Search Results (11)

Background and Objectives: Despite developments in cervical cancer (CC) treatment, an advanced stage is a poor prognostic factor. Cervical cancer is an immunogenic tumor in which viruses, like HPV, play a role in carcinogenesis. Therefore, systemic inflammatory markers (SIMs) may have prognostic value. Most studies on SIMs focus on the early stage by evaluating pretreatment levels. This study aims to evaluate the prognostic and predictive values of both pretreatment and post-treatment parameters at the advanced stage, as well as treatment efficacy after progression with first-line treatment. Materials and Methods: A total of 133 advanced-stage CC patients with progression on first-line platin–paclitaxel and bevacizumab were evaluated retrospectively. Demographic and histopathological characteristics were recorded along with treatment details. Pre-treatment baseline blood parameters and post-treatment follow-up values were recorded to calculate SIMs as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and systemic inflammatory response index (SIRI). Results: Median values for SIMs were accepted as cut-off values. Post-treatment values demonstrated stronger predictive power, with pre-treatment SIRI and NLR being significant only in univariate analysis, but not in multivariate analysis. High post-treatment SIRI (>2.1) was correlated with shorter overall survival (OS) and considered a poor prognostic factor. High post-treatment SIRI (>2.1), -SII (>746), and -PLR (>197) emerged as independent prognostic factors for progression-free survival (PFS). Their prognostic values were clearer in the whole population and the metachronous metastatic subgroup. Rechallenge of platinum-based chemotherapy was an option for those who had at least 6 months of PFS with first-line platinum-based chemotherapy. Bevacizumab addition to single-agent or combination regimens led to improved ORR as well. Conclusions: Post-treatment SIRI is a promising prognostic factor for OS, while post-treatment SIRI, SII, and PLR may serve as convenient SIMs for PFS. Platinum-based combination chemotherapy reinduction is a feasible second-line treatment strategy, especially with the addition of bevacizumab. Full article

Osimertinib has been the standard treatment for advanced Epidermal Growth Factor Receptor (EGFR)-driven non-small cell lung cancer (NSCLC) for many years. However, even with remarkable response rate, progression-free survival (PFS) and survival benefit as compared to the old generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, treatment outcomes for these subsets of patients remain a challenge. Recently, in order to go beyond osimertinib, new treatment strategies have been developed. In particular, in the FLAURA 2 phase III randomized trial, the combination of platin-based chemotherapy and osimertinib showed impressive PFS benefits as compared to single-agent osimertinib. Furthermore, in the MARIPOSA phase III randomized study, the combination of the anti-EGFR and anti-MET monoclonal antibody amivantamab combined with the new anti-EGFR TKI lazertinib demonstrated remarkable PFS benefit as compared to single agent osimertinib. This paper will discuss these new treatment options and potential selection criteria for personalized treatment of patients. Full article

Background/Objectives: Patients with germ cell tumors have a good prognosis, which is partly due to platin-based chemotherapy. However, the long-term effects of CTx may play a relevant role in the long-term effects. Up to now, little is known about the knowledge that testicular tumor survivors have about these long-term effects. Methods: A survey of testicular tumor patients treated at the University Hospital Dresden from 2011 up to 2021 was conducted. Patients who had received CTx were asked about their knowledge of the therapy and long-term effects. Results: Of the 279 returns (6 deceased, 46 unavailable, 64% response), 198 patients had received CTx. This was followed up by 63 different urologists. The follow-up period was 5.3 ± 2.9 years. A total of 5% (10/197) did not remember receiving CTx. A total of 55% (102/187) could not name the type of CTx. The most commonly known long-term effects were the risk of second tumors (63%) and andrological problems (59–60%). A total of 18.7% of patients did not know any long-term effects. Half of the patients (54.3%) knew a maximum of 5/14 long-term effects. In a multivariate analysis, a low educational degree (OR 2.2 (1.2–4.3); p = 0.02) and one course of carboplatin (OR 3.1 (1.1–9.3); p = 0.04) were the independent predictors for a knowledge deficit. Conclusions: Germ cell tumor patients have a low level of awareness of the long-term effects of CTx. This results in a risk of inadequate prevention and follow-up, which, in turn, may have an impact on patients’ long-term survival. Full article

