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Öğe Androgen receptor CAG repeat polymorphism might be a possible cause of familial constitutional delay of growth and puberty(Springer Science and Business Media Deutschland GmbH, 2024) Kağızmanlı, Gözde Akın; Sevim, Reyhan Deveci; Manyas, Hayrullah; Paketçi, Ahu; Demir, Korcan; Böber, Ece; Çatlı, Gönül; Anık, Ahmet; Abacı, AyhanBackground: Induction of puberty in boys with constitutional delay of growth and puberty (CDGP) through a short course of low-dose testosterone therapy indicates the critical interaction between testosterone and the androgen receptor (AR) during the activation and maturation of the hypothalamic-pituitary-gonadal axis at puberty onset. Previous studies have shown an inverse relationship between the CAG repeat length and the transactivation function or expression level of the AR gene. Objective: We aimed to investigate whether the AR CAG repeat polymorphism has any implications on pubertal delay. Subjects and methods: Thirty-three male patients with CDGP were enrolled in the study group, while 53 age-matched healthy individuals who had entered puberty on time were included in the control group. The CAG repeat length was determined through direct DNA sequencing analysis. Results: The median chronological age of boys with CDGP was 14.2 (14.1–14.6) years, compared to 14.2 (13.65–14.8) years for healthy subjects (p = 0.5). In the CDGP group, 22 (66.7%) children had a family history of the condition. There was no significant difference between the groups in terms of AR CAG repeat length (median AR CAG repeat length: 21 (20–24.5) and 20 (20–24), respectively, p = 0.1). However, in boys with CDGP with a similar family history (n = 22), a significantly longer AR CAG repeat length was found compared to the control group (n = 53) (median AR CAG repeat length: 22 (20–25) and 20 (20–24), respectively, p = 0.03). The median AR CAG repeat length in boys without a family history was 21 (20–22) triplets. Although boys with a family history had a slightly longer AR CAG repeat length than those without, the difference was not statistically significant (p = 0.07). Additionally, no significant differences were observed between boys with non-familial CDGP and control subjects (p = 0.8). Furthermore, no significant differences in anthropometric characteristics or hormonal parameters were found when patients with CDGP were categorized by AR CAG repeat length quartiles. Conclusion: This is the first study to investigate the role of AR CAG polymorphism in the etiopathogenesis of CDGP. Our findings suggest that the AR CAG repeat length may be associated with familial CDGP. © The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE) 2024.Öğe Changing trends in the etiology of cirrhosis in Türkiye: a multicenter nationwide study(Aves, 2024) Üçbilek, Enver; Yıldırım, Abdullah Emre; Ellik, Zeynep; Turan, İlker; Haktanıyan, Büşra; Karatay, EylemBackground/Aims: The aim of our study was to investigate the underlying causes behind the etiology of cirrhosis in T & uuml;rkiye.Materials and Methods: The study was comprised of patients with cirrhosis located in the gastroenterology clinics of 28 centers in T & uuml;rkiye between January 2000 and June 2021. Results: The study group consisted of 4953 cirrhotic patients (median age: 62.2 years, male / female: 58% / 42%). Among the patients, 39% of the patients were compensated, and 61% were decompensated. Furthermore, 47.5% had Child-Pugh class A, 38% had Child-Pugh class B, and 14.5% had Child-Pugh class C. The most frequent complaints were abdominal bloating (28%). Ascites (54.2%) was the most common manifestation of decompensation. The median Child-Pugh and MELD-Na scores were 7.0 and 10.0, respectively. The most common cause of cirrhosis was chronic viral hepatitis (43%), followed by cryptogenic cirrhosis (CC) (19%), metabolic dysfunc-tion-associated steatotic liver disease (MASLD)-related cirrhosis (13%), and alcohol-related cirrhosis (11%). Among the 950 patients with CC, 416 had metabolic abnormalities. If these 416 CC patients with metabolic abnormalities were categorized as having MASLD-related cirrhosis, the proportion of MASLD-related cirrhosis increased to 21%. Thirteen percent of the patients were diagnosed with HCC, while 4% had extrahepatic malignancy. Female breast cancer (18%) and colorectal cancer (18%) were the most frequent extra-hepatic malignancies. Conclusion: Viral hepatitis remains the main cause of cirrhosis in T & uuml;rkiye. However, its prevalence seems to be declining, whereas the prevalence of steatotic liver disease-related cirrhosis is increasingÖğe Association Between Body Mass Index and Survival in Patients with De Novo Metastatic Non-Small Cell Lung Cancer(International Scientific Information, Inc., 2024) Ürün, Müslih; Güner, Gürkan; Sezgin, Yasin; Sakin, Abdullah; Kılıçkap, SaadettinBackground: This retrospective study from a single center included 289 patients diagnosed with advanced non-small cell lung cancer (NSCLC) between 2010 to 2017 and aimed to evaluate the effects of body mass index (BMI) on overall survival. Material/Methods: