Giuseppe Giudice

Nonsentinel Lymph Node Status in Patients With Cutaneous Melanoma: Results From a Multi-Institution Prognostic Study

PURPOSE We investigated whether the nonsentinel lymph node (NSLN) status in patients with melanoma improves the prognostic accuracy of common staging features; then we formulated a proposal for including the NSLN status in the current melanoma staging system. PATIENTS AND METHODS We retrospectively collected the clinicopathologic data of 1,538 patients with positive SLN status who underwent completion lymph node dissection (CLND) at nine Italian centers. Multivariable Cox regression survival analysis was used to identify independent prognostic factors. Literature meta-analysis was used to summarize the available evidence on the prognostic value of the NSLN status in patients with positive SLN. RESULTS NSLN metastasis was observed in 353 patients (23%). After a median follow-up of 45 months, NSLN status was an independent prognostic factor for melanoma-specific survival (hazard ratio [HR] = 1.34; 95% CI, 1.18 to 1.52; P < .001). NSLN status efficiently stratified the prognosis of patients with two to three positive lymph nodes (n = 387; HR = 1.39; 95% CI, 1.07 to 1.81; P = .013), independently of other staging features. Searching the literature, this patient subgroup was investigated in other two studies. Pooling the results (n = 620 patients; 284 NSLN negative and 336 NSLN positive), we found that NSLN status is a highly significant prognostic factor (summary HR = 1.59; 95% CI, 1.27 to 1.98; P < .001) in patients with two to three positive lymph nodes. CONCLUSION These findings support the independent prognostic value of the NSLN status in patients with two to three positive lymph nodes, suggesting that this information should be considered for the routine staging in patients with melanoma.

Number of Excised Lymph Nodes as a Quality Assurance Measure for Lymphadenectomy in Melanoma

IMPORTANCE Although the number of excised lymph nodes (LNs) represents a quality assurance measure in lymphadenectomy for many solid tumors, the minimum number of LNs to be dissected has not been established for melanoma. OBJECTIVE To investigate the distribution of the number of excised LNs in a large patient series (N = 2526) to identify values that may serve as benchmarks for monitoring the quality of lymphadenectomy in patients with melanoma. DESIGN, SETTING, AND PARTICIPANTS A retrospective multicenter study was conducted (1992-2010) in tertiary referral centers for treatment of cutaneous melanoma. Medical records on 2526 patients who underwent lymphadenectomy for regional LN metastasis associated with cutaneous melanoma were examined. EXPOSURE Patients had undergone lymphadenectomy for regional LN metastasis. MAIN OUTCOMES AND MEASURES The mean, median, and 10th percentile of the number of excised LNs were calculated for the axilla (3 levels), neck (≤3 or ≥4 dissected levels), inguinal, and ilioinguinal LN fields. RESULTS After 3-level axillary (n = 1150), 3-level or less neck (n = 77), 4-level or more neck (n = 135), inguinal (n = 209), and ilioinguinal (n = 955) dissections, the median (interquartile range [IQR]) and mean (SD) number of excised LNs were as follows: 3-level axillary dissection, 20 (15-27) and 22 (8); 3-level or less neck, 21 (14-33) and 24 (15); 4-level or more neck, 29 (21-41) and 31 (14); inguinal, 11 ( 9-14) and 12 (5); and ilioinguinal, 21 (16-26) and 22 (4). A total of 90% of the patients had 12, 7, 14, 6, and 13 excised LNs (10th percentile of the distribution) after 3-level axillary, 3-level or less neck, 4-level or more neck, inguinal, and ilioinguinal dissections, respectively. More excised LNs were detected in younger (21 for those <54 years of age and 19 for ≥54 years, P < .001) and male (21 for male sex and 19 for female sex, P < .001) patients from high-volume institutions (21 for volume of ≥300 vs 18 for volume <300, P < .001) with a more recent year of diagnosis (21 for years 2002-2010 vs 18 for years 1992-2001, P < .001), LN micrometastasis vs macrometastasis (20 vs 19, P = .005), and more positive LNs (R² = 0.03, P < .001); however, the differences between median values were small. CONCLUSIONS AND RELEVANCE These minimum numbers of excised LNs are reproducible across the institution, patient, and tumor factors evaluated. They can be taken into consideration when monitoring the quality of lymphadenectomy in melanoma and can represent entry criteria for randomized trials investigating adjuvant therapies.

