Innovative strategies for effective paclitaxel delivery: Recent developments and prospects.

PURPOSE: Paclitaxel is an effective chemotherapeutic agent against a variety of cancer types. However, the clinical utility of paclitaxel is restricted by its poor solubility in water and high toxicity, resulting in low drug tolerance. These difficulties could be resolved by using suitable pharmacological carriers. Hence, it is essential to determine innovative methods of administering this effective medication to overcome paclitaxel's inherent limitations. METHODS: An extensive literature search was conducted using multiple electronic databases to identify relevant studies published. RESULTS: In this comprehensive analysis, many different paclitaxel delivery systems are covered and discussed, such as albumin-bound paclitaxel, polymeric micelles, paclitaxel-loaded liposomes, prodrugs, cyclodextrins, and peptide-taxane conjugates. Moreover, the review also covers various delivery routes of conventional paclitaxel or novel paclitaxel formulations, such as oral administration, local applications, and intraperitoneal delivery. CONCLUSION: In addition to albumin-bound paclitaxel, polymeric micelles appear to be the most promising formulations for innovative drug delivery systems at present. A variety of variants of polymeric micelles are currently undergoing advanced phases of clinical trials.

Prognostic factors in refractory metastatic colorectal cancer patients treated with Trifluridine/Tipiracil.

PURPOSE: The systemic treatment options for metastatic colorectal cancer (mCRC) are unsatisfactory, and the disease recurs despite the use of numerous medications and their combinations. Trifluridine/Tipiracil is a relatively new drug used in refractory mCRC. Little is known about its real-world effectiveness and prognostic and predictive factors. Therefore, this study aimed to develop a prognostic model for refractory mCRC treated with Trifluridine/Tipiracil. METHODS: We retrospectively evaluated the data from 163 patients who had received Trifluridine/Tipiracil as a third or fourth line of treatment for refractory mCRC. RESULTS: After starting Trifluridine/Tipiracil, 21.5% of patients survived one year, and the median overall survival after Trifluridine/Tipiracil initiation was 251 days (SD: 17.855; 95%CI: 216-286). Median progression-free survival after Trifluridine/Tipiracil initiation was 56 days (SD: 4.826; 95%CI 47-65). Moreover, the median overall survival from diagnosis was 1333 days (SD: 82.84; 95%CI: 1170-1495). In forward stepwise multivariate Cox regression analysis, initial radical treatment (HR = 0.552, 95% CI 0.372-0.819, p < 0.003), the number of cycles of first-line chemotherapy (HR = 0.978, 95% CI 0.961-0.995, p < 0.011), the number of cycles of second-line chemotherapy (HR = 0.955, 95% CI 0.931-0.98, p < 0.011), BRAF mutation (HR = 3.016, 95% CI = 1.207-7.537, p = 0.018), and hypertension (HR = 0.64, 95% CI = 0.44-0.931, p = 0.02) were all associated with survival after Trifluridine/Tipiracil initiation. Our model and model-based nomogram displayed an AUC of 0.623 for one-year survival estimation in the testing cohort. The C-index for the prediction nomogram was 0.632. CONCLUSION: We have developed a prognostic model for refractory mCRC treated with Trifluridine/Tipiracil based on five variables. Moreover, we reported a nomogram which could be used by oncologists in clinic visits on a daily basis.

Current and promising treatment strategies in glioma.

Gliomas are the most common primary central nervous system tumors; despite recent advances in diagnosis and treatment, glioma patients generally have a poor prognosis. Hence there is a clear need for improved therapeutic options. In recent years, significant effort has been made to investigate immunotherapy and precision oncology approaches. The review covers well-established strategies such as surgery, temozolomide, PCV, and mTOR inhibitors. Furthermore, it summarizes promising therapies: tumor treating fields, immune therapies, tyrosine kinases inhibitors, IDH(Isocitrate dehydrogenase)-targeted approaches, and others. While there are many promising treatment strategies, none fundamentally changed the management of glioma patients. However, we are still awaiting the outcome of ongoing trials, which have the potential to revolutionize the treatment of glioma.

An analysis of the significance of the lymph node ratio and extracapsular involvement in the prognosis of endometrial cancer patients.

