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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.Öğe Microsurgical Resection of a PediatricTegmentum Tumor Through the Paramedian Supracerebellar Transtentorial Approach with the Tentorial Cut Technique: 2-Dimensional Operative Video(Lippincott Williams and Wilkins, 2024) Rahmanov, Serdar; Doǧruel, Yücel; Güngör, Abuzer; Türe, UǧurThe brainstem contains a highly complex group of nuclei and major white matter tracts within a small volume.1 The complex nature of its anatomy creates challenges for surgery in this area, impeding the standardization of approaches. Therefore, the concept of the "safe entry zone" should be considered with caution, and the strategy for each patient should be tailored based on the relevant subunit of the brainstem and individual patient characteristics. The critical parameter to target in patients is achieving the highest possible extent of resection while preserving function.1 The paramedian supracerebellar transtentorial approach is usually suitable for midbrain lesions. This approach allows for targeting tegmental tumors through the posterolateral midbrain surface.1 It is typically performed through a paramedian suboccipital craniotomy, ideally with the patient in the semisitting position, and is now considered a standard and safe approach.2 In patients with a spontaneous atrial right-to-left shunt, lateral or semilateral positions are viable alternatives, with the semilateral preferred for intraoperative magnetic resonance imaging.1 The cerebellar hemispheric tentorial bridging veins are usually located in the surgical route, narrowing the surgical corridor.3 Sacrifice or unintended rupture of these veins can sometimes lead to unexpected serious complications. Therefore, it is essential to preserve these veins during supracerebellar approaches.3 In this study, we demonstrate the resection of a pediatric tegmentum tumor through the left-sided paramedian supracerebellar transtentorial approach. In addition, we show the tentorial cut technique used to preserve the cerebellar hemispheric tentorial bridging veins. The patient's parents consented to the procedure and to the publication of his image. © 2024 Lippincott Williams and Wilkins. All rights reserved.Öğe Hand, foot, and mouth disease: could EPs® 7630 be a treatment option? a prospective randomized open-label multicenter clinical study(Frontiers media, 2024) Sütçü, Murat; Kara, Manolya; Yıldız, Funda; Kılıç, Ömer; Tural Kara, Tuğçe; Akkoç, Gülşen; Büyükçam, Ayşe; Elmas Bozdemir, Şefika; Özgür Gündeşlioğlu, Özlem; Gül, Doruk; İseri Nepesov, Merve; Kara, AteşPurpose Hand, foot and mouth disease (HFMD) is a viral contagious disease of children caused by human enteroviruses (EVs) and coxsackieviruses (CVs). There is no specific treatment option for HFMD. EPs (R) 7630's anti-infective and immunomodulatory properties have previously been demonstrated in several in vitro and in vivo studies; however, the use of this herbal medicine in children with HFMD has not previously been investigated. Methods This prospective randomized multicenter clinical study included 208 children with HFMD. The diagnosis was made by pediatricians. The patients who were within the first 48 h of symptom onset (according to the first onset of fever and skin findings) were enrolled. The study participants were assigned into 2 groups as EPs (R) 7630 and control groups. All patients were followed up twice more, 48 h after the first admission and on the 5th-7th day. Another phone evaluation was conducted for those with continued complaints from the previous visit. Results The median age was 27 (12-112) months. The male-female ratio was 0.98. One hundred thirty one (63%) of 190 patients had no history of household contact. EPs (R) 7630 group included 94 and control group included 96 patients. A significant difference was found between the groups in terms of complaint scores at the visits made at the 48th h of the treatment and on days 5-7 (p < 0.001). The mean +/- SD disease duration of EPs (R) 7630 users was significantly shorter 6.07 +/- 0.70 days (95% CI: 5.92-6.21)] than the control group [8.58 +/- 0.94 days (95% CI: 8.39-8.77)] (p < 0.001). Besides, the hospitalization rate among the EPs (R) 7630 users were significantly lower (p = 0.019). No side effects were observed, except for unpleasant taste, which was reported in 5 patients (EPs (R) 7630 group). Conclusion Considering its efficacy and safety profile EPs (R) 7630 may represent a feasible herbal-based treatment option for children with HFMD. Clinical Trial Registration ClinicalTrials.gov, identifier (NCT06353477).