Famke Schneiders - Academia.edu (original) (raw)

Papers by Famke Schneiders

Journal of Surgical Oncology, Jul 21, 2023

IntroductionLocal control following stereotactic ablative radiotherapy (SABR) for patients with c... more IntroductionLocal control following stereotactic ablative radiotherapy (SABR) for patients with colorectal pulmonary metastases is reportedly lower than for metastases from other tumors. Such recurrences may still be amenable to salvage therapy. We describe our experience with salvage surgery in 17 patients.MethodsPatients who underwent salvage metastasectomy for a local recurrence following SABR for colorectal pulmonary metastases were identified from the surgical institutional databases of three Dutch major referral hospitals. Kaplan–Meier survival analysis was performed to determine survival.ResultsSeventeen patients underwent 20 salvage resections for local recurrence of colorectal pulmonary metastases. All patients had a progressive lesion on consecutive CT scans, with local uptake on 18fluorodeoxyglucose‐positron emission tomography computed tomography (FDG‐PET CT), and were discussed in a thoracic oncology tumor board. Median time to local recurrence following SABR was 20 months (interquartile range [IQR]: 13−29). Fourteen procedures were performed minimally invasively. Extensive adhesions were observed during three procedures. A Clavien–Dindo grade III–IV complication occurred after four resections (20%). The 90‐day mortality was 0%. The estimated median overall survival and progression‐free survival following salvage resection were 71 months (confidence intervals [CI]: 50–92) and 39 months (CI: 19–58), respectively. Salvage resections were significantly more extensive, compared to the potential resection assessed on pre‐SABR imaging.ConclusionsOur experience with 20 salvage pulmonary metastasectomy procedures for local recurrences following SABR in colorectal cancer patients demonstrates that salvage resection is a feasible option with acceptable morbidity and good oncological outcome in a highly selected cohort.

Physics and Imaging in Radiation Oncology, Oct 1, 2021

Stereotactic ablative radiotherapy (SABR) planning for adrenal metastases aims to minimize doses ... more Stereotactic ablative radiotherapy (SABR) planning for adrenal metastases aims to minimize doses to the adjacent kidney. Renal dose constraints for SABR delivery are not well defined. In 20 patients who underwent MR-guided breath-hold SABR in five daily fractions of 8–10 Gy, ipsilateral renal volumes receiving ≥20 Gy best correlated with loss of renal volumes, with median renal volume reduction being 6% (range: 3%-11%, 10th-90th percentiles). Organ function did not deteriorate in 18 patients, who had post treatment renal function tests available. This suggests that the ipsilateral renal volume receiving 20 Gy can be used as partial organ dose constraint for SABR to targets in the upper abdomen.

$Research paper thumbnail of PO-1331 Local control rates after MR-guided single fraction SABR for lung tumors$

Radiotherapy and Oncology, May 1, 2023

Nature Reviews Clinical Oncology, Jul 5, 2021

Advances in cancer immunotherapy have led to clinical trials of immunotherapy-based neoadjuvant t... more Advances in cancer immunotherapy have led to clinical trials of immunotherapy-based neoadjuvant treatments for early stage non-small-cell lung cancer. Evidence for priming of the immune system using both preoperative short-course radiotherapy and immunotherapy in this setting has now emerged from a randomized phase II study incorporating pathological and immunological end points.

European Respiratory Review, May 5, 2021

Technical advances have led to a changing perception of the role of radiation therapy in multidis... more Technical advances have led to a changing perception of the role of radiation therapy in multidisciplinary care of lung cancer. This article provides an overview of recent developments in radiation therapy as a cornerstone of modern lung cancer treatment.

