Validation of the ANDON KD-595 automated upper-arm blood pressure monitor according to the universal standard.

OBJECTIVE: To validate the ANDON KD-595 automated upper-arm blood pressure monitor for clinical use and self-measurement blood pressure measurement according to the Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization (AAMI/ESH/ISO) Universal Standard. METHODS: Same left-arm blood pressure was sequentially measured in 90 qualified adult participants and compared with a standard mercury sphygmomanometer. A total of 270 comparison pairs were obtained and analyzed according to the universal standard. RESULTS: For the validation Criterion 1 of the universal standard, the mean ± SD of the differences between the test device and reference blood pressure readings was 0.96 ±â€…5.35 and 0.82 ±â€…5.08 mmHg for SBP and DBP, respectively. For Criterion 2, the SDs of the averaged blood pressure differences between the test device and reference blood pressure per subject were 4.84 and 4.64 mmHg (with maximum allowed SDs of 6.87 and 6.89 mmHg) for SBP and DBP, respectively. CONCLUSION: The ANDON KD-595 automated upper-arm blood pressure monitor passed all the validation requirements according to the AAMI/ESH/ISO Universal Standard and can be recommended for clinical use and self-measurement blood pressure measurement in the general population.

Validation of the Wellvii VitalDetect blood pressure monitor in general population according to the International Standardization Organization 81060-2:2018.

OBJECTIVE: To evaluate the accuracy of the Wellvii VitalDetect automated oscillometric finger blood pressure monitor (single cuff size) for self/home blood pressure measurement according to the AAMI/ESH/ISO Universal Standard (ISO 81060-2:2018). METHODS: According to the universal standard, a total of 92 participants were recruited and finally blood pressure of 85 eligible participants was sequentially measured and compared with a standard mercury sphygmomanometer. RESULTS: A total of 255 comparison pairs were obtained and analyzed based on the universal standard. For the validation criterion 1 of the ISO 81060-2:2018 universal standard, the mean ± SD of the differences between the test device and reference blood pressure readings was 1.66 ±â€…7.67 and 1.04 ±â€…6.45 mmHg for systolic and diastolic blood pressure, respectively. For criterion 2, the SD of the averaged blood pressure differences between the test device and reference blood pressure per subject was ± 6.49 mmHg (pass ≤ 6.73 mmHg) and ± 5.67 mmHg (pass ≤ 6.86 mmHg) for systolic and diastolic blood pressure, respectively. CONCLUSION: The Wellvii VitalDetect automated finger blood pressure monitor passed all the requirements for validation by the ISO 81060-2:2018 universal standard and can be recommended for self/home blood pressure measurement in general population.

Treatment with a flow diverter-assisted coil embolization for ruptured blood blister-like aneurysms of the internal carotid artery: a technical note and analysis of single-center experience with pooled data.

