Prevention of Secondary Lymphedema after Complete Lymph Node Dissection in Melanoma Patients: The Role of Preventive Multiple Lymphatic-Venous Anastomosis in Observational Era.

Background and Objectives: Current guidelines have limited the performance of complete lymph node dissection (CLND) for patients with clinically detectable lymphatic metastases. Despite the limitations of this surgical procedure, secondary lymphedema (SL) is an unsolved problem that affects approximately 20% of patients undergoing CLND. Preventive lymphatic-venous micro-anastomoses (PMLVA) has already demonstrated its efficacy in the prevention of SL in melanoma patients with a positive sentinel lymph node biopsy (SLNB), but the efficacy of this procedure is not demonstrated in patients with clinically detectable lymphatic metastases. Materials and Methods: This retrospective cohort study, was performed in two observation periods. Until March 2018, CLND was proposed to all subjects with positive-SLNB andPMLVA was performed in a subgroup of patients with risk factors for SL (Group 1). From April 2018, according to the modification of melanoma guidelines, all patients with detectable metastatic lymph nodes underwent PMLVA during CLND (Group 2). The frequency of lymphedema in subjects undergoing PMLVA was compared with the control group. Results: Database evaluation revealed 172 patients with melanoma of the trunk with follow-up information for at least 6 mounts. Twenty-three patients underwent PMLVA during CLND until March 2018, 29 from April 2018, and 120 subjects underwent CLND without any preventive surgery (control Group). The frequency of SL was significantly lower in both Group 1 (4.3% vs. 24.2%, p = 0.03) and Group 2 (3.5%, p = 0.01). Patients undergoing PMLVA showed a similar recurrence-free periods and overall survival when compared to the control group. Conclusions: PMLVA significantly reduces the frequency of SL both in immediate and delayed CLND. This procedure is safe and does not lead to an increase in length of hospitalization.

Lower risk of death and cardiovascular events in patients with diabetes initiating glucagon-like peptide-1 receptor agonists or sodium-glucose cotransporter-2 inhibitors: A real-world study in two Italian cohorts.

AIM: To examine the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors compared with other antihyperglycaemic agents (AHAs) in large and unselected populations of the Lombardy and Apulia regions in Italy. MATERIALS AND METHODS: An observational cohort study of first-time users of GLP-1RAs, SGLT2 inhibitors or other AHAs was conducted from 2010 to 2018. Death and cardiovascular (CV) events were evaluated using conditional Cox models in propensity-score-matched populations. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for each region and in a meta-analysis for pooled risks. RESULTS: After propensity-score matching, the Lombardy cohort included 18 716 and 11 683 patients and the Apulia cohort 9772 and 6046 patients for the GLP-1RA and SGLT2 inhibitor groups, respectively. Use of GLP-1RAs was associated with lower rates of death (HR 0.61, CI 0.56-0.65, Lombardy; HR 0.63, CI 0.55-0.71, Apulia), cerebrovascular disease and ischaemic stroke (HR 0.70, CI 0.63-0.79; HR 0.72, CI 0.60-0.87, Lombardy), peripheral vascular disease (HR 0.72, CI 0.64-0.82, Lombardy; HR 0.80, CI 0.67-0.98, Apulia), and lower limb complications (HR 0.67, CI 0.56-0.81, Lombardy; HR 0.69, CI 0.51-0.93, Apulia). Compared with other AHAs, SGLT2 inhibitor use decreased the risk of death (HR 0.47, CI 0.40-0.54, Lombardy; HR 0.43, CI 0.32-0.57, Apulia), cerebrovascular disease (HR 0.75, CI 0.61-0.91, Lombardy; HR 0.72, CI 0.54-0.96, Apulia), and heart failure (HR 0.56, CI 0.46-0.70, Lombardy; HR 0.57, CI 0.42-0.77, Apulia). In the pooled cohorts, a reduction in heart failure was also observed with GLP-1RAs (HR 0.89, 95% CI 0.82-0.97). Serious adverse events were quite low in frequency. CONCLUSION: Our findings from real-world practice confirm the favourable effect of GLP-1RAs and SGLT2 inhibitors on death and CV outcomes across both regions consistently. Thus, these drug classes should be preferentially considered in a broad type 2 diabetes population beyond those with CV disease.

