Dynamic CD8+ T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes.

CD8+ T cell responses are critical for anti-tumor immunity. While extensively profiled in the tumor microenvironment, recent studies in mice identified responses in lymph nodes (LNs) as essential; however, the role of LNs in human cancer patients remains unknown. We examined CD8+ T cells in human head and neck squamous cell carcinomas, regional LNs, and blood using mass cytometry, single-cell genomics, and multiplexed ion beam imaging. We identified progenitor exhausted CD8+ T cells (Tpex) that were abundant in uninvolved LN and clonally related to terminally exhausted cells in the tumor. After anti-PD-L1 immunotherapy, Tpex in uninvolved LNs reduced in frequency but localized near dendritic cells and proliferating intermediate-exhausted CD8+ T cells (Tex-int), consistent with activation and differentiation. LN responses coincided with increased circulating Tex-int. In metastatic LNs, these response hallmarks were impaired, with immunosuppressive cellular niches. Our results identify important roles for LNs in anti-tumor immune responses in humans.

Effectiveness of a video-based smoking cessation intervention focusing on maternal and child health in promoting quitting among expectant fathers in China: A randomized controlled trial.

BACKGROUND: Secondhand smoke can cause adverse pregnancy outcomes, yet there is a lack of effective smoking cessation interventions targeted at expectant fathers. We examined the effectiveness of a video-based smoking cessation intervention focusing on maternal and child health in promoting quitting among expectant fathers. METHODS AND FINDINGS: A single-blind, 3-arm, randomized controlled trial was conducted at the obstetrics registration centers of 3 tertiary public hospitals in 3 major cities (Guangzhou, Shenzhen, and Foshan) in China. Smoking expectant fathers who registered with their pregnant partners were invited to participate in this study. Between 14 August 2017 to 28 February 2018, 1,023 participants were randomized to a video (n = 333), text (n = 322), or control (n = 368) group. The video and text groups received videos or text messages on the risks of smoking for maternal and child health via instant messaging. The control group received a leaflet with information on smoking cessation. Follow-up visits were conducted at 1 week and at 1, 3, and 6 months. The primary outcome, by intention to treat (ITT), was validated abstinence from smoking at the 6-month follow-up. The secondary outcomes included 7-day point prevalence of abstinence (PPA) and level of readiness to quit at each follow-up. The mean age of participants was 32 years, and about half of them were first-time expectant fathers. About two-thirds of participants had completed tertiary education. The response rate was 79.7% (815 of 1,023) at 6 months. The video and text groups had higher rates of validated abstinence than the control group (video group: 22.5% [75 of 333], P < 0.001; text group: 14.9% [48 of 322], P = 0.02; control group: 9.2% [34 of 368]) with adjusted odds ratios (ORs) of 2.80 (95% confidence interval [CI]: 1.79-4.37, P < 0.001) in the video group and 1.70 (95% CI: 1.06-2.74, P = 0.03) in the text group. The video and text groups differed in the rates of validated abstinence (22.5% versus 14.9%, P = 0.008; adjusted OR: 1.64, 95% CI: 1.10-2.46, P = 0.02). The video and text groups had higher rates of 7-day PPA than the control group at 6 months (video group: 24.6% [82 of 333] versus 11.4% [42 of 368], P < 0.001; text group: 17.4% [56 of 333] versus 11.4% [42 of 368], P = 0.02). The video and text groups also differed in the rates of 7-day PPA (24.6% versus 17.4%, P = 0.02). Excluding the quitters, the video and text groups had higher levels of readiness to quit than the control group at 6 months (video group: 43.5% [109 of 251] versus 31.6% [103 of 326], P = 0.002; text group: 40.6% [108 of 266] versus 31.6% [103 of 326], P = 0.01), No such difference was detected between the video and text groups (43.5% versus 40.6%, P = 0.29). The study was limited in that the long-term effectiveness of the intervention is uncertain. CONCLUSIONS: This smoking cessation intervention for expectant fathers that focused on explaining the ramifications of smoking on maternal and child health was effective and feasible in promoting quitting, and video messages were more effective than texts in delivering the information. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03236025.

Maternal Black Race and Persistent Wheezing Illness in Former Extremely Low Gestational Age Newborns: Secondary Analysis of a Randomized Trial.

