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This retrospective analysis reports the mid-term (>2 years) outcomes of capsulodesis, (modified) Brunelli tenodesis and bone-ligament-bone reconstruction for scapholunate ligament instability. In total, 60 patients (64 wrists) returned the Patient-Rated Wrist Evaluation and Disabilities of the Arm, Shoulder, and Hand questionnaires. Of these participants, 42 (46 wrists) returned for a wrist examination and radiographs. In the questionnaire group, the mean follow-up for capsulodesis was 11.8 years, tenodesis 5.9 years and bone-ligament-bone 8.9 years. In the objective outcomes group, the mean follow-up was 10.2 years for capsulodesis, 5.7 for tenodesis and 8.9 for bone-ligament-bone. In all groups, some patients showed radiographic deterioration, which did not always correlate with poor functional outcome. With a mean follow-up greater than 5 years, there was no substantial difference in clinical outcomes and patient-based outcome questionnaires between capsulodesis, tenodesis or bone-ligament-bone reconstruction for the treatment of scapholunate instability. This study emphasizes the need for further research. Surgeons should use the technique that produces the fewest complications. Level of evidence III., Competing Interests: Declaration of conflicting interestsThe authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

This study described the challenges, personal goals, and interventions of patients with lymphoma in various domains of life that emerged from an aftercare consultation based on shared decision-making principles with a nurse practitioner. A cross-sectional exploratory design was used with a sample of 49 patients. Challenges, goals, and interventions were measured based on 4 domains of life: "my health," "my activities," "my environment" and "my own way." Most challenges were experienced in the domain of "my health," which included a loss of physical condition, reduced muscle strength, and fatigue. Patients set personal goals related to the experienced challenges, such as restoring physical condition to prediagnosis levels. Accordingly, 45 patients (84%) chose an intervention to improve physical condition and muscle strength and 33 patients (67%) chose to be referred to specialized care., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background  Scapholunate (SL) ligament injuries are rarely diagnosed in children. This study reports the outcomes of surgically treated SL ligament injuries in patients younger than 18 years. Methods  A retrospective review was performed on 20 pediatric patients with SL ligament injuries. Records were reviewed for preoperative and postoperative radiographic data, intraoperative findings, classifications of interosseous ligament injury, and postoperative course. Results  Thirteen girls and seven boys sustained SL injuries requiring operative intervention and were followed for an average of 26 months. Magnetic resonance imaging (MRI) was performed in 15 patients, which revealed an SL tear in 7 patients. Arthroscopically, SL injuries were classified as Geissler grade III in 12 patients and grade IV in 5 patients. Based on the Mayo Wrist Score, nine patients had excellent or good results, while six demonstrated fair results. The mean wrist flexion-extension arc was 109 degrees, while the mean grip strength was 82% of the unaffected side. Patients treated >1 year following injury had significantly decreased grip strength and Mayo Wrist Score. Conclusion  In this study, worse results were seen in children with a protracted course prior to treatment of an SL injury. A high index of suspicion is necessary to detect an SL injury in the younger age group and should be in the differential for those with persistent dorsal wrist pain, tenderness over the dorsal SL joint, and/or positive Watson's test. MRI may assist in diagnosis but is not definitive to rule out injury. Arthroscopy is valuable to determine the extent of injury., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU). Genetic variations in DPD have emerged as predictive risk factors for severe fluoropyrimidine toxicity. Here, we report novel and rare genetic variants underlying DPD deficiency in 9 cancer patients presenting with severe fluoropyrimidine-associated toxicity. All patients possessed a strongly reduced DPD activity, ranging from 9 to 53% of controls. Analysis of the DPD gene (DPYD) showed the presence of 21 variable sites including 4 novel and 4 very rare aberrations: 3 missense mutations, 2 splice-site mutations, 1 intronic mutation, a deletion of 21 nucleotides and a genomic amplification of exons 9-12. Two novel/rare variants (c.2843T>C, c.321+1G>A) were present in multiple, unrelated patients. Functional analysis of recombinantly-expressed DPD mutants carrying the p.I948T and p.G284V mutation showed residual DPD activities of 30% and 0.5%, respectively. Analysis of a DPD homology model indicated that the p.I948T and p.G284V mutations may affect electron transfer and the binding of FAD, respectively. cDNA analysis showed that the c.321+1G>A mutation in DPYD leads to skipping of exon 4 immediately upstream of the mutated splice-donor site in the process of DPD pre-mRNA splicing. A lethal toxicity in two DPD patients suggests that fluoropyrimidines combined with other therapies such as radiotherapy might be particularly toxic for DPD deficient patients. Our study advocates a more comprehensive genotyping approach combined with phenotyping strategies for upfront screening for DPD deficiency to ensure the safe administration of fluoropyrimidines., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Inhibition of B-cell receptor (BCR) signaling pathways in chronic lymphocytic leukemia (CLL) provides significant clinical benefit to patients, mainly by blocking adhesion of CLL cells in the lymph node microenvironment. The currently applied inhibitors ibrutinib and idelalisib have limited capacity however to induce cell death as monotherapy and are unlikely to eradicate the disease. Acquired resistance to therapy in CLL is often caused by mutations in the response network being targeted, both for DNA damage or BCR signaling pathways. Thus, drugs with dual targeting capacity could offer improved therapeutic value. Here, the potency of CC-115, a novel inhibitor of mammalian target of rapamycin kinase (TORK) and DNA-dependent protein kinase (DNA-PK), was evaluated in primary CLL cells in vitro and in CLL patients. Combined TORK and DNA-PK inhibition in vitro resulted in caspase-dependent cell killing irrespective of p53, ATM, NOTCH1, or SF3B1 status. Proliferation induced by CD40(+) interleukin-21 stimulation was completely blocked by CC-115, and CD40-mediated resistance to fludarabine and venetoclax could be reverted by CC-115. BCR-mediated signaling was inhibited by CC-115 and also in CLL samples obtained from patients with acquired resistance to idelalisib treatment. Clinical efficacy of CC-115 was demonstrated in 8 patients with relapsed/refractory CLL/small lymphocytic lymphoma harboring ATM deletions/mutations; all but 1 patient had a decrease in lymphadenopathy, resulting in 1 IWCLL partial response (PR) and 3 PRs with lymphocytosis. In conclusion, these preclinical results, along with early promising clinical activity, suggest that CC-115 may be developed further for treatment of CLL. The trial was registered at www.clinicaltrials.gov as #NCT01353625., (© 2016 by The American Society of Hematology.)

