Treatment of secondary CNS lymphoma using CD19-targeted chimeric antigen receptor (CAR) T cells.

BACKGROUND: Aggressive B cell lymphoma with secondary central nervous system (CNS) involvement (SCNSL) carries a dismal prognosis. Chimeric antigen receptor (CAR) T cells (CAR-T) targeting CD19 have revolutionized the treatment for B cell lymphomas; however, only single cases with CNS manifestations successfully treated with CD19 CAR-T have been reported. METHODS: We prospectively enrolled 4 patients with SCNSL into our study to assess clinical responses and monitor T cell immunity. RESULTS: Two of four SNCSL patients responded to the CD19-targeted CAR-T. Only one patient showed a substantial expansion of peripheral (PB) CAR-T cells with an almost 100-fold increase within the first week after CAR-T. The same patient also showed marked neurotoxicity and progression of the SNCSL despite continuous surface expression of CD19 on the lymphoma cells and an accumulation of CD4+ central memory-type CAR-T cells in the CNS. Our studies indicate that the local production of chemokine IP-10, possibly through its receptor CXCR3 expressed on our patient's CAR-T, could potentially have mediated the local accumulation of functionally suboptimal anti-tumor T cells. CONCLUSIONS: Our results demonstrate expansion and homing of CAR-T cells into the CNS in SNCSL patients. Local production of chemokines such as IP-10 may support CNS infiltration by CAR-T cells but also carry the potential of amplifying local toxicity. Future studies investigating numbers, phenotype, and function of CAR-T in the different body compartments of SNSCL patients receiving CAR-T will help to improve local delivery of "fit" and highly tumor-reactive CAR-T with low off-target reactivity into the CNS.

3D Specimen Scanning and Mapping in Musculoskeletal Oncology: A Feasibility Study.

BACKGROUND: Surgical resection is the primary treatment for bone and soft tissue tumors. Negative margin status is a key factor in prognosis. Given the three-dimensional (3D) anatomic complexity of musculoskeletal tumor specimens, communication of margin results between surgeons and pathologists is challenging. We sought to perform ex vivo 3D scanning of musculoskeletal oncology specimens to enhance communication between surgeons and pathologists. METHODS: Immediately after surgical resection, 3D scanning of the fresh specimen is performed prior to frozen section analysis. During pathologic grossing, whether frozen or permanent, margin sampling sites are annotated on the virtual 3D model using computer-aided design (CAD) software. RESULTS: 3D scanning was performed in seven cases (six soft tissue, one bone), with specimen mapping on six cases. Intraoperative 3D scanning and mapping was performed in one case in which the location of margin sampling was shown virtually in real-time to the operating surgeon to help achieve a negative margin. In six cases, the 3D model was used to communicate final permanent section analysis. Soft tissue, cartilage, and bone (including lytic lesions within bone) showed acceptable resolution. CONCLUSIONS: Virtual 3D scanning and specimen mapping is feasible and may allow for enhanced documentation and communication. This protocol provides useful information for anatomically complex musculoskeletal tumor specimens. Future studies will evaluate the effect of the protocol on positive margin rates, likelihood that a re-resection contains additional malignancy, and exploration of targeted adjuvant radiation protocols using a patient-specific 3D specimen map.

More than meets the eye: Augmented reality in surgical oncology.

BACKGROUND AND OBJECTIVES: In the field of surgical oncology, there has been a desire for innovative techniques to improve tumor visualization, resection, and patient outcomes. Augmented reality (AR) technology superimposes digital content onto the real-world environment, enhancing the user's experience by blending digital and physical elements. A thorough examination of AR technology in surgical oncology has yet to be performed. METHODS: A scoping review of intraoperative AR in surgical oncology was conducted according to the guidelines and recommendations of The Preferred Reporting Items for Systematic Review and Meta-analyzes Extension for Scoping Reviews (PRISMA-ScR) framework. All original articles examining the use of intraoperative AR during surgical management of cancer were included. Exclusion criteria included virtual reality applications only, preoperative use only, fluorescence, AR not specific to surgical oncology, and study design (reviews, commentaries, abstracts). RESULTS: A total of 2735 articles were identified of which 83 were included. Most studies (52) were performed on animals or phantom models, while the remaining included patients. A total of 1112 intraoperative AR surgical cases were performed across the studies. The most common anatomic site was brain (20 articles), followed by liver (16), renal (9), and head and neck (8). AR was most often used for intraoperative navigation or anatomic visualization of tumors or critical structures but was also used to identify osteotomy or craniotomy planes. CONCLUSIONS: AR technology has been applied across the field of surgical oncology to aid in localization and resection of tumors.

