Use of Mastectomy for Overdiagnosed Breast Cancer in the United States: Analysis of the SEER 9 Cancer Registries.

AIM: We investigated use of mastectomy as treatment for early breast cancer in the US and applied the resulting information to estimate the minimum and maximum rates at which mastectomy could plausibly be undergone by patients with overdiagnosed breast cancer. Little is currently known about overtreatments undergone by overdiagnosed patients. METHODS: In the US, screening is often recommended at ages ≥40. The study population was women age ≥40 diagnosed with breast cancer in the US SEER 9 cancer registries during 2013 (n=26,017). We evaluated first-course surgical treatments and their associations with case characteristics. Additionally, a model was developed to estimate probability of mastectomy conditional on observed case characteristics. The model was then applied to evaluate possible rates of mastectomy in overdiagnosed patients. To obtain minimum and maximum plausible rates of this overtreatment, we respectively assumed the cases that were least and most likely to be treated by mastectomy had been overdiagnosed. RESULTS: Of women diagnosed with breast cancer at age ≥40 in 2013, 33.8% received mastectomy. Mastectomy was common for most investigated breast cancer types, including for the early breast cancers among which overdiagnosis is thought to be most widespread: mastectomy was undergone in 26.4% of in situ and 28.0% of AJCC stage-I cases. These rates are substantively higher than in many European nations. The probability-based model indicated that between >0% and <18% of the study population could plausibly have undergone mastectomy for overdiagnosed cancer. This range reduced depending on the overdiagnosis rate, shrinking to >0% and <7% if 10% of breast cancers were overdiagnosed and >3% and <15% if 30% were overdiagnosed. CONCLUSIONS: Screening-associated overtreatment by mastectomy is considerably less common than overdiagnosis itself but should not be assumed to be negligible. Screening can prompt or prevent mastectomy, and the balance of this harm-benefit tradeoff is currently unclear.

Long-term relationships between screening rates, breast cancer characteristics, and overdiagnosis in US counties, 1975-2009.

Effects of mammography screening in the general population are disputed. Screening rates differ greatly between US counties, providing a natural opportunity to investigate effects of screening. We compared mammography screening rates with the types and outcomes of breast cancers diagnosed in US counties. The county screening rate was defined as the proportion of women age ≥40 with ≥1 mammogram in the past 2 years (range, 34-91%). Two periods were analyzed: 1975-2009 (612,941 breast cancer cases, 195 counties) and 1996-2009 (645,057 cases, 211-547 counties). Multiple signs of overdiagnosis were observed: First, breast cancer incidence increased as screening became common. Second, incidence stopped increasing once screening rates stabilized. Third, the increases in incidence were limited to age groups receiving screening. Fourth, the increases were larger in counties where screening became more common. Fifth, the increases were limited to small and early-stage breast cancers (which are consistent with overdiagnosis). Sixth, compensatory reductions in large and advanced-stage breast cancers were much smaller than the increases. Difference-in-differences regression analysis suggested 31% (95% CI: 28-34%) of breast cancers diagnosed in 1996-2009 were overdiagnosed. Screening rates correlated with increased incidence for all hormone receptor statuses, HER2 statuses, and grades. Reductions in breast cancer mortality during 1975-2009 were similar in screened and unscreened age groups. Overall, we found repeated signs that breast cancer overdiagnosis is widespread in the US, but the biological nature of overdiagnosed tumors remains unclear. Mortality benefits of screening, though they may be present and substantial, could not be detected at the population level.

Metastatic cholangiocarcinoma in a llama (Lama glama).

A 2-year-old female llama (Lama glama), from a private zoological park, with anorexia, ataxia, dyspnea, ascites, and emaciation, was necropsied. Gross inspection, and cytological, histological, and immunohistochemical analyses were performed. A firm, white, multinodular mass, 25 cm in diameter was found in the liver parenchyma. Similar nodules up to 3 cm were found in lymph nodes, lung, diaphragm, and peritoneum. Histologically, the affected organs were replaced by an infiltrative growth of undifferentiated neoplastic cells. Immunohistochemically, neoplastic cells were positive for pancytokeratin (panCK), CK20, and CK19, and negative for thyroid transcription factor 1, CK7, and carcinoembryonic antigen. A diagnosis of poorly differentiated metastatic cholangiocarcinoma was made.