This retrospective study involved 289 patients diagnosed with metastatic-stage NSCLC at a single institution between January 2010 and December 2017. Patients were categorized into 2 groups based on their BMI at diagnosis: those with a BMI <25 kg/m2 and those with a BMI 325 kg/m2. Univariate and multivariate Cox regression analyses were conducted to identify factors associated with overall survival. Results: A total of 289 patients (241 men, 48 women) were included in the study, with a mean age of 60.1±11.1 years. Among them, 175 patients (60.6%) had a BMI less than 25 kg/m2. Multivariate analysis revealed that BMI, pathological diagnosis, and complete response after first-line treatment were independently associated with survival in patients with lung cancer. Predicted survival time was significantly shorter in the BMI <25 group than in the BMI 325 group (9.3 months vs 13.0 months, P<0.05). Conclusions: The study demonstrated that a higher BMI at the time of diagnosis is associated with improved overall survival in patients with de novo metastatic NSCLC. BMI may serve as an important prognostic factor in this patient population. Future prospective, multi-center studies are necessary to further validate the role of BMI in predicting survival outcomes in NSCLC patients across different treatment modalities. © Med Sci Monit.Öğe Association of the Naples Prognostic Score with Long-Term Adverse Events in Chronic Limb-Threatening Ischemia After Below-the-Knee Endovascular Revascularization(Multidisciplinary Digital Publishing Institute (MDPI), 2024) Derviş, Emir; Hakgör, Aykun; Göksu, Muhammed Mert; Yakut, İdris; Konte, Hasan Can; Gürbak, İsmail; Kalkan, Ali Kemal; Pusuroğlu, Hamdi; Yalçın, Ahmet Arif; Ertürk, MehmetObjectives: Chronic limb-threatening ischemia (CLTI) is the most severe manifestation of peripheral artery disease (PAD) and is associated with high morbidity and mortality. The Naples prognostic score (NPS), a composite marker incorporating serum albumin, total cholesterol, neutrophil-to-lymphocyte ratio (NLR), and lymphocyte-to-monocyte ratio (LMR), has shown prognostic value in various cardiovascular conditions. This study aimed to evaluate the prognostic significance of the NPS in predicting all-cause mortality and any kind of amputation in patients with CLTI undergoing endovascular treatment (EVT) for below-the-knee (BTK) lesions. Methods: In this retrospective analysis, 191 patients diagnosed with CLTI and treated with EVT for BTK lesions between 2017 and 2023 were stratified into three groups based on the NPS: low (0–1), intermediate (2), and high (3–4). The primary endpoint was all-cause mortality, while the secondary endpoint was any kind of amputation. Results: A higher NPS was significantly associated with increased all-cause mortality (hazard ratio: 3.66; 95% confidence interval: 1.72–7.78; p < 0.001), while no significant association was observed between the NPS and major amputation. Independent predictors of mortality included a high NPS, reduced left ventricular ejection fraction, and impaired renal function. Conclusions: The NPS is an independent predictor of long-term mortality in CLTI patients undergoing EVT for BTK lesions. © 2024 by the authors.Öğe Associations Between Echocardiographic Right Heart Measurements With Short-Term Prognosis in Heart Failure: A Prospective Study(John Wiley and Sons Inc, 2024) Dinç Asarcıklı, Lale; İnan, Duygu; Murat, Selda; Çöllüoğlu, İnci Tuğçe; Bakhshaliyev, Nijat; Ulutaş, Zeynep; Çabuk, Gizem; Hasırcı, Senem; Naser, Abdulrahman; Ünal Dayı, Şennur; Çelik, Ahmet; Güvenç, Tolga SinanBackground: Echocardiographic right ventricular (RV) dysfunction is a strong risk determinant for prognosis in patients with heart failure (HF). Although parameters of RV systolic function are widely used to define RV dysfunction, there is scarce data to suggest these parameters are best suited to predict HF-related outcomes. Aims: We aimed to understand which morphologic or functional parameters are most closely associated with short-term mortality and HF-related hospitalization in patients with HF. Methods: A total of 191 patients from eight study centers were included to this study. A detailed echocardiographic examination was done at enrollment, and patients were followed up for 6 months via direct interviews or phone calls. Results: All right-sided echocardiographic parameters other than tricuspid annular plane systolic excursion were associated with outcomes. In a proportional hazards model that included right-heart parameters, RV longitudinal diameter (HR: 1.07, 95%CI: 1.04–1.10, p < 0.001), wall thickness (HR: 1.3, 95%CI: 1.13–1.50, p < 0.001), and tricuspid annular systolic velocity (HR: 0.90, 95%CI: 0.82–0.96, p = 0.02) were found as the independent predictors. However, only RV longitudinal dimension (HR: 1.04, 95%CI: 1.01–1.08, p = 0.01) and RV wall thickness (HR: 1.32, 95%CI: 1.10–1.60, p = 0.004) were associated with short-term outcomes after adjusting for other clinical and left-sided echocardiographic variables. On a Bayesian logistic regression model that included right-sided echocardiography variables, there was strong evidence for including either RV longitudinal diameter (BF10: 190.4) or wall thickness (BF10: 30.7) to the final model. Conclusion: Parameters of RV morphology were better predictors of short-term outcomes in HF patients. © 2024 Wiley Periodicals LLC.