Papers by Dimitrios Trafalis
Personalized Medicine, Jul 1, 2020
Considering the 'differentiated thyroid carcinoma (DTC) epidemic', the indolent nature of DTC imp... more Considering the 'differentiated thyroid carcinoma (DTC) epidemic', the indolent nature of DTC imposes a treatment paradigm shift toward elimination of recurrence. Lymph node metastases in cervical compartments, encountered in 20-90% of DTC, are the main culprit of recurrent disease, affecting 5-30% of patients. Personalized risk-stratified cervical prophylactic lymph node dissection (PLND) at initial thyroidectomy in DTC with no clinical, sonographic or intraoperative evidence of lymph node metastases (clinically N0) has been advocated, though not unanimously. The present review dissects the controversy over PLND. Weighing the benefit yielded from PLND up against the PLND-related morbidity is so far hampered by the inconsistent profit yielded by PLND and the challenging patient selection. Advances in tailoring PLND are anticipated to empower optimal patient care.
Plants, Apr 9, 2023
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Blood, Nov 16, 2005
Clinical protocols combining a topoisomerase I (topo I) and a topoisomerase IIalpha (topo II inhi... more Clinical protocols combining a topoisomerase I (topo I) and a topoisomerase IIalpha (topo II inhibitor) have shown major responses against several tumours including acute leukemia and myelodysplastic syndromes. However, combinations with topoisomerase targeting drugs should be considered with caution because antagonistic effects have been observed when administering camptothecin or topotecan (topo I inhibitors) with doxorubicin (topo II inhibitor). Octreotide (OCT) is an eight amino-acid peptide, which attains its biological effects on target cells by binding preferentially to sst2 and, to a lesser extent, to sst3 and sst5 somatostatin receptors (SS-Rs). The presence of SS-Rs in human lymphoid leukemia cell lines, in malignant lymphomas and in lymphoproliferative diseases is clearly detected. We studied the in vitro effect of combinations of OCT with doxorubicin (DOX) and topotecan (TP) on cell growth and viability in four human lymphoblastic leukemia cell lines (CCRF-CEM, RPMI-8226, JURKAT, MOLT-4) and on the Topo I, IIalpha and sst2 expression in JURKAT, MOLT-4 leukemia cell lines, as well as the in vivo effect on rodent P388 lymphocytic and L1210 lymphoid leukemias. In vitro growth inhibition and cytotoxicity were evaluated with the MTT colormetric metabolic assay. Topo I, IIalpha and sst2 mRNAs were detected with RT-PCR and the quantification of the electrophoresed specific PCR products was accomplished with Molecular Imager FX. In vivo antitumour activity was estimated by the % survival ratio of treated to untreated (control) mice and the ratio of 70-day tumour free survivors (cures). The in vitro growth inhibition and cytotoxicity that were induced by the DOX and TP combinations were neither synergistic nor additive and were similar to the activity of DOX alone. However, with the addition of OCT to the DOX and TP combinations a significant (p<0.001) synergistic effect was resulted in all tested cell lines. Treatment of cell lines with DOX produced almost a total consumption of Topo I and IIalpha mRNAs and with TP induced increase of Topo IIalpha mRNA levels (0.5–1.5 folds). OCT is clearly upregulates the Topo IIalpha expression (>2.5 folds) and restores Topo I mRNA production in cells treated with DOX. The sst2 mRNA levels were not affected in any case. In vivo antitumour activity of DOX and TP combinations was neither synergistic nor additive and it was similar to the activity of DOX alone. The addition of OCT to DOX and TP combinations produced an important synergistic antitumour effect increasing significantly survival time and cures (p<0.01) in both P388 and L1210 leukemias. Our data indicate that the antagonistic effects of Topo I and Topo II inhibitors may be due to effects on the regulation of topoisomerases expression. OCT significantly enhances the antileukemic activity of combinations with such important anticancer drugs, upregulating Topo I and IIalpha expression.
