CD4(+) T cells can "help" or "license" conventional type 1 dendritic cells (cDC1s) to induce CD8(+) cytotoxic T lymphocyte (CTL) anticancer responses, as proven in mouse models. We recently... Show moreCD4(+) T cells can "help" or "license" conventional type 1 dendritic cells (cDC1s) to induce CD8(+) cytotoxic T lymphocyte (CTL) anticancer responses, as proven in mouse models. We recently identified cDC1s with a transcriptomic imprint of CD4(+) T-cell help, specifically in T-cell-infiltrated human cancers, and these cells were associated with a good prognosis and response to PD-1-targeting immunotherapy. Here, we delineate the mechanism of cDC1 licensing by CD4(+) T cells in humans. Activated CD4(+) T cells produce IFN beta via the STING pathway, which promotes MHC-I antigen (cross-)presentation by cDC1s and thereby improves their ability to induce CTL anticancer responses. In cooperation with CD40 ligand (L), IFN beta also optimizes the costimulatory and other functions of cDC1s required for CTL response induction. IFN-I-producing CD4(+) T cells are present in diverse T-cell-infiltrated cancers and likely deliver "help" signals to CTLs locally, according to their transcriptomic profile and colocalization with "helped/licensed" cDCs and tumor-reactive CD8(+) T cells. In agreement with this scenario, the presence of IFN-I-producing CD4(+) T cells in the TME is associated with overall survival and the response to PD-1 checkpoint blockade in cancer patients. Show less
Valero, C.; Golkaram, M.; Vos, J.L.; Xu, B.; Fitzgerald, C.; Lee, M.; ... ; Morris, L.G.T. 2023
BACKGROUND. Recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) is generally an incurable disease, with patients experiencing median survival of under 10 months and... Show moreBACKGROUND. Recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) is generally an incurable disease, with patients experiencing median survival of under 10 months and significant morbidity. While immune checkpoint blockade (ICB) drugs are effective in approximately 20% of patients, the remaining experience limited clinical benefit and are exposed to potential adverse effects and financial costs. Clinically approved biomarkers, such as tumor mutational burden (TMB), have a modest predictive value in HNSCC.METHODS. We analyzed clinical and genomic features, generated using whole-exome sequencing, in 133 ICB-treated patients with R/M HNSCC, of whom 69 had virus-associated and 64 had non-virus-associated tumors.RESULTS. Hierarchical clustering of genomic data revealed 6 molecular subtypes characterized by a wide range of objective response rates and survival after ICB therapy. The prognostic importance of these 6 subtypes was validated in an external cohort. A random forest-based predictive model, using several clinical and genomic features, predicted progression-free survival (PFS), overall survival (OS), and response with greater accuracy than did a model based on TMB alone. Recursive partitioning analysis identified 3 features (systemic inflammatory response index, TMB, and smoking signature) that classified patients into risk groups with accurate discrimination of PFS and OS.CONCLUSION. These findings shed light on the immunogenomic characteristics of HNSCC tumors that drive differential responses to ICB and identify a clinical-genomic classifier that outperformed the current clinically approved biomarker of TMB. This validated predictive tool may help with clinical risk stratification in patients with R/M HNSCC for whom ICB is being considered. Show less
Simple Summary: Mucosal melanoma (MM) is rare and entails a poor prognosis. MM is biologically different from cutaneous melanoma (CM). For advanced CM, overall survival has improved since the... Show moreSimple Summary: Mucosal melanoma (MM) is rare and entails a poor prognosis. MM is biologically different from cutaneous melanoma (CM). For advanced CM, overall survival has improved since the introduction of immune and targeted therapy. In contrast, little is known about the effect of their introduction on the survival of MM. This study presents the incidence, clinical characteristics, treatment characteristics, and survival of MM over 30 years (1990-2019) in the Netherlands. We conclude that the incidence of MM remained stable, and survival has slightly improved when comparing the timeframe 2014-2019 with previous years. However, the prognosis of MM remains poor as compared to CM. Future studies addressing the effect of immune and targeted therapy in MM are needed to improve outcomes for patients with MM. Background: Mucosal melanoma (MM) is a rare tumour with a poor prognosis. Over the years, immune and targeted therapy have become available and have improved overall survival (OS) for patients with advanced cutaneous melanoma (CM). This study aimed to