Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44-GeparQuinto)†.

BACKGROUND: The GeparQuinto study showed that adding bevacizumab to 24 weeks of anthracycline-taxane-based neoadjuvant chemotherapy increases pathological complete response (pCR) rates overall and specifically in patients with triple-negative breast cancer (TNBC). No difference in pCR rate was observed for adding everolimus to paclitaxel in nonearly responding patients. Here, we present disease-free (DFS) and overall survival (OS) analyses. PATIENTS AND METHODS: Patients (n = 1948) with HER2-negative tumors of a median tumor size of 4 cm were randomly assigned to neoadjuvant treatment with epirubicin/cyclophosphamide followed by docetaxel (EC-T) with or without eight infusions of bevacizumab every 3 weeks before surgery. Patients without clinical response to EC ± Bevacizumab were randomized to 12 weekly cycles paclitaxel with or without everolimus 5 mg/day. To detect a hazard ratio (HR) of 0.75 (α = 0.05, ß = 0.8) 379 events had to be observed in the bevacizumab arms. RESULTS: With a median follow-up of 3.8 years, 3-year DFS was 80.8% and 3-year OS was 89.7%. Outcome was not different for patients receiving bevacizumab (HR 1.03; P = 0.784 for DFS and HR 0.974; P = 0.842 for OS) compared with patients receiving chemotherapy alone. Patients with TNBC similarly showed no improvement in DFS (HR = 0.99; P = 0.941) and OS (HR = 1.02; P = 0.891) when treated with bevacizumab. No other predefined subgroup (HR+/HER2-; locally advanced (cT4 or cN3) or not; cT1-3 or cT4; pCR or not) showed a significant benefit. No difference in DFS (HR 0.997; P = 0.987) and OS (HR 1.11; P = 0.658) was observed for nonearly responding patients receiving paclitaxel with or without everolimus overall as well as in subgroups. CONCLUSIONS: Long-term results, in opposite to the results of pCR, do not support the neoadjuvant use of bevacizumab in addition to an anthracycline-taxane-based chemotherapy or everolimus in addition to paclitaxel for nonearly responding patients. CLINICAL TRIAL NUMBER: NCT 00567554, www.clinicaltrials.gov.

Predictive value of HER2 serum levels in patients treated with lapatinib or trastuzumab -- a translational project in the neoadjuvant GeparQuinto trial.

BACKGROUND: We were able to demonstrate a predictive value of serum HER2 (sHER2) in patients receiving trastuzumab in the neoadjuvant GeparQuattro trial. However, the role of sHER2 in patients receiving neoadjuvant therapy (NT) with lapatinib is still unclear. METHODS: The neoadjuvant GeparQuinto trial compared trastuzumab vs lapatinib in addition to chemotherapy in HER2-positive primary breast cancer patients. The sHER2 levels were measured by enzyme-linked immunosorbant assay in 210 patients, of whom 109 (52%) patients received trastuzumab and 101 (48%) lapatinib at three different time points. RESULTS: Twenty-two percent of patients had elevated baseline sHER2 levels (>15 ng ml⁻¹). A decrease of sHER2 levels (>20%) in the trastuzumab and lapatinib-treated group during NT was seen in 44% and 24% of the patients, an increase of sHER2 levels (>20%) was seen in 6% and 41% of patients, respectively. Higher pre-chemotherapy sHER2 levels were associated with higher pathological complete remission (pCR) rates in the entire study cohort (OR 1.8, 95% CI 1.02-3.2, P=0.043). A decline of sHER2 levels (>20%) during NT was a predictor for pCR in the lapatinib-treated patient group (OR: 11.7, 95% CI 1.3-110, P=0.031). CONCLUSION: Results of this study demonstrate that sHER2 levels change differently during NT depending on the anti-HER2 treatment strategy. Elevated baseline sHER2 levels (>15 ng ml⁻¹) and a decrease of sHER2 levels (>20%) early after therapy initiation are both relevant criteria to predict response to lapatinib-based treatment.

A multi-centre cohort study of the physical health of 5-year-old children conceived after intracytoplasmic sperm injection, in vitro fertilization and natural conception.

