Azathioprine in the therapy of paediatric inflammatory bowel disease – part I: treatment indications, dosing and thiopurine-related adverse events

Background: Thiopurines (in Europe mainly azathioprine) are widely used in the treatment of inflammatory bowel diseases in children. Due to a prolonged time until the onset of therapeutic effect, those drugs are aimed to be used in the maintenance phase of the therapy rather than for induction of remission. Thiopurines are sometimes used in combination therapy (with aminosalicylates or biological treatment agents). The adverse events of these drugs occur as often as in 15–40% cases and may lead to treatment cessation in a significant number of patients. Aims: To overview available information on (mainly) children suffering from inflammatory bowel disease. Conclusion: Genetic examination accompanied with laboratory monitoring of blood count parameters (specifically at the beginning of therapy) and biochemistry can help prevent some of the severe adverse events. Keywords Crohn’s disease, ulcerative colitis, pediatrie, merkaptopurin, thiopuriny

Impact of Frailty and Age on Clinical Outcomes in Patients Who Underwent Endovascular Therapy

Purpose: Information on the relationship between frailty and the outcome of endovascular therapy (EVT) in elderly patients with lower extremity peripheral artery disease (PAD) is scarce. This study aimed to reveal the impact of frailty on the prognosis of super-elderly patients who underwent EVT. Materials and Methods: From August 2015 to August 2016, 335 consecutive patients who underwent EVT were enrolled in the I-PAD registry from 7 institutes in Nagano prefecture. Among them, we categorized 323 patients into 4 groups according to age and the presence or absence of frailty as follows: elderly with frailty (age ≥ 75, Clinical Frailty Scale [CFS] ≥ 5), elderly without frailty (age ≥ 75, CFS ≤ 4), young with frailty (age < 75, CFS ≥ 5), and young without frailty (age < 75, CFS ≤ 4); we analyzed them accordingly. The primary endpoints were major adverse cardiovascular and limb events (MACLE), defined as a composite of cardiovascular death, myocardial infarction, stroke, admission for heart failure, major amputation, and revascularization. The secondary endpoint was cardiovascular death. Results: The median follow-up period was 2.7 years. In the elderly with frailty, elderly without frailty, young with frailty, and young without frailty groups, the freedom rates from MACLE were 34.9%, 55.7%, 35.4%, and 63.0%, respectively (p<0.001) and from all-cause death were 43.5%, 73.4%, 50.7%, and 90.9%, respectively (p<0.001). The freedom rates from MACLE were significantly higher among elderly patients with frailty than among young patients without frailty (55.7% vs 35.4%, p=0.01). In multivariate analysis, frailty was independently associated with MACLE incidence. Conclusion: Frailty as defined by CFS might be a predictor of MACLE incidence in patients with PAD who underwent EVT. By considering treatment indications for patients with PAD by focusing on frailty rather than age, we may examine whether EVT policies are appropriate and manage patient and caregiver expectations for potential improvement in functional outcomes. Further studies are expected to investigate whether changes in frailty after EVT change prognosis.

Optical Coherence Tomography to Assess Neurodegeneration in Phenylalanine Hydroxylase Deficiency

In phenylalanine hydroxylase (PAH) deficiency, an easily feasible method to access the progression of neurodegeneration is warranted to contribute to current discussions on treatment indications and targets. The objective of the present study was to investigate whether optical coherence tomography (OCT) measures as markers of neurodegeneration differ between patients with PAH deficiency and healthy controls (HCs) according to phenotype and metabolic control. In this single-center cross-sectional study, 92 patients with different phenotypes of PAH deficiency [PAH deficiency not requiring treatment, early treated phenylketonuria (ETPKU), and late-diagnosed phenylketonuria (PKU)] compared with 76 HCs were examined using spectral-domain OCT. Indices of phenylalanine elevation and variability were correlated with OCT parameters. Late-diagnosed PKU patients showed reduced peripapillary retinal nerve fiber layer (pRNFL) thickness and combined ganglion cell and inner plexiform layer (GCIPL) volume. Adult ETPKU patients were found to have lower GCIPL volume (p = 0.016), which correlated with the indices of phenylalanine control. In pediatric ETPKU patients with poor metabolic control, pRNFL was significantly reduced (p = 0.004). Patients with PAH deficiency not requiring treatment did not exhibit retinal degeneration. Inner nuclear layer (INL) was significantly increased in the pediatric ETPKU patients, driven by those with current poor metabolic control (p = 0.006). Our data provide evidence of retinal neuroaxonal degeneration and INL swelling, depending on the phenotype, current age, and metabolic control. These findings suggest that OCT is suitable to investigate neurodegeneration in PKU and we propose OCT as a sensitive, reliable, safe, low-burden, and low-cost examination for future multicenter studies.