The number of excised lymph nodes is associated with survival of melanoma patients with lymph node metastasis

BACKGROUND Although the number of excised LNs has been associated with patient prognosis in many solid tumors, this association has not been widely investigated in cutaneous melanoma. This study aims to evaluate the association between the number of excised regional lymph nodes (LNs) and melanoma-specific survival. PATIENT AND METHODS Clinico-pathological data from 2507 patients with LN metastasis treated at nine Italian centers were retrospectively collected. RESULTS The number of excised LNs correlated with younger age (P < 0.001), male sex (P < 0.001), neck LN field (P < 0.001), LN micrometastasis (P < 0.001) and number of positive LNs (P < 0.001). The number of excised LNs was an independent prognostic factor (HR = 0.85; P = 0.002) after adjustment for other staging features. Upon subgroup analysis, the number of excised LNs had a significant prognostic value in patients bearing 1.01-2.00 mm (HR = 0.79; P = 0.032) and 2.01-4.00 mm (HR = 0.71; P < 0.001) thick melanomas, primary tumors showing ulceration (HR = 0.86; P = 0.033) and Clark level V of invasion (HR = 0.86; P = 0.010), LN micrometastasis (HR = 0.83; P = 0.014) and two to three positive LNs (HR = 0.71; P = 0.001). Finally, this study investigated the influence of the number of excised LNs on patient staging: only when ≥11 nodes were excised the AJCC N stage could stratify prognosis (P < 0.001). Considering the number of excised LNs for each lymphatic field, at least 14, 11, 10 and 12 LNs were needed to stage patients according to the AJCC N stage after a lymphadenectomy of the neck, axilla, inguinal and ilioinguinal LN fields, respectively. CONCLUSIONS The number of excised LNs can be considered for risk stratification of patients with regional LN metastasis from cutaneous melanoma. We demonstrated that a minimum number of LNs is required for the correct staging of patients. Further research is needed to evaluate the effectiveness of the minimum number of LNs to be dissected.

High activity of sequential low dose chemo-modulating Temozolomide in combination with Fotemustine in metastatic melanoma. A feasibility study

Metastatic melanoma (MM) is an incurable cancer with poor prognosis. Preclinical and clinical experiences support the concept that continuous exposure to low-dose alkilating agent Temozolomide (TMZ) can deplete cells of the DNA repair enzyme O6-methylguanine-DNA-methyltransferare (MGMT) which is the primary mechanism of tumor resistance to alkylating agents like nitrosureaa Fotemusrine (FM). Our study valued the hypothesis that depletion of MGMT induced by TMZ could render melanoma cells more susceptible to FM. Since no data exist regarding the optimal timing, doses and schedules of this association, we investigated two different schedules as first line therapy in MM to verify the safety, feasibility and tumor response. This is the first clinical experience in MM using sequential non-therapeutic dose TMZ previous FM.

