Non-prescribed pharmaceutical stimulants use among adolescents: A way to self-care or peer success?

BACKGROUND: the use of pharmaceutical stimulants without a medical prescription (PSWMP) among adolescents is considered an established public health issue. The present study aimed to investigate the potential links between different patterns of non-medical use of pharmaceutical stimulants, psycho-social factors, and other risky behaviours (e.g. psychoactive substance use). METHODS: For this purpose, data from a sample of 14,685 adolescents aged 15-19 participating in the ESPAD®Italia 2019 study were analysed by conducting descriptive analyses and multinomial logistic regressions. RESULTS: The findings highlight the key role of psycho-social factors and engagement in other risky behaviours in either reducing or promoting the risk of PSWMP use. Particularly, being satisfied with peer relationships and with oneself is significantly associated with lower use of PSWMP. Conversely, the consumption of other psychoactive substances (both legal and illegal) and engagement in other risky behaviours (e.g., gambling and cyberbullying) may increase this phenomenon. CONCLUSIONS: Considering their representativeness, the results of the present study could be used as groundwork for the development of effective and targeted prevention programs and interventions.

Genetic Alterations of Melanoma Brain Metastases: A Systematic Review and Meta-Analysis.

BACKGROUND: Data on molecular alterations harbored by melanoma brain metastases (MBMs) are limited, and this has hampered the development of more effective therapeutic strategies. We conducted a systematic review and meta-analysis of all the studies reporting DNA sequencing data of MBMs, in order to identify recurrently mutated genes and molecular pathways significantly enriched for genetic alterations. METHODS: We searched PubMed, Embase and Scopus for articles published from the inception of each database to June 30, 2021. We included in the analysis all the studies that reported individual patient data on DNA sequencing of MBMs, assessing single nucleotide variants (SNVs) and/or gene copy number variations (CNVs) in at least five tumor samples. Meta-analysis was performed for genes evaluated for SNVs and/or CNVs in at least two studies. Pooled proportions of samples with SNVs and/or CNVs was calculated by applying random-effect models based on the DerSimonian-Laird method. Gene-set enrichment analysis (GSEA) was performed to identify molecular pathways significantly enriched for mutated genes. RESULTS: Ten studies fulfilled the inclusion criteria and were included in the analysis, for a total of 531 samples of MBMs evaluated. Twenty-seven genes were found recurrently mutated with a meta-analytic rate of SNVs higher than 5%. GSEA conducted on the list of these 27 recurrently mutated genes revealed vascular endothelial growth factor-activated receptor activity and transmembrane receptor protein tyrosine kinase activity to be among the top 10 gene ontology (GO) molecular functions significantly enriched for mutated genes, while regulation of apoptosis and cell proliferation were among the top 10 significantly enriched GO biological processes. Notably, a high meta-analytic rate of SNVs was found in several actionable cancer-associated genes, such as all the vascular endothelial growth factor (VEGF) receptor isoforms (i.e., Flt1 and Flt2 genes, for both SNV rate: 0.22, 95% CI 0.04-0.49; KDR gene, SNV rate: 0.1, 95% CI 0.05-0.16). Finally, two tumor suppressor genes were characterized by a high meta-analytic rate of CNVs: CDKN2A/B (CNV rate: 0.59, 95% CI 0.23-0.90) and PTEN (CNV rate: 0.31, 95% CI 0.02-0.95). CONCLUSION: MBMs harbored actionable molecular alterations that could be exploited as therapeutic targets to improve the poor prognosis of patients.

Adolescents' Psychoactive Substance Use During the First COVID-19 Lockdown: A Cross Sectional Study in Italy.

Background: Italy was one of the first European countries to be affected by Covid-19. Due to the severity of the pandemic, the Italian government imposed a nationwide lockdown which had a great impact on the population, especially adolescents. Distance-learning, moving restrictions and pandemic-related concerns, resulted in a particularly stressful situation. Objective: This cross-sectional study aims to analyse substance consumption and its associated factors during the Covid-19 lockdown imposed by the Italian government. Methods: ESPAD is a questionnaire that is administered yearly in Italian high schools. In 2020, it was administered online during dedicated hours of distance learning, collecting data from 6027 Italian students (52.4% were male) aged 15-19. Data collected from the 2020 questionnaire was matched with that collected in 2019, in order to make them comparable. Results: The prevalence of consumption of each substance decreased during the restriction period, and the most used substance during the lockdown period was alcohol (43.1%). There were some changes in factors associated with psychoactive substance use, especially painkillers and non-prescription drugs. For instance, unlike what was observed in the 2019 model, in 2020 spending money without parental control was associated with painkillers and non-prescription drug use while risk perception was not. Conclusions: The restrictions and the increased difficulties in obtaining psychoactive substances did not prevent their consumption, and students with particular risk factors continued to use them, possibly changing the substance type of substance. This information is useful in order to better understand adolescents' substance use during the ongoing pandemic.

