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Međudjelovanje heterozigotne mutacije gena za ribosomski protein L24 i p53 u patogenezi bolesti : Plan upravljanja istraživačkim podacima
No full textDiagnostic considerations in the clinical management of sudden swelling of the knee: a case report and review of the literature
No full textBackground: Reactive arthritis and septic arthritis rarely present concomitantly in the same joint and patient. Reactive arthritis presenting after coronavirus disease 2019 is also exceedingly rare, with less than 30 cases reported thus far. Less common pathogens such as Clostridium difficile have been reported to cause reactive arthritis, especially in patients with a positive human leukocyte antigen B27, and therefore should be considered in diagnostic algorithms. The aim of this case report is to highlight the difficulties and precautions in discerning and diagnosing patients presenting with sudden swelling of the knee. Case presentation: We report the case of a 70-year-old Caucasian male with a recent history of coronavirus disease 2019 upper respiratory infection and diarrhea and negating trauma, who presented with a swollen and painful knee. Pain and swelling worsened and inflammatory parameters increased after an intraarticular corticosteroid injection. The patient was therefore treated with arthroscopic lavage and intravenous antibiotics for suspected septic arthritis. Synovial fluid and synovium samples were taken and sent for microbiological analysis. Synovial fluid cytology showed increased leukocytes at 10,980 × 106/L, while polymerase chain reaction and cultures came back sterile. Clostridium difficile toxin was later detected from a stool sample and the patient was treated with oral vancomycin. The patient was tested for the presence of human leukocyte antigen B27, which was positive. We present a review of the literature about the challenges of distinguishing septic from reactive arthritis, and about the mechanisms that predispose certain patients to this rheumatological disease. Conclusions: It is still a challenge to differentiate between septic and reactive arthritis of the knee, and it is even more challenging to identify the exact cause of reactive arthritis. This case report of a human leukocyte antigen-B27-positive patient highlights the necessity of contemplating different, less common causes of a swollen knee joint as a differential diagnosis of an apparent septic infection, especially in the coronavirus disease 2019 era. Treating the patient for septic arthritis prevented any possible complications of such a condition, while treating the C. difficile infection contributed to the substantial relief of symptoms
Hysteroscopic diode laser myolysis: from a case series to literature review of incisionless myolysis techniques for managing heavy menstrual bleeding in premenopausal women
No full textPurpose: This case series examined the safety and effectiveness of hysteroscopic myolysis using laser-induced interstitial thermo-therapy (LITT) for treating heavy menstrual bleeding (HMB) in premenopausal women with FIGO type 1 or 2 uterine fibroids, not planning for future fertility. Additionally, a comprehensive review of innovative, minimally invasive, incisionless myolysis techniques was conducted.
Methods: Women with HMB, sonographically diagnosed with a single FIGO type 1 or 2 fibroid, underwent hysteroscopic myolysis using the Leonardo® diode laser. Effectiveness was assessed via transvaginal ultrasound measurement of myoma size, volume and vascularization pre and post-procedure. Moreover, we also evaluated any improvements in symptoms using the Pictorial Blood Loss Assessment Chart (PBAC score) scores.
Results: The procedure resulted in significant HMB reductions and noticeable fibroid size, volume, and vascularization decrease in all three patients, with no reported complications. The literature review revealed both advantages and limitations of the minimally invasive, incisionless myolysis techniques.