Introduction: We assessed the incidence and timing of first cardiac events, impact on trastuzumab prescription, and role of left ventricular ejection fraction (LVEF) monitoring in daily practice of trastuzumab-treated patients with human epidermal growth receptor 2 (HER2)-positive early breast cancer., Methods: We included all patients with stage I-III breast cancer diagnosed in the early years (2005-2007) after the introduction of adjuvant trastuzumab in five hospitals in Southeast Netherlands. We studied the incidence and timing of cardiotoxicity in patients treated with adjuvant trastuzumab, using similar cardiac endpoints as in the Herceptin Adjuvant (HERA) trial., Results: Of 2,684 included patients, 476 (17.7%) had a HER2-positive tumor. Of these, 269 (56.9%) were treated with adjuvant chemotherapy, and of these, 230 (85.5%) also received trastuzumab. Cardiotoxicity was observed in 29 of 230 patients (12.6%). Twenty of the 230 patients (8.7%) had symptomatic cardiotoxicity, defined as a drop in LVEF of at least 10 percentage points and to below 50%, accompanied by symptoms of congestive heart failure. Trastuzumab was definitely discontinued because of supposed cardiotoxicity in 36 patients (15.6%), of whom only 15 (6.5%) had a significant LVEF drop. Of the 36 patients who prematurely discontinued trastuzumab (including the 29 in whom cardiotoxicity was observed), 84.8% stopped in the first 6 months. No cardiac deaths were seen., Conclusion: In the first years after implementation of trastuzumab for treatment of early breast cancer, physicians frequently based their decision to discontinue treatment on patient symptoms apart from LVEF outcome. We suggest that focusing LVEF monitoring on the first 6 months might be more cost-effective without compromising patient safety. Nonetheless, further research is needed., Implications for Practice: Knowledge of when cardiotoxicity occurs in daily practice will help shape the best follow-up method for cardiac monitoring in trastuzumab-treated patients with human epidermal growth receptor 2-positive early breast cancer. In the first years after implementation of trastuzumab for treatment of early breast cancer, physicians frequently based their decision to discontinue treatment on patient symptoms apart from left ventricular ejection fraction (LVEF) outcome. When cardiotoxicity was found in daily practice, it occurred mainly in the first 6 months after start of trastuzumab. This study suggests that focusing LVEF monitoring on the first 6 months might be more cost-effective without compromising patient safety. This insight stresses the relevance of performing real-world analyses., (©AlphaMed Press.)