Initial evidence for the role of CACNA1C on subcortical brain morphology in patients with bipolar disorder.

BACKGROUND: The polymorphism rs1006737 within the CACNA1C gene is associated with increased risk for bipolar disorder (BD) and variations in brain morphology and function of subcortical regions. Here we sought to investigate the influence of CACNA1C polymorphism on key subcortical brain structures implicated in the pathophysiology of BD. METHODS: Structural magnetic resonance imaging scans were acquired from 41 euthymic patients with BD and 40 healthy controls, who were also genotyped for the CACNA1C rs1006737 polymorphism. The effect of diagnosis, genotype and their interaction was examined in predefined volumes of interest in the basal ganglia, hypothalamus and amygdala extracted using SPM5. RESULTS: Carriers of the CACNA1C rs1006737 risk allele showed increased grey matter density in the right amygdala and right hypothalamus irrespective of diagnosis. An interaction between genotype and diagnosis was observed in the left putamen which was smaller in BD patients carrying the risk allele than in healthy controls. CONCLUSIONS: The CACNA1C rs1006737 polymorphism influences anatomical variation within subcortical regions involved in emotional processing.

Highly preferential association of NonF508del CF mutations with the M470 allele.

BACKGROUND: On the basis of previous findings on random individuals, we hypothesized a preferential association of CF causing mutations with the M allele of the M470V polymorphic site of the CFTR gene. METHODS: We have determined the M/V-CF mutation haplotype in a series of 201 North East Italian and 73 Czech CF patients who were not F508del homozygotes, as F508del was already known to be fully associated with the M allele. RESULTS: Out of 358 not F508del CF genes, 84 carried the V allele and 274 the less common M allele. In the N-E Italian population, MM subjects have a risk of carrying a CF causing mutation 6.9x greater than VV subjects when F508del is excluded and 15.4x when F508del is included. In the Czech population a similar, although less pronounced, association is observed. CONCLUSIONS: Besides the possible biological significance of this association, the possibility of exploiting it for a pilot screening program has been explored in a local North East Italian population for which CF patients were characterized for their CF mutation. General M470V genotyping followed by common CF mutation screening limited to couples in which each partner carries at least one M allele would need testing only 39% of the couples, which contribute 89% of the total risk, with a cost benefit.

Cardiac protection by volatile anaesthetics: a multicentre randomized controlled study in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass.

BACKGROUND AND OBJECTIVES: To evaluate the effects of total intravenous anaesthesia vs. volatile anaesthesia on cardiac troponin release in coronary artery bypass grafting with cardiopulmonary bypass, we performed a multicentre randomized controlled study to compare postoperative cardiac troponin release in patients receiving two different anaesthesia plans. METHODS: We randomly assigned 75 patients to propofol (intravenous anaesthetic) and 75 patients to desflurane (volatile anaesthetic) in addition to an opiate-based anaesthesia for coronary artery bypass grafting. Peak postoperative troponin I release was measured as a marker of myocardial necrosis. RESULTS: There was a significant (P < 0.001) difference in the postoperative median (25th-75th percentiles) peak of troponin I in patients receiving propofol 5,5 (2,3-9,5) ng dL(-1) when compared to patients receiving desflurane 2,5 (1,1-5,3) ng dL(-1). The median (interquartile) troponin I area under the curve analysis confirmed the results: 68 (30.5-104.8) vs. 36.3 (17.9-86.6) h ng dL(-1) (P = 0.002). Patients receiving volatile anaesthetics had reduced need for postoperative inotropic support (24/75, 32.0% vs. 31/75, 41.3%, P = 0.04), and tends toward a reduction in number of Q-wave myocardial infarction, time on mechanical ventilation, intensive care unit and overall hospital stay. CONCLUSIONS: Myocardial damage measured by cardiac troponin release could be reduced by volatile anaesthetics in coronary artery bypass surgery.

Maternal-conceptus cross talk--a review.