PubMed, Feb 20, 2007
Purpose: We have developed a copper(II) chelate complex with a tridentate ONN-Schiff ligand and t... more Purpose: We have developed a copper(II) chelate complex with a tridentate ONN-Schiff ligand and the anion of salicylate, showing a potent cytotoxic activity against a panel of human and murine cancer cell lines. In this experiment we have explored the combination effect between Cu(SalNEt(2))salicylate (Cu-Sal) complex and two widely used drugs in cancer chemotherapy, bleomycin (BLM) and 5-fluorouracil (5-FU), against T47D human breast cancer cells. Previous theoretical quantum-chemical studies of this complex and ass adducts with biological molecules elucidated the underlying mechanism of action of this complex. Materials and methods: Cells grown in adherence in 96-well microplates were exposed simultaneously to both agents for 48 h. During cytotoxicity was assessed via the XTT colorimetric assay. The combined drug interaction was assessed with the median-effect analysis and the combination index (CI). Results: Concurrent treatment of cells with Cu-Sal complex and the chemotherapeutic drugs BLM and 5-FU and the antioxidant agent ascorbic acid (AsA) resulted mainly in synergistic interaction for most concentration ratios. Conclusion: Cu-Sal complex interacts synergistically with the chemotherapeutic drugs for most schedules of administration. These findings call for prompting to search for possible interaction of this complex with other cellular elements of fundamental importance in cell proliferation.
PubMed, Feb 20, 2007
Purpose: The activity of topotecan (TPT) against a number of hematological malignancies is now no... more Purpose: The activity of topotecan (TPT) against a number of hematological malignancies is now notably increased. TPT is a drug which inhibits the DNA enzyme topoisomerase I (topo I), thereby leading to the induction of tumor cell apoptosis. On the other hand, octreotide (OCT) is a synthetic analogue of somatostatin, which can induce apoptosis and antiproliferative effects on various human tumor cell lines, human xenografts and animal tumors, as well as on lymphoproliferative neoplasms. Hereby, we studied the effects of TPT and OCT, and their combination in the treatment of the rodent P388 lymphocytic leukemia, in vitro and in vivo. Materials and methods: Cell cultures of P388 lymphocytic leukemia cells, as well as BDF1 male and female mice implanted with the P388 leukemia cells, were used for the in vitro and in vivo evaluation of the antineoplastic activity of OCT and TPT. Results: A significant increase of antileukemic activity of the combined treatment with both TPT and OCT was demonstrated. These results suggest that OCT enhances the effectiveness of TPT in the treatment of leukemia. Conclusion: Our results indicate that the combination of OCT with TPT in the treatment of hematological neoplasias is effective, and represents an interesting addition to the future therapeutic options, because os its mechanism of action and its toxicity profile.
Proceedings of SPIE, Dec 29, 1997
ABSTRACT
Oncology Letters, Mar 1, 2010
Erlotinib is an oral, small-molecule targeting therapy that inhibits epidermal growth factor tyro... more Erlotinib is an oral, small-molecule targeting therapy that inhibits epidermal growth factor tyrosine kinase receptors. Erlotinib has been administered for the treatment of advanced pancreatic cancer and non-small cell lung cancer. In the present trial, erlotinib was administered as second-line monotherapy in pretreated patients with advanced non-small cell lung cancer. Our objectives were to determine response, survival and toxicity. Fifty-four patients pretreated with cisplatin or its analogue-based combinations were evaluated. The disease stage of the patients was IIIB and IV. Thirty-eight patients were male, 16 were female, the median age was 65 years, and the WHO performance status was 0-2. Twenty-five cases were adenocarcinomas, 19 squamous cell carcinomas and 10 were undifferentiated. Erlotinib was administered at a dose of 150 mg daily. In case of intolerable adverse reactions, the dose was either reduced to 100 mg daily or treatment was interrupted for a maximum of two weeks. A partial response was observed in 10 (18.52%) and stable disease in 40 (74.07%) patients. The median time to disease progression was 3 months (95% CI 1.7-10.3), and the median survival was 6 months. Concerning toxicity, 53 patients (98.15%) developed a grade 1-2 skin rash, and 1 (1.85%) grade 3. Diarrhea occurred in 9 (16.67%) patients, nausea and vomiting in 4 (7.41%) and gastritis in 2 (3.70%). The majority of patients tolerated the erlotinib treatment. Of note were the 18.52% response rate and 74.07% stable disease.
