), while 1-year OS rate was 62%. INTERPRETATION: To date, this is the largest clinical experience with nivolumab in a real-world setting. Our data support its use in clinical practice for pretreated non-squamous NSCLC, including patients with older age or CNS metastases.

Association of Systemic Inflammation Index and Body Mass Index with Survival in Patients with Renal Cell Cancer Treated with Nivolumab.

PURPOSE: Inflammation indexes and body mass index (BMI) are easily evaluated, predict survival, and are potentially modifiable. We evaluated the potential association of inflammatory indexes and BMI with the clinical outcome of patients with renal cell carcinoma (RCC) undergoing immune checkpoint inhibitor therapy. EXPERIMENTAL DESIGN: A prospective cohort of patients with metastatic RCC treated with nivolumab enrolled in the Italian Expanded Access Program from July 2015 through April 2016 was examined. Reference measures of inflammation were identified for neutrophil-to-lymphocyte ratio (NLR)

Targeting the PTTG1 oncogene impairs proliferation and invasiveness of melanoma cells sensitive or with acquired resistance to the BRAF inhibitor dabrafenib.

The pituitary tumor transforming gene 1 (PTTG1) is implicated in tumor growth, metastasis and drug resistance. Here, we investigated the involvement of PTTG1 in melanoma cell proliferation, invasiveness and response to the BRAF inhibitor (BRAFi) dabrafenib. We also preliminary assessed the potential value of circulating PTTG1 protein to monitor melanoma patient response to BRAFi or to dabrafenib plus trametinib. Dabrafenib-resistant cell lines (A375R and SK-Mel28R) were more invasive than their drug-sensitive counterparts (A375 and SK-Mel28), but expressed comparable PTTG1 levels. Dabrafenib abrogated PTTG1 expression and impaired invasion of the extracellular matrix (ECM) in A375 and SK-Mel28 cells. In contrast, it affected neither PTTG1 expression in A375R and SK-Mel28R cells, nor ECM invasion in the latter cells, while further stimulated A375R cell invasiveness. Assessment of proliferation and ECM invasion in control and PTTG1-silenced A375 and SK-Mel28 cells, exposed or not to dabrafenib, demonstrated that the inhibitory effects of this drug were, at least in part, dependent on its ability to down-regulate PTTG1 expression. PTTG1-silencing also impaired proliferation and invasiveness of A375R and SK-Mel28R cells, and counteracted dabrafenib-induced stimulation of ECM invasion in A375R cells. Further experiments performed in A375R cells indicated that PTTG1-silencing impaired cell invasiveness through inhibition of MMP-9 and that PTTG1 expression and ECM invasion could be also reduced by the CDK4/6 inhibitor LEE011. PTTG1 targeting might, therefore, represent a useful strategy to impair proliferation and metastasis of melanomas resistant to BRAFi. Circulating PTTG1 also appeared to deserve further investigation as biomarker to monitor patient response to targeted therapy.

Placenta growth factor and neuropilin-1 collaborate in promoting melanoma aggressiveness.

The placenta growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family, which shares with VEGF-A the tyrosine kinase receptor VEGFR-1 and the co-receptor neuropilin-1 (NRP-1). In melanoma models, PlGF enhances tumour growth and neovessel formation, whereas NRP-1 promotes the metastatic process. Increased secretion of PlGF and expression of NRP-1 have also been involved in intrinsic or acquired resistance to anti­angiogenic therapies. In this study we investigated whether PlGF and NRP-1 cooperate in promoting melanoma aggressiveness independently of VEGFR-1. For this purpose, the melanoma cell clones M14-N, expressing NRP-1 and lacking VEGFR-1, and M14-C, devoid of both receptors, were used. M14-N cells are characterized by an invasive phenotype and vasculogenic mimicry, whereas M14-C cells possess a negligible invasive capacity. The results indicated that M14-N cells secrete higher levels of PlGF than M14-C cells and that PlGF is involved in the invasion of the extracellular matrix (ECM) and vasculogenic mimicry of M14-N cells. In fact, neutralizing antibodies against PlGF reverted ECM invasion in response to PlGF and markedly reduced the formation of tubule-like structures. Moreover, M14-N cells migrated in response to PlGF and chemotaxis was specifically abrogated by anti-NRP-1 antibodies, demonstrating that PlGF directly activates NRP-1 in the absence of VEGFR-1. We also compared the levels of PlGF in the plasma of patients affected by metastatic melanoma with those of healthy donors and evaluated whether PlGF levels could be affected by a bevacizumab-containing chemotherapy regimen. Melanoma patients showed a 20-fold increase in plasma PlGF and the bevacizumab-containing regimen induced a reduction of VEGF-A and in a further increase of PlGF. In conclusion, our studies suggest that the activation of NRP-1 by PlGF directly contributes to melanoma aggressiveness and represents a potential compensatory pro-angiogenic mechanism that may contribute to the resistance to therapies targeting VEGF-A.