assess trends in the incidence and survival of MM in the Netherlands against the background of new effective treatments that became available for advanced melanoma. Methods: We obtained information on patients diagnosed with MM during 1990-2019 from the Netherlands Cancer Registry. The age-standardized incidence rate and estimated annual percentage change (EAPC) were calculated over the total study period. OS was calculated using the Kaplan-Meier method. Independent predictors for OS were assessed by applying multivariable Cox proportional hazards regression models. Results: In total, 1496 patients were diagnosed with MM during 1990-2019, mostly in the female genital tract (43%) and the head and neck region (34%). The majority presented with local or locally advanced disease (66%). The incidence remained stable over time (EAPC 3.0%, p = 0.4). The 5-year OS was 24% (95%CI: 21.6-26.0%) with a median OS of 1.7 years (95%CI: 1.6-1.8). Age >= 70 years at diagnosis, higher stage at diagnosis, and respiratory tract location were independent predictors for worse OS. Diagnosis in the period 2014-2019, MM located in the female genital tract, and treatment with immune or targeted therapy were independent predictors for better OS. Conclusion: Since the introduction of immune and targeted therapies, OS has improved for patients with MM. However, the prognosis of MM patients is still lower compared to CM, and the median OS of patients treated with immune and targeted therapies remains fairly short. Further studies are needed to improve outcomes for patients with MM. Show less
Zijlker, L.P.; Bakker, M.; Hiel, B. van der; Bruining, A.; Klop, W.M.C.; Zuur, C.L.; ... ; Akkooi, A.C.J. van 2022
Background: Merkel cell carcinoma (MCC) is a cutaneous tumor with a high tendency to metastasize, and a significant proportion of patients have metastases at first presentation. This study aims to... Show moreBackground: Merkel cell carcinoma (MCC) is a cutaneous tumor with a high tendency to metastasize, and a significant proportion of patients have metastases at first presentation. This study aims to determine the value of baseline ultrasound (US) and (18)fluorodeoxyglucose-positron emission tomography/computed tomography ((18)FDG-PET/CT) imaging in both patients with clinically localized MCC (Stage I/II) and patients who present with palpable lymph nodes (Stage III). Methods: This retrospective cohort included 135 MCC patients who underwent baseline US (with fine needle aspiration cytology (FNAC)) and/or FDG-PET/CT imaging between 2015 and 2021. Results: Of the 104 patients with clinically localized disease, 48% were upstaged to Stage III and 3% to Stage IV by imaging or sentinel lymph node biopsy (SLNB). FDG-PET/CT imaging identified regional metastases in 23%, while US with FNAC identified regional metastases in 19%. SLNB was performed in 56 patients, of whom 57% were upstaged to Stage III. Of the 31 patients who presented with palpable lymph nodes, 16% were upstaged to Stage IV by FDG-PET/CT imaging. Conclusion: Baseline imaging frequently upstages Stage I/II MCC patients to Stage III, both by US and FDG-PET/CT, Stage IV disease is rarely identified. Patients who present with palpable nodes are frequently upstaged to Stage IV by FDG-PET/CT imaging. Show less
Hulst, H.J. van der; Vos, J.L.; Tissier, R.; Smit, L.A.; Martens, R.M.; Beets-Tan, R.G.H.; ... ; Castelijns, J.A. 2022
Simple Summary Immunotherapy may induce early treatment response in head and neck squamous cell carcinoma (HNSCC) for some patients. Routine imaging parameters fail to diagnose these responses;... Show moreSimple Summary Immunotherapy may induce early treatment response in head and neck squamous cell carcinoma (HNSCC) for some patients. Routine imaging parameters fail to diagnose these responses; however, magnetic resonance (MR) diffusion-weighted imaging (DWI) may be able to do so. This study sought to correlate DWI parameters with treatment response early after immunotherapy treatment in HNSCC. We analyzed 24 patients with advanced HNSCC with imaging before and after the immunotherapy. We found that rounder tumors that were smaller in diameter before treatment were more likely to respond. A decrease in skewness of the tumor after treatment compared to before treatment, as well as an overall low skewness post-treatment, were linked to better treatment response. Though this study was explorative in nature, these results are promising for the predictive use of MR-DWI in HNSCC treated with immunotherapy. Background: Neoadjuvant immune checkpoint blockade (ICB) prior to surgery may induce early pathological responses in head and neck squamous cell carcinoma (HNSCC) patients. Routine imaging parameters fail to diagnose these responses early on. Magnetic resonance (MR) diffusion-weighted imaging (DWI) has proven to be useful for detecting HNSCC tumor mass after (chemo)radiation therapy. METHODS: 32 patients with stage II-IV, resectable HNSCC, treated at a phase Ib/IIa IMCISION trial (NCT03003637), were retrospectively analyzed using MR-imaging before and after two doses of single agent nivolumab (anti-PD-1) (n = 6) or nivolumab with ipilimumab (anti-CTLA-4) ICB (n = 26). The primary tumors were delineated pre- and post-treatment. A total of 32 features were derived from the delineation and correlated with the tumor regression percentage in the surgical specimen. Results: MR-DWI data was available for 24 of 32 patients. Smaller baseline tumor diameter (p = 0.01-0.04) and higher sphericity (p = 0.03) were predictive of having a good pathological response to ICB. Post-treatment skewness and the change in skewness between MRIs were negatively correlated with the tumor's regression (p = 0.04, p = 0.02). Conclusion: Pre-treatment DWI tumor diameter and sphericity may be quantitative biomarkers for the prediction of an early pathological response to ICB. Furthermore, our data indicate that ADC skewness could be a marker for individual response evaluation. Show less
Simple Summary: Hearing loss (HL) can be a side effect of paediatric cancer treatment and can be caused by chemotherapy but also local therapies such as radiotherapy and/or surgery of the head and... Show moreSimple Summary: Hearing loss (HL) can be a side effect of paediatric cancer treatment and can be caused by chemotherapy but also local therapies such as radiotherapy and/or surgery of the head and neck region. In this study, the frequency and patterns of HL were assessed in survivors of head and neck rhabdomyosarcoma (HNRMS). Our secondary aim was to look into the dose-effect relationship between radiotherapy dose on the cochlea and the presence of HL. Forty-nine survivors of HNRMS were included in this study, forty-two of them underwent audiological evaluation. HL was found in up to 19% of the survivors. Four survivors had low frequencies HL with normal hearing or milder HL in the higher frequencies. In our series, HL (>= Muenster 2b) was significantly associated with the maximum cochlear irradiation dose (p = 0.047). More research is needed on HL patterns in HNRMS survivors and on the radiotherapy dose-effect relationship. Purpose: The frequency and patterns of HL in a HNRMS survivor cohort were investigated. A dose-effect relationship between the dose to the cochlea and HL was explored. Methods: Dutch survivors treated for HNRMS between 1993 and 2017 with no relapse and at least two years after the end of treatment were eligible for inclusion. The survivors were evaluated for HL with pure-tone audiometry. HL was graded according to the Muenster, Common Terminology Criteria for Adverse Events (CTCAE) v4.03 and International Society for Paediatric Oncology (SIOP) classification. We defined deleterious HL as Muenster >= 2b, CTCAE >= 2, and SIOP >= 2. Mixed-effects logistic regression was used to search for the dose-effect relationship between the irradiation dose to the cochlea and the occurrence of HL. Results: Forty-two HNRMS survivors underwent pure-tone audiometry. The Muenster, CTCAE and SIOP classification showed that 19.0% (n = 8), 14.2% (n = 6) and 11.9% (n = 5) of survivors suffered from HL, respectively. A low-frequency HL pattern with normal hearing or milder hearing loss in the higher frequencies was seen in four survivors. The maximum cochlear irradiation dose was significantly associated with HL (>= Muenster 2b) (p = 0.047). In our series, HL (>= Muenster 2b) was especially observed when the maximum dose to the cochlea exceeded 19 Gy. Conclusion: HL occurred in up to 19% of survivors of HNRMS. More research is needed on HL patterns in HNRMS survivors and on radiotherapy dose-effect relationships. Show less
Image-to-patient registration in navigated mandibular surgery is complex due to the mobile nature of the mandible compared with other craniofacial bones. As a result, surgical navigation is rarely... Show moreImage-to-patient registration in navigated mandibular surgery is complex due to the mobile nature of the mandible compared with other craniofacial bones. As a result, surgical navigation is rarely employed in the mandibular region. This systematic review provides an overview of the different registration methods that are used for surgical navigation of the mandible. A systematic search was performed in the MEDLINE Ovid, Scopus, and Embase databases on March 25, 2021. Search terms included synonyms for mandibular surgery, surgical navigation, and registration methods. Articles about navigated mandibular surgery, where the registration method was explicitly mentioned, were included. The database search yielded a total of 2952 articles, from which 81 articles remained for analysis. Four main registration methods were identified: point registration, surface registration, hybrid registration, and computer vision-based registration. The mobility of the mandible is accounted for by either keeping the mandible in a fixed position during preoperative imaging and surgery, or by tracking the mandibular movements. Although different registration methods are available for navigated mandibular surgery, there is always a trade-off between accuracy, registration time, usability, and invasiveness. Future studies should focus on testing the different methods in larger patient studies and should report the registration accuracy. Show less