The implantation process requires a functionally normal conceptus and a receptive endometrium, but also a communication link between them. This paracrine dialogue involves not only gonadal steroids but also a variety of other biologic molecules secreted by the conceptus and the reproductive tissues themselves in a communicative, interconnected network. The factors facilitating this dialogue includes chemokines, cytokines, adhesion molecules, growth factors. Recently, the soluble form of HLA-G and the vitamin D system have also been proposed as components of this cross-talk. Inherent among the factors involved is the fact that their effects are redundant and pleiotropic. Normal implantation and placentation are critical for a successful pregnancy. Therefore, a better understanding of the molecular mechanisms responsible for these processes will lead to the development of new regulating agents with novel diagnostic, biological and therapeutic potential for both facilitating and hindering a normal reproductive function.

Italian version of the Epworth sleepiness scale: external validity.

We assessed the validity of an Italian language version of the Epworth sleepiness scale (ESS). The translated ESS was compared to the multiple sleep latency test (MSLT), considered the gold standard for the diagnosis of excessive daytime sleepiness (EDS). Within the context of a multicentric national study on narcolepsy (Gruppo Italiano Narcolessia Studio Epidemiologico Nazionale, GINSEN) involving 17 Italian sleep centres, we compared the two diagnostic tests on 91 prospectively recruited subjects with suspected EDS (34 with narcolepsy, 16 with obstructive sleep apnea syndrome, 19 with idiopathic hypersomnia, and 22 with other sleep, neurologic or psychiatric disorders). ESS scores were inversely correlated with mean sleep latency values, as measured with MSLT (rho = -0.31, p<0.01). ESS cut-off scores with best sensitivity and specificity were 12 and 17. For the 5-min MSLT cut-off, sensitivity was 87% and 47% respectively; specificity 39% and 74%. For the 8-min MSLT cut-off, sensitivity was 84% and 49%; specificity 50% and 88%. The Italian version of the ESS is an easy-to-use form useful for preliminary screening of daytime sleepiness level in specialist settings.

[The therapy of endometriosis. New prospects]. / La terapia dell'endometriosi. Nuove prospettive.

Surgery is still the first line of therapy for endometriosis. At present, medical therapy is mostly indicated for treatment and prevention of recurrences. Current pharmacological regimens induce a hypoestrogenic state; this effect tends, on one hand, to inhibit the growth of endometriotic implants while, on the other hand, it significantly interferes with the integrity of the hypothalamus-pituitary-ovarian axis. The aim of this study is to review current knowledge on the new experimental therapeutic approaches to the disease. English articles on this topic have been searched by Medline. A particular attention has been paid to experimental therapeutic interventions supported by in vivo results. Three different novel strategies have been identified: 1) To act on estrogenic dependence of endometriosis using new drugs such as aromatase inhibitors and raloxifene. These drugs may have the advantage to act more specifically on the disease. 2) To treat the disease with immuno-modulators and anti-inflammatory drugs. These compounds may be helpful in both limiting the growth of endometriotic implants and in controlling the symptoms of the disease. 3) To prevent adhesion reformation after surgical lysis. Adhesions are an important hallmark of endometriosis which cannot be adequately eliminated by surgery. The use of barrier and fluid agents after surgical lysis seems to be effective in this regard. Results from studies aimed to investigate the effectiveness of these approaches are appealing. However, controlled clinical trials are now required to appropriately determine their real benefits and their specific indications.

Phased array element shapes for suppressing grating lobes.

Most techniques for suppressing grating lobes in phased arrays while relaxing the interelement spacing requirement involve redistributing array elements in sparse aperiodic patterns, or varying the transmit-receive beam patterns. An alternative is presented which uses oversized array elements to eliminate grating lobes as a direct consequence of the element shape. It is shown that by using carefully shaped, overlapping elements, maximum scan angle can be exchanged for a reduced interelement spacing requirement.

Age distribution of cancer in mice: the incidence turnover at old age.

