Efficacy and Safety of Cell-based Immunotherapy in The Treatment of Recurrent or Metastatic Nasopharyngeal Carcinoma - A Systematic Review and Meta-analysis.

BACKGROUND: Recurrent/Metastatic Nasopharyngeal Carcinoma (RM-NPC) remains difficult to treat and contributes to considerable mortality. The first-line treatment for RM-NPC is Gemcitabine and Cisplatin and second-line treatment options differ. The endemic variant of NPC is associated with Epstein-Barr Virus (EBV). Therefore, Cell-based Immunotherapy (CBI) targeting EBV-specific RM-NPC may be effective. METHODS: We systematically searched PubMed, Embase and the Cochrane Library for randomised or observational studies investigating the efficacy and safety of CBI in the treatment of RM-NPC. We performed all meta-analyses using the random-effects model. Studies were further stratified by endemicity, nature of disease and drug type to investigate for potential between-study heterogeneity and additional pre-specified tests were employed to assess for publication bias. RESULTS: We screened 1,671 studies and included 13 studies with 403 participants in the systematic review, of which nine studies were eligible for meta-analysis. The use of CBI monotherapy as second or subsequent line treatment for EBV-positive RM-NPC revealed an ORR of 10 % (95 %CI = 3 %-29 %), median PFS of 2.37 months (95 %CI = 1.23-3.51) and median OS of 10.16 months (95 %CI = 0.67-19.65). For EBV-specific Cytotoxic T-Lymphocyte monotherapy, the pooled PD rate was 54 % (95 %CI = 9 %-93 %), SD rate was 22 % (95 %CI = 2 %-75 %) and incidence rate of any grade adverse events was 45 %. For Dendritic Cell monotherapy, a PD rate of 80 % (95 % CI = 29 %-98 %), SD rate of 11 % (95 % CI = 0 %-82 %) and incidence rate of any grade adverse events of 29 % was achieved. CONCLUSION: CBI monotherapy demonstrates some activity in pre-treated RM-NPC. More trials are needed to better understand how to integrate CBI into RM-NPC care.

Patterns of recurrence in HNSCC patients treated definitively with upfront surgery, chemoradiation.

PURPOSE: Locally-advanced oropharynx (LA-OPSCC) and hypopharynx/larynx (LA-HPLSCC) cancers may be treated with surgical or non-surgical modalities. While survival outcomes are comparable, patterns of disease recurrence are not well established. METHODS: Retrospective review of 98 consecutive patients with LA-OPSCC or LA-HPLSCC treated by either surgery plus adjuvant therapy (S-POAT, n = 48) or chemoradiation (CRT, n = 50). RESULTS: CRT-treated patients had higher recurrence risk (42% vs 14.6%, p = 0.003). This was significant only among LA-OPSCC (p = 0.002) but not LA-HPLSCC patients (p = 0.159). Median time to recurrence in LA-OPSCC was 16.8 vs 11.6 months, and 16.6 vs 15.1 months in LA-HPLSCC, comparing surgically treated and CRT cohorts. Surgically-treated p16-negative LA-OPSCC experienced improved locoregional control than CRT-treated patients (100% vs 12.5%, p = 0.045) and 3-year RFS (83.0% vs 33.3%, p < 0.001). CONCLUSION: Locoregional control and RFS benefit was observed in surgically treated p16 negative LA-OPSCC patients. Locoregional recurrence is the main reason of treatment failure in LA-HNSCC, occurring commonly within the first 2 years post-treatment, regardless of treatment option.

Performance of a multigene genomic classifier and clinical parameters in predicting malignancy in a Southeast Asian cohort of patients with cytologically indeterminate thyroid nodules.