Treatment of blood blister-like aneurysms (BBAs) of the supraclinoid internal carotid artery (ICA) with flow diverters (FDs) has become widespread in recent years. However, ruptured blood blister-like aneurysm (BBA) of ICA treatment with flow diverter-assisted coil embolization (FDAC) remains controversial. Moreover, limited direct comparative studies have been conducted between the two treatment modalities, FDs and FDAC, for BBAs. The purpose of this study was to document our experience and evaluate the effectiveness and safety of FDAC. We conducted a retrospective analysis of clinical and radiological information from ten patients who experienced ruptured BBAs of the supraclinoid ICA at our center from January 2021 to February 2023. The technical details of FDAC for ruptured BBAs were described, and the technical steps were named "pipeline embolization device (PED)-Individualized shaping(microcatheter)-Semi deploying-Rivet(coils)-Massage(microwire)" as the PEISSERM technique. Clinical outcomes were assessed using the modified Rankin Scale (mRS), whereas radiological results were determined through angiography. A pooled analysis was implemented, incorporating data from literature sources that reported perioperative and long-term clinical and angiographic outcomes of ruptured BBAs treated with FD and FDAC strategies, along with our data. Data in our analysis pool were categorized into FD and FDAC strategy groups to explore the preferred treatment modalities for BBAs. The PEISSERM technique was utilized to treat ten patients, seven males, and three females, with an average age of 41.7 years. A single PED was deployed in conjunction with coils in all ten patients. All PEDs were documented to have good wall apposition. The immediate postoperative angiograms demonstrated Raymond grade I in ten aneurysms. Angiographic follow-up of nine patients at 4-25 months showed total occlusion of the aneurysms. At the most recent follow-up, the mRS scores of nine patients hinted at a good prognosis. Pooled analysis of 233 ICA-BBA cases of FD revealed a technical success rate of 91% [95% confidence interval (CI), 0.88 to 0.95], a rate of complete occlusion of 79% (95% CI, 0.73 to 0.84), a recurrence rate of 2% (95% CI, 0.00 to 0.04), a rebleed rate of 2% (95% CI, 0.00 to 0.04), and the perioperative stroke rate was 8% (95% CI, 0.04 to 0.11). The perioperative mortality was 4% (95% CI, 0.01 to 0.07). The long-term good clinical outcome rate was 85% (95% CI, 0.80 to 0.90). The mortality rate was 6% (95% CI, 0.03 to 0.09). Results from the subgroup analysis illustrated that the FDAC strategy for BBAs had a significantly higher immediate postoperative complete occlusion rate (P < 0.001), total occlusion rate (P = 0.016), and a good outcome rate (P = 0.041) compared with the FD strategy. The FDAC strategy can yield a higher rate of good outcomes than the FD strategy. The PEISSERM technique employed by the FDAC is a reliable and effective treatment approach as it can minimize the hemodynamic burden of BBA's fragile dome, thereby achieving an excellent occlusion rate. The PEISSERM technique in the FDAC strategy contributes to understanding the BBA's treatment and offers a potentially optimal treatment for BBA.

Diagnostic accuracy of an oscillometric blood pressure monitor for atrial fibrillation screening.

OBJECTIVE: Atrial fibrillation is the most common arrhythmia of clinical significance and hypertension is one of its major risk factors. This study aimed to evaluate the diagnostic accuracy of an automated oscillometric blood pressure (BP) monitor with the function of atrial fibrillation detection for atrial fibrillation screening. MATERIALS AND METHODS: Patients attending outpatient cardiology clinics were recruited for atrial fibrillation screening by the BP monitor with triplicate BP measurements for atrial fibrillation detection. Furthermore, a single-lead ECG was recorded simultaneously for comparison as the reference standard. The diagnostic test's evaluation index were analyzed, including sensitivity, specificity, and receiver operator characteristic (ROC) analysis. RESULTS: A total of 295 participants were analyzed including 166 males and 129 females, with an average age of 72.5 ±â€…5.9 years. The sensitivity and specificity for atrial fibrillation detection by the device were 1.000 and 0.904, respectively, with the area under the ROC curve of 0.952 (95% confidence interval: 0.929-0.975, P  < 0.001). Furthermore, the device had a Kappa-value of 0.781 ( P  < 0.001) with the single-lead ECG in detecting atrial fibrillation. CONCLUSION: The automated oscillometric BP monitor (G.LAB MD41A0) with atrial fibrillation detection function has high sensitivity and specificity with good accuracy for atrial fibrillation screening, which could be used as a reliable screening tool for the early detection of atrial fibrillation with potential benefits.

A Tuned Microwave Resonant System for Subcutaneous Imaging.

A compact and planar imaging system was developed using a flexible polymer substrate that can distinguish subcutaneous tissue abnormalities, such as breast tumors, based on electromagnetic-wave interactions in materials where permittivity variations affect wave reflection. The sensing element is a tuned loop resonator operating in the industrial, scientific, and medical (ISM) band at 2.423 GHz, providing a localized high-intensity electric field that penetrates into tissues with sufficient spatial and spectral resolutions. The resonant frequency shifts and magnitudes of the reflection coefficients indicate the boundaries of abnormal tissues under the skin due to their high contrasts to normal tissues. The sensor was tuned to the desired resonant frequency with a reflection coefficient of -68.8 dB for a radius of 5.7 mm, with a tuning pad. Quality factors of 173.1 and 34.4 were achieved in simulations and measurements in phantoms. An image-processing method was introduced to fuse raster-scanned 9 × 9 images of resonant frequencies and reflection coefficients for image-contrast enhancement. The results showed a clear indication of the tumor's location at a depth of 15 mm and the capability to identify two tumors both at the depth of 10 mm. The sensing element can be expanded to a four-element phased array for deeper field penetration. Field analysis showed the depths of -20 dB attenuation were improved from 19 to 42 mm, giving wider coverage in tissues at resonance. Results showed that a quality factor of 152.5 was achieved and a tumor could be identified at a depth of up to 50 mm. In this work, simulations and measurements were conducted to validate the concept, showing great potential for subcutaneous imaging in medical applications in a noninvasive, efficient, and lower-cost way.

