Clinical, genomic and immune microenvironmental determinants of nivolumab response in head and neck squamous cell carcinoma.

Background: In view of improving biomarkers predicting the efficacy of immunotherapy for head and neck squamous cell carcinoma (R/M HNSCC), this multicenter retrospective study aimed to identify clinical, tumor microenvironmental, and genomic factors that are related to therapeutic response to the anti- Programmed cell death protein 1 (PD-1) antibody, nivolumab, in patients with R/M HNSCC. Methods: The study compared 53 responders and 47 non-responders, analyzing formalin-fixed paraffin-embedded samples using 14-marker multiplex immunohistochemistry and targeted gene sequencing. Results: Of 100 patients included, responders had significantly lower smoking and alcohol index, higher incidence of immune related adverse events, and higher PD-1 ligand (PD-L1) expression in immune cells as well as PD-L1 combined positive score (CPS) than non-responders. The frequency of natural killer cells was associated with nivolumab response in patients with prior cetuximab use, but not in cetuximab-naïve status. Age-stratified analysis showed nivolumab response was linked to high CPS and lymphoid-inflamed profiles in patients aged ≥ 65. In contrast, lower NLR in peripheral blood counts was associated with response in patients aged < 65. Notably, TP53 mutation-positive group had lower CPS and T cell densities, suggesting an immune-excluded microenvironment. Patients with altered tumor suppressor gene pathways, including TP53, CDKN2A, and SMAD4 mutations, had lower CPS, higher smoking index, and were associated with poor responses. Conclusion: Nivolumab treatment efficacy in HNSCC is influenced by a combination of clinical factors, age, prior treatment, immune environmental characteristics, and gene mutation profiles.

NF1 with 47,XYY mosaicism diagnosed by mandibular neurofibromas.

Neurofibromatosis type 1 (NF1) is an autosomal dominant nevus disease characterized by multiple manifestations, primarily café-au-lait macules and neurofibromas. Here, we present the case of an NF1 patient with 47,XYY mosaicism whose diagnosis was prompted by café-au-lait macules on the skin and mandibular neurofibromas. Targeted next-generation sequencing of the patient's blood sample revealed a novel frameshift mutation in NF1 (NM_000267.3:c.6832dupA:p.Thr2278Asnfs*8) that is considered a pathogenic variant.

Long- term outcomes of congenital tracheal stenosis after slide tracheoplasty.

PURPOSE: Long-term outcomes of slide tracheoplasty in patients with congenital tracheal stenosis (CTS) have rarely been reported. This study aimed to clarify the long-term outcomes of CTS after slide tracheoplasty. METHODS: The medical records of 33 patients who underwent slide tracheoplasty for CTS at our institution between January 2005 and July 2018, with a follow-up duration > 5 years, were retrospectively reviewed. Patients' characteristics, perioperative condition, operative management, postoperative course, tracheal stenosis rates and growth data, were collected from medical records. RESULTS: The median operative age, minimum tracheal diameter, length of stenosis, duration of hospital stays, and follow-up duration were 8 months, 2.4 mm, 35 mm, 39 days, and 90 months, respectively. One patient died of bleeding in the right lung at 126 months postoperatively. Among the 10 patients requiring postoperative tracheostomy, seven were successfully decannulated at a median of 65 months postoperatively. Tracheal stenosis rates improved postoperatively and were subsequently maintained. Growth impairment and psychomotor delay were observed in 9 and 16 patients, respectively with significant differences found only in cases with genetic abnormalities and not in tracheal stenosis severity. CONCLUSION: Slide tracheoplasty for CTS leads to favorable long-term outcomes. However, various associated anomalies may influence growth and psychomotor development, emphasizing the importance of adequate support.

Incidence of congenital tracheal stenosis in left pulmonary artery sling diagnosed by bronchoscopy.

