Biomarker Dynamics and Long-Term Treatment Outcomes in Breast Cancer Patients with Residual Cancer Burden after Neoadjuvant Therapy.

A residual cancer burden after neoadjuvant therapy (NAT) for breast cancer (BC) is associated with worse treatment outcomes compared to patients who achieved pathologic complete remission. This single-institutional retrospective study of 767 consecutive patients, including 468 patients with assessable residual cancer burden (aRCB) after NAT, with a median follow-up of 36 months, evaluated the biomarkers assessed before NAT from a biopsy and after NAT from a surgical specimen, their dynamics, and effect on long-term outcomes in specific breast cancer subtypes. The leading focus was on proliferation index Ki-67, which was significantly altered by NAT in all BC subtypes (p < 0.001 for HER2 positive and luminal A/B HER2 negative and p = 0.001 for TNBC). Multivariable analysis showed pre-NAT and post-NAT Ki-67 as independent predictors of survival outcomes for luminal A/B HER2 negative subtype. For TNBC, post-NAT Ki-67 was significant alone, and, for HER2 positive, the only borderline association of pre-NAT Ki-67 was observed in relation to the overall survival. Steroid and HER2 receptors were re-assessed just in a portion of the patients with aRCB. The concordance of both assessments was 92.9% for ER status, 80.1% for PR, and 92.2% for HER2. In conclusion, these real-world data of a consecutive cohort confirmed the importance of biomarkers assessment in patients with aRCB, and the need to consider specific BC subtypes when interpreting their influence on prognosis.

Can Previous Chemotherapy Affect the Outcome of Nivolumab Treatment in Non-small Cell Lung Cancer?

AIM: This study compared the results of nivolumab treatment in patients with pulmonary adenocarcinomas based upon previous chemotherapeutic regimens. PATIENTS AND METHODS: The data source for this retrospective study was the Czech VILP registry of patients with nivolumab-treated adenocarcinomas in second and higher lines of treatment. In relation to objective response rate, progression-free interval, and overall survival, three comparisons of patient were made: A: Those treated in first line with cisplatin and pemetrexed versus carboplatin with paclitaxel or vinorelbine; B: treatment with cisplatin and pemetrexed versus carboplatin with paclitaxel/vinorelbine and bevacizumab; and C: treatment in previous lines with pemetrexed (first-line cisplatin and pemetrexed plus those treated in second line with pemetrexed) versus treatment with taxane (first-line carboplatin and paclitaxel only plus those treated with second-line docetaxel). RESULTS: We observed no differences in objective response rate or progression-free survival between patients treated with the stated chemotherapeutic regimens. We observed a trend towards better overall survival for patients treated with carboplatin plus taxanes or vinorelbine with/without bevacizumab. CONCLUSION: From our overall survival data, a chemotherapeutic regimen of carboplatin plus taxanes or vinorelbine with/without bevacizumab might be a better partner for immunotherapy than a cisplatin and pemetrexed-based one.

Modifications of Parylene by Microstructures and Selenium Nanoparticles: Evaluation of Bacterial and Mesenchymal Stem Cell Viability.

Parylene-based implants or coatings introduce surfaces suffering from bacteria colonization. Here, we synthesized polyvinylpyrrolidone-stabilized selenium nanoparticles (SeNPs) as the antibacterial agent, and various approaches are studied for their reproducible adsorption, and thus the modification of parylene-C-coated glass substrate. The nanoparticle deposition process is optimized in the nanoparticle concentration to obtain evenly distributed NPs on the flat parylene-C surface. Moreover, the array of parylene-C micropillars is fabricated by the plasma etching of parylene-C on a silicon wafer, and the surface is modified with SeNPs. All designed surfaces are tested against two bacterial pathogens, Escherichia coli (Gram-negative) and Staphylococcus aureus (Gram-positive). The results show no antibacterial effect toward S. aureus, while some bacteriostatic effect is observed for E. coli on the flat and microstructured parylene. However, SeNPs did not enhance the antibacterial effect against both bacteria. Additionally, all designed surfaces show cytotoxic effects toward mesenchymal stem cells at high SeNP deposition. These results provide valuable information about the potential antibacterial treatment of widely used parylene-C in biomedicine.

Drug interaction profile of TKI alectinib allows effective and safe treatment of ALK+ lung cancer in the kidney transplant recipient.