Causal association between cardiovascular diseases and erectile dysfunction, a Mendelian randomization study.

Background: Cardiovascular diseases (CVD), including coronary heart disease (CHD), heart failure, ischemic heart disease (IHD), and atrial fibrillation, are prevalent in the aged. However, the influence of CVD on ED is less investigated. This study was performed to clarify the causal association between CVD and ED. Materials and methods: Genome-wide association studies (GWAS) datasets targeting CHD, heart failure, IHD, and atrial fibrillation were downloaded to retrieve single nucleotide polymorphisms (SNPs). Further, single-variable Mendelian randomization and multivariable Mendelian randomization (MVMR) were adopted to explore the causal association between CVD and ED. Results: Genetically predicted CHD and heart failure were found to increase the risks of ED (OR = 1.09, P < 0.05 and OR = 1.36, P < 0.05, respectively). However, no causal association was disclosed among IHD, atrial fibrillation and ED (all P > 0.05). These findings remained consistent in sensitivity analyses. After controlling for body mass index, alcohol, low density lipoprotein, smoking and total cholesterol levels, the results of MVMR support the causal role of CHD on ED (P < 0.05). Similarly, the direct causal effect estimates of heart failure on ED were significant in MVMR analyses (P < 0.05). Conclusion: Using genetic data, this study revealed that genetically predicted CHD and heart failure may predict better ED compared with atrial fibrillation and IHD. The results should be interpreted with caution and the insignificant causal inference of IHD still needs further verification in future studies.

Microcatheter-guided compartment packing of acutely ruptured complex intracerebral aneurysms (ARCIAs): Preliminary experience and technical note.

Objective: We present our initial experience using the microcatheter-guided compartment packing (MCP) technique for endovascular embolization of acutely ruptured complex intracerebral aneurysms (ARCIAs) and evaluate the safety, feasibility, and efficiency of this technique. Methods: This retrospective, single-center study included 28 patients who underwent coil embolization using the MCP technique for ARCIAs at our institution between January 2021 and January 2022. The MCP technique was the placement of microcatheters in different compartments within the aneurysm to deploy the coils simultaneously or sequentially. Patient demographics, aneurysm characteristics, procedural parameters, grade of occlusion, complications, and clinical results were analyzed. The clinical outcomes were evaluated with modified Rankin Scale (mRS) scores. Results: Of the 28 patients successfully treated with the MCP technique, 24 (85.7%) aneurysms were considered as complete occlusions (Raymond I) based on the immediate postembolization angiogram results. Complications occurred in 2/28 treatments, including guidewire perforation with subarachnoid hemorrhage and cerebral vasospasm-related cerebral infarction. An angiography follow-up demonstrated complete occlusion in 25/28 aneurysms. Twenty-six (92.9%) patients had favorable 90-day outcomes (mRS 0-2) after the endovascular coil embolization. Conclusion: The MCP technique is simple, safe, and effective, achieving good packing density and initial occlusion rate when used to treat ARCIAs.

BsTup1 is required for growth, conidiogenesis, stress response and pathogenicity of Bipolaris sorokiniana.