Augmented-Reality Surgery to Guide Head and Neck Cancer Re-resection: A Feasibility and Accuracy Study.

BACKGROUND: Given the complex three-dimensional (3D) anatomy of head and neck cancer specimens, head and neck surgeons often have difficulty relocating the site of an initial positive margin to perform re-resection. This cadaveric study aimed to determine the feasibility and accuracy of augmented reality surgery to guide head and neck cancer re-resections. METHODS: This study investigated three cadaveric specimens. The head and neck resection specimen was 3D scanned and exported to the HoloLens augmented reality environment. The surgeon manually aligned the 3D specimen hologram into the resection bed. Accuracy of manual alignment and time intervals throughout the protocol were recorded. RESULTS: The 20 head and neck cancer resections performed in this study included 13 cutaneous and 7 oral cavity resections. The mean relocation error was 4 mm (range, 1-15 mm) with a standard deviation of 3.9 mm. The mean overall protocol time, from the start of 3D scanning to alignment into the resection bed, was 25.3 ± 8.9 min (range, 13.2-43.2 min). Relocation error did not differ significantly when stratified by greatest dimension of the specimen. The mean relocation error of complex oral cavity composite specimens (maxillectomy and mandibulectomy) differed significantly from that of all the other specimen types (10.7 vs 2.8; p < 0.01). CONCLUSIONS: This cadaveric study demonstrated the feasibility and accuracy of augmented reality to guide re-resection of initial positive margins in head and neck cancer surgery.

Talking with Patients about Surgical Trainees.

AbstractTraining of resident physicians is essential for the care of future patients. While surgical trainee involvement is necessary, its disclosure to patients can often be omitted or underplayed by surgeons. The informed consent process and the underlying ethical principles make evident that patients should be informed of trainee involvement. In this review we explore the importance of disclosure, current themes in practice, and the optimal discussion for which we should strive.

Cutting Edge: Mitochondrial Assembly of the NLRP3 Inflammasome Complex Is Initiated at Priming.

The NLRP3 inflammasome is activated in response to microbial and danger signals, resulting in caspase-1-dependent secretion of the proinflammatory cytokines IL-1ß and IL-18. Canonical NLRP3 inflammasome activation is a two-step process requiring both priming and activation signals. During inflammasome activation, NLRP3 associates with mitochondria; however, the role for this interaction is unclear. In this article, we show that mouse NLRP3 and caspase-1 independently interact with the mitochondrial lipid cardiolipin, which is externalized to the outer mitochondrial membrane at priming in response to reactive oxygen species. An NLRP3 activation signal is then required for the calcium-dependent association of the adaptor molecule ASC with NLRP3 on the mitochondrial surface, resulting in inflammasome complex assembly and activation. These findings demonstrate a novel lipid interaction for caspase-1 and identify a role for mitochondria as supramolecular organizing centers in the assembly and activation of the NLRP3 inflammasome.

Development of an augmented reality guidance system for head and neck cancer resection.