Cardiovascular mortality and morbidity burden in successive and age pre-stratified case-control cohorts of breast cancer women. A population-based study.

AIMS: To assess the existence, components and clinical relevance of cardiac causes of death and cardiovascular (CV) hospitalizations in a population-wide database of patients with breast cancer (BC). METHODS AND RESULTS: A population-wide database of the Puglia Region, Italy was analyzed, with a prospective comparative design. Three successive closely matched case/control cohorts representing current care in the period 2007-2014 were also stratified according to age to focus specifically on the potential interaction of treatment-related cardiac toxicity and the expected different baseline CV risk profiles. RESULTS: At 3-year follow-up, in the successive cohorts the incidence of BC-related (7.7, 7.0, 6.5%) and cardiac causes of death, specifically attributed to heart failure (HF, 1.3, 0.5, 0.5%), decreased. Significant mortality hazard ratio (HR) for HF was found in the total population (1.47, 95% CI 1.14-1.90), in particular in the 2007-2009 cohort (1.71, 95% CI 1.19-2.46) and in the 50-69 age group (7.96, 95% CI 2.81-22.55). Results at 5 years confirm the mortality findings, and a significant HR for hospitalizations for HF, non-atrial arrhythmias and ischemic heart disease in the younger than 50 subpopulation pointed to a late expression of toxicity in the youngest BC population. CONCLUSIONS: The incidence of CV causes of death 3 and 5 years after BC diagnosis was very low, even if an excess in risk of death for HF as compared with the control cohort was observed. While younger patients seems to tolerate BC and BC therapy better in the short term, HF mortality and morbidity resulted significantly increased at 5-year follow-up. As the risk for hospitalization for CV reasons increased at 5-year follow-up in particular in women aged less than 50 years, CV monitoring in this subgroup of patients seems mandatory.

Microvascular coupler device versus hand-sewn venous anastomosis: A systematic review of the literature and data meta-analysis.

BACKGROUND: Successful vascular anastomosis is essential for the survival of free tissue transfer. The aim of the study is to review the current literature and perform a meta-analysis to assess the potential advantages of a mechanical anastomosis coupler device (MACD) over the hand-sewn (HS) technique for venous anastomoses. METHODS: A systematic Medline search was performed to gather all reports of articles related to MACD from 1984 until now. The following data were extracted: first author and publication date, study design, number of patients and anastomosis, coupler size, site and type of reconstruction, venous anastomotic time, flap failure. A meta-analysis was performed on articles that met the following inclusion criteria: studies comparing MACD and HS technique in venous anastomosis, reporting anastomotic time, and postoperative complications. RESULTS: Thirty-three studies were included for the analysis. Twenty-four were retrospective case series and nine were retrospective comparative studies. A total of 12,304 patients were enrolled with a mean age of 49.23 years (range 31-72). A total of 13,669 flaps were accomplished. The thrombosis rate recorded with MACD was 1.47%. The meta-analysis revealed that MACD significantly decreased anastomotic time (standard difference in means = -0.395 ± 0.105; Z = -3.776; p < .001) and postoperative flap failure risk (odds ratio [OR] = 0.362, 95% confidence interval [CI] = 0.218-0.603, Z = -3.908, p < .001), but it did not decrease postoperative venous thrombosis risk (OR = 0.504, 95% CI = 0.255-1.129, Z = -1.666, p = .096). CONCLUSIONS: MACDs are a safe and effective alternative to traditional anastomosis. The anastomotic coupler is easier, much faster, and requires less technical skills than a HS microvascular anastomosis.

The effects of the introduction of a chronic care model-based program on utilization of healthcare resources: the results of the Puglia care program.

