Sentinel Lymph Node Biopsy Versus Axillary Dissection in Node-Negative Early-Stage Breast Cancer: 15-Year Follow-Up Update of a Randomized Clinical Trial

Background

Sentinel lymph node biopsy (SLNB) allows for staging of the axillary node status in early-stage breast cancer (BC) patients and avoiding complete axillary lymph node dissection (ALND) when the sentinel lymph node (SLN) is proven to be free of disease. In a previous randomized trial we compared SLNB followed by ALND (ALND arm) with SLNB followed by ALND only if the SLN presented metastasis (SLNB arm). At a mid-term of ≈ 6 years median follow-up, the two strategies appeared to ensure similar survival and locoregional control. We have revised these previous findings and update the results following a 15-year observation period.

Methods

Patients were randomly assigned to either the ALND or SLNB arm. The main endpoints were event-free survival (EFS), overall survival (OS), and axillary disease recurrence. EFS and OS were assessed using Kaplan–Meier analysis and the log-rank test.

Results

The ALND and SLNB arms included 115 and 110 patients, respectively. At 14.3 years median follow-up, 39 primary BC-related recurrences occurred, 22 (19 %) of which occurred in the ALND arm and 17 (16 %) occurred in the SLNB arm (p = 0.519). No axillary relapse developed in the SLNB arm, while two were observed in the ALND arm. OS (82.0 vs. 78.8 %) and EFS (72.8 vs. 72.9 %) were not statistically different between the ALND and SLNB arms (p = 0.502 and 0.953, respectively).

Conclusions

SLNB is a safe and efficacious component of the surgical treatment of early-stage BC patients. In the long-term, SLNB is equivalent to ALND in terms of locoregional nodal disease control and survival in this subset of patients.

     

Divergences in antihypertensive therapy in special situations in nephrology.

CONTEXT AND OBJECTIVE: The choice of an antihypertensive drug is based on several criteria and specific situations give rise to doubt and controversy. The aim here was to evaluate physicians approaches towards treatment with antihypertensive agents in specific situations. DESIGN AND SETTING: Cross-sectional study, at Universidade Federal de S?o Paulo, S?o Paulo. METHODS: A questionnaire was applied during a nephrology meeting to evaluate individual approaches towards each hypothetical clinical situation. The questionnaire consisted of five multiple-choice questions (clinical cases) concerning controversial aspects of antihypertensive therapy. RESULTS: A total of 165 questionnaires were analyzed. Most participants were nephrologists (93.2%). There was a preference for angiotensin-converting enzyme (ACE) inhibitors in at least two of the cases. Only 57.2% of the physicians were correct in choosing beta-blockers as the first-line drugs for patients with ischemic coronary disease. Moreover, 66.2% chose ACE inhibitors as the first-line drugs for patients with chronic kidney disease and proteinuria. About 5% of the physicians did not follow the current recommendations for the use of ACE inhibitors in diabetic patients with microalbuminuria. The most controversial question concerned the first-line drug for advanced chronic kidney disease. Most physicians were correct in choosing calcium channel blockers and avoiding ACE inhibitors in renovascular hypertension in the case of a patient with a single functioning kidney. CONCLUSIONS: Most physicians adopted the correct approach, but some had an alternative strategy for the same situations that was not based on evidence.     

Immunogenicity of a tetravalent meningococcal glycoconjugate vaccine in infants: a randomized controlled trial