ALK targeting with tyrosine kinase inhibitors (TKIs) is a highly potent treatment option for the therapy of ALK positive non-small cell lung cancer (NSCLC). However, pharmacokinetics of TKIs leads to clinically significant drug interactions, and the interfering co-medication may hamper the anti-cancer therapeutic management. Here, we present for the first time a drug interaction profile of ALK-TKIs, crizotinib and alectinib, and immunosuppressive agent cyclosporine A in kidney transplant recipients diagnosed with ALK+ lung cancer. Based on therapeutic drug monitoring of cyclosporin A plasma level, the dose of cyclosporine A has been adjusted to achieve a safe and effective therapeutic level in terms of both cancer treatment and kidney transplant condition. Particularly, 15 years upon the kidney transplantation, the stage IV lung cancer patient was treated with the 1st-line chemotherapy, the 2nd-line ALK-TKI crizotinib followed by ALK-TKI alectinib. The successful therapy with ALK-TKIs has been continuing for more than 36 months, including the period when the patient was treated for COVID-19 bilateral pneumonia. Hence, the therapy of ALK+ NSCLC with ALK-TKIs in organ transplant recipients treated with cyclosporine A may be feasible and effective.

Neoadjuvant Chemotherapy of Triple-Negative Breast Cancer: Evaluation of Early Clinical Response, Pathological Complete Response Rates, and Addition of Platinum Salts Benefit Based on Real-World Evidence.

Pathological complete response (pCR) achievement is undoubtedly the essential goal of neoadjuvant therapy for breast cancer, directly affecting survival endpoints. This retrospective study of 237 triple-negative breast cancer (TNBC) patients with a median follow-up of 36 months evaluated the role of adding platinum salts into standard neoadjuvant chemotherapy (NACT). After the initial four standard NACT cycles, early clinical response (ECR) was assessed and used to identify tumors and patients generally sensitive to NACT. BRCA1/2 mutation, smaller unifocal tumors, and Ki-67 ≥ 65% were independent predictors of ECR. The total pCR rate was 41%, the achievement of pCR was strongly associated with ECR (OR = 15.1, p < 0.001). According to multivariable analysis, the significant benefit of platinum NACT was observed in early responders ≥45 years, Ki-67 ≥ 65% and persisted lymph node involvement regardless of BRCA1/2 status. Early responders with pCR had a longer time to death (HR = 0.28, p < 0.001) and relapse (HR = 0.26, p < 0.001). The pCR was achieved in only 7% of non-responders. However, platinum salts favored non-responders' survival outcomes without statistical significance. Toxicity was significantly often observed in patients with platinum NACT (p = 0.003) but not for grade 3/4 (p = 0.155). These results based on real-world evidence point to the usability of ECR in NACT management, especially focusing on the benefit of platinum salts.

Penis as a primary site of an extraskeletal Ewing sarcoma: A case report.

RATIONALE: The Ewing sarcoma family of malignant tumors is a group of tumors characterized by morphologically similar round-cell neoplasms and by the presence of a common chromosomal translocation; Ewing sarcoma family of tumors typically occur in children and young adults between 4 to 15 years of age. The primary tumor usually originates in the bone, extraskeletal localization is rare. PATIENT CONCERN: We present a case report concerning a 32-year-old male patient with a primary involvement of the penis. DIAGNOSIS: The histopathology from the first penile biopsy showed a small-cell neuroendocrine carcinoma; however, that result was based on a sample obtained at a different facility than the Sarcoma Center, where the investigating pathologist did not have the adequate expertise. The patient then underwent a radical penectomy and a second reading of the histology was demanded after a radical penile amputation when Ewing sarcoma with R1 resection was confirmed. INTERVENTIONS: The patient was referred to the national Sarcoma Center, where - using a multidisciplinary approach - the treatment was started with curative intent. However, it was preceded by a non-standard initiation of the therapy due to the poor primary diagnosis. OUTCOMES: The non-standard therapy at the onset of the disease caused a poor prognosis of an otherwise curable diagnosis. Despite all that, the patient survived for a relatively long time. LESSONS: The treatment of sarcomas with atypical localizations should be conducted by an experienced multidisciplinary team in a center with experience in sarcoma treatment.

Impact of Concomitant Medication Administered at the Time of Initiation of Nivolumab Therapy on Outcome in Non-small Cell Lung Cancer.

