Relationship between HER2-low status and efficacy of CDK4/6 inhibitors in advanced breast cancer: a real-world study.

AIMS AND OBJECTIVES: Human epidermal growth factor receptor 2 (HER2)-low breast cancer (BC) is a new entity considered a biologically distinct subtype from HER2-zero BC. However, the importance of HER2 low expression on the activity of cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) remains unclear. METHODS/MATERIALS: We conducted a single-center retrospective study including hormone receptor-positive (HR +) /HER2- metastatic BC (mBC) patients treated with CDK4/6i plus endocrine treatment (ET) as first-line therapy. Clinical outcomes were analyzed according to HER2 expression. RESULTS: 258 women were analyzed with a median follow-up of 25.4 months; 39.9% had HER2 low, and 60.1% had HER2 zero BC. Median progression-free survival (mPFS) in the HER2-low group was 27.6 months compared with 44.3 months in the HER2-zero group (p = 0.341). In patients receiving ribociclib, the mPFS in the HER2-low group was 24.2 months compared with 53.1 months in the HER2-zero group (multivariate-adjusted HR: 1.981, 95 Cl 1.094-3.586; p = 0.024). The survival probabilities at 24, 36 and 48 months for the HER2 low and HER2 zero groups were 82%, 69%, 69% and 83%, 75% and 69%, respectively (p = 0.336). Objective response rate (p = 0.179) and disease control rate (p = 0.338) did not significantly differ between HER-2-low and HER-2-zero groups. CONCLUSIONS: The mPFS in the Her2-zero group was almost twice that of the Her2-low group, but the difference was not statistically significant. mPFS was significantly longer in the HER2-zero group compared to the HER2-low group in patients receiving ribociclib. More prospective studies are needed to understand the actual consequences of this biomarker.

Dynamic thiol-disulphide homeostasis as a biomarker for predicting the development of contrast medium-associated acute kidney injury in the endovascular treatment of peripheral arterial disease: should intravenous N-acetylcysteine be given before the procedure?

AIM: To determine the predictive ability of serum thiol-disulphide levels for contrast medium-associated acute kidney injury (CA-AKI) after endovascular treatment (EVT) of peripheral arterial disease (PAD) and evaluate the efficacy of intravenous N-acetylcysteine (NAC) in preventing CA-AKI. MATERIAL AND METHODS: This double-blind, randomised controlled study included 85 consecutive adult patients who underwent EVT for PAD. Patients were divided into NAC negative (NAC-) and positive (NAC+) groups. While the NAC- group received only 500 ml saline, the NAC + group received 500 ml saline plus intravenous 600 mg NAC before the procedure. Intra- and intergroup patient characteristics, procedural details, preoperative thiol-disulphide levels, and ischaemia-modified albumin (IMA) levels were recorded. RESULTS: There was a significant difference between NAC- and NAC + groups regarding native thiol, total thiol, disulphide/native thiol ratio (D/NT), and disulphide/total thiol ratio (D/TT). There was also a significant difference between the NAC- (33.3%) and NAC+ (13%) groups in CA-AKI development. Logistic regression analysis showed that the D/TT (OR 2.463) and D/NT (OR 2.121) were the most influential parameters for CA-AKI development. In the receiver operating characteristic (ROC) curve analysis, the sensitivity of native thiol to detect the development of CA-AKI was 89.1%. The negative predictive values of native thiol and total thiol were 95.6% and 94.1%, respectively. CONCLUSION: The serum thiol-disulphide level can be used as a biomarker to detect CA-AKI development and reveal patients with a low risk for CA-AKI development before EVT of PAD. Furthermore, thiol-disulphide levels allow for the indirect quantitative monitoring of NAC. Preprocedural intravenous NAC administration significantly inhibits CA-AKI development.

Relationship between graft failure following anterior cruciate ligament reconstruction and hamstring autograft diameter.