Rede uitgesproken door Prof. dr. C.L. Zuur bij de aanvaarding van het ambt van bijzonder hoogleraarKeel-, Neus- en Oorheelkunde, in het bijzonder oncologisch translationeel onderzoek, vanwege het... Show moreRede uitgesproken door Prof. dr. C.L. Zuur bij de aanvaarding van het ambt van bijzonder hoogleraarKeel-, Neus- en Oorheelkunde, in het bijzonder oncologisch translationeel onderzoek, vanwege het Nederlands Kanker Instituut aan de Universiteit Leiden op maandag 19 september 2022 Show less
Single-agent Talimogene Laherparepvec (T-VEC) was developed for treatment of unresectable and injectable stage III-IV melanoma. Since its approval and reimbursement, studies have reported varying... Show moreSingle-agent Talimogene Laherparepvec (T-VEC) was developed for treatment of unresectable and injectable stage III-IV melanoma. Since its approval and reimbursement, studies have reported varying response rates. The purpose of this systematic review and meta-analysis was to investigate the efficacy and safety of T-VEC. Of 341 publications that were identified, eight studies with a total of 642 patients were included. In patients with stage IIIB-IVM1a, the pooled complete-and overall response rate (CRR and ORR) were 41% and 64%, respectively. In patients with stage IIIB-IVM1c, the pooled CRR and ORR were 30% and 44%, respectively. In patients with stage IVM1b and IVM1c, the pooled CRR and ORR were 4% and 9%, respectively. Adverse events (AEs) were seen in 41-100% of all patients and 0-11% of AEs were severe. In conclusion, single agent T-VEC achieves the highest response rates in patients with early metastatic melanoma and is well-tolerated with generally only mild toxicities. Show less
Neoadjuvant ipilimumab and nivolumab induces high pathologic response rates (pRRs) in clinical stage III nodal melanoma, and pathologic response is strongly associated with prolonged relapse-free... Show moreNeoadjuvant ipilimumab and nivolumab induces high pathologic response rates (pRRs) in clinical stage III nodal melanoma, and pathologic response is strongly associated with prolonged relapse-free survival (RFS). The PRADO extension cohort of the OpACIN-neo trial (NCT02977052) addressed the feasibility and effect on clinical outcome of using pathologic response after neoadjuvant ipilimumab and nivolumab as a criterion for further treatment personalization. In total, 99 patients with clinical stage IIIb-d nodal melanoma were included and treated with 6 weeks of neoadjuvant ipilimumab 1 mg kg(-1) and nivolumab 3 mg kg(-1). In patients achieving major pathologic response (MPR, <= 10% viable tumor) in their index lymph node (ILN, the largest lymph node metastasis at baseline), therapeutic lymph node dissection (TLND) and adjuvant therapy were omitted. Patients with pathologic partial response (pPR; >10 to <= 50% viable tumor) underwent TLND only, whereas patients with pathologic non-response (pNR; >50% viable tumor) underwent TLND and adjuvant systemic therapy +/- synchronous radiotherapy. Primary objectives were confirmation of pRR (ILN, at week 6) of the winner neoadjuvant combination scheme identified in OpACIN-neo; to investigate whether TLND can be safely omitted in patients achieving MPR; and to investigate whether RFS at 24 months can be improved for patients achieving pNR. ILN resection and ILN-response-tailored treatment were feasible. The pRR was 72%, including 61% MPR. Grade 3-4 toxicity within the first 12 weeks was observed in 22 (22%) patients. TLND was omitted in 59 of 60 patients with MPR, resulting in significantly lower surgical morbidity and better quality of life. The 24-month relapse-free survival and distant metastasis-free survival rates were 93% and 98% in patients with MPR, 64% and 64% in patients with pPR, and 71% and 76% in patients with pNR, respectively. These findings provide a strong rationale for randomized clinical trials testing response-directed treatment personalization after neoadjuvant ipilimumab and nivolumab. Show less