Öğe Peripheral blood stem cells mobilization in patients with relapsed or refractory lymphomas: A single‑center experience(Wolters kluwer medknow publications, 2024) Halaçoglu, Aysun; Şerefhanoğlu, SongülContext: High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (AHSCT) is an established treatment for chemosensitive patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Aims: We present the results of using different salvage chemotherapy plus granulocyte colony stimulating factor (G-CSF) for mobilization of peripheral blood stem cells in R/R lymphoma patients. Subjects and Methods: For salvage chemotherapy, 93 patients received platinum-containing regimens, 4 patients received cytarabine-containing regimens, and 5 patients received other regimens. Patient distributions were HL (n = 35) and NHL (n = 67). Results: In 87.2% of patients, first mobilization trial was successful (>2 × 106 CD34+ cells/kg). In 58.8% of patients, first apheresis season >5 × 106 CD34+ cells/kg collections was achieved. All 12.7% of patients were poorly mobilized at the first mobilization. There was no statistical difference between the previous chemotherapy numbers and failed mobilization (P > 0.05). Five patients who were poorly mobilized and 4 patients who were successfully mobilized underwent a previous radiotherapy (P < 0.05). Thirteen patients who were poorly mobilized in the first mobilization underwent a platinum-containing salvage regimen. At the time of the first mobilization, the average peripheral CD 34 counts in the successfully mobilized group were statistically higher than that in the poorly mobilized group (P < 0.01). Conclusions: We demonstrated that peripheral CD 34 cell count in the peripheral blood on the first apheresis day was a significant factor for more stem cell mobilization, fewer apheresis sessions, less volume, and earlier neutrophil engraftment for patients with R/R lymphoma and eligible for AHSCT. The history of the previous radiotherapy was a significant factor for poor mobilization.Öğe MIS-C Treatment: Is glucocorticoid monotherapy enough for mild cases?(W B saunders co-elsevier, 2024) Sütçü, Murat; Kara, Emine Manolya; Yıldız, Funda; Gül, Doruk; Yıldız, Raif; Yılmaz, Duygu; Atik, Fatih; Özkaya, OzanBackground: The effectiveness of using only glucocorticoids (GCs) in mild multisystem in flammatory syndrome (MIS-C) cases was compared with combined treatment [GCs + Intravenous immune globulin (IVIG)]. Methods: This retrospective cohort study was conducted between June 1, 2020, and June 1, 2022, in a tertiary care center in Istanbul, Turkey. Clinical and investigational data of the MIS-C patients were analyzed. The patients were divided into two groups: those who received only GCs and those who received the GCs + IVIG combination. The primary outcome focused on assessing the deterioration of the patient's clinical condition, the occurrence of shock, admission to the pediatric intensive care unit (PICU), and the need for additional immunosuppressive medication. Secondary outcomes included evaluating the course of cardiovascular and infection-related complications observed at the one-year follow-up. Results: Ninety-seven MIS-C patients with a median age of 41 (3 - 214) months were enrolled. Fifty-six (57.7%) patients were male. All the patients had fever at admission with a temperature of 39 degrees C (37.5 degrees C -40.1 degrees C). Thirty-two patients (33%) had cardiac findings