We have studied cancer incidence in mice as a function of age in those cohorts where the rodents are allowed to live very close to their full natural lifetime. We find that the incidence rises as a function of age, but then flattens and turns over at an age of about 800 days. This behaviour is similar to that which we observed (Pompei and Wilson, 2001) in the Surveillance, Epidemiology, and End Results (SEER) data where the age distribution of human cancer incidence turns over at about age 80. Although other fits are possible, the three-parameter beta function model fits both the mouse data and the human data well. The beta model implies, and the data do not deny, the interpretation that cancer is not a certainty and mice may also outlive their cancers, although high-dose cohort results suggest cancer might be certain if dose is sufficiently high. Limited data suggest that the cancer age distribution, including the turnover, may be time shifted by dietary restriction.

Latitude-correlated genetic polymorphisms: selection or gene flow?

Latitude-correlated polymorphisms can be due to either selection-driven evolution or gene flow. To discriminate between them, we propose an approach that studies subpopulations springing from a single population that have lived for generations at different latitudes and have had a low genetic admixture. These requirements are fulfilled to a large extent by Ashkenazi and Sephardi Jews. The original population lived at a latitude of 35 degrees N, where the Sephardis still live. The Ashkenazis, however, moved to a latitude of 50 degrees N, starting about 10 centuries ago. The present study examines 3 latitude-correlated polymorphisms: PGP, PGM1, and AHSG. We found that PGP*2 and AHSG*2 alleles most likely underwent selection-driven evolution, but that PGM1*ts allele was not similarly affected. Since temperature might have been considered a reasonable selective factor, we also studied a population living at >800 m above sea level from Aosta Valley (Italy).

A new approach for identifying non-pathogenic mutations. An analysis of the cystic fibrosis transmembrane regulator gene in normal individuals.

Given q as the global frequency of the alleles causing a disease, any allele with a frequency higher than q minus the cumulative frequency of the previously known disease-causing mutations (threshold) cannot be the cause of that disease. This principle was applied to the analysis of cystic fibrosis transmembrane conductance regulator (CFTR) mutations in order to decide whether they are the cause of cystic fibrosis. A total of 191 DNA samples from random individuals from Italy, France, and Spain were investigated by DGGE (denaturing gradient gel electrophoresis) analysis of all the coding and proximal non-coding regions of the gene. The mutations detected by DGGE were identified by sequencing. The sample size was sufficient to select essentially all mutations with a frequency of at least 0.01. A total of 46 mutations was detected, 20 of which were missense mutations. Four new mutations were identified: 1341+28 C/T, 2082 C/T, L1096R, and I11131V. Thirteen mutations (125 G/C, 875+40 A/G, TTGAn, IVS8-6 5T, IVS8-6 9T, 1525-61 A/G, M470V, 2694 T/G, 3061-65 C/A, 4002 A/G, 4521 G/A, IVS8 TG10, IVS8 TG12) were classified as non-CF-causing alleles on the basis of their frequency. The remaining mutations have a cumulative frequency far exceeding q; therefore, most of them cannot be CF-causing mutations. This is the first random survey capable of detecting all the polymorphisms of the coding sequence of a gene.

Two ethnic-specific polymorphisms in the human beta pseudogene of hemoglobin.

Two polymorphic sites, -107 C-->T and -100 G-->C with respect to the cap site of the human beta pseudogene of the hemoglobin gene, are described. They have been studied in five European, one Indian, two Asian, and two sub-Saharan African populations. The -107 C-->T site turned out to be polymorphic in all five European populations and the Indian population (pooled q = 0.142 +/- 0.018) and in the two Asian populations (pooled q = 0.073 +/- 0.025), but it was monomorphic in the two sub-Saharan populations. On the contrary, the -100 G-->C site was polymorphic in the two sub-Saharan samples (q = 0.093 +/- 0.024), but the variant allele was not found in any of the European, Indian, or Asian samples. Thus this only 8-bp-long stretch of DNA is informative for estimating the extent of genetic admixture in sub-Saharan Africans.

Recurrent simple tandem repeat mutations during human Y-chromosome radiation in Caucasian subpopulations.