Öğe Can Serum Albumin Level At Diagnosis Be A Guide for Clinical Features, Time to Treatment, and Response in Patients with Follicular Lymphoma?(2024) Karışmaz Abdülkadir; Gülbağcı, Burcu; Eren, Rafet; Aslan, Ceyda; Suyanı, ElifAim: The aim of the present study was to determine the association between serum albumin level and treatment demand, time to treatment and treatment response in patients with follicular lymphoma (FL). Materials and Methods: We retrospectively evaluated the data of 25 FL patients. The data comprised gender, age, lactate dehydrogenase (LDH) level, number of nodal sites, presence of extranodal involvement, B symptoms and bulky mass, presence of bone marrow, liver and spleen involvement, Follicular Lymphoma International Prognostic Index score, Eastern Cooperative Oncology Group (ECOG) performance score, tumor grade, albumin level, globulin level, white blood cell count, platelet count and hemoglobin level at diagnosis; treatment demand, time to treatment, and response to treatment. Results: The median age of the patients was 53 years. The patients were divided into 2 groups according to the median albumin level as >4.4 gr/dL and <4.4 gr/dL. While 13 (52%) patients had an albumin level of <= 4.4 gr/dL, 12 (48%) patients had an albumin level of >4.4 gr/dL. Two groups were comparable in terms of treatment demand, time to treatment and treatment response in patients who were applied treatment (p>0.05). No correlation was found between the level of serum albumin and the need for treatment in patients with FL. Conclusion: FL, constituting approximately 20% of all non-hodgkin lymphomas, is the second most common lymphoma in adults. The age, LDH and hemoglobin levels, ECOG performance score, stage, extranodal, involvement, number of nodal sites involved, beta 2 microglobulin level, bone marrow involvement, presence of B symptoms and bulky mass are the conventional risk factors used to determine prognosis in FL. Although we found that treatment requirement was higher and time to treatment was shorter in patients with low serum albumin levels, they did not reach a statistical significance.Öğe A review on hydrogen sulfide: Is it pro-nociceptive or anti-nociceptive?(İstanbul Üniversitesi Yayınevi, 2022) Eken, Hazal; Bektaş, NurcanPain is sensed by the activation of painful nociceptors in the periphery or by pain mediators, such as bradykinin, serotonin, histamine, and prostaglandin, released from the damaged tissue, afferent transmission to the medulla spinalis, and by trans- mission stages to the high centers over the dorsal horn. Pain, which was seen as only a warning sign in the past, is now ac- cepted as a phenomenon in itself that needs to be treated and the search for new, stronger active substances with fewer side effects in the treatment of pain is in demand. Hydrogen sulfide (H 2S) is a modulator of T-type Ca+2 channels, especially in Cav3.2, which are known to play a critical role in the processing of pain. H2S can also show an anti-nociceptive effect by open- ing K + channels and blocking nociceptors. Exciting preclinical data has demonstrated that H2S-derived Non-steroidal anti- inflammatory drugs (NSAIDs) and analgesic agents can be used to treat various types of pain. H2S increases the resistance of gastric mucosa against injury occurred by drugs used for pain relief and accelerates its repair, so it provides an advantage to derivatized drugs. In addition, H2S donors have also been shown to induce analgesia through μ-opioid receptors. Based on the studies, it is thought that the combination of H2S with opioid receptor agonists may provide an additive or even synergistic analgesic effect. It is estimated that the modification of H2S, with currently used analgesic drugs to prevent various side ef- fects and increase analgesic effects, is a promising and wise approach.Öğe Defective kinase activity of IKKα leads to combined immunodeficiency and disruption of immune tolerance in humans(Nature Research, 2024) Çıldır, Gökhan; Aba, Ümran; Pehlivan, Damla; Tvorogov, Denis; Warnock, Nicholas I.; İpşir, Canberk; Arık, Elif; Kok, Chung Hoow; Bozkurt, Ceren; Tekeoğlu, Sidem; İnal, Gaye; Cesur, Mahmut; Küçükosmanoğlu, Ercan; Karahan, İbrahim; Savaş, Berna; Balcı, Deniz; Yaman, Ayhan; Demirbaş, Nazlı Deveci; Tezcan, İlhan; Haskoloğlu, Şule; Doğu, Figen; İkincioğulları, Aydan; Keskin, Özlem; Tümes, Damon J.; Erman, BaranIKKα is a multifunctional serine/threonine kinase that controls various biological processes, either dependent on or independent of its kinase activity. However, the importance of the kinase function of IKKα in human physiology remains unknown since no biallelic variants disrupting its kinase activity have been reported. In this study, we present a homozygous germline missense variant in the kinase domain of IKKα, which is present in three children