1. Mechanism of action, potency and efficacy : considerations for cell therapiesCarl G. Simon Jr., Erich H. Bozenhardt, Christina M. Celluzzi, David Dobnik, Melanie L. Grant, Uma Lakshmipathy, Thiana Nebel, 2024, izvirni znanstveni članek Povzetek: One of the most challenging aspects of developing advanced cell therapy products (CTPs) is defining the mechanism of action (MOA), potency and efficacy of the product. This perspective examines these concepts and presents helpful ways to think about them through the lens of metrology. A logical framework for thinking about MOA, potency and efficacy is presented that is consistent with the existing regulatory guidelines, but also accommodates what has been learned from the 27 US FDA-approved CTPs. Available information regarding MOA, potency and efficacy for the 27 FDA-approved CTPs is reviewed to provide background and perspective. Potency process and efficacy process charts are introduced to clarify and illustrate the relationships between six key concepts: MOA, potency, potency test, efficacy, efficacy endpoint and efficacy endpoint test. Careful consideration of the meaning of these terms makes it easier to discuss the challenges of correlating potency test results with clinical outcomes and to understand how the relationships between the concepts can be misunderstood during development and clinical trials. Examples of how a product can be “potent but not efficacious” or “not potent but efficacious” are presented. Two example applications of the framework compare how MOA is assessed in cell cultures, animal models and human clinical trials and reveals the challenge of establishing MOA in humans. Lastly, important considerations for the development of potency tests for a CTP are discussed. These perspectives can help product developers set appropriate expectations for understanding a product’s MOA and potency, avoid unrealistic assumptions and improve communication among team members during the development of CTPs.
Ključne besede: cell therapy product, efficacy endpoint test, mechanism of action, potency test, metrology
Objavljeno v DiRROS: 27.05.2024; Ogledov: 68; Prenosov: 51
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2. Electrotransfer of plasmid DNA radiosensitizes B16F10 tumors through activation of immune responseMonika Savarin, Urška Kamenšek, Maja Čemažar, Richard Heller, Gregor Serša, 2017, izvirni znanstveni članek Povzetek: Tumor irradiation combined with adjuvant treatments, either vascular targeted or immunomodulatory, is under intense investigation. Gene electrotransfer of therapeutic genes is one of these approaches. The aim of this study was to determine, whether gene electrotransfer of plasmid encoding shRNA for silencing endoglin, with vascular targeted effectiveness, can radiosensitize melanoma B16F10 tumors. Materials and methods. The murine melanoma B16F10 tumors, growing on the back of C57Bl/6 mice, were treated by triple gene electrotransfer and irradiation. The antitumor effect was evaluated by determination of tumor growth delay and proportion of tumor free mice. Furthermore, histological analysis of tumors (necrosis, apoptosis, proliferation, vascularization, presence of hypoxia and infiltration of immune cells,) was used to evaluate the therapeutic mechanisms. Results. Gene electrotransfer of plasmid silencing endoglin predominantly indicated vascular targeted effects of the therapy, since significant tumor growth delay and 44% of tumor free mice were obtained. In addition, irradiation had minor effects on radioresistant melanoma, with 11% of mice tumor free. The combined treatment resulted in excellent effectiveness with 88% of mice tumor free, with more than half resistant to secondary tumor challenge, which was observed also with the plasmid devoid of the therapeutic gene. Histological analysis of tumors in the combined treatment group, demonstrated similar mode of action of the gene electrotransfer of plasmid encoding shRNA for silencing endoglin and devoid of it, both through the induction of an immune response. Conclusions. The results of this study indicate that irradiation can in radioresistant melanoma tumors, by release of tumor associated antigens, serve as activator of the immune response, besides directly affecting tumor cells and vasculature. The primed antitumor immune response can be further boosted by gene electrotransfer of plasmid, regardless of presence of the therapeutic gene, which was confirmed by the high radiosensitization, resulting in prolonged tumor growth delay and 89% of tumor free mice that were up to 63% resistant to secondary challenge of tumor. In addition, gene electrotransfer of therapeutic plasmid for silencing endoglin has also a direct effect on tumor vasculature and tumors cells; however in combination with radiotherapy this effect was masked by pronounced immune response.