Dermoscopic patterns of cutaneous melanoma metastases.

Although the long experience acquired with the widespread use of dermoscopy has allowed the establishment of criteria for the recognition of benign and malignant skin lesions, very few data are available on cutaneous melanoma metastases. As the characteristic clinical aspects are multiform and even histological evaluation may sometimes be difficult, we have studied and characterized the patterns of cutaneous melanoma metastases in dermoscopy. In this paper, we report dermoscopic data on 130 histologically confirmed metastases observed in 32 patients affected by melanoma, with particular emphasis on dermoscopic features. Nine dermoscopic elements (homogeneous, saccular, amelanotic, polymorphic and vascular patterns, colour, perilesional erythema, pigmentary halo, peripheral grey spots) were studied in 130 cutaneous melanoma metastases and compared with those of 350 melanomas, 150 common naevi, 40 blue naevi, 40 haemangiomas and 50 basal cell carcinomas. The saccular and vascular patterns (especially polymorphic atypical vessels and winding vessels), as well as pigmentary halo and peripheral grey spots, seem to be the most significant elements suggestive of cutaneous melanoma metastases. The interest in and importance of the dermoscopic aspects of cutaneous melanoma metastases cannot be neglected if the American Joint Committee has determined that microsatellitosis and micrometastases are fundamental in the new TNM staging classification for cutaneous melanoma.

High expression of the mismatch repair protein MSH6 is associated with poor patient survival in melanoma.

OBJECTIVES: The outcome of patients with primary melanoma (PM) cannot be completely explained based on currently adopted clinical-histopathologic criteria. In this study, we evaluated the potential prognostic value of mismatch repair protein expression in PMs. METHODS: We examined the immunohistochemical staining of mismatch repair proteins in 18 benign nevi and 101 stage I to III PMs and investigated their association with tumor clinicopathologic variables and melanoma mortality. RESULTS: Expression of MSH2, MLH1, and PMS2 was high in benign nevi and reduced in a subset of PMs. Conversely, MSH6 expression was absent or extremely low in benign nevi and increased in a subset of PMs. In the multivariate analysis, including sex, age, Breslow thickness, and ulceration, high MSH6 expression in PMs (ie, immunostaining in >20% of tumor cells) was significantly associated with an increased risk of melanoma mortality (relative risk, 3.76; 95% confidence interval, 1.12-12.70). CONCLUSIONS: MSH6 protein expression can be a valuable marker to improve prognosis assessment in PMs.

Information needs of patients with melanoma: a nursing challenge.

Evidence continues to suggest that patients with cancer require more information about their disease and its consequences. To evaluate the information needs of patients with advanced melanoma compared to patients with other malignancies, a cross-sectional study was conducted on 221 unselected patients from the oncology department of a dermatologic hospital In Italy. Patients completed the Edmonton Symptom Assessment System and the Need Evaluation Questionnaire, two standardized tools for symptoms and psychosocial needs assessment. Results highlight that patients with advanced melanoma have, in general, a higher need for information compared to patients with other cancers, even if they report fewer symptoms. Future studies on the needs of patients with melanoma may contribute to tailored and more satisfactory patient-centered care. Recommendations for clinical practice include that particular attention should be paid by the oncology team to the need for a strong therapeutic relationship.