from two Turkish families. This variant, referred to as IKKαG167R, is in the activation segment of the kinase domain and affects the conserved (DF/LG) motif responsible for coordinating magnesium atoms for ATP binding. As a result, IKKαG167R abolishes the kinase activity of IKKα, leading to impaired activation of the non-canonical NF-κB pathway. Patients carrying IKKαG167R exhibit a range of immune system abnormalities, including the absence of secondary lymphoid organs, hypogammaglobulinemia and limited diversity of T and B cell receptors with evidence of autoreactivity. Overall, our findings indicate that, unlike a nonsense IKKα variant that results in early embryonic lethality in humans, the deficiency of IKKα‘s kinase activity is compatible with human life. However, it significantly disrupts the homeostasis of the immune system, underscoring the essential and non-redundant kinase function of IKKα in humans. © The Author(s) 2024.Öğe The effect of lactobacillus rhamnosus GG in infants with food protein-induced allergic proctocolitis(Galenos publishing house, 2024) Avcı, Özgecan; Usta, Merve; Kaya, Ayşenur; Kaya, Nesrin; Urgancı, NafiyeBACKGROUND/AIMS: Most infants with food protein-induced allergic proctocolitis (FPIAP) achieve clinical tolerance between 1 and 3 years of age. The aim of this study was to investigate the effect of Lactobacillus rhamnosus GG on the development of tolerance in infants who are exclusively breastfed and diagnosed with FPIAP. MATERIALS AND METHODS: Sixty infants with FPIAP were divided into two groups: group 1 (study); who received probiotic Lactobacillus rhamnosus GG for 3 months, and group 2 (control); who did not. Clinical characteristics, allergy tests, and tolerance development were examined. RESULTS: Thirty patients [mean age: 3.9 +/- 1.3, range: 2-6 months, male/female (M/F): 1.7] in group 1 and 30 patients (mean age: 4.1 +/- 1.3, range: 1.4-6 months, M/F: 0.7) in group 2 were included in the study. The reintroduction of trigger foods into the mothers' diet at 9 months was significantly higher in group 1 than in group 2 (63.3% versus 26.7% of the patients, respectively, p=0.004). No significant difference was observed in terms of the resolution time of symptoms and time of tolerance development between groups and subgroups. CONCLUSION: A significant difference was observed in the mean time to reintroduce trigger foods into the maternal diet, the number of mothers who first reintroduced trigger foods back into their diet at 9 months, and the resolution of symptoms at 9 and 12 months in infants with multiple food allergies.Öğe Long-term mortality risk in obstructive sleep apnea: the critical role of oxygen desaturation index(Springer Science and Business Media Deutschland GmbH, 2024) Azaklı, Damla; Satıcı, Celal; Sokucu, Sinem Nedime; Aydın, Şenay; Atasever, Furkan; Özdemir, CengizBackground: Mortality predictors in obstructive sleep apnea (OSA) patients yet to be comprehensively understood, especially within large cohorts undergoing long-term follow-up. We aimed to determine the independent predictors of mortality in OSA patients. Methods: In our retrospective cohort study, 3,541 patients were included and survival data was obtained from electronic medical records. Demographic characteristics, anthropometric measurements, comorbidities, laboratory tests, and polysomnography parameters were analyzed for the survived and deceased patient groups. Univariate and multivariate Cox regression analyses were performed to determine independent predictors of all-cause mortality in patients followed for at least 5 years. Results: Among all patients, 2,551 (72%) patients were male, with a mean age of 49.7 years. 231 (6.5%) patients had died. Deceased patients were significantly older and had higher waist-to-hip ratio and Epworth Sleepiness Scale (p < 0.001, p < 0.001, p = 0.003). OSA (nonpositional and not-rapid eye movement-related), periodic limb movements in sleep and Comorbidities of Sleep Apnea Score ≥ 1 were found to be associated with increased mortality (p < 0.001). Systemic immune-inflammation index was also significantly higher in the deceased group (p < 0.001). Higher oxygen desaturation index (ODI) and apnea-hypopnea index (AHI) were associated with increased mortality (p < 0.001). Due to the high correlation between ODI and AHI, two separate multivariate Cox regression models were created. While AHI lost its significance in the multivariate analysis, ODI remained significantly higher in the deceased patient group (HR = 1.007, 1.001–1.013, p = 0.01). Conclusion: ODI, as the only polysomnography parameter, emerged as an independent predictor of mortality in OSA patients. © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2024.