Background: The objective of this study was to present initial systemic treatment choices and the outcome of hormone receptor-positive (HR+) metastatic breast cancer., Patients and Methods: All the 815 consecutive patients diagnosed with metastatic breast cancer in 2007-2009 in eight participating hospitals were identified. From the 611 patients with HR+ disease, a total of 520 patients with HER2-negative (HER2-) breast cancer were included. Initial palliative systemic treatment was registered. Progression-free survival (PFS) and overall survival (OS) per initial palliative systemic therapy were obtained using the Kaplan-Meier method and compared using the log-rank test., Results: From the total of 520 patients with HR+/HER2- metastatic breast cancer, 482 patients (93%) received any palliative systemic therapy. Patients that received initial chemotherapy (n = 116) were significantly younger, had less comorbidity, had received more prior adjuvant systemic therapy and were less likely to have bone metastasis only compared with patients that received initial endocrine therapy (n = 366). Median PFS of initial palliative chemotherapy was 5.3 months [95% confidence interval (CI) 4.2-6.2] and of initial endocrine therapy 13.3 months (95% CI 11.3-15.5), with a median OS of 16.1 and 36.9 months, respectively. Initial chemotherapy was also associated with worse outcome in terms of PFS and OS after adjustment for prognostic factors., Conclusions: A high percentage of patients with HR+ disease received initial palliative chemotherapy, which was associated with worse outcome, even after adjustment of relevant prognostic factors., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose In an attempt to restore natural carpal kinematics more closely, bone-ligament-bone (BLB) grafts have been described for treating scapholunate (SL) injury. In this article we report the long-term results of capitohamate BLB autograft for the treatment of SL dissociation. Methods The medical records of patients treated with capitohamate BLB grafts for SL dissociation were retrospectively reviewed. Twenty-three patients were available for evaluation. Patients were sent a Disabilities of the Arm, Shoulder, and Hand (DASH) and a Patient-Rated Wrist Evaluation (PRWE) questionnaire and returned for exam. Thirteen patients returned the questionnaire, and 12 wrists were examined. Range of motion, grip strength, pain, complications, return to work, and radiographic parameters were documented. Results The average length of follow-up evaluation was 9.2 years. The average SL gap was 4.5 mm preoperatively and 3.6 mm at final follow-up. The average SL angle was 70 degrees preoperatively and 73 degrees at final follow-up. There was no statistically significant difference in preoperative versus postoperative flexion, extension, radial deviation, ulnar deviation, or grip strength. The average postoperative visual analog scale (VAS) score was 1.25 at rest and 3.58 with activity. The average Mayo Wrist Score was 66.8 preoperatively and 70.9 postoperatively (p = 0.158). The average postoperative PRWE was 20.5, and average postoperative DASH was 15.1. At final follow-up, four patients had no radiographic evidence of arthritis. Two patients had evidence of early-stage radiocarpal arthritis, four had evidence of midcarpal arthritis, and two had radiographic evidence of mild scaphotrapeziotrapezoid arthritis. One patient required a salvage procedure with four-corner fusion. Discussion BLB reconstruction can be used to treat SL instability. At final follow-up, the majority of patients did not worsen clinically or functionally or require secondary salvage procedures; however, radiologic progression of arthritis was not prevented. These outcomes are comparable to midterm results of other SL reconstructive options; thus, we have abandoned this technique for other less technically demanding procedures. Level of Evidence IV.

