Beta-blockers in early-stage breast cancer: a systematic review and meta-analysis.

BACKGROUND: Preclinical and retrospective studies suggest that beta-blockers are active against breast cancer. We carried out a systematic review and meta-analysis to assess the impact of beta-blockers on the outcomes of patients with early-stage breast cancer. METHODS: A systematic literature search was performed to identify studies comparing outcomes of patients with early-stage breast cancer according to beta-blocker use (yes versus no). The primary endpoint was recurrence-free survival (RFS), defined as the occurrence of breast cancer recurrence or death. Secondary objectives were pathologic complete response (pCR), breast cancer recurrence, breast cancer-specific mortality and overall survival (OS). Hazard ratios (HRs) or odds ratios (ORs) and 95% confidence intervals (CIs) were extracted from each study and a pooled analysis with the random-effect model was conducted. The Higgins' I-squared test was used to quantify heterogeneity. Egger's test was applied to assess publication bias. All P values were two-sided and considered significant if ≤0.05. RESULTS: Overall, 13 studies were included as follows: RFS (6), pCR (2), breast cancer recurrence (6), breast cancer-specific mortality (7) and OS (5). The use of beta-blockers was associated with a significant RFS improvement in the overall population (N = 21 570; HR 0.73; 95% CI, 0.56-0.96; P = 0.025) and in patients with triple-negative disease (N = 1212; HR 0.53; 95% CI, 0.35-0.81; P = 0.003). No significant differences in terms of pCR (N = 1554; OR 0.77; 95% CI, 0.44-1.36; P = 0.371), breast cancer recurrence (N = 37 957; OR 0.66; 95% CI, 0.42-1.03; P = 0.065), breast cancer-specific mortality (N = 64 830; HR 0.77; 95% CI, 0.56-1.08; P = 0.130) or OS (N = 103 065; HR 1.03; 95% CI, 0.87-1.23; P = 0.692) were observed according to beta-blocker use. DISCUSSION: In this meta-analysis, beta-blocker use was associated with a longer RFS in patients with early-stage breast cancer, with a more pronounced effect observed in those with triple-negative disease. Beta-blockers arise as an interesting option to be explored in prospective studies for patients with early-stage breast cancer.

Association between increased BMI and severe school absenteeism among US children and adolescents: findings from a national survey, 2005-2008.

OBJECTIVE: School absenteeism may be an underlying cause of poor school performance among overweight and obese children. We examined the associations between school absenteeism and body mass index (BMI) in a nationally representative sample. DESIGN AND SUBJECTS: We analyzed the data of 1387 children (6-11 years) and 2185 adolescents (12-18 years), who completed an interview and anthropometric measurement as a part of the National Health and Nutrition Examination Survey, 2005-2008. The CDC 2000 growth chart was used to categorize BMI status, and the number of school days missed during the past 12 months was assessed by asking the proxies or interviewees. RESULTS: The prevalence of obesity and overweight were 18.96±1.44% (s.e.) and 16.41±0.78%, respectively, among study populations. The means of school days missed in the last 12 months were not statistically different between the normal-weight, overweight and obese groups, 3.79±0.56, 3.86±0.38 and 4.31±0.01 days, respectively. However, when >2 days missed per school month was defined as severe absence, the prevalence of severe absence were 1.57%, 2.99% and 4.94% respectively, among 6-11-year-old children with normal, overweight and obese. The adjusted odds of severe school absence were 2.27 (95% confidence interval=0.64-8.03) and 3.93 (1.55-9.95), respectively, among overweight and obese children compared with normal-weight peers (P for trend test <0.01). No significant association was found among adolescents. CONCLUSION: Increased body weight is independently associated with severe school absenteeism in children but not adolescents. Future research is needed to determine the nature, and academic and social significance of this association.

Doctor, how long?

This study aimed to quantify the average survival time of cancer patients once terminal sedation was started until death and identify potential variables that may influence their survival time on sedation. This is a retrospective cohort analysis of all consecutive terminal cancer patients who died after starting terminal sedation at public tertiary Brazilian Hospital. A total of 532 cancer patients died in Hospital Estadual Mário Covas during this period and 181 out of them who received terminal sedation were included in this analysis. The median survival was 27 h. By multivariate analysis, increase in the dose of sedative drug during sedation (odds ratio 1.576, 95% CI 1.113-2.232), use of opioids alone for sedation (odds ratio 1.438, 95% CI 1.046-1.977) and dyspnoea as cause of sedation (odds ratio 1.564 95% CI 1.045-2.341) were independent risk factors for a shorter survival time after starting terminal sedation. Sedated, terminal cancer patients usually live about 1 day. We identified risk factors for a shorter sedation period. This study is limited by its retrospective design and by the frequent use of opioids as the main sedative medications. Prospective studies must be carried out in order to validate these data.

