Purpose: Chondrosarcomas are a group of cartilaginous malignant neoplasms characterized by the deposition of chondrogenic extracellular matrix. Surgical resection is currently the only curative... Show morePurpose: Chondrosarcomas are a group of cartilaginous malignant neoplasms characterized by the deposition of chondrogenic extracellular matrix. Surgical resection is currently the only curative treatment option, due to their high resistance to conventional chemotherapy and radiotherapy. Novel therapeutic treatment options may improve outcome. Predominantly used cell line monolayer in vitro models lack in vivo complexity, such as the presence of extracellular matrix, and differing oxygen access. Hence, we aimed to improve pre-clinical chondrosarcoma research by developing an alginate-based 3D cell culture model.Method: An alginate scaffold was applied to generate spheroids of three chondrosarcoma cell lines (CH2879, JJ012, SW1353). Morphological, histological and immunohistochemical assessment of the spheroids were used to characterize the chondrosarcoma model. Presto blue assay, morphological and immunohistochemical assessment were applied to assess spheroid response to a panel of chemotherapeutics and targeted therapies, which was compared to conventional 2D monolayer models. Synergistic effect of doxorubicin and ABT-737 (Bcl-2 inhibitor) was compared between monolayer and spheroid models using excess over Bliss. A 3D colony formation assay was developed for assessment of radiotherapy response.Results: Chondrosarcoma spheroids produced chondrogenic matrix and remained proliferative after 2 weeks of culture. When treated with chemotherapeutics, the spheroids were more resistant than their monolayer counterparts, in line with animal models and clinical data. Moreover, for sapanisertib (mTOR inhibitor) treatment, a recovery in chondrosarcoma growth, previously observed in mice models, was also observed using long-term treatment. Morphological assessment was useful in the case of YM-155 (survivin inhibitor) treatment where a fraction of the spheroids underwent cell death, however a large fraction remained proliferative and unaffected. Synergy was less pronounced in 3D compared to 2D. A 3D clonogenic assay confirmed increased resistance to radiotherapy in 3D chondrosarcoma spheroids.Conclusion: We demonstrate that the chondrosarcoma alginate spheroid model is more representative of chondrosarcoma in vivo and should be used instead of the monolayer model for therapy testing. Improved selection at in vitro stage of therapeutic testing will increase the amount of information available for experimental design of in vivo animal testing and later, clinical stages. This can potentially lead to increased likelihood of approval and success at clinical trials. Show less
Nejad, E.B.; Labrie, C.; Sluis, T.C. van der; Duikeren, S. van; Franken, K.L.M.C.; Roosenhoff, R.; ... ; Burg, S.H. van der 2020
High serum levels of interleukin-6 (IL-6) correlate with poor prognosis and chemotherapy resistance in several cancers. The underlying mechanisms and its effects on immunotherapy are largely... Show moreHigh serum levels of interleukin-6 (IL-6) correlate with poor prognosis and chemotherapy resistance in several cancers. The underlying mechanisms and its effects on immunotherapy are largely unknown. To address this, we developed a human papillomavirus type 16 (HPV16)-associated tumor model expressing IL-6 to investigate the impact of tumor-expressed IL-6 during cisplatin chemotherapy and HPV16 synthetic long peptide vaccination as immunotherapy. The effects of tumor-produced IL-6 on tumor growth, survival and the tumor microenvironment were analyzed. Our data demonstrated that tumor-produced IL-6 conferred resistance to cisplatin and therapeutic vaccination. This was not caused by a changed in vitro or in vivo growth rate of tumor cells, or a changed sensitivity of tumor cells to chemotherapy or T-cell-mediated killing. Furthermore, no overt differences in the frequencies of tumor-infiltrating subsets of T cells or CD11b(+)myeloid cells were observed. IL-6, however, affected the systemic and local function of myeloid cells, reflected by a strong reduction of major histocompatibility complex (MHC) class II expression on all major myeloid cell subtypes. Resistance to both therapies was associated with a changed intratumoral influx of MHC class II(+)myeloid cells toward myeloid cells with no or lower MHC class II expression. Importantly, while these IL-6-mediated effects provided resistance to the immunotherapy and chemotherapy as single therapies, their combination still successfully mediated tumor control. In conclusion, IL-6-mediated therapy resistance is caused by an extrinsic mechanism involving an impaired function of intratumoral myeloid cells. The fact that resistance can be overcome by combination therapies provides direction to more effective therapies for cancer. Show less