BACKGROUND: Most thyroid nodules are benign. It is important to determine the likelihood of malignancy in such nodules to avoid unnecessary surgery. The primary objective of this study was to characterize the genetic landscape and the performance of a multigene genomic classifier in fine-needle aspiration (FNA) biopsies of cytologically indeterminate thyroid nodules in a Southeast Asian cohort. The secondary objective was to assess the predictive contribution of clinical characteristics to thyroid malignancy. METHODS: This prospective, multicenter, blinded study included 132 patients with 134 nodules. Molecular testing (MT) with ThyroSeq v3 was performed on clinical or ex-vivo FNA samples. Centralized pathology review also was performed. RESULTS: Of 134 nodules, consisting of 61% Bethesda category III, 20% category IV, and 19% category V cytology, and 56% were histologically malignant. ThyroSeq yielded negative results in 37.3% of all FNA samples and in 42% of Bethesda category III-IV cytology nodules. Most positive samples had RAS-like (41.7%), followed by BRAF-like (22.6%), and high-risk (17.9%) alterations. Compared with North American patients, the authors observed a higher proportion of RAS-like mutations, specifically NRAS, in Bethesda categories III and IV and more BRAF-like mutations in Bethesda category III. The test had sensitivity, specificity, negative predictive value, and positive predictive value of 89.6%, 73.7%, 84.0%, and 82.1%, respectively. The risk of malignancy was predicted by positive MT and high-suspicion ultrasound characteristics according to American Thyroid Association criteria. CONCLUSIONS: Even in the current Southeast Asian cohort with nodules that had a high pretest cancer probability, MT could lead to potential avoidance of diagnostic surgery in 42% of patients with Bethesda category III-IV nodules. MT positivity was a stronger predictor of malignancy than clinical parameters.

Boosted abscopal effect from radiotherapy and pembrolizumab in anaplastic thyroid cancer: a mini-review and case report.

BACKGROUND: The abscopal effect, in which radiation induces a systemic anti-tumour immune response, has been demonstrated with radiotherapy. Immunotherapy boosts the abscopal effect by facilitating the immune response to radiation. Radiotherapy and programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) blockade has resulted in the boosted abscopal effect in solid cancers, but its role in anaplastic thyroid cancer (ATC) is unknown. In this mini-review, we describe the abscopal effect and summarise its proposed underlying mechanisms. We then present a potential case of boosted abscopal effect in ATC. CASE DESCRIPTION: In our case presentation, we describe a 51-year-old female who presented with 3 weeks of rapidly enlarging thyroid mass. Examination revealed a 3-cm thyroid nodule which was Bethesda V on fine needle aspiration cytology (FNAC). Intraoperatively, there was a gross extrathyroidal extension into the cricoid cartilage. After total thyroidectomy, post-operative histopathology showed widely invasive follicular thyroid cancer with anaplastic transformation (>50%). Immunohistochemistry showed high PD-L1 expression [combined positive score (CPS) >70%]. Due to residual cricoid cartilage disease and several peri-hilar and lung metastases on positron emission tomography-computed tomography (PET-CT) scan, she underwent post-operative palliative radiotherapy and pembrolizumab. After two cycles of pembrolizumab, repeat PET-CT scan showed complete response (CR) of local and distant disease. She remained well for 32 months, before recent discovery of a right mandible bony metastasis planned for radiotherapy. CONCLUSIONS: This case demonstrates exceptional response to radiotherapy and anti-PD-1 immunotherapy in ATC, potentially illustrating the first known abscopal effect in ATC with this treatment.

Concordance of the ACR TI-RADS Classification With Bethesda Scoring and Histopathology Risk Stratification of Thyroid Nodules.