OBJECTIVE: To evaluate the relationship between maternal self-reported race/ethnicity and persistent wheezing illness in former high-risk, extremely low gestational age newborns, and to quantify the contribution of socioeconomic, environmental, and biological factors on this relationship. STUDY DESIGN: We assessed persistent wheezing illness determined at 18-24 months corrected (for prematurity) age in survivors of a randomized trial. Parents/caregivers were surveyed for wheeze and inhaled asthma medication use quarterly to 12 months, and at 18 and 24 months. We used multivariable analysis to evaluate the relationship of maternal race to persistent wheezing illness, and identified mediators for this relationship via formal mediation analysis. RESULTS: Of 420 infants (25.2 ± 1.2 weeks of gestation and 714 ± 166 g at birth, 57% male, 34% maternal black race), 189 (45%) had persistent wheezing illness. After adjustment for gestational age, birth weight, and sex, infants of black mothers had increased odds of persistent wheeze compared with infants of nonblack mothers (OR = 2.9, 95% CI 1.9, 4.5). Only bronchopulmonary dysplasia, breast milk diet, and public insurance status were identified as mediators. In this model, the direct effect of race accounted for 69% of the relationship between maternal race and persistent wheeze, whereas breast milk diet, public insurance status, and bronchopulmonary dysplasia accounted for 8%, 12%, and 10%, respectively. CONCLUSIONS: Among former high-risk extremely low gestational age newborns, infants of black mothers have increased odds of developing persistent wheeze. A substantial proportion of this effect is directly accounted for by race, which may reflect unmeasured environmental influences, and acquired and innate biological differences. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01022580.

The Randomized, Controlled Trial of Late Surfactant: Effects on Respiratory Outcomes at 1-Year Corrected Age.

OBJECTIVE: To determine the effects of late surfactant on respiratory outcomes determined at 1-year corrected age in the Trial of Late Surfactant (TOLSURF), which randomized newborns of extremely low gestational age (≤28 weeks' gestational age) ventilated at 7-14 days to late surfactant and inhaled nitric oxide vs inhaled nitric oxide-alone (control). STUDY DESIGN: Caregivers were surveyed in a double-blinded manner at 3, 6, 9, and 12 months' corrected age to collect information on respiratory resource use (infant medication use, home support, and hospitalization). Infants were classified for composite outcomes of pulmonary morbidity (no PM, determined in infants with no reported respiratory resource use) and persistent PM (determined in infants with any resource use in ≥3 surveys). RESULTS: Infants (n = 450, late surfactant n = 217, control n = 233) were 25.3 ± 1.2 weeks' gestation and 713 ± 164 g at birth. In the late surfactant group, fewer infants received home respiratory support than in the control group (35.8% vs 52.9%, relative benefit [RB] 1.28 [95% CI 1.07-1.55]). There was no benefit of late surfactant for No PM vs PM (RB 1.27; 95% CI 0.89-1.81) or no persistent PM vs persistent PM (RB 1.01; 95% CI 0.87-1.17). After adjustment for imbalances in baseline characteristics, relative benefit of late surfactant treatment increased: RB 1.40 (95% CI 0.89-1.80) for no PM and RB 1.24 (95% CI 1.08-1.42) for no persistent PM. CONCLUSION: Treatment of newborns of extremely low gestational age with late surfactant in combination with inhaled nitric oxide decreased use of home respiratory support and may decrease persistent pulmonary morbidity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01022580.

Early Cumulative Supplemental Oxygen Predicts Bronchopulmonary Dysplasia in High Risk Extremely Low Gestational Age Newborns.

OBJECTIVE: To assess the prognostic accuracy of early cumulative supplemental oxygen (CSO) exposure for prediction of bronchopulmonary dysplasia (BPD) or death, and to evaluate the independent association of CSO with BPD or death. STUDY DESIGN: We performed a secondary analysis of the Trial of Late Surfactant, which enrolled 511 infants born at ≤28 weeks gestational age who were mechanically ventilated at 7-14 days of life. Our primary outcome was BPD or death at 36 weeks postmenstrual age, as determined by a physiological oxygen/flow challenge. Average daily supplemental oxygen (fraction of inspired oxygen - 0.21) was calculated. CSO was calculated as the sum of the average daily supplemental oxygen over time periods of interest up to 28 days of age. Area under the receiver operating curve (AUROC) values were generated to evaluate the accuracy of CSO for prediction of BPD or death. The independent relationship between CSO and BPD or death was assessed in multivariate modeling, while adjusting for mean airway pressure. RESULTS: In the study infants, mean gestational age at birth was 25.2 ± 1.2 weeks and mean birth weight was 700 ± 165 g. The AUROC value for CSO at 14 days was significantly better than that at earlier time points for outcome prediction (OR, 0.70; 95% CI, 0.65-0.74); it did not increase with the addition of later data. In multivariate modeling, a CSO increase of 1 at 14 days increased the odds of BPD or death (OR, 1.7; 95% CI, 1.3-2.2; P < .0001), which corresponds to a 7% higher daily supplemental oxygen value. CONCLUSION: In high-risk extremely low gestational age newborns, the predictive accuracy of CSO plateaus at 14 days. CSO is independently associated with BPD or death. This index may identify infants who could benefit from early intervention to prevent BPD.