Efficacy, Safety and Pharmacoeconomic Analysis of Intravenous Ferric Carboxymaltose in Anemic Hemodialysis Patients Unresponsive to Ferric Gluconate Treatment: A Multicenter Retrospective Study.

Patients undergoing hemodialysis with iron deficiency anemia (IDA) receiving treatment with erythropoiesis-stimulating agents (ESAs) who were intolerant or non-responsive to intravenous (i.v.) ferric gluconate (FG) (hemoglobin; Hb values < 10.5 g/dL or increase in <1 g/dL) or % transferrin saturation; TSAT of <20%) in the previous 6 months were switched to i.v. ferric carboxymaltose (FCM). Changes in iron status parameters, economic and safety measures were also assessed. Seventy-seven hemodialysis patients aged 68 ± 15 years were included. Erythropoietin resistance index decreased from 24.2 ± 14.6 at pre-switch to 20.4 ± 14.6 after 6 months of FCM treatment and Hb levels ≥10.5 g/dL improved from 61% to 75.3% patients (p = 0.042). A 1 g/dL increase in Hb levels was also seen in 26% of patients as well as a 37.7% increase in patients achieving >20% increase in TSAT after FCM. Levels of Hb, TSAT and ferritin parameters increased during FCM treatment with a concomitant decrease in ESA. A mixed-model analysis, which also considered gender, confirmed these trends. Safety variables remained stable, no hypersensitivity reaction was recorded and only one patient reported an adverse event after FCM. FCM treatment was associated with a cost saving of 11.11 EUR/patient/month. These results confirm the efficacy, safety and cost-effectiveness of FCM in correcting IDA in hemodialysis patients.

Vitamin D Supplementation and Disease-Free Survival in Stage II Melanoma: A Randomized Placebo Controlled Trial.

Patients with newly resected stage II melanoma (n = 104) were randomized to receive adjuvant vitamin D3 (100,000 IU every 50 days) or placebo for 3 years to investigate vitamin D3 protective effects on developing a recurrent disease. Median age at diagnosis was 50 years, and 43% of the patients were female. Median serum 25-hydroxy vitamin D (25OHD) level at baseline was 18 ng/mL, interquartile range (IQ) was 13-24 ng/mL, and 80% of the patients had insufficient vitamin D levels. We observed pronounced increases in 25OHD levels after 4 months in the active arm (median 32.9 ng/mL; IQ range 25.9-38.4) against placebo (median 19.05 ng/mL; IQ range 13.0-25.9), constantly rising during treatment. Remarkably, patients with low Breslow score (<3 mm) had a double increase in 25OHD levels from baseline, whereas patients with Breslow score ≥3 mm had a significantly lower increase over time. After 12 months, subjects with low 25OHD levels and Breslow score ≥3 mm had shorter disease-free survival (p = 0.02) compared to those with Breslow score <3 mm and/or high levels of 25OHD. Adjusting for age and treatment arm, the hazard ratio for relapse was 4.81 (95% CI: 1.44-16.09, p = 0.011). Despite the evidence of a role of 25OHD in melanoma prognosis, larger trials with vitamin D supplementation involving subjects with melanoma are needed.

MC1R variants in childhood and adolescent melanoma: a retrospective pooled analysis of a multicentre cohort.