Importance: Although most thyroid nodules are benign, 10% to 15% of them harbor cancer. Thyroid ultrasonography is useful for risk stratification of nodules, and American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) classification provides recommendations for fine-needle aspiration cytology (FNAC) based on objective ultrasonographic features of these nodules. Objective: To validate the concordance of ACR TI-RADS classification with Bethesda classification and histopathology. Design, Setting, and Participants: This retrospective cohort study was performed to evaluate the concordance of ACR TI-RADS classification with Bethesda classification and histopathology and was conducted in Singapore General Hospital Outpatient Otolaryngology clinic in March 2021 to May 2021. Data analysis was performed in May 2021. Main Outcomes and Measures: Results were deemed concordant when ACR TI-RADS recommendations aligned with Bethesda scores. Conversely, results were classified as nonconcordant with Bethesda scores and/or histopathology results when nodules that were recommended for FNAC yielded benign results or nodules that were not recommended for FNAC yielded malignant results. Results: A total of 446 patients (370 women [83%]; mean [range] age, 60 [24-89] years) who underwent ultrasonography of the thyroid and ultrasonography-guided thyroid FNACs were identified. A total of 492 of 630 nodules (78.1%) were benign on FNAC (Bethesda II). Score 3 ACR TI-RADS nodules yielded the highest negative predictive values: 94.6% (95% CI, 92.9%-95.9%; P < .001) compared with Bethesda scoring and 100.0% (95% CI, 15.8%-100.0%; P = .003) compared with histopathology. Score 4 or 5 ACR TI-RADS nodules yielded positive predictive values of 2.8% and 16.2%, respectively, compared with Bethesda scoring and 6.1% and 66.7%, respectively, compared with histopathology. Small (<1.5 cm) ACR TI-RADS nodules of scores of 4 and 5 that were not recommended for FNAC yielded a malignant risk of 5.7% and 25.0% on Bethesda 5 and 6, respectively. On surgical excision, 5 of 46 (10.9%) ACR TI-RADS 4 nodules and 15 of 21 (71.4%) of ACR TI-RADS 5 nodules were confirmed to be malignant. Among nodules initially not recommended for FNAC, histopathology-proven cancer was found in 4 of 13 (30.7%) and 3 of 6 (50.0%) of nodules, respectively. Conclusions and Relevance: These findings suggest that ACR TI-RADS score 3 nodules have a low risk of cancer and should be considered for FNAC only if nodules are 2.5 cm or larger. Patients with small (<1.5 cm) ACR TI-RADS 4 and 5 nodules should be appropriately counseled for FNAC to exclude cancer.

Real-time in vivo cancer staging of nasopharyngeal carcinoma patients with rapid fiberoptic Raman endoscopy.

Cancer staging is important to guide treatment and for prognostication. This work aims to demonstrate the ability of rapid fiberoptic Raman endoscopy for real-time in vivo cancer staging of nasopharyngeal cancer (NPC) patients. We interrogate 278 tissue sites on the primary NPC with different cancer stages from 61 NPC patients and 50 healthy volunteers using rapid fiberoptic Raman endoscopy examination. Distinct Raman spectral differences of NPC at different cancer stages are observed through simultaneous fingerprint and high-wavenumber (FP/HW) Raman spectral measurements, reflecting the biomolecular differences of NPC tumor across various cancer stages. Raman staging model is established based on in vivo FP/HW tissue Raman spectra together with partial-least-squares linear-discriminant-analysis (PLS-LDA) and leave-one-tissue-site-out cross-validation (LOOCV). In vivo FP/HW Raman endoscopy provides an overall diagnostic accuracy of 92.81% for identifying different stages of NPC (i.e., NPC stage I&II and NPC stage III&IV) from normal nasopharynx. Specifically, the diagnostic sensitivity of 91.18% is obtained for identifying NPC stage I& II; and the sensitivity of 93.04% is achieved for classifying NPC stage III&IV from normal tissue. The key tissue biomolecular variations responsible for different NPC stages have been identified using biomolecular Raman modeling developed based on non-negative linear regression. The essential biomolecules (chondroitin sulfate, glucose, hemoglobin, oleic acid and triolein) are uncovered from the Raman spectra of NPC tissues through biomolecular modeling with significant variations (p < 0.05) between early-stage NPC (stage I and stage II) and late-stage NPC patients (stage III and stage IV). Our pivotal work demonstrates for the first time that fiberoptic Raman endoscopy is a robust analytical tool for real-time in vivo NPC staging in clinical settings.