With the increase in the number of individuals participating in sports, anterior cruciate ligament (ACL) injuries are also increasing gradually and the number of patients requiring surgical treatment is increasing in parallel. The primary aim of this study was to investigate the relationship between the need for revision surgery and graft diameter following primary ACL reconstruction (ACLR) using hamstring autografts. The secondary aim of the study was to clarify relationships between anthropometric characteristics and graft diameter. Patients who underwent ACLR with hamstring autografts were included in this retrospective study. The age, body mass index, height, and weight of all patients were recorded preoperatively and the diameters of the grafts were recorded during surgery. The relationship between revision rate and graft diameter and the relationships between anthropometric measurements and graft diameter were investigated for these patients at least one year after surgery. This study included 58 people with graft diameters of ≤7 mm and 261 people with graft diameters of >7 mm. A statistically significant difference was found between the graft diameters of the group that needed revision surgery and the group that did not (p<0.001). A positive relationship was also found between the patient's height and graft diameter (r=0.168). In this study, it was found that the risk of ACL revision surgery increased by 5.5 times among patients with graft diameters of ≤7 mm. The positive relationship between the patient's height and graft diameter can make a significant difference in terms of the need for revision surgery.

Measurement of the Charge-Averaged Elastic Lepton-Proton Scattering Cross Section by the OLYMPUS Experiment.

We report the first measurement of the average of the electron-proton and positron-proton elastic scattering cross sections. This lepton charge-averaged cross section is insensitive to the leading effects of hard two-photon exchange, giving more robust access to the proton's electromagnetic form factors. The cross section was extracted from data taken by the OLYMPUS experiment at DESY, in which alternating stored electron and positron beams were scattered from a windowless gaseous hydrogen target. Elastic scattering events were identified from the coincident detection of the scattered lepton and recoil proton in a large-acceptance toroidal spectrometer. The luminosity was determined from the rates of Møller, Bhabha, and elastic scattering in forward electromagnetic calorimeters. The data provide some selectivity between existing form factor global fits and will provide valuable constraints to future fits.

Revealing Color Forces with Transverse Polarized Electron Scattering.

The Spin Asymmetries of the Nucleon Experiment measured two double spin asymmetries using a polarized proton target and polarized electron beam at two beam energies, 4.7 and 5.9 GeV. A large-acceptance open-configuration detector package identified scattered electrons at 40° and covered a wide range in Bjorken x (0.3

Hard Two-Photon Contribution to Elastic Lepton-Proton Scattering Determined by the OLYMPUS Experiment.

The OLYMPUS Collaboration reports on a precision measurement of the positron-proton to electron-proton elastic cross section ratio, R_{2γ}, a direct measure of the contribution of hard two-photon exchange to the elastic cross section. In the OLYMPUS measurement, 2.01 GeV electron and positron beams were directed through a hydrogen gas target internal to the DORIS storage ring at DESY. A toroidal magnetic spectrometer instrumented with drift chambers and time-of-flight scintillators detected elastically scattered leptons in coincidence with recoiling protons over a scattering angle range of ≈20° to 80°. The relative luminosity between the two beam species was monitored using tracking telescopes of interleaved gas electron multiplier and multiwire proportional chamber detectors at 12°, as well as symmetric Møller or Bhabha calorimeters at 1.29°. A total integrated luminosity of 4.5 fb^{-1} was collected. In the extraction of R_{2γ}, radiative effects were taken into account using a Monte Carlo generator to simulate the convolutions of internal bremsstrahlung with experiment-specific conditions such as detector acceptance and reconstruction efficiency. The resulting values of R_{2γ}, presented here for a wide range of virtual photon polarization 0.456<ε<0.978, are smaller than some hadronic two-photon exchange calculations predict, but are in reasonable agreement with a subtracted dispersion model and a phenomenological fit to the form factor data.

Association between the ACE gene I/D polymorphism and osteoporosis in a Turkish population.