BACKGROUND: Germline variants in the melanocortin 1 receptor gene (MC1R) might increase the risk of childhood and adolescent melanoma, but a clear conclusion is challenging because of the low number of studies and cases. We assessed the association of MC1R variants with childhood and adolescent melanoma in a large study comparing the prevalence of MC1R variants in child or adolescent patients with melanoma to that in adult patients with melanoma and in healthy adult controls. METHODS: In this retrospective pooled analysis, we used the M-SKIP Project, the Italian Melanoma Intergroup, and other European groups (with participants from Australia, Canada, France, Greece, Italy, the Netherlands, Serbia, Spain, Sweden, Turkey, and the USA) to assemble an international multicentre cohort. We gathered phenotypic and genetic data from children or adolescents diagnosed with sporadic single-primary cutaneous melanoma at age 20 years or younger, adult patients with sporadic single-primary cutaneous melanoma diagnosed at age 35 years or older, and healthy adult individuals as controls. We calculated odds ratios (ORs) for childhood and adolescent melanoma associated with MC1R variants by multivariable logistic regression. Subgroup analysis was done for children aged 18 or younger and 14 years or younger. FINDINGS: We analysed data from 233 young patients, 932 adult patients, and 932 healthy adult controls. Children and adolescents had higher odds of carrying MC1R r variants than did adult patients (OR 1·54, 95% CI 1·02-2·33), including when analysis was restricted to patients aged 18 years or younger (1·80, 1·06-3·07). All investigated variants, except Arg160Trp, tended, to varying degrees, to have higher frequencies in young patients than in adult patients, with significantly higher frequencies found for Val60Leu (OR 1·60, 95% CI 1·05-2·44; p=0·04) and Asp294His (2·15, 1·05-4·40; p=0·04). Compared with those of healthy controls, young patients with melanoma had significantly higher frequencies of any MC1R variants. INTERPRETATION: Our pooled analysis of MC1R genetic data of young patients with melanoma showed that MC1R r variants were more prevalent in childhood and adolescent melanoma than in adult melanoma, especially in patients aged 18 years or younger. Our findings support the role of MC1R in childhood and adolescent melanoma susceptibility, with a potential clinical relevance for developing early melanoma detection and preventive strategies. FUNDING: SPD-Pilot/Project-Award-2015; AIRC-MFAG-11831.

Alcohol, alcoholic beverages, and melanoma risk: a systematic literature review and dose-response meta-analysis.

PURPOSE: Several studies in recent years have investigated the relationship between alcohol intake and melanoma risk, with conflicting results. To help clarify this issue, we conducted a literature review and dose-response meta-analysis of studies published until June 30th, 2017, that examined the association between alcohol intake (overall and by beverage type) and melanoma risk. METHODS: We used random effect models with maximum likelihood estimation to calculate summary relative risk (SRR) and 95% confidence intervals (95%CI). RESULTS: We included 20 independent studies (encompassing 10,555 melanoma cases and over 1.6 million non-cases/controls) published during 1986-2016, of which six had a prospective cohort study design. Adjustment for phenotypic characteristics and sunlight exposure was performed in 11 and nine studies, respectively. Alcohol intake was moderately associated with melanoma risk: the SRR were 1.29 (95% CI 1.14-1.45) for those in the highest vs. lowest category of current alcohol intake, and 1.96 (95% CI 1.02-3.76, I2 = 0%) for cumulative intake. In the dose-response analysis, the increase in risk associated with a 10 g increment in daily alcohol intake was 1.07 (95% CI 1.03-1.11). Risk estimates did not differ by gender, study design and adjustment for confounders; between-studies heterogeneity was acceptable, and there was no evidence of publication bias. CONCLUSIONS: Our findings suggest that alcohol drinking may be moderately associated with increased melanoma risk, although residual confounding and bias cannot be ruled out. Further research is needed to confirm these findings, clarify the role of the different alcohol sources, and investigate the interaction with known melanoma risk factors.

Baseline relative eosinophil count as a predictive biomarker for ipilimumab treatment in advanced melanoma.

As diverse therapeutic options are now available for advanced melanoma patients, predictive markers that may assist treatment decision are needed. A model based on baseline serum lactate dehydrogenase (LDH), peripheral blood relative lymphocyte counts (RLC) and eosinophil counts (REC) and pattern of distant metastasis, has been recently proposed for pembrolizumab-treated patients. Here, we applied this model to advanced melanoma patients receiving chemotherapy (n = 116) or anti-CTLA-4 therapy (n = 128). Visceral involvement, LDH and RLC were associated with prognosis regardless of treatment. Instead, when compared to chemotherapy-treated patients with REC < 1.5%, those with REC ≥ 1.5% had improved overall survival when receiving anti-CTLA-4 [Hazard Ratio (HR) = 0.56 (0.4-0.93)] but not chemotherapy [HR = 1.13, (0.74-1.74)], and the treatment-by-REC interaction was significant for both overall (p = 0.04) and progression free survival (p = 0.009). These results indicate baseline REC ≥ 1.5% as a candidate predictive biomarker for benefit from anti-CTLA-4. Further studies are needed to confirm these findings in patients receiving immune-modulating agents.

