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Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/6
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Publication Open Access What is the current role and what are the prospects of the robotic approach in liver surgery?(Multidisciplinary Digital Publishing Institute (MDPI), 2022) Sijberden, J.P.; Hilal, M.A.; Bozkurt, Emre; Koç University HospitalRobotic liver surgery is being applied with increasing frequency. Comparable, and in specific settings superior, perioperative outcomes compared to laparoscopic liver surgery have been reported. In its current form, the most commonly mentioned advantage of robotic surgery is improved dexterity. Important obstacles to its wider implementation in daily clinical practice are the associated costs, technical difficulties, and a scarce amount of evidence. Robotic liver surgery will likely continue to evolve in parallel with technological developments that enhance the robots' abilities. In parallel with the historical development of minimally invasive surgery, the laparoscopic and robotic approaches are now frequently utilized to perform major abdominal surgical procedures. Nevertheless, the role of the robotic approach in liver surgery is still controversial, and a standardized, safe technique has not been defined yet. This review aims to summarize the currently available evidence and prospects of robotic liver surgery. Minimally invasive liver surgery has been extensively associated with benefits, in terms of less blood loss, and lower complication rates, including liver-specific complications such as clinically relevant bile leakage and post hepatectomy liver failure, when compared to open liver surgery. Furthermore, comparable R0 resection rates to open liver surgery have been reported, thus, demonstrating the safety and oncological efficiency of the minimally invasive approach. However, whether robotic liver surgery has merits over laparoscopic liver surgery is still a matter of debate. In the current literature, robotic liver surgery has mainly been associated with non-inferior outcomes compared to laparoscopy, although it is suggested that the robotic approach has a shorter learning curve, lower conversion rates, and less intraoperative blood loss. Robotic surgical systems offer a more realistic image with integrated 3D systems. In addition, the improved dexterity offered by robotic surgical systems can lead to improved intra and postoperative outcomes. In the future, integrated and improved haptic feedback mechanisms, artificial intelligence, and the introduction of more liver-specific dissectors will likely be implemented, further enhancing the robots' abilities.Publication Open Access Autophagy and cancer dormancy(Frontiers, 2021) Akçay, Arzu; Akkoç, Yunus; Peker, Nesibe; Gözüaçık, Devrim; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; N/A; N/A; 40248Metastasis and relapse account for the great majority of cancer-related deaths. Most metastatic lesions are micro metastases that have the capacity to remain in a non-dividing state called "dormancy" for months or even years. Commonly used anticancer drugs generally target actively dividing cancer cells. Therefore, cancer cells that remain in a dormant state evade conventional therapies and contribute to cancer recurrence. Cellular and molecular mechanisms of cancer dormancy are not fully understood. Recent studies indicate that a major cellular stress response mechanism, autophagy, plays an important role in the adaptation, survival and reactivation of dormant cells. In this review article, we will summarize accumulating knowledge about cellular and molecular mechanisms of cancer dormancy, and discuss the role and importance of autophagy in this context.Publication Open Access Salvage radiotherapy versus observation for biochemical recurrence following radical prostatectomy for prostate cancer: a matched pair analysis(Multidisciplinary Digital Publishing Institute (MDPI), 2022) Preisser, Felix; Thamm, Reinhard; Pompe, Raisa S.; Chun, Felix K. -H.; Graefen, Markus; Siegmann, Alessandra; Boehmer, Dirk; Budach, Volker; Wiegel, Thomas; Tilki, Derya; Other; School of Medicine; Koç University HospitalSalvage radiotherapy improves oncologic outcomes in prostate cancer patients who develop biochemical recurrence after radical prostatectomy. However, the evidence on hard clinical endpoints is scarce. Within this study, we compare the long-term oncologic outcomes of patients with biochemical recurrence after prostatectomy, who were treated with either salvage radiotherapy or no radiotherapy. Our results show that patients who were treated with salvage radiotherapy after the development of biochemical recurrence following radical prostatectomy had a lower risk of developing metastasis and lower risk of death within the follow-up. These findings further underline the curative potential of salvage radiotherapy in the case of biochemical recurrence after radical prostatectomy, and should be discussed with these patients. Background: Salvage radiotherapy (SRT) improves oncologic outcomes in prostate cancer (PCa) patients who develop biochemical recurrence (BCR) after radical prostatectomy (RP). However, evidence on hard clinical endpoints is scarce. We compare long-term oncologic outcomes of SRT versus no radiotherapy (noRT) in patients with BCR after RP. Patients and methods: within a multi-institutional database, we identified patients with BCR after RP between 1989 and 2016 for PCa. Patients with lymph node invasion, with adjuvant radiotherapy, or with additional androgen deprivation therapy at BCR were excluded. In all patients with SRT, SRT was delivered to the prostatic bed only. Propensity score matching (PSM) was performed to account for differences in pathologic tumor characteristics. Kaplan-Meier analyses and Cox regression models tested the effect of SRT versus no RT on metastasis-free (MFS) and overall survival (OS). Results: of 1832 patients with BCR, 32.9% (n = 603) received SRT without ADT. The median follow-up was 95.9 months. Median total SRT dose was 70.2 Gy. After 1:1 PSM, at 15 years after RP, MFS and OS rates were 84.3 versus 76.9% (p < 0.001) and 85.3 versus 74.4% (p = 0.04) for SRT and noRT, respectively. In multivariable Cox regression models, SRT was an independent predictor for metastasis (HR: 0.37, p < 0.001) and OS (HR: 0.64, p = 0.03). Conclusion: this is the first matched-pair analysis investigating the impact of SRT versus observation only in post-RP recurrent PCa. After compensating for established risk factors, SRT was associated with better long-term MFS and OS. These results on clinical endpoints underline the curative potential of SRT.Publication Open Access Metabolic reprogramming in adipose tissue during cancer cachexia(Frontiers, 2022) Department of Molecular Biology and Genetics; Weber, Bahar Zehra Camurdanoğlu; Arabacı, Hilal Dilşad; Kır, Serkan; Faculty Member; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; College of Sciences; N/A; N/A; 274185Cancer cachexia is a disorder of energy balance characterized by the wasting of adipose tissue and skeletal muscle resulting in severe weight loss with profound influence on morbidity and mortality. Treatment options for cancer cachexia are still limited. This multifactorial syndrome is associated with changes in several metabolic pathways in adipose tissue which is affected early in the course of cachexia. Adipose depots are involved in energy storage and consumption as well as endocrine functions. In this mini review, we discuss the metabolic reprogramming in all three types of adipose tissues - white, brown, and beige - under the influence of the tumor macro-environment. Alterations in adipose tissue lipolysis, lipogenesis, inflammation and adaptive thermogenesis of beige/brown adipocytes are highlighted. Energy-wasting circuits in adipose tissue impacts whole-body metabolism and particularly skeletal muscle. Targeting of key molecular players involved in the metabolic reprogramming may aid in the development of new treatment strategies for cancer cachexia.Publication Open Access Pulsed radiation therapy to improve systemic control of metastatic cancer(Frontiers, 2021) He, Kewen; Barsoumian, Hampartsoum B.; Puebla-Osorio, Nahum; Hsu, Ethan Y.; Verma, Vivek; Abana, Chike O.; Chen, Dawei; Patel, Roshal R.; Gu, Meidi; Cortez, Maria Angelica; Welsh, James W.; Sezen, Duygu; Faculty Member; School of Medicine; 170535Radiation therapy (RT) is emerging as an interventional modality in the cancer-immunity cycle, augmenting the activation of an adaptive immune response against tumors. RT, particularly in combination with immunotherapy, can enhance immune memory effects and shape the tumor-directed T-cell populations. However, a single cycle of RT delivered to a limited number of polymetastatic lesions is rarely sufficient to achieve systemic control. We hypothesize that several rounds of RT, akin to several rounds of immunotherapeutic drugs, is likely to provide greater clinical benefit to patients with metastatic disease. We propose that the repeated exposure to tumor antigens released by ""pulsed-RT"" (i.e., treating 2-4 tumor lesions with 3 irradiation cycles given one month apart) may amplify the adaptive immune response by expanding the tumor-specific T-cell receptor repertoire, the production of high-affinity tumor antibodies, and the generation of memory lymphocytes and thereby improve immune control of systemic disease.