Clinical Immunology, Feb 1, 2012

Vγ9Vδ2-T cells constitute a proinflammatory lymphocyte subpopulation with established antitumor a... more Vγ9Vδ2-T cells constitute a proinflammatory lymphocyte subpopulation with established antitumor activity. Phosphoantigens activate Vγ9Vδ2-T cells in vivo and in vitro. We studied whether the antitumor activity of Vγ9Vδ2-T cells can be potentiated by invariant NKT cells (iNKT), an important immunoregulatory T cell subset. When activated by the glycolipid αgalactosylceramide (α-GalCer), iNKT produce large amounts of cytokines involved in antitumor immune responses. Monocyte-derived dendritic cells were loaded with both phosphoantigens (using aminobisphosphonates) and α-GalCer during maturation and subsequently co-cultured with Vγ9Vδ2-T and iNKT cells. Aminobisphosphonates dose-dependently enhanced Vγ9Vδ2-T cell activation, and this was potentiated by α-GalCer-induced iNKT co-activation. iNKT co-activation also enhanced the IFN-γ production and cytolytic potential of Vγ9Vδ2-T cells against tumor cells. Using transwell experiments and neutralizing antibodies cross-talk between iNKT and Vγ9Vδ2-T cells was found to be mediated by TNF-α. Our data provide a rationale for combining both activating ligands to improve Vγ9Vδ2-T cell based approaches in cancer-immunotherapy.

Cancer immunology research, May 1, 2015

Melanoma-induced suppression of dendritic cells (DC) in the sentinel lymph node (SLN) interferes ... more Melanoma-induced suppression of dendritic cells (DC) in the sentinel lymph node (SLN) interferes with the generation of protective antitumor immunity. In an effort to strengthen immune defense against metastatic spread, we performed a three-arm phase II study comprising 28 patients with stage I-II melanoma randomized to receive intradermal injections around the primary tumor excision site of saline or low-dose CpG-B, alone or combined with GM-CSF, before excision of the SLNs. After pathologic examination, 5 patients were diagnosed with stage III melanoma based on the presence of tumor cells in the SLNs. Combined CpG/GM-CSF administration resulted in enhanced maturation of all identifiable conventional (cDC) and plasmacytoid (pDC) DC subsets and selectively induced increased frequencies of SLN-resident BDCA3/CD141 þ cDC subsets that also expressed the C-type lectin receptor CLEC9A. Correlative in vivo analyses and in vitro studies provided evidence that these subsets were derived from BDCA3 þ cDC precursors in the blood that were recruited to the SLNs in a type I IFN-dependent manner and subsequently matured under the combined influence of CpG and GM-CSF. In line with their reported functional abilities, frequencies of in vivo CpG/GM-CSF-induced BDCA3/CD141 þ DCs correlated with increased ex vivo cross-presenting capacity of SLN suspensions. Combined local CpG/GM-CSF delivery thus supports protective antimelanoma immunity through concerted activation of pDC and cDC subsets and recruitment of BDCA3 þ cDC subsets with T cell-stimulatory and cross-priming abilities. Cancer Immunol Res; 3(5); 495-505. Ó2015 AACR.

Invariant Natural Killer T (iNKT) cells recognize glycolipid antigens presented by the CD1d antig... more Invariant Natural Killer T (iNKT) cells recognize glycolipid antigens presented by the CD1d antigen-presenting molecule. They have been shown to play an important role in various types of immune responses, including antitumor immune responses. Upon activation with α-galactosylceramide (α-GalCer) iNKT cells can produce different kinds of cytokines, like IFN-γ, resulting in activation of other T cell subsets. However, production of IL-2 by iNKT cells has been shown to contribute to the expansion of immunosuppressive regulatory T cells (Tregs). Although Tregs are critically dependent on the X-chromosome encoded FoxP3 gene, it is also known that FoxP3 is expressed in conventional T cells upon activation. Recently it was reported that freshly isolated iNKT cells can express FoxP3 upon stimulation with TGF-β and acquire suppressive capacities in the presence of rapamycin. In addition, IL-10 has been reported to stimulate iNKT cells resulting in CD25 upregulation and proliferation. In order to assess whether it is possible to induce FoxP3 expression and suppressive capacities in iNKT cell lines, iNKT cell lines were cultured with IL-10, TGF-β and/ or rapamycin. Phenotypic analysis was performed and upregulation of FoxP3 was seen in all conditions cultured with IL-10 and rapamycin while, in contrast to a previous report, TGF-β was found to inhibit iNKT cell FoxP3 expression. To investigate whether these FoxP3+ iNKT cells acquired suppressive abilities, they were co-cultured with CFSE labeled responder cells. These assays showed that while IL10 resulted in a moderate increase in FoxP3 expressing iNKT cells, only iNKT cultured in the presence of rapamycin were able to suppress responder cells. Therefore, while IL-10 can enhance FoxP3 expression in proliferating iNKT cells, rapamycin is required and responsible for the induction of suppressive function of iNKT cells. As recent evidence indicates that FoxP3 is differentially localized in subcellular compartments in suppressive T cells versus activated T cells, we are currently performing FoxP3 localization experiments to identify different localization patterns in suppressive vs. non-suppressive FoxP3+ iNKT cells. With these experiments we show that rapamycin is required for the induction of suppressive capacities in iNKT cells. Further studies are required to evaluate the clinical relevance of this modulating effect of mTOR inhibitors on iNKT cells in the field of transplantation medicine and anticancer therapies in renal cell carcinoma, breast cancer, and pancreatic neuroendocrine carcinomas. Citation Format: Charlotte M. Huijts, Famke L. Schneiders, Henk M. Verheul, Tanja D. de Gruijl, Hans J. van der Vliet. mTOR inhibition is required for conversion of invariant NKT cells into immunosuppressive regulatory cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4720. doi:10.1158/1538-7445.AM2013-4720