Introduction: The primary aim of our study was to analyse the impact of the lymph node ratio (LNR) and extracapsular involvement (ECI) on the prognosis of endometrial cancer (EC) patients. Material and methods: We carried out a retrospective analysis of 886 patients surgically treated for EC between 2000 and 2015. In the subgroup of patients with lymph node metastases (LNM), we evaluated the impact of the number and localization of the LNM, LNR, and ECI on patients' overall survival (OS). Results: In the group of patients with LNM, 0.3 was the optimal LNR cut-off for differentiating between short- and long-term survivors [HR = 2.94 (95% CI: 1.49-5.80)]. Patients with a LNR ≥ 0.3 had a significantly shorter OS period (35.0 months, range 0.2-175 months) compared to patients with a LNR < 0.3 [median OS - mOS, was 143, range 15-169 months; (p = 0.003]. We observed significant differences in the mOS of EC patients without LNM compared to patients with LNM, as well as those with both LNM and ECI (p < 0.0001). In the group of patients with LNM, we also found that a poorer prognosis depended on the extension of the primary tumour. Conclusions: Our results suggest that when LNM are found, the long-term outcomes of EC patients are worse in those who have a LNR ≥ 0.3, the presence of ECI, and a more advanced extension of the primary tumour.

Tissue engineering in reconstructive urology-The current status and critical insights to set future directions-critical review.

Advanced techniques of reconstructive urology are gradually reaching their limits in terms of their ability to restore urinary tract function and patients' quality of life. A tissue engineering-based approach to urinary tract reconstruction, utilizing cells and biomaterials, offers an opportunity to overcome current limitations. Although tissue engineering studies have been heralding the imminent introduction of this method into clinics for over a decade, tissue engineering is only marginally applied. In this review, we discuss the role of tissue engineering in reconstructive urology and try to answer the question of why such a promising technology has not proven its clinical usability so far.

Application of Graphene in Tissue Engineering of the Nervous System.

Graphene is the thinnest two-dimensional (2D), only one carbon atom thick, but one of the strongest biomaterials. Due to its unique structure, it has many unique properties used in tissue engineering of the nervous system, such as high strength, flexibility, adequate softness, electrical conductivity, antibacterial effect, and the ability to penetrate the blood-brain barrier (BBB). Graphene is also characterized by the possibility of modifications that allow for even wider application and adaptation to cell cultures of specific cells and tissues, both in vitro and in vivo. Moreover, by using the patient's own cells for cell culture, it will be possible to produce tissues and organs that can be re-transplanted without transplant rejection, the negative effects of taking immunosuppressive drugs, and waiting for an appropriate organ donor.

The association between lymph node metastases and long-term survival in patients with epithelial ovarian cancer.

INTRODUCTION: A key survival prognosis factor for patients treated for ovarian cancer is complete cytoreductive surgery where all macroscopic neoplastic implants, including enlarged metastatic lymph nodes, are removed. We presume that investigating the involvement of the lymphatic system can result in a more individualized approach to the treatment of ovarian cancer patients. The main aim of our study was to analyze the relationship between the presence, number and types of lymph node metastases and ovarian cancer patient prognosis. MATERIAL AND METHODS: We carried out a retrospective analysis of patients who underwent cytoreduction due to primary ovarian cancer, between 2010 and 2015. We analyzed the number of metastatic lymph nodes, the lymph node ratio defined as the ratio of the number of metastatic lymph nodes to the total number of lymph nodes removed, extracapsular involvement, and the histopathological pattern of metastases. RESULTS: The study group included 651 patients. Of these, 377 had lymphadenectomy, 144 presented with lymph node metastases, and 233 had no lymph node metastases. We also included a group of 274 patients who did not have lymphadenectomy. Patients with more than 4 metastatic lymph nodes and a lymph node ratio of ≥ 0.1 had significantly poorer overall survival. Extracapsular involvement had no relation to patient overall survival. Multivariant survival analysis indicated that a lymph node ratio of ≥ 0.1 was an independent predictor of poor survival. CONCLUSIONS: The analysis of lymph node metastases in ovarian cancer patients can have predictive value for patient overall survival.

Analysis of long-term outcomes in 44 patients following pelvic exenteration due to cervical cancer.