Ključne besede: gene therapy, electrotransfer, plasmid, irradiation, immune response, melanoma
Objavljeno v DiRROS: 24.05.2024; Ogledov: 90; Prenosov: 57
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3. Prognostic factors of choroidal melanoma in Slovenia, 1986-2008Boris Jančar, Marjan Budihna, Brigita Drnovšek-Olup, Katrina Novak-Andrejčič, Irena-Hedvika Brovet-Zupančič, Dušica Pahor, 2016, izvirni znanstveni članek Povzetek: Introduction. Choroidal melanoma is the most common primary malignancy of the eye, which frequently metastasizes. The Cancer Registry of Slovenia reported the incidence of choroid melanoma from 1983 to 2009 as stable, at 7.8 cases/million for men and 7.4/million for women. The aim of the retrospective study was to determinate the prognostic factors of survival for choroidal melanoma patients in Slovenia. Patients and methods. From January 1986 to December 2008 we treated 288 patients with malignant choroidal melanoma; 127 patients were treated by brachytherapy with beta rays emitting ruthenium-106 applicators; 161 patients were treated by enucleation. Results. Patients with tumours thickness < 7.2 mm and base diameter < 16 mm were treated by brachytherapy and had 5- and 10-year overall mortality 13% and 32%, respectively. In enucleated patients, 5- and 10-year mortality was higher, 46% and 69%, respectively, because their tumours were larger. Thirty patients treated by brachytherapy developed local recurrence. Twenty five of 127 patients treated by brachytherapy and 86 of 161 enucleated patients developed distant metastases. Patients of age >/= 60 years had significantly lower survival in both treatment modalities. For patients treated by brachytherapy the diameter of the tumour base and treatment time were independent prognostic factors for overall survival, for patients treated by enucleation age and histological type of tumour were independent prognosticators. In first few years after either of treatments, the melanoma specific annual mortality rate increased, especially in older patients, and then slowly decreased. Conclusions. It seems that particularly younger patients with early tumours can be cured, whereby preference should be given to eyesight preserving brachytherapy over enucleation.
Ključne besede: choroidal melanoma, therapy, brachytherapy, prognostic factors
Objavljeno v DiRROS: 09.05.2024; Ogledov: 112; Prenosov: 77
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4. Aggressive anticancer treatment in the last 2 weeks of lifeNena Golob, Teja Oblak, Luka Čavka, Maša Kušar, Boštjan Šeruga, 2024, izvirni znanstveni članek Povzetek: Background: There is a concern that terminally ill cancer patients may be aggressively treated due to the rapidly growing possibilities of anticancer treatment. The aim of this study was to evaluate the use of anticancer treatment at the end of life (EoL). Materials and methods: This retrospective study included adult patients with advanced solid cancers who were treated at the Institute of Oncology Ljubljana and died of cancer between January 2015 and December 2019. A multiple logistic regression model was used to assess an association between the aggressiveness of anticancer treatment (i.e. systemic therapy, radiotherapy and surgery) in the last 2 weeks of life and year of death, age at death, sex, prognosis of cancer and enrolment into the specialist palliative care (SPC). Results: We included 1736 patients in our analysis. Overall, 13.7% of patients were enrolled into the SPC and 14.4% received anticancer treatment in the last 2 weeks of life. The odds of receiving anticancer treatment significantly increased over time [odds ratio (OR) 1.15, 95% confidence interval (CI) 1.04-1.27]. There was an increased use of novel systemic therapy (e.g. small-molecule targeted therapy and immunotherapy) at the EoL. Older patients had significantly lower odds to receive anticancer treatment in the last 2 weeks of life as compared to younger patients (OR 0.96, 95% CI 0.95-0.98). As compared to patients receiving only a standard oncology care, those also enrolled into the SPC had significantly lower odds for anticancer treatment in the last 2 weeks of life (OR 0.22, 95% CI 0.12-0.43). Conclusions: Terminally ill cancer patients have increased odds for receiving anticancer treatment, especially novel systemic therapies, in the last 2 weeks of life. Younger patients and those not enrolled into the SPC are at particular risk for anticancer treatment at the EoL
Ključne besede: systemic therapy, aggressive treatment, anticancer drugs, palliative care
Objavljeno v DiRROS: 18.04.2024; Ogledov: 142; Prenosov: 74