British Journal of Haematology, Feb 1, 2005
Summary NSC290205 (A) is an hybrid synthetic antineoplastic ester that is a combination of a d-la... more Summary NSC290205 (A) is an hybrid synthetic antineoplastic ester that is a combination of a d-lactam derivative of androsterone and an alkylating derivative of N,N-bis(2-chloroethyl)aniline. We tested NSC290205 for synergistic antileukaemic activity with adriamycin (ADR), (i) in vitro against the human lymphoid leukaemia cell lines: CCRF-CEM, MOLT-4, and RPMI-8226, (ii) in vivo against P388 lymphocytic and L1210 lymphoid murine leukaemias (at incipient and advanced phase). Our results indicated significant cytostatic and cytotoxic synergy of NSC290205 and ADR in vitro. We further examined these results in vivo by replacing cyclophosphamide in the standard CHOP (cyclophosphamide, hydroxydaunomycin, Oncovin, prednisone) regimen with NSC290205 (AHOP) and comparing the efficiency of these two regimens in vivo. Although treatment of P388 and L1210 with cyclophosphamide or NSC290205 alone yielded equivalent results, AHOP produced a clear benefit for survival compared with CHOP against advanced leukaemias, confirming the in vitro observations [higher percentage increase in median lifespan of treated animals over the untreated (control): 188% and 239% in L1210, 308% and 353% in P388, P < 0.01, for CHOP and AHOP respectively]. AHOP also proved to be more genotoxic and cytostatic than CHOP, inducing higher sister chromatid exchange levels and cell division delays on P388 cells in vivo. NSC290205 showed superior antineoplastic potential against lymphoid leukaemia and significant synergy with ADR, producing an excellent therapeutic outcome.
Oncology, 2010
tion. None of these side effects was observed in arm B patients. Conclusion: No statistically sig... more tion. None of these side effects was observed in arm B patients. Conclusion: No statistically significant difference in median overall survival in patients with advanced colorectal cancer treated with bevacizumab plus a combination therapy (arm A) and those treated with the combination only, without bevacizumab (arm B), was observed.
Personalized Medicine, Dec 1, 2022
Hypothyroidism in the setting of cancer is a puzzling entity due to the dual role of the thyroid ... more Hypothyroidism in the setting of cancer is a puzzling entity due to the dual role of the thyroid hormones (TH) in cancer – promoting versus inhibitory – and the complexity of the hypothyroidism itself. The present review provides a comprehensive overview of the personalized approach to hypothyroidism in patients with solid nonthyroid cancer, focusing on current challenges, unmet needs and future perspectives. Major electronic databases were searched from January 2011 until March 2022. The milestones of the refinement of such a personalized approach are prompt diagnosis, proper TH replacement and development of interventions and/or pharmaceutical agents to exploit hypothyroidism or, on the contrary, TH replacement as an anticancer strategy. Further elucidation of the dual role of TH in cancer – especially of the interference of TH signaling with the hallmarks of cancer – is anticipated to inform decision-making and optimize patient selection.
Social Science Research Network, 2022
Expert Opinion on Biological Therapy, 2021
ABSTRACT Introduction: The incorporation of immune checkpoint inhibitors in the oncologists’ arse... more ABSTRACT Introduction: The incorporation of immune checkpoint inhibitors in the oncologists’ arsenal is a milestone in cancer therapeutics, though not being devoid of toxicities. Areas covered: The present review provides a comprehensive and up-to-date overview of the immune-related hypophysitis with focus on the elusive biological background, the wide spectrum of the epidemiological profile, the varying clinical aspects, and the diagnostic and therapeutic challenges. Expert opinion: Historically considered distinctive of anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibodies (mAbs), the immune-related hypophysitis is increasingly correlated with the anti-programmed cell-death (PD) protein 1 (PD-1)/anti-PD ligand 1 (PD-L1) mAbs. The distinct phenotype of hypophysitis related to anti-PD1/anti-PD-L1 mAbs is highlighted with focus on the immune-related isolated adrenocorticotropic (ACTH) deficiency. The immune-related central diabetes insipidus is discussed as a rare aspect of anti-CTL-A4 mAbs-induced hypophysitis, recently related to anti-PD1/anti-PD-L1 mAbs as well. The present review builds on existing literature concerning immune-related hypophysitis underscoring the pending issues still to be addressed, including (i) pathogenesis; (ii) correlation with preexisting autoimmunity; (iii) predictive value; (iv) utility of high-dose glucocorticoids; and (v) establishment of evidence-based diagnostic and therapeutic protocols. Increased awareness and constant vigilance are advocated as cornerstone of a multidisciplinary approach to ensure optimal patients’ care.