Introduction Most surgical techniques for scapholunate interosseous ligament (SLIL) repair address only the dorsal component of the ligament, potentially leading to high surgical failure rates. We introduce a new technique to reconstruct the volar SLIL using a portion of the long radiolunate ligament (LRL). A biomechanical evaluation was performed to evaluate the rupture strength of this repair, and a subsequent anatomic study was performed to verify that this repair would not compromise the blood supply to either the scaphoid or the lunate. Methods A reconstruction of the volar SLIL was developed utilizing a lunate-based strip of the LRL. Fourteen cadaver arms were injected with red-colored epoxide and latex. The blood supply of the volar wrist capsule was dissected. The vascular supply to the ligaments, scaphoid, and lunate were investigated. The biomechanical strength of this reconstruction was tested on five cadaver arms by potting the scaphoid, lunate, and radius and subjecting the repair to a tensile load using a servohydraulic vertical displacement testing machine. Results In all arms, a branch of the radial artery or radiocarpal arch supplied the radioscapholunate ligament at the medial border of the LRL. The proximal half of the scaphoid was supplied by dorsal branches of the radial artery. In all cases, a vessel entered the lunate on its ulnar volar side, away from the repair. The average strength of the intact LRL strip was 97.4 N, and the average strength of the ligament-suture interface used for the capsulodesis was 43.5 N. Conclusion This volar approach to the SLIL does not compromise the vascularity of the scaphoid or the lunate. This approach allows the possibility of repairing or augmenting the volar SLIL. The strength of this repair appears to be less than the strength of the native SLIL. Further clinical studies are warranted.

Background: The impact of drug prescriptions in real life as opposed to strict clinical trial prescription is only rarely assessed, although it is well recognized that incorrect use may harm patients and may have a significant impact on health care resources. We investigated the use and effectiveness of adjuvant trastuzumab in daily practice compared with the effectiveness in clinical trials., Methods: We included all patients with stage I-III invasive breast cancer, irrespective of human epidermal growth factor receptor 2 (HER2) status, diagnosed in five hospitals in the southeast of The Netherlands in 2005-2007. We aimed to assess the actual use of adjuvant trastuzumab in early HER2-positive breast and its efficacy in daily practice., Results: Of 2,684 patients included, 476 (17.7%) had a HER2-positive tumor. Of these, 251 (52.7%) patients had an indication for trastuzumab treatment of which 196 (78.1%) patients actually received it. Of the 225 patients without an indication, 34 (15.1%) received trastuzumab. Five-year disease-free survival was 80.7% for (n = 230) patients treated with versus 68.2% for (n = 246) patients not treated with trastuzumab (p = .0023), and 5-year overall survival rates were 90.7% and 77.4%, respectively (p = .0002). The hazard ratio for disease recurrence was 0.63 (95% confidence interval, 0.37-1.06) for trastuzumab when adjusting for potential confounders., Conclusion: This study shows that in real life, patients treated with trastuzumab in early-stage HER2-positive breast cancer had a 5-year disease-free and overall survival comparable to prior randomized trials. For informative decision making, real-life data are of additional value, providing insight on outcome of patients considered ineligible for treatment., (©AlphaMed Press.)