Context  Immunization with a meningococcal tetravalent (serogroup ACWY) glycoconjugate vaccine is recommended for all US adolescents. However, the currently licensed vaccine is poorly immunogenic in infancy, when the highest rates of disease are observed. Objective  To determine the immunogenicity of a novel tetravalent CRM₁₉₇-conjugated meningococcal vaccine (MenACWY) in infants. Design, Setting, and Participants  Randomized, open-label, controlled study of 225 UK and 196 Canadian 2-month-olds from August 2004 to September 2006. Intervention  UK infants received a primary course of MenACWY (at 2, 3, and 4 months or 2 and 4 months) or Neisseria meningitidis serogroup C monovalent meningococcal glycoconjugate vaccine (MenC) (at 2 and 4 months). All received MenACWY at 12 months. Canadian infants received MenACWY at 2, 4, and 6 months or 2 and 4 months; at 12 months they received MenACWY, a plain tetravalent polysaccharide vaccine, or no vaccine. Main Outcome Measure  Percentage of infants with a human complement serum bactericidal activity (hSBA) titer 1:4 after a primary course of MenACWY and after a 12-month booster. Safety and reactogenicity of MenACWY were also assessed. Results  According to the prespecified per-protocol analysis, the percentages (95% CIs) of MenACWY 2-, 3-, and 4-month recipients with hSBA titers 1:4 after primary immunization were serogroup A, 93% (84%-98%); C, 96% (89%-99%); W-135, 97% (90%-100%); and Y, 94% (86%-98%). With a post hoc intention-to-treat analysis with imputed values for missing data, these values were unchanged for serogroups C and Y; for serogroup A, values were 92% (84%-97%), and for W-135, 97% (91%-99%). For the per-protocol analysis of MenACWY 2-, 4-, and 6-month recipients, the percentages (95% CIs) of responders were A, 81% (71%-89%); C, 98% (92%-100%); W-135, 99% (93%-100%); and Y, 98% (92%-100%). With the imputed value analysis, these values were A, 83% (74%-89%); C, 98% (93%-99%); W-135, 99% (94%-100%); and Y, 98% (92%-99%). At least 84% of MenACWY 2- and 4-month recipients achieved hSBA titers 1:4 for serogroups C, W-135, and Y after primary immunization, as did at least 60% for serogroup A (per-protocol and imputation analysis). At least 95% of primary and booster MenACWY recipients achieved hSBA titers 1:4 for serogroups C, W-135, and Y at 13 months, as did at least 84% for serogroup A (per-protocol and imputation analysis). During the primary immunization course, postimmunization pain on leg movement was observed in 2% of UK MenACWY 2- and 4-month recipients and 4% of MenC 2- and 4-month recipients; a temperature of 38°C or greater was observed in 4% and 2% in these groups, respectively. Conclusion  MenACWY is well tolerated and immunogenic in infancy. Trial Registration  clinicaltrials.gov Identifier: NCT00262002      

Muscle strength and power, maximum oxygen consumption, and body composition in middle-aged short-stature adults with childhood-onset growth hormone deficiency

BACKGROUND: Growth hormone (GH) replacement in adult GH-deficient (GHD) patients is reported to have a long-term beneficial effect on muscle mass and function, these effects being greater in young males and in adult-onset compared with those with childhood-onset GHD. To date, more discordant data are reported on the degree of muscle impairment in untreated GHD patients, due to the large heterogeneity of this syndrome. METHODS: Muscle maximum total isotonic strength (ST), lower limb maximum power output (W), maximum aerobic capacity (VO(2)max) and body composition (by tetrapolar bio-impedentiometry) were evaluated in seven short-stature adults with childhood-onset GHD and in seven age-matched normal-stature controls with comparable lifestyle and daily physical activity. RESULTS: Significant differences were found in body composition between control subjects and GHD patients, who presented higher adiposity (mean BMI+/-SD: GHD, 27.8+/-5.8 kg/m(2); controls, 22.1+/-0.8 kg/m(2); p=0.047), larger fat mass (GHD, 21.8+/-10.7 kg; controls, 8.8+/-3.5 kg; p=0.008), and lower fat-free mass (GHD, 65.8+/-11.4 %; controls, 87.0+/-6.5 %; p=0.002). In absolute terms, GHD patients attained significantly lower values in ST (GHD, 2479+/-493 N; controls, 4578+/-1476 N; p=0.008), W (GHD, 1092+/-452 W; controls, 1910+/-781 W; p=0.035) and VO(2)max (GHD, 1.68+/-0.40 l/min; controls, 2.67+/-0.84 l/min; p=0.035) than those attained by controls. The differences were still evident when the results were normalized by unit body mass, whereas they disappeared when the parameters were expressed per unit fat-free mass, suggesting for these patients the presence of an intrinsic muscle function in the same range as that of control subjects. CONCLUSIONS: Middle-aged and short-stature adults with childhood-onset GHD, who received discontinuous pit-GH substitution therapy only during childhood and have uncorrected long-lasting GHD, still retain a normal intrinsic muscle capability in attaining isotonic strength, generating anaerobic power as well as accomplishing oxidative processes. Nonetheless, it is not known which age-dependent evolution in motor dysfunction could be expected in this subgroup of GHD patients, when ageing processes add up to hormonal deficiencies.     