Flexible Needle Steering with Tethered and Untethered Actuation: Current States, Targeting Errors, Challenges and Opportunities.

Accurate needle targeting is critical for many clinical procedures, such as transcutaneous biopsy or radiofrequency ablation of tumors. However, targeting errors may arise, limiting the widespread adoption of these procedures. Advances in flexible needle (FN) steering are emerging to mitigate these errors. This review summarizes the state-of-the-art developments of FNs and addresses possible targeting errors that can be overcome with steering actuation techniques. FN steering techniques can be classified as passive and active. Passive steering directly results from the needle-tissue interaction forces, whereas active steering requires additional forces to be applied at the needle tip, which enhances needle steerability. Therefore, the corresponding targeting errors of most passive FNs and active FNs are between 1 and 2 mm, and less than 1 mm, respectively. However, the diameters of active FNs range from 1.42 to 12 mm, which is larger than the passive steering needle varying from 0.5 to 1.4 mm. Therefore, the development of active FNs is an area of active research. These active FNs can be steered using tethered internal direct actuation or untethered external actuation. Examples of tethered internal direct actuation include tendon-driven, longitudinal segment transmission and concentric tube transmission. Tendon-driven FNs have various structures, and longitudinal segment transmission needles could be adapted to reduce tissue damage. Additionally, concentric tube needles have immediate advantages and clinical applications in natural orifice surgery. Magnetic actuation enables active FN steering with untethered external actuation and facilitates miniaturization. The challenges faced in the fabrication, sensing, and actuation methods of FN are analyzed. Finally, bio-inspired FNs may offer solutions to address the challenges faced in FN active steering mechanisms.

Task-aware asynchronous multi-task model with class incremental contrastive learning for surgical scene understanding.

PURPOSE: Surgery scene understanding with tool-tissue interaction recognition and automatic report generation can play an important role in intra-operative guidance, decision-making and postoperative analysis in robotic surgery. However, domain shifts between different surgeries with inter and intra-patient variation and novel instruments' appearance degrade the performance of model prediction. Moreover, it requires output from multiple models, which can be computationally expensive and affect real-time performance. METHODOLOGY: A multi-task learning (MTL) model is proposed for surgical report generation and tool-tissue interaction prediction that deals with domain shift problems. The model forms of shared feature extractor, mesh-transformer branch for captioning and graph attention branch for tool-tissue interaction prediction. The shared feature extractor employs class incremental contrastive learning to tackle intensity shift and novel class appearance in the target domain. We design Laplacian of Gaussian-based curriculum learning into both shared and task-specific branches to enhance model learning. We incorporate a task-aware asynchronous MTL optimization technique to fine-tune the shared weights and converge both tasks optimally. RESULTS: The proposed MTL model trained using task-aware optimization and fine-tuning techniques reported a balanced performance (BLEU score of 0.4049 for scene captioning and accuracy of 0.3508 for interaction detection) for both tasks on the target domain and performed on-par with single-task models in domain adaptation. CONCLUSION: The proposed multi-task model was able to adapt to domain shifts, incorporate novel instruments in the target domain, and perform tool-tissue interaction detection and report generation on par with single-task models.

Efficacy of Anti-PD1 Blockade in Treating Recurrent or Metastatic Nasopharyngeal Cancer: A Systematic Review and Meta-analysis.

