Upsala journal of medical sciences最新文献

Background: Staging and treatment of rectal cancer have evolved over several decades with considerably fewer locoregional recurrences but no marked improved survival since systemic recurrence risks remain virtually unchanged. This development will briefly be summarised followed by a thorough discussion of two recent developments.

Methods: A systematic approach towards the literature is aimed at focusing on organ preservation and the delivery of all non-surgical treatments prior to surgery or total neoadjuvant treatment (TNT).

Results: Organ preservation, that is to defer surgery if the tumour happens to disappear completely after any pre-treatment given to locally advanced tumours to decrease recurrence risks has increased in popularity and is, if not universally, widely accepted. To give neo-adjuvant treatment to intentionally obtain a clinically complete remission to avoid surgery is practised in some environments but is mostly still experimental. TNT, that is to provide both radiotherapy and chemotherapy aimed at killing microscopic disease in the pelvis or elsewhere has been subject to several trials. Collectively, they show that the chance of achieving a complete response, pathologically or clinically, has approximately doubled, increasing the chance for organ preservation, and the risk of distant metastasis has decreased at least in some trials. The best schedule remains to be established.

Conclusions: To obtain substantial progress and also improve survival, the systemic treatments need to be improved even if preoperative delivery is more effective and better tolerated than postoperative. The locoregional treatment may be further optimised through better risk prediction.

Background: Treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduces low-density lipoprotein cholesterol (LDL-C) levels and decreases the incidence of major ischaemic events in clinical trials. However, less is known about the efficacy of PCSK9 inhibition in clinical practice. This study aimed to describe the change in LDL-C levels over time and LDL-C goal achievement in patients with/without atherosclerotic cardiovascular disease (ASCVD), who were prescribed evolocumab in clinical practice, and to describe adherence to and persistence with treatment.

Methods: Patients in Sweden with at least one evolocumab prescription filled between July 2015 and May 2020 were included. Medical history and lipid-lowering therapy (LLT) were sourced from national registries. LDL-C levels before and after treatment initiation were assessed using medical records. Persistence with and adherence to evolocumab and oral LLT were assessed up to 12 months after treatment initiation using the refill-gap method and proportion of days covered, respectively.

Results: Of the 2,360 patients with at least one prescription for evolocumab, 2,341 were included; 1,858 had ASCVD. Persistence with (76%) and adherence to (86%) evolocumab were high throughout the 12 months following initiation. Mean LDL-C levels decreased by 53% (95% confidence interval [CI]: 51-55%) in patients adherent to evolocumab (n = 567) and 59% (95% CI: 55-63%) in patients adherent to evolocumab and oral LLT (n = 186). Similar reductions in LDL-C were observed in patients with/without ASCVD. Reduced LDL-C levels remained stable during follow-up. Amongst patients adherent to evolocumab and those adherent to evolocumab and oral LLT, 23 and 55% achieved the LDL-C goal of <1.4 mmol/L, respectively.

Conclusions: The evolocumab LDL-C-lowering effect observed in clinical trials was confirmed in clinical practice in Sweden, particularly in patients also treated with oral LLT. During follow-up, adherence to and persistence with evolocumab were high, with stable reduced levels of LDL-C during observation.

Background: Inflammatory bowel disease (IBD; mainly ulcerative colitis and Crohn's disease) is associated with the development of colorectal cancer (CRC) referred to as colitis-associated colorectal cancer (CAC). In inflammatory flares of IBD, the production of luminal nitric oxide (NO) increases due to the increased inducible nitric oxide synthase (iNOS) activity in inflamed tissue. It is believed that iNOS parallels pro-inflammatory interleukin-1β (IL-1β). How these biomarkers relate to CAC pathogenesis or survival is unknown.

Aim: The primary aim of this study was to investigate iNOS and IL-1β immunoreactivity in CAC tumors in comparison with CRC and normal colonic mucosa, and the secondary aim was to determine if immunoreactivity correlates with 5-year survival of CAC.

Methods: Immunohistochemistry was performed on tissue sections as follows: CAC (n = 59); sporadic CRC (sCRC) (n = 12); colonic mucosa >2 cm outside sCRC margin (normal mucosa) (n = 22); paracancerous IBD (pIBD) (n = 12). The expression of iNOS and IL-1β was quantified separately for epithelium and stroma. Data were evaluated using the Mann-Whitney U-test and the log-rank test for 5-year Kaplan-Meier survival curves. Results were compared with online mRNA databases.

Results: Immunoreactivity occurred predominantly in epithelial cells and to lesser extent in stroma. Compared with normal mucosa, immunoreactivity for iNOS (P < 0.01) and IL-1β (P < 0.005) was higher in CAC epithelium. In CAC stroma, iNOS immunoreactivity was lower than normal mucosa (P < 0.001), whereas IL-1β was higher (P < 0.05). Immunoreactivity differences of iNOS or IL-1β among CAC patients failed to correlate with 5-year survival. These findings were supported by online mRNA databases.

Conclusion: Consistent with high NO production in IBD, there is more iNOS in CAC epithelium, albeit not in stroma. This immunoreactivity difference exists for IL-1β in both epithelium and stroma. The intervention of arginine or iNOS activity for CAC chemotherapy is not straightforward.

Background: Chloroquine and hydroxychloroquine (C/HC) received considerable international media attention due to anticipated treatment effect in COVID-19. This led to increased prescriptions threatening to generate product shortages for patients prescribed within approved indications.We evaluated effects of a temporary regulation mandating pharmacies to only dispense C/HC prescribed by physicians with defined specialties.

Methods: Data from Region Stockholm, which include 2.4 out of 10 million Sweden's population, were used. Weekly time trends of prescriptions and requisitions of C/HC by prescriber's workplace during January to April 2020 were followed.