The use of head-mounted augmented reality (AR) for surgeries has grown rapidly in recent years. AR aids in intraoperative surgical navigation through overlaying three-dimensional (3D) holographic reconstructions of medical data. However, performing AR surgeries on complex areas such as the head and neck region poses challenges in terms of accuracy and speed. This study explores the feasibility of an AR guidance system for resections of positive tumour margins in a cadaveric specimen. The authors present an intraoperative solution that enables surgeons to upload and visualize holographic reconstructions of resected cadaver tissues. The solution involves using a 3D scanner to capture detailed scans of the resected tissue, which are subsequently uploaded into our software. The software converts the scans of resected tissues into specimen holograms that are viewable through a head-mounted AR display. By re-aligning these holograms with cadavers with gestures or voice commands, surgeons can navigate the head and neck tumour site. This workflow can run concurrently with frozen section analysis. On average, the authors achieve an uploading time of 2.98 min, visualization time of 1.05 min, and re-alignment time of 4.39 min, compared to the 20 to 30 min typical for frozen section analysis. The authors achieve a mean re-alignment error of 3.1 mm. The authors' software provides a foundation for new research and product development for using AR to navigate complex 3D anatomy in surgery.

Cardiac markers in left-sided breast cancer patients receiving adjuvant radiotherapy: a prospective study.

OBJECTIVES: To investigate the association between radiotherapy (RT) and cardiac biomarkers in women with left-sided breast cancer. METHODS: This prospective observational study recruited patients with stage I-III left-sided breast cancer without coronary heart disease who required adjuvant RT. High-sensitivity troponin I(hsTnI), N-terminal pro-brain natriuretic peptide(NT-proBNP), and high-sensitivity C-reactive protein(hsCRP) levels were measured pre-RT, immediately after RT, and 3 months post-RT. Cardiac-sparing RT techniques were utilized (Field-in-Field IMRT/VMAT ± voluntary deep inspiration breath-hold). Statistical analyses were performed using non-parametric tests and multivariable quantile regression (QR). RESULTS: One hundred five patients completed the study, with 63 evaluable at three months post-RT. Pre- and post-RT biomarkers showed no significant differences. Median pre-RT and post-RT values were: hsTnI (0.012ng/mL; 0.012ng/mL), hsCRP (3.1 mg/L; 2.8 mg/L), and NT-proBNP (59pg/mL; 45pg/mL). Three months post-RT, hsTnI, hsCRP and NT-proBNP levels also showed no significant differences. Multivariable QR revealed no association between heart Dmean [median(IQR): 2.87 Gy (2.05-3.94)] and post-RT biomarkers. Age and BMI were associated with hsCRP and NT-proBNP, respectively. CONCLUSIONS: hsTnI, NT-proBNP, and hsCRP are not correlated with contemporary low cardiac exposure in left-sided breast cancer patients treated with contemporary RT techniques.

#OtoTwitter: The Top 75 Twitter Influencers in Otolaryngology and Association With Academic Impact.

OBJECTIVES: Social media has enabled discussion of relevant topics within otolaryngology. With increasing academic discourse occurring on virtual platforms, it is important to examine who is influencing these discussions. This study thus aims to: (1) identify the top Twitter influencers in otolaryngology and (2) assess the relationship between Twitter influence and academic impact. STUDY DESIGN: Cross-sectional analysis. SETTING: Twitter. METHODS: The Right Relevance program was used to identify and rank the top 75 Twitter influencers, excluding organizations, according to the search terms "otolaryngology," "head and neck surgery," "ear nose throat," "rhinology," "head and neck," "laryngology," "facial plastics," and "otology." Demographic data and h-index were collected for each influencer. Correlational analyzes were performed to assess the relationships between Twitter rank and geographic location, sex, subspecialty, and h-index. RESULTS: The majority of the top 75 influencers were otolaryngologists (87%), female (68%), and located in the United States (61%). General otolaryngology (n = 20, 31%) was more well-represented than any individual subspecialty including facial plastics (n = 10, 15%), rhinology (n = 10, 15%), and neurotology (n = 9, 14%). There was a significant relationship between Twitter rank and h-index (Spearman ρ value of -0.32; 95% confidence interval: -0.51 to -0.01; P = .006). Twitter rank was not significantly correlated with subspecialty, sex, or geographic location (P > .05). CONCLUSION: The majority of Twitter influencers within otolaryngology were otolaryngologists, female, and located in the United States. Social media influence is positively associated with academic impact among otolaryngologists.