The haplotypes at four polymorphic loci of the Y chromosome were determined in 245 Caucasian males from 12 subpopulations. The data show that haplotype radiation occurred among Caucasians. Haplotype radiation was accompanied by recurrent mutations at STR loci that caused partial randomization of haplotype structure. The present distribution of alleles at short tandem repeats (STRs) can be explained by a mutation pattern similar to those described for autosomal STRs. The degree of variation among groups of subpopulations was assayed by using the Analysis of Molecular Variance. The results confirm a faster divergence of the Y chromosome as compared to the rest of the genome.

Genetic heterogeneity among the Hindus and their relationships with the other "Caucasoid" populations: new data on Punjab-Haryana and Rajasthan Indian states.

The genetic structure of Rajasthan Hindus and Punjab-Haryana Hindus and Sikhs has been studied for ABO, RH, APOC2, C6, C7, F13A, F13B, HP, ORM1, ACP1, ADA, AK1, ESD, GLO1, PGD, PGM1 subtyping, and PGP. This is the first genetic survey on Hindus of Rajasthan. Furthermore, many of these markers have never been studied on Hindus before (APOC2, C6, C7, F13A, F13B, ORM1, PGP). These data, together with those previously available for Hindus, have been utilized to analyze the within-Hindus genetic heterogeneity by RST statistic and correspondence analysis. The genetic relationships of Hindus to other Causcasoid populations were also investigated. In the first analysis, two eastern states (Orissa and Andhra Pradesh) were found to be quite separate from each other and clearly distinct from the northwestern and western states. Out of the markers which could not be utilized in this analysis, PGM1 subtyping turned out to discriminate between the Dravidian-speaking and the Indo-Aryan-speaking Hindus. The second analysis shows a clear-cut separation of Hindus from Europeans, with Near Eastern and Middle Eastern populations genetically in an intermediate position.

Effects of temperature on bleeding time and clotting time in normal male and female volunteers.

OBJECTIVE: This study was done to assess the effects of temperature on bleeding time and clotting time in normal male and female volunteers. DESIGN: Open study utilizing normal volunteers. SETTING: University research laboratory. SUBJECTS: Fifty-four healthy male and female volunteers, ranging in age from 19 to 35 yrs, who were not receiving medications. The study was done and the samples of venous blood and shed blood collected at the template bleeding time site were obtained at a convenient time for each volunteer. INTERVENTIONS: Skin temperature was changed from +20 degrees to +38 degrees C and blood samples were obtained from the antecubital vein of each volunteer. MEASUREMENTS AND MAIN RESULTS: The effect of local skin temperature ranging from +20 degrees to +38 degrees C on bleeding time was evaluated in 38 normal volunteers (19 male and 19 female). Skin temperature was maintained at +20 degrees to +38 degrees C by cooling or warming the forearm. At each temperature, measurements were made of complete blood count, bleeding time, and thromboxane B2 concentrations in shed blood collected at the template bleeding time site and in serum and plasma isolated from blood collected from the antecubital vein. Clotting time studies were measured in 16 normal volunteers (eight male and eight female) at temperatures ranging from +22 degrees to +37 degrees C. At +32 degrees C, the bleeding time was longer and hematocrit was lower in female than in male volunteers. However, at local skin temperatures of < +32 degrees C, both the males and females exhibited significantly increased bleeding times, which were associated with a reduction in shed blood thromboxane B2. Each 1 degree C decrease in temperature was associated with a 15% decrease in the shed blood thromboxane B2 concentration. Clotting times were three times longer at +22 degrees C than at +37 degrees C. Each 1 degree C reduction in the temperature of the clotted blood was associated with a 15% reduction in the serum thromboxane B2 concentration. CONCLUSION: Our data indicate that during surgical procedures, it is important to maintain normothermia to ensure that platelets and clotting proteins function optimally.

[Propofol, fentanyl, nitrous oxide: useful and current combination?]. / Propofol, fentanyl, protossido di azoto: associazione utile ed attuale?

The introduction of use of propofol in the anesthetists' pharmacopoeia has reinvigorated the research for a totally intravenous anaesthesia, for which the Authors propose a diagram. However, in experience related to the supplementary use of N2O, in virtue of its analgesic power, demonstrates yet another utility, permitting an easier anesthetical administration with minor consumption of intravenous drugs.