Future Developments in Charged Particle Therapy: Improving Beam Delivery for Efficiency and Efficacy

The physical and clinical benefits of charged particle therapy (CPT) are well recognized. However, the availability of CPT and complete exploitation of dosimetric advantages are still limited by high facility costs and technological challenges. There are extensive ongoing efforts to improve upon these, which will lead to greater accessibility, superior delivery, and therefore better treatment outcomes. Yet, the issue of cost remains a primary hurdle as utility of CPT is largely driven by the affordability, complexity and performance of current technology. Modern delivery techniques are necessary but limited by extended treatment times. Several of these aspects can be addressed by developments in the beam delivery system (BDS) which determines the overall shaping and timing capabilities enabling high quality treatments. The energy layer switching time (ELST) is a limiting constraint of the BDS and a determinant of the beam delivery time (BDT), along with the accelerator and other factors. This review evaluates the delivery process in detail, presenting the limitations and developments for the BDS and related accelerator technology, toward decreasing the BDT. As extended BDT impacts motion and has dosimetric implications for treatment, we discuss avenues to minimize the ELST and overview the clinical benefits and feasibility of a large energy acceptance BDS. These developments support the possibility of advanced modalities and faster delivery for a greater range of treatment indications which could also further reduce costs. Further work to realize methodologies such as volumetric rescanning, FLASH, arc, multi-ion and online image guided therapies are discussed. In this review we examine how increased treatment efficiency and efficacy could be achieved with improvements in beam delivery and how this could lead to faster and higher quality treatments for the future of CPT.

ML-18 High-dose chemotherapy supported by autologous stem cell transplant in relapsed and refractory primary CNS lymphoma

While whole brain radiation therapy (WBRT) has been performed as consolidation therapy in primary central nervous system lymphoma (PCNSL), high-dose chemotherapy supported by autologous stem cell transplant (HDC/ASCT) is widely investigated today as an alternative treatment strategy, given the high risk for radiation-induced neurotoxicity in WBRT. Various conditioning regimens have been investigated in phase II trials, which report non-inferiority of HDC/ASCT in efficacy and preservation of neurocognitive function in comparison with WBRT. Besides its promising efficacy, treatment-related deaths are reported in 11% in patients treated by a conditioning regimen using thiotepa, busulfan and cyclophosphamide (TBC), which raises a concern for safety. Among several conditioning regimens, analysis using registry data of Japan Society for Hematopoietic Cell Transplantation has revealed that the use of conditioning regimens containing thiotepa was a positive factor for longer PFS. According to the result of a phase I trial in Japan which investigated HDC/ASCT using thiotepa and busulfan (BuTT), thiotepa was approved by the pharmaceuticals and medical devices agency (PMDA) on March 2020. In comparison with the TBC regimen, cyclophosphamide is omitted, and the dose of thiotepa is lower (250 mg/m2, 3 days in TBC; 5 mg/kg, 2 days in BuTT) in BuTT, therefore BuTT could be less toxic in comparison with TBC, and no treatment-related deaths were observed in the phase I study in Japan. Further investigation on the efficacy and safety of BuTT in actual clinical practice is warranted. We have constituted a multi-disciplinary team in our institution in order to perform HDC/ASCT using BuTT in relapsed/refractory PCNSL. Treatment indications are as follows; 65 years old or younger, previously treated by rituximab, methotrexate, procarbazine and vincristine (R-MPV), good organ function and neurological status. Future directions along with preliminary treatment results will be discussed at the meeting.