OBJECTIVES: Anti-PD1 antibody has emerged as a promising immunotherapeutic option in patients with recurrent and/or metastatic nasopharyngeal cancers (RM-NPC). We aim to summarise existing evidence on the use of anti-PD1 antibodies in the treatment of these patients and compare its effectiveness with standard-of-care palliative chemotherapy. Our secondary aim is to explore potential combination therapies with anti-PD1 antibodies. MATERIALS AND METHODS: PubMed, Embase and Cochrane databases were systematically searched for studies comparing the efficacy of various anti-PD1 antibodies in the treatment of RM-NPC (either as first or second line treatment) from inception to 2 September 2022. Meta-analyses were performed to correlate the various anti-PD1 antibodies with primary endpoints including overall response rate disease control rate (DCR), progression free survival (PFS) and overall survival (OS). RESULTS: Eighteen studies with 1,887 patients met the inclusion criteria. The use of anti-PD1 antibody monotherapy as second-line treatment of RM-NPC revealed an ORR of 23 % (95 % CI = 19 %-28 %) and DCR of 51 % (95 % CI = 42 %-60 %). The ORRs for first-line as well as a combination of first and second-line treatments were 21 % (95 % CI = 15 % - 30 %) and 22 % (95 % CI = 6 % - 56 %, I2 = 75 %) respectively. The 12-month PFS and 12-month OS was also 27 % (95 % CI = 21 %-33 %) and 63 % (95 % CI = 53 %-72 %) respectively. ORR was much higher at 73 % (95 % CI = 32 %-94 %) when anti-PD1 antibodies were combined with Gemcitabine plus Cisplatin. CONCLUSION: Anti-PD1 antibody demonstrate considerable activity in previously treated RM-NPC patients. Combining anti-PD1 antibodies with gemcitabine and cisplatin chemotherapy enhanced the efficacy of treatment.

Biomimetic Incremental Domain Generalization with a Graph Network for Surgical Scene Understanding.

Surgical scene understanding is a key barrier for situation-aware robotic surgeries and the associated surgical training. With the presence of domain shifts and the inclusion of new instruments and tissues, learning domain generalization (DG) plays a pivotal role in expanding instrument-tissue interaction detection to new domains in robotic surgery. Mimicking the ability of humans to incrementally learn new skills without forgetting their old skills in a similar domain, we employ incremental DG on scene graphs to predict instrument-tissue interaction during robot-assisted surgery. To achieve incremental DG, incorporate incremental learning (IL) to accommodate new instruments and knowledge-distillation-based student-teacher learning to tackle domain shifts in the new domain. Additionally, we designed an enhanced curriculum by smoothing (E-CBS) based on Laplacian of Gaussian (LoG) and Gaussian kernels, and integrated it with the feature extraction network (FEN) and graph network to improve the instrument-tissue interaction performance. Furthermore, the FEN's and graph network's logits are normalized by temperature normalization (T-Norm), and its effect in model calibration was studied. Quantitative and qualitative analysis proved that our incrementally-domain generalized interaction detection model was able to adapt to the target domain (transoral robotic surgery) while retaining its performance in the source domain (nephrectomy surgery). Additionally, the graph model enhanced by E-CBS and T-Norm outperformed other state-of-the-art models, and the incremental DG technique performed better than the naive domain adaption and DG technique.

Analytical and clinical validation of an amplicon-based next generation sequencing assay for ultrasensitive detection of circulating tumor DNA.

Next-generation sequencing of circulating tumor DNA presents a promising approach to cancer diagnostics, complementing conventional tissue-based diagnostic testing by enabling minimally invasive serial testing and broad genomic coverage through a simple blood draw to maximize therapeutic benefit to patients. LiquidHALLMARK® is an amplicon-based next-generation sequencing assay developed for the genomic profiling of plasma-derived cell-free DNA (cfDNA). The comprehensive 80-gene panel profiles point mutations, insertions/deletions, copy number alterations, and gene fusions, and further detects oncogenic viruses (Epstein-Barr virus (EBV) and hepatitis B virus (HBV)) and microsatellite instability (MSI). Here, the analytical and clinical validation of the assay is reported. Analytical validation using reference genetic materials demonstrated a sensitivity of 99.38% for point mutations and 95.83% for insertions/deletions at 0.1% variant allele frequency (VAF), and a sensitivity of 91.67% for gene fusions at 0.5% VAF. In non-cancer samples, a high specificity (≥99.9999% per-base) was observed. The limit of detection for copy number alterations, EBV, HBV, and MSI were also empirically determined. Orthogonal comparison of epidermal growth factor receptor (EGFR) variant calls made by LiquidHALLMARK and a reference allele-specific polymerase chain reaction (AS-PCR) method for 355 lung cancer specimens revealed an overall concordance of 93.80%, while external validation with cobas® EGFR Mutation Test v2 for 50 lung cancer specimens demonstrated an overall concordance of 84.00%, with a 100% concordance rate for EGFR variants above 0.4% VAF. Clinical application of LiquidHALLMARK in 1,592 consecutive patients demonstrated a high detection rate (74.8% circulating tumor DNA (ctDNA)-positive in cancer samples) and broad actionability (50.0% of cancer samples harboring alterations with biological evidence for actionability). Among ctDNA-positive lung cancers, 72.5% harbored at least one biomarker with a guideline-approved drug indication. These results establish the high sensitivity, specificity, accuracy, and precision of the LiquidHALLMARK assay and supports its clinical application for blood-based genomic testing.