Conclusions: Hysteroscopic laser myolysis is a safe and effective therapeutic intervention for patients experiencing HMB, diagnosed with FIGO type 1 or 2 fibroids, and not planning for future fertility. The procedure resulted in significant reductions in menstrual blood loss and fibroid size. Despite the promising results, it is essential to note the limitations of this report, including its case series design, a small number of patients, and a short follow-up period. Further research is necessary to confirm these results
Clinical and Demographic Characteristics of Herpetic Keratitis Patients—Tertiary Centre Experience
No full textBackground and Objectives: Herpes simplex keratitis (HSK) is the leading infectious cause of corneal damage and associated loss of visual acuity. Because of its frequent recurrence, it represents a major health problem; thus, timely and accurate diagnosis is the key to successful treatment. To enable this, we aimed to determine HSK patients’ demographic and clinical features. Materials and Methods: This prospective study included 55 patients diagnosed with HSK between March 2019 and August 2022 at the Department of Ophthalmology, Clinical Hospital Rijeka. Results: We found that HSK is most prevalent in the elderly, with 72.73% of patients older than 60. The most common HSK types were dendritic (HSK-D; 43.64%) and stromal with epithelial ulceration (HSK-SEU 23.64%). HSK recurrences occurred in 65.45% of patients, with most having two to five recurrences (55.56%). Visual acuity at presentation (65.5%) and after treatment (50.9%) was mostly in the 20/50 range. The longest period until the disease symptoms were resolved was in the group with stromal HSK without epithelial ulceration (HSK-SnEU), for which symptoms lasted more than 11 weeks in 87.5% of patients. The overall incidence of HSK-related complications was high (85.45%), with 76.4% of patients having corneal scarring. The average time from symptom to treatment was 15.78 days. Interestingly, we observed a strong seasonality in the incidence of HSK, which was most prevalent in the colder months, with 63.6% of cases occurring between October and March. Conclusions: To the best of our knowledge, this is the first prospective study in Croatia, and one of the few in Europe, to describe the demographic and clinical features of HSK patients. We found that HSK is most common in the elderly population, with its dendritic form as a clinical presentation. We have shown that HSK is prone to recurrence and secondary complications, with a worryingly long time between symptom and treatment, indicating the need for diagnostic testing in routine practice
Internal jugular vein thrombosis caused by invasive pharyngeal cancer: a case report and literature review
No full textImplementing Whole Genome Sequencing (WGS) in Clinical Practice: Advantages, Challenges, and Future Perspectives
No full textThe integration of whole genome sequencing (WGS) into all aspects of modern medicine represents the next step in the evolution of healthcare. Using this technology, scientists and physicians can observe the entire human genome comprehensively, generating a plethora of new sequencing data. Modern computational analysis entails advanced algorithms for variant detection, as well as complex models for classification. Data science and machine learning play a crucial role in the processing and interpretation of results, using enormous databases and statistics to discover new and support current genotype–phenotype correlations. In clinical practice, this technology has greatly enabled the development of personalized medicine, approaching each patient individually and in accordance with their genetic and biochemical profile. The most propulsive areas include rare disease genomics, oncogenomics, pharmacogenomics, neonatal screening, and infectious disease genomics. Another crucial application of WGS lies in the field of multi-omics, working towards the complete integration of human biomolecular data. Further technological development of sequencing technologies has led to the birth of third and fourth-generation sequencing, which include long-read sequencing, single-cell genomics, and nanopore sequencing. These technologies, alongside their continued implementation into medical research and practice, show great promise for the future of the field of medicine
FROM CRISIS TO CONTROL - UNDERSTANDING THE CONCEPT DAMAGE CONTROL RESUSCITATION
No full textThe term Damage Control originates from the British Royal Navy, where it described intermediate emergency measures to bring damaged ships back into their harbor for definite repair. The term nowadays is analogously used in trauma care to describe an emergency treatment regimen for managing severely injured patients with life threatening hemorrhage. Damage Control comprises of Damage Control Resuscitation, which aims to initially stabilize the patient and Damage Control Surgery, which pursues to achieve rapid hemorrhage control in order to maintain the patient’s physiological functions, often at the cost of initial correct anatomical restoration.
Three main factors, that is to say coagulopathy, hypothermia, and acidosis, drive the physiological deterioration in trauma patients and are collectively referred to as the lethal triad. Beyond, there are several additional aggravating factors as for example shock and hemodilution. For a sufficient treatment all of them have to be addressed.
Permissive hypotension with blood pressure guided fluid resuscitation is a good way to initially combat hemodynamic instability. Additionally, the use of blood products is a pillar of DCR as it addresses coagulopathy and increases the tissue oxygen supply at the same time. Massive Transfusion Protocols facilitate blood product administration in trauma patients and provide pRBC, FFP and thrombocyte transfusion usually in the ratio 1:1:1. Blood pressure control can further be achieved by the use of vasopressors and coagulopathy of trauma is addressed by the early use of TXA, coagulation factor substitution and Ca2+ supplementation. Hypothermia is best approached by covering the patient adequately, warming infusions before administration, and the use of heating devices.