BACKGROUND: Over a million children have been born from assisted conception worldwide. Newer techniques being introduced appear less and less 'natural', such as intracytoplasmic sperm injection (ICSI), but there is little information on these children beyond the neonatal period. METHODS: 540 ICSI conceived 5-year-old children from five European countries were comprehensively assessed, along with 538 matched naturally conceived children and 437 children conceived with standard IVF. RESULTS: Of the 540 ICSI children examined, 63 (4.2%) had experienced a major congenital malformation. Compared with naturally conceived children, the odds of a major malformation were 2.77 (95% CI 1.41-5.46) for ICSI children and 1.80 (95% CI 0.85-3.81) for IVF children; these estimates were little affected by adjustment for socio-demographic factors. The higher rate observed in the ICSI group was due partially to an excess of malformations in the (boys') urogenital system. In addition, ICSI and IVF children were more likely than naturally conceived children to have had a significant childhood illness, to have had a surgical operation, to require medical therapy and to be admitted to hospital. A detailed physical examination revealed no further substantial differences between the groups, however. CONCLUSIONS: Singleton ICSI and IVF 5-year-olds are more likely to need health care resources than naturally conceived children. Assessment of singleton ICSI and IVF children at 5 years of age was generally reassuring, however, we found that ICSI children presented with more major congenital malformations and both ICSI and IVF children were more likely to need health care resources than naturally conceived children. Ongoing monitoring of these children is therefore required.

Children conceived after intracytoplasmic sperm injection (ICSI): is there a role for the paediatrician?

AIM: The aim of the study was to evaluate current medical knowledge about children born after intracytoplasmic sperm injection (ICSI) with respect to congenital malformations, chromosome abnormalities and postnatal growth. RESULTS: The total malformation rate in children conceived after ICSI was comparable to the background population in nine of the 11 articles studied. In two of the studies, a significant increase in congenital malformations was found. More specifically, children born after ICSI appear to have a higher risk of urogenital malformations, especially hypospadias, which may be related to paternal subfertility. There is insufficient knowledge about chromosomal or genetic anomalies and auxological data in children born after ICSI. The methodological approach to follow-up the children was inconsistent, as the clinical examinations were not done with standardized ascertainment. CONCLUSION: Paediatricians and obstetricians should collaborate with fertility clinics to obtain valid longitudinal observations with respect to congenital malformations, neurological development, growth, pubertal maturation, fertility and morbidity in children conceived by ICSI.

Difference in prevalence of congenital cryptorchidism in infants between two Nordic countries.

BACKGROUND: Several investigators have shown striking differences in semen quality and testicular cancer rate between Denmark and Finland. Since maldescent of the testis is a shared risk factor for these conditions we undertook a joint prospective study for the prevalence of congenital cryptorchidism. METHODS: 1068 Danish (1997-2001) and 1494 Finnish boys (1997-99) were consecutively recruited prenatally. We also established prevalence data for all newborns at Turku University Central Hospital, Finland (1997-99, n=5798). Testicular position was assessed by a standardised technique. All subtypes of congenital cryptorchidism were included, but retractile testes were considered normal. FINDINGS: Prevalence of cryptorchidism at birth was 9.0% (95% CI 7.3-10.8) in Denmark and 2.4% (1.7-3.3) in Finland. At 3 months of age, prevalence rates were 1.9% (1.2-3.0) and 1.0% (0.5-1.7), respectively. Significant geographic differences were still present after adjustment for confounding factors (birthweight, gestational age, being small for gestational age, maternal age, parity, mode of delivery); odds ratio (Denmark vs Finland) was 4.4 (2.9-6.7, p<0.0001) at birth and 2.2 (1.0-4.5, p=0.039) at three months. The rate in Denmark was significantly higher than that reported 40 years ago. INTERPRETATION: Our findings of increasing and much higher prevalence of congenital cryptorchidism in Denmark than in Finland contribute evidence to the pattern of high frequency of reproductive problems such as testicular cancer and impaired semen quality in Danish men. Although genetic factors could account for the geographic difference, the increase in reproductive health problems in Denmark is more likely explained by environmental factors, including endocrine disrupters and lifestyle.

Inhibin A, inhibin B, follicle-stimulating hormone, luteinizing hormone, estradiol, and sex hormone-binding globulin levels in 473 healthy infant girls.

The early postnatal regulation of reproductive hormones seems to be more complex in girls than in boys. The aim of this study was to describe inhibins A and B, FSH, LH, estradiol, and SHBG in a large prospective cohort of 473 unselected, healthy, 3-month-old girls. In full term, appropriate-for- gestational-age girls (n = 355) hormones showed a marked interindividual variation, with concentrations up to pubertal values [medians (95% confidence intervals): inhibin B, 82 pg/ml (<20-175); FSH, 3.8 IU/liter (1.2-18.8); LH, 0.07 IU/liter (<0.05-1.07); estradiol, 31 pM (<18-83); SHBG, 137 nM (72-260)]. In 38%, FSH levels exceeded 4.5 IU/liter. Weight at 3 months had significant inverse relationships with estradiol and SHBG (P = 0.048 and P = 0.001, respectively). Gestational age was negatively correlated to estradiol (P = 0.001), with a similar trend for LH, FSH, and inhibin B. Inhibin B was higher in premature girls [126 pg/ml (<20-265)] than in term [80 pg/ml (<20-181), P = 0.002] and postmature girls [59 pg/ml (<20-152), P = 0.012]. Likewise, estradiol levels in prematures were higher than in mature girls [51 pM (<18-128) vs. 31 pM (<18-85), P = 0.009]. Estradiol was also higher in small-for-gestational-age than in appropriate-for-gestational-age girls (P = 0.046), with inhibin B and LH, but not FSH, showing a similar trend. In conclusion, reproductive hormones showed a large variation, and concentrations corresponded to those observed in puberty. Our findings support the concept of a minipuberty in infant girls similar to that in boys.