Tup1, a conserved transcriptional repressor, plays a critical role in the growth and development of fungi. Here, we identified a BsTup1 gene from the plant pathogenic fungus Bipolaris sorokiniana. The expression of BsTup1 showed a more than three-fold increase during the conidial stage compared with mycelium stage. Deletion of BsTup1 led to decrease hyphal growth and defect in conidia formation. A significant difference was detected in osmotic, oxidative, or cell wall stress responses between the WT and ΔBsTup1 strains. Pathogenicity assays showed that virulence of the ΔBsTup1 mutant was dramatically decreased on wheat and barely leaves. Moreover, it was observed that hyphal tips of the mutants could not form appressorium-like structures on the inner epidermis of onion and barley coleoptile. Yeast two-hybrid assays indicated that BsTup1 could interact with the BsSsn6. RNAseq revealed significant transcriptional changes in the ΔBsTup1 mutant with 2369 genes down-regulated and 2962 genes up-regulated. In these genes, we found that a subset of genes involved in fungal growth, sporulation, cell wall integrity, osmotic stress, oxidation stress, and pathogenicity, which were misregulated in the ΔBsTup1 mutant. These data revealed that BsTup1 has multiple functions in fungal growth, development, stress response and pathogenesis in B. sorokiniana.

A Resonant Coupler for Subcutaneous Implant.

A resonator coupler for subcutaneous implants has been developed with a new impedance matching pattern added to the conventional loop antenna. The tuning element of a concentric metal pad contributes distributed capacitance and inductance to the planar inductive loop and improves resonance significantly. It provides a better qualify factor for resonant coupling and a much lower reflection coefficient for the implant electronics. Practical constraints are taken into account for designs including the requirement of operation within a regulated frequency band and the limited thickness for a monolithic implant. In this work, two designs targeting to operate in the two industrial, scientific, and medical (ISM) bands at 903 MHz and 2.45 GHz are considered. The tuning metal pad improves their resonances significantly, compared to the conventional loop designs. Since it is difficult to tune the implant antenna after implantation, the effects of tissue depth variations due to the individual's surgery and the appropriate implant depths are investigated. Simulations conducted with the dielectric properties of human skin documented in the literature are compared to measurements done with hydrated ground pork as phantoms. Experiments and simulations are conducted to explain the discrepancies in frequency shifts due to the uses of pork phantoms. The design method is thus validated for uses on human skin. A noninvasive localization method to identify the implant under the skin has been examined and demonstrated by both simulations and measurements. It can efficiently locate the subcutaneous implant based on the high quality-factor resonance owing to the tuning elements in both implant and transmitter couplers. The planar resonant coupler for wireless power transfer shows good performance and promise in subcutaneous applications for implants.

A Novel Titanium Cranioplasty Technique of Marking the Coronal and Squamosoparietal Sutures in Three-Dimensional Titanium Mesh as Anatomical Positioning Markers to Increase the Surgical Accuracy and Reduce Postoperative Complications.

Objective: The objective of this research is to modify the titanium cranioplasty (Ti-CP) technique to increase the surgical accuracy and preliminarily verify the effectiveness and safety of this improvement. Methods: We developed a novel technique of marking the coronal and squamosoparietal sutures in three-dimensional (3D) titanium mesh as anatomical positioning markers and designed a prospective trial in patients with a unilateral frontotemporoparietal skull defect. Patients were randomly divided into two groups by the presence or absence of the anatomical positioning markers, and the therapeutic effects of these two groups were compared. Results: Forty-four patients were included in this study, including 28 (64%) males and 16 (36%) females. The mean age was 44.8 ± 15.2 years (range, 13-75 years). Overall postoperative complication rate of the intervention group (18%) was significantly (P = 0.03) lower than the control group (50%). Surgical accuracy of the intervention group (97.8%) was significantly (P < 0.001) higher than the control group (94%). Visual analog scale for cosmesis (VASC) of the intervention group (8.4) was significantly (P < 0.001) higher than the control group (7). The overall postoperative complication rate was 34%. Multivariate analyses showed that surgical accuracy <95.8% (OR = 19.20, 95% CI = 3.17-116.45, P = 0.001) was significantly associated with overall postoperative complications. Independent predictor of overall postoperative complications was surgical accuracy (OR = 0.57, 95% CI = 0.40-0.82, P = 0.002). Conclusions: This novel technique for repairing frontotemporoparietal skull defects increases surgical accuracy, improves cosmetic prognosis, and reduces postoperative complications. Therefore, it is a safe and effective improvement for Ti-CP.

