MART-1 TCR gene-modified peripheral blood T cells for the treatment of metastatic melanoma: a phase I/IIa clinical trial.

Background: Adoptive cell therapy with peripheral blood T cells expressing transgenic T-cell receptors (TCRs) is an innovative therapeutic approach for solid malignancies. We investigated the safety and feasibility of adoptive transfer of autologous T cells expressing melanoma antigen recognized by T cells 1 (MART-1)-specific TCR, cultured to have less differentiated phenotypes, in patients with metastatic melanoma. Materials and methods: In this phase I/IIa trial, peripheral blood T cells from HLA-A2∗02:01-positive patients with unresectable stage IIIC/IV melanoma expressing MART-1 were selected and stimulated with anti-CD3/CD28 beads, transduced with a modified MART-1(26-35)-specific 1D3 TCR (1D3HMCys) and expanded in interleukin (IL)-7 and IL-15. Patients received a single infusion of transgenic T cells in a dose-escalating manner. Feasibility, safety and objective response rate were assessed. Results: Twelve pretreated metastatic cutaneous (n = 7) and uveal (n = 5) melanoma patients were included. Patient 1 received 4.6 × 109 1D3HMCys T cells and experienced grade 5 toxicity after 9 days. Subsequent patients received 5.0 × 107 [n = 3; cohort (c) 2], 2.5 × 108 (n = 2; c3) and 1.0 × 108 (n = 6; c4) 1D3HMCys T cells. The study was prematurely terminated because of dose-dependent toxicity, concerning skin (10/12), eyes (3/12), ears (4/12) and cytokine release syndrome (5/12), with 7 patients experiencing grade 3-5 toxicity. Partial responses were seen in 2/11 (18%) assessable patients and persistence of 1D3HMCys T cells corresponded to infused cell dose. Conclusions: Production of TCR-modified cells as described leads to highly potent T cells. Partial responses were seen in 18% of patients with dose-dependent 'on-target, off-tumor' toxicity and a maximum tolerated dose of 1.0 × 108 cells.

A hybrid registration method using the mandibular bone surface for electromagnetic navigation in mandibular surgery.

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 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.

Registration methods for surgical navigation of the mandible: a systematic review.

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 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.

Pathological response and tumour bed histopathological features correlate with survival following neoadjuvant immunotherapy in stage III melanoma.

BACKGROUND: 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-lymphocyte-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 (κ = 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.

Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma.

Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN ( NCT02437279 ) and phase 2 OpACIN-neo ( NCT02977052 ) studies1,2. 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-γ score) were associated with pathologic response and low risk of relapse; pRR was 100% in patients with high IFN-γ score/high TMB; patients with high IFN-γ score/low TMB or low IFN-γ score/high TMB had pRRs of 91% and 88%; while patients with low IFN-γ 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-γ 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.

Hearing loss in survivors of childhood head and neck rhabdomyosarcoma: a long-term follow-up study.

OBJECTIVES: To determine the hearing status of survivors treated for head and neck rhabdomyosarcoma (HNRMS) at long-term follow-up. DESIGN: Cross-sectional long-term follow-up study. SETTING: Tertiary comprehensive cancer centre. PARTICIPANTS: Survivors treated for HNRMS during childhood in two concurrent cohorts; survivors in London had been treated with external beam radiotherapy (EBRT-based local therapy); survivors in Amsterdam were treated with AMORE (Ablative surgery, MOuld technique afterloading brachytherapy and surgical REconstruction) if feasible, otherwise EBRT (AMORE-based local therapy). MAIN OUTCOME MEASURES: We assessed hearing status of HNRMS survivors at long-term follow-up. Hearing thresholds were obtained by pure-tone audiometry. METHODS: We assessed the hearing thresholds, the number of patients with clinically relevant hearing loss and hearing impairment graded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAEv4) and Boston criteria. Furthermore, we compared hearing loss between survivors treated with EBRT-based local therapy (London) and AMORE-based local therapy (Amsterdam). RESULTS: Seventy-three survivors were included (median follow-up 11 years). We found clinically relevant hearing loss at speech frequencies in 19% of survivors. Multivariable analysis showed that survivors treated with EBRT-based treatment and those with parameningeal tumours had significantly more hearing impairment, compared to survivors treated with AMORE-based treatment and non-parameningeal tumours. CONCLUSIONS: One in five survivors of HNRMS developed clinically relevant hearing loss. AMORE-based treatment resulted in less hearing loss compared to EBRT-based treatment. As hearing loss was highly prevalent and also occurred in survivors with orbital primaries, we recommend systematic audiological follow-up in all HNRMS survivors.