Thought Field Therapy clinical applications: utilization in an HMO in behavioral medicine and behavioral health services.

Thought Field Therapy (TFT) is a self-administered treatment developed by psychologist Roger Callahan. TFT uses energy meridian treatment points and bilateral optical-cortical stimulation while focusing on the targeted symptoms or problem being addressed. The clinical applications of TFT summarized included anxiety, adjustment disorder with anxiety and depression, anxiety due to medical condition, anger, acute stress, bereavement, chronic pain, cravings, depression, fatigue, nausea, neurodermatitis, obsessive traits, panic disorder without agoraphobia, parent-child stress, phobia, posttraumatic stress disorder, relationship stress, trichotillomania, tremor, and work stress. This uncontrolled study reports on changes in self-reported Subjective Units of Distress (SUD; Wolpe, 1969) in 1,594 applications of TFT, treating 714 patients. Paired t-tests of pre- and posttreatment SUD were statistically significant in 31 categories reviewed. These within-session decreases of SUD are preliminary data that call for controlled studies to examine validity, reliability, and maintenance of effects over time. Illustrative case and heart rate variability data are presented.

[Rupture of the symphysis after spontaneous delivery. Surgical treatment of four cases]. / Symfyseruptur opstået i forbindelse med spontan fødsel. Operativ behandling i fire tilfaelde.

Rupture of the symphysis pubis is a rare, but known, complication during labour. We describe four cases of rupture of the symphysis, for which surgical treatment was chosen shortly after labour (2-30 days). Internal fixation was done in two cases and external fixation in the other two. There were no postoperative complications. The patients were mobile soon after the operation, and had no pain and normal function at follow-up 6-12 months later.

'Upenamide: An unprecedented macrocyclic alkaloid from the Indonesian sponge Echinochalina sp.

'Upenamide (1) represents a new class of macrocyclic marine alkaloid possessing both spirooxaquinolizidinone and hemiaminal ring systems. It was isolated from the Indonesian sponge Echinochalina sp. The gross structure of 1 was elucidated by spectroscopic methods and accurate mass measurements. A suggestion is made as to its biogenetic origin.

A calmodulin-related protein that suppresses posttranscriptional gene silencing in plants.

Posttranscriptional gene silencing (PTGS) is an ancient eukaryotic regulatory mechanism in which a particular RNA sequence is targeted and destroyed. The helper component-proteinase (HC-Pro) of plant potyviruses suppresses PTGS in plants. Using a yeast two-hybrid system, we identified a calmodulin-related protein (termed rgs-CaM) that interacts with HC-Pro. Here we report that rgs-CaM, like HC-Pro itself, suppresses gene silencing. Our work is the first report identifying a cellular suppressor of PTGS.

High level expression of Ricinus communis casbene synthase in Escherichia coli and characterization of the recombinant enzyme.

Casbene synthase catalyzes the cyclization of geranylgeranyl diphosphate (2) to casbene (1), a diterpene phytoalexin with antibacterial and antifungal activity that is produced by seedlings of castor bean (Ricinus communis L.) in response to fungal attack. We report the high-level expression of casbene synthase cDNA in Escherichia coli as insoluble inclusion bodies, the solubilization and refolding of active casbene synthase, and the kinetic and product analysis of the recombinant enzyme. To overcome problems apparently associated with the presence in the casbene synthase gene of rare Arg codons, as well as the intrinsic antibacterial activity of casbene itself, the casbene synthase gene was expressed in an E. coli host harboring the pSM102 vector that encodes the dnaY gene for tArg(AGA/G), using an expression vector, pET-21d(+), carrying the tightly controlled T7lac promoter.

Cloning of casbene synthase cDNA: evidence for conserved structural features among terpenoid cyclases in plants.