Effects of Leisure Obstacles, Job Satisfaction, and Physical and Mental Health on Job Intentions of Medical Workers Exposed to COVID-19 Infection Risk and Workplace Stress.

The purpose of this study was to investigate the effects of leisure obstacles, job satisfaction, physical and mental health, and work intentions of medical workers in Taiwan. SPSS 26.0 and AMOS 24.0 statistical software were used to analyze 208 questionnaires by basic statistical tests, t-tests, and structural model analysis. Results: Under the epidemic, medical workers were unable to develop job identity due to low promotion opportunities and low job achievement. The lack of recreational exercise skills, time, and information created leisure obstacles. In addition, they were unable to express their true selves freely at work, which led to health problems such as reduced enthusiasm, mental weakness, and emotional irritability. In particular, female medical workers felt more strongly about the issues of leisure obstacles and the intention to stay in their jobs. The study found that the higher their job satisfaction, the higher their intention to stay in the job, while the more pronounced the leisure obstacles and physical and mental health problems, the more pronounced their intention to leave.

MiRNA-seq-based profiles of miRNAs in mulberry phloem sap provide insight into the pathogenic mechanisms of mulberry yellow dwarf disease.

A wide range of miRNAs have been identified as phloem-mobile molecules that play important roles in coordinating plant development and physiology. Phytoplasmas are associated with hundreds of plant diseases, and the pathogenesis involved in the interactions between phytoplasmas and plants is still poorly understood. To analyse the molecular mechanisms of phytoplasma pathogenicity, the miRNAs profiles in mulberry phloem saps were examined in response to phytoplasma infection. A total of 86 conserved miRNAs and 19 novel miRNAs were identified, and 30 conserved miRNAs and 13 novel miRNAs were differentially expressed upon infection with phytoplasmas. The target genes of the differentially expressed miRNAs are involved in diverse signalling pathways showing the complex interactions between mulberry and phytoplasma. Interestingly, we found that mul-miR482a-5p was up-regulated in the infected phloem saps, and grafting experiments showed that it can be transported from scions to rootstock. Based on the results, the complexity and roles of the miRNAs in phloem sap and the potential molecular mechanisms of their changes were discussed. It is likely that the phytoplasma-responsive miRNAs in the phloem sap modulate multiple pathways and work cooperatively in response to phytoplasma infection, and their expression changes may be responsible for some symptoms in the infected plants.

The Latex Protein MLX56 from Mulberry (Morus multicaulis) Protects Plants against Insect Pests and Pathogens.

Biotic stresses are major constraints limiting the leaf quality and productivity of mulberry. MLX56 is a unique chitin-binding protein isolated from Shin-Ichinose (Morus alba) latex that displays toxicity against lepidopteran caterpillars. In this study, the full-length cDNA encoding MLX56 was isolated from Husang 32 (M. multicaulis) and designated HMLX56. Amino acid sequence analysis and protein modeling of three MLX56 proteins showed that they were highly conserved among Morus species. Tissue expression pattern analysis showed that the HMLX56 gene was strongly expressed in mulberry bark and leaves but only slightly expressed in fruits. In addition, analysis of GUS expression indicated that the promoter of HMLX56 showed higher transcriptional activity along the vascular strands, and its activity can be regulated by various environmental factors. Like the MLX56 protein from M. alba, the HMLX56 protein showed toxicity to Plutella xylostella. Moreover, when the HMLX56 gene was ectopically expressed in Arabidopsis, the transgenic plants showed enhanced resistance to aphids, the fungal pathogen Botrytis cinerea and the bacterial pathogen Pseudomonas syringae pv. tomato DC3000. Our data suggest that the HMLX56 protein has a lectin-like molecular structure consisting of two hevein-like chitin-binding domains which provide not only chitin-binding activities but also other mechanisms of defense. The information provided here improves our understanding of the potential functions and defense mechanisms of MLX56 proteins, enabling in-depth functional analysis of latex exudates and perhaps facilitating mulberry genetic improvement in the future.

Validation of the Grandway MD2301 digital automatic blood pressure monitor according to the European Society of Hypertension International Protocol.