BACKGROUND: Pelvic exenteration (PE) may be associated with prolonged overall survival (OS) in selected patients with advanced or recurrent cervical cancer. However, the factors related to improved survival following PE are not clearly defined. The aim of this study was to perform a retrospective analysis of OS rates in a group of patients undergoing PE in order to identify the factors related to improved long-term outcomes. METHODS: Our study group consisted of 44 patients, including 21 squamous cell cancer (SCC) patients, 22 patients with adenocarcinomas (AC) of the cervix, and one patient with undifferentiated cervical carcinoma. The patients were categorized according to the type of surgery, namely, primary surgery (12 patients) or surgery due to cancer recurrence (32 patients). RESULTS: In the group of patients with recurrent cervical cancer, we found that improved OS correlated with the SCC histological type and the presence of vaginal fistula. The need for reoperation within 30 days and the presence of severe adverse events significantly worsened the prognosis. We found a non significant trend toward improved survival in those patients with tumor-free margins. Lymph node metastases, the initial stage of the disease, the time to recurrence, and a history of hysterectomy had no impact on patients' OS. In the group of patients undergoing primary PE, we observed a trend toward improved survival among those diagnosed with vaginal fistula. CONCLUSIONS: Pelvic exenteration seemed to improve the long-term outcomes for patients with SCC cancer recurrence and vaginal fistula whose surgery was unrelated to severe adverse events.

Cytoplasmic and membranous receptor-binding cancer antigens expressed on SiSo cells (RCAS1) immunoreactivity in epithelial ovarian cancer cells represent differing biological function of RCAS1.

INTRODUCTION: Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is a selective suppressor of the immune response that has been linked to the evasion of immune surveillance by cancer cells. However, the exact prognostic impact of RCAS1 on epithelial ovarian cancer (EOC) has not been fully elucidated. The main aim of our study was to evaluate the influence of RCAS1 immunoreactivity (RCAS1-Ir) in EOC cells and in tumor stroma cells on patient overall survival. We also focused on RCAS1-Ir and the structure of the tumor stroma. MATERIAL AND METHODS: RCAS1-Ir was evaluated by means of immunohistochemistry in 67 patients with EOC. We distinguished cytoplasmic and membranous immunoreactivity patterns. RESULTS: We found that high cytoplasmic RCAS1-Ir in cancer cells was associated with more than a two-time shortened period of overall survival. Membranous RCAS1-Ir in cancer cells, as well as in tumor stroma macrophages and fibroblasts, did not correlate with patient survival. RCAS1-Ir in the cytoplasm of cancer cells was positively correlated with the degree of tumor stroma infiltration by fibroblasts and macrophages, but not with RCAS1-Ir in these cells. On the other hand, membranous RCAS1-Ir in cancer cells was positively correlated with RCAS1-Ir in fibroblasts and macrophages, but not with their quantity. CONCLUSIONS: Due to their different impacts on patient prognosis and tumor stroma structure, it seems that cytoplasmic and membranous RCAS1-Ir in EOC cells may have different biological functions.

Analysis of the treg cell population in the peripheral blood of ovarian cancer patients in relation to the long-term outcomes.

OBJECTIVES: There is growing evidence that Treg cell infiltration into the cancer nest is associated with poor prognosis. How- ever, the Treg cell population in the peripheral blood may change when a different type of anticancer therapy is applied. Since Treg cells may support tumor growth by enhancing the suppressive profile of the cancer microenvironment, the assessment of Treg cells can bring to light important information regarding prognosis. Thus we decided to analyze the Treg cell population in the peripheral blood in relation to long-term outcomes in the group of patients with ovarian cancer. MATERIAL AND METHODS: The 80 patients included in the study were treated surgically followed by chemiotherapy for ovar- ian cancer between October 2010 through May 2011.The peripheral blood samples from the patients were collected directly prior to chemotherapy. Information on any patients who died was retrieved from the database of the Cuiavia-Pomerania Regional Office of the National Health System of Poland. CD4+CD25+FOXP3+ lymphocytes T were assed by flow cytometry. We have analyzed the long term outcomes of treatment regarding to the level of Treg cells in peripheral blood. RESULTS: We found that patients with serous adenocarcinomas had significantly higher Treg levels compared to those patients with non-serous types. Patients who had a higher percentage of Treg cells within the CD4+ cell population prior to the beginning of the treatment had worse long-term outcomes from the applied therapy. CONCLUSIONS: The assessment of Treg levels prior to the start of chemotherapy is clinically useful and may predict overall survival in ovarian cancer patients.