Öğe Managing recurrent parvovirus B19-associated anemia after a pediatric kidney transplant(Springer, 2024) Sabancı, Mehmet; Taşdemir, Mehmet; Öksüz, Burcu; Torun, Yasemin Altuner; Sütçü, Murat; Özkaya, OzanA 13-year-old girl who had a kidney transplant four weeks prior presented with a 10-day history of fatigue, paleness, and headache. On physical examination, tachycardia and paleness were noted. Laboratory testing was notable for severe anemia and mild leukopenia and thrombocytopenia. Polymerase chain reaction (PCR) test for Epstein-Barr virus (EBV) and cytomegalovirus (CMV) were negative and for parvovirus B19 (PVB19) was positive. Despite lower immunosuppression and administration of intravenous immunoglobulin (IVIG) it persisted for 15 months, and frequent red blood cell transfusions were needed. PVB19 is a less common but significant complication. The patient's clinical course demonstrates the importance of this complication and the challenges in its management. A notable void exists in the literature regarding standardized treatment protocols for PVB19-induced recurrent anemia after kidney transplant. This case indicates the need for further research and consensus to guide effective clinical interventions in similar cases.Öğe Long-term Home Mechanical Ventilation of Children in İstanbul(AVES, 2025) Yanaz, Mürüvvet; Ünal, Füsun; Hepkaya, Evrim; Yazan, Hakan; Can Oksay, Sinem; Köstereli, Ebru; Yılmaz Yeğit, Cansu; Başkan, Azer Kılıç; Onay, Zeynep Reyhan; Gulieva, Aynur; Soyyiğit, Aslınur; Kalyoncu, Mine; Küçük, Hanife Büşra; Ayhan, Yetkin; Ergenekon, Almala Pınar; Atağ, Emine; Uzuner, Selçuk; İkizoğlu, Nilay Baş; Kılınç, Ayşe Ayzıt; Ay, Pınar; Eralp, Ela Erdem; Gökdemir, Yasemin; Öktem, Sedat; Çakır, Erkan; Girit, Saniye; Uyan, Zeynep Seda; Çokuğraş, Haluk; Ersu, Refika; Karadağ, Bülent; Karakoç, FaziletOBJECTIVE: The aims of this multi-center study were to describe the characteristics of children receiving long-term home mechanical ventilation (HMV) in İstanbul and to compare the patients receiving non-invasive and invasive ventilation. MATERIAL AND METHODS: This cross-sectional multicenter study included all children receiving long-term HMV followed by admission to six tertiary hospitals. The data were collected between May 2020 and May 2021. Demographic data and data regarding HMV were collected from the patient charts. RESULTS: The study included 416 participants. The most common diagnoses were neuromuscular (35.1%) and neurological diseases (25.7%). Among the patients, 49.5% (n = 206) received non-invasive ventilation (NIV), whereas 50.5% (n = 210) received invasive ventilation. The median age at initiation was significantly younger in the invasive ventilation group than in the NIV group (10 vs. 41 months, P < 0.001). Most subjects in the NIV group (81.1%) received ventilation support only during sleep, whereas most subjects in the invasive ventilation group (55.7%) received continuous ventilator support (P < 0.001). In addition to ventilation support, 41.9% of the subjects in the invasive ventilation group and 28.6% in the NIV group received oxygen supplementation (P = 0.002). Within the last year, 59.1% (n = 246) of the subjects were hospitalized. The risk factors for hospitalization were invasive ventilation, continuous ventilatory support, oxygen supplementation, tube feeding, and swallowing dysfunction (P = 0.002, 0.009, <0.001, <0.001 and <0.001 respectively). CONCLUSION: Despite the increasing use of NIV in most studies, half of the study population received invasive ventilation. Patients receiving invasive ventilation were more likely to require continuous ventilator support and oxygen supplementation and were at increased risk of hospitalization. © 2025 The Author.Öğe Kidney transplantation in children and adolescents with C3 glomerulopathy or immune complex membranoproliferative glomerulonephritis: a real-world study within the CERTAIN research network(Springer, 2024) Patry, Christian; Webb, Nicholas J. A.; Feisst, Manuel; Krupka, Kai; Becker, Jan; Bald, Martin; Antoniello, Benedetta; Bilge, Ilmay; Gülhan, Bora; Hogan, Julien; Kanzelmeyer, Nele; Özkaya, Ozan; Buescher, Anja; Sellier-Leclerc, Anne-Laure; Shenoy, Mohan; Weber, Lutz T.; Fichtner, Alexander; Hoecker, Britta; Meier, MatthiasBackgroundComplement 3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) are ultra-rare chronic kidney diseases with an overall poor prognosis, with approximately 40-50% of patients progressing to kidney failure within 10 years of diagnosis. C3G is characterized by a high rate of disease recurrence in the transplanted kidney. However, there is a lack of published data on clinical outcomes in the pediatric population following transplantation.MethodsIn this multicenter longitudinal cohort study of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, we compared the post-transplant outcomes of pediatric patients with C3G (n = 17) or IC-MPGN (n = 3) with a matched case-control group (n = 20).ResultsEleven of 20 children (55%) with C3G or IC-MPGN experienced a recurrence within 5 years post-transplant. Patients with C3G or IC-MPGN had a 5-year graft survival of 61.4%, which was significantly (P = 0.029) lower than the 5-year graft survival of 90% in controls; five patients with C3G or IC-MPGN lost their graft due to recurrence during this observation period. Both the 1-year (20%) and the 5-year (42%) rates of biopsy-proven acute rejection episodes were comparable between patients and controls. Complement-targeted therapy with eculizumab, either as prophylaxis or treatment, did not appear to be effective.ConclusionsThese data in pediatric patients with C3G or IC-MPGN show a high risk of post-transplant disease recurrence (55%) and a significantly lower 5-year graft survival compared to matched controls with other primary kidney diseases. These data underscore the need for post-transplant patients for effective and specific therapies that target the underlying disease mechanism.