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5. The cost of systemic therapy for metastatic colorectal carcinoma in Slovenia : discrepancy analysis between cost and reimbursementTanja Mesti, Biljana Mileva Boshkoska, Mitja Kos, Metka Tekavčič, Janja Ocvirk, 2015, izvirni znanstveni članek Povzetek: The aim of the study was to estimate the direct medical costs of metastatic colorectal cancer (mCRC) treated at the Institute of Oncology Ljubljana and to question the healthcare payment system in Slovenia. Methods. Using an internal patient database, the costs of mCRC patients were estimated in 2009 by examining (1) mCRC direct medical related costs, and (2) the cost difference between payment received by Slovenian health insurance and actual mCRC costs. Costs were analysed in the treatment phase of the disease by assessing the direct medical costs of hospital treatment with systemic therapy together with hospital treatment of side effects, without assessing radiotherapy or surgical treatment. Follow-up costs, indirect medical costs, and nonmedical costs were not included. Results. A total of 209 mCRC patients met all eligibility criteria. The direct medical costs of mCRC hospitalization with systemic therapy in Slovenia for 2009 were estimated as the cost of medications (cost of systemic therapy + cost of drugs for premedication) + labor cost (the cost of carrying out systemic treatment) + cost of lab tests + cost of imaging tests + KRAS testing cost + cost of hospital treatment due to side effects of mCRC treatment, and amounted to %3,914,697. The difference between the cost paid by health insurance and actual costs, estimated as direct medical costs of hospitalization of mCRC patients treated with systemic therapy at the Institute of Oncology Ljubljana in 2009, was %1,900,757.80. Conclusions. The costs paid to the Institute of Oncology Ljubljana by health insurance for treating mCRC with systemic therapy do not match the actual cost of treatment. In fact, the difference between the payment and the actual cost estimated as direct medical costs of hospitalization of mCRC patients treated with systemic therapy at the Institute of Oncology Ljubljana in 2009 was %1,900,757.80. The model Australian Refined Diagnosis Related Groups (AR-DRG) for cost assessment in oncology being currently used is probably one of the reasons for the discrepancy between pay-outs and actual costs. We propose new method for more precise cost assessment in oncology.
Ključne besede: cost of treatment, metastatic colorectal cancer, cost of targeted therapy, monitoring costs
Objavljeno v DiRROS: 17.04.2024; Ogledov: 189; Prenosov: 48
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6. Bevacizumab and irinotecan in recurrent malignant glioma, a single institution experienceTanja Mesti, Maja Ebert Moltara, Marko Boc, Martina Reberšek, Janja Ocvirk, 2015, izvirni znanstveni članek Povzetek: Treatment options of recurrent malignant gliomas are very limited and with a poor survival benefit. The results from phase II trials suggest that the combination of bevacizumab and irinotecan is beneficial. Patients and methods. The medical documentation of 19 adult patients with recurrent malignant gliomas was retrospectively reviewed. All patients received bevacizumab (10 mg/kg) and irinotecan (340 mg/m2 or 125 mg/m2) every two weeks. Patient clinical characteristics, drug toxicities, response rate, progression free survival (PFS) and overall survival (OS) were evaluated. Results. Between August 2008 and November 2011, 19 patients with recurrent malignant gliomas (median age 44.7, male 73.7%, WHO performance status 0%2) were treated with bevacizumab/irinotecan regimen. Thirteen patients had glioblastoma, 5 anaplastic astrocytoma and 1 anaplastic oligoastrocytoma. With exception of one patient, all patients had initially a standard therapy with primary resection followed by postoperative chemoradiotherapy. Radiological response was confirmed after 3 months in 9 patients (1 complete response, 8 partial responses), seven patients had stable disease and three patients have progressed. The median PFS was 6.8 months (95% confidence interval [CI]: 5.3-8.3) with six-month PFS rate 52.6%. The median OS was 7.7 months (95% CI: 6.6-8.7), while six-month and twelve-month survival rates were 68.4% and 31.6%, respectively. There were 16 cases of hematopoietic toxicity grade (G) 1-2. Non-hematopoietic toxicity was present in 14 cases, all G1-2, except for one patient with proteinuria G3. No grade 4 toxicities, no thromboembolic event and no intracranial hemorrhage were observed. Conclusions. In recurrent malignant gliomas combination of bevacizumab and irinotecan might be an active regimen with acceptable toxicity.