In the end, these measures serve to stabilize the patient, but chances for survival are slim without immediate surgical hemorrhage control. This starts at the site of injury by compression of the wound or the use of bandages and tourniquets. More advanced techniques include Balloon Catheter Tamponades and Temporary Intravascular Shunts. Especially in a combat situation, these measures can be performed even outside an operating room.
For most severe trauma cases, especially in abdominal trauma, Damage Control Surgery is performed before definite surgical treatment. It is important that DCR and DCS act together synchronously. The key to an unimpeded and sufficient management of a heavily injured patient is good communication amongst all members of the medical team at all times
Advancing rare disease treatment: EMA’s decade-long insights into engineered adoptive cell therapy for rare cancers and orphan designation
No full textAbstract Adoptive cell therapy (ACT), particularly chimeric antigen receptor (CAR)-T cell therapy, has emerged as a promising approach for targeting and treating rare oncological conditions. The orphan medicinal product designation by the European Union (EU) plays a crucial role in promoting development of medicines for rare conditions according to the EU Orphan Regulation. This regulatory landscape analysis examines the evolution, regulatory challenges, and clinical outcomes of genetically engineered ACT, with a focus on CAR-T cell therapies, based on the European Medicines Agency’s Committee for Orphan Medicinal Products review of applications evaluated for orphan designation and maintenance of the status over a 10-year period. In total, 30 of 36 applications were granted an orphan status, and 14 subsequently applied for maintenance of the status at time of marketing authorisation or extension of indication. Most of the products were autologous cell therapies using a lentiviral vector and were developed for the treatment of rare haematological B-cell malignancies. The findings revealed that 80% (29/36) of the submissions for orphan designation were supported by preliminary clinical data showing a potential efficacy of the candidate products and an added clinical benefit over currently authorised medicines for the proposed orphan condition. Notably, in 89% (32/36) of the cases significant benefit of the new products was accepted based on a clinically relevant advantage over existing therapies. Twelve of fourteen submissions reviewed for maintenance of the status at time of marketing authorisation or extension of indication demonstrated significant benefit of the products over existing satisfactory methods of treatment within the approved therapeutic indications, but one of the applications was withdrawn during the regulatory evaluation. This article summarises the key findings related to the use of engineered ACT, primarily CAR-T cell therapies, in targeting and treating rare cancers in the EU. It emphasises the importance of use of clinical data in supporting medical plausibility and significant benefit at the stage of orphan designation and highlights the high success rate for these products in obtaining initial orphan designations and subsequent maintaining the status at the time of marketing authorisation or extension of indication
REGULATION OF PD-1/PD-L1 PATHWAY IN MALIGNANT MELANOMA
No full textCilj istraživanja: Da bi se predvidjela učinkovitost i optimiziranje anti-PD-1 i anti-PD L1 terapije važno je razjasniti regulaciju tih molekula. Imunohistokemijskim metodama i metodama molekularne dijagnostike ispitivali smo ulogu tri skupine regulacije: promjene u genetskom materijalu i signalnim putevima melanomske stanice, regulacija od strane imunološkog sustava i regulacija od strane enzima tumorskog mikrookoliša. Ispitanici i metode: Iz reprezentativnog dijela tkiva melanoma koristilo se 3 cilindra promjera 1 mm za izradu tkivnih mikroareja (TMA). U istraživanje smo uključili 39 bioptata primarnih melanoma (Breslow 1,5 mm) te 31 uzorak metastaza melanoma. Uz određivanje ekspresije PD 1 i PD-L1 molekula identificirali smo limfocite koji infiltriraju tumor (TIL) imunohistokemijskim bojanjem na CD3 molekulu. Nadalje, ispitivali smo prisutnost CD8+ , CD4+ i Foxp3+ limfocita kao i CD20+ B limfocita. TIL je kategoriziran u BRISK kategorije. Određen je odnos ekspresije MITF, ciklina D1 i Bcl-2 proteina kao i enzima metaloproteinaza s istraživanim molekulama. Genetska preuredba MITF gena analizirana je metodom qReal-time PCR.