Background: We aimed to determine the prognostic impact of time between primary breast cancer and diagnosis of distant metastasis (metastatic-free interval, MFI) on the survival of metastatic breast cancer patients., Methods: Consecutive patients diagnosed with metastatic breast cancer in 2007-2009 in eight hospitals in the Southeast of the Netherlands were included and categorised based on MFI. Survival curves were estimated using the Kaplan-Meier method. Cox proportional hazards model was used to determine the prognostic impact of de novo metastatic breast cancer vs recurrent metastatic breast cancer (MFI ⩽24 months and >24 months), adjusted for age, hormone receptor and HER2 status, initial site of metastasis and use of prior (neo)adjuvant systemic therapy., Results: Eight hundred and fifteen patients were included and divided in three subgroups based on MFI; 154 patients with de novo metastatic breast cancer, 176 patients with MFI <24 months and 485 patients with MFI >24 months. Patients with de novo metastatic breast cancer had a prolonged survival compared with patients with recurrent metastatic breast cancer with MFI <24 months (median 29.4 vs 9.1 months, P<0.0001), but no difference in survival compared with patients with recurrent metastatic breast cancer with MFI >24 months (median, 29.4 vs 27.9 months, P=0.73). Adjusting for other prognostic factors, patients with MFI <24 months had increased mortality risk (hazard ratio 1.97, 95% CI 1.49-2.60, P<0.0001) compared with patients with de novo metastatic breast cancer. When comparing recurrent metastatic breast cancer with MFI >24 months with de novo metastatic breast cancer no significant difference in mortality risk was found. The association between MFI and survival was seen irrespective of use of (neo)adjuvant systemic therapy., Conclusion: Patients with de novo metastatic breast cancer had a significantly better outcome when compared with patients with MFI <24 months, irrespective of the use of prior adjuvant systemic therapy in the latter group. However, compared with patients with MFI >24 months, patients with de novo metastatic breast cancer had similar outcome.

The conventional free radial forearm flap is a very reliable, long-pedicled flap with thin, pliable skin. These properties make it an excellent choice for high-risk reconstructions or defects requiring only a thin cover. The split radial forearm flap allows primary closure of the donor site and has a large variability in shape and size. In this report, the cutaneous perforators of the radial artery were investigated in fresh cadavers and we present our clinical experience with the split radial artery flap in 9 patients with lower leg defects. Sufficient perforators exist to safely divide the flap proximally and distally into segments. In all clinical cases, the donor site could be closed primarily. All flaps remained viable and 8 of 9 patients obtained an esthetically pleasing result. The split radial forearm free flap is an elegant option for reconstruction of small- to moderate-sized soft tissue defects in the lower extremity.

Contrary to the situation in early breast cancer, little is known about the prognostic relevance of the hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) in metastatic breast cancer. The objectives of this study were to present survival estimates and to determine the prognostic impact of breast cancer subtypes based on HR and HER2 status in a recent cohort of metastatic breast cancer patients, which is representative of current clinical practice. Patients diagnosed with metastatic breast cancer between 2007 and 2009 were included. Information regarding patient and tumor characteristics and treatment was collected. Patients were categorized in four subtypes based on the HR and HER2 status of the primary tumor: HR positive (+)/HER2 negative (-), HR+/HER2+, HR-/HER2+ and triple negative (TN). Survival was estimated using the Kaplan-Meier method. Cox proportional hazards model was used to determine the prognostic impact of breast cancer subtype, adjusted for possible confounders. Median follow-up was 21.8 months for the 815 metastatic breast cancer patients included; 66 % of patients had the HR+/HER2- subtype, 8 % the HR-/HER2+ subtype, 15 % the TN subtype and 11 % the HR+/HER2+ subtype. The longest survival was observed for the HR+/HER2+ subtype (median 34.4 months), compared to 24.8 months for the HR+/HER2- subtype, 19.8 months for the HR-/HER2+ subtype and 8.8 months for the TN subtype (P < 0.0001). In the multivariate analysis, subtype was an independent prognostic factor, as were initial site of metastases and metastatic-free interval. The HR+/HER2+ subtype was associated with the longest survival after diagnosis of distant metastases.