</p>Publication Open Access Determining the origin of synchronous multifocal bladder cancer by exome sequencing(BioMed Central, 2015) Özkurt, Ezgi; Demir, Gulfem; Alkan, Can; Somel, Mehmet; N/A; N/A; Esen, Tarık; Lack, Nathan Alan; Acar, Ömer; Saraç, Hilal; Faculty Member; Faculty Member; Faculty Member; PhD Student; School of Medicine; 50536; 120842; 237530; N/ABackground: Synchronous multifocal tumours are commonly observed in urothelial carcinomas of the bladder. The origin of these physically independent tumours has been proposed to occur by either intraluminal migration (clonal) or spontaneous transformation of multiple cells by carcinogens (field effect). It is unclear which model is correct, with several studies supporting both hypotheses. A potential cause of this uncertainty may be the small number of genetic mutations previously used to quantify the relationship between these tumours. Methods: To better understand the genetic lineage of these tumours we conducted exome sequencing of synchronous multifocal pta urothelial bladder cancers at a high depth, using multiple samples from three patients. Results: Phylogenetic analysis of high confidence single nucleotide variants (SNV) demonstrated that the sequenced multifocal bladder cancers arose from a clonal origin in all three patients (bootstrap value 100 %). Interestingly, in two patients the most common type of tumour-associated snvs were cytosine mutations of tpc* dinucleotides (Fisher's exact test p < 10-41), likely caused by APOBEC-mediated deamination. Incorporating these results into our clonal model, we found that tpc* type mutations occurred 2-5x more often among snvs on the ancestral branches than in the more recent private branches (p < 10-4) suggesting that tpc* mutations largely occurred early in the development of the tumour. Conclusions: These results demonstrate that synchronous multifocal bladder cancers frequently arise from a clonal origin. Our data also suggests that APOBEC-mediated mutations occur early in the development of the tumour and may be a driver of tumourigenesis in non-muscle invasive urothelial bladder cancer.Publication Open Access Breast cancer survivorship: the role of rehabilitation according to the international classification of functioning disability and health-a scoping review(Springer, 2022) Pinto, Monica; Calafiore, Dario; Piccirillo, Maria Carmela; Costa, Massimo; de Sire, Alessandro; Taşkıran, Özden Özyemişçi; Faculty Member; School of Medicine; 133091Purpose of review: the population of breast cancer (BC) survivors is growing due to earlier diagnosis and effective combined treatments. A scoping review was performed to explore the role of rehabilitation in BC survivorship and the major issues in BC survivors with International Classification of Functioning Disability and Health (ICF) perspective. Recent Findings The authors searched PubMed from January 1, 2018, up until November 9, 2021. The 65 selected publications were analyzed with the Comprehensive ICF BC Core Set (CCS) perspective and assigned to the categories of the CCS components along with the 3 areas of health (physical, mental, and social health). The multidimensional aspects of BC survivor disability are evident, whereas the topics of the articles concern several categories of the ICF BC CCS and all 3 areas of health. However, the current ICF BC CCS does not include certain categories related to emerging issues of BC survivorship recurring in the papers. Rehabilitation is crucial in BC survivorship management to give personalized answers to women beyond BC, and the ICF BC CCS remains an essential tool in rehabilitation assessment for BC survivors although it needs updating.Publication Open Access Quantitative proteomics identifies secreted diagnostic biomarkers as well as tumor-dependent prognostic targets for clear cell Renal Cell Carcinoma(American Association for Cancer Research (AACR), 2021) Erdem, Selçuk; Bağbudar, Sidar; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Şentürk, Aydanur; Şahin, Ayşe Tuğçe; Armutlu, Ayşe; Kiremit, Murat Can; Acar, Ömer; Esen, Tarık; Tunçbağ, Nurcan; Faculty Member; Teaching Faculty; Faculty Member; Faculty Member; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; College of Sciences; Graduate School of Sciences and Engineering; Graduate School of Health Sciences; School of Medicine; College of Engineering; 105301; N/A; N/A; 133567; N/A; 237530; 50536; 245513Clear cell renal cell carcinoma (ccRCC) is the third most common and most malignant urological cancer, with a 5-year survival rate of 10% for patients with advanced tumors. Here, we identified 10,160 unique proteins by in-depth quantitative proteomics, of which 955 proteins were significantly regulated between tumor and normal adjacent tissues. We verified four putatively secreted biomarker candidates, namely, PLOD2, FERMT3, SPARC, and SIRPa, as highly expressed proteins that are not affected by intratumor and intertumor heterogeneity. Moreover, SPARC displayed a significant increase in urine samples of patients with ccRCC, making it a promising marker for the detection of the disease in body fluids. Furthermore, based on molecular expression profiles, we propose a biomarker panel for the robust classification of ccRCC tumors into two main clusters, which significantly differed in patient outcome with an almost three times higher risk of death for cluster 1 tumors compared with cluster 2 tumors. Moreover, among the most significant dustering proteins, 13 were targets of repurposed inhibitory FDA-approved drugs. Our rigorous proteomics approach identified promising diagnostic and tumor-discriminative biomarker candidates which can serve as therapeutic targets for the treatment of