Characterization of clinicopathological features, treatment practices, and outcomes among Finnish advanced breast cancer patients in real-life clinical practice.

PURPOSE: In recent years, several new targeted therapies have emerged for advanced breast cancer (aBC). However, real-life data specific to aBC and different breast cancer subtypes are scarce. This retrospective cohort study was designed to describe the distribution of aBC subtypes, incidence, treatment patterns, survival, and PIK3CA hotspot mutation frequency. METHODS: The study included all patients in the Hospital District of Southwest Finland diagnosed with aBC between 2004 and 2013 and with a sample available in Auria Biobank. In addition to registry-based data collection, 161 HR+/HER2- aBCs were screened for PIK3CA mutations. RESULTS: Altogether, 54.7% of the 444 patients included in the study had luminal B subtype. The smallest representations were in HR-/HER2+ (4.5%) and triple-negative (5.6%) subgroups. The percentage of aBC among all diagnosed breast cancers increased until 2010, after which it remained stable. The triple-negative cancers were associated with shorter median overall survival (5.5 months) compared to other subgroups (16.5-24.6 months). Most (84%) triple-negative cancers also metastasized during the first two years, whereas this was more evenly distributed over time in other subgroups. Of the HR+/HER2- tumors, 32.3% harbored a PIK3CA hotspot mutation. These patients, however, did not have inferior survival compared to patients with PIK3CA wild-type cancers. CONCLUSION: This study described real-world aBC subgroups and indicated that the clinical outcomes of subgroups vary. Although PIK3CA hotspot mutations did not lead to inferior survival, they are relevant as possible treatment targets. Overall, these data could be utilized to further evaluate the subgroup-specific medical needs in breast cancer.

Overall survival of individuals with metastatic cancer in Sweden: a nationwide study.

AIMS: Consistent improvements for overall survival (OS) have been reported for individuals with metastatic cancer. Swedish population-based registers allow national coverage and long follow-up time. The aim of this study was to estimate and explore long-term OS of individuals diagnosed with metastatic cancer using Swedish nationwide health registers. METHODS: Individuals with metastatic breast (MBC), non-small cell lung (MNSCLC), ovary (MOC) or colorectal cancer (MCRC) or metastatic malignant melanoma (MMM) were identified in the Swedish national cancer register and national patient registers. Survival was estimated and stratified by available variables. Potential cure fractions were estimated using mixture cure models. RESULTS: In total, approximately 69,000 individuals were identified. The most common cancers were MCRC (36.2%) and MNSCLC (29.5%). Men were more frequently diagnosed with MNSCLC, MCRC, and MMM compared to women. Except for MOC, about 50% of individuals were 70 years or older at diagnosis. Throughout the study period survival differed across cancers. The longest median OS was observed for individuals with MOC and MBC. At 10 years of follow-up, the survival curves flatten at a survival rate of approximately 10% for all cancers except MNSCLC. The youngest age groups had the longest median OS. Increased survival was also observed for individuals diagnosed in 2015 and 2018 compared to individuals diagnosed during earlier years. The estimated cure fractions were 4% for MBC, 1.5% for MNSCLC, 6.8% for MCRC, 8.6% for MOC and MMM. CONCLUSIONS: Long-term survival has been assessed across all indications except for NSCLC.. The findings may be relevant for healthcare planning to meet the needs of future patients and potential long-term survivors.

Overall survival of patients with metastatic breast cancer in Sweden: a nationwide study.

BACKGROUND: Breast cancer is the most common cancer among women in Sweden. Whereas survival for the overall breast cancer population is well-documented, survival of patients with metastatic breast cancer (MBC) is harder to quantify due to the lack of reliable data on disease recurrence in national cancer registers. METHODS: This study used machine learning to classify the total MBC population in Sweden diagnosed between 2009 and 2016 using national registers, with the aim to estimate overall survival (OS). RESULTS: The total population consisted of 13,832 patients-2528 (18.3%) had de novo MBC whereas 11,304 (81.7%) were classed as having a recurrent MBC. Median OS for patients with MBC was found to be 29.8 months 95% confidence interval (CI) [28.9, 30.6]. Hormone-receptor (HR)-positive MBC had a median OS of 37.0 months 95% CI [35.9, 38.3] compared to 9.9 months 95% CI [9.1, 11.0] for patients with HR-negative MBC. CONCLUSION: This study covered the entire MBC population in Sweden during the study time and may serve as a baseline for assessing the effect of new treatment strategies in MBC introduced after the study period.

Use of classifiers to optimise the identification and characterisation of metastatic breast cancer in a nationwide administrative registry.