Objectives: To compare the biomechanical properties of a new nitinol intramedullary (IM) scaffold implant with those of volar plates for the treatment of dorsally comminuted extra-articular distal radius fractures using an established model., Methods: A dorsal wedge osteotomy was performed on a bone model to simulate a dorsally comminuted extra-articular distal radius fracture. This model was used to compare stiffness of 3 different distal radius fixation devices--an IM scaffold implant, a commercially available titanium volar locking plate, and a stainless steel non-locking T-plate. Six constructs were tested per group. Tolerance for physiological loading was assessed by applying 10,000 cycles of axial loading up to 100 N applied at 2 Hz. Axial and eccentric load stiffness were assessed before cyclic loading and axial stiffness again after cyclic loading. Groups were compared using analysis of variance., Results: Initial axial stiffness (in Newton per millimeter) was significantly (P = 0.011) different only between the volar locking plate (427 ± 43) and non-locking T-plate (235 ± 69). After cyclic loading, axial stiffness was not significantly different between the volar locking plate (392 ± 67) and IM scaffold implant (405 ± 108), but both were significantly (P < 0.001) stiffer than the non-locking T-plate (187 ± 53). Eccentric loading stiffness was not significantly different between the IM scaffold implant (67 ± 140) and volar locking plate (63 ± 5), but both were significantly (P < 0.001) stiffer than the non-locking T-plate (25 ± 4)., Conclusions: Stiffness of the IM scaffold implant and volar locking plate fracture model constructs was equivalent. Biomechanical testing suggests that this novel IM scaffold provides sufficient stability for clinical use, and further testing is warranted.

Objective: Health technology assessments (HTAs) intend to inform real-world decisions. They often draw on data from explanatory trials and hence are not always applicable to the decision problem. HTAs may therefore not meet the needs of decision makers. Our objective was to develop and apply a checklist to: 1) systematically frame HTAs in a way that they are applicable to the decision problem; and 2) assess if a decision problem can be informed by an available HTA., Methods: We reviewed published literature to identify factors that should be considered when framing HTAs for resource allocation decisions. The checklist was finalized in collaboration with clinicians and policy makers. We applied the checklist to the economic evaluation of trastuzumab in early breast cancer. We defined a reference case and for each study, retrieved through a systematic review, we examined if each factor was explicitly considered., Results: A checklist was developed with 11 factors (e.g., clinical practice, consequences, and patient use). In the case of trastuzumab, most factors were considered by the 11 retrieved economic evaluations. Two factors, being the inclusion of all relevant comparators and professional use, were considered by none of the studies., Conclusions: We developed a comprehensive checklist with 11 factors to frame HTAs and to assess the applicability of HTAs to resource allocation decisions. Economic evaluations on trastuzumab considered some of these factors, but overlooked others. The proposed checklist assists in systematically considering all factors in developing the conceptual model of an HTA, to make HTAs better reflect the decision problem., (Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Purpose: To analyze the outcome, including nonrelapse mortality (NRM), relapse rate (RR), progression-free survival (PFS), and overall survival (OS), of patients with diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) relapsed after an autologous stem-cell transplantation (ASCT) and treated with an allogeneic stem-cell transplantation (allo-SCT)., Patients and Methods: The European Group for Blood and Marrow Transplantation database was scanned for a first allo-SCT in relapsed DLBCL after a previous ASCT between 1997 and 2006. Other inclusion criteria were age at allo-SCT ≥ 18 years and availability of an HLA-identical sibling or a matched unrelated donor. A total of 101 patients (57 males; median age, 46 years) were included. Median follow-up for survivors was 36 months., Results: Myeloablative conditioning regimen was used in 37 patients and reduced intensity conditioning (RIC) was used in 64 patients. Three-year NRM was 28.2% (95% CI, 20% to 39%), RR was 30.1% (95% CI, 22% to 41%), PFS was 41.7% (95% CI, 32% to 52%), and OS was 53.8% (95% CI, 44% to 64%). NRM was significantly increased in patients ≥ 45 years (P = .01) and in those with an early relapse (< 12 months) after ASCT (P = .01). RR was significantly higher in refractory patients (P = .03). A time interval to relapse after ASCT of < 12 months was associated with lower PFS (P = .03). The use of RIC regimens was followed by a trend to a lower NRM (P = .1) and a trend to a higher RR (P = .1), with no differences in PFS and OS. No differences were seen between HLA-identical siblings and matched unrelated donors., Conclusion: Allo-SCT in relapsed DLBCL after ASCT is a promising therapeutic modality. Patients with a long remission after ASCT and with sensitive disease at allo-SCT are the best candidates for this approach.