Ključne besede: recurrent malignant glioma, systemic therapy, bevacizumab
Objavljeno v DiRROS: 17.04.2024; Ogledov: 145; Prenosov: 34
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7. Effect of graded exercise therapy and medical care on chronic fatigue syndromeTamara Zličić, Darinka Korovljev, Tijana Šćepanović, Ivana Milovanović, 2023, pregledni znanstveni članek Povzetek: Purpose: Chronic Fatigue Syndrome (CFS) / Myalgic Encephalomyelitis (ME) is a complex condition with debilitating symptoms that significantly impact individuals, particularly those in the working population. This study aims to investigate the effec-tiveness of Graded Exercise Therapy (GET) and Cognitive Behavioral Therapy (CBT) along with additional methods such as Graded Exercise Self-help (GES), Adaptive Pac-ing Therapy (APT), and Specialist Medical Care (SMC), in managing Chronic Fatigue Syndrome (CFS) / Myalgic Encephalomyelitis (ME) among the working population. Methods: A systematic analysis of five randomized controlled trials conducted be-tween 2013 and 2023, encompassing GET, CBT, APT, SMC, and GES was performed using PubMed.Results: The selected studies consistently demonstrate that GET positively impacts physical functioning and reduces fatigue levels in working individuals with CFS. Ad-ditionally, CBT proves valuable, emphasizing the importance of addressing the mental aspects of CFS in occupational contexts.Conclusion: This review underscores the need for further research, advocating for direct assessment methods like biomarkers to enhance our understanding of CFS and improve treatment outcomes. These insights are crucial for healthcare practitioners, researchers, and policymakers navigating the complexities of CFS within the work-place. Emphasizing the integration of psychological interventions with physical therapies is essential for a comprehensive approach to managing CFS among the working population.
Ključne besede: Chronic Fatigue Syndrome / Myalgic Encephalomyelitis, CFS/ME, graded exercise therapy, cognitive behavioral therapy, adaptive pacing therapy, specialist medical care, working population
Objavljeno v DiRROS: 17.04.2024; Ogledov: 137; Prenosov: 83
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8. The role of PET-CT in radiotherapy planning of solid tumoursStaša Jelerčič, Mirjana Rajer, 2015, pregledni znanstveni članek Povzetek: PET-CT is becoming more and more important in various aspects of oncology. Until recently it was used mainly as part of diagnostic procedures and for evaluation of treatment results. With development of personalized radiotherapy, volumetric and radiobiological characteristics of individual tumour have become integrated in the multistep radiotherapy (RT) planning process. Standard anatomical imaging used to select and delineate RT target volumes can be enriched by the information on tumour biology gained by PET-CT. In this review we explore the current and possible future role of PET-CT in radiotherapy treatment planning. After general explanation, we assess its role in radiotherapy of those solid tumours for which PET-CT is being used most. Conclusions. In the nearby future PET-CT will be an integral part of the most radiotherapy treatment planning procedures in an every-day clinical practice. Apart from a clear role in radiation planning of lung cancer, with forthcoming clinical trials, we will get more evidence of the optimal use of PET-CT in radiotherapy planning of other solid tumours.