European journal of medicinal chemistry, Mar 1, 2023
Through the syntheses of its C-1 desvinyl, C-7 methylene, C-7 exocyclic ethylidene, and various C... more Through the syntheses of its C-1 desvinyl, C-7 methylene, C-7 exocyclic ethylidene, and various C-3 phenylmethyl analogues, the structure−activity relationship of antimitotic ottelione A (4) against tubulin and various cancer cells was established. The results indicated that compound 4 was a colchicine-competitive inhibitor and that the C-1 vinyl group is unnecessary for its potency, whereas the C-7 exocyclic double bond is essential, possibly because of its irreversible interaction with tubulin. Further optimization of the substituents on the phenylmethyl group at the C-3 position generated compound 10g with a 3′-fluoro-4′-methoxyphenylmethyl substituent, which was 6−38-fold more active against MCF-7, NCI-H460, and COLO205 cancer cells relative to 4. Results from in vitro tubulin polymerization assay confirmed the potency of compounds 4, 10g, and 11a.
Research Square (Research Square), Oct 27, 2020
Background: Tumor molecular pro le is of great importance for the detection of biomarkers of resp... more Background: Tumor molecular pro le is of great importance for the detection of biomarkers of response to targeted treatment due to the increased availability, with concomitant reduction of cost, of Next Generation Sequencing technology (NGS). In parallel to targeted therapies', immunotherapies are also evolving, revolutionizing cancer therapy, with Programmed Death-ligand 1 (PD-L1), Microsatellite Instability (MSI), and Tumor Mutational Burden (TMB) analysis being the biomarkers employed most commonly. Methods: In the present study, a 161 gene NGS panel, containing the majority of clinically signi cant genes for cancer treatment selection, was used for tumor molecular pro le analysis. A variety of tumor types have been analyzed, including aggressive and hard to treat cancers such as pancreatic cancer. Besides, the clinical utility of immunotherapy biomarkers (TMB, MSI, PD-L1), was also studied. Results: Molecular pro le analysis was conducted in 610 cancer patients, while in 393 of them a at least one biomarker for immunotherapy response was requested. At least one actionable alteration was detected in 77.70% of the patients. 54.59% of them received information related to on-label or off-label treatment (Tiers 1A.1, 1A.2, 2B, and 2C.1) and 21.31% received a variant that could be used for clinical trial inclusion. The addition to immunotherapy biomarker to targeted biomarkers' analysis in 191 cases increased the number of patients with an on-label treatment recommendation by 22.40%, while an option for on-label or off-label treatment was provided in 71.35% of the cases. Conclusions: Tumor molecular pro le analysis by NGS is a rst-tier methodology for a variety of tumor types, which provides critical information for treatment decision making in cancer patients. Importantly, simultaneous analysis for targeted therapy and immunotherapy biomarkers could lead to a better tumor characterization and provide actionable information in the majority of patients. Moreover, our results indicate that one in two patients is eligible for ICI treatment based on the biomarkers' analysis. However, when these analyses are performed, the challenge is their implementation in clinical practice. Multidisciplinary patient management is critical to the re nement of the strategy incorporating such information.
PubMed, May 3, 2007
Purpose: To investigate the in vitro and in vivo activity of an homo-aza-steroid alkylating ester... more Purpose: To investigate the in vitro and in vivo activity of an homo-aza-steroid alkylating ester, namely 13beta-hydroxy- 13alpha-amino-13,17-seco-5alpha-androstan-17-oic-13,17- lactam-p-bis (2-chloro ethyl) aminophenoxy acetate (HASE), in comparison with dacarbazine (DTIC) in the treatment of malignant melanoma. Materials and methods: Cytotoxicity was assessed in vitro by the MTT assay using a panel of 6 malignant melanoma human cell lines, with or without the presence of rat liver microsome assay. B16 melanoma-bearing mice were used to evaluate in vivo the antitumor activity of the tested compounds. Results: In all cases of in vitro screening, HASE displayed significantly higher (p <0.0001) cytostatic and cytotoxic activity than DTIC. Moreover, the antitumor activity of HASE in B16 melanoma-bearing mice was satisfactory, prolonging the mice lifespan at 67%, compared to 43% achieved by DTIC. Furthermore, HASE significantly inhibited the tumor growth (tumor growth rate: <42%) as this was defined by tumor volume and weight differences, presenting higher antitumor effect than DTIC. Conclusion: HASE displayed superior in vitro and in vivo activity than DTIC in the treatment of melanoma. Thus, HASE may be considered as a significant candidate anticancer agent for further development.