Sunny holidays before and after melanoma diagnosis are respectively associated with lower Breslow thickness and lower relapse rates in Italy.

BACKGROUND: Previous studies have reported an association between sun exposure and improved cutaneous melanoma (CM) survival. We analysed the association of UV exposure with prognostic factors and outcome in a large melanoma cohort. METHODS: A questionnaire was given to 289 (42%) CM patients at diagnosis (Group 1) and to 402 CM patients (58%) during follow-up (Group 2). Analyses were carried out to investigate the associations between sun exposure and melanoma prognostic factors and survival. RESULTS: Holidays in the sun two years before CM diagnosis were significantly associated with lower Breslow thickness (p=0.003), after multiple adjustment. Number of weeks of sunny holidays was also significantly and inversely associated with thickness in a dose-dependent manner (p=0.007). However when stratifying by gender this association was found only among women (p=0.0004) the risk of CM recurrence in both sexes was significantly lower in patients (n=271) who had holidays in the sun after diagnosis, after multiple adjustment including education: HR=0.30 (95%CI:0.10-0.87; p=0.03) conclusions: Holidays in the sun were associated with thinner melanomas in women and reduced rates of relapse in both sexes. However, these results do not prove a direct causal effect of sun exposure on survival since other confounding factors, such as vitamin D serum levels and socio-economic status, may play a role. Other factors in sun seeking individuals may also possibly affect these results.

Electrochemotherapy for cutaneous and subcutaneous tumor lesions: a novel therapeutic approach.

Electroporation uses pulsed, high-intensity electric fields to temporarily increase cell membrane permeability by creation of pores, through which small molecules, such as chemotherapeutic agents, can diffuse inside cells before they reseal. The combination of electroporation with the administration of otherwise low-permeant cytotoxic drugs is known as electrochemotherapy (ECT). The two most commonly used drugs are bleomycin and cisplatin. ECT has already been proven to be effective in diverse tumor histotypes, including melanoma and basal and squamous cell carcinoma, Kaposi sarcoma, and breast cancer, also in those cases nonresponding to classical chemotherapies or other loco-regional treatment modalities, with a good safety profile. ECT can be proposed as loco-regional therapy for disseminated cutaneous and subcutaneous tumor lesions as alternative treatment modality to conventional therapies or as palliative care, in order to improve patients' quality of life.

Pelvic sentinel lymph node biopsy in melanoma patients: is it worthwhile?

The original procedure of intraoperative lymphatic mapping by using vital blue dye initially described by Morton and colleagues in 1992 was implemented in subsequent years by the introduction of preoperative lymphoscintigraphy (LS) and intraoperative gamma detection probe to allow a better identification of sentinel nodes (SNs). However, it is common, in practice, to detect more than one radioactive node with the gamma detection probe. Whether these additional lymph nodes represent true SNs is not yet clear. The aims of this study are: to investigate the role of pelvic sentinel node biopsy in recurrent pelvic disease in those patients with negative inguinal SN, having one or more deep hot spots identified by preoperative LS (follow-up group). One hundred and four stage I/II melanoma patients with primary tumor of the lower limb and lower trunk were enrolled in a restrospective study at the European Institute of Oncology, Milan, Italy, between 2000 and 2007. All patients presented hot spots both in superficial (groin) and deep (iliac-obturator) areas during dynamic LS. The study population consisted of 35 men and 69 women with a median age of 57 years at the time of diagnosis. The median follow-up period was 49 months (SD 22.4; range, 10-98 months). Of the 104 patients, 83 had a negative SN (80%). All sentinel-lymph-node-positive patients underwent superficial and deep inguinal dissection. Two patients (2.4%; 95% confidence interval: 1.5-8.8%) with negative SNs had pelvic recurrence. Among patients who underwent ilioinguinal dissection, three (14%; 95% confidence interval: 4-35%) had positive pelvic lymph nodes. After a 60-month follow-up, 79% of patients were alive and 66% were disease free. In SN-negative patients, disease-free survival was 69% and in SN-positive patients 53%. No significant difference was found by SN status (log-rank P values 0.15). Even if the sample size of our study cannot bring to conclusive results, and further studies are needed, it might be possible that harvesting pelvic SN in those patients with pelvic hot spots at LS could modify the natural history of melanoma patients in terms of pelvic recurrence and disease free survival. We recommend to improve our knowledge in the role of pelvic sentinel node in the natural history of melanoma.