PURPOSE: The purpose of this study was to assess the relationship between osteoporosis and the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism in a Turkish population. METHODS: The study group consisted of 238 unrelated women with osteoporosis and 124 unrelated healthy female controls. All participants, patients and healthy controls, were of Turkish origin from the central region of Turkey. Genomic DNA was isolated from whole venous blood samples using a commercial DNA isolation kit. The ACE gene I/D polymorphism was analysed by polymerase chain reaction and gel electrophoresis. RESULTS: Frequencies of the DD, ID and II genotypes in the patients were 44.5, 41.2 and 14.3 %, and in the controls they were 25.0, 51.6 and 23.4 %, respectively. A significant difference was observed between patients and controls according to genotype frequency (p=0.001). D and I allele frequencies of the I/D polymorphism were 65.1 and 34.9 % in the patient group and 50.8 and 49.2 % in the control group, respectively (p<0.001). CONCLUSION: The ACE gene I/D polymorphism could be a genetic factor associated with osteoporosis.

IL-6 gene promoter polymorphisms: genetic susceptibility to recurrent pregnancy loss.

Recurrent pregnancy loss (RPL) is defined as three or more pregnancy losses before 20 weeks. RPL is a multifactorial condition with several etiologic factors including genetic abnormalities of the parents, anatomical, endocrinological, hematologic and immunologic abnormalities, infections, nutritional and environmental factors. The causes of pregnancy loss in about half of the women with RPL even after extensive investigations remain unknown. We analyzed IL-6 -174 G/C, -572 G/C, -597 G/A, -1363 G/T, -2954 G/C promoter region polymorphisms in 113 RPL patients and 113 healthy subjects by using polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) assay. The -174G/C genotypic and -174C allelic frequency and the -2954G/C genotypic and -2954C allelic frequency of IL-6 was higher in RPL patients than healthy controls and a significant association was found between RPL and -174G/C, -2954G/C polymorphisms (p < 0.0001, OR: 0.28, 95% CI: 0.15-0.51, p < 0.034, OR: 0.16, 95% CI: 0.01-1.12 respectively). We found remarkably similar frequencies in RPL patients compared to controls for IL-6 -572G/C,-597G/A and -1363G/T genotypes/alleles and no association was observed between RPL and these polymorphisms. Our study supported that IL-6 -174G/C and -2954G/C polymorphisms were associated with an increased risk of RPL in Turkish patients (Tab. 3, Ref. 24).

Predicting survival after brain metastases in patients with bladder cancer.

AIMS AND OBJECTIVES: Because of its rarity, limited data concerning brain metastasis (BM) from bladder cancer (BCa) are available, so this phenomenon remains unclear. We aimed to contribute to understanding this unique patient population's clinical behavior and outcomes. METHODS/MATERIALS: This retrospective cohort study included 27 BCa patients with BM treated at our Cancer Institute between April 2009 and December 2022. The time from initial diagnosis to BM and overall survival from BM diagnosis were calculated (Kaplan-Meier method). Cox regression was used to test key clinicopathologic associations. RESULTS: A total of 27 patients were included in the study (male/female = 23/4). The median patient age at BM diagnosis was 62.0 (47-79) years. The median interval from initial diagnosis to BM was 11.0 ± 2.59 (95 % CI, 5.91-16.08) months. Twenty (74.0 %) patients were diagnosed with BM by postsymptomatic imaging. The most common symptoms were headache-dizziness (n = 9, 33.3 %), seizure (n = 3, 11.1 %), hemiparesis (n = 2, 7.4 %), and vision defects (n = 2, 7.4 %). The most common sites of extracranial metastasis were the lung (n = 10, 52.6 %), bone (n = 7, 36.8 %), and lymph nodes (n = 6, 31.5 %). More than half of the patients (55.5 %) had multiple BMs. Eight (29.6 %) patients underwent surgery for BM. All of the patients received radiotherapy (RT) for BM (whole-brain radiotherapy (WBRT)/stereotactic radiotherapy (SRT) = 24/3), and eight patients received RT for the second time. Six patients were treated with systemic chemotherapy (CT) after BM. The median survival from BM was 3.0 ± 1.2 (95 % Cl, 0.4-5.5) months in the entire cohort. A low number of BMs (HR 0.270, 95 % CI 0.083-0.885; p = 0.031), surgery for BM (HR 0.174, 95 % CI 0.043-0.712; p = 0.015), CT after BM (HR 0.207, 95 % CI 0.057-0.755; p = 0.017), and better ECOG performance score (HR 0.248, 95 % CI 0.074-0.836; p = 0.025) were associated with better OS. CONCLUSIONS: Factors associated with improved survival in BCa patients with BM include a few brain lesions, intracranial resection, CT after BM, and better ECOG performance scores. Larger-scale prospective studies are needed to define the optimal management strategy further.