Purpose: To utilize navigated mandibular (reconstructive) surgery, accurate registration of the preoperative CT scan with the actual patient in the operating room (OR) is required. In this phantom... Show morePurpose: To utilize navigated mandibular (reconstructive) surgery, accurate registration of the preoperative CT scan with the actual patient in the operating room (OR) is required. In this phantom study, the feasibility of a noninvasive hybrid registration method is assessed. This method consists of a point registration with anatomic landmarks for initialization and a surface registration using the bare mandibular bone surface for optimization. Methods: Three mandible phantoms with reference notches on two osteotomy planes were 3D printed. An electromagnetic tracking system in combination with 3D Slicer software was used for navigation. Different configurations, i.e., different surface point areas and number and configuration of surface points, were tested with a dentate phantom (A) in a metal-free environment. To simulate the intraoperative environment and different anatomies, the registration procedure was also performed with an OR bed using the dentate phantom and two (partially) edentulous phantoms with atypical anatomy (B and C). The accuracy of the registration was calculated using the notches on the osteotomy planes and was expressed as the target registration error (TRE). TRE values of less than 2.0 mm were considered as clinically acceptable. Results: In all experiments, the mean TRE was less than 2.0 mm. No differences were found using different surface point areas or number or configurations of surface points. Registration accuracy in the simulated intraoperative setting was-mean (SD)-0.96 (0.22), 0.93 (0.26), and 1.50 (0.28) mm for phantom A, phantom B, and phantom C. Conclusion: Hybrid registration is a noninvasive method that requires only a small area of the bare mandibular bone surface to obtain high accuracy in phantom setting. Future studies should test this method in clinical setting during actual surgery. Show less
IMPORTANCE Neoadjuvant checkpoint inhibition in patients with high-risk stage III melanoma shows high pathologic response rates associated with a durable relapse-free survival. Whether a... Show moreIMPORTANCE Neoadjuvant checkpoint inhibition in patients with high-risk stage III melanoma shows high pathologic response rates associated with a durable relapse-free survival. Whether a therapeutic lymph node dissection (TLND) can be safely omitted when a major pathologic response in the largest lymph node metastasis at baseline (index lymph node; ILN) is obtained is currently being investigated. A previous small pilot study (n = 12) showed that the response in the ILN may be representative of the pathologic response in the entire TLND specimen.OBJECTIVE To assess the concordance of response between the ILN and the total lymph node bed in a larger clinical trial population.DESIGN, SETTING, AND PARTICIPANTS Retrospective pathologic response analysis of a multicenter clinical trial population of patients from the randomized Study to Identify the Optimal Adjuvant Combination Scheme of Ipilimumab and Nivolumab in Melanoma Patients (OpACIN) and Optimal Neo-Adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) trials. Included patients were treated with 6 weeks neoadjuvant ipilimumab plus nivolumab. Patient inclusion into the trials was conducted from August 12, 2015, to October 24, 2016 (OpACIN), and November 24, 2016, and June 28, 2018 (OpACIN-neo). Data were analyzed from April 1, 2020, to August 31, 2021.MAIN OUTCOMES AND MEASURES Concordance of the pathologic response between the ILN and the TLND tumor bed. The pathologic response of the ILN was retrospectively assessed according to the International Neoadjuvant Melanoma Consortium criteria and compared with the pathologic response of the entire TLND specimen.RESULTS A total of 82 patients treated with neoadjuvant ipilimumab and nivolumab followed by TLND (48 [59%] were male; median age, 58.5 [range, 18-80] years) were included. The pathologic response in the ILN was concordant with the entire TLND specimen response in 81 of 82 patients (99%) and in 79 of 82 patients (96%) concordant when comparing the ILN response with the response in every individual lymph node. In the single patient with a discordant response, the ILN response (20% viable tumor, partial pathologic response) underestimated the entire TLND specimen response (5% viable, near-complete pathologic response). Two other patients each had 1 small nonindex node that contained 80% viable tumor (pathologic nonresponse) whereas all other lymph nodes (including the ILN) showed a partial pathologic response. In these 2 patients, the risk of regional relapse might potentially have been increased if TLND had been omitted.CONCLUSIONS AND RELEVANCE The results of this study suggest that the pathologic response of the ILN may be considered a reliable indicator of the entire TLND specimen response and may support the ILN response-directed omission of TLND in a prospective trial. Show less