Extracapillary glomerulonephritis during etanercept treatment for juvenile psoriatic arthritis.

Juvenile psoriatic arthritis was diagnosed in a girl of 15 and a half years old, who presented with severe poly-arthritis and psoriasis. Treatment with etanercept 25 mg by subcutaneous injections, twice a week was started. After 5 months of treatment, she developed microscopic hematuria, proteinuria and progressive acute renal failure with anaemia and hypertension. Renal histology, IF, and EM findings were consistent with severe extracapillary crescentic pauciimmune glomerulonephritis. The histology findings, the onset of renal symptoms after beginning treatment with etanercept, and the absence of any abnormality in the urine tests before administration of the drug, support the hypothesis of a rare case of secondary nephropathy due to treatment with an anti-TNF-alpha drug.

Tuberculosis in socio-economically deprived neighborhoods: missed opportunities for prevention.

OBJECTIVE: To evaluate tuberculosis (TB) risk in three different US locations--Chicago, Illinois; Fulton County, Georgia; and the state of South Carolina--using two census-based measures of neighborhood-level deprivation and a geographic information system. METHOD: Individual-level data, including race and ZIP code of residence, were obtained for the three sites. TB cases were geocoded at the ZIP code tabulation area (ZCTA) level. Socio-economic status (SES) was defined at the ZCTA level using two Census 2000-based measures of socio-economic disadvantage: 1) percentage of population below poverty and 2) Townsend Deprivation Index. Based separately on the distributions of poverty and Townsend social deprivation scores, ZCTAs in each site were grouped into quartiles reflecting relative socio-economic well-being. To evaluate TB incidence in low- vs. high-SES neighborhoods, average annual TB incidence rates were calculated for the highest and lowest ZCTA quartiles. RESULTS: In all sites, TB incidence rates were significantly higher in high poverty/high social deprivation ZCTAs (P < 0.0001). CONCLUSIONS: Both census-based indicators performed well in distinguishing areas with high TB incidence rates from areas with little or no TB. Due to simplicity, the single poverty measure rather than the multifactorial Townsend index might be especially useful in identifying high-risk neighborhoods for targeted TB prevention efforts.

Percutaneous endoscopic gastrostomy for feeding. A comparison between neurologic and neoplastic indications.

The most common indications for percutaneous endoscopic gastrostomy (PEG) are neurologic deficits precluding adequate oral nutrition. The aim of this study was to ascertain whether PEG is as feasible, safe and effective in patients with advanced oropharyngeal, oesophageal and pulmonary carcinoma as it is in patients with neurologic deficit. PEG, attempted in 108 consecutive patients, was successful in 100 (overall success rate of 92%). On the basis of primary disease, the patients were subdivided into two groups: patients with neurologic diseases (group A, n = 50) and patients with oropharyngeal, oesophageal and lung carcinoma precluding adequate oral nutrition (group B, n = 50). No statistically significant difference was found between the PEG placement success rates of the two groups. Of the patients PEG placement 1 died and 2 had major complications. 15 out of 50 patients in group A and 11 out of 50 in group B had minor complications. No statistically significant differences were found between the mortality and morbidity rates of the two groups. Duration of nutrition was similar in both groups. In particular, 46% group A patients and 46% group B patients were PEG-fed for more than 3 months. A wider use of PEG is suggested in patients with advanced oropharyngeal, oesophageal and pulmonary carcinoma precluding adequate oral nutrition.

Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: a study by the Gruppo di Studio sui Tumori della Testa e del Collo.