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary informationÖğe Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma(Massachussetts Medical Society, 2024) Facon, Thierry; Dimopoulos, Meletios Athanasios; Leleu, Xavier P.; Beksaç, Meral; Pour, Ludek; Hájek, Roman; Liu, Zhuogang; Minarik, Jiri; Moreau, Philippe; Romejko Jarosinska, Joanna; Spicka, Ivan; Vorobyev, Vladimir I.; Besemer, Britta; Ishida, Tadao; Janowski, Wojciech; Kalayoğlu Beşisik, Sevgi; Parmar, Gurdeep; Robak, Pawel; Zamagni, Elena; Goldschmidt, Hartmut; Martin, Thomas G.; Manier, Salomon; Mohty, Mohamad; Oprea, Corina; Brégeault, Marie France; Macé, Sandrine; Berthou, Christelle; Bregman, David; Klippel, Zandra; Orlowski, Robert Z.Background Bortezomib, lenalidomide, and dexamethasone (VRd) is a preferred first-line treatment option for patients with newly diagnosed multiple myeloma. Whether the addition of the anti-CD38 monoclonal antibody isatuximab to the VRd regimen would reduce the risk of disease progression or death among patients ineligible to undergo transplantation is unclear. Methods In an international, open-label, phase 3 trial, we randomly assigned, in a 3:2 ratio, patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation to receive either isatuximab plus VRd or VRd alone. The primary efficacy end point was progression-free survival. Key secondary end points included a complete response or better and minimal residual disease (MRD)-negative status in patients with a complete response. Results A total of 446 patients underwent randomization. At a median follow-up of 59.7 months, the estimated progression-free survival at 60 months was 63.2% in the isatuximab-VRd group, as compared with 45.2% in the VRd group (hazard ratio for disease progression or death, 0.60; 98.5% confidence interval, 0.41 to 0.88; P<0.001). The percentage of patients with a complete response or better was significantly higher in the isatuximab-VRd group than in the VRd group (74.7% vs. 64.1%, P=0.01), as was the percentage of patients with MRD-negative status and a complete response (55.5% vs. 40.9%, P=0.003). No new safety signals were observed with the isatuximab-VRd regimen. The incidence of serious adverse events during treatment and the incidence of adverse events leading to discontinuation were similar in the two groups. Conclusions Isatuximab-VRd was more effective than VRd as initial therapy in patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation. © 2024 Massachusetts Medical Society.Öğe Intravenous high-dose anakinra drops venous thrombosis and acute coronary syndrome in severe and critical COVID-19 patients: a propensity score matched study(Nature portfolio, 2024) Çakmak, Ramazan; Yüce, Servet; Ay, Mustafa; Uyar, Muhammed Hamdi; Kılıç, Muhammed İkbal; Bektaş, MuratIn our study, we aimed to evaluate the effect of high-dose intravenous anakinra treatment on the development of thrombotic events in severe and critical COVID-19 patients. This retrospective observational study was conducted at a tertiary referral center in Aksaray, Turkey. The study population consisted of two groups as follows; the patients receiving high-dose intravenous anakinra (anakinra group) added to background therapy and the patients treated with standard of care (SoC) as a historical control group. Age, gender, mcHIS scores, and comorbidities such as diabetes mellitus, hypertension, and coronary heart disease of the patients were determined as the variables to be matched. We included 114 patients in SoC and 139 patients in the Anakinra group in the study. Development of any thromboembolic event (5% vs 12.3%, p = 0.038; OR 4.3) and PTE (2.9% vs 9.6%, p = 0.023; OR 5.1) were lower in the Anakinra group than SoC. No patient experienced cerebrovascular accident and/or clinically evident deep venous thrombosis both in two arms. After 1:1 PS matching, 88 patients in SoC and 88 patients in the Anakinra group were matched and included in the analysis. In survival analysis, the development of any thromboembolic event, pulmonary thromboembolism, and acute coronary syndrome (ACS) were higher in SoC compared to Anakinra. Survival rate was also lower in patients with SoC arm than Anakinra in patients who had any thromboembolic event as well as ACS. In our study, the development of thrombosis was associated with hyperinflammation in patients with severe and critical COVID-19. Intravenous high-dose anakinra treatment decreases both venous and arterial events in patients with severe and critical COVID-19.