ccRCC. Implications: Our in-depth quantitative proteomics analysis of ccRCC tissues identifies the putatively secreted protein SPARC as a promising urine biomarker and reveals two molecular tumor phenotypes.Publication Open Access Stereotactic radiosurgery versus active surveillance for asymptomatic, skull-based meningiomas: an international, multicenter matched cohort study(Springer Nature, 2022) Mantziaris, Georgios; Pikis, Stylianos; Nabeel, Ahmed M.; Reda, Wael A.; Tawadros, Sameh R.; El-Shehaby, Amr M. N.; Abdelkarim, Khaled; Emad, Reem M.; Delabar, Violaine; Mathieu, David; Lee, Cheng-chia; Yang, Huai-che; Liscak, Roman; Hanuska, Jaromir; Alvarez, Roberto Martinez; Moreno, Nuria Martinez; Tripathi, Manjul; Speckter, Herwin; Albert, Camilo; Benveniste, Ronald J.; Bowden, Greg N.; Patel, Dev N.; Kondziolka, Douglas; Bernstein, Kenneth; Lunsford, L. Dade; Jenkinson, Michael D.; Islim, Abdurrahman I.; Sheehan, Jason; Peker, Selçuk; Samancı, Mustafa Yavuz; Faculty Member; School of Medicine; Koç University Hospital; 11480; N/AObjective: the optimal management of asymptomatic, skull-based meningiomas is not well defined. The aim of this study is to compare the imaging and clinical outcomes of patients with asymptomatic, skull-based meningiomas managed either with upfront stereotactic radiosurgery (SRS) or active surveillance. Methods: this retrospective, multicenter study involved patients with asymptomatic, skull-based meningiomas. The study end-points included local tumor control and the development of new neurological deficits attributable to the tumor. Factors associated with tumor progression and neurological morbidity were also analyzed. Results: the combined unmatched cohort included 417 patients. Following propensity score matching for age, tumor volume, and follow-up 110 patients remained in each cohort. Tumor control was achieved in 98.2% and 61.8% of the SRS and active surveillance cohorts, respectively. SRS was associated with superior local tumor control (p < 0.001, HR = 0.01, 95% CI = 0.002-0.13) compared to active surveillance. Three patients (2.7%) in the SRS cohort and six (5.5%) in the active surveillance cohort exhibited neurological deterioration. One (0.9%) patient in the SRS-treated and 11 (10%) patients in the active surveillance cohort required surgical management of their meningioma during follow-up. Conclusions: SRS is associated with superior local control of asymptomatic, skull-based meningiomas as compared to active surveillance and does so with low morbidity rates. SRS should be offered as an alternative to active surveillance as the initial management of asymptomatic skull base meningiomas. Active surveillance policies do not currently specify the optimal time to intervention when meningioma growth is noted. Our results indicate that if active surveillance is the initial management of choice, SRS should be recommended when radiologic tumor progression is noted and prior to clinical progression.Publication Open Access Molecular response to combined molecular- and external radiotherapy in head and neck squamous cell carcinoma (HNSCC)(Multidisciplinary Digital Publishing Institute (MDPI), 2021) Rassamegevanon, Treewut; Feindt, Louis; Koi, Lydia; Müller, Johannes; Freudenberg, Robert; Löck, Steffen; Sihver, Wiebke; Kühn, Ariane Christel; Von Neubeck, Cläre; Linge, Annett; Pietzsch, Hans-Jürgen; Kotzerke, Jörg; Baumann, Michael; Krause, Mechthild; Dietrich, Antje; Çevik, Enes; School of MedicineCombination treatment of molecular targeted and external radiotherapy is a promising strategy and was shown to improve local tumor control in a HNSCC xenograft model. To enhance the therapeutic value of this approach, this study investigated the underlying molecular response. Subcutaneous HNSCC FaDuDD xenografts were treated with single or combination therapy (X-ray: 0, 2, 4 Gy; anti-EGFR antibody (Cetuximab) (un-)labeled with Yttrium-90 (90Y)). Tumors were excised 24 h post respective treatment. Residual DNA double strand breaks (DSB), mRNA expression of DNA damage response related genes, immunoblotting, tumor histology, and immunohistological staining were analyzed. An increase in number and complexity of residual DNA DSB was observed in FaDuDD tumors exposed to the combination treatment of external irradiation and90Y-Cetuximab relative to controls. The increase was observed in a low oxygenated area, suggesting the expansion of DNA DSB damages. Upregulation of genes encoding p21cip1/waf1 (CDKN1A) and GADD45? (GADD45A) was determined in the combination treatment group, and immunoblotting as well as immunohistochemistry confirmed the upregulation of p21cip1/waf1. The increase in residual H2AX foci leads to the blockage of cell cycle transition and subsequently to cell death, which could be observed in the upregulation of p21cip1/waf1 expression and an elevated number of cleaved caspase-3 positive cells. Overall, a complex interplay between DNA damage repair and programmed cell death accounts for the potential benefit of the combination therapy using90Y-Cetuximab and external radiotherapy.