PURPOSE: Congenital tracheal stenosis (CTS) has been reported to occur in 50-65% of cases of left pulmonary artery sling (LPAS), but the exact incidence rate is unknown. This study aimed to determine the actual rate using bronchoscopy and to elucidate morphological features in computed tomography (CT) diagnosis. METHODS: We performed a single institutional retrospective review of all patients with LPAS between January 2010 and March 2022. The percentage of complete tracheal rings in patients with LPAS was evaluated using bronchoscopy. The anteroposterior/lateral diameter ratios at the smallest and largest diameters of each CTS patient's trachea were measured on CT. The Wilcoxon signed-rank test was used to analyze the differences between the two parts. RESULTS: Fifty-two patients with LPAS were enrolled. All patients had complete tracheal rings on bronchoscopy. CT analysis of 32 patients with CTS was performed. The median anteroposterior/lateral diameter ratio at the smallest diameter was 1.05 (interquartile range [IQR] 0.95-1.15); the median ratio at the largest diameter was 0.94 (IQR 0.89-0.99). There was a significant difference between the two parts (p = 0.013). CONCLUSION: CTS might be universally associated with LPAS. The circular tracheal cross-section on CT might imply the existence of a complete tracheal ring.

Clinical features of a tracheoesophageal fistula associated with complete tracheal rings.

PURPOSE: A tracheoesophageal fistula (TEF) associated with complete tracheal rings (CTR) is extremely rare. This study aimed to elucidate the clinical features of this combination. METHODS: Records of 39 patients diagnosed with TEF with or without CTR between January 2013 and February 2023 were retrospectively reviewed. Data collected included location of the TEF and CTR, esophageal gap, surgery of TEF/esophageal atresia (EA), and symptoms of CTR. RESULTS: Seven patients had CTR, while 32 patients did not have CTR. TEF was frequently located higher than the T4 vertebra, and the median esophageal gap was shorter in patients with CTR than in those without (5/7 [71.4%] vs. 6/32 [18.8%], P = 0.012; 0 (range: 0-15) mm vs. 13.3 (range: 0-40) mm, P = 0.017, respectively). TEF was located just above the beginning of the CTR in all patients. All patients with CTR underwent primary esophageal anastomosis. Additionally, two patients were diagnosed with CTR before TEF/EA repair. A tracheal tube was prevented from contacting the CTR during TEF/EA repair, and respiratory insufficiency did not occur. CONCLUSIONS: Our results may help pediatric surgeons in the management of TEF with CTR.

Spindle cell sarcoma with KIAA1549-BRAF resembling infantile fibrosarcoma morphologically: A case report and literature review.

Infantile fibrosarcoma (IFS) commonly harbors ETS variant transcription factor 6 (ETV6)-neurotrophic receptor tyrosine kinase 3 (NTRK3) fusion. However, the recent accessibility to clinical next-generation sequencing (NGS) has revealed ETV6-NTRK3 negative spindle cell sarcomas resembling IFS morphologically, involving NTRK1/2, MET, RET and BRAF. The present report describes a pediatric case of spindle cell sarcoma with KIAA1549-BRAF resembling IFS morphologically. A 20-month-old female patient was referred to Kobe Children's Hospital (Kobe, Japan) for the treatment of intrathoracic spindle cell sarcoma. Pathologically, the intrathoracic tumor cells were composed of spindle cells with focal hemagiopericytomatous pattern. In immunohistochemistry analysis, the intrathoracic tumor cells focally expressed desmin and WT-1 and were negative for pan-tropomyosin receptor kinase (TRK), S-100 and CD34. Fluorescence in situ hybridization analysis for ETV6 and capicua transcriptional repressor revealed negative split signals. Although the patient was initially diagnosed with IFS morphologically, KIAA1549-BRAF fusion transcript was detected by comprehensive genomic profiling with NGS using intrathoracic tumor tissues and confirmed by reverse transcription-PCR. Chemotherapy induced a reduction in the tumor size. At present, the patient is alive with the disease and has been receiving therapy for 8 months since the initiation of chemotherapy. Review of BRAF-altered spindle cell sarcomas resembling IFS morphologically revealed the inconsistency in immunohistochemical expression patterns and the diversity of BRAF fusion genes and mutations. Therefore, the elucidation of genomic profiling by NGS may assist in making an appropriate diagnosis and selecting novel alternative therapies in ETV6-NTRK3-negative spindle cell sarcomas resembling IFS morphologically.

