First-in-human study of AMG 193, an MTA-cooperative PRMT5 inhibitor, in patients with MTAP-deleted solid tumors: results from phase I dose exploration.

BACKGROUND: Homozygous deletion of methylthioadenosine phosphorylase (MTAP) occurs in ∼10%-15% of solid tumors. AMG 193, a CNS-penetrant methylthioadenosine-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor, selectively induces synthetic lethality in MTAP-deleted tumor cells. Here, we report results of the completed monotherapy dose exploration evaluating AMG 193 in patients with MTAP-deleted solid tumors. PATIENTS AND METHODS: In this first-in-human, multicenter, open-label, phase I study, patients with advanced CDKN2A-deleted and/or MTAP-deleted solid tumors received AMG 193 orally [once (o.d.) or twice (b.i.d.) daily] continuously in 28-day cycles. Primary objectives were safety and tolerability assessed by dose-limiting toxicities and determination of the maximum tolerated dose; secondary objectives included pharmacokinetics and preliminary antitumor activity measured by RECIST v1.1. RESULTS: As of 23 May 2024, 80 patients in dose exploration received AMG 193 at doses 40-1600 mg o.d. or 600 mg b.i.d. The most common treatment-related adverse events were nausea (48.8%), fatigue (31.3%), and vomiting (30.0%). Dose-limiting toxicities were reported in eight patients at doses ≥240 mg, including nausea, vomiting, fatigue, hypersensitivity reaction, and hypokalemia. The maximum tolerated dose was determined to be 1200 mg o.d. Mean exposure of AMG 193 increased in a dose-proportional manner from 40 mg to 1200 mg. Among the efficacy-assessable patients treated at the active and tolerable doses of 800 mg o.d., 1200 mg o.d., or 600 mg b.i.d. (n = 42), objective response rate was 21.4% (95% confidence interval 10.3% to 36.8%). Responses were observed across eight different tumor types, including squamous/non-squamous non-small-cell lung cancer, pancreatic adenocarcinoma, and biliary tract cancer. At doses ≥480 mg, complete intratumoral PRMT5 inhibition was confirmed in paired MTAP-deleted tumor biopsies, and molecular responses (circulating tumor DNA clearance) were observed. CONCLUSIONS: AMG 193 demonstrated a favorable safety profile without clinically significant myelosuppression. Encouraging antitumor activity across a variety of MTAP-deleted solid tumors was observed based on objective response rate and circulating tumor DNA clearance.

Single organ metastatic sites in non-small cell lung cancer: Patient characteristics, treatment patterns and outcomes from a large retrospective Canadian cohort.

BACKGROUND: There is a paucity of information about the characteristics, treatment patterns, and outcomes of non-small cell lung cancer (NSCLC) patients with single organ metastasis (SOM). METHODS: This retrospective cohort study includes all patients with a diagnosis of stage IV NSCLC diagnosed from 2014 to 2016 and treated at Princess Margaret Cancer Centre. We compared baseline characteristics and patterns of metastatic sites between patients with SOM versus multiple (M)OM. Additionally, we identified treatment modalities and outcomes for patients with SOM. Cox multivariable models (MVA) were utilized to evaluate differences in overall survival (OS) between the SOM and MOM cohorts. RESULTS: Of 893 pts analyzed, 457 (51 %) had SOM, while 436 (49 %) had MOM at initial diagnosis. Demographics were comparable between the two groups. Brain was the most common site of metastasis for SOM patients. When compared to the MOM group, the SOM group had lower percentages of liver and adrenal metastases. Amongst SOM patients, 54 % received single modality treatment, and 20 % did not receive any treatment for their SOM. In MVA, patients with liver (HR 2.4), bone (HR 1.8), and pleural (HR 1.7) metastasis as their SOM site had the worst outcomes, with median OS of 6.8 months, 12.1 months, and 13.0 months respectively. Patients with SOM had a significantly improved median OS compared to those with MOM (15.9 months vs. 10.6 months; HR 0.56, 95 % CI 0.47-0.66, p < 0.001). CONCLUSION: In NSCLC patients who presented with SOM, survival correlated with the initial organ involved and was better overall compared to patients with MOM. SOM NSCLC may benefit from specific management strategies and SOM patients could be considered as a specific subgroup for survival analyses in observational and non-randomized interventional studies. In clinical trials, SOM can be considered as a stratification factor in the future.