Management of oral feeding following total laryngectomy around the world: YO-IFOS international study.

BACKGROUND: To analyze worldwide practices regarding the initiation of oral feeding after total laryngectomy (TL). METHODS: Online survey. RESULTS: Among the 332 responses received, 278 from 59 countries were analyzed. Our results showed that 45.6% of respondents started water and 45.1% started liquid diet between postoperative days 7 and 10. Semi-solid feeds were initiated between days 10 and 14 for 44.9% of respondents and a free diet was allowed after day 15 for 60.8% of respondents. This timing was significantly delayed in cases of laryngo-pharyngectomy and after prior radiotherapy (p < 0.001). A greater proportion of respondents in Africa and Oceania allowed early oral feeding before day 6 as compared with the rest of the world (p < 0.001). CONCLUSION: Despite increasing number of publications, there is still a lack of evidence to support early oral feeding. The majority of respondents preferred to delay its initiation until at least 7 days after surgery.

Epstein-Barr virus-induced ectopic CD137 expression helps nasopharyngeal carcinoma to escape immune surveillance and enables targeting by chimeric antigen receptors.

Non-keratinizing nasopharyngeal carcinoma (NPC) is a malignancy with a poor prognosis for relapsing patients and those with metastatic disease. Here, we identify a novel disease mechanism of NPC which may be its Achilles' heel that makes it susceptible to immunotherapy. CD137 is a potent costimulatory receptor on activated T cells, and CD137 agonists strongly enhance anti-tumor immune responses. A negative feedback mechanism prevents overstimulation by transferring CD137 from T cells to CD137 ligand (CD137L)-expressing antigen presenting cells (APC) during cognate interaction, upon which the CD137-CD137L complex is internalized and degraded. We found ectopic expression of CD137 on 42 of 122 (34.4%) NPC cases, and that CD137 is induced by the Epstein-Barr virus latent membrane protein (LMP) 1. CD137 expression enables NPC to hijack the inbuilt negative feedback mechanism to downregulate the costimulatory CD137L on APC, facilitating its escape from immune surveillance. Further, the ectopically expressed CD137 signals into NPC cells via the p38-MAPK pathway, and induces the expression of IL-6, IL-8 and Laminin γ2. As much as ectopic CD137 expression may support the growth and spread of NPC, it may be a target for its immunotherapeutic elimination. Natural killer cells that express a CD137-specific chimeric antigen receptor induce death in CD137+ NPC cells, in vitro, and in vivo in a murine xenograft model. These data identify a novel immune escape mechanism of NPC, and lay the foundation for an urgently needed immunotherapeutic approach for NPC.