BACKGROUND: Ageing is continuously increasing the prevalence of patients with chronic conditions, putting pressure on the sustainability of Healthcare Systems. Chronic Care Models (CCM) have been used to address the needs of frail people in the continuum of care, testifying to an improvement in health outcomes and more efficient access to healthcare services. The impact of CCM deployment has already been experienced in a selected cohort of patients affected by specific chronic illnesses. We have investigated its effects in a heterogeneous frail cohort included in a regional CCM-based program. METHODS: a retrospective population-based cohort study was carried out involving a non-oncological cohort of adult subjects with chronic diseases included in the CCM-oriented program (Puglia Care). Individuals in usual care with comparable demographic and clinical characteristics were selected for matched pair analysis. Study cohorts were defined by using a record linkage analysis of administrative databases and electronic medical records, including data on the adult population in the 6 local area health authorities of Puglia in Italy (approximately 2 million people). The effects of Puglia Care on the utilizations of healthcare resources were evaluated both in a before-after and in a case-control analysis. RESULTS: There were 1074 subjects included in Puglia Care and 2126 matched controls. In before-after analysis of the Puglia Care cohort, 240 unplanned hospitalizations occurred in the pre-inclusion period, while 239 were registered during follow-up. The incidence of unplanned hospitalization was 10.3 per 100 person/year (95% CI, 9.1-11.7) during follow-up and 12.1 per 100 person/year (95% CI, 10.7-13.8) in the pre-inclusion period (IRR, 0.84; 95% CI, 0.80-0.99). During follow-up a significant reduction in costs related to unplanned hospitalizations (IRR, 0.92; 95% CI, 0.91-0.92) was registered, while costs related to drugs (IRR, 1.14; p < 0.01), out-patient specialist visits (IRR, 1.19; p < 0.01), and planned hospitalization (IRR 1.03; p < 0.01) increased significantly. These modifications can be related to the aging of the population and modifications to healthcare delivery; for this reason, a case-control analysis was performed. The results testify to a significantly lower number (IRR, 0.79; 95% CI, 0.68-0.91), length of hospital stay (IRR, 0.80; 95% CI, 0.76-0.84), and costs related to unplanned hospitalizations (IRR, 0.80; 95% CI, 0.80-0.80) during follow-up in the intervention group. However, there was a higher increase in costs of hospitalizations, drugs and out-patients specialist visits during follow-up in Puglia Care when compared with patients in usual care. CONCLUSION: In a population-based cohort, inclusion of chronic patients in a CCM-based program was significantly associated with a lower recourse to unplanned hospital admissions when compared with patients in usual care with comparable clinical and demographic characteristics.

On the hypothetical universal use of statins in primary prevention: an observational analysis on low-risk patients and economic consequences of a potential wide prescription rate.

PURPOSE: Recent guidelines expand indications for statins. However, research on practical economic feasibility and cost-effectiveness in low-risk people is lacking. We aimed to describe the incidence of cardiovascular events (CVE), their total direct costs and the hypothetical effects of wide provision of statins on those rates and expenditures. METHODS: We conducted a population-based cohort study using administrative data among low risk individuals. Estimators of effects of statins were taken from Cholesterol Treatment trialist metaanalysis and from Heart Protection Study trial. Two statin prices were used for analyses: National Italian Health System (€ 0.36) and the International Drug Price Indicator (€ 0.021). RESULTS: Overall, 920,067 persons at low risk were identified and 14,849 CVE were registered (incidence rate 27.3 per 10,000 person-years). Direct costs for hospitalizations for CVE were 143 M €. Universal provision of statins would result in a significant decrease in CVE rates, from 27.3 to 17.5 per 10,000 person-years (PY) (95% confidence interval (CI): 15.8-19.4). Universal prescription of simvastatin 20 mg would cost 802 M €. Otherwise, provision of simvastatin at International Drug Price Indicator's prices would be both clinically effective and cost saving in men older than age 44 (observed expenditures 120 M €, expected 97.4 M €) but not in women (observed expenditures 22.7 M €, expected 36.5 M €). CONCLUSIONS: Among a low-risk population, hypothetical universal provision of low-cost simvastatin to men over 44 years could be both clinically effective and a cost-saving strategy.

Cancer Incidence and Mortality According to Pre-Existing Heart Failure in a Community-Based Cohort.