Polarization components in π0 photoproduction at photon energies up to 5.6 GeV.

We present new data for the polarization observables of the final state proton in the (1)H(γ,p)π(0) reaction. These data can be used to test predictions based on hadron helicity conservation and perturbative QCD. These data have both small statistical and systematic uncertainties and were obtained with beam energies between 1.8 and 5.6 GeV and for π(0) scattering angles larger than 75° in the center-of-mass frame. The data extend the polarization measurements database for neutral pion photoproduction up to E(γ)=5.6 GeV. The results show a nonzero induced polarization above the resonance region. The polarization transfer components vary rapidly with the photon energy and π(0) scattering angle in the center-of-mass frame. This indicates that hadron helicity conservation does not hold and that the perturbative QCD limit is still not reached in the energy regime of this experiment.

Can transcription factors in the intervertebral disc of lopinavir/ritonavir prevent degeneration in the nucleus pulposus by mediating the regulation of inflammation through signaling pathways?

OBJECTIVE: This study was conducted to examine whether lopinavir/ritonavir (Lop/r), an HIV protease inhibitor, can improve disc physiology and slow down intervertebral disc (IVD) degeneration through in vitro experimental methods, as well as whether it can suppress inflammation with interleukin-1 beta (IL-1ß) and sex-determining region Y (SRY) protein-related high-mobility group box genes-9 (SOX9) through hypoxia-inducible factor 1-alpha (HIF-1α) and the nuclear factor kappa B (NF-κB) signaling pathway. The aim was to investigate whether Lop/r application is toxic to IVD cells and the microenvironment simultaneously. PATIENTS AND METHODS: Human primary cell cultures were prepared using herniated IVD tissues obtained from patients with lumbar disc hernia who were unresponsive to conservative and medical treatment, and thereby, were operated on. The untreated culture samples served as control group, and the samples treated with Lop/r served as study group. Microscopic evaluations were performed simultaneously using fluorescent and supravital dyes in all groups. In addition to cell viability, toxicity, and proliferation analysis through a commercial kit, IL-1ß, SOX9, HIF-1α, and NF-κB protein expressions were evaluated using Western blotting. In the statistical comparison of the obtained data, an alpha value less than 0.05 was considered significant. RESULTS: Cell proliferation decreased in the Lop/r group, but no cell death was observed (p < 0.05). Moreover, at the end of 72 hours after Lop/r application, IL-1ß and NF-kB protein expressions decreased by 40% and 52%, respectively, while HIF-1α and SOX9 protein expressions increased by 4% and 59%, respectively (p< 0.05). CONCLUSIONS: Although these data were obtained from an in vitro experimental study, it is believed that these findings could make significant contributions to the pharmaco-regenerative treatment modalities of IVD degeneration. Lop/r suppresses the IL-1ß and NF-κB and induces SOX9 and HIF-1α, since these signaling pathways may be related to human IVD degeneration.

Search for effects beyond the born approximation in polarization transfer observables in e(over→)p elastic scattering.

Intensive theoretical and experimental efforts over the past decade have aimed at explaining the discrepancy between data for the proton electric to magnetic form factor ratio, G(E)/G(M), obtained separately from cross section and polarization transfer measurements. One possible explanation for this difference is a two-photon-exchange contribution. In an effort to search for effects beyond the one-photon-exchange or Born approximation, we report measurements of polarization transfer observables in the elastic H(e[over →],e(')p[over →]) reaction for three different beam energies at a Q(2)=2.5 GeV(2), spanning a wide range of the kinematic parameter ε. The ratio R, which equals µ(p)G(E)/G(M) in the Born approximation, is found to be independent of ε at the 1.5% level. The ε dependence of the longitudinal polarization transfer component P(ℓ) shows an enhancement of (2.3±0.6)% relative to the Born approximation at large ε.

