Lutetium-177-PSMA therapy for recurrent/metastatic salivary gland cancer: a prospective pilot study.

There is an urgent need for novel systemic therapies for recurrent/systemic salivary gland cancer, as current treatment options are scarce. [68Ga]Ga-PSMA-11 PET/CT revealed relevant uptake of prostate-specific membrane antigen (PSMA) in adenoid cystic carcinoma (AdCC) and salivary duct carcinoma (SDC). Therefore, we assessed the safety, feasibility, efficacy and radiation dosimetry of [177Lu]Lu-PSMA-I&T treatment in AdCC and SDC patients in a prospective pilot study. Methods: This single-center, single-arm study intended to include 10 recurrent/metastatic AdCC patients and five recurrent/metastatic SDC patients. AdCC patients could only participate in case of progressive and/or symptomatic disease. Patients required ≥ 1 lesion ≥ 1.5 cm with an SUVmax on [68Ga]Ga-PSMA-11 PET/CT above liver SUVmean. Patients were planned to receive four cycles ~ 7.4 GBq [177Lu]Lu-PSMA-I&T. In case of progressive disease per RECIST 1.1 at mid-treatment evaluation after two cycles, treatment was discontinued. Safety was the primary endpoint. Secondary endpoints included objective response rate (ORR), tumor- and organ-absorbed radiation doses and progression-free survival. Results: After screening, 10 out of 15 (67%) AdCC and two out of 10 (20%) SDC patients were eligible. Two patients (17%) demonstrated grade 3 treatment-related toxicity: lymphocytopenia (8%) and hyponatremia (8%). No dose-limiting toxicities occurred. In the AdCC cohort, six patients (60%) completed the four treatment cycles. Due to progressive disease, treatment was discontinued after two cycles in three patients (30%) and after one cycle in one patient (10%). No objective responses were observed (ORR: 0%). Three AdCC patients (30%) showed stable disease ≥ 6 months (7, 17 and 23 months). None of the two SDC patients completed the treatment: one patient deteriorated after the first cycle, while the other had progressive disease after two cycles. The high screen failure rate due to insufficient PSMA uptake resulted in premature closure of the SDC cohort. Dosimetry revealed low tumor-absorbed doses (median 0.07 Gy/GBq, range 0.001-0.63 Gy/GBq). Conclusions: [177Lu]Lu-PSMA-I&T in AdCC and SDC patients was safe and generally well-tolerated. However, efficacy was limited, likely due to low tumor-absorbed doses. For SDC, [177Lu]Lu-PSMA-I&T appears unfeasible due to insufficient PSMA uptake.

Adenoid cystic carcinoma of trachea mimicking a thyroid follicular tumor: A case report and literature review.

Cervical tracheal adenoid cystic carcinoma (TACC) invading the thyroid gland is very rare and easily misdiagnosed as thyroid tumor, this paper reports a TACC invading thyroid in a 33-year-old woman who had been diagnosed as a thyroid follicular tumor in right lobe of thyroid by sonography and ultrasound guided fine needle aspiration in other hospital. She accepted surgical treatment in our hospital and was diagnosed as TACC by pathology, locally involving the thyroid. This paper presents the patient's clinical data, imaging findings, pathological diagnosis, treatment process and reviews the literature of TACC mimicking a thyroid tumor.

Efficacy of Online Adaptive Radiotherapy Using Surface Guidance in Treatment of Tracheal Adenoid Cystic Carcinoma.