BAKGROUND: The prognosis for patients with metastatic breast cancer (MBC) is substantially worse when compared with patients with earlier stage disease. Therefore, understanding the differences in epidemiology between these two patient groups is important. Studies using population-based cancer registries to identify MBC are hampered by the quality of reporting. Patients are registered once (at time of initial diagnosis); hence only data for patients with de novo MBC are identifiable, whereas data for patients with recurrent MBC are not. This makes accurate estimation of the epidemiology and healthcare utilisation of MBC challenging. This study aimed to investigate whether machine-learning could improve identification of MBC in national health registries. MATERIAL AND METHODS: Data for patients with confirmed MBC from a regional breast cancer registry were used to train machine-learning algorithms (or 'classifiers'). The best performing classifier (accuracy 97.3%, positive predictive value 85.1%) was applied to Swedish national registries for 2008 to 2016. RESULTS: Mean yearly MBC incidence was estimated at 14 per 100,000 person-years (with 18% diagnosed de novo and 76% of the total with HR-positive MBC). CONCLUSION: To our knowledge, this is the first study to use machine learning to identify MBC regardless of stage at diagnosis in health registries covering the entire population of Sweden.

Prevalence, Patient Characteristics, and Pharmacological Treatment of Children, Adolescents, and Adults Diagnosed With ADHD in Sweden.

OBJECTIVE: The objective of this study was to describe the epidemiology of diagnosed ADHD and the pharmacological treatment of patients with ADHD in Sweden. Specifically, this study estimates the prevalence of patients with a newly registered diagnosis of ADHD over a 5-year period, and the prevalence of all patients with a registered ADHD diagnoses over a 6-year period in Sweden. METHOD: Two population-based registries were used as data sources for this study; the National Patient Register (NPR) and the Prescribed Drug Register (PDR). The international Classification of Diseases 10th Revison (ICD-10) was used to identify patients with ADHD. RESULTS: The annual prevalence of ADHD in the general population of Sweden was found to be 1.1 per 1,000 persons in the year 2006 increasing to 4.8 per 1,000 persons in 2011. The corresponding prevalence for newly diagnosed patients increased from 0.6 per 1,000 persons in 2007 to 1.3 per 1,000 persons in 2011. The majority of diagnosed patients received pharmacological treatment, with methylphenidate being the most common dispensed drug. Comorbidities in the autism spectrum were most common for younger patients, while substance abuse, anxiety, and personality disorder were the most common comorbidities in older patients. CONCLUSION: From 2006 to 2011, the number of patients diagnosed with ADHD has increased in Sweden over all ages. The majority of patients diagnosed with ADHD in Sweden received a pharmacological treatment regardless of age. An ADHD diagnosis was often accompanied with psychiatric comorbidity.

Epilepsy in tuberous sclerosis patients in Sweden - Healthcare utilization, treatment, morbidity, and mortality using national register data.

PURPOSE: This study is designed to estimate the prevalence of epilepsy associated with TSC in Sweden and to describe treatment, morbidity, and mortality of TSC patients with epilepsy. METHODS: Register data for 2004-2014 was obtained from the National Board of Health and Welfare in Sweden. Patients with TSC were identified using ICD-10 codes. Epilepsy was identified using ICD-10 codes, interventions aimed to treat epilepsy, or prescriptions for antiepileptic drugs. RESULTS: The prevalence of TSC was 5.38 per 100 000 individuals. We identified 551 unique patients with TSC, of which 386 (70.1%) had epilepsy. The mean study period was 8.82 years. Antiepileptic drugs were dispensed to 97.9% of patients with epilepsy. The most prescribed antiepileptic drug was sodium valproate. Ketogenic diet was used in 6 (1.6%) patients, vagus nerve stimulation in 23 (6.0%) patients, and epilepsy surgery was performed in 25 (6.5%) patients. The mean number of outpatient visits per year was 4.70 (SD 4.17) and the mean number of inpatient days per year was 3.25 (SD 5.61). The mean number of outpatient visits per year with an ICD-10 code for epilepsy was 1.65 (SD 1.95) and the corresponding number of inpatient days was 2.06 (SD 4.50). A total of 30 patients with TSC and epilepsy died during the study period. CONCLUSIONS: The prevalence of epilepsy in this study was in the lower range of previously reported numbers, suggesting that epilepsy may be overestimated in non-population based studies. A substantial part of the healthcare utilization was directly related to epilepsy.

Local Electron Attachment Energy and Its Use for Predicting Nucleophilic Reactions and Halogen Bonding.

A new local property, the local electron attachment energy [E(r)], is introduced and is demonstrated to be a useful guide to predict intermolecular interactions and chemical reactivity. The E(r) is analogous to the average local ionization energy but indicates susceptibility toward interactions with nucleophiles rather than electrophiles. The functional form E(r) is motivated based on Janak's theorem and the piecewise linear energy dependence of electron addition to atomic and molecular systems. Within the generalized Kohn-Sham method (GKS-DFT), only the virtual orbitals with negative eigenvalues contribute to E(r). In the present study, E(r) has been computed from orbitals obtained from GKS-DFT computations with a hybrid exchange-correlation functional. It is shown that E(r) computed on a molecular isodensity surface, ES(r), reflects the regioselectivity and relative reactivity for nucleophilic aromatic substitution, nucleophilic addition to activated double bonds, and formation of halogen bonds. Good to excellent correlations between experimental or theoretical measures of interaction strengths and minima in ES(r) (ES,min) are demonstrated.