Changes in postoperative quality of life of pediatric total colonic aganglionosis patients: effect of pull-through technique.

AIM: To assess mid-/long-term quality of life (QOL) of total colonic aganglionosis (TCA) patients. METHODS: Modified pre-existing QOL assessment tools for general lifestyle (GL), bowel function (BF), and mental health (MH) were administered to postoperative TCA patients from five institutions, who were at least 7 years old to compare Duhamel (with pouch) and Swenson/Soave (without pouch) techniques between children (Ch 7-12 years old), teenagers (Tn 13-19), and adults (Ad 20 and over). For MH, caregivers were also interviewed, but separately. Maximum scores were 12 for GL/MH and 18 for BF. RESULTS: There were 32 subjects. GL and BF scores increased significantly from Ch (GL 4.8 ± 2.5, BF: 11.3 ± 4.6) to Tn (GL 7.8 ± 2.6, BF 16.2 ± 3.0); scores for MH did not change significantly. Mean caregiver MH scores were significantly lower than mean subject MH scores for all age groups (subject scores: 10.1, 10.7, 10.7 versus caregiver scores: 6.8, 7.8, 8.1 for Ch, Tn, Ad, respectively). PT technique/presence of a pouch did not influence the incidence of enterocolitis or QOL scores. CONCLUSION: MH responses showed subjects felt better than caregivers believed. This discrepancy could cause conflict despite steadily improving GL/BF. QOL was unaffected by PT technique/presence of a pouch.

Quality of life after type-A esophageal atresia surgery: changes over time and effect of pre-anastomotic elongation.

AIM: To assess mid-/long-term postoperative quality of life (QOL) of esophageal atresia (EA) patients. METHODS: Modified gastrointestinal quality-of-life index surveys were administered to postoperative EA patients who were at least 7 years old at evaluation to assess three topics about general lifestyle (GL), five topics about EA, and four topics about mental health (MH). For MH, caregivers were also interviewed, but separately. Subjects were divided according to age: children (7-12 years old), teenagers (13-19), and adults (20 and over) and compared according to Foker or Kimura elongation (FK) or bougienage stretching (BS). RESULTS: There were 22 patients evaluated. Responses for GL, EA, and MH did not differ significantly between age groups, but MH responses by caregivers for subjects who were children or teenagers scored significantly lower than responses they made themselves. For primary esophageal elongation technique (PET), age at esophagoesophagostomy was significantly higher in FK. Despite FK scoring 15.1 versus 12.4 for BS during EA evaluation, this difference was not statistically significant. CONCLUSION: Changes in QOL responses according to age were unremarkable. However, discrepancies in MH indicate that subjects felt better than their caregivers thought. PET did not appear to influence QOL.

Surgical management of congenital tracheal stenosis associated with complex cardiovascular anomalies.