Tarsal tunnel syndrome: current rationale, indications and results

Tarsal tunnel syndrome (TTS) is a neuropathy due to compression of the posterior tibial nerve and its branches. It is usually underdiagnosed and its aetiology is very diverse. In 20% of cases it is idiopathic. There is no test that diagnoses it with certainty. The diagnosis is usually made by correlating clinical history, imaging tests, nerve conduction studies (NCSs) and electromyography (EMG). A differential diagnosis should be made with plantar fasciitis, lumbosacral radiculopathy (especially S1 radiculopathy), rheumatologic diseases, metatarsal stress fractures and Morton’s neuroma. Conservative management usually gives good results. It includes activity modification, administration of pain relief drugs, physical and rehabilitation medicine, and corticosteroid injections into the tarsal tunnel (to reduce oedema). Abnormally slow nerve conduction through the posterior tibial nerve usually predicts failure of conservative treatment. Indications for surgical treatment are failure of conservative treatment and clear identification of the cause of the entrapment. In these circumstances, the results are usually satisfactory. Surgical success rates vary from 44% to 96%. Surgical treatment involves releasing the flexor retinaculum from its proximal attachment near the medial malleolus down to the sustentaculum tali. Ultrasound-guided tarsal tunnel release is possible. A positive Tinel’s sign before surgery is a strong predictor of surgical relief after decompression. Surgical treatment achieves the best results in young patients, those with a clear aetiology, a positive Tinel’s sign prior to surgery, a short history of symptoms, an early diagnosis and no previous ankle pathology. Cite this article: EFORT Open Rev 2021;6:1140-1147. DOI: 10.1302/2058-5241.6.210031

Prognostic value of glucose fluctuation in patients undergoing thrombolysis or thrombectomy due to acute ischemic stroke

Background Hyperglycemia during acute ischemic stroke is associated with worse outcomes, and this glucose altitude may persist in the initial days. In this study, we investigate the effect of glucose fluctuations in the first 4 days in patients diagnosed with acute ischemic stroke and who underwent ivr-tPA ± interventional thrombectomy or only interventional thrombectomy on stroke prognosis. Study was designed bicentered retrospective case series. Patients older than 18 years were included and those suitable for acute treatment, treatment indications, contraindications, and treatment management of hyperglycemia were selected according to the 2018 American Stroke Association guidelines. The effect of fasting glucose values of patients in the first 4 days on admission and 24th hour NIHSS scores, duration of hospitalization, disability, mortality, and prognosis were analyzed. We aimed to demostred the effect of the first 4-day glucose values measured in patients treated in a stroke center on clinical prospect. Results One hundred and seventy-six patients were included in the study. Group 1 included 30 (17%) patients with severe clinical condition (NIHSS at admission ≥ 16), and Group 2 comprised 146 (83%) patients with moderate and mild clinical condition (NIHSS at admission < 16). The glucose values of Groups 1 and 2 were found as follows: day 1 (admission): 178.7 ± 10.3 mg/dl and 138.3 ± 54.9 mg/dl, day 2: 197.7 ± 99.8 mg/dl and 137.6 ± 51.8 mg/dl, day 3: 186.1 ± 97.6 mg/dl and 127.5 ± 50.0 mg/dl, and day 4: 169.2 ± 85.0 mg/dl and 126.7 ± 49.3 mg/dl (p < 0.05). Mortality risk of patients with glucose ≥ 200 mg/dl was 43.5% on day 1 (p > 0.05), 57.1% on day 2, 68.4% on day 3, and 76.5% on day 4 (p < 0.05). Conclusions The glucose level of patients in severe clinical condition peaked on the second day and that 4 days of resilient severe hyperglycemia is a negative risk factor for sequela and mortality.