Longitudinal health utilities, symptoms and toxicities in patients with ALK-rearranged lung cancer treated with tyrosine kinase inhibitors: a prospective real-world assessment.

Background: Tyrosine kinase inhibitors (tkis) have dramatically improved the survival of patients with ALK-rearranged (ALK+) non-small-cell lung cancer (nsclc). Clinical trial data can generally compare drugs in a pair-wise fashion. Real-world collection of health utility data, symptoms, and toxicities allows for the direct comparison between multiple tki therapies in the population with ALK+ nsclc. Methods: In a prospective cohort study, outpatients with ALK+ recruited between 2014 and 2018, treated with a variety of tkis, were assessed every 3 months for clinico-demographic, patient-reported symptom and toxicity data and EQ-5D-derived health utility scores (hus). Results: In 499 longitudinal encounters of 76 patients with ALK+ nsclc, each tki had stable longitudinal hus when disease was controlled, even after months to years: the mean overall hus for each tki ranged from 0.805 to 0.858, and longitudinally from 0.774 to 0.912, with higher values associated with second- or third-generation tkis of alectinib, brigatinib, and lorlatinib. Disease progression was associated with a mean hus decrease of 0.065 (95% confidence interval: 0.02 to 0.11). Health utility scores were inversely correlated to multiple symptoms or toxicities: rho values ranged from -0.094 to -0.557. Fewer symptoms and toxicities were associated with the second- and third-generation tkis compared with crizotinib. In multivariable analysis, only stable disease state and baseline Eastern Cooperative Oncology Group performance status were associated with improved hus. Conclusions: There was no significant decrease in hus when patients with ALK+ disease were treated longitudinally with each tki, as long as patients were clinically stable. Alectinib, brigatinib, and lorlatinib had the best toxicity profiles and exhibited high mean hus longitudinally in the real-world setting.

Novel properties of a mouse gamma-aminobutyric acid transporter (GAT4).

We expressed the mouse gamma-aminobutyric acid (GABA) transporter GAT4 (homologous to rat/ human GAT-3) in Xenopus laevis oocytes and examined its functional and pharmacological properties by using electrophysiological and tracer uptake methods. In the coupled mode of transport (Na+/ Cl-/GABA cotransport), there was tight coupling between charge flux and GABA flux across the plasma membrane (2 charges/GABA). Transport was highly temperature-dependent with a temperature coefficient (Q10) of 4.3. The GAT4 turnover rate (1.5 s(-l); -50 mV, 21 degrees C) and temperature dependence suggest physiological turnover rates of 15-20 s(-1). No uncoupled current was observed in the presence of Na+. In the absence of external Na+, GAT4 exhibited two distinct uncoupled currents. (i) A Cl- leak current (ICl(leak)) was observed when Na+ was replaced with choline or tetraethylammonium. The reversal potential of (ICl(leak)) followed the Cl- Nernst potential. (ii) A Li+ leak current (ILi(leak)) was observed when Na+ was replaced with Li+. Both leak currents were inhibited by Na+, and both were temperature-independent (Q10 approximately 1). The two leak modes appeared not to coexist, as Li+ inhibited (ICl(leak)). The results suggest the existence of cation- and anion-selective channel-like pathways in GAT4. Flufenamic acid inhibited GAT4 Na+/Cl-/GABA cotransport, ILi(leak), and ICl(leak), (Ki approximately 30 microM), and the voltage-induced presteady-state charge movements (Ki approximately 440 microM). Flufenamic acid exhibited little or no selectivity for GAT1, GAT2, or GAT3. Sodium and GABA concentration jicroumps revealed that slow Na+ binding to the transporter is followed by rapid GABA-induced translocation of the ligands across the plasma membrane. Thus, Na+ binding and associated conformational changes constitute the rate-limiting steps in the transport cycle.

Indications of coronary artery bypass graft in 2003.

UNLABELLED: During the last 3 decades, coronary artery bypass grafting (CABG) emerged, was developed and has progressed. Additionally, recent surgical innovations have been introduced aimed at reducing the trauma without deviating from the efficiency of conventional procedure. At the same time significant evolution in preventive, medical treatment and percutaneous procedures has been observed. The introduction of new treatment has improved the result in medically treated patients. Percutaneous procedures emerged and were developed. New technologies and advances available to adjunctive medical therapies have appeared and have impacted the effectiveness initially established for percutaneous coronary intervention (PCI). Larger use of stent permits a significant decrease in restenosis and the introduction of coated stent will probably improve the RESULTS: Indication is a moving field. Continuing improvement in medical treatment, technical procedure and development of less invasive surgery modifies the place of each treatment and continuing evaluation and comparison are necessary. Introduction of new treatment, aimed at treating ischemic cardiomyopathy like transmyocardial revascularization, cell transplantation or gene therapy will probably modify indications in the future.