OBJECTIVE: The aim of the present study was to validate the Grandway MD2301 digital automatic blood pressure monitor according to the European Society of Hypertension International Protocol (ESH-IP) revision 2010. METHODS: The ESH-IP revision 2010 for the validation of blood pressure-measuring devices in adults was followed precisely. Systolic and diastolic blood pressure (SBP and DBP, respectively) were measured sequentially in 33 adult patients and compared with a standard mercury sphygmomanometer (two observers). A total of 99 comparison pairs were obtained. RESULTS: The device produced 78, 95 and 99 measurements within 5, 10, and 15 mmHg for SBP and 83, 96, and 99 for DBP, respectively. The average device-observer difference was -1.81±4.22 mmHg for SBP and -0.15±3.93 mmHg for DBP. All of the data were within the standards requirements to pass the testing. CONCLUSION: The Grandway MD2301 digital automatic blood pressure monitor meets the standards of the ESH-IP revision 2010 and can be recommended for self/home measurement in the general population.

Validation of the Microlife BP A200 Comfort and W2 Slim automated blood pressure monitors in a general adult population according to the European Society of Hypertension and the ANSI/AAMI/ISO 81060-2: 2013 protocols.

OBJECTIVE: This study aimed to determine the accuracy of the Microlife BP A200 Comfort and W2 Slim automated blood pressure monitors according to the European Society of Hypertension International Protocol revision 2010 and the ANSI/AAMI/ISO 81060-2:2013 protocols. METHODS: The devices were assessed on 33 participants according to the European Society of Hypertension requirements and were then tested on 85 participants according to the ANSI/AAMI/ISO 81060-2:2013 criteria. Procedures and data analysis were carried out following protocol guidelines precisely. RESULTS: The Microlife BP A200 Comfort and W2 Slim devices passed the criteria of the European Society of Hypertension International Protocol revision 2010 for both systolic blood pressure and diastolic blood pressure. The devices also fulfilled the ANSI/AAMI/ISO 81060-2:2013 criteria, with mean differences of SBP and DPB between the devices and observers of 0.38±5.12 and 0.28±4.29 mmHg for the BP A200 Comfort and 1.01±6.80 and 0.34±5.62 mmHg for the W2 Slim, respectively. CONCLUSION: The Microlife BP A200 Comfort and W2 Slim automated blood pressure monitors fulfilled the European Society of Hypertension revision 2010 and the ANSI/AAMI/ISO 81060-2:2013 protocols, and can be recommended for self-measurement in the general population.

Phosphate-modified carbon nanotubes in the oxidative dehydrogenation of isopentanes.

Ketonic/quinonic C=O groups on the surface of a carbon matrix are capable of abstracting hydrogen in C=H bonds from hydrocarbons and enable them to selectively convert into corresponding unsaturated hydrocarbons; this process is the oxidative dehydrogenation (ODH) reaction. However, a variety of inevitable defects or graphene edges and other oxygen-containing groups on the carbon matrix are detrimental to the selective production of alkenes due to their high activity towards overoxidation. Herein, we show that phosphate can not only impede the total oxidation but also cover the selective C=O groups, hence allowing its use as a modulator to defects and oxygen-containing functional groups on the multiwalled carbon nanotubes, regulating the distribution of active sites and related catalytic targets.

Validation of the Pangao PG-800B11 blood pressure monitor according to the European Society of Hypertension and the British Hypertension Society protocols.

OBJECTIVE: The study aimed to determine the accuracy of the fully automated oscillometric upper-arm blood pressure (BP) monitor Pangao PG-800B11 according to the European Society of Hypertension-International Protocol (ESH-IP) revision 2010 and the British Hypertension Society (BHS) protocol 1993. MATERIALS AND METHODS: Data from 33 participants were initially examined according to the ESH-IP revision 2010. Furthermore, 52 participants were then enrolled to fulfill the BHS protocol requirements. In all participants, sequential left arm measurements were performed by two trained observers using a mercury sphygmomanometer and one supervisor using the device. The protocols' requirements were followed precisely. RESULTS: The device passed all parts of the ESH protocol for systolic blood pressure (SBP) and diastolic blood pressure (DBP) and was graded A according to the criteria of the BHS protocol for both SBP and DBP. The A/A grade was achieved in low (<130/80 mmHg), medium (130-160/80-100 mmHg), and high (>160/100 mmHg) BP categories. The mean BP difference between PG-800B11 and observers in the 85 participants was -0.6±5.0 mmHg for SBP and -0.6±4.5 mmHg for DBP; thus, the device also fulfilled the requirements of the Association for the Advancement of Medical Instrumentation (AAMI). CONCLUSION: The Pangao PG-800B11 passed all requirements of the ESH-IP revision 2010 and achieved A/A grade of the BHS protocol across a wide range of BPs.