AIM: To investigate potential association between administration of corticosteroids, antibiotics, probiotics, proton pump inhibitors, non-steroidal anti-inflammatory drugs (NSAID), statins and metformin and outcome in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. PATIENTS AND METHODS: A total of 224 patients with advanced NSCLC treated at nine comprehensive cancer centers were analyzed in this national retrospective study. Survival statistics were evaluated using Kaplan-Meier method and Cox analysis. RESULTS: Only corticosteroid use had a significant negative effect on the objective response rate. In the univariate analysis, there was no significant effect of the studied concomitant medications on the efficacy of nivolumab. In a subsequent multifactorial analysis, a possible positive effect of the concomitant use of NSAID at the initiation of nivolumab treatment was revealed. CONCLUSION: The results of the present retrospective exploratory analysis underscore the importance of knowing the exact type of concomitant medication, the route of administration, the dose of medication, and the region of the ongoing study. The present data indicated a significantly higher rate of progression in patients treated with corticosteroids and the possible positive effect of NSAID use at the initiation of nivolumab treatment.

Antibacterial activity of AgNPs-TiO2 nanotubes: influence of different nanoparticle stabilizers.

Enhanced antibacterial properties of nanomaterials such as TiO2 nanotubes (TNTs) and silver nanoparticles (AgNPs) have attracted much attention in biomedicine and industry. The antibacterial properties of nanoparticles depend, among others, on the functionalization layer of the nanoparticles. However, the more complex information about the influence of different functionalization layers on antibacterial properties of nanoparticle decorated surfaces is still missing. Here we show the array of ∼50 nm diameter TNTs decorated with ∼50 nm AgNPs having different functionalization layers such as polyvinylpyrrolidone, branched polyethyleneimine, citrate, lipoic acid, and polyethylene glycol. To assess the antibacterial properties, the viability of Gram-positive (Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) has been assessed. Our results showed that the functional layer of nanoparticles plays an important role in antibacterial properties and the synergistic effect such nanoparticles and TiO2 nanotubes have had different effects on adhesion and viability of G- and G+ bacteria. These findings could help researchers to optimally design any surfaces to be used as an antibacterial including the implantable titanium biomaterials.

Effectiveness of Neoadjuvant Therapy with Platinum-Based Agents for Patients with BRCA1 and BRCA2 Germline Mutations - A Retrospective Analysis of Breast Cancer Patients Treated at MMCI Brno.

BACKGROUND: Mutations in the BRCA1 and BRCA2 genes are associated with a high risk of developing breast cancer. Tumors arising from this mutation are expected to be more sensitive to platinum-based drugs. The role of platinum-based drugs in systemic neoadjuvant BRCA1/2 breast cancer therapy, and its efficacy in increasing the probability of pathological complete remission (pCR) are discussed repeatedly; however, there are no clear recommendations. PATIENTS AND METHODS: We retrospectively evaluated the contribution of a platinum-based antineoplastic drug to the achievement of pCR in a set of patients with BRCA1/2 mutant breast cancer treated with neoadjuvant chemotherapy from 2010 to 2017. The response to neoadjuvant chemotherapy was evaluated by a pathologist using definitive surgical specimens. A pCR was defined as a condition in which complete invasive breast cancer, and (eventually) positive lymph nodes, had disappeared. RESULTS: Of 76 patients (median age, 39 years; 62% with triple negative breast cancer (TNBC); 70% with BRCA1 positivity), 37 were treated with platinum-based drugs. More patients treated with platinum derivatives achieved pCR (57% vs. 23%, p = 0.005). Patients treated in a neoadjuvant setting with platinum-based antineoplastic drugs had a 4.4× greater chance of achieving pCR than those not treated with platinum, assuming the same tumor phenotype (TNBC or SR+/HER2). CONCLUSION: Neoadjuvant platinum-based chemotherapy for patients with a BRCA1/2 mutation is associated with a higher probability of achieving pCR, which is important for subsequent prognosis. This treatment should be considered particularly for patients with BRCA1 mutation and a TNBC phenotype. This work was supported by grant of the Ministry of Health of the Czech Republic - Conceptual. Development of a Reaserch Organization (MMCI 00209805). This work was supported by grant of the Ministry of Education, Youth and Sport of the Czech Republic (NPU I - LO1413). The authors declare they have no potential confl icts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 21. 3. 2019 Accepted: 14. 5. 2019.

Oncology Case Report - When Is the Appropriate Time to Integrate Palliative Care?

Many patients with advanced, non-curable cancer experience disease progression to a stage requiring symptomatic care alone. The integration of palliative care into oncology practice is therefore important, with many studies showing the benefits of early introduction of palliative care. In addition to symptom relief, palliative care can include psychological, social, and spiritual support. Although all oncologists provide basic palliative care, recent data indicate that the parallel involvement of a specialist palliative team that addresses the psychological, social, and spiritual needs of patients may be advantageous for both patients and their families. This mode of early integration of palliative care has been found to enhance patient quality of life and to provide more effective use of costly treatments. In Czech hospitals, however, this mode is rarely employed. Palliative care is usually perceived as an end-stage approach, which is initiated only when all other anticancer treatment modalities have been exhausted. This case describes the challenges and missed opportunities when palliative care was initiated late during the dying phase of a young female patient with metastatic colorectal cancer, and it discusses the potential benefits of early integration of palliative care. Supported by Ministry of Health of the Czech Republic, grant No. 15-33590A. All rights reserved. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 27. 11. 2018 Accepted: 7. 6. 2019.