Presteady-state and steady-state kinetics and turnover rate of the mouse gamma-aminobutyric acid transporter (mGAT3).

We expressed mouse gamma-aminobutyric acid (GABA) transporter (mGAT3) in Xenopus laevis oocytes and examined its steady-state and presteady-state kinetics and turnover rate by using tracer flux and electrophysiological methods. In oocytes expressing mGAT3, GABA evoked a Na+-dependent and Cl(-)-facilitated inward current. The dependence on Na+ was absolute, whereas that for Cl(-) was not. At a membrane potential of -50 mV, the half-maximal concentrations for Na+, Cl(-), and GABA were 14 mM, 5 mM, and 3 microM. The Hill coefficient for GABA activation and Cl(-) enhancement of the inward current was 1, and that for Na+ activation was > or =2. The GABA-evoked inward current was directly proportional to GABA influx (2.2 +/- 0.1 charges/GABA) into cells, indicating that under these conditions, there is tight ion/GABA coupling in the transport cycle. In response to step changes in the membrane voltage and in the absence of GABA, mGAT3 exhibited presteady-state current transients (charge movements). The charge-voltage (Q-V) relation was fitted with a single Boltzmann function. The voltage at half-maximal charge (V(0.5)) was +25 mV, and the effective valence of the moveable charge (zdelta) was 1.6. In contrast to the ON transients, which relaxed with a time constant of < or =30 msec, the OFF transients had a time constant of 1.1 sec. Reduction in external Na+ ([Na+]o) and Cl(-) ([Cl(-)]o) concentrations shifted the Q-V relationship to negative membrane potentials. At zero [Na+]o (106 mM Cl(-)), no mGAT3-mediated transients were observed, and at zero [Cl(-)]o (100 mM Na+), the charge movements decreased to approximately 30% of the maximal charge (Q(max)). GABA led to the elimination of charge movements. The half-maximal concentrations for Na+ activation, Cl(-) enhancement, and GABA elimination of the charge movements were 48 mM, 19 mM, and 5 mM, respectively. Q(max) and I(max) obtained in the same cells yielded the mGAT3 turnover rate, 1.7 sec(-1) at -50 mV. The low turnover rate of mGAT3 may be due to the slow return of the empty transporter from the internal to the external membrane surface.

Prognostic factors for the time of occurrence and dynamics of distant metastases and local recurrences after radical treatment in patients with rectal cancer.

BACKGROUND: A remarkable increase has been noted in the rate of incidence of rectal cancer. Post- or preoperative adjuvant treatment has significantly decreased the risk of local recurrence, but still only about 50% of all patients with rectal cancer treated radically can achieve a permanent cure. The majority of failures are due to distant metastases (DM) and/or local recurrences (LR). The risk and dynamics of failure after treatment of neoplasmtic disease has been analyzed on several occasions. MATERIAL AND METHODS: This retrospective study involved 161 consecutive patients with rectal cancer treated by radical surgery between 1972 and 1989. The mean age was 57 years. All patients underwent radical abdominoperineal rectum excision. The average follow-up was 10 years. In terms of the time elapsing to failure, the entire group of patients was divided into two subgroups: 'early' (occurring within 18 months after surgery) and 'late' (more than 18 months after surgery). RESULTS: The actuarial 5-year disease-free survival rate was 61.3%. Distant metastases occurred in 42 cases (26%), of whom 50% developed 'early' relapses, whereas local recurrences (29 cases - 18%) developed 'early' in 72% of the cases. Male gender was found to be an independent factor increasing the risk of 'early' relapses, particularly in the pN2 group. The stage of the disease is an indisputable risk factor for distant metastases and 'early' local recurrences. CONCLUSIONS: The time to failure varied significantly regarding local and distant relapses, suggesting different dynamics and origin. It seems that aggressive systemic and local treatment may decrease the incidence of relapses and improve long-term results. There is an urgent need to define new prognostic factors for identifying patients threatened by early dissemination.

Transport of L-carnitine in isolated cerebral cortex neurons.