on echocardiography [left ventricular dysfunction ( n = 13, 13.5%), coronary artery involvement ( n = 11, 11.3%), and dilation of cardiac cavities and/or increased cardiac muscle thickness ( n = 8, 8.2%)]. Thirteen patients (13.5%) required intensive care. All patients received GCs [only GCs (group I; n = 65, 67%)], and 32 patients (33%) with severe manifestations and/or cardiac involvement received GCs + IVIG (group II). No mortality was observed. None of the patients had any complaints at the oneyear follow-up, and all echocardiography findings were normal. Conclusion: This study provides preliminary evidence that GC monotherapy is a safe treatment alternative for mild MIS-C cases without cardiac involvement. (c) 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.Öğe Telisotuzumab vedotin monotherapy in patients with previously treated c-met protein-overexpressing advanced nonsquamous EGFR-wildtype non-small cell lung cancer in the phase II LUMINOSITY trial(Lippincott williams and wilkins, 2024) Camidge, D. Ross; Bar, Jair; Horinouchi, Hidehito; Goldman, Jonathan; Moiseenko, Fedor; Filippova, Elena; Çiçin, İrfanPURPOSE Telisotuzumab vedotin (Teliso-V) is a c-Met-directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic payload. The phase II LUMINOSITY trial (ClinicalTrials.gov identifier: NCT03539536) aimed to identify the optimal c-Met protein-overexpressing non-small cell lung cancer (NSCLC) population for treatment with Teliso-V (stage I) and expand the selected group for efficacy evaluation (stage II). Stage II enrolled patients with nonsquamous epidermal growth factor receptor (EGFR)-wildtype NSCLC. METHODS Eligible patients had locally advanced/metastatic c-Met protein-overexpressing NSCLC and <= 2 previous lines of therapy (including <= 1 line of systemic chemotherapy). c-Met protein overexpression in nonsquamous EGFR-wildtype NSCLC was defined as >= 25% tumor cells with 3+ staining (high [>= 50% 3+]; intermediate [>= 25%-<50%]). Teliso-V was administered at 1.9 mg/kg once every 2 weeks. The primary end point was overall response rate (ORR) by independent central review. RESULTS In total, 172 patients with nonsquamous EGFR-wildtype NSCLC received Teliso-V in stages I and II. ORR was 28.6% (95% CI, 21.7 to 36.2; c-Met high, 34.6% [95% CI, 24.2 to 46.2]; c-Met intermediate, 22.9% [95% CI, 14.4 to 33.4]). The median duration of response was 8.3 months (95% CI, 5.6 to 11.3; c-Met high, 9.0 [95% CI, 4.2 to 13.0]; c-Met intermediate: 7.2 [95% CI, 5.3 to 11.5]). The median overall survival was 14.5 months (95% CI, 9.9 to 16.6; c-Met high, 14.6 [95% CI, 9.2 to 25.6]; c-Met intermediate, 14.2 [95% CI, 9.6 to 16.6]). The median progression-free survival was 5.7 months (95% CI, 4.6 to 6.9; c-Met high, 5.5 [95% CI, 4.1 to 8.3]; c-Met intermediate: 6.0 [95% CI, 4.5 to 8.1]). Most common any-grade treatment-related adverse events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%); the most common grade >= 3 AE was peripheral sensory neuropathy (7%). CONCLUSION Teliso-V was associated with durable responses in c-Met protein-overexpressing nonsquamous EGFR-wildtype NSCLC, especially in those with high c-Met. AEs were generally manageable.Öğe Objective Response Rate is a Surrogate Marker for Long-Term Overall Survival in Metastatic Urothelial Carcinoma Patients Treated With Immune Checkpoint Inhibitors(Elsevier Inc., 2024) Tural, Deniz; Arslan, Çağatay; Selçukbiricik, Fatih; Ölmez, Ömer Fatih; Erman, Mustafa; Ürün, Yüksel; Erdem, Dilek; Kılıçkap, SaadettinBackground: This study aimed to evaluate the utility of RECIST criteria-based objective response rate (ORR) as a potential surrogate endpoint for long-term overall survival (OS) in patients with metastatic urothelial carcinoma who were treated with immune checkpoint inhibitors (ICIs). Methods: The primary endpoint was overall ORR and OS, duration of treatment (DoR) with ICIs. ORR was analyzed using Fisher's exact test. Median follow-up and OS were estimated by using the Kaplan–Meier method. Results: The median follow-up was 58 (1.15-71) months. Progression developed in 94 (47%) patients during the first 3 months of ICIs therapy. The treatment response to ICIs included complete response (CR), partial response (PR) and stable disease in 10% (n = 20), 23% (n = 46), and 20% (n = 41) of patients, respectively. The responder and nonresponder groups differed in terms of certain baseline characteristics, such as Bellmunt risk factors, and neutrophil-to-lymphocyte ratio (NLR). The 5-year OS rates for patients with CR and PR were 73% and 23%, respectively. The median DoR for CR, PR, and SD were 51.8 months (44.5-59.1), 20.7 months (16.7-24.6), and 8.8 months (5.5-12.1), respectively. Overall, 16(80%) patients with CR and 14(30%) patients with PR had an ongoing response at the time of the analysis. In the univariate analysis, NLR > 3, liver metastases, ECOG PS ≥ 1, and hemoglobin levels < 10 mg/dl, as well as the PR and CR, were all significantly associated with OS. In multivariate analysis, presence of liver metastases (HR 2.3; 95% CI, 1.3-4.2; P < .004) was found to be an independent determinant of short OS, while PR (HR 0.3; 95% CI, 0.15-0.5; P < .001) and CR (HR 0.06; 95% CI, 0.014-0.27; P < .001) were associated with improved OS. Conclusions: In conclusion, this 5-year analysis of real-world data in the setting of metastatic urothelial cancer indicated a significant correlation between ORR, especially CR, and OS in patients who received ICIs. Therefore, identifying a potential surrogate marker for survival in patients treated with ICIs would represent an important advance in the early identification of patients’ response or resistance to ICIs. © 2024 Elsevier Inc.Öğe Nitrate-Induced Headache Response in Patients with Coronary Artery Disease and Coronary Artery Ectasia: A Retrospective Case-Control Study(Wolters Kluwer Medknow Publications, 2024) Aksu, Ekrem; Çuğlan, Bilal; Öztürk, Selçuk; Eren, Ali; Yalta, Kenan; Turhan, Hasan; Atmaca, Hasan; Yetkin, ErtanBackground: Coronary artery ectasia (CAE), while being considered a variant of atherosclerosis, harbors distinct features that significantly differ from atherosclerosis in terms of pathophysiological mechanisms. On the other hand, headache appears to be the most common side effect of nitrates that have been used traditionally for decades. In this context, we aimed to compare the frequency and temporal characteristics of nitrate-induced headache (NIH) between subjects with sole coronary artery disease (CAD) and subjects with CAD and coexisting CAE. Materials and Methods: Two hundred and forty-four patients who had undergone coronary angiogram (CAG) and received a single dose of sublingual isosorbide dinitrate during the procedure comprised in this retrospective study population. CAG is performed in the indications due to guidelines. All patients who had undergone CAG were held under close supervision, at least, for 6 h following CAG (and administration of sublingual nitrate); duration and emergence time of NIH were recorded for all patients. Of these 244 patients, 225 patients having sole CAD were assigned to Group I, whereas 19 patients having both CAD and CAE were assigned to Group II. Results: NIH was observed in 19 out of 225 patients (8%) with sole CAD and in 9 out of 19 patients (56%) with CAD and CAE (P = 0.003). The mean interval between the administration of sublingual isosorbide dinitrate and NIH onset was significantly lower in Group II in comparison to Group I (44 ± 14 min vs. 87 ± 63 min, respectively, P = 0.018). However, the duration of NIH was comparable between the two groups (Group I: 203 ± 53 min vs. Group II: 173 ± 61 min, P = 0.24); logistic regression analysis revealed an independent association between NIH and CAE (odds ratio: 11.5, 95% confidential interval: 3.9-33.8, P < 0.001). Conclusion: We have demonstrated that sublingual nitrates might induce NIH more frequently in subjects with CAE and CAD in comparison to those with sole CAD. Furthermore, NIH has been demonstrated to be independently associated with CAE. © 2024 Heart and Mind.