PURPOSE: Although surgical outcomes have improved in patients with congenital tracheal stenosis (CTS), the management of such patients with complex cardiovascular anomalies (CVAs) remains a challenge. This study aimed to clarify the clinical features of this combination. METHODS: Medical records of 14 patients with complex CVAs who had undergone slide tracheoplasty for CTS between May 2016 and February 2022 were retrospectively reviewed. Complex CVAs were defined as CVAs without left pulmonary artery sling and simple cardiac shunts. Data collected included age and body weight at tracheal reconstruction, preoperative respiratory support, surgery details, and mortality. RESULTS: The median age and body weight at tracheal reconstruction were 3.5 (range, 1-17) months and 4.7 (range, 2.3-8.2) kg, respectively. Simultaneous repair of CTS and CVAs was performed in eight patients and staged repair in six patients. Patients who underwent simultaneous repair required preoperative respiratory support more frequently than those who underwent staged repair (8/8 [100%] vs 2/6 [33.3%]; P = 0.015). No mortality occurred. CONCLUSIONS: Patients with complex CVAs often require tracheal reconstruction in early infancy. Surgical management strategy for this combination was generally decided on the basis of the severity of respiratory symptoms due to CTS.

Computational fluid dynamics assessment of congenital tracheal stenosis.

PURPOSE: The severity of congenital tracheal stenosis (CTS) is commonly evaluated based on the degree of stenosis. However, it does not always reflect the clinical respiratory status. We applied computational fluid dynamics (CFD) to the assessment of CTS. The aim of this study was to evaluate its validity. METHODS: CFD models were constructed on 15 patients (12 preoperative models and 15 postoperative models) with CTS before and after surgery, using the computed tomographic data. Energy flux, needed to drive airflow, measured by CFD and the minimum cross-sectional area of the trachea (MCAT) were quantified and evaluated retrospectively. RESULTS: The energy flux correlated positively with the clinical respiratory status before and after surgery (rs = 0.611, p = 0.035 and rs = 0.591, p = 0.020, respectively). Although MCAT correlated negatively with the clinical respiratory status before surgery (rs = -0.578, p = 0.044), there was not significant correlation between the two after surgery (p = 0.572). CONCLUSIONS: The energy flux measured by CFD assessment reflects the respiratory status in CTS before and after surgery. CFD can be an additional objective and quantitative evaluation tool for CTS.

Airway performance in infants with congenital tracheal stenosis associated with unilateral pulmonary agenesis: effect of tracheal shape on energy flux.

Congenital tracheal stenosis (CTS) with unilateral pulmonary agenesis (UPA) is characterized by the absence of one or both lungs in the hemithorax and is often associated with airway distortion. Some UPA patients have high mortality and morbidity even postoperatively, and it remains unclear whether surgery increases the energy flux needed to drive airflow. Here, we used pre- and postoperative patient-specific airway models to numerically investigate tracheal flow in patients with CTS, especially flow associated with right UPA (CTS-RUPA). Airflow was simulated with the large-eddy model, and energy flux was investigated to quantify airway performance and the contribution of surgical intervention. Although energy flux decreased postoperatively, clinical respiratory status did not improve. Standard surgical intervention for CTS, which expands the minimal cross-sectional area, decreased energy flux, i.e., improved airway performance. The simulation also included artificial airways with a straightened bend or reduced tracheal lumen roughness. The numerical results clearly showed interindividual differences in the percent reduction of energy flux caused by straightening the tracheal bend versus correcting tracheal lumen roughness. Although this study was limited to small sample size, these numerical results indicated that energy flux alone is insufficient to evaluate breathing performance in patients with CTS-RUPA but it can be used to estimate airway performance.

Changes in the condylar volume and skeletal relapse following orthognathic surgery in patients with dentofacial deformity: A retrospective study.

OBJECTIVE: To evaluate the relationship between the changes in condylar volume and maxillofacial skeletal morphology according to sex as well as the relationship between condylar volume reduction and skeletal relapse in patients who underwent orthognathic surgery. METHODS: Ninety-five patients were categorized into skeletal Class III, Class II, and facial asymmetry groups. Computed tomography scans taken preoperatively and at 1 year postoperatively were used for quantitative measurement. RESULTS: Postoperative condylar volume was reduced in both the Class II group and the deviated side of the asymmetry group. Both female and Class II deformity were significant predictors of postoperative reduction in the condylar volume. There was a significant correlation between skeletal relapse and postoperative change in condylar volume in the Class II group. CONCLUSION: Postoperative condylar resorption may be associated with preoperative maxillofacial skeletal morphology and sex and also with skeletal relapse in the Class II group.