The accumulation of carnitine was measured in cerebral cortex neurons isolated from adult rat brain. This process was found to be lowered by 40% after preincubation with ouabain and with SH-group reagents (N-ethylmaleimide and mersalyl). The initial velocity of carnitine transport was found to be inhibited by 4-aminobutyrate (GABA) in a competitive way (Ki = 20.9 +/- 2.4 mM). However, of various inhibitors of GABA transporters, only nipecotic acid and very high concentrations of 1-[2-([(diphenylmethylene)amino]oxy)ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride (NO-711) acid decreased carnitine accumulation while betaine, taurine and beta-alanine had no effect. The GABA transporters expressed in Xenopus laevis oocytes did not transport carnitine. Moreover, carnitine was not observed to diminish the accumulation of GABA in cerebral cortex neurons, which further excluded a possible involvement of the GABA transporter GAT1 in the process of carnitine accumulation, despite the expression of this protein in the cells under study. The absence of carnitine transporter OCTN2 in rat cerebral cortex neurons (K. A. Nalecz, D. Dymna, J. E. Mroczkowska, A. Broër, S. Broër, M. J. Nalecz and R. Cecchelli, unpublished results), together with the insensitivity of carnitine accumulation towards betaines, implies that a novel transporting protein is present in these cells.

Properties of the mammalian and yeast metal-ion transporters DCT1 and Smf1p expressed in Xenopus laevis oocytes.

Transition metals are essential for many metabolic processes, and their homeostasis is crucial for life. Metal-ion transporters play a major role in maintaining the correct concentrations of the various metal ions in living cells. Little is known about the transport mechanism of metal ions by eukaryotic cells. Some insight has been gained from studies of the mammalian transporter DCT1 and the yeast transporter Smf1p by following the uptake of various metal ions and from electrophysiological experiments using Xenopus laevis oocytes injected with RNA copies (c-RNA) of the genes for these transporters. Both transporters catalyze the proton-dependent uptake of divalent cations accompanied by a 'slippage' phenomenon of different monovalent cations unique to each transporter. Here, we further characterize the transport activity of DCT1 and Smf1p, their substrate specificity and their transport properties. We observed that Zn(2+) is not transported through the membrane of Xenopus laevis oocytes by either transporter, even though it inhibits the transport of the other metal ions and enables protons to 'slip' through the DCT1 transporter. A special construct (Smf1p-s) was made to enhance Smf1p activity in oocytes to enable electrophysiological studies of Smf1p-s-expressing cells. 54Mn(2+) uptake by Smf1p-s was measured at various holding potentials. In the absence of Na(+) and at pH 5.5, metal-ion uptake was not affected by changes in negative holding potentials. Elevating the pH of the medium to 6.5 caused metal-ion uptake to be influenced by the holding potential: ion uptake increased when the potential was lowered. Na(+) inhibited metal-ion uptake in accordance with the elevation of the holding potential. A novel clutch mechanism of ion slippage that operates via continuously variable stoichiometry between the driving-force pathway (H(+)) and the transport pathway (divalent metal ions) is proposed. The possible physiological advantages of proton slippage through DCT1 and of Na(+) slippage through Smf1p are discussed.

Personnel exposure during gamma endovascular brachytherapy.

PURPOSE: The use of 192Ir brachytherapy for the treatment of in-stent restenosis of the coronary arteries has shown promising clinical results. This paper investigates the radiation exposure of catheterization laboratory staff associated with the performance of this procedure. METHODS AND MATERIALS: Cath lab staff were monitored using personal monitors (shielded against fluoroscopic x-rays) during the performance of eleven cases using nominal 10 GBq 192Ir sources. Staff positions in the lab were simultaneously tracked by video cameras. Direct measurements were also made using a survey meter. Treatments were administered in a conventional cardiac-catheterization-laboratory. RESULTS: The dosimeter readings were analyzed in combination with the radiation survey and time motion survey. Brachytherapy procedural times for the cardiologist, oncologist, physicist, and angiographic assistants were, respectively, 26 +/- 24, 401 +/- 132, 486 +/- 148, and 7 +/- 13 s per case (mean +/- standard deviation). Readings of the personnel monitors were low. Credible upper limits of the respective doses are estimated to be less than 10, 10, 7, and 5 microSv per procedure. Auxiliary shields reduced the dose to individuals located outside of the catheterization laboratory to less than 0.5 microSv per procedure. CONCLUSIONS: The average radiation dose received by laboratory personnel during a representative 192Ir endocoronary brachytherapy procedure is estimated to be less than 0.1% of the NCRP recommended annual radiation worker's Maximum Permissible Dose (1% of the general public's MPD). This level is justifiable as long as the use of 192Ir benefits patients by producing an improved clinical outcome relative to the use of a less penetrating radionuclide or the application of alternative therapies. Further optimization of the delivery procedure is expected to reduce staff dose.