UICC stage IV small-cell lung cancer (SCLC) is a highly aggressive malignancy without curative treatment options. Several randomized trials have demonstrated improved survival rates through the addition of checkpoint inhibitors to first-line platin-based chemotherapy. Consequently, a combination of chemo- and immunotherapy has become standard palliative treatment. However, no reliable predictive biomarkers for treatment response exist. Neither PD-L1 expression nor tumor mutational burden have proven to be effective predictive biomarkers. In this study, we compared the cellular immune statuses of SCLC patients to a healthy control cohort and investigated changes in peripheral blood B, T, and NK lymphocytes, as well as several of their respective subsets, during treatment with immunochemotherapy (ICT) using flow cytometry. Our findings revealed a significant decrease in B cells, while T cells showed a trend to increase throughout ICT. Notably, high levels of exhausted CD4+ and CD8+ cells, alongside NK subsets, increased significantly during treatment. Furthermore, we correlated decreases/increases in subsets after two cycles of ICT with survival. Specifically, a decrease in Th17 cells indicated a better overall survival. Based on these findings, we suggest conducting further investigation into Th17 cells as a potential early predictive biomarkers for response in patients receiving palliative ICT for stage IV SCLC. Full article

Platin-based chemotherapy is the standard treatment for patients with non-small cell lung cancer (NSCLC). However, resistance to this therapy is a major obstacle in successful treatment. In this study, we aimed to investigate the impact of several pharmacogenetic variants in patients with unresectable NSCLC treated with platin-based chemotherapy. Our results showed that DPYD variant carriers had significantly shorter progression-free survival and overall survival compared to DPYD wild-type patients, whereas DPD deficiency was not associated with a higher incidence of high-grade toxicity. For the first time, our study provides evidence that DPYD gene variants are associated with resistance to platin-based chemotherapy in NSCLC patients. Although further studies are needed to confirm these findings and explore the underlying mechanisms of this association, our results suggest that genetic testing of DPYD variants may be useful for identifying patients at a higher risk of platin-based chemotherapy resistance and might be helpful in guiding future personalized treatment strategies in NSCLC patients. Full article

Ovarian cancer (OC) accounts for approximately 4% of cancer deaths in women worldwide and is the deadliest gynecologic malignancy. High-grade serous ovarian cancer (HGSOC) is the most predominant ovarian cancer, in which BRCA1/2 gene mutation ranges from 3 to 27%. PARP inhibitors (PARPi) have shown promising results as a synthetically lethal therapeutic approach for BRCA mutant and recurrent OC in clinical use. However, emerging data indicate that BRCA-deficient cancers may be resistant to PARPi, and the mechanisms of this resistance remain elusive. We found that amplification of KRAS likely underlies PARPi resistance in BRCA2-deficient HGSOC. Our data suggest that PLK1 inhibition restores sensitivity to PARPi in HGSOC with KRAS amplification. The sequential combination of PLK1 inhibitor (PLK1i) and PARPi drastically reduces HGSOC cell survival and increases apoptosis. Furthermore, we were able to show that a sequential combination of PLK1i and PARPi enhanced the cellular apoptotic response to carboplatin-based chemotherapy in KRAS-amplified resistant HGSOC cells and 3D spheroids derived from recurrent ovarian cancer patients. Our results shed new light on the critical role of PLK1 in reversing PARPi resistance in KRAS-amplified HGSOC, and offer a new therapeutic strategy for this class of ovarian cancer patients where only limited options currently exist. Full article

Nasopharyngeal carcinoma (NPC) in children and young adults has been treated within two consecutive prospective trials in Germany, the NPC-91 and the NPC-2003 study of the German Society of Pediatric Oncology and Hematology (GPOH). In these studies, multimodal treatment with induction chemotherapy, followed by radio (chemo)therapy and interferon-beta maintenance, yielded promising survival rates even after adapting total radiation doses to tumor response. The outcome of 45 patients in the NPC-2003 study was reassessed after a median follow-up of 85 months. In addition, we analyzed 21 further patients after closure of the NPC-2003 study, recruited between 2011 and 2017, and treated as per the NPC-2003 study protocol. The EFS and OS of 66 patients with locoregionally advanced NPC were 93.6% and 96.7%, respectively, after a median follow-up of 73 months. Seven patients with CR after induction therapy received a reduced radiation dose of 54 Gy; none relapsed. In young patients with advanced locoregional NPC, excellent long-term survival rates can be achieved by multimodal treatment, including interferon-beta. Radiation doses may be reduced in patients with complete remission after induction chemotherapy and may limit radiogenic late effects. Full article