Primary tracheal tumors are rare, with adenoid cystic carcinoma (ACC) of the trachea being the second most common malignancy of the trachea. Radical surgical resection is found to have better survival outcomes in tracheal ACC. However, with higher submucosal spread rates in tracheal ACC and the inability to achieve clear margins, complete resection is not usually achievable. In these cases, the use of a 60-70 Gy radiation dose is deemed to be sufficient for definitive treatment with or without concurrent chemotherapy. We report a case of an unresectable ACC treated with online daily adaptive cone beam computed tomography (CBCT) radiotherapy on Ethos™ (Varian Medical Systems, Palo Alto, CA). She was planned to receive 59.4 Gy in 33 fractions in two phases. For daily treatment delivery, the patient was set up on the couch using the surface-guided radiotherapy (SGRT) system of AlignRT™ (Vision RT Ltd., London, UK) and translated to the treatment isocenter. A CBCT scan was acquired, followed by rigid registration with the planning scan and PET CT. Organs at risk (OAR) and primary targets were auto-generated by the AI in a two-step process, reviewed, and edited by the radiation oncologist. Adapted and scheduled plans were compared regarding planning target volume (PTV) coverage and dose to OAR. Better PTV coverage was seen in 26 of 33 fractions with the adapted plan. On the days with lesser coverage, adapted plans demonstrated improvement in the hotspot reduction and reduction in hard dose constraints of the esophagus and lungs. Hence, adapted plans were selected for all treatment days. Our results highlight the superior target coverage and improved OAR-sparing plans in daily online adaptive radiotherapy (o-ART) compared to image-guided radiotherapy (IGRT) plans. The system's ability to adapt to daily anatomical changes, improved target coverage, and better sparing of OARs make it an encouraging option for malignancies requiring motion management.

The effectiveness of targeted therapy for recurrence or metastasis adenoid cystic carcinoma: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Several clinical studies have demonstrated the potential of molecular-targeted agents for the treatment of recurrent or metastatic adenoid cystic carcinoma (R/M ACC). However, there is currently no consensus regarding the efficacy of molecular-targeted agents for patients with R/M ACC. This study aimed to evaluate the therapeutic efficacy and safety of molecular-targeted agents in patients with R/M ACC and provide insights to guide clinical decision-making. MATERIALS AND METHODS: Five databases (PubMed, Embase, Cochrane, ProQuest, and Scopus) were searched based on the search strategy and selection criteria. Primary endpoints were objective response rate (ORR) and progression-free survival (PFS). The secondary endpoints were disease control rate (DCR), overall survival (OS), metastatic sites, and adverse events (AE). Pooled estimates were calculated using a random-effects meta-analysis. RESULTS: Finally, 28 studies, involving 849 patients, were included. The most common metastatic sites were the lungs, bones, liver, lymph nodes, and kidneys. The pooled ORR was 4.0% (95% CI, 0.7-8.8%), the pooled DCR was 80.5% (95% CI, 72.2%-87.7%). Compared with other-target drugs, multiple kinase inhibitors (MKIs) improved the ORR (pooled ORR for single-target drugs vs. MKIs: 5.9% vs. 0%). The combination of MKIs and immune checkpoint inhibitors (ICIs) had a significantly higher ORR (17.9% in the axitinib + avelumab group). The pooled median PFS and OS were 8.35 and 25.62 months, respectively. MKIs improved the median PFS compared to other-target drugs (9.43 months vs 5.06 months). In addition, the most common adverse events (AEs) were fatigue (51.6%), hypertension (44.2%), and nausea (40.0%), followed by hand-foot skin syndrome (36.8%), diarrhoea (34.4%), weight loss (34.2%), anorexia (31.8%), rash (31.7%), and headache (29.0%). CONCLUSION: The findings of this study suggest that MKIs have a better therapeutic efficacy than single-target drugs in patients with R/M ACC. Future studies are warranted to verify the synergistic role of the combination strategy of MKIs plus ICIs, given the limited number of studies on this topic conducted and published to date.

Adenoid Cystic Carcinoma with Sebaceous Differentiation and MYB::NFIB Fusion Arising in the External Auditory Canal.

Adenoid cystic carcinoma arising in the external auditory canal is rare, and even rarer are cases with sebaceous differentiation mimicking sebaceous carcinoma. This case with clinical, radiologic, gross, and histologic images exemplifies an unusual occurrence of adenoid cystic carcinoma in the external auditory canal with sebaceous differentiation, confirmed by MYB::NFIB fusion.

Evaluation of Dentofacial Angles in Children with Severe Adenoid Hypertrophy.