The association between BsmI variant of vitamin D receptor gene and susceptibility to tuberculosis.

Vitamin D receptor (VDR) gene variants may play a key role in the susceptibility to tuberculosis (TB). We have investigated the association BsmI, TaqI, FokI polymorphisms in the VDR gene with susceptibility to tuberculosis. This study included 128 patients with TB (pulmonary and extrapulmonary TB) and 80 healthy subjects living in Istanbul, Turkey. Genetic polymorphisms were studied by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) techniques at genomic DNA isolated from whole blood-EDTA. The present study results indicate that the genotype and allele frequencies for patient group (BB:22, Bb:53, bb:25; B allele:48%, b allele:52%) was significantly different from the control group (BB:6, Bb:48, bb: 46; B allele:30 b allele:70) due to an overrepresentation of B allele (P: 0.000 OR: 1.61 95% 1.23-2.11). However there were no significant differences in distribution of allele/genotype frequencies of FokI, TaqI variants between TB and healthy controls. This study results suggest that BsmI variant of VDR gene may play an important role in susceptibility to tuberculosis.

Analysis of transforming growth factor beta 1 (TGF-beta1) gene polymorphisms in Turkish patients with scleroderma.

Systemic sclerosis (SSc) is an autoimmune disease characterized by inflammation and fibrosis of the skin and visceral organs. Fibrosis associated with SSc is characterized by an increased synthesis of a wide range of extracellular matrix (ECM). TGF-beta is a pluripotent cytokine in a wide range of cell types. In particular it has been found to be a potent inducer of ECM protein synthesis and fibroblast migration. The TGF-beta1 gene is highly polymorphic and two signal sequence polymorphisms at codon 10 and codon 25 are linked to disease outcomes. In this study, we analysed two polymorphic sites of the TGF-beta1 gene, codon 10 and codon 25, in 43 Turkish SSc female patients with interstitial lung involvement and in 75 healty individuals by ARMS-PCR. In our study no significant difference was found in codon 10, codon 25 genotype frequencies between patient with SSc and the control group (p = 0.676, 0.375, respectively). Our findings suggest that codon 10 and 25 polymorphism cannot be related with SSc for Turkish population.

Indirect inguinal hernia repair conducted with single conventional port intracorporeal conventional equipment-endoscopic surgery.

PURPOSE: Laparoscopic or laparoscopy-assisted inguinal hernia repair (IHR) can be performed using one port plus two stab wounds. We herein present our experience with laparoscopic IHR conducted using a single conventional port and a single working instrument. METHODS: The records patients who underwent single conventional port intracorporeal IHR during November 2013-December 2018 were evaluated. The main outcome measurements were patient's demographic characteristics, hernia side, presence of incarceration, operative time, and complications. RESULTS: A total of 132 inguinal hernias (52 right, 40 left, and 20 bilateral) were repaired in 112 patients (76 boys, 36 girls). The mean ages of the patients were 69.8 ± 53.4 months (3 months to 17 years). In six patients, contralateral processus vaginalis was found to be patent during operation. Incarcerated inguinal hernia was present in two patients. Mean operative time was 17.9 ± 3.8 min (9-30 min) in unilateral hernias and 28.9 ± 6.5 min (24-45 min) in bilateral hernias. No intraoperative and postoperative complications were encountered. The mean hospital stay of the patients was 8.8 ± 5.0 h (4-36 h). Postoperative follow-up was 16.5 ± 5.1 months (6-24 months). No recurrent inguinal hernias were detected during follow-up. CONCLUSION: Single conventional port intracorporeal IHR obviates additional stab wounds. Additionally, present technique eliminates the risk of skin puckering, subcutaneous granuloma, infection, nerve, and muscle damage development induced by the subcutaneously placed knot in laparoscopy-assisted IHR. Single conventional port intracorporeal IHR in children is a feasible and safe operative technique with low complication rates.