BACKGROUND: The standard treatment for advanced (stage III and IV) head and neck squamous cell carcinoma (i.e., surgery with postoperative radiotherapy in operable patients and radiotherapy alone in inoperable patients) has had poor results. A series of randomized trials of induction chemotherapy have up to now failed to demonstrate an improvement in survival. PURPOSE: This trial was designed to determine whether intensive induction chemotherapy administered before loco-regional treatment would improve survival of patients with advanced disease. METHODS: Patients had previously untreated, advanced nonmetastatic (stages III and IV) squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and paranasal sinuses. The study design was a randomized, multi-institutional, phase III trial. Eligible patients (n = 237) were randomly assigned to receive either initial chemotherapy (cisplatin and infusional fluorouracil) followed by loco-regional treatment (group A, n = 118) or loco-regional treatment alone (group B, n = 119). For operable patients (group A, n = 34; group B, n = 32), loco-regional treatment included resection followed by adjuvant radiotherapy. For inoperable patients, radical irradiation was performed with a planned dose of 65-70 Gy to involved areas. A dose of 45-50 Gy was also planned to the uninvolved neck or postoperatively. The statistical (log-rank) test was performed no earlier than 2 years after the randomization of the last patient. RESULTS: Seventy-one patients (60%) in group A and 67 patients (56%) in group B were considered free of disease after they completed the treatment sequence. The analysis of time to distant metastases showed an advantage for group A patients. (Respective 2- and 3-year values for inoperable patients were 15% and 24% for group A versus 36% and 42% for group B, P = .04; only one operable group A patient had distant metastases after 49 months versus 26% [2 years] and 31% [3 years] for operable group B patients, P = .01.) For inoperable patients, the combined treatment was significantly associated with an increase in complete remission rate (group A, 44%) as compared with radiotherapy alone (group B, 30%) (P = .037). Inoperable patients also benefitted from induction chemotherapy in terms of disease-free survival (49% and 34% for group A versus 28% and 26% for group B; P = .06) and of overall survival (30% and 24% for group A versus 19% and 10% for group B; P = .04). CONCLUSIONS: When all 237 randomly assigned patients were analyzed, there were no significant differences in the two treatment strategies in loco-regional failure or in disease-free or overall survival, although the development of distant metastases was reduced. For operable patients, the only benefit from neoadjuvant chemotherapy was a significant reduction in the incidence of distant metastases. For inoperable patients, neoadjuvant chemotherapy improved local control, decreased the incidence of distant metastases, and improved the complete remission rate and overall survival. IMPLICATIONS: Confirmatory studies with effective chemotherapy regimens delivered for an adequate number of cycles are required.

Determination of the NMR solution structure of the Hoechst 33258-d(GTGGAATTCCAC)2 complex and comparison with the X-ray crystal structure.

BACKGROUND: The chromosomal stain, Hoechst 33258, binds to the minor groove of the DNA double helix and specifically recognizes a run of four A-T base pairs. Extensive biochemical and biophysical studies have been aimed at understanding the binding of the dye to DNA at the atomic level. Among these studies there have been several crystal structure determinations and some preliminary structural studies by NMR. RESULTS: On the basis of our own previously reported NMR data, we have now determined the three-dimensional solution structure of the 1:1 complex between Hoechst 33258 and the self-complementary DNA duplex d(GTGGAATTCCAC)2. Two coexisting families of con formers, which exhibit differences in their intermolecular hydrogen bonding pattern, were found and the two terminal rings of the dye displayed greater internal mobility than the rest of the molecule. CONCLUSIONS: The observed multiple ligand-binding modes in the complex between Hoechst 33258 and DNA and differential internal mobility along the bound ligand provide a novel, dynamic picture of the specific inter actions between ligands that bind in the minor groove and DNA. The dynamic state revealed by these studies may account for some of the significant differences previously observed between different crystal structures of Hoechst 33258 complexed with a different DNA duplex, d(CGCGAATTCGCG)2.

A pilot study of concomitant radiation and chemotherapy in patients with locally advanced head and neck cancer.

Cisplatin and 5-fluorouracil act as radiosensitizers and are active cytotoxic drugs in head and neck cancer. Therefore, from May 1987 to June 1990, we gave a continuous course of radiotherapy (70 Gy/35 fractions/7 weeks) combined with the simultaneous administration, once a week, of cisplatin (40 mg/m2, i.v. bolus) and 5-fluorouracil (400 mg/m2, i.v. bolus) to 21 patients with locally advanced or recurrent tumors of the head and neck. The complete and partial response rates were 65% and 15%, respectively. With a median follow-up of 17 months (range: 4-42) and with 19/21 patients having stages III and IV tumors, 12 patients are NED (no evidence of disease), 8 died with tumor, and 1 died of bronchopneumonia during the treatment. The main toxicity was mucositis and the median length of therapy was higher than with irradiation alone. This regimen appears very encouraging and could be an improvement over radiation alone for patients with locally advanced head and neck cancer.

Dynamics and binding mode of Hoechst 33258 to d(GTGGAATTCCAC)2 in the 1:1 solution complex as determined by two-dimensional 1H NMR.