Persistence of pulmonary hypertension by echocardiography predicts short-term outcomes in congenital diaphragmatic hernia.

OBJECTIVES: To describe the natural history of pulmonary hypertension (PH) and the risk of death and pulmonary morbidity associated with the persistence of PH through the neonatal hospitalization for these infants. STUDY DESIGN: We performed a retrospective cohort study of infants with congenital diaphragmatic hernia (CDH) cared for at University of California San Francisco (2002-2012). Infants with other major anomalies or syndromes were excluded (n = 43). Clinical echocardiograms were performed weekly for up to 6 weeks or until PH resolved off respiratory support or until hospital discharge. Echocardiograms were re-read by a blinded reviewer and categorized by severity of elevation in estimated pulmonary arterial pressure. PH was defined as ≥2/3 systemic blood pressure. Severity was determined by a hierarchy of ductus arteriosus level shunt, interventricular septal position, and tricuspid regurgitant jet velocity. RESULTS: Of 140 infants with ≥1 echo, 98 resolved their PH prior to death/discharge. Mean time to resolution was 18 days (median 14 days, IQR 8, 21 days). Those with persistence of PH had a higher rate of extracorporeal membrane oxygenation (P < .001) and death (P < .001), and fewer ventilator-free days (P < .001). Persistence of PH at 14 days predicted mortality (area under the receiver operating characteristic curve 0.87) and adverse respiratory outcomes (area under the receiver operating characteristic curve 0.80-0.83). CONCLUSIONS: The majority of infants with CDH resolve PH between 1 and 3 weeks of life. At 2 weeks of age, severity of PH by echocardiogram strongly predicts short-term pulmonary morbidity and death. Further evaluation of physiological alterations during that time may lead to novel therapies for severe CDH.

Psychometric properties of the Chinese version of the fatigue scale-adolescent.

BACKGROUND: The availability of a valid and reliable instrument that accurately assesses the level of fatigue among adolescent cancer survivors is crucial before any appropriate interventions to reduce their fatigue can be appropriately planned and evaluated. The study aimed to test the psychometric properties of the Chinese version of the Fatigue Scale for Adolescents. In particular, confirmatory factor analysis was conducted to examine its factorial structure. METHODS: A cross-sectional study was employed. Adolescents (13- to 18-year-olds) who had survived cancer and attended medical follow-up at the outpatient clinic in Hong Kong were invited to participate. The internal consistency, content validity and construct validity and test-retest reliability of the Chinese version of the Fatigue Scale for Adolescents were assessed. RESULTS: The content validity index was 0.92. There was a strong positive correlation between adolescents' levels of fatigue and depressive symptoms (r = 0.53) and a strong negative correlation between adolescents' levels of fatigue and quality of life (r = -0.58). The mean levels of fatigue of the survivors group was significantly lower than that of those still receiving treatment in hospital, but significantly higher than that of their healthy counterparts. Confirmatory factor analysis indicated that there were 4 factors underlying the Chinese version of the Cancer Module. CONCLUSIONS: The findings of the study add further evidence that the Chinese version of the Fatigue Scale for Adolescents (12-item) can be used as a reliable and valid tool in assessing cancer-related fatigue among Hong Kong Chinese adolescents who have survived cancer.

Fetal ultrasound markers of severity predict resolution of pulmonary hypertension in congenital diaphragmatic hernia.

OBJECTIVE: Congenital diaphragmatic hernia (CDH) results in morbidity and death from lung hypoplasia and persistent pulmonary hypertension (PH). We sought to define the relationship between fetal ultrasound markers of severity in CDH and the time to resolution of neonatal PH. STUDY DESIGN: We conducted a retrospective study of fetuses with an antenatal ultrasound scan and left-sided CDH cared for at the University of California San Francisco (2002-2012). Fetal liver position was classified on ultrasound scan as abdominal (entire liver within the abdomen) or thoracic (any portion of the liver within the thorax). Fetal stomach position was classified from least to most aberrant: abdominal, anterior left chest, mid-posterior left chest, or retrocardiac (right chest). Lung-to-head ratio (LHR) was determined from available scans at 20-29 weeks of gestational age (GA). Routine neonatal echocardiograms were performed weekly for up to 6 weeks or until PH resolved or until discharge. PH was assessed by echocardiogram with the use of a hierarchy of ductus arteriosus level shunt, interventricular septal position, and tricuspid regurgitant jet velocity. Days to PH-free survival was defined as the age at which pulmonary artery pressure was estimated to be <2/3 systemic blood pressure. Cox proportional hazards models adjusted for GA at birth, era of birth, fetal surgery, and GA at ultrasound scan (LHR model only), with censoring at 100 days. RESULTS: Of 118 patients, the following fetal markers were available: LHR (n = 53), liver position (n = 112), and stomach position (n = 80). Fewer infants experienced resolved PH if they had LHR <1 (P = .006), thoracic liver position (P = .001), or more aberrant stomach position (P < .001). There was also a decreased rate of resolution of PH in infants with LHR <1 (hazard ratio, 0.30; P = .007), thoracic liver position (hazard ratio, 0.38; P < .001), and more aberrant stomach position (hazard ratios, 0.28 [P = .002]; 0.1 [P < .001]; and 0.07 [P < .001]). CONCLUSION: Fetal ultrasound markers of CDH severity are predictive not only of death but also of significant morbidity. LHR <1, thoracic liver, and aberrant stomach position are associated with delayed time to resolution of PH in infants with CDH and may be used to identify fetuses at high risk of persistent PH.