Rare tumours of the liver are occasionally seen; thorium dioxide-related haemangiosarcoma of the liver, with an estimated frequency of 0.14 to 0.25 per million in the normal population, is one of these. Causes, epidemiology and pathobiology are described related to a clinical case of angiosarcoma. A differentiation of hepatic tumours with imaging techniques is presented. Last, a short review on up-to-date treatment of haemangiosarcoma is discussed. Lessons can always be learned from history: will the contrast agent gadolinium be the Th232 of this era?

A 38-year-old man presented with severe methanol intoxication after inhaling methanol over a period of 36 hours in a poorly-ventilated laboratory. He complained of visual disturbances, mild photophobia, hyperventilation and nausea. Laboratory results showed severe metabolic acidosis with a toxic serum-methanol level. He was treated by acute haemodialysis and ethanol infusions. After 9 hours of haemodialysis the serum-methanol value fell below toxic levels. Therapy resulted in the complete disappearance of symptoms and he was able to leave the intensive-care unit 24 hours after presentation. Often, late presentation is a cause of serious morbidity and even mortality in severe methanol intoxication, so early recognition is essential. This is the first published case of methanol intoxication due to inhalation, which is as serious and requires the same treatment as ingestion of methanol.

The hemostatic activity of plasma is determined by platelet activation and coagulation, which processes are mutually stimulatory. We studied this interaction by measuring the cleavage of fluorescent thrombin substrate in platelet-rich plasma (PRP), using the calibrated thrombogram method. In freshly isolated human plasma, thrombin formation triggered by tissue factor was fully dependent on the presence of platelets. It was abolished by annexin A5, indicating dependence on phosphatidylserine (PS) exposure at activated platelets. Comparison of plasmas from various subjects showed considerable interindividual variation in total amount of thrombin generation, regardless of whether platelets or PS-containing phospholipids were present. Integrin alphaIIbbeta3 antagonists and ADP receptor blockage, but not aspirin, decreased the rate of thrombin generation (thrombin peak level) and extended the time of onset. Platelet inhibition with cAMP-elevating agents decreased the thrombin-forming rate, but surprisingly shortened the onset time. Stimulation of platelets with agonists of Gi/q-coupled receptors and, to a larger extent, with collagen or Ca2+-ionophore increased the rate of thrombin generation and shortened its onset. In PRP from donors with low and high generation, platelet inhibitors and activators were similarly effective. Taken together, these results indicate that, in tissue factor-triggered PRP, PS exposure on activated platelets regulates both onset and rate of thrombin generation. However, coagulant activity rather than platelet activation determines the total amount of thrombin formed, i.e. the endogenous thrombin potential. Thus, kinetics of thrombin generation in PRP are controlled by platelet inhibitors and agonists, but the process is restricted in amount by the subject-dependent variation in coagulation.