Dentin Morphology of Root Canal Surface: A Quantitative Evaluation Based on a Scanning Electronic Microscopy Study

Dentin is a vital, hydrated composite tissue with structural components and properties that vary in the different topographic portions of the teeth. These variations have a significant implication for biomechanical teeth properties and for the adhesive systems utilized in conservative dentistry. The aim of this study is to analyse the root canal dentin going from coronal to apical zone to find the ratio between the intertubular dentin area and the surface occupied by dentin tubules varies. Observations were conducted on 30 healthy premolar teeth extracted for orthodontic reasons in patients aged between 10 and 14. A SEM analysis of the data obtained in different canal portions showed that, in the coronal zone, dentinal tubules had a greater diameter (4.32 μm) than the middle zone (3.74 μm) and the apical zone (1.73 μm). The average number of dentinal tubules (in an area of 1 mm2) was similar in coronal zone (46,798 ± 10,644) and apical zone (45,192 ± 10,888), while in the middle zone they were lower in number (30,940 ± 7,651). However, intertubular dentin area was bigger going from apical to coronal portion. The differences between the analysed areas must be considered for the choice of the adhesive system.

The immune escape in melanoma: role of the impaired dendritic cell function.

Melanoma is an immunogenic cancer that overcomes the control of the immune system through the production of tolerogenic cytokines and growth factors in the microenvironment. In melanoma, dendritic cells (DC) show severe alterations in maturation, cross-priming and antigenic presentation, while other accessory cells infiltrating the tumor milieu also suppress DCs through the activation of the STAT pathway by IL-10 and IL-6. Novel immunotherapy strategies blocking cytotoxic T-lymphocyte antigen (CTLA-4) are successful in advanced disease, while melanoma cells carrying the BRAFV600E mutation further reinforce the immune suppression by activating MAPKs. Here, we review the major mechanisms involved in the cross-talk between melanoma cells and the immune system as well as the issue of defects in DCs in relation to novel studies aimed at restoring their anti-tumor activity.

The role of functional orthodontic stress on implants in residual alveolar cleft.

Background: The most widely accepted protocol for alveolar cleft reconstruction is repair during the mixed dentition stage (age, 9 to 11 years), before eruption of the canine teeth. Alveolar bone grafting should not be considered as an isolated therapy but always as an integrated part of comprehensive orthodontic treatment. Methods: The authors evaluate the results of transitional secondary osteoplasty, comparing the use of autogenous cancellous bone versus heterogenetic implants, in patients with unilateral complete clefts who did or did not undergo orthodontic treatment. From 1990 to 1994, 48 patients aged between 9 and 11 years with unilateral alveolar cleft underwent alveolar grafting by transitional secondary osteoplasty. In 30 patients (group A), autogenous cancellous bone was used, and in 18 patients (group B), a heterogenetic implant consisting of demineralized bone powder containing bone morphogenetic protein and hydroxylapatite was used. Results: Twenty-two patients in group A and 12 patients in group B underwent orthodontic treatment. After 10 to 12 years of follow-up, the clinical and radiographic examinations revealed that the best alveolar bone repair results were obtained using autologous bone graft in association with orthodontic treatment. Also, in the patients who underwent heterogenetic implantation, the orthodontic treatment clearly improved the quality of the osteoplasty. Conclusions: The essential conditions for a successful osteoplasty include meticulous operative technique and orthodontic treatment. The latter plays an essential role at several stages of development in children with clefts. The “functional stress” on the autologous or heterogenetic implant exerts a decisive influence on the quality and volume of the osteoplasty, preventing progressive resorption.