Direct epoxidation in Candida antarctica lipase B studied by experiment and theory.

Candida antarctica lipase B (CALB) is a promiscuous serine hydrolase that, besides its native function, catalyzes different side reactions, such as direct epoxidation. A single-point mutant of CALB demonstrated a direct epoxidation reaction mechanism for the epoxidation of alpha,beta-unsaturated aldehydes by hydrogen peroxide in aqueous and organic solution. Mutation of the catalytically active Ser105 to alanine made the previously assumed indirect epoxidation reaction mechanism impossible. Gibbs free energies, activation parameters, and substrate selectivities were determined both computationally and experimentally. The energetics and mechanism for the direct epoxidation in CALB Ser105Ala were investigated by density functional theory calculations, and it was demonstrated that the reaction proceeds through a two step-mechanism with formation of an oxyanionic intermediate. The active-site residue His224 functions as a general acid-base catalyst with support from Asp187. Oxyanion stabilization is facilitated by two hydrogen bonds from Thr40.

[(NHC)AuI]-catalyzed formation of conjugated enones and enals: an experimental and computational study.

The [(NHC)AuI]-catalyzed (NHC=N-heterocyclic carbene) formation of alpha,beta-unsaturated carbonyl compounds (enones and enals) from propargylic acetates is described. The reactions occur at 60 degrees C in 8 h in the presence of an equimolar mixture of [(NHC)AuCl] and AgSbF6 and produce conjugated enones and enals in high yields. Optimization studies revealed that the reaction is sensitive to the solvent, the NHC, and, to a lesser extent, to the silver salt employed, leading to the use of [(ItBu)AuCl]/AgSbF6 in THF as an efficient catalytic system. This transformation proved to have a broad scope, enabling the stereoselective formation of (E)-enones and -enals with great structural diversity. The effect of substitution at the propargylic and acetylenic positions has been investigated, as well as the effect of aryl substitution on the formation of cinnamyl ketones. The presence or absence of water in the reaction mixture was found to be crucial. From the same phenylpropargyl acetates, anhydrous conditions led to the formation of indene compounds via a tandem [3,3] sigmatropic rearrangement/intramolecular hydroarylation process, whereas simply adding water to the reaction mixture produced enone derivatives cleanly. Several mechanistic hypotheses, including the hydrolysis of an allenol ester intermediate and SN2' addition of water, were examined to gain an insight into this transformation. Mechanistic investigations and computational studies support [(NHC)AuOH], produced in situ from [(NHC)AuSbF6] and H2O, instead of cationic [(NHC)AuSbF6] as the catalytically active species. Based on DFT calculations performed at the B3LYP level of theory, a full catalytic cycle featuring an unprecedented transfer of the OH moiety bound to the gold center to the C[triple chemical bond]C bond leading to the formation of a gold-allenolate is proposed.

A theoretical analysis of a classic example of supramolecular catalysis.

Computational chemistry is used to study a 1,3-dipolar cycloaddition between an azide and an alkyne inside the macrocycle cucurbit[6]uril, in order to elucidate the catalytic function of a highly efficient supramolecular catalyst.

Exploring the active-site of a rationally redesigned lipase for catalysis of Michael-type additions.

Michael-type additions of various thiols and alpha,beta-unsaturated carbonyl compounds were performed in organic solvent catalyzed by wild-type and a rationally redesigned mutant of Candida antarctica lipase B. The mutant lacks the nucleophilic serine 105 in the active-site; this results in a changed catalytic mechanism of the enzyme. The possibility of utilizing this mutant for Michael-type additions was initially explored by quantum-chemical calculations on the reaction between acrolein and methanethiol in a model system. The model system was constructed on the basis of docking and molecular-dynamics simulations and was designed to simulate the catalytic properties of the active site. The catalytic system was explored experimentally with a range of different substrates. The kca values were found to be in the range of 10(-3) to 4 min(-1), similar to the values obtained with aldolase antibodies. The enzyme proficiency was 10(7). Furthermore, the Michael-type reactions followed saturation kinetics and were confirmed to take place in the enzyme active site.

Computational study of the amination of halobenzenes and phenylpentazole. A viable route to isolate the pentazolate anion?