Background: Studies assessing whether heart failure (HF) is associated with cancer and cancer-related mortality have yielded conflicting results. Objectives: This study assessed cancer incidence and mortality according to pre-existing HF in a community-based cohort. Methods: Among individuals ≥50 years of age from the Puglia region in Italy with administrative health data from 2002 to 2018, no cancer within 3 years before the baseline evaluation, and ≥5-year follow-up, the study matched 104,020 subjects with HF at baseline with 104,020 control subjects according to age, sex, drug-derived complexity index, Charlson comorbidity index, and follow-up duration. Cancer incidence and mortality were defined based on International Classification of Diseases-Ninth Revision codes in hospitalization records or death certificates. Results: The incidence rate of cancer in HF patients and control subjects was 21.36 (95% CI: 20.98-21.74) and 12.42 (95% CI: 12.14-12.72) per 1000 person-years, respectively, with the HR being 1.76 (95% CI: 1.71-1.81). Cancer mortality was also higher in HF patients than control subjects (HR: 4.11; 95% CI: 3.86-4.38), especially in those <70 years of age (HR: 7.54; 95% CI: 6.33-8.98 vs HR: 3.80; 95% CI: 3.44-4.19 for 70-79 years of age; and HR: 3.10; 95% CI: 2.81-3.43 for ≥80 years of age). The association between HF and cancer mortality was confirmed in a competing risk analysis (subdistribution HR: 3.48; 95% CI: 3.27-3.72). The HF-related excess risk applied to the majority of cancer types. Among HF patients, prescription of high-dose loop diuretic was associated with higher cancer incidence (HR: 1.11; 95% CI: 1.03-1.21) and mortality (HR: 1.35; 95% CI: 1.19-1.53). Conclusions: HF is associated with an increased risk of cancer and cancer-related mortality, which may be heightened in decompensated states.

Insulin treatment in patients with diabetes mellitus and heart failure in the era of new antidiabetic medications.

BACKGROUND: Coexistent heart failure (HF) and diabetes mellitus (DM) are associated with marked morbidity and mortality. Optimizing treatment strategies can reduce the number and severity of events. Insulin is frequently used in these patients, but its benefit/risk ratio is still not clear, particularly since new antidiabetic drugs that reduce major adverse cardiac events (MACEs) and renal failure have recently come into use. Our aim is to compare the clinical effects of insulin in a real-world setting of first-time users, with sodium-glucose cotransporter-2 inhibitor (SGLT-2i), glucagon-like peptide-1 receptor agonist (GLP-1RA) and the other antihyperglycemic agents (other-AHAs). METHODS: We used the administrative databases of two Italian regions, during the years 2010-2018. Outcomes in whole and propensity-matched cohorts were examined using Cox models. A meta-analysis was also conducted combining the data from both regions. RESULTS: We identified 34 376 individuals ≥50 years old with DM and HF; 42.0% were aged >80 years and 46.7% were women. SGLT-2i and GLP-1RA significantly reduced MACE compared with insulin and particularly death from any cause (SGLT-2i, hazard ratio (95% CI) 0.29 (0.23 to 0.36); GLP-1RA, 0.482 (0.51 to 0.42)) and first hospitalization for HF (0.57 (0.40 to 0.81) and 0.67 (0.59 to 0.76)). CONCLUSIONS: In patients with DM and HF, SGLT-2i and GLP-1RA significantly reduced MACE compared with insulin, and particularly any cause of death and first hospitalization for HF. These groups of medications had high safety profiles compared with other-AHAs and particularly with insulin. The inadequate optimization of HF and DM cotreatment in the insulin cohort is noteworthy.

Long-Term Outcomes of a Cohort of Hypertensive Subjects in Rural Ecuador.

BACKGROUND: In contrast with the abundance of global epidemiological descriptive data on cardiovascular diseases and their risk factors, information on the outcomes of real populations prospectively followed up in their life and care settings is much rarer, especially in low-income countries. OBJECTIVES: This study sought to evaluate the feasibility and the overall results of a hypertension control program, based mainly on a network of community nonprofessional health promoters, in the poor rural region of Borbon (Ecuador). METHODS: This is a prospective cohort study describing the results of a program of hypertension diagnosis, treatment and follow-up from 2004 to 2015 in the area, carried out mainly by the health promoters. RESULTS: The number of hypertensive patients identified and followed over the years increased from 1,024 in 2004 to 1,733 in 2015. The percentage of patients with no visits during a year was reduced to <10%, whereas the proportion of hypertensive subjects attending all 4 scheduled annual checks approached and, in some years, exceeded 50%. From 2004 to 2015, the proportion of patients at high or very high cardiovascular risk progressively decreased from 26.6% in 2004 to 17.5% in 2015 (p for trend <0.01), whereas the proportion of hypertensive patients at low or very low risk increased from 30.4% in 2004 to 45.0% in 2015 (p for trend <0.01). CONCLUSIONS: In a poor, disadvantaged area, a strategy of control mainly based on the involvement and responsibility of community health promoters (with health professionals as supporters more than direct actors) can achieve adequate follow-up of the population of hypertensive patients and improve their global cardiovascular risk level.