We have investigated the interaction of the bisbenzimidazole derivative Hoechst 33258 with the self-complementary dodecadeoxynucleotide duplex d(GTGGAATTCCAC)2 using one-dimensional (1D) and two-dimensional (2D) proton nuclear magnetic resonance (1H NMR) spectroscopy. To monitor the extent of complex formation, we used the imino proton region of the 1D 1H NMR spectra acquired in H2O solution. These spectra show that the DNA duplex loses its inherent C2v symmetry upon addition of the drug, indicating that the two molecules form a kinetically stable complex on the NMR time scale (the lifetime of the complex has been measured to be around 450 ms). We obtained sequence-specific assignments for all protons of the ligand and most protons of each separate strand of the oligonucleotide duplex using a variety of homonuclear 2D 1H NMR experiments. The aromatic protons of the DNA strands, which are symmetrically related in the free duplex, exhibit exchange cross peaks in the complex. This indicates that the drug binds in two equivalent sites on the 12-mer, with an exchange rate constant of 2.2 +/- 0.2 s-1. Twenty-five intermolecular NOEs were identified, all involving adenine 2 and sugar 1' protons of the DNA and protons in all four residues of the ligand, indicating that Hoechst 33258 is located in the minor groove at the AATT site. Only protons along the same edge of the two benzimidazole moieties of the drug show NOEs to DNA protons at the bottom of the minor groove. Using molecular mechanics, we have generated a unique model of the complex using distance constraints derived from the intermolecular NOEs. We present, however, evidence that the piperazine group may adopt at least two locally different conformations when the drug is bound to this dodecanucleotide.

Serum SCC-Ag in head and neck squamous cell carcinoma.

We estimated the serum levels of SCC-Ag, CEA and TPA in 69 patients with head or neck neoplasia and 31 healthy patients using a radioimmunometric method (double antibody). SCC-Ag concentrations were significantly increased in 43.4% cancer patients with respect to the cut-off point value (1.7 ng/ml) of the control group, and the specificity was 96.7%. The data varied according to the evolutive phase of disease. Since the combined evaluation of SCC-Ag, TPA and CEA serum levels increased the sensitivity, that was 71.0%, we thought it opportune to use all these markers in the tumoral pathology taken into consideration.

[Antibiotic prophylaxis of infectious complications of cervico-facial surgery]. / Antibiotico profilassi delle complicanze infettive nella chirurgia cervico-facciale.

Head and neck surgery presents a high operating risk of infectious complications. We agree upon the fact that 60% of the so-called infected operations would be complicated by secondary infections if they are not treated by antibiotic therapy. Such a premise justifies the more and more used application of a chemoprophylaxis in surgery, carried out preoperatively. The AA. report 81 cases of patients, from 15 o 70 years old (62 males, 19 females), subjected to head and neck surgery and subdivided into two groups according to the kind of the operation. I group: 40 patients subjected to operations of minor infectious risk, the whole number subjected only to the prophylactic pre-operational treatment with 1 gr. of Ceftriaxone by intravenous injection, 30-60 min. before the operation. II group: 41 patients subjected to infected operations: 21 patients treated with 1 gr. of Ceftriaxone by intravenous injection, 30-60 min. before the operation, and 20 patients treated with Cefazolin, 1 gr. per daily administration, carried out after the surgical operation. As dealing with infected operations of high risk infectious complications, the antibiotic treatment has been carried out for 7-8 days for all the patients. In operations with minor infectious risk (group I) we have had a good post-operational course, without any infectious complication; the use of Ceftriaxone, with only one preoperational dose, is extremely useful for this group of patients. In infected operations of head and neck oncological surgery (group II) the cases of infectious complications have been 2 in the subgroup treated with Ceftriaxone, and 4 in the subgroup treated with Cefazolin.(ABSTRACT TRUNCATED AT 250 WORDS)

Normovolemic hemodilution in head and neck surgery.

As the transfusion risks to which patients are exposed are gradually understood, every effort is being made to find both a valid and safe alternative to homologous blood transfusions. Bearing this in mind, the most sensible solution appears to be the practice of a self-donor procedure with normovolemic hemodilution prior to elective surgery. However, even repeated bloodlettings do not modify the oxygen delivery to tissues since, with a reduction in the hemoglobin content of the circulating blood, there is a corresponding increase in oxygen availability. Since the reduction of circulating erythrocytes brings with it a reduction in blood viscosity, there is in turn an improvement in the microcirculation. The generally better tissue oxygenation, the reduction of the blood's viscosity and the increased circulatory perfusion all also favor a prophylaxis against deep vein thrombosis. We have currently performed 72 surgical procedures for head and neck neoplasms that were undertaken at the Clinical ENT Division of Treviso Hospital precisely with the normovolemic hemodilution described above. The self-donor transfusion technique was adopted with the help of the hospital's transfusion service. We have analyzed the data relative to this method and have found that the normovolemic hemodilution represents the treatment of choice in surgery-induced stress, particularly since this approach allows a better tissue oxygenation.