Phase I study of expanded natural killer cells in combination with cetuximab for recurrent/metastatic nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) cells express high levels of epidermal growth factor receptor (EGFR). Cetuximab is an anti-EGFR monoclonal antibody that promotes natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) via engagement of CD16. We studied safety and efficacy of combining cetuximab with autologous expanded NK cells in patients with recurrent and/or metastatic NPC who had failed at least two prior lines of chemotherapy. METHODS: Seven subjects (six patients) received cetuximab every 3 weeks (six doses maximum) in the pre-trial phase. Autologous NK cells, expanded by co-culture with irradiated K562-mb15-41BBL cells, were then infused on the day after administration of cetuximab. Primary and secondary objectives were to determine safety of this combination therapy and to assess tumor responses, respectively. RESULTS: Median NK cell expansion from peripheral blood mononucleated cells after 10 days of culture with K562-mb15-41BBL was 274-fold (range, 36-534, n = 10), and the median expression of CD16 was 98.4% (range, 67.8-99.7%). Skin rash, the commonest side effect of cetuximab in the pre-trial phase, was not exacerbated by NK cell infusion. No intolerable side effects were observed. Stable disease was observed in four subjects and progressive disease in three subjects. Three patients who received NK cells twice had time to disease progression of 12, 13, and 19 months. CONCLUSION: NK cells with high ADCC potential can be expanded from patients with heavily pre-treated NPC. The safety profile and encouraging clinical responses observed after combining these cells with cetuximab warrant further studies of this approach. (clinicalTrials.gov NCT02507154, 23/07/2015). PRECIS: Engaging NK cell-mediated ADCC using cetuximab plus autologous NK cells in EGFR-positive NPC was well tolerated among heavily pre-treated recurrent NPC. Promising results were observed with 3 out of 7 subjects demonstrating durable stable disease.

Dendritic cell therapy with CD137L-DC-EBV-VAX in locally recurrent or metastatic nasopharyngeal carcinoma is safe and confers clinical benefit.

INTRODUCTION: Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC), and provides a target for a dendritic cell (DC) vaccine. CD137 ligand (CD137L) expressed on antigen presenting cells, costimulates CD137-expressing T cells, and reverse CD137L signaling differentiates monocytes to CD137L-DC, a type of DC, which is more potent than classical DC in stimulating T cells. METHODS: In this phase I study, patients with locally recurrent or metastatic NPC were administered CD137L-DC pulsed with EBV antigens (CD137L-DC-EBV-VAX). RESULTS: Of the 12 patients treated, 9 received full 7 vaccine doses with a mean administered cell count of 23.9 × 106 per dose. Treatment was well tolerated with only 4 cases of grade 1 related adverse events. A partial response was obtained in 1 patient, and 4 patients are still benefitting from a progression free survival (PFS) of currently 2-3 years. The mean pre-treatment neutrophil: lymphocyte ratio was 3.4 and a value of less than 3 was associated with prolonged median PFS. Progressors were characterized by a high frequency of naïve T cells but a low frequency of CD8+ effector T cells while patients with a clinical benefit (CB) had a high frequency of memory T cells. Patients with CB had lower plasma EBV DNA levels, and a reduction after vaccination. CONCLUSION: CD137L-DC-EBV-VAX was well tolerated. The use of CD137L-DC-EBV-VAX is demonstrated to be safe. Consistent results were obtained from all 12 patients, indicating that CD137L-DC-EBV-VAX induces an anti-EBV and anti-NPC immune response, and warranting further studies in patients post effective chemotherapy. PRECIS: The first clinical testing of CD137L-DC, a new type of monocyte-derived DC, finds that CD137L-DC are safe, and that they can induce an immune response against Epstein-Barr virus-associated nasopharyngeal carcinoma that leads to tumor regression or prevents tumor progression.

Epstein-Barr Virus Epithelial Cancers-A Comprehensive Understanding to Drive Novel Therapies.