Neoadjuvant ipilimumab and nivolumab induces high pathologic response rates (pRRs) in clinical stage III nodal melanoma, and pathologic response is strongly associated with prolonged relapse-free... Show moreNeoadjuvant ipilimumab and nivolumab induces high pathologic response rates (pRRs) in clinical stage III nodal melanoma, and pathologic response is strongly associated with prolonged relapse-free survival (RFS). The PRADO extension cohort of the OpACIN-neo trial ( NCT02977052 ) addressed the feasibility and effect on clinical outcome of using pathologic response after neoadjuvant ipilimumab and nivolumab as a criterion for further treatment personalization. In total, 99 patients with clinical stage IIIb-d nodal melanoma were included and treated with 6 weeks of neoadjuvant ipilimumab 1 mg kg-1 and nivolumab 3 mg kg-1. In patients achieving major pathologic response (MPR, ≤10% viable tumor) in their index lymph node (ILN, the largest lymph node metastasis at baseline), therapeutic lymph node dissection (TLND) and adjuvant therapy were omitted. Patients with pathologic partial response (pPR; >10 to ≤50% viable tumor) underwent TLND only, whereas patients with pathologic non-response (pNR; >50% viable tumor) underwent TLND and adjuvant systemic therapy ± synchronous radiotherapy. Primary objectives were confirmation of pRR (ILN, at week 6) of the winner neoadjuvant combination scheme identified in OpACIN-neo; to investigate whether TLND can be safely omitted in patients achieving MPR; and to investigate whether RFS at 24 months can be improved for patients achieving pNR. ILN resection and ILN-response-tailored treatment were feasible. The pRR was 72%, including 61% MPR. Grade 3-4 toxicity within the first 12 weeks was observed in 22 (22%) patients. TLND was omitted in 59 of 60 patients with MPR, resulting in significantly lower surgical morbidity and better quality of life. The 24-month relapse-free survival and distant metastasis-free survival rates were 93% and 98% in patients with MPR, 64% and 64% in patients with pPR, and 71% and 76% in patients with pNR, respectively. These findings provide a strong rationale for randomized clinical trials testing response-directed treatment personalization after neoadjuvant ipilimumab and nivolumab. Show less
Purpose To investigate the utility of [F-18]FDG-PET as an imaging biomarker for pathological response early upon neoadjuvant immune checkpoint blockade (ICB) in patients with head and neck squamous... Show morePurpose To investigate the utility of [F-18]FDG-PET as an imaging biomarker for pathological response early upon neoadjuvant immune checkpoint blockade (ICB) in patients with head and neck squamous cell carcinoma (HNSCC) before surgery.Methods In the IMCISION trial (NCT03003637), 32 patients with stage II-IVb HNSCC were treated with neoadjuvant nivolumab with (n = 26) or without (n = 6) ipilimumab (weeks 1 and 3) before surgery (week 5). [F-18]FDG-PET/CT scans were acquired at baseline and shortly before surgery in 21 patients. Images were analysed for SUVmax, SUVmean, metabolic tumour volume (MTV), and total lesion glycolysis (TLG). Major and partial pathological responses (MPR and PPR, respectively) to immunotherapy were identified based on the residual viable tumour in the resected primary tumour specimen (<= 10% and 11-50%, respectively). Pathological response in lymph node metastases was assessed separately. Response for the 2 [F-18]FDG-PET-analysable patients who did not undergo surgery was determined clinically and per MR-RECIST v.1.1. A patient with a primary tumour MPR, PPR, or primary tumour MR-RECIST-based response upon immunotherapy was called a responder.Results Median Delta SUVmax, Delta SUVmean, Delta MTV, and Delta TLG decreased in the 8 responders and were significantly lower compared to the 13 non-responders (P = 0.05, P = 0.002, P < 0.001, and P < 0.001). A Delta MTV or Delta TLG of at least - 12.5% detected a primary tumour response with 95% accuracy, compared to 86% for the EORTC criteria. None of the patients with a Delta TLG of - 12.5% or more at the primary tumour site developed a relapse (median FU 23.0 months since surgery). Lymph node metastases with a PPR or MPR (5 metastases in 3 patients) showed a significant decrease in SUVmax (median - 3.1, P = 0.04). However, a SUVmax increase (median + 2.1) was observed in 27 lymph nodes (in 11 patients), while only 13 lymph nodes (48%) contained metastases in the corresponding neck dissection specimen.Conclusions Primary tumour response assessment using [F-18]FDG-PET-based Delta MTV and Delta TLG accurately identifies pathological responses early upon neoadjuvant ICB in HNSCC, outperforming the EORTC criteria, although pseudoprogression is seen in neck lymph nodes. [F-18]FDG-PET could, upon validation, select HNSCC patients for response-driven treatment adaptation in future trials. Show less
Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30-50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32... Show moreSurgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30-50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Primary endpoints are feasibility to resect no later than week 6 (phase Ib) and primary tumor pathological response (phase IIa). Surgery is not delayed or suspended for any patient in phase Ib, meeting the primary endpoint. Grade 3-4 immune-related adverse events are seen in 2 of 6 (33%) NIVO MONO and 10 of 26 (38%) total COMBO patients. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). We observe a major pathological response (MPR, 90-100% response) in 35% of patients after COMBO ICB, both in phase IIa (6/17) and in the whole trial (8/23), meeting the phase IIa primary endpoint threshold of 10%. NIVO MONO's MPR rate is 17% (1/6). None of the MPR patients develop recurrent HSNCC during 24.0 months median postsurgical follow-up. FDG-PET-based total lesion glycolysis identifies MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia RNA signature are observed in MPR patients. Our data indicate that neoadjuvant COMBO ICB is feasible and encouragingly efficacious in HNSCC.Immune checkpoint blockade has become standard care for patients with recurrent metastatic head and neck squamous cell carcinoma (HNSCC). Here the authors present the results of a non-randomized phase Ib/IIa trial, reporting safety and efficacy of neoadjuvant nivolumab monotherapy and nivolumab plus ipilimumab prior to standard-of-care surgery in patients with HNSCC. . Show less
Background and purpose: We aim to retrospectively investigate whether reducing GTV to high-risk CTV margin will significantly reduce acute and late toxicity without jeopardizing outcome in head-and... Show moreBackground and purpose: We aim to retrospectively investigate whether reducing GTV to high-risk CTV margin will significantly reduce acute and late toxicity without jeopardizing outcome in head-and neck squamous cell carcinoma (HNSCC) treated with definitive (chemo)radiation. Materials and methods: Between April 2015 and April 2019, 155 consecutive patients were treated with GTV to high-risk CTV margin of 10 mm and subsequently another 155 patients with 6 mm margin. The CTV-PTV margin was 3 mm for both groups. All patients were treated with volumetric-modulated arc therapy with daily image-guidance using cone-beam CT. End points of the study were acute and late toxicity and oncologic outcomes. Results: Overall acute grade 3 toxicity was significantly lower in 6 mm, compared to 10 mm group (48% vs. 67%, respectively, p < 0.01). The same was true for acute grade 3 mucositis (18% vs. 34%, p < 0.01) and grade > 2 dysphagia (67% vs. 85%, p < 0.01). Also feeding tube-dependency at the end of treatment (25% vs. 37%, p = 0.02), at 3 months (12% and 25%, p < 0.01), and at 6 months (6% and 15%, p = 0.01) was significantly less in 6 mm group. The incidence of late grade 2 xerostomia was also significantly lower in the 6 mm group (32% vs. 50%, p < 0.01). The 2-year rates of loco-regional control, disease-free and overall survival were 78.7% vs. 73.1%, 70.6% vs. 61.4%, and 83.2% vs. 74.4% (p > 0.05, all). Conclusion: The first study reporting on reduction of GTV to high-risk CTV margin from 10 to 6 mm showed significant reduction of the incidence and severity of radiation-related toxicity without reducing local-regional control and survival. (c) 2021 Elsevier B.V. All rights reserved. Radiotherapy and Oncology 162 (2021) 170-177 Show less
Background: Guidelines for pathological evaluation of neoadjuvant specimens and pathological response categories have been developed by the International Neoadjuvant Melanoma Consortium (INMC). As... Show moreBackground: Guidelines for pathological evaluation of neoadjuvant specimens and pathological response categories have been developed by the International Neoadjuvant Melanoma Consortium (INMC). As part of the Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) clinical trial of neoadjuvant combination anti-programmed cell death protein 1/anti-cytotoxic T-Iymphocyte-associated protein 4 immunotherapy for stage III melanoma, we sought to determine interobserver reproducibility of INMC histopathological assessment principles, identify specific tumour bed histopathological features of immunotherapeutic response that correlated with recurrence and relapse-free survival (RFS) and evaluate proposed INMC pathological response categories for predicting recurrence and RFS.Patients and methods: Clinicopathological characteristics of lymph