Systemic therapy as a first choice treatment for idiopathic granulomatous mastitis.

Idiopathic granulomatous mastitis clinically and histologically mimics an inflammatory carcinoma. A correct approach including ultrasound, clinical and histological analysis can safely identify a patient with this pathology, orienting to adequate therapy with anti-inflammatory and antibiotic drugs and leaving the surgical approach only for case unresponsive to medical therapy.

Clinical considerations on sentinel node biopsy in melanoma from an Italian multicentric study on 1,313 patients (SOLISM-IMI).

BACKGROUND: Although widely used for the management of patients with cutaneous melanoma, the sentinel lymph node (SLN) biopsy (SNB) procedure raises several issues. This study was designed to investigate: the predictive factors of SLN status, the false-negative (FN) rate, and patients' prognosis after SNB. PATIENTS AND METHODS: This is an observational, prospective study conducted on a large series of consecutive patients (n = 1,313) enrolled by 23 Italian centers from 2000 through 2002. A commonly shared protocol was adopted for the SNB surgical procedure and the SLN pathological examination. RESULTS: The SLN positive and false-negative (FN) rates were 16.9% and 14.4%, respectively (median follow-up, 4.5 years). At multivariable logistic regression analysis, the frequency of positive SLN increased with increasing Breslow thickness (p < 0.0001) and decreased in patients with melanoma regression (p = 0.024). At the multivariable Cox regression analysis, SLN status was the most important prognostic factor (hazards ratio (HR) = 3.08) for overall survival; the other statistically significant factors were sex, age, Breslow thickness, and Clark's level. Considering SLN and NSLN status, including FN cases, we identified four groups of patients with different prognoses. The 5-year overall survival of patients with positive SLNs was 71.3% in those with negative nonsentinel lymph nodes (NSLNs) and 50.4% if NSLNs were positive. CONCLUSIONS: Regression in the primary melanoma seems to be a protective factor from metastasis in the SLN. When correctly calculated, the SNB FN rate is 15-20%. Furthermore, the SNB is important to more precisely assess the prognosis of patients with melanoma.

Modification of lymphoscintigraphic sentinel node identification before and after excisional biopsy of primary cutaneous melanoma.

The aim of this study was to determine whether excision biopsy and primary closure of primary cutaneous melanoma modifies lymphatic drainage and accuracy of sentinel node biopsy. Thirty patients with 31 cutaneous melanomas were prospectively enrolled to undergo lymphoscintigraphy (LS) before and after excision biopsy. Tc-human serum albumin nanocolloid was first injected intradermally around the primary tumor and subsequently, after excision biopsy, adjacent to the scar. Sentinel nodes were identified by preoperative LS and the gamma-probe. Patent Blue V dye was injected intraoperatively before sentinel node biopsy. Intraoperative sentinel node identification was 100%. In 23 of 31 cases, both LSs were concordant in terms of nodal basins visualized. Two patients had a basin downstaged and six patients had a basin upstaged by the second LS. Only 50% of LS hot nodes stained blue (42 of 84). In 24 of 31 cases, the sentinel node was negative for metastases. Seven patients underwent complete lymph node dissection because of sentinel node positivity. Only one patient had metastases also to a non-sentinel node. After a median follow-up of 30 months lymph node metastases have not been observed in the eight discordant cases. This study shows that sentinel node identification and biopsy after lymphatic mapping is accurate after excision biopsy of primary cutaneous melanoma. Excision biopsy may, however, modify lymphatic drainage and a narrow excision margin should be performed if melanoma is suspected.

The impact of lymphoscintigraphy technique on the outcome of sentinel node biopsy in 1,313 patients with cutaneous melanoma: an Italian Multicentric Study (SOLISM-IMI).