Öğe Prevalence of EGFR mutations in patients with resected stages I to III NSCLC: results from the EARLY-EGFR study(Elsevier, 2024) Soo, Ross A.; Reungwetwattana, Thanyanan; Perroud, Herman Andres; Batra, Ullas; Kılıçkap, Saadettin; Tejado Gallegos, Luis Fernand; Donner, Natalia; Alsayed, Mohamed; Huggenberger, Reto; Van Tu, DaoIntroduction: There is limited literature on the prevalence of EGFR mutations in early stage NSCLC. EARLY-EGFR (NCT04742192), a cross-sectional study, determined the prevalence of EGFR mutations in early stage NSCLC. Methods: This noninterventional, real-world study enrolled consecutive patients with resected stages IA to IIIB (American Joint Committee on Cancer eighth edition) NSCLC from 14 countries across Asia, Latin America, and the Middle East and Africa. The primary end point was prevalence of EGFR mutations and secondary end points included prevalence of EGFR mutation subtypes and treatment patterns. Results: Of 601 patients (median [range] age: 62.0 [30.0–86.0] y) enrolled, 52.7% were females and 64.2% were nonsmokers. Most had stages IA to IB NSCLC (64.1%) and adenocarcinoma (98.7%). Overall prevalence of EGFR mutations was 51.0%; most reported exon 19 deletions (48.5%) followed by exon 21 L858R mutations (34.0%). Women had a higher EGFR mutation rate than men (64.0% versus 36.4%). Compared with no EGFR mutations, patients with EGFR mutations were more likely to be nonsmokers (35.1% versus 60.9%) and have stage I NSCLC than stages II and III NSCLC (54.8% versus 47.3% and 35.6%). Systemic adjuvant therapy was planned in 33.8% of the patients with stages IB to IIIB disease and adjuvant chemoradiotherapy in 6.8%. Age above or equal to 60 years, females, and Asians were found to have a significantly (p < 0.05) higher odds of EGFR mutations, whereas smoking history and stage III disease had lower odds of EGFR mutations. Conclusions: The EARLY-EGFR study provides an overview of EGFR mutations and subtype prevalence in patients with early stage NSCLC. The study highlights the limited adherence to treatment guidelines suggesting an unmet need for improved adjuvant therapy.Öğe Safety and efficiency of Wharton's Jelly-derived mesenchymal stem cell administration in patients with traumatic brain injury: First results of a phase I study(Baishideng publishing group, 2024) Kabataş, Serdar; Civelek, Erdinç; Boyalı, Osman; Sezen, Gülseli Berivan; Özdemir, Ömer; Bahar-Özdemir, Yeliz; Kaplan, Necati; Savrunlu, Eyüp Can; Karaöz, ErdalBACKGROUND Traumatic brain injury (TBI) is characterized by a disruption in the normal function of the brain due to an injury following a trauma, which can potentially cause severe physical, cognitive, and emotional impairment. Stem cell transplantation has evolved as a novel treatment modality in the management of TBI, as it has the potential to arrest the degeneration and promote regeneration of new cells in the brain. Wharton's Jelly-derived mesenchymal stem cells (WJ-MSCs) have recently shown beneficial effects in the functional recovery of neurological deficits. AIM To evaluate the safety and efficiency of MSC therapy in TBI. METHODS We present 6 patients, 4 male and 2 female aged between 21 and 27 years who suffered a TBI. These 6 patients underwent 6 doses of intrathecal, intramuscular (i.m.) and intravenous transplantation of WJ-MSCs at a target dose of 1 x 10(6)/kg for each application route. Spasticity was assessed using the Modified Ashworth scale (MAS), motor function according to the Medical Research Council Muscle Strength Scale, quality of life was assessed by the Functional Independence Measure (FIM) scale and Karnofsky Performance Status scale. RESULTS Our patients showed only early, transient complications, such as subfebrile fever, mild headache, and muscle pain due to i.m. injection, which resolved within 24 h. During the one year follow-up, no other safety issues or adverse events were reported. These 6 patients showed improvements in their cognitive abilities, muscle spasticity, muscle strength, performance scores and fine motor skills when compared before and after the intervention. MAS values, which we used to assess spasticity, were observed to statistically significantly decrease for both left and right sides (P < 0.001). The FIM scale includes both motor scores (P < 0.05) and cognitive scores (P < 0.001) and showed a significant increase in pretest posttest analyses. The difference observed in the participants' Karnofsky Performance Scale values pre and post the intervention was statistically significant (P < 0.001). CONCLUSION This study showed that cell transplantation has a safe, effective and promising future in the management of TBI.