Tumefactive perivascular space demonstrated with post-contrast time-of-flight MR angiography.

The cerebral perivascular spaces are interstitial fluid-filled anatomic structures surrounding the perforating arteries. They appear as small, round or curvilinear structures on magnetic resonance (MR) imaging. Occasionally, these structures may become very large and cause mass effect. In this case, they may imitate malignant processes and are referred to as tumefactive perivascular spaces. In this study, we present a case of tumefactive perivascular space demonstrated with post-contrast time-of-flight (TOF) MR angiography. To our knowledge, there have been no previous clear demonstrations of the perforating artery in tumefactive perivascular space with contrast-enhanced TOF MR angiography. The purpose of this study was to describe advanced imaging findings in this unusual condition.

NRAMP1 (SLC11A1) gene polymorphisms that correlate with autoimmune versus infectious disease susceptibility in tuberculosis and rheumatoid arthritis.

NRAMP1 gene has multiple pleiotropic effects on macrophage activation pathways. These pleiotropic effects may increase resistance to infections such as tuberculosis (TB), but may also lead to susceptibility of autoimmune diseases such as rheumatoid arthritis (RA). It has been hypothesized that allele 3 would be associated with autoimmune diseases, whereas allele 2 would be associated with infectious diseases, and genetic factors that enhanced survival in the epidemics of TB might have led to susceptibility for the development of RA. We analysed four NRAMP1 gene polymorphisms including 5' promoter (GT)(n) (rs34448891), INT4 (469 + 14G/C) (rs3731865), 3'UTR (1729 + 55del4) (rs17235416) and D543N (codon 543, Asp to Asn) (rs17235409) in 112 patients with TB, 98 patients with RA, 80 healthy controls for TB and 122 healthy controls for RA using ARMS-PCR and PCR-RFLP. We found a significant association between INT4 and RA (P = 0.004, odds ratio: 2.06, 95% CI: 1.24-3.41), but no significant differences between 5' promoter, D543N, 3'UTR polymorphisms and RA. There were no associations between NRAMP1 gene polymorphisms and TB. Similarly, no significant differences were observed between NRAMP1 polymorphisms and rheumatoid factor positivity and erosive disease in RA and localization of TB. INT4 polymorphism may be associated with RA in Turkish patients.

Oxidative DNA damage in retinopathy of prematurity.

PURPOSE: This study examines the levels of oxidative damage in patients with retinopathy of prematurity (ROP). METHODS: Fifty patients were recruited with a birthweight below 1500 g or gestational age below 32 weeks. The cases were classified into those who developed ROP (n=25) and those without ROP (n=25). The authors obtained blood and urine samples from each infant, for measuring 8-hydroxy 2-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) levels, at the time of the first examination at 4-6 postnatal weeks. RESULTS: A significant difference was observed in leukocyte and urine 8-OHdG levels in patients with ROP compared to those without ROP (p<0.001 for both). Similarly, a significant difference was observed in plasma and urine MDA levels in patients with ROP compared to those without ROP (p<0.001 for both). In addition, significant correlations were found between levels of 8-OHdG in leukocyte DNA and plasma MDA (r=0.859, p<0.001), and between levels of urine 8-OHdG excretion and urine MDA (r=0.563, p<0.001). CONCLUSIONS: 8-OHdG in leukocyte DNA and urine levels in premature infants can be useful as an indicator for ROP screening.

Central retinal vein thrombosis and hyperhomocysteinemia in a young patient with renal transplantation.

A 28-year-old woman was admitted with a sudden loss of vision in the right eye. She underwent renal transplantation in June 1999 for chronic renal failure secondary to amyloidosis. Upon ophthalmologic examination, the patient was diagnosed with central retinal vein occlusion. Physical and laboratory examinations failed to disclose any remarkable pathology except for high homocysteine levels. Hyperhomocysteinemia has been reported as a potential risk factor requiring treatment and a significant association has been found between this condition and central retinal vein thrombosis.