The potential predictive value of serum srCaS1 levels for overall survival in endometrial cancer.

OBJECTIVES: The main aim of the study was to evaluate the impact of levels of serum soluble receptor-binding cancer antigen expressed on SiSo cells (sRCAS1) on the overall survival (OS) rates in patients with endometrial cancer. Furthermore, we analyzed sRCAS1 levels according to the clinicopathological characteristics of the disease. MATERIAL AND METHODS: The study group comprised 43 patients who were being treated for endometrial cancer. We included 10 low-risk, 20 intermediate-risk and 13 high-risk endometrial cancers using the criteria of the European Society for Medical Oncology (ESMO), the European Society for Radiotherapy & Oncology (ESTRO) and the European Society of Gynaecological Oncology (ESGO). Serum sRCAS1 levels were obtained before and after surgery. Serum sRCAS1 levels were assessed using the ELISA method. RESULTS: In our univariate analysis, both the pre- and post-surgery high sRCAS1 groups of patients with endometrial cancer indicated a shortened OS. However, in our multivariate analysis, when patients' age and disease-related risk was taken into consideration, only the post-surgery sRCAS1 levels remained as independent prognostic factors of a poor OS. Pre-treatment serum sRCAS1 levels were statistically significantly higher than post-surgery sRCAS1 levels; however, the difference between pre- and post-surgery sRCAS1 levels did not influence the patients' OS rate. Pre- and post-surgery sRCAS1 levels did not differ according to tumor grade, stage of the disease or the disease-related risk group. CONCLUSIONS: High post-surgery serum sRCAS1 levels seem to be an independent indicator of shortened overall survival in patients with endometrial cancer.

High tumor cell vimentin expression indicates prolonged survival in patients with ovarian malignant tumors.

OBJECTIVES: The main aims of the study were to investigate the expression of vimentin and its correlation with the overall survival (OS) of patients with malignant ovarian tumors, and the correlation between vimentin expression and tumor stroma characteristics. MATERIAL AND METHODS: The study focused on 94 malignant ovarian tumors that had been collected from women who were treated in the Department of Gynecology and Oncology of the Lukaszczyk Oncological Center, Bydgoszcz, Poland. Vimentin expression was assessed in both the cancer cells (expression intensity and quantitative analysis) and the tumor stroma (expression intensity). Vimentin expression was analyzed according to both stromal cellularity and the clinicopatho- logical features of the disease. RESULTS: Both high cancer cell vimentin expression intensity and high quantitative vimentin expression (up to and includ- ing 30% of cells) indicated a significantly prolonged OS. Low vimentin stromal expression was associated with prolonged OS, although the difference did not reach the level of significance. High tumor cell vimentin expression intensity was as- sociated with significantly higher vimentin stromal expression. High vimentin expression in the tumor stroma indicated a significantly higher cellularity of the tumor stroma. Vimentin expression in cancer cells and the tumor stroma were not dependent on the histopathological type, the tumor grade or the FIGO stageof the disease. CONCLUSIONS: High cancer cell vimentin expression is associated with an improved OS of patients with malignant ovar- ian tumors. The expression of vimentin in ovarian malignancies may influence the structure of the tumor stroma.

The analysis of the long-term outcomes in elderly women treated for locally advanced cervical cancer.

PURPOSE: Locally advanced cervical cancer (LACC) should be treated with a combination of external irradiation and brachytherapy with concurrent chemotherapy. However, as cervical carcinoma cells can disperse by way of the lymphatic system to either pelvic or para-aortic nodes, planning the extent of radiation requires precise information about the spread of the disease to the lymph nodes, especially to the para-aortic area. MATERIAL AND METHODS: All of the 75 women included in our study underwent chemoradiotherapy, which started with brachytherapy. Out of them, 54 have undergone radical hysterectomy with lymphadenectomy followed by chemoradiation. We have retrospectively analyzed the 5-year overall survival (OS) rates relative to the lymph node involvement, the type of lymphadenectomy performed (pelvic, para-aortic, or both), the size of the tumor (> or < 4 cm), the histological type, grading, and the age of patients. RESULTS: We observed significant differences in the OS rates relative to the age of the patients with LACC. We noted significant differences in the OS rates related to para-aortic lymphadenectomy and presence of lymph node metastases. CONCLUSIONS: Para-aortic lymphadenectomy seems to have a positive influence on long-term outcomes in the LACC patients, and elderly patients may benefit more from applied therapy.