Sun exposure and melanoma prognostic factors

Previous studies have reported an association between sun exposure and the increased survival of patients with cutaneous melanoma (CM). The present study analyzed the association between ultraviolet (UV) light exposure and various prognostic factors in the Italian Clinical National Melanoma Registry. Clinical and sociodemographic features were collected, as well as information concerning sunbed exposure and holidays with sun exposure. Analyses were performed to investigate the association between exposure to UV and melanoma prognostic factors. Between December 2010 and December 2013, information was obtained on 2,738 melanoma patients from 38 geographically representative Italian sites. A total of 49% of the patients were >55 years old, 51% were men, 50% lived in the north of Italy and 57% possessed a high level of education (at least high school). A total of 8 patients had a family history of melanoma and 56% had a fair phenotype (Fitzpatrick skin type I or II). Of the total patients, 29% had been diagnosed with melanoma by a dermatologist; 29% of patients presented with a very thick melanoma (Breslow thickness, >2 mm) and 25% with an ulcerated melanoma. In total, 1% of patients had distant metastases and 13% exhibited lymph node involvement. Holidays with sun exposure 5 years prior to CM diagnosis were significantly associated with positive prognostic factors, including lower Breslow thickness (P<0.001) and absence of ulceration (P=0.009), following multiple adjustments for factors such as sociodemographic status, speciality of doctor performing the diagnosis and season of diagnosis. Sunbed exposure and sun exposure during peak hours of sunlight were not significantly associated with Breslow thickness and ulceration. Holidays with sun exposure were associated with favorable CM prognostic factors, whereas no association was identified between sunbed use and sun exposure during peak hours of sunlight with favorable CM prognostic factors. However, the results of the present study do not prove a direct causal effect of sun exposure on melanoma prognosis, as additional confounding factors, including vitamin D serum levels, may have a role.

Classic and HIV-related Kaposi sarcoma treated with 0.1% topical timolol gel

T cells, or CD56 NK cells expressing NKG2D. We collected blood samples 4 times, and the FACS analysis was also performed by dividing into 4 times. Therefore, final data were represented as a fold change of each cells expressing NKG2D over the healthy control (control set to 1). The patients were segregated into 2 or 3 subgroups according to AA severity, activity, type, and treatment modalities for subgroup analysis. Statistical analysis was performed using the ManneWhitney U test and KruskaleWallis analysis. Double-labeling immunofluorescence microscopy in 2 representative cases using freshly frozen specimens was also performed. The results showed that the levels of NKG2DCD8 T cells and NKG2DCD56 NK cells were higher in the AA group compared with the control group (P \ .05). Interestingly, a 2.49-fold increase in the CD4 T cells subset expressing NKG2D was detected in the peripheral blood from patients with AA compared with healthy controls (P \ .05; Fig 1). Although not statistically significant, the proportion of NKG2DCD4 T cells was lower in patients who had mild severity AA and in those who received systemic immunosuppressive therapy. Double label immunofluorescence revealed NKG2D cells coexpressed CD4 around the hair follicles of the AA lesion (Fig 2). Recently, the role of NKG2DCD4 T cells in other chronic autoimmune diseases, such as Crohn’s disease and rheumatoid arthritis, was highlighted. A subset of CD4 T cells expressing NKG2D was higher in the lamina propria of patients with Crohn’s disease. These NKG2DCD4 T cell clones were functionally active through major histocompatibility complex class I-related chain A (MICA) eNKG2D interactions, producing IFNand killing targets expressing MICA. We hypothesize that NKG2DCD4 T cells might exhibit a TH1 cytokine profile in patients with AA. Our results suggest that IFNeproducing NKG2DCD4 T cells have the potential to become therapeutic targets and biologic markers of disease activity in AA. However, additional studies are needed to characterize the functional properties of NKG2DCD4 T cells in patients with AA.

Rhinocerebral Mucormycosis with Orosinusal Involvement: Diagnostic and Surgical Treatment Guidelines

BACKGROUND Rhinocerebral mucormycosis is a rare, rapidly progressive and potentially lethal disease almost exclusively affecting immunocompromised hosts or patients with metabolic disorders, such as poorly controlled diabetes mellitus. METHODS This work is aimed to describe five cases of rhinocerebral mucormycosis to review and possibly define diagnostic and surgical treatment guidelines. In all the patients, surgical debridement, systemic and local antifungal therapy, and oral rehabilitation using filling prostheses were performed. RESULTS None of the patients revealed recurrence of the infection, as confirmed by radiological and clinical long term follow up. CONCLUSION Given the lethal nature of the disease, the authors underline the importance of early diagnosis and of a multidisciplinary approach in order to undertake correct surgical and medical treatments, while keeping the underlying disease under control.