Amination of halobenzenes, which proceeds via the benzyne intermediate (1), has been studied using quantum chemical methods. The computational data are in agreement with experimentally observed trends in reactivity and provide a qualitative explanation for the observed hydrogen isotope effects. To investigate if this is a viable way to isolate the pentazolate anion (2), the reactivities of the halobenzenes have been compared to phenylpentazole (3). The reaction energetics for phenylpentazole become favorable after complexation with Zn(2+).

Rational design of a lipase to accommodate catalysis of Baeyer-Villiger oxidation with hydrogen peroxide.

The mechanism and potential energy surface for the Baeyer-Villiger oxidation of acetone with hydrogen peroxide catalyzed by a Ser105-Ala mutant of Candida antarctica Lipase B has been determined using ab initio and density functional theories. Initial substrate binding has been studied using an automated docking procedure and molecular dynamics simulations. Substrates were found to bind to the active site of the mutant. The activation energy for the first step of the reaction, the nucleophilic attack of hydrogen peroxide on the carbonyl carbon of hydrogen peroxide, was calculated to be 4.4 kcal x mol(-1) at the B3LYP/6-31+G* level. The second step, involving the migration of the alkyl group, was found to be the rate-determining step with a computed activation energy of 19.9 kcal x mol(-1) relative the reactant complex. Both steps were found to be lowered considerably in the reaction catalyzed by the mutated lipase, compared to the uncatalyzed reaction. The first step was lowered by 36.0 kcal x mol(-1) and the second step by 19.5 kcal x mol(-1). The second step of the reaction, the rearrangement step, has a high barrier of 27.7 kcal x mol(-1) relative to the Criegee intermediate. This could lead to an accumulation of the intermediate. It is not clear whether this result is an artifact of the computational procedure, or an indication that further mutations of the active site are required. Figure Second TS (18TS) in the Baeyer-Villiger oxidation in a mutant of CALB. Distances in A

Thermochemistry of arylselanyl radicals and the pertinent ions in acetonitrile.

Reduction and oxidation potentials of a series of parasubstituted phenylselanyl radicals, XC(6)H(4)Se(*), have been measured using photomodulated voltammetry in acetonitrile. The thermodynamic significance of these data was substantiated through a study of the oxidation process of the pertinent selenolates in linear sweep voltammetry. Both the reduction and the oxidation potentials correlate linearly with the Hammett substituent coefficients sigma and sigma(+) leading in the latter case to slopes, rho(+), of 2.5 and 3.8, respectively. Through comparison of these slopes with those published previously for the O- and S-centered analogues, it is revealed that the pi-interaction becomes progressively smaller as the size of the radical center increases in the order O, S, and Se. Solvation energies of the pertinent selenolates and selanylium ions have been extracted from thermochemical cycles incorporating the measured electrode potentials for XC(6)H(4)Se(*) as well as electron affinities and ionization potentials obtained from theoretical calculations at the B3LYP/6-31+G(d) level. The extracted data show the expected overall substituent dependency for both kinds of ions; that is, the absolute value of the solvation energy decreases as the charge becomes more delocalized. The data have also been compared with solvation energies computed using the polarizable continuum model (PCM). Interestingly, we find that, while the model seems to work well for selenolates, it underestimates the solvation of selanylium ions in acetonitrile by as much as 25 kcal mol(-)(1). These large deviations are ascribed to the fact that the PCM method does not take specific solvent effects into account as it treats the solvent as a continuum described solely by its dielectric constant. Gas-phase calculations show that the arylselanylium ions can coordinate covalently to one or two molecules of acetonitrile in strong Ritter-type adducts. When this strong interaction is included in the solvation energy calculations by means of a combined supermolecule and PCM approach, the experimental data are reproduced within a few kcal mol(-)(1). Although the energy difference of the singlet and triplet spin states of the arylselanylium ions is small for the gas-phase structures, the singlet cation is undoubtedly the dominating species in solution because the triplet cation lacks the ability to form covalent bonds.

Carbon-carbon bonds by hydrolytic enzymes.

Enzymes are efficient catalysts in synthetic chemistry, and their catalytic activity with unnatural substrates in organic reaction media is an area attracting much attention. Protein engineering has opened the possibility to change the reaction specificity of enzymes and allow for new reactions to take place in their active sites. We have used this strategy on the well-studied active-site scaffold offered by the serine hydrolase Candida antarctica lipase B (CALB, EC 3.1.1.3) to achieve catalytic activity for aldol reactions. The catalytic reaction was studied in detail by means of quantum chemical calculations in model systems. The predictions from the quantum chemical calculations were then challenged by experiments. Consequently, Ser105 in CALB was targeted by site-directed mutagenesis to create enzyme variants lacking the nucleophilic feature of the active site. The experiments clearly showed an increased reaction rate when the aldol reaction was catalyzed by the mutant enzymes as compared to the wild-type lipase. We expect that the new catalytic activity, harbored in the stable protein scaffold of the lipase, will allow aldol additions of substrates, which cannot be reached by traditional aldolases.