Squamous cell carcinoma (SCC) is the second most frequent form of skin cancer after basal cell carcinoma. While most SCC can be treated by surgery or radiotherapy, some progress into an advanced form and are no longer suitable for these treatments. Guidelines and staging systems have help to define these advanced SCC (aSCC), for which prognosis was very poor until recently. Platin-based chemotherapy was traditionally used, but few prospective trials and no treatment regimen was recommended. Furthermore, toxicity in elderly patients limited its use. The development of immunotherapy has improved the prognosis of these difficult-to-treat aSCC. In this review, we define high risk and aSCC and explored current treatment strategies for these tumors. Full article

Less toxic treatment strategies for testicular germ cell tumor (TGCT) patients are needed, as overtreatment is a concern due to the long-term side effects of platin-based chemotherapy. Although clinical benefit from classical hypomethylating agents has to date been limited, TGCTs show an abnormal DNA methylome indicating the potential of treating TGCTs with hypomethylating drugs. We tested, for the first time in TGCT cell lines, a new synthetic flavonoid compound (MLo1302) from the 3-nitroflavanone family of DNA methyltransferase (DNMT) inhibitors. We show that MLo1302 reduces cell viability (including of cisplatin resistant cell line NCCIT-R), with IC₅₀s (inhibitory concentration 50) within the nanomolar range for NCCIT and NTERA-2 cells, and proved its cytotoxic effect. Exposure to MLo1302 reduced DNMT protein expression, similar to decitabine, and showed a partial effect in cell differentiation, reducing protein expression of pluripotency markers. RT² profiler expression array indicated several dysregulated targets, related to activation of apoptosis, differentiation, and cell cycle arrest. We validated these data by showing increased apoptosis, increased protein expression of cleaved caspase 8 and activated caspase 2, and reduced proliferation (BrdU assay), with increase in CDKN1A and decrease in MIB-1 expression. Therefore, synthetic drugs designed to target DNA methylation in cells may uncover effective treatments for TGCT patients. Full article

In cancer chemotherapy, metal-based complexes have been recognized as the most promising means of inhibiting cancer growth due to the successful application of cis-platin and its derivatives above many of the existing organic anticancer agents. The limitations in their rational design can be traced to the complexity of the mechanism of their operations, lack of proper knowledge of their targets and lack of force fields in docking packages to appropriately define the metal centre of the organometallic complexes. In this paper, some of the promising anticancer complexes of Ru(II) such as the rapta-based complexes formulated as [Ru(η⁶-p-cymene)L₂(pta)] and those with unusual ligands are considered. CatB and kinases which have been experimentally confirmed as possible targets of the complexes are also predicted by the three methods as one of the most targeted receptors while TopII and HDAC7 are predicted by two and one of the methods as best targets. The interesting features of the binding of the complexes show that some of the complexes preferentially target specific macromolecules than the others, which is an indication of their specificity and possibility of their therapeutic combination without severe side effects that may come from competition for the same target. Also, introduction of unusual ligands is found to significantly improve the activities of most of the complexes studied. Strong correlations are observed for the predicted binding sites and the orientation of the complexes within the binding site by the three methods of docking. However there are disparities in the ranking of the complexes by the three method of docking, especially that of Glide. Full article

Treatment of the clinically and prognostically heterogeneous neuroendocrine neoplasms (NEN) should be based on a multidisciplinary approach, including surgical, interventional, medical and nuclear medicine-based therapeutic options. Medical therapies include somatostatin analogues, interferon-a, mTOR inhibitors, multikinase inhibitors and systemic chemotherapy. For the selection of the appropriate medical treatment the hormonal activity, primary tumor localization, tumor grading and growth behaviour as well as the extent of the disease must be considered. Somatostatin analogues are mainly indicated in hormonally active tumors for symptomatic relief, but antiproliferative effects have also been demonstrated, especially in well-differentiated intestinal NET. The efficacy of everolimus and sunitinib in patients with pancreatic neuroendocrine tumors (pNET) has been demonstrated in large placebo-controlled clinical trials. pNETs are also chemosensitive. Streptozocin-based chemotherapeutic regimens are regarded as current standard of care. Temozolomide in combination with capecitabine is an alternative that has shown promising results that need to be confirmed in larger trials. Currently, no comparative studies and no molecular markers are established that predict the response to medical treatment. Therefore the choice of treatment for each pNET patient is based on individual parameters taking into account the patient’s preference, expected side effects and established response criteria such as proliferation rate and tumor load. Platin-based chemotherapy is still the standard treatment for poorly differentiated neuroendocrine carcinomas. Clearly, there is an unmet need for new systemic treatment options in patients with extrapancreatic neuroendocrine tumors. Full article