In vivo characterization of the inflammatory infiltrate and apoptotic status in imiquimod-treated basal cell carcinoma

Background Imiquimod use in the treatment of basal cell carcinoma (BCC) has proven to be successful in a large percentage of cases, inducing tumor regression; however, the exact cellular mechanism has not been fully clarified. Aim To measure the morphological changes in the tumor microenvironment and the markers of apoptosis in skin biopsies from patients with BCC before and after imiquimod treatment. Methods In this open label study, skin biopsies obtained from 11 patients with BCC were evaluated before and after imiquimod treatment for: (i) morphological changes in the tumor microenvironment, with specific emphasis on the immunophenotype of inflammatory cells around the tumor; and (ii) markers of apoptosis, including expression of death receptors. Results Imiquimod treatment induced a significant increase in the mononuclear inflammatory response. In the majority of cases, the cellular infiltrate was predominantly composed of CD3⁺/CD4⁺ T cells, suggesting that the effector response is mediated by CD3⁺/CD4⁺ lymphocytes, with a minor cytotoxic and natural killer (NK) component. An increase in the cytotoxic CD3⁺/CD8⁺ T‐cell population was also observed. Imiquimod treatment was associated with a marked increased in CD20⁺ B cells, and a less pronounced enhancement in cells of monocyte–macrophage origin (CD68⁺) surrounding, or within, the tumor. This finding indicates either that macrophages play a minor role in the imiquimod‐induced response, or the recruitment of these cells is related to time and dose. Imiquimod treatment decreased CD1A⁺ Langerhans cells in the epidermis and increased the number of CD1A⁺ dendritic cells within the tumor aggregates. Imiquimod reduced Bcl‐2 expression, but no difference was found in Bax, Fas/FasL, and p53 expression in BCC cells. Conclusions Our results support the hypothesis that imiquimod activity in the treatment of BCC is partly a result of a pro‐inflammatory action mediated by CD3⁺/CD4⁺ lymphoid cells and of a pro‐apoptotic activity associated with decreased Bcl‐2 expression.     

Human papillomavirus type 5 in primary keratinocytes from psoriatic skin

The role of human papillomaviruses (HPVs) in the pathogenesis of psoriasis is uncertain, and it has been postulated that the virus can act as a putative superantigen or it is activated from a latent status by inflammatory cytokines. To determine the involvement of HPV in the pathogenesis of psoriasis, primary cultures of keratinocytes from psoriatic lesions were analysed for the viral presence and for the production of inflammatory cytokines. Biopsies were taken from psoriatic lesions of 11 patients and from healthy donors undergoing plastic surgery. HPV DNA/RNAs were detected by nested polymerase chain reaction methods. The secretion of interleukin-6 (IL-6), IL-8 and IL-18 was determined in the conditioned medium by commercial enzyme-linked immunosorbent assay kits. Sixty-four per cent of the psoriatic keratinocytes were positive to HPV type 5 (HPV5), whereas no normal samples showed the presence of viral sequences. In the corresponding paraffin-embedded sections, multiple infection by HPV5 and HPV1 was detected. Comparable results in the production of inflammatory cytokines were obtained from HPV-infected vs. non-infected cell cultures. Specific HPV5 mRNAs were detected in the keratinocytes in the absence of cytokine stimulation, indicating that the expression of the viral genome may not be a consequence of the activation of the viral promoter by cytokines. The results are suggestive of an involvement of HPV5 in the psoriasis and reinforce the hypothesis that the replication of this virus in the psoriatic keratinocytes may cause the epidermal hyperproliferation as well as the antigen stimulation, which induces autoimmune phenomena.     