node dissection specimens of 83 patients enrolled in the OpACIN-neo clinical trial were evaluated. Two methods of assessing histological features of immunotherapeutic response were evaluated: the previously described immune-related pathologic response (irPR) score and our novel immunotherapeutic response score (ITRS). For a subset of cases (n = 29), cellular composition of the tumour bed was analysed by flow cytometry.Results: There was strong interobserver reproducibility in assessment of pathological response (kappa = 0.879) and percentage residual viable melanoma (intraclass correlation coefficient = 0.965). The immunotherapeutic response subtype with high fibrosis had the strongest association with lack of recurrence (P = 0.008) and prolonged RFS (P = 0.019). Amongst patients with criteria for pathological non-response (pNR, >50% viable tumour), all who recurred had >= 70% viable melanoma. Higher ITRS and irPR scores correlated with lack of recurrence in the entire cohort (P = 0.002 and P <= 0.0001). The number of B lymphocytes was significantly increased in patients with a high fibrosis subtype of treatment response (P = 0.046).Conclusions: There is strong reproducibility for assessment of pathological response using INMC criteria. Immunotherapeutic response of fibrosis subtype correlated with improved RFS, and may represent a biomarker. Potential B-cell contribution to fibrosis development warrants further study. Reclassification of pNR to a threshold of >= 70% viable melanoma and incorporating additional criteria of <10% fibrosis subtype of response may identify those at highest risk of recurrence, but requires validation. Show less
Duinkerken, C.W.; Weger, V.A. de; Dreschler, W.A.; Molen, L. van der; Pluim, D.; Rosing, H.; ... ; Zuur, C.L. 2021
Objectives: To determine safety, feasibility, and preliminary activity of transtympanic injection of sodium thiosulfate (STS) against cisplatin-induced hearing loss (CIHL). DESIGN Randomized... Show moreObjectives: To determine safety, feasibility, and preliminary activity of transtympanic injection of sodium thiosulfate (STS) against cisplatin-induced hearing loss (CIHL). DESIGN Randomized controlled trial. SETTING Tertiary cancer hospital. PATIENTS Adults to be treated with high-dose cisplatin (>= 75 mg/m(2)). INTERVENTION Selected by randomization, 0.1 M STS gel on one side and placebo gel on the other side was transtympanically applied to the middle ear 3 hours before cisplatin administration. After amendment, the placebo ear was left untreated. Main Outcome Measure: Primary outcome was safety and feasibility. Secondary outcomes included pharmacokinetic analysis of systemic cisplatin and preliminary activity of STS. Clinically relevant CIHL was defined as a >= 10 dB threshold shift at pure-tone average 8-10-12.5 kHz (PTA(8-12.5)). Response to STS was defined as a threshold shift at PTA(8-12.5) in the STS-treated ear of >= 10 dB smaller than the untreated ear. Results: Twelve patients were treated. Average CIHL at PTA(8-12.5) was 12.7 dB in untreated ears and 8.8 dB SPL in STS-treated ears (p = 0.403). Four patients did not develop CIHL. Four out of eight patients with CIHL responded to STS: CIHL at PTA(8-12.5) in STS-treated ears was 18.4 dB less compared to untreated ears (p = 0.068). Grade 1 adverse events were reported. Pharmacokinetic results were available for 11 patients. Conclusion: Transtympanic application of STS was safe and feasible. Based on our pharmacokinetic analysis, we postulate that transtympanic STS does not interfere with the systemically available cisplatin. Our results provide a preliminary proof of concept for transtympanic application of STS in preventing CIHL and warrants further evaluation on a larger scale. Show less
Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN () and phase 2 OpACIN-neo () studies(1,2).... Show moreNeoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN () and phase 2 OpACIN-neo () studies(1,2). While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response (n = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo (n = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (P < 0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-gamma score) were associated with pathologic response and low risk of relapse; pRR was 100% in patients with high IFN-gamma score/high TMB; patients with high IFN-gamma score/low TMB or low IFN-gamma score/high TMB had pRRs of 91% and 88%; while patients with low IFN-gamma score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-gamma score. Our findings provide a strong rationale for a randomized phase 3 study comparing neoadjuvant ipilimumab plus nivolumab versus standard adjuvant therapy with antibodies against the programmed cell death protein-1 (anti-PD-1) in macroscopic stage III melanoma. Show less