Breast cancer cutaneous metastases mimicking Papilloma Cutis Lymphostatica. Biopsy to avoid pitfalls.

INTRODUCTION: Secondary lymphedema is the most frequent long-term complication of axillary lymphadenectomy. It can result in complication as erysipelas, warts, Papilloma Cutis Lymphostatica (PCL), or angiosarcomas. Moreover, in women affected by breast cancer an accurate differential diagnosis among these conditions or complication related to radiation dermatitis or cutaneous metastasis is essential. PRESENTATION OF CASE: We report the case of a 60-year-old postmenopausal Caucasian woman affected by secondary lymphedema following complete mastectomy for breast cancer. The patient after surgery was treated with radiotherapy, chemotherapy and hormone therapy, developing a lympedema of left arm after few months. These lesions had clinical typical features of PCL, but histopathological analysis revealed dermo-hypodermic metastasis of breast carcinoma. DISCUSSION: The presence of skin lesions in secondary lymphedema after oncological lymphadenectomy requires an accurate differential diagnosis. In fact, these lesions can emulate degenerative or infective skin diseases; anyway, in patients affected by secondary lymphedema other less common conditions - as PLC, nodular-type lichen myxedematosus or Gottron's carcinoid papillomatosis - should be taken into account. CONCLUSION: Our case reports the possibility that metastases of breast cancer might also mimic these conditions.

Surgical management of tumor-positive interval node in melanoma patients: An observational study.

The presence of interval nodes (IN) in melanoma is testified in several studies and sometimes these lymph nodes can contain metastatic disease. Currently there are no guidelines about the management of patients with tumor-positive INs.We enrolled all patients affected by melanoma who underwent sentinel lymph node biopsy (SLNB) in a single institution. All patients with tumor-positive IN underwent the lymphadenectomy of the subsequent draining lymphatic field. Prognosis of IN+-patients was compared with subjects with positive SLNB in usual field through Kaplan-Meier and multivariate Cox regression analysis.Overall 596 subjects underwent lymphoscintigraphy and one or more INs were identified in 94 (15.8%) patients. The mean number of sentinel lymph nodes (SNs) identified per patient was significantly higher in patients with INs. Macrometastasis were more common in patients with INs. Matched pair analysis testified a statistically significant better prognosis in patients with positive-INs when compared with patients with positive SNs in usual side with the same demographic and clinical characteristics. These findings were confirmed both in analysis of 10-year recurrence-free period, then in 10-years overall survival analysis.Lymphadenectomy of the lymphatic draining field beyond positive-IN testify has proved to be a safe procedure that may improve prognosis in melanoma patients with tumor-positive INs. The better prognosis of patients with tumor-positive INs undergoing lymphadenectomy may be justified by the earlier treatment of lymphatic metastases. Further multicentric comparative studies are needed to evaluate possible impact of this procedure on prognosis of melanoma patients.

Treatment with insulin is associated with worse outcome in patients with chronic heart failure and diabetes.