LASEK and photorefractive keratectomy for myopia: clinical and confocal microscopy comparison

PURPOSE: To compare postoperative visual acuity and corneal morphology after laser epithelial keratomileusis (LASEK) versus photorefractive keratectomy (PRK) in the correction of low to moderate myopia. METHODS: In a double-blind, randomized clinical trial, 50 myopic patients (mean: -4.5 +/- 1.35 diopters) were randomized to receive LASEK in one eye and PRK in the fellow eye. No mitomycin C eye drops were used in this study. Patients were observed daily for 4 days, then at 1 month and every 3 months up to 1 year. Uncorrected and best-corrected visual acuity (UCVA and BSCVA), manifest refraction, corneal epithelium healing time, postoperative pain, and corneal haze were evaluated. Corneal wound healing was quantified with corneal confocal microscopy. RESULTS: Refractive error, UCVA, and BSCVA were not statistically different between eyes treated with LASEK and PRK. Corneal epithelium healing time was 2.52 +/- 0.99 days in the eyes treated with PRK and 2.29 +/- 0.52 days in the eyes treated with LASEK (P=.22). The postoperative pain score was 2.17 +/- 0.87 in the eyes treated with PRK and 2.62 +/- 0.60 (P=.02) in the eyes treated with LASEK. Corneal confocal microscopy showed fewer stromal activated keratocytes and less extracellular matrix deposition in the eyes treated with LASEK than in the eyes treated with PRK at 1 month postoperatively (P=.003). CONCLUSIONS: LASEK is an effective and safe procedure for low to moderate myopia, but it seems more painful until full corneal reepithelization. In the early postoperative period, the corneal wound healing process is significantly less intense in eyes treated with LASEK than in eyes treated with PRK. The role of LASEK in corneal wound healing modulation remains controversial.     

Seasonal variation of Lutzomyia longipalpis (Lutz & Neiva, 1912) (Diptera: Psychodidae: Phlebotominae) in endemic area of visceral leishmaniasis, Campo Grande, state of Mato Grosso do Sul, Brazil

The seasonal distribution of Lutzomyia longipalpis was studied in two forested and five domiciliary areas of the urban area of Campo Grande; MS, from December 2003 to November 2005. Weekly captures were carried out with CDC light traps positioned on ground and in the canopy inside a residual forest and on the edge (ground) of a woodland and in at least one of the following ecotopes in peridomiciles-a cultivated area, a chicken coop, a pigsty, a kennel, a goat and sheep shelter and an intradomicile. A total of 9519 sand flies were collected, 2666 during the first year and 6853 during the second. L. longipalpis was found throughout the 2-year period, presenting smaller peaks at intervals of 2-3 months and two greater peaks, the first in February and the second in April 2005, soon after periods of heavy rain. Only In one of the woodlands was a significant negative correlation (p<0.05) between the number of insects and temperature during the first year and the climatic factors (temperature, RHA and rain) was observed. In the domiciliary areas in four domiciles some positive correlations (p< or =0.05) occurred in relation to one or more climatic factors; however, the species shows a clear tendency to greater frequency (72%) in the rainy season than in the dry (28%). Thus, we recommend an intensification of the VL control measures applied in Campo Grande, MS, during the rainy season with a view to reducing the risk of the transmission of the disease.