A phase I study of prolonged infusion of triapine in combination with fixed dose rate gemcitabine in patients with advanced solid tumors.

PURPOSE: Prolonged exposure of cancer cells to triapine, an inhibitor of ribonucleotide reductase, followed by gemcitabine enhances gemcitabine activity in vitro. Fixed-dose-rate gemcitabine (FDR-G) has improved efficacy compared to standard-dose. We conducted a phase I trial to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of prolonged triapine infusion followed by FDR-G. EXPERIMENTAL DESIGN: Triapine was given as a 24-hour infusion, immediately followed by FDR-G (1000 mg/m(2) over 100-minute). Initially, this combination was administered days 1 and 8 of a 21-day cycle (Arm A, triapine starting dose 120 mg); but because of myelosuppression, it was changed to days 1 and 15 of a 28-day cycle (Arm B, starting dose of triapine 75 mg). Triapine steady-state concentrations (Css) and circulating ribonucleotide reductase M2-subunit (RRM2) were measured. RESULTS: Thirty-six patients were enrolled. The MTD was determined to be triapine 90 mg (24-hour infusion) immediately followed by gemcitabine 1000 mg/m(2) (100-minute infusion), every 2 weeks of a 4-week cycle. DLTs included grade 4 thrombocytopenia, leukopenia and neutropenia. The treatment was well tolerated with fatigue, nausea/vomiting, fever, transaminitis, and cytopenias being the most common toxicities. Among 30 evaluable patients, 1 had a partial response and 15 had stable disease. Triapine PK was similar, although more variable, compared to previous studies using doses normalized to body-surface-area. Steady decline in circulating levels of RRM2 may correlate with outcome. CONCLUSIONS: This combination was well tolerated and showed evidence of preliminary activity in this heavily pretreated patient population, including prior gemcitabine failure.

A dose escalation and pharmacodynamic study of triapine and radiation in patients with locally advanced pancreas cancer.

PURPOSE: Triapine, a novel inhibitor of the M2 subunit of ribonucleotide reductase (RR), is a potent radiosensitizer. This phase 1 study, sponsored by the National Cancer Institute Cancer Therapy Evaluation Program, assessed the safety and tolerability of triapine in combination with radiation (RT) in patients with locally advanced pancreas cancer (LAPCA). METHODS AND MATERIALS: We evaluated 3 dosage levels of triapine (24 mg/m2, 48 mg/m2, 72 mg/m2) administered with 50.4 Gy of RT in 28 fractions. Patients with LAPCA received triapine thrice weekly, every other week during the course of RT. Dose-limiting toxicity (DLT) was assessed during RT and for 4 weeks after its completion. Dynamic contrast-enhanced magnetic resonance imaging and serum RR levels were evaluated as potential predictors for early response. RESULTS: Twelve patients were treated. Four patients (1 nonevaluable) were enrolled at dosage level 1 (DL1), 3 patients at DL2, and 5 patients (2 nonevaluable) at DL3. No DLTs were observed, and the maximum tolerated dose was not reached. Two patients (17%) achieved partial response, and 6 patients (50%) had stable disease. One patient underwent R0 resection after therapy. Ninety-two percent of patients (100% at DL3) experienced freedom from local tumor progression. In 75% of patients who eventually experienced progression, metastases developed without local progression. RR levels did not seem to predict outcome. In 4 patients with available data, dynamic contrast-enhanced magnetic resonance imaging may predict early response or resistance to therapy. CONCLUSION: The combination of triapine at 72 mg/m2 3 times weekly every other week and standard RT is tolerable with interesting activity in patients with LAPCA.