AIMS: Up to one-third of patients with diabetes mellitus and heart failure (HF) are treated with insulin. As insulin causes sodium retention and hypoglycaemia, its use might be associated with worse outcomes. METHODS AND RESULTS: We examined two datasets: 24 012 patients with HF from four large randomized trials and an administrative database of 4 million individuals, 103 857 of whom with HF. In the former, survival was examined using Cox proportional hazards models adjusted for baseline variables and separately for propensity scores. Fine-Gray competing risk regression models were used to assess the risk of hospitalization for HF. For the latter, a case-control nested within a population-based cohort study was conducted with propensity score. Prevalence of diabetes mellitus at study entry ranged from 25.5% to 29.5% across trials. Insulin alone or in combination with oral hypoglycaemic drugs was prescribed at randomization to 24.4% to 34.5% of the patients with diabetes. The rates of death from any cause and hospitalization for HF were higher in patients with vs. without diabetes, and highest of all in patients prescribed insulin [propensity score pooled hazard ratio for all-cause mortality 1.27 (1.16-1.38), for HF hospitalization 1.23 (1.13-1.33)]. In the administrative registry, insulin prescription was associated with a higher risk of all-cause death [odds ratio (OR) 2.02, 95% confidence interval (CI) 1.87-2.19] and rehospitalization for HF (OR 1.42, 95% CI 1.32-1.53). CONCLUSIONS: Whether insulin use is associated with poor outcomes in HF should be investigated further with controlled trials, as should the possibility that there may be safer alternative glucose-lowering treatments for patients with HF and type 2 diabetes mellitus.

Single-stage excision and sentinel lymph node biopsy in cutaneous melanoma in selected patients: a retrospective case-control study.

Sometimes, diagnostic excision of a primary melanoma would already necessitate skin grafting or transposition skin flaps, especially in areas with an esthetic or functional importance. The utility of sentinel lymph node biopsy (SLNB) after skin reconstruction is controversial. We carried out a single-institution retrospective case-control study. In patients with a wide primary lesion at high clinical-dermatoscopic suspicion for invasive melanoma in anatomical region in which a reconstruction with a skin graft or a flap is required, we proposed the performance of a confocal microscopy examination and an incisional biopsy of the primary lesion. If these diagnostic methodologies confirmed the suspicion of melanoma, lymphatic mapping was performed before the wide excision (WE) of the primary lesion, and WE and SLNB were performed during the same operative procedure. The database evaluation showed 496 patients who had undergone a previous complete local excision and a subsequent SLNB (two-stage group), whereas 61 patients underwent WE and SLNB during the same surgical time (one-stage group). Histological results of the excisional biopsy confirmed the diagnosis of melanoma in all patients of the one-stage group. The false-negative rate was lower in the one-stage group (5.5%) than in the two-stage group (16.7%). Patients of the two groups showed a similar recurrence-free and overall survival period even when corrected for clinic-demographical variables. The concomitant execution of SLNB and WE after confocal microscopy examination and incisional biopsy appears to be a safe and accurate procedure in patients with a wide primary melanoma that requires a skin flaps or a skin graft to cover the residual defect.

The surgical treatment of a melanoma patient with macroscopic metastasis in peri and retrocaval lymph nodes and with a positive sentinel lymph node in the groin.

BACKGROUND: The extension of iliac-obturator dissection in melanoma patient with metastatic sentinel node of the groin is very debated. More recent studies - in accord with guidelines for urogenital cancers - suggest the extension to pelvic lymph nodes. At present, however, anatomical limits and indications to pelvic dissection are not defined in melanoma patients with metastatic lymph nodes of groin. CASE REPORT: A 46-year-old man affected by nodular cutaneous melanoma (Breslow-thickness 10 mm, Clark-level V) on the anterior-medial surface of the right leg underwent sentinel node biopsy of groin. Three macro-metastatic sentinel lymph nodes were removed in right inguinal field and, after 2 weeks, an ipsi-lateral inguinal lymphadenectomy with an extended pelvic dissection was performed. During the surgery, we reported the presence of macrometastases also in retro/peri caval lymph nodes. As a result of these findings, we decided to perform the super-extended pelvic lymphadenectomy. Overall we removed 56 lymph nodes with 9 peri-caval and 2 retro-caval macro metastatic lymph nodes. After a period of 49 months, the patients came to our attention with multiple scrotal metastases. The imagining restaging of the patient was already negative for other melanoma localizations. DISCUSSION: Currently there are no guidelines about indications and anatomical limits of iliac-obturator extension in melanoma patients. The extended pelvic dissection is the gold-standard procedure used in urogenital carcinomas. In case of finding of macro-metastases during the surgical procedure, the approach to follow is even more uncertain. We perform a super-extended pelvic dissection with a good prognosis for the patient. KEY WORDS: Caval-metastasis, Extended-pelvic-lymphadenectomy, Metastatic-melanoma.