Results: Numbers of unique individuals with filled prescriptions of chloroquine increased tenfold and of hydroxychloroquine more than threefold from January to March. In the first week of April, filled prescriptions of C/HC dropped. In the later weeks of April, the number of filled prescriptions was back at similar levels as before the SARS-CoV-2 outbreak.During January and February, specialists in rheumatology accounted for 686 out of all 979 prescriptions dispensed (70.1%) of C/HC. In March, a large proportion of prescriptions dispensed were from specialists not usually prescribing C/HC, and rheumatology accounted for 628 out of all 1,639 prescriptions (38.3%). In April, specialists in rheumatology accounted for 386 out of all 641 prescriptions dispensed (60.0%).

Conclusion: After an observed increase in prescriptions of C/HC, a temporary regulation was introduced on 2nd April 2020 to reduce prescriptions from specialists not usually prescribing C/HC to avoid shortages for patients within approved indications. Subsequently, dispensed prescriptions decreased from April and remained at pre-COVID-19 levels thereafter.

Recent advances have driven the development of immunotherapies that act by either promoting or suppressing a patient's immune system to treat inflammation, autoimmune disease, cardiovascular disease, infectious diseases, and several cancers. In addition, research conducted over the past 25 years has identified therapeutic targets and indicated that immunotherapy could be used to treat Alzheimer's disease (AD). Despite a number of setbacks, this approach has now led to the development of the first disease-modifying treatments for this devastating disease. A key neuropathological feature of AD is the accumulation of a ~40-amino acid peptide known as amyloid β (Aβ) in the brain and cerebrovasculature. Our detection of an Aβ precursor protein mutation that caused early-onset AD in a Swedish family by enhancing Aβ protofibril formation sharpened the focus on soluble Aβ aggregates (oligomers and protofibrils) as viable therapeutic targets. Initial studies developed and tested a mouse monoclonal antibody (mAb158) with specific conformation-dependent binding to these soluble Aβ aggregates. Treatment with mAb158 selectively reduced Aβ protofibrils in the brain and cerebrospinal fluid of a transgenic mouse model of AD. A humanized version of mAb158 (lecanemab) subsequently entered clinical trials. Based on promising Phase 2 data showing plaque clearance and reduced cognitive decline, a Phase 3 trial found that lecanemab slowed decline on the primary cognitive endpoint by 27% over 18 months and also produced positive effects on secondary clinical endpoints and key biomarkers. In July 2023, the FDA granted lecanemab a full approval, and this therapeutic antibody will be marketed as Leqembi®. This represents a significant advance for patients with AD, although many challenges remain. In particular, it is now more important than ever to identify individuals who are vulnerable to AD, so that treatment can be initiated at an early stage in the disease process.

Background: Patients with type 1 diabetes have a high prevalence of upper extremity impairments (UEIs), such as frozen shoulder, carpal tunnel syndrome, and trigger finger. The UEIs are strongly associated with activity limitations and impaired quality of life. The etiology of the UEI is not clear. Vitamin D deficiency has been considered to play a role in the pathogenesis of type 1 diabetes and in the development of macro- and microvascular complications in diabetes.

Aim: To characterize vitamin D status in a large population of patients with type 1 diabetes, if vitamin D deficiency is associated with metabolic factors and possible association with UEI.

Material and methods: Patients who diagnosed before 35 years of age, whose diabetes duration >20 years, and who are not older than 65 years were invited to participate in this cross-sectional case-control, multicenter study. Controls matched for age and sex were obtained from the national population registry. Fasting blood samples were collected and stored at -80°C until analyzed regarding 25-hydroxy-vitamin D (25(OH)D3) by a liquid chromatographic-mass spectrometric method (LC-MS/MS).

Results: Vitamin D levels varied with season as expected in the northern hemisphere. The association between 25(OH)D3 and clinical variables was analyzed in a univariate general linear model, which indicated no difference in 25(OH)D3 in men with and without diabetes but higher values in women with diabetes. About 30% of both patients and controls had vitamin D deficiency (≤50 nmol/L). Analyzed by binary logistic regression UEIs was not associated with 25(OH)D3 levels. In both patients and controls, 25(OH)D3 was correlated to apolipoprotein A1 (r = 0.153; 0.220, P < 0.001).

Conclusion: In patients with type 1 diabetes and a duration of 20 years or more, vitamin D level is not lower than in nondiabetic controls and is not associated with UEIs.

Background: Increased cup-disc ratio (CDR) is a hallmark of open-angle glaucoma (OAG), an age-related neurodegenerative disease of significant importance for public health. There are few studies on the distribution of CDR in the Nordic populations.

Methods: The distribution of CDR was studied in 749 subjects aged 65-74 years in a population survey in the rural district of Tierp, Sweden, from 1984 to 86. The optic discs were assessed with binocular ophthalmoscopy at a slit lamp. Drawings of the discs were made in the protocol and used for the calculation of vertical CDRs. Odds ratios, adjusted for age and sex, according to Mantel-Haenszel (OR_MH), were determined to estimate predictors of increased CDR, defined as a ratio in the upper quartile. For these analyses, the eye with the most advanced OAG or the highest pressure was chosen. Automated perimetry was used to identify OAG.

Results: The distribution of vertical CDR was fairly close to that of other European-derived populations. The mean CDR was 0.45 in both eyes, with no difference between women and men. An increased ratio was associated with the age ≥70 years, a positive family history of OAG and intraocular pressure ≥20 mmHg. OAG increased the risk 8-fold (OR_MH 8.06; 95% CI 4.12-15.8).

Conclusions: In this study, the distribution of CDR was fairly close to that of other European-derived populations. As expected, OAG increased the risk of having a CDR in the upper quartile. The CDR increased with age.