Is it too early to recommend local treatment in oligometastatic non-small cell lung cancer: a plea for equipoise.

Oligometastatic non-small cell lung cancer (OMD NSCLC) has been proposed to bridge the spectrum between non-metastatic and widely metastatic states and is perceived as an opportunity for potential cure if removed. Twelve clinical trials on local treatment have been reported, yet none are conclusive. These trials informed the development of a joint clinical practice guideline by the American & European Societies for Radiation Oncology, which endorses local treatment for OMD NSCLC. However, the heterogeneity between prognostic factors within these trials likely influenced outcomes and can only support guidance at this time. Caution against an uncritical acceptance of the guideline is discussed, as strong recommendations are offered based on expert opinion and inconclusive evidence. The guideline is also examined by a patient's caregiver, who emphasizes that uncertain evidence impedes shared decision making.

Identification of variables and development of a prediction model for DIBH eligibility in left-sided breast cancer radiotherapy: a prospective cohort study with temporal validation.

OBJECTIVE: To identify variables associated with a patients' ability to reproducibly hold their breath for deep-inspiration breath-hold (DIBH) radiotherapy (RT) and to develop a predictive model for DIBH eligibility. METHODS: This prospective, single-institution, IRB-approved observational study included women with left-sided breast cancer treated between January 2023 and March 2024. Patients underwent multiple breath-hold sessions over 2-3 consecutive days. DIBH waveform metrics and clinical factors were recorded and analysed. Logistic mixed modelling was used to predict DIBH eligibility, and a temporal validation cohort was used to assess model performance. RESULTS: In total, 253 patients were included, with 206 in the model development cohort and 47 in the temporal validation cohort. The final logistic mixed model identified increasing average breath-hold duration (OR, 95% CI: 0.308, 0.104-0.910. p = 0.033) and lower amplitude (OR, 95% CI: 0.737, 0.641-0.848. p < 0.001) as significant predictors of DIBH eligibility. Increasing age was associated with higher odds of being ineligible for DIBH (OR, 95% CI: 1.040, 1.001-1.081. p = 0.044). The model demonstrated good discriminative performance in the validation cohort with an AUC of 80.9% (95% CI: 73.0-88.8). CONCLUSION: The identification of variables associated with DIBH eligibility and development of a predictive model has the potential to serve as a decision-support tool. Further external validation is required before its integration into routine clinical practice.

Formaldehyde and the transient receptor potential ankyrin-1 contribute to electronic cigarette aerosol-induced endothelial dysfunction in mice.

Electronic nicotine delivery systems (ENDS) aerosol exposures can induce endothelial dysfunction (ED) in healthy young humans and animals. Thermal degradation of ENDS solvents, propylene glycol, and vegetable glycerin (PG: VG), generates abundant formaldehyde (FA) and other carbonyls. Because FA can activate the transient receptor potential ankyrin-1 (TRPA1) sensor, we hypothesized that FA in ENDS aerosols provokes TRPA1-mediated changes that include ED and "respiratory braking"-biomarkers of harm. To test this, wild-type (WT) and TRPA1-null mice were exposed by inhalation to either filtered air, PG: VG-derived aerosol, or FA (5 ppm). Short-term exposures to PG: VG and FA-induced ED in female WT but not in female TRPA1-null mice. Moreover, acute exposures to PG: VG and FA stimulated respiratory braking in WT but not in TRPA1-null female mice. Urinary metabolites of FA (ie, N-1,3-thiazolidine-4-carboxylic acid, TCA; N-1,3-thiazolidine-4-carbonyl glycine, TCG) and monoamines were measured by LC-MS/MS. PG: VG and FA exposures significantly increased urinary excretion of both TCA and TCG in both WT and TRPA1-null mice. To confirm that inhaled FA directly contributed to urinary TCA, mice were exposed to isotopic 13C-FA gas (1 ppm, 6 h). 13C-FA exposure significantly increased the urine level of 13C-TCA in the early collection (0 to 3 h) supporting a direct relationship between inhaled FA and TCA. Collectively, these data suggest that ENDS use may increase CVD risk dependent on FA, TRPA1, and catecholamines, yet independently of either nicotine or flavorants. This study supports that levels of FA in ENDS-derived aerosols should be lowered to mitigate CVD risk in people who use ENDS.