Introduction: Hypertrophy of adenoids is a common condition in childhood, resulting in obstructive symptoms such as sleep apnea, snoring, and rhinosinusitis. Adenotonsillectomy is recommended to improve prognosis and quality of life. This case-control study compared facial angles and lip position related to dentofacial and mouth growth in symptomatic children with adenoid hypertrophy and asymptomatic control groups. Materials and Methods: The study included children aged 5 to 7 who presented with obstructive symptoms and confirmed severe adenoid hypertrophy in lateral neck radiography. Standard lateral photography was taken. The Nasofacial and Nasomental angles, and upper and lower lip positions and their distance behind the Ricketts line, were measured and compared with the normal control group. Results: This study included 54 children with severe adenoid hypertrophy and 66 normal children. Facial angles were not significantly different between the two groups, but the mean horizontal position of the upper and lower lip in children with adenoid hypertrophy was significantly lower than in the control group (P value = 0.05). The lips were too close to the Ricketts line compared with the control group. Conclusions: This research demonstrates that children with severe adenoid hypertrophy have more dentofacial disorders than others. Adenotonsillectomy surgery is necessary for children with obstructive symptoms caused by tonsil enlargement, and if symptoms like snoring persist post-surgery, complementary orthodontic treatments should be considered.

Beyond mitochondrial transfer, cell fusion rescues metabolic dysfunction and boosts malignancy in adenoid cystic carcinoma.

Cancer cells with mitochondrial dysfunction can be rescued by cells in the tumor microenvironment. Using human adenoid cystic carcinoma cell lines and fibroblasts, we find that mitochondrial transfer occurs not only between human cells but also between human and mouse cells both in vitro and in vivo. Intriguingly, spontaneous cell fusion between cancer cells and fibroblasts could also emerge; specific chromosome loss might be essential for nucleus reorganization and the post-hybrid selection process. Both mitochondrial transfer through tunneling nanotubes (TNTs) and cell fusion "selectively" revive cancer cells, with mitochondrial dysfunction as a key motivator. Beyond mitochondrial transfer, cell fusion significantly enhances cancer malignancy and promotes epithelial-mesenchymal transition. Mechanistically, mitochondrial dysfunction in cancer cells causes L-lactate secretion to attract fibroblasts to extend TNTs and TMEM16F-mediated phosphatidylserine externalization, facilitating TNT formation and cell-membrane fusion. Our findings offer insights into mitochondrial transfer and cell fusion, highlighting potential cancer therapy targets.

Update on the Treatment of Salivary Gland Carcinomas.

Salivary gland carcinoma is a rare form of head and neck carcinoma, but it comprises a variety of subsites and histologic subtypes that each present with unique clinical courses and management challenges. Preoperative work-up generally consists of fine-needle aspiration cytology and MRI. However, because of the large variety of subtypes, there are often challenges obtaining a histologic diagnosis before surgery. Upfront surgery at the primary site leads to the greatest improvement in survival. Posttreatment surveillance of these patients is important. This article discusses some of the current controversies in the management of salivary gland carcinomas.

Pseudonormal Morphology of Salivary Gland Adenoid Cystic Carcinoma Cells Subverts the Antitumor Reactivity of Immune Cells: A Tumour-Cell-Based Initiation of Immune Evasion.

INTRODUCTION: Salivary gland adenoid cystic carcinoma (ACC), mucoepidermoid carcinoma (MEC) and oral squamous cell carcinoma (OSCC) occurs within the head and neck region. So far immune check point inhibitors failed in ACC. Gipie (CCDC88B) is a microtubule linker protein that activates immune cells. Gipie expressions found in head and neck cancer cells. We hypothesised that the presence of Gipie diminishes anti-tumour reactivity of immune cells towards head and neck cancer. METHOD: To determine the effect of Gipie in oral and salivary gland cancer cells, Gipie was silenced in cancer cells in cancer-immune cells co-culture models and we performed 3D Z series confocal imaging, annexin V and immune activation flow cytometry, proteome profiler and discovery phase proteomics. RESULTS: ACC cells morphed into pseudonormal morphology in immune co-culture models. Silencing Gipie in ACC cells showed significant increase of apoptotic cells and activated natural killer cells, and lowering of regulatory T cells. Other salivary and oral cancer cells showed negligible effect of Gipie. Proteome profiler and proteomics assay confirmed Gipie affecting proliferation mechanism and immune activated proteins in ACC immune co-culture models. CONCLUSION: Overall, we conclude that the presence of Gipie has a confounding role during the ACC-immune cell interaction.