(1) Background: doxorubicin is a potent chemotherapeutic agent, but it has limitations regarding its side effects and therapy resistance. Hydrogels potentially deal with these problems, but several... Show more(1) Background: doxorubicin is a potent chemotherapeutic agent, but it has limitations regarding its side effects and therapy resistance. Hydrogels potentially deal with these problems, but several characterizations need to be optimized to better understand how hydrogel assisted chemotherapy works. Poloxamer 407 (P407) hydrogels were mixed with doxorubicin and physico-chemical, biological, and pharmacological characterizations were considered. (2) Methods: hydrogels were prepared by mixing P407 in PBS at 4 degrees C. Doxorubicin was added upon solutions became clear. Time-to-gelation, hydrogel morphology, and micelles were studied first. The effects of P407-doxorubicin were evaluated on MC-38 colon cancer cells. Furthermore, doxorubicin release was assessed and contrasted with non-invasive in vivo whole body fluorescence imaging. (3) Results: 25% P407 had favorable gelation properties with pore sizes of 30-180 mu m. P407 micelles were approximately 5 nm in size. Doxorubicin was fully released in vitro from 25% P407 hydrogel within 120 h. Furthermore, P407 micelles strongly enhanced the anti-neoplastic effects of doxorubicin on MC-38 cells. In vivo fluorescence imaging revealed that hydrogels retained fluorescence signals at the injection site for 168 h. (4) Conclusions: non-invasive imaging showed how P407 gels retained drug at the injection site. Doxorubicin P407 micelles strongly enhanced the anti-tumor effects. Show less
Alphen, K. van; Versluis, A.; Dercksen, W.; Haas, H. de; Lugtenberg, R.; Tiemensma, J.; ... ; Hurk, C. van den 2020
Objective: Individuals with cancer experience the impact of chemotherapy on hair loss in different ways. The aim of this pilot study was to explore patients' experiences of alopecia through... Show moreObjective: Individuals with cancer experience the impact of chemotherapy on hair loss in different ways. The aim of this pilot study was to explore patients' experiences of alopecia through patients' drawings. Methods: Fifteen female patients diagnosed with cancer and treated with chemotherapy were recruited at the oncological day-care unit of a teaching hospital in the Netherlands. Participants completed a semi-structured interview about alopecia. They drew their head and hair before and during chemotherapy and completed the Brief Illness Perception Questionnaire (B-IPQ).Results: The drawings revealed predominantly physical effects, rather than emotions. Emotions were evident in the text that patients wrote under the drawings and in the B-IPQ open question about the perceived consequences of alopecia. The overall impact of alopecia that emerged from the drawings and the B-IPQ corresponded to the information retrieved from the interviews, namely disappointment, insecurity, sadness, and confrontation.Conclusions: Drawings expose cognitive and emotional responses to alopecia that may be relatively unexplored when using traditional assessment methods such as questionnaires or interviews. In future research, the drawing instructions need to be more specifically focused on feelings in order to better capture emotional reactions to hair loss. Show less
Lohman, E.D.; Bitter, T. de; Verhoeven, R.; Geest, L. van der; Hagendoorn, J.; Mohammad, N.H.; ... ; Reuver, P. de 2020
Gallbladder cancer (GBC) is rare in Western populations and data about treatment and outcomes are scarce. This study aims to analyze survival and identify opportunities for improvement using... Show moreGallbladder cancer (GBC) is rare in Western populations and data about treatment and outcomes are scarce. This study aims to analyze survival and identify opportunities for improvement using population-based data from a low-incidence country. GBC patients diagnosed between 2005 and 2016 with GBC were identified from the Netherlands Cancer Registry. Patients were grouped according to time period (2005-2009/2010-2016) and disease stage. Trends in treatment and overall survival (OS) were analyzed. In total 1834 patients were included: 661 (36%) patients with resected, 278 (15%) with non-resected non-metastatic, and 895 (49%) with metastatic GBC. Use of radical versus simple cholecystectomy (12% vs. 26%, p < 0.001) in early (pT1b/T2) GBC increased. More patients with metastatic GBC received chemotherapy (11% vs. 29%, p < 0.001). OS