Breast Cancer in Young Women: Poor Survival Despite Intensive Treatment

The general aim of the thesis was to gain increased insight into the long-term prognosis for young women with breast cancer. In a population-based cohort of 22,017 women with breast cancer, we studied prognosis by age. Women aged <35 (n=471), 35–39 (n=858) and 40–49 (n=4789) were compared with women aged 50–69. The cumulative 5-year relative survival ratio (RSR) and the relative excess risk (RER) of mortality were calculated. Women <35 years of age had a worse survival than middle-aged women, partly explained by a later stage at diagnosis. After correction for stage, tumor characteristics and treatment, young age remained an independent risk factor for death. The excess risk of death in young women was only present in stage I-II disease and was most pronounced in women with small tumors. For in-depth studies on a large subpopulation from the original cohort (all 471 women aged <35 and a random sample of 700 women aged 35–69), we collected detailed data from the medical records, re-evaluated slides and produced TMAs from tumor tissue. Breast cancer- specific survival (BCSS), distant disease-free survival (DDFS) and locoregional recurrence- free survival (LRFS) by age were analysed. In a multivariate analysis, age <35 and age 35– 39 years conferred a risk in LRFS but not in DDFS and BCSS. The age-related differences in prognosis were most pronounced in early stage luminal Her2-negative tumors, where low age was an independent prognostic factor also for DDFS (HR 1.87 (1.03–3.44)). To study the importance of proliferation markers for the long-term prognosis in young women, protein expression of Ki-67, cyclin A2, B1, D1 and E1 was analysed in 504 women aged <40 and in 383 women aged ≥40. The higher expression of proliferation markers in young women did not have a strong impact on the prognosis. Proliferation markers are less important in young women, and Ki-67 was prognostic only in young women with Luminal PR+ tumors. Age <40 years was an independent risk factor of DDFS exclusively in this subgroup (adjusted HR 2.35 (1.22-4.50)). The only cyclin adding prognostic value beyond subtype in young women was cyclin E1. In a cohort of 469 women aged <40 and 360 women aged ≥40 we examined whether Her2 status assessed by silver enhanced in situ hybridization (SISH) for all cases, would reveal a proportion of women undiagnosed by routine Her2 testing and whether this would affect their prognosis. With SISH testing for all women, the Her2-positive rate increased from 20.0% to 24.4% (p<0.001), and similarly for women aged <40 and ≥40 years. Young women had Her2+ breast cancer twice as often as middle-aged women. Her2 amplification was present in 4.6% of cases scored 0 with IHC, while the corresponding proportions for scores 1+, 2+ and 3+ were 36.0%, 83.7% and 96.8%, respectively. All Her2 amplified cases, both true positive and false negative, had a significantly worse BCSS than the true negative cases

Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial

Background Third-generation aromatase inhibitors are more effective than tamoxifen for preventing recurrence in postmenopausal women with hormone-receptor-positive invasive breast cancer. However, it is not known whether anastrozole is more effective than tamoxifen for women with hormone-receptor-positive ductal carcinoma in situ (DCIS). Here, we compare the efficacy of anastrozole with that of tamoxifen in postmenopausal women with hormone-receptor-positive DCIS. Methods In a double-blind, multicentre, randomised placebo-controlled trial, we recruited women who had been diagnosed with locally excised, hormone-receptor-positive DCIS. Eligible women were randomly assigned in a 1:1 ratio by central computer allocation to receive 1 mg oral anastrozole or 20 mg oral tamoxifen every day for 5 years. Randomisation was stratified by major centre or hub and was done in blocks (six, eight, or ten). All trial personnel, participants, and clinicians were masked to treatment allocation and only the trial statistician had access to treatment allocation. The primary endpoint was all recurrence, including recurrent DCIS and new contralateral tumours. All analyses were done on a modified intention-to-treat basis (in all women who were randomised and did not revoke consent for their data to be included) and proportional hazard models were used to compute hazard ratios and corresponding confidence intervals. This trial is registered at the ISRCTN registry, number ISRCTN37546358. Results Between March 3, 2003, and Feb 8, 2012, we enrolled 2980 postmenopausal women from 236 centres in 14 countries and randomly assigned them to receive anastrozole (1449 analysed) or tamoxifen (1489 analysed). Median follow-up was 7·2 years (IQR 5·6–8·9), and 144 breast cancer recurrences were recorded. We noted no statistically significant difference in overall recurrence (67 recurrences for anastrozole vs 77 for tamoxifen; HR 0·89 [95% CI 0·64–1·23]). The non-inferiority of anastrozole was established (upper 95% CI <1·25), but its superiority to tamoxifen was not (p=0·49). A total of 69 deaths were recorded (33 for anastrozole vs 36 for tamoxifen; HR 0·93 [95% CI 0·58–1·50], p=0·78), and no specific cause was more common in one group than the other. The number of women reporting any adverse event was similar between anastrozole (1323 women, 91%) and tamoxifen (1379 women, 93%); the side-effect profiles of the two drugs differed, with more fractures, musculoskeletal events, hypercholesterolaemia, and strokes with anastrozole and more muscle spasm, gynaecological cancers and symptoms, vasomotor symptoms, and deep vein thromboses with tamoxifen. Conclusions No clear efficacy differences were seen between the two treatments. Anastrozole offers another treatment option for postmenopausal women with hormone-receptor-positive DCIS, which may be be more appropriate for some women with contraindications for tamoxifen. Longer follow-up will be necessary to fully evaluate treatment differences

Single-cell level decision-making between growth and dormancy.

Journal Articleinfo:eu-repo/semantics/publishe

Elucidating the structure-function relationship of a bacterial GTPase in DNA replication through random mutagenesis

status: publishe

Elucidating the structure-function relationship of a bacterial GTPase in DNA replication through random mutagenesis.

Journal Articleinfo:eu-repo/semantics/publishe

Pimobendane (UD-CG 115 BS) in the treatment of severe congestive heart failure. An acute haemodynamic cross-over and double-blind study with two different doses.

1. We compared the effects of two doses (5 and 10 mg) of oral pimobendane (UD-CG 115) on haemodynamics in eight patients suffering from chronic congestive heart failure. The two doses were given according to a randomized cross-over double-blind protocol; haemodynamics and plasma levels of pimobendane and its main metabolite UD-CG 212, were determined 1, 2, 3, 5, 7, 9, 11 and 12 h after each dose. 2. Both doses significantly improved the left and right ventricular functions of these patients, with a peak action 3 h after drug intake and long duration (more than 12 h). A significant dose-effect relationship was observed only for pulmonary wedge pressure and right atrial pressure. Significant correlations were found between UD-CG 212 plasma levels and cardiac index (r = 0.54, P less than 0.05), and pulmonary wedge pressure (r = 0.74, P less than 0.001); no correlation was found between these haemodynamic variables and pimobendane plasma levels. 3. One patient developed a transient drop in blood platelets together with a cutaneous rash, while three others had a transient and mild decrease of thrombocytes. 4. In conclusion, pimobendane improved right and left ventricular functions in severe heart failure. Both doses (5 and 10 mg) were effective. The higher dose induced marked improvement of the haemodynamic variables but the difference between doses was only significant for right atrial and pulmonary wedge pressures

Ruptured aortic dissection into the left atrium which presented as congestive heart failure and was diagnosed by transoesophageal echocardiography.

A 72 year old man was admitted with severe dyspnoea. Ten days before he had had intense thoracic pain with loss of consciousness that was followed by increased dyspnoea. A continuous murmur was heard in the precordial and the left infrascapular regions. Lung auscultation showed stasis over the lower half of both lungs. Transthoracic echocardiography showed a bicuspid aortic valve and a dissection of the proximal aorta, which was considerably enlarged. Transoesophageal echocardiography confirmed dissection of the proximal aorta and showed a communication from the false lumen of the aortic dissection to the left atrium; and colour flow Doppler showed a continuous shunt to the left atrium. After transoesophageal echocardiography the patient had emergency surgical repair, which was successful. He had no complications in the post-operative period