Successful carinal reconstruction with right main bronchial flap rotational embedded augmentation: a case report.

Background: Tracheo-carinal resection and reconstruction in cases of extensive malignant tumors present a significant surgical challenge, often complicated by high anastomotic tension and potential for incomplete anastomosis. Case Description: We report on a 45-year-old male with a primary adenoid cystic carcinoma. The tumor was about 3 cm in size and invaded about 1 cm of the lower trachea, 2 cm of the left main bronchus (LMB), and 1 cm of the right main bronchus (RMB), blocking about 70% of the tracheal lumen, 90% of the LMB, and 50% of the RMB. Resection of the lower trachea and part of the LMB and RMB was performed via the right chest. We used the right main bronchial flap as a bridge, suturing it separately to the lower tracheal segment and the LMB, thereby completing the carinal reconstruction. This technique was crucial for bridging the defect between the trachea and LMB, which was impossible to anastomose directly due to the tumor's extensive involvement. The elliptical-shaped lingual flap from the RMB provided a stable and tension-free foundation for the reconstruction, overcoming the limitations of conventional methods. Conclusions: The novel carinal reconstruction technique demonstrated a reliable alternative for complex tracheo-carinal defects, ensuring tension-free anastomosis and complete tumor resection with clear margins.

Automatic detection of adenoid hypertrophy on lateral nasopharyngeal radiographs of children based on deep learning.

Background: Adenoid hypertrophy is a prevalent cause of upper airway obstruction in children, potentially leading to various otolaryngological complications and even systemic sequelae. The lateral nasopharyngeal radiograph is routinely employed for the diagnosis of adenoid hypertrophy. This study aimed to evaluate the accuracy and reliability of deep learning, using lateral nasopharyngeal radiographs, for the diagnosis of adenoid hypertrophy in pediatric patients. Methods: In the retrospective study, the lateral nasopharyngeal X-ray images were collected from children receiving therapy in the Children's Hospital of Soochow University, the 983th Hospital of Joint Logistics Support Forces of Chinese PLA and the Suzhou Wujiang District Children's Hospital from January 2023 to November 2023. Five deep learning models, i.e., AlexNet, VGG16, Inception v3, ResNet50 and DenseNet121, were used for model training and validation. Receiver operating characteristic (ROC) curve analyses were used to evaluate the performance of each model. The best algorithm was compared with interpretations from three radiologists on 208 images in the internal validation group. Results: The lateral nasopharyngeal X-ray images were collected from 1,188 children, including 705 males (59.3%) and 483 females (40.7%), aged 8 months to 13 years, with a mean age of 5.57±2.66 years. Among the five deep learning models, DenseNet-121 performed the best, with area under the curve (AUC) values of 0.892 and 0.872, with accuracy of 0.895 and 0.878, sensitivity of 0.870 and 0.838, and specificity of 0.913 and 0.906 in the internal and external validation groups, respectively. The diagnostic performance of DenseNet-121 was higher than that of the junior and mid-level radiologists (0.892 vs. 0.836, 0.892 vs. 0.869), close to the senior radiologist (0.892 vs. 0.901). However, Delong's test revealed no significant difference between DenseNet121 and each radiologist in the validation group (P=0.24, P=0.52, P=0.79). Conclusions: All the five deep learning models in the study showed good performance for the diagnosis of adenoid hypertrophy, with DenseNet121 being the best, which was clinically relevant for the automatic identification of adenoid hypertrophy.

Breast cylindroma: A rare and unexpected diagnosis.

Cylindroma is a benign adnexal tumor histologically characterized by clusters of small basaloid cells arranged in a pattern resembling a jigsaw puzzle. Breast cylindromas are extremely rare with approximately 20 reported cases throughout literature. We present a case of a 71-year-old female with a slow growing cystic breast mass, originally identified 8 years prior to biopsy. Mammography and ultrasound demonstrated features of a simple cyst with circumscribed margins and anechoic internal echogenicity, respectively. Biopsy was performed due to increase in size, revealing the pathologic entity of cylindroma. The patient ultimately underwent surgical excision, which confirmed the diagnosis. We discuss the radiology, pathology and clinical course of breast cylindroma.