A near-full-length casbene synthase cDNA clone, pCS7, was isolated by using a partial cDNA clone, pCS4, to probe a lambda gt10 library constructed from poly(A)+ RNA from elicited castor bean seedlings. The cDNA insert had a length of 1983 bases with a polyadenylate tail of 19 bases. Translation of the cDNA sequence revealed an open reading frame encoding a 601-aa protein with a predicted M(r) of 68,960. Search of the GenBank data base with the deduced translation product revealed 42% identity and 65% similarity with 5-epi-aristolochene synthase from tobacco and 31% identity and 53% similarity with limonene synthase from spearmint. Each of the three proteins catalyzes an intramolecular cyclization of a prenyl diphosphate substrate to a specific cyclic terpenoid hydrocarbon product. The proposed reaction mechanisms for the three catalytic processes share common chemical features, even though the products being formed are members of three different classes of terpenoid compounds. Analysis of the alignment of the three proteins suggests that both primary and secondary structural elements are conserved. These similarities suggest that the genes that encode terpenoid cyclization enzymes of this type in angiosperms have undergone divergent evolution from an ancestral progenitor gene. In support of this proposition, the locations of five of the six introns in the casbene synthase gene align very closely with those of the five introns in the 5-epi-aristolochene synthase gene.

[Contrast medium intolerance in computerized tomography]. / Kontrastmittelunverträglichkeit im Computertomogramm.

An adverse reaction to a contrast medium with swelling of the nasal mucosa was incidentally documented during a computer tomographic examination of the skull, showing how fast liberation of mediator substances can cause mucosal edema.

Chemical and enzymatic degradation of ganciclovir prodrugs: enhanced stability of the diadamantoate prodrug under acid conditions.

We report the chemical and enzymatic hydrolysis of two hydrophobic prodrugs of ganciclovir (3 = dipropionate ester; 4 = diadamantoate ester). Both prodrugs undergo hydrolysis showing a pH dependence of kobs = kH+aH+ + ko + kHO-aHO- and a pH of maximum stability near pH 5. Only 4 exhibited a shelf life (t90) greater than 2 years. Compound 4 reacts significantly slower than ganciclovir in acidic media, even though the adamantyl esters provide additional reaction sites (which would be expected to increase the rate of degradation) that are distally removed from the guanine ring system, offering negligible steric or electronic substituent effects. Both 3 and 4 hydrolyzed in tissue homogenate, where kobs followed liver greater than intestine much greater than skin. Based on these findings of chemical stability, lipophilicity, and acceptable rate of enzymatic cleavage by skin esterases, 4 meets several of the criteria required for the topical sustained delivery of ganciclovir.

[Has the dynamic hip screw justifiably replaced Ender nailing in the management of hip para-articular femoral fractures of the A1-A3 and B2 type?]. / Hat die dynamische Hüftschraube zu recht die Ender-Nagelung in der Versorgung hüftgelenksnaher Femurfrakturen vom Typ A1-A3 und B2 verdrängt?

The results obtained in 167 extracapsular fractures of the hip are presented. Ender's pins were used in 82 cases and the dynamic hip screw (DHS) in 85. Comparison of different aspects (handling, postoperative mobility, complication rate, mortality) shows that the second operating procedure named DHS is highly suitable for the treatment of fractures A1-A3 and B2 (Müller classification) and superior to the procedure with Ender's pins.

Chloroplast transport of a ribulose bisphosphate carboxylase small subunit-5-enolpyruvyl 3-phosphoshikimate synthase chimeric protein requires part of the mature small subunit in addition to the transit peptide.

Ribulose bisphosphate carboxylase small subunit protein is synthesized in the cytoplasm as a precursor and transported into the chloroplast where the amino-terminal portion, the transit peptide, is removed proteolytically. To obtain chloroplast delivery of the 43-kDa 5-enolpyruvyl 3-phosphoshikimate (EPSP) synthase of Salmonella typhimurium, we constructed fusion proteins between the bacterial EPSP synthase and the ribulose bisphosphate carboxylase small subunit. A fusion protein consisting of the transit peptide fused to the EPSP synthase was not transported in vitro or in vivo into chloroplasts. A second fusion protein consisting of the transit peptide and 24 amino acids of the mature small subunit fused to the EPSP synthase was transported both in vitro and in vivo into chloroplasts. It was processed into two polypeptides of 46 and 47 kDa, respectively. This heterogeneity in processing was not caused by the presence of the aroA start codon, since its removal resulted in the same pattern. Substituting 24 different amino acids for the 24 amino acids of the mature small subunit resulted in a fusion protein that was not transported into the chloroplast. It was concluded that a portion of the mature small subunit was needed for efficient chloroplast delivery.

[Nodular lymphoid hyperplasia of the duodenum in cancers of the gastrointestinal tract]. / Zur Frage der nodulären lymphoiden Hyperplasie des Duodenums bei Karzinomen des Gastrointestinalktraktes.

In an autoptic study the coincidence of carcinomas of the gastrointestinal tract and nodular lymphoid hyperplasia (NLH) of the duodenum was studied histologically. Out of sixty cases of carcinomas in the gastrointestinal tract not one case of concomitant NLH in the duodenum could be demonstrated, nor in the first section of the jejunum, which was examined for comparison's sake. A connection between NLH and carcinomas of the gastrointestinal tract, as pointed out in the literature, could not be confirmed through this study.