Audiometric patterns in ototoxicity of intra-arterial Cisplatin chemoradiation in patients with locally advanced head and neck cancer.

This study describes audiometric patterns of ototoxicity in a consecutive series of patients uniformly treated with intra-arterial high-dose cisplatin chemoirradiation for advanced cancer of the head and neck. Air conduction thresholds were measured from 0.125 to 16 kHz and bone conduction thresholds were measured from 0.5 to 4 kHz. The overall audiometric pattern was characterized by maximum threshold shifts after the 2nd cisplatin infusion and a maximum total threshold shift at 8 kHz, irrespective of gender, age, pretreatment sensorineural hearing loss (SNHL) or subjective complaints during therapy. A hearing deterioration gradient was observed from (ultra-) high to low frequencies, worse with increasing pre-existent SNHL and with increasing cumulative dose of cisplatin chemoradiation. Cisplatin chemoradiation-induced hearing loss seemed to reach a plateau at higher levels (75-80 dB HL) for frequencies above 8 kHz compared to frequencies up to 8 kHz (45-60 dB HL). Recovery of SNHL was found after therapy in 27 ears characterized by extensive hearing loss at frequencies 1, 2 and 4 kHz.

Retrospective analysis of early postoperative hearing results obtained after stapedotomy with implantation of a new titanium stapes prosthesis.

OBJECTIVE: To evaluate the early postoperative hearing results of a new titanium stapes prosthesis (K-Piston) implanted in patients with otosclerosis. STUDY DESIGN: A retrospective analysis of preoperative and early postoperative hearing thresholds. SETTING: One tertiary referral and teaching hospital. PATIENTS: Eighteen men and 40 women, mean age 47 years, with otosclerosis. INTERVENTION: Primary stapedotomy. MAIN OUTCOME MEASURE: Main outcome measures were the mean gains in bone-conduction and air-conduction pure-tone thresholds, and pure-tone averages for different frequency combinations. Success and failure of the individual cases were presented using Amsterdam Hearing Evaluation Plots. RESULTS: The overall postoperative air-bone gap for the frequency combination 0.5-1-2-4 kHz was 8.4 (standard deviation: 5.2) dB. In 79% of the patients the postoperative air-bone gap was less than 10 dB. Air-conduction improved even in higher frequencies, while the Carhart effect was not seen in most cases. In three patients a deterioration of bone-conduction was observed ranging from 11 to 16 dB sound pressure level (SPL), and in four patients the gain in air-conduction was insufficient (3-29 dB SPL) to close the preoperative air-bone gap to within 20 dB. CONCLUSION: The new low-weight, full-titanium stapes prosthesis with its slight rough surface and its good mechanical stability and biocompatibility can safely and successfully restore the function of the middle ear when implanted in patients with otosclerosis.

Diagnosis and treatment of isolated neck metastases of adenocarcinomas.

AIMS: Cervical metastases of adenocarcinoma or undifferentiated large cell carcinoma (ULCC) (non-squamous cell carcinoma) of unknown primary origin are rare and often accompanied by distant metastases at multiple sites in the body. Nevertheless, in the past decades, several patients have presented in our clinic with isolated neck metastases of this type of malignancy. The aim of our study is to evaluate the clinical behaviour of these cases and to define the role of surgery and radiotherapy. METHODS: Over the past 24 years, we selected 15 out of 270 patients (6%) with isolated cervical lymph node metastases of adenocarcinoma (six) or ULCC (nine) of unknown primary origin. Diagnosis was made either by histology or by fine needle aspiration cytology. Treatment consisted of (selective) neck dissection and/or radiotherapy. RESULTS: The clinical presentation of isolated cervical metastases of adenocarcinoma compared with ULCC is equivalent, with an overall median survival time of 25 months (confidence interval 21--29 months). Combined therapy was correlated with an increased and persistent regional control and was associated with longer duration of survival. CONCLUSIONS: Patients with isolated cervical neck node metastases of adenocarcinoma or ULCC of unknown primary origin are rare and the diagnostic process to identify this subgroup requires a systemic work-up. In selected cases treatment should concentrate on (selective) neck dissection combined with radiotherapy to achieve a prolonged survival.