Adenoid cystic carcinoma: insights from molecular characterization and therapeutic advances.

Adenoid cystic carcinoma (ACC) is a malignant tumor primarily originating from the salivary glands, capable of affecting multiple organs. Although ACC typically exhibits slow growth, it is notorious for its propensity for neural invasion, local recurrence, and distant metastasis, making it a particularly challenging cancer to treat. The complexity of ACC's histological and molecular features poses significant challenges to current treatment modalities, which often show limited effectiveness. Recent advancements in single-cell RNA-sequencing (scRNA-seq) have begun to unravel unprecedented insights into the heterogeneity and subpopulation diversity within ACC, revealing distinct cellular phenotypes and origins. This review delves into the intricate pathological and molecular characteristics of ACC, focusing on recent therapeutic advancements. We particularly emphasize the insights gained from scRNA-seq studies that shed light on the cellular landscape of ACC, underscoring its heterogeneity and pathobiology. Moreover, by integrating analyses from public databases, this review proposes novel perspectives for advancing treatment strategies in ACC. This review contributes to the academic understanding of ACC by proposing novel therapeutic approaches informed by cutting-edge molecular insights, paving the way for more effective, personalized therapeutic approaches for this challenging malignancy.

Disparities in pediatric parotid cancer treatment and presentation: A National study.

OBJECTIVES: Although parotid gland malignancies are uncommon, they nevertheless represent a cause of morbidity and mortality in the pediatric population. Few studies have sought to identify disparities related to their presentation, treatment, and survival. There is a need to understand these variations to improve care for historically underrepresented groups. STUDY DESIGN: Retrospective Cohort Study. SETTING: Surveillance, Epidemiology, and End Results (SEER) Program Database. METHODS: Analysis of pediatric patients with parotid gland malignancies between 2000 and 2019. Race and ethnicity were classified as Non-Hispanic White, Non-Hispanic Black, Asian, and Hispanic for multivariable analysis. Outcomes included tumor size and stage at diagnosis, survival, and need for facial nerve sacrifice. Kaplan-Meier analysis was used to analyze survival. Multivariable logistic regression was conducted to identify predictors of outcomes. RESULTS: 149 patients met the criteria for inclusion. Stratified by race/ethnicity, Non-Hispanic Black (Median 23 mm, IQR 15-33), Asian (30 mm, 14-32), and Hispanic (23 mm, 20-28) patients had larger tumors at presentation than Non-Hispanic White patients (18 mm, 12-25, p = 0.017). Disease-specific survival differed by time-to-treatment (log-rank, p = 0.01) and overall survival differed by income (p < 0.001). On multivariable analysis, Hispanic patients were more likely to experience facial nerve sacrifice (OR 3.71, 95%CI 1.25-11.6, p = 0.020), and Non-Hispanic Black (OR 3.37, 0.95-11.6, = 0.053) and Asian (OR 5.67, 1.46-22.2, p = 0.011) patients presented with larger tumors compared to Non-Hispanic White patients. CONCLUSIONS: Variations in presentation and treatment exist across race and ethnicity in pediatric parotid cancer. Identifying these disparities may help improve access and outcomes for underserved patient populations. LEVEL OF EVIDENCE: III.

An Uncommon Case of Sinonasal Adenoid Cystic Carcinoma Metastatic to the Kidney Treated with Metastasectomy.