Epstein-Barr virus (EBV) is a ubiquitous oncovirus associated with specific epithelial and lymphoid cancers. Among the epithelial cancers, nasopharyngeal carcinoma (NPC), lymphoepithelioma-like carcinoma (LELC), and EBV-associated gastric cancers (EBVaGC) are the most common. The role of EBV in the pathogenesis of NPC and in the modulation of its tumour immune microenvironment (TIME) has been increasingly well described. Much less is known about the pathogenesis and tumour-microenvironment interactions in other EBV-associated epithelial cancers. Despite the expression of EBV-related viral oncoproteins and a generally immune-inflamed cancer subtype, EBV-associated epithelial cancers have limited systemic therapeutic options beyond conventional chemotherapy. Immune checkpoint inhibitors are effective only in a minority of these patients and even less efficacious with molecular targeting drugs. Here, we examine the key similarities and differences of NPC, LELC, and EBVaGC and comprehensively describe the clinical, pathological, and molecular characteristics of these cancers. A deeper comparative understanding of these EBV-driven cancers can potentially uncover targets in the tumour, TIME, and stroma, which may guide future drug development and cast light on resistance to immunotherapy.

Deep Learning-Guided Fiberoptic Raman Spectroscopy Enables Real-Time In Vivo Diagnosis and Assessment of Nasopharyngeal Carcinoma and Post-treatment Efficacy during Endoscopy.

In this work, we develop a deep learning-guided fiberoptic Raman diagnostic platform to assess its ability of real-time in vivo nasopharyngeal carcinoma (NPC) diagnosis and post-treatment follow-up of NPC patients. The robust Raman diagnostic platform is established using innovative multi-layer Raman-specified convolutional neural networks (RS-CNN) together with simultaneous fingerprint and high-wavenumber spectra acquired within sub-seconds using a fiberoptic Raman endoscopy system. We have acquired a total of 15,354 FP/HW in vivo Raman spectra (control: 1761; NPC: 4147; and post-treatment (PT): 9446) from 888 tissue sites of 418 subjects (healthy control: 85; NPC: 82; and PT: 251) during endoscopic examination. The optimized RS-CNN model provides an overall diagnostic accuracy of 82.09% (sensitivity of 92.18% and specificity of 73.99%) for identifying NPC from control and post-treatment patients, which is superior to the best diagnosis performance (accuracy of 73.57%; sensitivity of 89.74%; and specificity of 58.10%) using partial-least-squares linear-discriminate-analysis, proving the robustness and high spectral information sensitiveness of the RS-CNN model developed. We further investigate the saliency map of the best RS-CNN models using the correctly predicted Raman spectra. The specific Raman signatures that are related to the cancer-associated biomolecular variations (e.g., collagens, lipids, and nucleic acids) are uncovered in the map, validating the diagnostic capability of RS-CNN models to correlate with biomolecular signatures. Deep learning-based Raman spectroscopy is a powerful diagnostic tool for rapid screening and surveillance of NPC patients and can also be deployed for longitudinal follow-up monitoring of post-treatment NPC patients to detect early cancer recurrences in the head and neck.

Deployable Telescopic Tubular Mechanisms With a Steerable Tongue Depressor Towards Self-Administered Oral Swab.

Swabbing tests have proved to be an effective method of diagnosis for a wide range of diseases. Potential occupational health hazards and reliance on healthcare workers during traditional swabbing procedures can be mitigated by self-administered swabs. Hence, we report possible methods to apply closed kinematic chain theory to develop a self-administered viral swab to collect respiratory specimens. The proposed sensorized swab models utilizing hollow polypropylene tubes possess mechanical compliance, simple construction, and inexpensive components. In detail, the adaptation of the slider-crank mechanism combined with concepts of a deployable telescopic tubular mechanical system is explored through four different oral swab designs. A closed kinematic chain on suitable material to create a developable surface allows the translation of simple two-dimensional motion into more complex multi-dimensional motion. These foldable telescopic straws with multiple kirigami cuts minimize components involved in the system as the characteristics are built directly into the material. Further, it offers a possibility to include soft stretchable sensors for realtime performance monitoring. A variety of features were constructed and tested using the concepts above, including 1) tongue depressor and cough/gag reflex deflector; 2) changing the position and orientation of the oral swab when sample collection is in the process; 3) protective cover for the swabbing bud; 4) a combination of the features mentioned above.