Autologous bone grafting with platelet-rich plasma for alveolar cleft repair in patient with cleft and palate.

PURPOSE: Bone grafting of the alveolus has become an essential part of the contemporary surgical management of the oral cleft. The aim of this retrospective study was to evaluate the results of bone grafting in association with PRP (plateletrich plasma) to enhance osteogenesis and osteointegration. PATIENTS AND METHODS: The study included 16 patients, aged between 9 and 11, affected with unilateral residual alveolar clefts, who underwent bone grafting using secondary alveoplasty. The eight patients belonging to the control group were administered autologous bone graft alone while the study group, consisting of 8 patients, underwent autologous bone grafting in association with PRP. All patients had pre and post surgery orthodontic treatment. The statistical analyses included Student's t test, 2 test and Kaplan-Meir time to event analysis. The p-value was considered significant if p<0.05. All statistical analyses were performed using SAS Software release 9.3 (SAS Institute, Cary, Nc). RESULTS: The control group (M 50%, mean age 10.2±2.3) underwent simple autologous bone graft while the study group (M 62.5%, mean age 9.9±2.2) was treated with a combination of autologous bone and PRP. No statistically significant differences were found between the two groups as regards age, gender and labial-palatal cleft clinical characteristics. 6, 12, 24 month follow-ups were performed by means of clinical and radiographic investigations. None of the study group developed oronasal fistulas or experienced bone height, bone bridging and bone quality loss; only two patients developed mild periodontal problems. The study group was able to undergo a significantly (p<0.001) earlier and shorter orthodontic treatment. CONCLUSIONS: In our experience, the use of PRP enhances the quality of osteoplasty, accelerates "creeping substitution" and bone healing and favours earlier orthodontic treatment. KEY WORDS: Alveolar cleft, Bone grafting, Palate, Platelet-rich plasma.

Interval sentinel lymph nodes in melanoma: a digital pathology analysis of Ki67 expression and microvascular density.

The presence of interval sentinel lymph nodes in melanoma is documented in several studies, but controversies still exist about the management of these lymph nodes. In this study, an immunohistochemical evaluation of tumor cell proliferation and neo-angiogenesis has been performed with the aim of establishing a correlation between these two parameters between positive and negative interval sentinel lymph nodes. This retrospective study reviewed data of 23 patients diagnosed with melanoma. Bioptic specimens of interval sentinel lymph node were retrieved, and immunohistochemical reactions on tissue sections were performed using Ki67 as a marker of proliferation and CD31 as a blood vessel marker for the study of angiogenesis. The entire stained tissue sections for each case were digitized using Aperio Scanscope Cs whole-slide scanning platform and stored as high-resolution images. Image analysis was carried out on three selected fields of equal area using IHC Nuclear and Microvessel analysis algorithms to determine positive Ki67 nuclei and vessel number. Patients were divided into positive and negative interval sentinel lymph node groups, and the positive interval sentinel lymph node group was further divided into interval positive with micrometastasis and interval positive with macrometastasis subgroups. The analysis revealed a significant difference between positive and negative interval sentinel lymph nodes in the percentage of Ki67-positive nuclei and mean vessel number suggestive of an increased cellular proliferation and angiogenesis in positive interval sentinel lymph nodes. Further analysis in the interval positive lymph node group showed a significant difference between micro- and macrometastasis subgroups in the percentage of Ki67-positive nuclei and mean vessel number. Percentage of Ki67-positive nuclei was increased in the macrometastasis subgroup, while mean vessel number was increased in the micrometastasis subgroup. The results of this study suggest that the correlation between tumor cell proliferation and neo-angiogenesis in interval sentinel lymph nodes in melanoma could be used as a good predictive marker to distinguish interval positive sentinel lymph nodes with micrometastasis from interval positive lymph nodes with macrometastasis subgroups.

The Drug Derived Complexity Index (DDCI) Predicts Mortality, Unplanned Hospitalization and Hospital Readmissions at the Population Level.