Enhanced antibacterial and anticancer properties of Se-NPs decorated TiO2 nanotube film.

Selenium nanoparticle modified surfaces attract increasing attention in the field of tissue engineering. Selenium exhibits strong anticancer, antibacterial and anti-inflammatory properties and it maintains relatively low off-target cytotoxicity. In our paper, we present the fabrication, characterization and cytocompatibility of titanium oxide (TiO2) nanotube surface decorated with various surface densities of chemically synthesized selenium nanoparticles. To evaluate antibacterial and anti-cancer properties of such nanostructured surface, gram negative bacteria E. coli, cancerous osteoblast like MG-63 cells and non-cancerous fibroblast NIH/3T3 were cultured on designed surfaces. Our results suggested that selenium nanoparticles improved antibacterial properties of titanium dioxide nanotubes and confirmed the anticancer activity towards MG-63 cells, with increasing surface density of nanoparticles. Further, the selenium decorated TiO2 nanotubes suggested deteriorating effect on the cell adhesion and viability of non-cancerous NIH/3T3 cells. Thus, we demonstrated that selenium nanoparticles decorated TiO2 nanotubes synthesized using sodium selenite and glutathione can be used to control bacterial infections and prevent the growth of cancerous cells. However, the higher surface density of nanoparticles adsorbed on the surface was found to be cytotoxic for non-cancerous NIH/3T3 cells and thus it might complicate the integration of biomaterial into the host tissue. Therefore, an optimal surface density of selenium nanoparticles must be found to effectively kill bacteria and cancer cells, while remaining favorable for normal cells.

Acetylsalicylic Acid and its Potential for Chemoprevention of Colorectal Carcinoma.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAID) represent a group of medicaments inhibiting cyclooxygenase (COX) enzyme, and, in parallel, these drugs show also analgesic, antipyretic and anti-inflammatory effects. Due to their efficiency, good tolerance and easy availability, they belong to the worlds most used drugs. For decades, evidence of their anti-tumor activity has been growing, with the largest amount of published work being related to colorectal cancer (CRC). Based on both in vitro and in vivo experiments and data obtained from epidemiological and clinical studies, potential application of NSAID as chemo-preventive treatment for CRC patients is recently discussed in order to prevent development or recurrence of precanceroses and tumors. Promising treatment for such indication would be acetylsalicylic acid (ASA), which is the oldest, more than 100 years used member of the NSAID family. Nonselective irreversible COX inhibition is an important but probably not solely mechanism of its anticancer activity. Notably, wider use of ASA in chemoprevention is also prevented due to particular concerns about gastrointestinal and renal toxicity caused especially by its long-term use. AIMS: This review introduces the role of COX in tumor biology of CRC and highlights the results of the most interesting experiments illustrating the anti-tumor effect of ASA. Moreover, our work evaluates the most important published clinical analyzes of the ASA chemopreventive effect on CRC and discusses the current state. Key words: non-steroidal anti-inflammatory agents - acetylsalicylic acid - colorectal carcinoma - cyclooxygenase - chemoprevention This work was supported by the projects MEYS - NPS I - LO1413, MH CZ - DRO (MMCI, 00209805) and by Czech Science Foundation project no. 16-14829S. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Accepted: 10. 9. 2017.

Soft tissue metastasis of mediastinal non-functioning paraganglioma with unusual TTF-1 expression: a potential diagnostic pitfall.

Metastatic extra-adrenal paragangliomas are very rare and can represent diagnostic challenges. We report a case of 69-year-old man with a tumor of the right shoulder. Histologic and immunohistochemical examinations confirmed the diagnosis of paraganglioma. Surprisingly, tumor cells were diffusely thyroid transcription factor 1 (TTF-1) positive. Succinate dehydrogenase complex subunit B (SDHB) deficiency has not been detected. Inherited syndromes associated with paragangliomas were ruled out. The primary tumor was identified in the mediastinum. This is the first report of TTF-1 expression in paraganglioma. To avoid misdiagnosis, careful clinical and pathological examination of any tumor with organoid growths pattern is necessary.