The clinical and hemodynamic effects of coenzyme Q10 in congestive cardiomyopathy.

Despite major advances in treatment congestive heart failure (CHF) is still one of the major causes of morbidity and mortality. Coenzyme Q(10) is a naturally occurring substance that has antioxidant and membrane stabilizing properties. Administration of coenzyme Q(10) in conjunction with standard medical therapy has been reported to augment myocardial kinetics, increase cardiac output, elevate the ischemic threshold, and enhance functional capacity in patients with congestive heart failure. The aim of this study was to investigate some of these claims. Seventeen patients (mean New York Heart Association functional class 3.0 +/- 0.4) were enrolled in an open-label study. After 4 months of coenzyme Q ( 10 ) therapy, functional class improved 20% (3.0 +/- 0.4 to 2.4 +/- 0.6, p < 0.001) and there was a 27% improvement in mean CHF score (2.8 +/- 0.4 to 2.2 +/- 0.4, p < 0.001). Percent change in the resting variables included the following: left ventricular ejection fraction (LVEF), +34.8%; cardiac output, +15.7%; stroke volume index, +18.9%; end-diastolic volume area, -8.4%; systolic blood pressure (SBP), -4. 4%; and E (max), (SBP / end-systolic volume index [ESVI]) +11.7%. MVo ( 2 ) decreased by 5.3% (31.9 +/- 2.6 to 30.2 +/- 2.4, p = NS). Therapy with coenzyme Q(10) was associated with a mean 25.4% increase in exercise duration and a 14.3% increase in workload. Percent changes after therapy include the following: exercise LVEF, +24.6%; cardiac output, +19.1%; stroke volume index, +13.2%; heart rate, +6.5%; SBP, -4.3%; SBP / ESVI, +18.6%; end-diastolic volume (EDV) area, -6.0%; MVo (2), -7.0%; and ventricular compliance (%Delta SV / EDV) improved >100%. In summary, coenzyme Q(10) therapy is associated with significant functional, clinical, and hemodynamic improvements within the context of an extremely favorable benefit-to-risk ratio. Coenzyme Q(10) enhances cardiac output by exerting a positive inotropic effect upon the myocardium as well as mild vasodilatation.

The standardized diagnosis of autism, Autism Diagnostic Interview-Revised: interrater reliability of the German form of the interview.

The feasibility and reliability of the German form of the revised parental interview to diagnose autism (Autism Diagnostic Interview-Revised, ADI-R) was investigated in this study. Brief examples of the description of formerly and currently used diagnostic guidelines are given and the outline of the interview algorithm which establishes thresholds for inclusion criteria. An excellent-to-good reliability could be demonstrated for the main symptoms according to the classification rules of the ICD-10 and DSM-IV for a sample of autistic subjects at different ages and intellectual levels. The results approve the use of this interview for research and clinical purposes.

First-pass radionuclide cineangiography in diagnosis of coronary artery disease in patients older than 75 years: evaluation of sensitivity.

The sensitivity of first-pass radionuclide cineangiography in the detection of coronary artery disease was evaluated in 60 patients subdivided equally according to age younger than or older than 75 years. The mean age of group 1 (age > or = 75 years) was 80.2 years +/- 5.3, and the mean age in group 2 (age < 75 years) was 62.0 years +/- 6.4. Disease prevalence in group 1 was 87% versus 80% in group 2. Group 1 had higher prevalence of hypertension (67% vs 33%) and lower prevalence of typical angina pectoris (23% vs 55%). Overall sensitivity of first-pass radionuclide cineangiography in group 1 was 93% versus 97% in group 2. Older patients had significantly lower maximal heart rates, workloads, and exercise durations, and age correlations were significant for exercise heart rate, workload, and exercise duration. Failure to achieve an adequate exercise endpoint had significant effect on testing sensitivity only in the younger subjects (98% vs 60%), indicating that sensitivity of first-pass radionuclide cineangiography is age independent.