OBJECTIVE: to develop and validate the Drug Derived Complexity Index (DDCI), a predictive model derived from drug prescriptions able to stratify the general population according to the risk of death, unplanned hospital admission, and readmission, and to compare the new predictive index with the Charlson Comorbidity Index (CCI). DESIGN: Population-based cohort study, using a record-linkage analysis of prescription databases, hospital discharge records, and the civil registry. The predictive model was developed based on prescription patterns indicative of chronic diseases, using a random sample of 50% of the population. Multivariate Cox proportional hazards regression was used to assess weights of different prescription patterns and drug classes. The predictive properties of the DDCI were confirmed in the validation cohort, represented by the other half of the population. The performance of DDCI was compared to the CCI in terms of calibration, discrimination and reclassification. SETTING: 6 local health authorities with 2.0 million citizens aged 40 years or above. RESULTS: One year and overall mortality rates, unplanned hospitalization rates and hospital readmission rates progressively increased with increasing DDCI score. In the overall population, the model including age, gender and DDCI showed a high performance. DDCI predicted 1-year mortality, overall mortality and unplanned hospitalization with an accuracy of 0.851, 0.835, and 0.584, respectively. If compared to CCI, DDCI showed discrimination and reclassification properties very similar to the CCI, and improved prediction when used in combination with the CCI. CONCLUSIONS AND RELEVANCE: DDCI is a reliable prognostic index, able to stratify the entire population into homogeneous risk groups. DDCI can represent an useful tool for risk-adjustment, policy planning, and the identification of patients needing a focused approach in everyday practice.

Non-Medical Risk Factors as Avoidable Determinants of Excess Mortality in Children with Chronic Kidney Disease. A Prospective Cohort Study in Nicaragua, a Model Low Income Country.

BACKGROUND: The widely recognized clinical and epidemiological relevance of the socioeconomic determinants of health-disease conditions is expected to be specifically critical in terms of chronic diseases in fragile populations in low-income countries. However, in the literature, there is a substantial gap between the attention directed towards the medical components of these problems and the actual adoption of strategies aimed at providing solutions for the associated socioeconomic determinants, especially in pediatric populations. We report a prospective outcome study on the independent contribution and reciprocal interaction of the medical and socioeconomic factors to the hard end-point of mortality in a cohort of children with chronic kidney disease in Nicaragua. METHODS AND FINDINGS: Every child (n = 309) diagnosed with chronic kidney disease (CKD) and referred to the tertiary unit of Pediatric Nephrology in Managua (Nicaragua) from a network of nine hospitals serving 80% of the country's pediatric population was registered between January 2005 and December 2013. The three main socioeconomic determinants evaluated were family income, living conditions and the family's level of education. Further potential determinants of the outcomes included duration of exposure to disease, CKD stage at the first visit as suggested by the KDOQI guidelines in children, the time it took the patients to reach the reference centre and rural or urban context of life. Well-defined and systematically collected medical and socioeconomic data were available for 257 children over a mean follow-up period of 2.5±2.5 years. Mortality and lost to follow-up were considered as outcome end-points both independently and in combination, because of the inevitably progressive nature of the disease. A high proportion (55%) of children presented in the advanced stages of CKD (CKD stage IV and V) at the first visit. At the end of follow-up, 145 (57%) of the 257 cohort children were alive, 47 (18%) were lost to follow-up and 65 (25%) had died. Cox regression analysis showed an independent contribution to mortality of CKD stage at diagnosis and of level of education, with overlapping HR values (HR and 95%CI: 2.66; 1.93-3.66 and 2.72; 1.71-4.33, respectively). CONCLUSIONS: The unfavourable socioeconomic and cultural background of the pediatric study cohort and the severity of kidney damage at diagnosis were the key determinants of the clinical risk conditions at baseline and of the mortality outcome. Long-term structural interventions on such backgrounds must be adopted to assure effectiveness of medical care and to assure an earlier diagnosis of CKD in these patients. The translation-extension of our results is currently underway with an agenda which includes: 1) better integration of chronic pediatric conditions into primary care strategies to promote prevention and early timely referral; 2) the consideration of socioeconomic conditions as a mandatory component of the packages of best-care; 3) the formulation and flexible adaptation of guidelines and educational programs, based on the information generated by a context-specific, epidemiological monitoring of needs and outcomes, guaranteed by an effective database.