Ključne besede: positron emission therapy, radiotherapy, radiotherapy planning, tumour biology
Objavljeno v DiRROS: 16.04.2024; Ogledov: 153; Prenosov: 33
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9. Induction gemcitabine in standard dose or prolonged low-dose with cisplatin followed by concurrent radiochemotherapy in locally advanced non-small cell lung cancer : a randomized phase II clinical trialMartina Vrankar, Matjaž Zwitter, Tanja Bavčar-Vodovnik, Ana Milič, Viljem Kovač, 2014, izvirni znanstveni članek Povzetek: The optimal combination of chemotherapy with radiation therapy for treatment locally advanced non-small cell lung cancer (NSCLC) remains an open issue. This randomized phase II study compared gemcitabine in two different schedules and cisplatin - as induction chemotherapy, followed by radiation therapy concurrent with cisplatin and etoposid. Patients and methods. Eligible patients had microscopically confirmed inoperable non-metastatic non-small cell lung cancer; fulfilled the standard criteria for platin-based chemotherapy; and signed informed consent. Patients were treated with 3 cycles of induction chemotherapy with gemcitabine and cisplatin. Two different aplications of gemcitabine were compared: patients in arm A received gemcitabine at 1250 mg/m2 in a standard half hour i.v. infusion on days 1 and 8; patients in arm B received gemcitabine at 250 mg/m2 in prolonged 6-hours i.v. infusion on days 1 and 8. In both arms, cisplatin 75 mg/m2 on day 2 was administered. All patients continued treatment with radiation therapy with 60-66 Gy concurrent with cisplatin 50 mg/m2 on days 1, 8, 29 and 36 and etoposid 50 mg/m2 on days 1-5 and 29-33. The primary endpoint was response rate (RR) after induction chemotherapy; secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). Results. From September 2005 to November 2010, 106 patients were recruited to this study. No statistically signifficant differences were found in RR after induction chemotherapy between the two arms (48.1% and 57.4%, p = 0.34). Toxicity profile was comparable and mild with grade 3/4 neutropenia as primary toxicity in both arms. One patient in arm B suffered from acute peripheral ischemia grade 4 and an amputation of lower limb was needed. With a median follow-up of 69.3 months, progression-free survival and median survival in arm A were 15.7 and 24.8 months compared to 18.9 and 28.6 months in arm B. The figures for 1- and 3-year overall survival were 73.1% and 30.8% in arm A, and 81.5 % and 44.4% in arm B, respectively. Conclusions. Among the two cisplatin-based doublets of induction chemotherapy for inoperable NSCLC, both schedules of gemcitabine have a comparable toxicity profile. Figures for RR, PFS and OS are among the best reported in current literature. While there is a trend towards better efficacy of the treament with prolonged infusion of gemcitabine, the difference between the two arms did not reach statistical significance
Ključne besede: induction chemotherapy, non-small cell lung cancer, radiation therapy, randomized clinical trial
Objavljeno v DiRROS: 11.04.2024; Ogledov: 346; Prenosov: 285
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10. Capecitabine in adjuvant radiochemotherapy for gastric adenocarcinomaIrena Oblak, Marija Skoblar Vidmar, Franc Anderluh, Vaneja Velenik, Ana Jeromen, Jasna But-Hadžić, 2014, izvirni znanstveni članek Povzetek: Background. In patients with non-metastatic gastric cancer surgery still remains the treatment of choice. Postoperative radiochemotherapy with 5-fluorouracil and leucovorin significantly improves the treatment outcome. The oral fluoropyrimidines, such as capecitabine, mimic continuous 5-fluorouracil infusion, are at least as effective as 5-fluorouracil, and such treatment is more comfortable for the patients. Patients and methods. In the period from October 2006 to December 2009, 101 patients with gastric cancer in stages Ib-IIIc were treated with postoperative chemoradiation with capecitabine. Distal subtotal resection of the stomach was performed in 46.3%, total resection in 50.5% and multivisceral resection in 3.2% of patients. The main endpoints of this study were loco-regional control (LRC), disease-free survival (DFS), disease-specific survival (DSS) and overall survival (OS). The rates of acute side-effects were also estimated. Results. Seventy-seven percent of patients completed the treatment according to the protocol. The median followup time of all patients was 3.9 years (range: 0.4-6.3 years) and in survivors it was 4.7 years (range: 3.2-6.3 years). No death occurred due to the therapy. Acute toxicity, such as nausea and vomiting, stomatitis, diarrhoea, hand-foot syndrome and infections of grade 3 or 4, occurred in 5%, 1%, 2%, 8.9% and 18.8% of patients, respectively. On the close-out date 63.4% patients were still alive and with no signs of the disease. The 4-years follow-up survey showed that LRC, DFS, DSS and OS were 95.5%, 69.2%, 70.7%, and 66.2%, respectively. Higher pN-stage and splenectomy were found to be independent prognostic factors for all four types of survival and perineural invasion and lower treatment intensity for DFS, DSS and OS.
Ključne besede: gastric cancer, adjuvant therapy, radiochemotherapy
Objavljeno v DiRROS: 11.04.2024; Ogledov: 161; Prenosov: 30
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