Adenoid cystic carcinoma (ACC) is a rare tumor, accounting for 1% of all head and neck cancers, with an aggressive nature characterized by local recurrence, delayed metastasis, and survival of less than 50% at 10 years. This is a case of biopsy-proven ACC to the kidney, 1 of 29 known occurrences, managed by metastasectomy by robotic-assisted nephrectomy, with plans for resection of lung metastasis. Thirteen years after diagnosis of sinonasal ACC treated with resection, the patient presented with shortness of breath. This prompted a CT scan of the chest, which led to the incidental finding of left renal mass and pulmonary lesion. Literature suggests improved disease-specific survival in locoregional recurrence treated with surgery versus radiation; in patients with metastasis to the lung, metastasectomy offers greater survival benefit than supportive therapy. But, this is not significantly better than chemotherapy or radiation alone. While the optimal therapeutic approach remains to be identified in distant metastatic ACC, metastasectomy remains a viable option for patients who have potentially completely resectable metastatic tumors, appropriate performance status, and adequate affected-organ function. Preoperative counseling should include discussion on partial nephrectomy with prioritization of nephron-sparing but potential for increased perioperative risk versus radical nephrectomy to ensure negative margins and expedite timeline to systemic therapy.

CCL2/CCR2 axis promotes perineural invasion of salivary adenoid cystic carcinoma via ITGß5-mediated nerve-tumor interaction.

Perineural invasion (PNI) is a notorious feature of salivary adenoid cystic carcinoma (SACC) and other neurotropic tumors. The pathogenesis of PNI that involves the molecular communication between the tumor and the suffered nerve is elusive. The in vitro co-culture assays of SACC cells with dorsal root ganglia (DRG) or neural cells showed that nerve-derived CCL2 activated CCR2 expression in SACC cells, promoting the proliferation, adhesion, migration, and invasion of SACC cells via the ERK1/2/ITGß5 pathway. Meanwhile, SACC-derived exosomes delivered ITGß5 to promote the neurite outgrowth of neural cells or DRG. Blocking of CCL2/CCR2 axis or ITGß5 inhibited the PNI of SACC cells in models in vitro by 3D co-culture of DRG with SACC cells and in vivo by xenografting SACC cells onto the murine sciatic nerve. High levels of ITGß5 in tissues or plasma exosomes were significantly correlated with CCL2 and CCR2 expression in the tissues and associated with PNI and poor prognosis of SACC cases. Our findings revealed a novel reciprocal loop between neural and tumor cells driven by the CCL2/CCR2 axis and exosomal ITGß5 during PNI of SACC. The present study may provide a prospective diagnostic and anti-PNI treatment strategy for SACC patients via targeting the nerve-tumor interactions.

Unveiling the Spectrum of Otorhinolaryngological Manifestations in Siblings With Bardet-Biedl Syndrome: A Report of Two Cases.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterized by diverse multisystem manifestations. This report discusses the unique otorhinolaryngological challenges faced by two pediatric siblings diagnosed with BBS. Case 1 involves a child with a history of chronic snoring, delayed developmental milestones, and a low intelligence quotient (IQ). The patient presented with obesity, retinitis pigmentosa, and a rare bifid epiglottis, adding to the complexity. Adenotonsillectomy was indicated due to chronic adenotonsillitis, but the presence of a grade 4 Mallampati score and restricted mouth opening required meticulous planning by the surgical and anesthesia teams. The collaborative approach led to a successful procedure, emphasizing the importance of interdisciplinary coordination in managing complex cases. Case 2, the younger sibling, presented with disturbed sleep cycles, mouth breathing, and difficulty swallowing. Adenotonsillectomy was performed for chronic adenotonsillitis, providing relief initially. However, recurrent adenoid hypertrophy, covering 90% of choanae, manifested two years later. The case highlights the need for long-term follow-up and raises questions about the underlying mechanisms contributing to recurrent adenoid hypertrophy in BBS. These cases underscore the rarity and intricacy of otorhinolaryngological manifestations in BBS, emphasizing the importance of comprehensive and multidisciplinary management. The challenges posed by anatomical abnormalities and recurrent adenoid hypertrophy necessitate ongoing research for effective long-term strategies in treating these complex genetic conditions. These findings contribute to the limited literature on BBS within the otorhinolaryngology domain and underscore the significance of continued collaboration and research efforts in optimizing patient care.

Subglottic adenoid cystic carcinoma associated with pulmonary Langerhans cell histiocytosis.

Pulmonary Langerhans cell histiocytosis can be associated with subglottic adenoid cystic carcinoma.