Rezultati: Molekule PD-1 i PD-L1 jače su izražene u melanomima svrstanim u kategoriju Breslow > 1.5 mm. Ekspresija PD-L1 proteina na tumorskim stanica gotovo uvijek iznosi > 50% kada je TIL u kategoriji BRISK B. U kategoriji BRISK B statistički je značajna razlika u ekspresiji PD-1 molekule (p=0.003). Nismo dokazali dominantno prisustvo određenih limfocita (CD8+ , CD4+ ili Treg) u nekom od kategorija TIL-a. Dokazana je statistički značajna korelacija ekspresije PD-1 i PD-L1 proteina s ekspresijom ciklina D1 u jezgri stanice i MITF te Bcl-2 proteina u citoplazmi tumorskih stanica stanica (p<0.001). Razlika u ekspresiji PD-L1 je statistički značajna ovisno o tome postoji li MUTF amplifikacija, u grupi metastaza(p=0.008). Nije pronađena povezanost između ekspresije metaloproteinaza s ekspresijom PD-1 i PD-L1 (p=0.723).
Zaključak: Ekspresija proteina uključenih u PD-1/PD-L1 signalni put regulirana je međusobnim djelovanjem stanice melanoma i stanica imunološkog sustava. Ovisi o smještaju limfocita i gustoći TIL-a, a ne o njihovoj vrsti. Ekspresija PD-L1 ovisna je o aktivnosti MITF čimbenika i njegovih ciljnih proteina, regulatora staničnog ciklusaSUMMARY
Objectives: Immunohistochemical methods and molecular diagnostic methods have
been used to examine the role of three groups of regulation: changes in the genetic
material and signalling pathways of the melanoma cell, regulation by the immune
system, and regulation by the enzyme of the tumour microenvironment. Patients and
methods: From a representative part of the melanoma tissue, 3 cylinders with a
diameter of 1 mm were used for the preparation of tissue microarrays (TMAs). The
study included 39 biopsies of primary melanoma (Breslow < 1.5 mm), 42 samples of
primary melanoma (Breslow > 1.5 mm) and 31 samples of metastatic melanoma. In
addition to determining the expression of the PD-1 and PD-L1 molecules, by
immunohistochemical staining of the CD3 molecule we identified tumour infiltrating
lymphocytes (TILs). Furthermore, we examined the presence of CD8+, CD4+ Foxp3+
and CD20+ B lymphocytes. TIL is classified into BRISK categories. The relationship
between the expression of MITF, cyclin D1 and Bcl-2 proteins, as well as the
metalloproteinase (MMPs) enzymes, and the investigated molecules has been
determined. The genetic rearrangement of the MITF gene was analysed using the
qReal-time PCR method. Results: PD-1 and PD-L1 are more strongly expressed in
melanomas categorized as Breslow > 1.5 mm. The expression of PD-1 and PD-L1
almost always > 50% when TIL is in BRISK B category. We did not prove the dominant
presence of certain lymphocytes (CD8+, CD4+ or Treg) in any of the TIL categories.
We proved a statistically significant correlation of expression of PD-1 and PD-L1
proteins with expression of cyclin D1 in the cell nucleus and MITF, as well as Bcl-2
proteins in the cytoplasm of tumour cells (p< 0.001). The difference in PD-L1
expression was statistically significant, depending on whether MITF amplification was
present, in the metastasis group (p=0.008). No correlation was found between the
expression of MMPs and the expression of PD-1 and PD-L1 (p=0.723). Conclusion:
The expression of proteins involved in the PD-1/PD-L1 signalling pathway is regulated
by the interaction of the melanoma cell and the immune system cells. It depends on
the location of the lymphocytes and the density of the TIL, not on their type. The
expression of PD-L1 is dependent on the activity of the MITF factor and its target
proteins, the cell cycle regulators