Surgical outcomes of pulmonary artery sling and congenital tracheal stenosis with right lung anomaly.

OBJECTIVES: This study aimed to investigate whether computed tomographic indices support surgical decision-making in patients with pulmonary artery sling, congenital tracheal stenosis and right lung underdevelopment. METHODS: A total of 38 patients with pulmonary artery sling and congenital tracheal stenosis underwent tracheoplasty. Patients were divided into 3 groups based on anatomical categorization: group normal lung (NL; n = 21), group H (right lung hypoplasia, n = 12) and group A (right lung agenesis or aplasia, n = 5). Using preoperative computed tomographic images, the severity of the tracheal bending due to the right posterior deviation of the aortic arch and the relative length of the left pulmonary artery for reimplantation was evaluated. RESULTS: Slide tracheoplasty posterior to the aortic arch with pulmonary artery reimplantation was performed in 32 patients (21, 10 and 1 in groups NL, H and A, respectively). Slide tracheoplasty anterior to the aortic arch was performed in 4 patients (2 patients each in groups H and A). Among the 6 patients with severe tracheal bending who underwent slide tracheoplasty posterior to the aortic arch, 5 required aortopexy for tracheomalacia. The overall mortality rate was 3% (group NL, n = 1). The relative length of the left pulmonary artery in group H (0.85) was significantly shorter than that in group NL (1.36, P < 0.0001). CONCLUSIONS: In patients with right lung underdevelopment, preoperative computed tomography elucidated the tracheal bending due to right posterior deviation of the aortic arch, which compromised tracheoplasty and shortness of the left pulmonary artery for pulmonary artery sling repair.

Short-Term Stability After Segmental Le Fort I Maxillary Impaction Surgery With Mandibular Autorotation in Seven High-Angle Class II Patients: A Case Series.

PURPOSE: To retrospectively evaluate skeletal stability after Le Fort I maxillary impaction surgery and mandibular autorotation without bilateral sagittal split osteotomy (BSSO) in high-angle class II patients. MATERIALS AND METHODS: Seven female high-angle class II patients who underwent maxillary impaction surgery and mandibular autorotation without bilateral sagittal split osteotomy were included in this study. Surgical changes and relapse were measured on lateral cephalograms taken preoperatively and at 1 month, 6 months and 1 year postoperatively. RESULTS: The horizontal movement of the maxilla at point A was 5.8 ±â€Š3.3 mm backward, and the upward movement at the posterior nasal spine was 3.3 ±â€Š1.4 mm. The mean horizontal change at point A during the 1-year follow-up period was 0.1 ±â€Š0.2 mm, and the vertical change at posterior nasal spine was 0.2 ±â€Š1.3 mm, which were not statistically significant. The horizontal surgical change at point B was 4.0 ±â€Š1.8 mm forward and the vertical surgical change at point B was 4.7 ±â€Š1.8 mm upward. Postoperative relapse was 10.9% and 13.7% in the horizontal and vertical directions, respectively. CONCLUSIONS: Le Fort I maxillary impaction surgery with mandibular autorotation may be 1 of the suitable procedures for high-angle class II patients.

Hemi-Clamshell Approach for Fetal Lung Interstitial Tumor Resection in a Neonate: A Case Report.