How far are we off? Analyzing the accuracy of surgical margin relocation in the head and neck.

BACKGROUND: Positive surgical margin rates remain high in head and neck cancer surgery. Relocation is challenging given the complex, three-dimensional (3D) anatomy. METHODS: Prospective, multi-institutional study to determine accuracy of head and neck surgeons and pathologists relocating margins on virtual 3D specimen models using written descriptions from pathology reports. Using 3D models of 10 head and neck surgical specimens, each participant relocated 20 mucosal margins (10 perpendicular, 10 shave). RESULTS: A total of 32 participants, 23 surgeons and 9 pathologists, marked 640 margins. Of the 320 marked perpendicular margins, 49.7% were greater than 1 centimeter from the true margin with a mean relocation error of 10.2 mm. Marked shave margins overlapped with the true margin a mean 54% of the time, with no overlap in 44 of 320 (13.8%) shave margins. CONCLUSIONS: Surgical margin relocation is imprecise and challenging even for experienced surgeons and pathologists. New communication technologies are needed.

Virtual 3D Specimen Mapping in Head & Neck Oncologic Surgery.

OBJECTIVES: Virtual 3D specimen mapping of oncologic surgical specimens provides a visual record of the specimen and margin sampling sites which can be utilized in a variety of cancer care settings. Our objective was to perform a retrospective review of head and neck surgical oncology cases where the specimen was mapped post-operatively and to evaluate the utility of these 3D specimen maps amongst the multidisciplinary cancer care team. METHODS: A retrospective review of our 3D specimen model biorepository was performed. Surgical specimens were 3D scanned and then graphically annotated (or "mapped") during routine pathologic processing. The resulting 3D specimen maps were distributed to the multidisciplinary oncologic care team. Final margin status and any use of the 3D specimen maps were recorded. RESULTS: A total of 28 cases were included. Virtual 3D specimen maps were utilized by the cancer care team in 8 cases (29%), including 2 positive margin cases, 2 close margin cases, and 4 indeterminate margin cases. 3D specimen maps were used to visualize positive margin sites for pathologist-surgeon communication as a visual reference during tumor board discussions and to inform radiation treatment planning. CONCLUSION: Post-operative virtual 3D specimen mapping of oncologic specimens creates a permanent visual record of the specimen and the margins sampled and may serve as a beneficial tool for communication amongst the multidisciplinary cancer care team. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:191-197, 2024.

Characterizing gender trends in head and neck fellowship graduates from 2008 to 2018.

OBJECTIVES: Evaluation of potential gender gaps among Head and Neck (H&N) surgeons can highlight areas for increased support of female H&N surgeons and improve gender diversity within the subspecialty. To evaluate gender trends in representation and career trajectory among recent H&N surgery fellowship graduates. METHODS: This cross-sectional analysis included graduates from Head and Neck Surgery fellowships accredited by the American Head and Neck Society (AHNS) from 2008 to 2018. Additional demographic data was collected via publicly available websites including gender, years in practice, practice location, type of practice, h-index, and academic rank. The primary outcomes were the proportion of female Head and Neck fellowship graduates and gender trends in career trajectory and academic productivity (via h-index). RESULTS: Between 2008 and 2018, 449 surgeons graduated from Head and Neck surgery fellowship with females comprising 99 of 449 graduates (22%). Female representation increased from 1 of 30 (3%) graduates in 2008 to 17 of 52 (33%) in 2018. A proportionally similar number of women graduating fellowship also practiced in an academic setting (23%). There were fewer female assistant, associate and full professors compared with their male counterparts. Women had lower h-indices compared with men even when controlling for years in practice (mean 11.4 vs. 8.2, p < 0.03). CONCLUSION: Despite the increase in women graduating from H&N surgery fellowships, gender disparities within academic rank and academic productivity as measured by h-index remain. While a proportional number of women completing fellowship are entering academic practice, additional investigation and support is needed to address the potential gender gaps identified within academic H&N surgery.