improved from 4.8 months (2005-2009) to 6.1 months (2010-2016) (p = 0.012). Median OS increased over time (2005-2009 vs. 2010-2016) in resected (19.4 to 26.8 months, p = 0.038) and metastatic (2.3 vs. 3.4 months, p = 0.001) GBC but not in unresected, non-metastatic GBC. In early GBC, patients with radical cholecystectomy had a median OS of 76.7 compared to 18.4 months for simple cholecystectomy (p < 0.001). Palliative chemotherapy showed superior (p < 0.001) survival in metastatic (7.3 versus 2.1 months) and non-resected non-metastatic (7.7 versus 3.5 months) GBC. In conclusion, survival of GBC remains poor. Radical surgery and palliative chemotherapy appear to improve prognosis but remain under-utilized. Show less
Delyon, J.; Rabate, C.; Euvrard, S.; Harwood, C.A.; Proby, C.; Gulec, T.; ... ; Skin Care Organ Transplant Patient 2019
Background: Systemic therapeutic management of post-transplant Kaposi sarcoma (KS) is mainly based on 3 axes: reduction of immunosuppression, conversion to mammalian target of rapamycin (mTOR)... Show moreBackground: Systemic therapeutic management of post-transplant Kaposi sarcoma (KS) is mainly based on 3 axes: reduction of immunosuppression, conversion to mammalian target of rapamycin (mTOR) inhibitors, chemotherapy, or a combination of these.Objective: To obtain an overview of clinical strategies about the current treatment of KS.Methods: We conducted a multicenter retrospective cohort study including 145 solid organ transplant recipients diagnosed with KS between 1985 and 2011 to collect data regarding first-line treatment and response at 6 months.Results: Overall, 95%, 28%, and 16% of patients had reduction of immunosuppression, conversion to mTOR inhibitor, and chemotherapy, respectively. Patients treated with chemotherapy or mTOR inhibitor conversion were more likely to have visceral KS. At 6 months, 83% of patients had response, including 40% complete responses.Limitations: The retrospective design of the study.Conclusion: Currently available therapeutic options seem to be effective to control KS in most patients. Tapering down the immunosuppressive regimen remains the cornerstone of KS management. Show less
The use of tumor megaprostheses in patients with bone tumors has provided a successful limb salvaging treatment option in oncology patients. Unfortunately, the prevalence of periprosthetic... Show moreThe use of tumor megaprostheses in patients with bone tumors has provided a successful limb salvaging treatment option in oncology patients. Unfortunately, the prevalence of periprosthetic infection is much higher after oncologic joint arthroplasty than after regular joint arthroplasty, ranging from 7% to 28%. This increased risk of infection is caused by local and systemic immunodeficiency due to chemotherapy and radiotherapy, long duration of surgery, large wound areas and the use of large implants. This review focused on specific issues regarding infected megaprostheses in oncology patients, aiming to give directions for the prevention, diagnosis and treatment of infected megaprostheses. Show less
Introduction: Although the majority of women with endometrial cancer have a favorable prognosis due to early symptoms, 15-20% have high-risk disease features and are at increased risk of recurrence... Show moreIntroduction: Although the majority of women with endometrial cancer have a favorable prognosis due to early symptoms, 15-20% have high-risk disease features and are at increased risk of recurrence. In order to improve prognosis for these patients, several trials have compared chemotherapy (CT), radiotherapy (RT) or the combination of CTRT. Areas covered: This review focuses on the current evidence on adjuvant treatment for women with high-risk endometrial cancer and future perspectives. Expert commentary: For stage I-II high-risk endometrial cancer, external beam radiotherapy ensured good local control and no significant benefit in progression-free or overall survival was found with the addition of chemotherapy in 2 recent randomized trials. For women with stage III disease, the combination of chemotherapy and radiotherapy improved progression-free survival with a non-significant improvement of overall survival. Adjuvant chemotherapy alone resulted in higher rates of pelvic and para-aortic recurrence. More toxicity and reduced quality of life were found during and after adjuvant CTRT. It is essential to discuss the benefits and disadvantages of chemotherapy and radiotherapy with individual patients for shared decision-making. Translational research is ongoing to further characterize individual tumors, identify sensitivity to (immuno)therapies and find new treatment targets to improve outcomes. Show less