The biological role of Treg cells in ectopic endometrium homeostasis.

Although retrograde menstruation is observed in up to 90% of women, endometriosis actually develops in only 15% of women. There is considerable evidence in the literature that ectopic endometrial cells are able to evade immune surveillance and that the immune response in the microenvironment of ectopic lesions is limited. Endometriosis develops when a deficiency in the local immune response has been generated, and progression of the disease is related to the intensity of this process. Over the last couple of decades it has been well known that T regulatory lymphocytes (Tregs) play a crucial role in controlling a variety of physiological and pathological immune responses. In this review we have focused on the physiological alteration of Treg cell infiltration into the endometrium during the reproductive processes of women. We discuss how a disturbance in Treg cell expansion is involved in generating such pathological processes as miscarriage and ectopic pregnancy development. We hypothesize about the role Treg cells might play in the survival of endometriosis foci in ectopic localization and in the evasion of such lesions from host immune surveillance.

The analysis of metallothionein immunoreactivity in stromal fibroblasts and macrophages in cases of uterine cervical carcinoma with respect to both the local and distant spread of the disease.

PROBLEM: The tumor microenvironment is made up of tissue that is responsible for the growth and progression of the tumor as well as its ability to initiate metastases. The cancer cells on the front of the tumor together with the macrophages and fibroblasts help to constitute the aggressive phenotype of the tumor. The presence of this aggressive phenotype is indicated by the local infiltration of cancer cells and by the development of lymph node metastases. In cases of uterine cancer, the extent of the local and distant spread of the disease is crucial for determining the type of therapeutic strategy to be applied - surgery alone, surgery followed by radio-chemotherapy, or radio-chemotherapy alone. In the interest of trying to improve the patient's quality of life, different studies supporting the therapeutic model of surgery alone have been conducted. While the cancer cells on the tumor front together with the macrophages and the fibroblasts help to constitute the aggressive phenotype of the tumor, metallothionein (MT) has been shown to have both pro-proliferative and anti-apoptotic activities and to participate in microenvironment remodeling. The aim of the current study was to determine the levels of MT immunoreactivity in the uterine cervical cancer cells as well as in the stromal fibroblasts and macrophages of the tumor microenvironment with respect to the depth of the local invasion and the extent of the distant metastases, so that its potential predictive value as a therapeutic strategy for cervical cancer can be ascertained. METHODS: We determined the levels of immunoreactivity of MT in a total of 57 carcinoma tissue samples (in the tumor front, in its central part, and in the macrophages and fibroblasts present within the tumor microenvironment). The patients from whom the samples derived were divided into groups with respect to the presence of lymph node metastases (distant spread) and to the depth of invasion (local spread) in relation to the FIGO stage. RESULTS: Metallothionein immunoreactivity was observed in uterine cervical cancer cells; it was also identified in the fibroblasts and macrophages found within the microenvironments of the tumors of patients suffering from the disease. The MT immunoreactivity level significantly increased within the whole cancer nest in relation to the FIGO stage (intensity of the local spread of the disease). Similarly, the infiltration of MT-positive CAFs and TAMs statistically significantly increased in relation to the FIGO stage. CONCLUSION: The level of MT immunoreactivity found in the fibroblasts and macrophages within the tumor microenvironment seems to be indicative of the intensity of the remodeled cervical tumor microenvironment, and this in turn may be related to the local advancement of the disease. Moreover, it appears that the intensity of the metallothionein immunoreactivity in the immunoreactivity profile of the cervical tumor may be linked to both the depth of the local invasion and the extent of the distant advancement of the disease.

The immunohistochemical analysis of antigens such as RCAS1 and B7H4 in the cervical cancer nest and within the fibroblasts and macrophages infiltrating the cancer microenvironment.