BMC Cancer, Aug 14, 2020

Background: The likelihood of a tumor recurrence in patients with T3-4N0-1 non-small cell lung ca... more Background: The likelihood of a tumor recurrence in patients with T3-4N0-1 non-small cell lung cancer following multimodality treatment remains substantial, mainly due distant metastases. As pathological complete responses (pCR) in resected specimens are seen in only a minority (28-38%) of patients following chemoradiotherapy, we designed the INCREASE trial (EudraCT-Number: 2019-003454-83; Netherlands Trial Register number: NL8435) to assess if pCR rates could be further improved by adding short course immunotherapy to induction chemoradiotherapy. Translational studies will correlate changes in loco-regional and systemic immune status with patterns of recurrence. Methods/design: This single-arm, prospective phase II trial will enroll 29 patients with either resectable, or borderline resectable, T3-4N0-1 NSCLC. The protocol was approved by the institutional ethics committee. Study enrollment commenced in February 2020. On day 1 of guideline-recommended concurrent chemoradiotherapy (CRT), ipilimumab (IPI, 1 mg/kg IV) and nivolumab (NIVO, 360 mg flat dose IV) will be administered, followed by nivolumab (360 mg flat dose IV) after 3 weeks. Radiotherapy consists of once-daily doses of 2 Gy to a total of 50 Gy, and chemotherapy will consist of a platinum-doublet. An anatomical pulmonary resection is planned 6 weeks after the last day of radiotherapy. The primary study objective is to establish the safety of adding IPI/NIVO to pre-operative CRT, and its impact on pathological tumor response. Secondary objectives are to assess the impact of adding IPI/NIVO to CRT on disease free and overall survival. Exploratory objectives are to characterize tumor inflammation and the immune contexture in the tumor and tumor-draining lymph nodes (TDLN), and to explore the effects of IPI/NIVO and CRT and surgery

ESMO open, Oct 1, 2021

Background The neoadjuvant use of immune checkpoint inhibitors (ICIs) in resectable non-small-cel... more Background The neoadjuvant use of immune checkpoint inhibitors (ICIs) in resectable non-small-cell lung cancer (NSCLC) is currently an area of active ongoing research. The place of neoadjuvant ICIs in the treatment guidelines needs to be determined. We carried out a systematic review of published data on neoadjuvant ICIs in resectable NSCLC to study its efficacy and safety. Patients and methods A literature search was carried out using the MEDLINE (PubMed) and Embase databases to retrieve articles and conference abstracts of clinical trials measuring the efficacy [major pathological response (MPR) and pathological complete response (pCR)] and safety (failure to undergo resection, surgical delay, treatment-related adverse events (trAEs) grade ≥3) of neoadjuvant immunotherapy in resectable NSCLC until July 2021. Results Nineteen studies with a total of 1066 patients were included in this systematic review. Neoadjuvant immunotherapy was associated with improved pathological response rates, especially in combination with chemotherapy. Using mono ICI, dual therapy–ICI, chemoradiation–ICI, radiotherapy–ICI, and chemo–ICI, the MPR rates were 0%-45%, 50%, 73%, 53%, and 27%-86%, respectively. Regarding pCR, the rates were 7%-16%, 33%-38%, 27%, 27%, and 9%-63%, respectively. Safety endpoints using monotherapy–ICI, dual therapy–ICI, chemoradiation–ICI, radiotherapy–ICI, and chemo–ICI showed a failure to undergo resection in 0%-17%, 19%-33%, 8%, 13%, and 0%-46%, respectively. The trAEs grade ≥3 rates were 0%-20%, 10%-33%, 7%, 23%, and 0%-67%, respectively. Conclusion In patients with resectable NSCLC stage, neoadjuvant immunotherapy can improve pathological response rates with acceptable toxicity. Further research is needed to identify patients who may benefit most from this approach, and adequately powered trials to establish clinically meaningful benefits are awaited.