UNLABELLED: An observational multicentric Italian trial on sentinel node biopsy (SNB) in melanoma patients was performed to diffuse a common SNB protocol nationwide (Italy). We report herein the results of this trial. The influence of some technical aspects on the outcome of SNB was also investigated, because a certain degree of variability was accepted in performing lymphoscintigraphy. METHODS: From January 2000 to December 2002, 1,313 consecutive patients with primary cutaneous melanoma (Breslow thickness, >1.0 mm or <1.0 mm but with ulceration, Clark level IV-V, presence of regression) were enrolled by 23 centers. One half to 1 mL of 99mTc-labeled human albumin colloid, at a suggested dosage of 5-15 or 30-70 MBq, was injected intradermally, closely around the scar, the same day or the day before SNB. Intraoperatively, Patent blue was associated when a definitive wide excision of the primary was required. A positive sentinel node (SN) was defined when containing melanoma cells detected by either hematoxylin-eosin or immunohistochemistry (S100 and HMB45 antibodies). All patients underwent regular follow-up. False-negative cases were considered when lymph node metastases occurred in the same lymphatic basin of SN biopsy (SNB) during follow-up. A quality control program has been performed for the surgical procedure and for the histologic diagnosis. RESULTS: The SN identification rate was 99.3%. The axilla was the site of the SN in 52.5% of the cases. The mean number of SNs was 2.0 (range, 1-17) and only 1 node was removed in 45.4%. The positivity and false-negative rates were 16.9% and 14.7%, respectively (median follow-up, 31 mo). On multivariate analysis (logistic and linear regression) only the number of peritumor injections was inversely associated with the number of excised SNs (P = 0.002), whereas none of the technical variables showed an independent impact on SN status when Breslow thickness was included as a control variable. CONCLUSION: The number of peritumor injections seems to influence the outcome of lymphoscintigrapy in melanoma patients undergoing SNB. If these results are confirmed in a controlled trial, 3 injections at least should be recommended.

Pulsed dose-rate perioperative interstitial brachytherapy for soft tissue sarcomas of the extremities and skeletal muscles of the trunk.

BACKGROUND: This study evaluated the role of pulsed dose-rate (PDR) brachytherapy (BRT), delivered alone or as a boost to external beam radiotherapy, as adjuvant therapy for the local control of soft tissue sarcomas of the extremities and skeletal muscles of the trunk that have undergone surgical treatment. METHODS: Between July 1998 and January 2002, 42 patients were treated with a combination of surgery and BRT alone (18 patients) or BRT/external beam radiotherapy (24 patients) for the treatment of primary (n = 32) and recurrent (n = 10) soft tissue sarcomas located in the proximal extremity (n = 17), distal extremity (n = 17), and trunk (n = 8). Tumor size was <5 cm in 20 cases and >5 cm in 22 cases, with histological grading of 1 (n = 7), 2 (n = 18), or 3 (n = 17). The median BRT dose delivered was 15 Gy, and the median external beam irradiation dose was 50 Gy. RESULTS: With a median follow-up of 34 months, the 36-month survival was 83.9% (SE, 6.1%), and the local control was 89%. CONCLUSIONS: PDR interstitial BRT for soft tissue sarcoma is an effective, well-tolerated adjuvant radiation treatment that offers several practical advantages, among which are low acute and late toxicity with maximum normal tissue and critical structure sparing and overall shorter radiotherapy and hospital stay.

The role of ultrasound of sentinel nodes in the pre- and post-operative evaluation of stage I melanoma patients.

We have investigated the role of high-resolution ultrasound (US) in the analysis of sentinel node(s) in melanoma patients in pre-operative staging and follow-up. One hundred and six lymph node basins in 88 melanoma patients undergoing sentinel node biopsy (SNB) were examined: 25 (23.6%) were US positive for metastases and 81 (76.4%) were negative. Subsequent histological analysis of the 81 negative lymph nodes confirmed the absence of metastases in 80 cases (98.8%), whereas, in the 25 US-positive lymph nodes, metastases were found in 16 cases (64%). The follow-up of all patients submitted to SNB in our unit included a US investigation of operated and contralateral nodal basins every 4 months for the first 3 years and then every 6 months. Of a total of 300 patients, four (1.6%) were found to have locoregional nodal disease during follow-up. In three of these four patients, US was crucial in indicating the presence of nodal metastases, which would have gone undetected on physical examination. The result of this study (negative predictive value of 98.7%) introduces the possibility of selecting patients who may avoid an SNB procedure based on the results of pre-operative US examination.