INTRODUCTION: The presence of the aggressive phenotype of the tumor seems to be indicated by the local infiltration of cancer cells and by the development of metastases in the lymph nodes. This phenotype is related to the intensity of the suppressive profile of the tumor microenvironment. The aim of our study has been to gather information about the expression of both RCAS1 and B7H4 proteins in the macrophages and fibroblasts present within both the microenvironment of cervical cancer tumors and the cancer cells present on the front of the cancer nest. METHODS: We analyzed the immunoreactivity levels of such antigens as B7H4 and RCAS1 in the macrophages and fibroblasts of the cancer microenvironment and within the cancer nest in the tissue samples derived from patients on whom both a radical hysterectomy and a lymphadenectomy had been performed following a diagnosis of uterine cervical carcinoma. These patients were then divided into two subgroups according to the extent of the local and distant advancement of the cancer - that is, according to the FIGO stage and the presence or absence of lymph node metastases. RESULTS: RCAS1 immunoreactivity levels on the front of the cancer nest statistically significantly increase according to the FIGO stage or the extent of the local spread of the disease while B7H4 immunoreactivity levels on the tumor front increase in relation to the extent of the distant spread of the disease or the presence of lymph nodes metastases. CONCLUSION: The intensity of the suppressive profile of the cervical cancer microenvironment indicated by the presence of both RCAS1 and B7H4 on the front of the tumor and in the macrophages and fibroblasts infiltrating the cancer stroma seems to correlate with the extent of both the local and distant advancement of the disease.

The analysis of receptor-binding cancer antigen expressed on SiSo cells (RCAS1) immunoreactivity within the microenvironment of the ovarian cancer lesion relative to the applied therapeutic strategy.

RCAS1 is involved in generating the suppressive profile of the tumor microenvironment that helps cancer cells evade immune surveillance. The status of the cells surrounding the cancer nest may affect both the progression of the cancer and the development of metastases. In cases of ovarian cancer, a large number of patients do not respond to the applied therapy. The patient's response to the applied therapy is directly linked to the status of the tumor microenvironment and the intensity of its suppressive profile. We analyzed the immunoreactivity of RCAS1 on the cells present in the ovarian cancer microenvironment in patients with the disease; these cells included macrophages and carcinoma-associated fibroblasts. Later we analyzed the immunoreactivity levels within these cells, taking into consideration the clinical stage of the cancer and the therapeutic strategy applied, such as the number of chemotherapy regiments, primary cytoreductive surgery, or the presence of advanced ascites. In the patients who did not respond to the therapy we observed significantly higher immunoreactivity levels of RCAS1 within the cancer nest than in those patients who did respond; moreover, in the non-responsive patients we found RCAS1 within both macrophages and carcinoma-associated fibroblasts. RCAS1 staining may provide information about the intensity of the immuno-suppressive microenvironment profile found in cases of ovarian cancer and its intensity may directly relate to the clinical outcome of the disease.

Analysis of Treg cell population alterations in the peripheral blood of patients treated surgically for ovarian cancer - a preliminary report.

PROBLEM: Treg cells constitute the main cell population that enables cancer cells to evade immune surveillance. An alteration in the Treg cell population might correspond to the diminishment of the tumour mass in patients with cancer and could therefore be a useful marker of the intensity of the selective suppression of the host immune system and also of the degree of radicalism of a procedure. Certainly, it is well known that in order for anti-cancer therapy to succeed the proper immune response against cancer cells must be restored. Furthermore, monitoring the level of selective immune system suppression during cancer therapy might yield information that would support a decision to supplement standard therapy by immunotherapy or to increase the degree of radicalism of the applied therapy. METHOD OF STUDY: We examined the Treg cell populations in the peripheral blood of a group of patients treated surgically for ovarian cancer. In each patient, the peripheral blood samples were collected both prior to and 1 day after the surgical procedure, and then again 5 days after the procedure. The presence of regulatory T cells in the samples was analyzed by means of flow cytometry. RESULTS: In our study, the percentages of FOXP3(+) cells in the subpopulation of CD4(+) T lymphocytes found in the peripheral blood of the patients before the surgical intervention were statistically significantly higher than those observed in the peripheral blood of these same patients after the surgical procedure. CONCLUSION: It would seem that the alteration in the Treg cell subpopulation could be a key factor in determining the status of the tumour microenvironment. Most likely, it could provide information about whether the proper level of anti-cancer immune response could be restored. The possibility of restoring the immune response may directly correspond to the degree of radicalism of the surgical intervention.