Fetal lung interstitial tumor (FLIT) is a rare primary lung mass in neonates. Classical incisions, such as posterolateral thoracotomy or median sternotomy, do not provide optimal exposure of the operative field for the resection of pediatric thoracic giant tumors. Herein, we report a rare case of a FLIT in a full-term male neonate, with complete resection achieved using a hemi-clamshell approach, which provided the required visualization of the operative field. The neonate was transferred to our hospital because of mild respiratory distress, which developed 18-hour after normal vaginal delivery. A mass in his right chest, without a midline shift, was observed on chest radiographs. Computed tomography showed a well-circumscribed solid anterior cervicothoracic mass, with a uniform density and no apparent cysts, diagnosed as a primary thoracic giant tumor. Once the patient was clinically stabilized, we proceeded with right upper lobectomy, using a hemi-clamshell approach, full sternotomy, and anterolateral thoracotomy, on postnatal day 22. Histopathologic examination revealed an 8.5 × 6.5 × 4.0 cm solid mass within the right upper lobe, which was diagnosed as a FLIT. His postoperative recovery was uneventful. The patient was followed up for 1 year, with no complaints or symptoms and no postoperative shoulder dysfunction. Gross total resection of primary thoracic giant tumors can be accomplished in neonates with optimal exposure of the chest cavity using a hemi-clamshell approach.

Detection of novel fusion genes by next-generation sequencing-based targeted RNA sequencing analysis in adenoid cystic carcinoma of head and neck.

OBJECTIVE: Adenoid cystic carcinoma (AdCC) is a rare, indolent salivary gland tumor that is reported to be driven by fusion genes. However, MYB/MYBL1-NFIB fusions have been detected in <60% of all AdCC cases and the oncogenic driver mutations in approximately 40% of AdCC remain unknown. Our aim was to identify novel gene fusions in AdCC. STUDY DESIGN: We investigated 20 AdCC cases using a targeted RNA sequencing panel to identify gene fusions and performed quantitative real-time reverse transcription polymerase chain reaction to assess MYB, MYBL1, and NFIB expression levels. RESULTS: A total of 36 fusion transcripts in 15 cases were detected and validated by Sanger sequencing. The MYB-NFIB and MYBL1-NFIB fusion genes were detected in 9 and 3 cases, respectively, in a mutually exclusive manner. Furthermore, novel gene fusions, namely, NFIB-EPB41L2, MAP7-NFIB, NFIB-MCMDC2, MYBL1-C8orf34, C8orf34-NFIB, and NFIB-CASC20, were identified. Among them, NFIB-EPB41L2 and NFIB-MCMDC2 are thought to activate MYB and MYBL1 expression, respectively, through the insertion of a genomic segment in proximity to MYB and MYBL1 genes, respectively. CONCLUSION: Six novel gene fusions other than MYB/MYBL1-NFIB were identified. The detection of novel fusion genes and investigation of the molecular mechanism will contribute to the development of novel molecular targeted therapies for this disease.

Infectious complications after tracheoplasty for congenital tracheal stenosis: a retrospective comparative study.

PURPOSE: The factors related to infectious complications after tracheoplasty for congenital tracheal stenosis (CTS) remain unclear; we, therefore, assessed these factors in this study. METHODS: We divided 47 patients who underwent slide tracheostomy and tracheal resection for CTS between May 2016 and December 2020 into an infected group and a non-infected group. Their characteristics were compared between groups. Results are presented as the median (range) or incidence. RESULTS: Infectious complications were observed in 12 patients (25.5%). Empyema and mediastinitis were seen in 5 cases (10.6%). There was a significant difference in the following factors in the infected and non-infected groups, respectively: weight, 5457 (2868-20,750) g and 6554 (2275-20,800) g (p = 0.025); surgical time, 575.5 (313-646) min and 349 (270-651) min (p < 0.001); extracorporeal circulation time, 303.5 (186-610) min and 216 (117-478) min (p = 0.001); and postoperative intubation time, 13 (7-28) days, and 6 (5-22) days (p < 0.001). Age, malnutrition, cardiovascular comorbidities, and preoperative methicillin-resistant Staphylococcus aureus detection were not significantly different between the two groups. CONCLUSION: There were a few serious infectious complications and no perioperative deaths. Attention should be paid to low body weight, long surgical and extracorporeal circulation time, and intubation time in relation to infectious complications.