[Annual chest X-ray in patients after treatment for laryngeal or oral cancer: only a limited number of second primary lung cancers detected]. / Jaarlijkse thoraxfoto bij patiënten na behandeling wegens een larynx- of een mondholtecarcinoom: slechts beperkt rendement ten aanzien van tweede primaire tumoren in de long.

OBJECTIVE: To evaluate the detection of second primary lung cancer in patients treated for laryngeal or oral cancer by means of the current annual chest radiography screening program. DESIGN: Retrospective follow-up. METHOD: In a source population of Utrecht University Hospital consisting of patients treated for laryngeal or oral cancer, the occurrence of non-simultaneous second primary lung cancer was analysed. The charts of the patients who developed second primary lung cancer were reviewed with respect to diagnosis (either by means of routine annual chest radiography or triggered by symptoms and signs) and treatment of lung cancer. A Kaplan-Meier survival analysis was performed for both routes of diagnosis and for each form of lung cancer treatment. RESULTS: The source population consisted of 2067 patients. Second primary lung cancer was diagnosed in 44 patients (37 with laryngeal and 7 with oral cancer). In 21 patients lung cancer was diagnosed by means of annual chest radiography (routine group). The remaining 23 patients presented with symptoms and signs (symptomatic group). In 13 patients, surgery with curative intent was performed. These patients had the best prognosis. Of the surgical cases, 12 out of 13 patients (27% of the total of 44) were in the routine group. Patients in the routine group had better survival than those in the symptomatic group. CONCLUSION: In view of the limited number of patients with second primary lung cancer and the small percentage of patients eligible for curative surgical treatment detected by annual radiography, screening in its present form is of little benefit.

Effects of postshock atrial pacing on atrial defibrillation outcome in the isolated sheep heart.

BACKGROUND: Failed atrial defibrillation shocks are associated with organization of postshock activity and a substantial postshock electrical quiescence. We investigated the ability of a train of pacing stimuli to capture or locally entrain atrial myocardium during the quiescent period after low-energy shocks and to alter defibrillation outcome. METHODS AND RESULTS: High-resolution video imaging of near-defibrillation-threshold atrial shocks was performed in 12 Langendorff-perfused sheep hearts. A train of 10 pacing stimuli (10-ms pulse width, 200-ms cycle length) was coupled to the shock at various delays in 7 hearts. Coupling intervals of 40 to 130 ms were investigated for feasibility of capture of the first pacing stimulus. The success rate of capture was 0, 0.08+/-0.08, 0.43+/-0.13, 0.73+/-0.13, and 0.11+/-0.1 for 40-, 60-, 80-, 100-, and 120-ms coupling intervals, respectively (P<0.001). In 5 experiments, the coupling interval was fixed at 100 ms (highest success, see above), and the pacing stimulus amplitude was varied between 1.0, 2.0, and 4.0 V. Successful capture rates were 0.38+/-0.08, 0.75+/-0.08, and 0.64+/-0.08, respectively (P<0.003 for 1.0 versus 2.0 V, P=0.2 for 2.0 versus 4.0 V). Rates of successful defibrillation for the groups without and with pacing were 0.56+/-0.07 and 0.64+/-0.04, respectively (P=0.3). With capture of the first pacing stimulus, the rate of successful defibrillation rose to 0.75+/-0.05 (P<0.01); it remained unchanged without capture (0.48+/-0.07 versus 0.56+/-0.07 for no pacing). CONCLUSIONS: Pacing during the quiescent period that follows defibrillation shocks is feasible. A pacing train whose first pacing stimulus successfully captures during the quiescent period of near-defibrillation-threshold shocks appears to alter the outcome.

Spatio-temporal patterns of atrial fibrillation: role of the subendocardial structure.

Despite many years of research and speculation, the precise mechanisms underlying atrial fibrillation remain elusive. Prevalent understanding relies on assumptions, which are based on two-dimensional numerical simulations and on the idea that atrial fibrillation is the result of total disorganization of electrical activity, with multiple wavelets wandering randomly throughout the atria. However, recent studies both clinical and basic, have suggested that focal mechanisms, either re-entrant or automatic, may explain fibrillatory activity in some cases. Here we review the major hypotheses that have prevailed at one time or another to explain this complex arrhythmia and discuss some recent experimental results that strongly suggest that, whatever the electrophysiological basis of atrial fibrillation may be, it must involve complex patterns of propagation through the intricate multidimensional anatomical structure of the atria.