Springer eBooks, 2014

Invariant natural killer T cells (iNKT) and dendritic cells (DC) play a central role in tumor imm... more Invariant natural killer T cells (iNKT) and dendritic cells (DC) play a central role in tumor immunity through downstream activation of immune effector cells by pro-inflammatory cytokines. Evidence is accumulating that the CD1d-iNKT cell axis can be effectively used to potentiate DC-based cancer vaccines. Here, we provide a detailed methodology for the generation of (CD1d-expressing) monocyte-derived DC (moDC) and their subsequent loading with the iNKT cell agonist α-galactosylceramide (α-GalCer) or their direct ligation by agonistic anti-CD1d monoclonal antibodies.

Annals of Oncology, Dec 1, 2021

Journal for ImmunoTherapy of Cancer, Nov 1, 2021

Radiotherapy and Oncology, Nov 1, 2020

Delivery of breath-hold MR-guided SABR is time-consuming, and the use of real-time tumor-tracking... more Delivery of breath-hold MR-guided SABR is time-consuming, and the use of real-time tumor-tracking in a sagittal plane may fail to detect out-of-plane displacements of organs-at-risk. Analysis of daily MR-scans performed pre-and post-SABR revealed frequent decreases in stomach volumes, and in the planned stomach doses.

Radiotherapy and Oncology, Oct 1, 2021

INTRODUCTION Stereotactic ablative radiotherapy (SABR) can achieve good local control for metasta... more INTRODUCTION Stereotactic ablative radiotherapy (SABR) can achieve good local control for metastatic adrenal lesions. Magnetic resonance (MR)-guidance with daily on-table plan adaptation can augment the delivery of SABR with greater dose certainty. The goal of this study was to quantify the potential clinical benefit MR-guided daily-adaptive adrenal SABR using the normal tissue complication probability (NTCP) framework. METHODS Patients treated with adrenal MR-guided SABR at a single institution were retrospectively reviewed. Lyman-Kutcher-Burman NTCP models were used to calculate the NTCP of upper abdominal organs-at-risk (OARs) at simulation and both before and after daily on-table plan adaptation. Differences in OAR NTCPs were assessed using signed-rank tests. Potential predictors of the benefits of adaptation were assessed by linear regression. RESULTS Fifty-two adrenal MR-guided SABR courses were analyzed. The baseline simulation plan underestimated the absolute stomach NTCP by 10.0% on average (95% confidence interval: 4.7-15.2%, p < 0.001). Daily on-table adaptation lowered absolute NTCP by 8.7% (4.2-13.2%, p < 0.001). The most significant predictor of the benefits of adaptation was lesion laterality (p = 0.018), with left-sided lesions benefitting more (13.3% [6.3-20.4%], p < 0.001) than right-sided lesions (2.1% [-1.6-5.7%], p = 0.25). Sensitivity analyses did not change the statistical significance of the findings. CONCLUSION NTCP analysis revealed that patients with left adrenal tumors were more likely to benefit from MR-guided daily on-table adaptive SABR using current dose/fractionation regimens due to reductions in predicted gastric toxicity. Right-sided adrenal lesions may be considered for dose escalation due to low predicted NTCP.

Journal of Thoracic Oncology, 2021

American Society of Clinical Oncology educational book, Jul 1, 2022

Author affiliations and support information (if applicable) appear at the end of this article.