European journal of medicinal chemistry reports, Dec 1, 2022
Cancer Chemotherapy and Pharmacology, Nov 18, 2012
Purpose The established treatment for small-cell lung cancer has been a cisplatin-etoposide combi... more Purpose The established treatment for small-cell lung cancer has been a cisplatin-etoposide combination, as the most effective chemotherapy regimen. Paclitaxel has also been used in combination with cisplatin and etoposide but this has been unacceptable due to the toxicity. This toxicity could be attributed to the three consequent days of treatment with etoposide plus the doses of each of the three drugs. Our objectives were to determine an equal or longer survival and lower toxicity by administering all 3 drugs with low dosage on day one, compared to the established guideline of 3-day administration. Methods We tested the aforementioned three-drug combination and avoided the toxicity in the majority of patients by administering all 3 drugs on day one. Fifty-one patients (50 evaluable) were recruited from 4 oncology clinics. All patients had histologically or cytologically confirmed small-cell lung cancer with limited and extensive disease in 40 and 60 % of the patients, respectively. The treatment was: cisplatin 75 mg/m 2 , etoposide 120 mg/m 2 (maximum 200 mg), and paclitaxel 135 mg/m 2. The agents were administered on day one and repeated every 3 weeks for 6 cycles. Results The median survival was 15 months (95 % CI 13.6-16.4) (mean 16 months). Forty-five (90 %) patients achieved a response: 20 (40 %) patients, a complete response and 25 (50 %), a partial response. Adverse reactions included grade 3 and 4 neutropenia in 12 and 2 % of the patients, respectively. Other side effects were of very low toxicity. Conclusion The 1-day, three-agent (cisplatin-etoposidepaclitaxel) treatment of small-cell lung cancer is beneficial with respect to response rate and survival, and the toxicity is low and well-tolerated. Keywords Small-cell lung cancer Á Three-drug combination treatment Á Three drugs small-cell lung cancer
European journal of medicinal chemistry, Dec 1, 2017
Social Science Research Network, 2022
Anti-Cancer Drugs, Jun 1, 2017
The PI3K/AKT pathway plays an important role in the initiation and progression of cancer, and the... more The PI3K/AKT pathway plays an important role in the initiation and progression of cancer, and the drug development efforts targeting this pathway with therapeutic interventions have been advanced by academic and industrial groups. However, the clinical outcome is moderate. Combination of inhibition of PI3K/AKT and other targeted agents became a feasible approach. In this study we assessed the combined effect of ARQ 092, a pan-AKT inhibitor, and ARQ 087, a pan-FGFR inhibitor, in vitro and in vivo. In a panel of 45 cancer cell lines, on 24% (11 out of 45) the compounds showed synergistic effect, on 62% (28 out of 45) additive, and on 13% (6 out of 45) antagonistic. The highest percentage of synergism was found on endometrial and ovarian cancer cell lines. Mutational analysis revealed that PIK3CA/PIK3R1 mutations and aberrant activation of FGFR2 predicted synergism, whereas Ras mutations showed a reverse correlation. Pathway analysis revealed that a combination of ARQ 092 and ARQ 087 enhanced the inhibition of both the AKT and FGFR pathways in cell lines in which synergistic effects were found (AN3CA and IGROV-1). Cell cycle arrest and apoptotic response occurred only in AN3CA cell, and was not seen in IGROV-1 cells. Furthermore, enhanced antitumor activity was observed in mouse models with endometrial cancer cell line and patient-derived tumors when ARQ 092 and ARQ 087 were combined. These results from in-vitro and in-vivo studies provide a strong rationale in treating endometrial and other cancers with the activated PI3K/AKT and FGFR pathways.
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Papers by Dimitrios Trafalis