Enhanced Communication of Tumor Margins Using 3D Scanning and Mapping.

After oncologic resection of malignant tumors, specimens are sent to pathology for processing to determine the surgical margin status. These results are communicated in the form of a written pathology report. The current standard-of-care pathology report provides a written description of the specimen and the sites of margin sampling without any visual representation of the resected tissue. The specimen itself is typically destroyed during sectioning and analysis. This often leads to challenging communication between pathologists and surgeons when the final pathology report is confirmed. Furthermore, surgeons and pathologists are the only members of the multidisciplinary cancer care team to visualize the resected cancer specimen. We have developed a 3D scanning and specimen mapping protocol to address this unmet need. Computer-aided design (CAD) software is used to annotate the virtual specimen clearly showing sites of inking and margin sampling. This map can be utilized by various members of the multidisciplinary cancer care team.

Ex vivo 3D scanning and specimen mapping in anatomic pathology.

Structured light three-dimensional (3D) scanning is a ubiquitous mainstay of object inspection and quality control in industrial manufacturing, and has recently been integrated into various medical disciplines. Photorealistic 3D scans can readily be acquired from fresh or formalin-fixed tissue and have potential for use within anatomic pathology (AP) in a variety of scenarios, ranging from direct clinical care to documentation and education. Methods for scanning and post-processing of fresh surgical specimens rely on relatively low-cost and technically simple procedures. Here, we demonstrate potential use of 3D scanning in surgical pathology in the form of a mixed media pathology report with a novel post-scan virtual inking and marking technique to precisely demarcate areas of tissue sectioning and details of final tumor and margin status. We display a sample mixed-media pathology report (3D specimen map) which integrates 3D and conventional pathology reporting methods. Finally, we describe the potential utility of 3D specimen modeling in both didactic and experiential teaching of gross pathology lab procedures.

Enhanced Intraoperative Communication of Tumor Margins Using 3D Scanning and Mapping: The Computer-Aided Design Margin.

We have implemented a novel intraoperative communication system for head and neck surgical pathology using 3D scanning technology and computer-aided design (CAD) software. Here, we highlight our CAD margin protocol, in which we 3D scan head and neck oncologic surgical specimens and map frozen section results. This enhances the communication of margin status between surgeons and pathologists and delivers visual anatomic guidance for re-resection when needed. Laryngoscope, 133:1914-1918, 2023.

Risk-Adapted Target Delineation for Breast Cancer: Controversies and Considerations.

The advent of computed tomography-based planning coupled with modern tools for target delineation and hypofractionated treatment schedules has increased efficiency and throughput for patients with breast cancer. While the benefit of adjuvant radiation therapy (RT) in reducing locoregional recurrences is established, disentangling local versus regional recurrence risks with modern treatment protocols has become an area of active research to de-escalate treatment. Delineation guidelines for nodal regions either attempt to replicate results of conventional RT techniques by translating bony landmarks to clinical target volumes or use landmarks based on the fact that lymphatic channels run along the vasculature. Because direct comparisons of both approaches are implausible, mapping studies of nodal recurrences have reported on the proportion of nodes included in these delineation guidelines, and larger, bony, landmark-based guidelines appear intuitively appealing for patients with unfavorable risk factors. A pooled analysis of these studies is reported here, along with literature supporting the exclusion of the true chest wall from postmastectomy/breast-conserving surgery clinical target volumes and the selective (versus routine) use of bolus during postmastectomy RT. The risk-adapted approach suggested here accounts for the risk of recurrence as well as toxicity and endorses nuanced target volume delineation rather than a one-size-fits-all approach.