Öğe Sacituzumab govitecan versus docetaxel for previously treated advanced or metastatic non-small cell lung cancer: the randomized, open-label phase III EVOKE-01 study(Lippincott williams and wilkins, 2024) Paz-Ares, Luis G.; Juan-Vidal, Oscar; Mountzios, Giannis S.; Felip, Enriqueta; Çiçin, İrfanPURPOSEThe open-label, phase III EVOKE-01 study evaluated sacituzumab govitecan (SG) versus standard-of-care docetaxel in metastatic non-small cell lung cancer (mNSCLC) with progression on/after platinum-based chemotherapy, anti-PD-(L)1, and targeted treatment for actionable genomic alterations (AGAs). Primary analysis is reported.METHODSPatients were randomly assigned 1:1 (stratified by histology, best response to last anti-PD-(L)1-containing regimen, and AGA treatment received or not) to SG (one 10 mg/kg intravenous infusion on days 1 and 8) or docetaxel (one 75 mg/m2 intravenous infusion on day 1) in 21-day cycles. Primary end point was overall survival (OS). Key secondary end points were investigator-assessed progression-free survival (PFS), objective response rate, patient-reported symptom assessment, and safety.RESULTSIn the intention-to-treat population (SG, n = 299; docetaxel, n = 304), 55.4% had one previous line of therapy. Median follow-up was 12.7 months (range, 6.0-24.0). The primary end point was not met. There was a numerical OS improvement for SG versus docetaxel (median, 11.1 v 9.8 months; hazard ratio [HR], 0.84 [95% CI, 0.68 to 1.04]; one-sided P = .0534), consistent across squamous and nonsquamous histologies. Median PFS was 4.1 versus 3.9 months (HR, 0.92 [95% CI, 0.77 to 1.11]). An OS benefit was observed for SG (n = 192) versus docetaxel (n = 191) in mNSCLC nonresponsive to last anti-PD-(L)1-containing regimen (3.5-month median OS increase; HR, 0.75 [95% CI, 0.58 to 0.97]); this was consistent across histologies. Among patients receiving SG and docetaxel, 6.8% and 14.2% discontinued because of treatment-related adverse events (TRAEs), respectively; 1.4% and 1.0%, respectively, had TRAEs leading to death.CONCLUSIONAlthough statistical significance was not met, OS numerically improved with SG versus docetaxel, which was consistent across histologies. Clinically meaningful improvement in OS was noted in mNSCLC nonresponsive to last anti-PD-(L)1-containing regimen. SG was better tolerated than docetaxel and consistent with its known safety profile, with no new safety signals.Öğe Impact of opioid analgesics on survival in cancer patients receiving immune checkpoint inhibitors(Springer, 2024) Kavgacı, Gözde; Güven, Deniz Can; Kaygusuz, Yunus; Karaca, Ece; Dizdar, Ömer; Kılıçkap, Saadettin; Aksoy, Sercan; Erman, Mustafa; Yalçın, SuayibPurpose This study aimed to assess the effects of concurrent opioid analgesic (OA) use with immune checkpoint inhibitors (ICIs) on progression-free survival (PFS) and overall survival (OS). Methods In this observational retrospective study, we included advanced cancer patients who received ICIs at Hacettepe University Hospital's Department of Medical Oncology between June 2018 and January 2023. Results Our study included 375 recurrent or metastatic cancer patients treated with ICIs in the first, second line, or beyond. There were no significant differences between the OA-treated and OA-untreated groups regarding median age, age group, gender, primary tumor location, ICI type, or the presence of baseline liver and lung metastases. However, the OA-treated group exhibited a significantly higher proportion of patients who had received three or more prior treatments before initiating ICIs (p = 0.015). OA-Untreatment was significantly correlated with prolonged mPFS (6.83 vs. 4.30 months, HR 0.59, 95% CI 0.44-0.79, p < 0.001) and mOS (17.05 vs. 7.68 months, HR 0.60, 95% CI 0.45-0.80, p < 0.001). Conclusions Our study demonstrates an association between the concurrent use of OAs and reduced OS and PFS in patients treated with ICIs. While OA treatment serves as a surrogate marker for higher disease burden, it may also suggest a potential biological relationship between opioids and immunotherapy efficacy.Öğe Biohybrids for Combined Therapies of Skin Wounds: Agglomerates of Mesenchymal Stem Cells with Gelatin Hydrogel Beads Delivering Phages and Basic Fibroblast Growth Factor(Multidisciplinary Digital Publishing Institute (MDPI), 2024) Moghtader, Farzaneh; Tabata, Yasuhiko; Karaöz, ErdalThere is great interest in developing effective therapies for the treatment of skin wounds accompanied by deep tissue losses and severe infections. We have attempted to prepare biohybrids formed of agglomerates of mesenchymal stem cells (MSCs) with gelatin hydrogel beads (GEL beads) delivering bacteriophages (phages) as antibacterial agents and/or basic fibroblast growth factor (bFGF) for faster and better healing, providing combined therapies for these types of skin wounds. The gelatin beads were produced through a two-step process using basic and/or acidic gelatins with different isoelectric points. Escherichia coli (E. coli) and its specific T4 phages were propagated. Phages and/or bFGF were loaded within the GELs and their release rates and modes were obtained. The phage release from the basic GEL beads was quite fast; in contrast, the bFGF release from the acidic GEL beads was sustained, as anticipated. MSCs were isolated from mouse adipose tissues and 2D-cultured. Agglomerates of these MSCs with GEL beads were formed and maturated in 3D cultures, and their time-dependent changes were followed. In these 3D culture experiments, it was observed that the agglomerates with GEL beads were very healthy and the MSCs formed tissue-like structures in 7 days, while the MSC agglomerates were not healthy and shrunk considerably as a result of cell death.