Current epidemiological trends and in-hospital mortality of acute pancreatitis in Germany: a systematic analysis of standardized hospital discharge data between 2008 and 2017

Background Acute pancreatitis (AP) represents a common gastrointestinal disorder. Complicated disease courses in particular still represent a major clinical challenge and are associated with high mortality. Evaluation of existing data sets and their careful interpretation can support a rational discussion to optimize outcomes of this common gastrointestinal disease. Methods We used standardized hospital discharge data provided by the Federal Statistical Office of Germany to evaluate hospital mortality and current developments of AP in Germany between 2008 and 2017. Results In this analysis, 516,618 hospitalized AP cases were included. Main disease etiologies featured biliary (29.9%) and alcoholic (22.7%) AP. The annual frequency of AP increased from 48,858 (2008) to 52,611 (2017), mainly due to a rising incidence of biliary AP. Average hospital mortality was 2.85% and significantly improved over time. While uncomplicated AP had low hospital mortality (1.38%), the presence of organ complications was associated with a mortality of 12.34%. The necessity of mechanical ventilation dramatically increased hospital mortality to 44.06%. Hospital mortality was significantly higher in female patients (3.31%) than males (2.55%) and showed a stepwise increase with patient age. We further identified type 2 diabetes mellitus and obesity as factors associated with increased hospital mortality. Hospital mortality was lowest among patients treated at departments specializing in gastroenterology. Finally, high case volume centers (defined as >98 annual AP cases) had the lowest hospital mortality for patients with complicated courses of AP. Conclusion With over 50,000 annual hospitalization cases, AP is one of the most important inpatient treatment indications in gastroenterology in Germany. Overall, AP mortality has improved in recent years, presumably due to improved interdisciplinary treatment concepts. In this study, we identified important clinical and epidemiological risk factors for an unfavorable course, which could help to improve risk prediction and triaging, and thus the management of AP.

Progesterone Concentrations during Canine Pregnancy

Pregnancy and lactation are amongst the most challenging times of a bitch’s life. Most studies focusing on the endocrinological aspect of pregnancy consider only a small number of animals. The aim of this study was to evaluate progesterone (P4) concentrations in a large number of bitches during early, mid and late pregnancy. In total, 126 bitches of various breeds were recruited following a thorough clinical and gynecological examination during estrus. Blood samples were collected three times (T1–T3) during pregnancy or from non-pregnant dogs in diestrus, and P4 was measured via chemiluminescence. At T1 (11–19 days post-ovulation (dpo)), serum P4 concentrations were 30.23 ± 6.65 ng/mL and 28.45 ± 6.26 ng/mL, at T2 (23–32 dpo) they were 22.73 ± 6.27 ng/mL and 22.59 ± 5.77 ng/mL and at T3 (52–60 dpo) they were 6.68 ± 2.18 ng/mL and 3.17 ± 2.26 ng/mL, in pregnant (n = 98) and non-pregnant (n = 23) dogs respectively. The P4 concentrations differed significantly between pregnant and non-pregnant animals at the last examination (p ≤ 0.001). In the context of hypoluteoidism, the gathered data yielded interesting results. Overall, 28 out of 98 pregnant bitches showed a greater decline (>15 ng/mL) in P4 concentrations from early to mid-pregnancy, and 56 bitches showed P4 concentrations lower than deemed adequate (>20 ng/mL at T1 and T2, >5 ng/mL at T3) according to existing recommendations. Despite not being supplemented with P4, none of those animals suffered from abortion or preterm delivery. Considering that supplementation of P4 can entail considerable risks for the bitch and the puppies, more research on P4 concentration patterns, diagnosis of hypoluteoidism and treatment indications and options is indicated.

Cardiac Sarcoidosis: When and How to Treat Inflammation

Sarcoidosis is a complex, multisystem inflammatory disease with a heterogeneous clinical spectrum. Approximately 25% of patients with systemic sarcoidosis will have cardiac involvement that portends a poorer outcome. The diagnosis, particularly of isolated cardiac sarcoidosis, can be challenging. A paucity of randomised data exist on who, when and how to treat myocardial inflammation in cardiac sarcoidosis. Despite this, corticosteroids continue to be the mainstay of therapy for the inflammatory phase, with an evolving role for steroid-sparing and biological agents. This review explores the immunopathogenesis of inflammation in sarcoidosis, current evidence-based treatment indications and commonly used immunosuppression agents. It explores a multidisciplinary treatment and monitoring approach to myocardial inflammation and outlines current gaps in our understanding of this condition, emerging research and future directions in this field.