B-type natriuretic peptide: prognostic marker in congenital diaphragmatic hernia.

BACKGROUND: B-type natriuretic peptide (BNP) has not been evaluated in newborns with congenital diaphragmatic hernia (CDH). We hypothesized that BNP and severity of pulmonary hypertension (PH) would predict clinical outcome in these infants. METHODS: We measured BNP levels and assessed severity of PH by echocardiography at 1 d and 1 wk of life. Outcome was classified by status at 56 d (or prior discharge): Good (n = 13) if alive on room air and Poor (n = 14) if expired or receiving respiratory support. We estimated area under the curve (AUC) and 95% confidence interval (CI). RESULTS: BNP levels were higher at 1 d in newborns with Poor outcome (median 220 pg/ml vs. 55 pg/ml, P < 0.01). At 1 wk, there was no significant difference in BNP level (median 547 pg/ml vs. 364 pg/ml, P = 0.70, for Poor and Good outcomes). At 1 d, BNP level predicted outcome (AUC = 0.91, 95% CI = 0.77-1.0), but this relationship dissipated by 1 wk (AUC = 0.55, 95% CI = 0.31-0.79). Severity of PH did not predict outcome at 1 d (AUC = 0.51, 95% CI = 0.27-0.74), but prediction improved at 1 wk (AUC = 0.80, 95% CI = 0.61-0.99). CONCLUSION: BNP is a strong predictor of clinical outcome in newborns with CDH at 1 d of life.

Management of Pediatric Persistent Asymptomatic Cervical Lymphadenopathy.

OBJECTIVE: Persistent asymptomatic cervical lymphadenopathy (PACL) is a common outpatient referral diagnosis for pediatric otolaryngologists. Historically, excisional biopsy under general anesthesia has been the gold standard for diagnosis but is associated with some risks. Current literature provides little guidance on less invasive monitoring. Our hypothesis is that the majority of children who present with PACL can be safely monitored with ultrasound and avoid the risks of excisional biopsy. STUDY DESIGN: A retrospective review was performed of patients <18 years of age, referred to a tertiary care children's hospital for PACL who also underwent at least 1 neck ultrasound from 2007 to 2021. Patients with acute neck infections, congenital masses, or known rheumatologic, immunologic, or malignant conditions were excluded. A multivariate logistic regression model was used to determine patient and nodal factors associated with the decision for operative management. SETTING: University of California, San Francisco Pediatric Otolaryngology Department. RESULTS: Among the 197 patients meeting inclusion criteria, 30 (15.2%) underwent surgical biopsy. Overall, 26% underwent repeat ultrasound with a mean interval of 6.6 months, and a mean decrease in nodal size of 0.34 cm. Of the 30 surgical cases, 27 (90%) patients had benign pathology. Multivariate regression analysis revealed pain (p = .04), firmness (p < .001), and lack of a normal fatty hilum on ultrasound (p = .04) as statistically significantly correlated with decisions for surgical management. CONCLUSION: The majority of pediatric PACL is benign and does not require an excisional biopsy to rule out lymphoma. Serial clinical follow-up with neck ultrasound can be used to safely monitor patients.

The tumor microenvironment of benign and malignant salivary gland tumors.

BACKGROUND: Treatment of salivary gland tumors (SGTs) remains challenging. Little is known about the immune landscape of SGTs. We aimed to characterize the tumor microenvironment in benign and malignant SGTs. METHODS: Eleven benign and nine malignant tumors were collected from patients undergoing curative intent surgery. Specimens were analyzed using mass cytometry by time-of-flight. Immune cell populations were manually gated, and T cells were clustered using the FlowSOM algorithm. Population frequencies were compared between high-grade and low-grade malignancies, corrected for multiple hypothesis testing. RESULTS: There were trends towards increased CD4+ and CD8+ T cells among malignant tumors. High-grade malignancies exhibited trends towards higher frequencies of CD8+ PD-1+ CD39+ CD103+ exhausted T cells, CD4+ FoxP3+ TCF-1+ CD127- Tregs, and CD69+ CD25- CD4+ T cells compared to low-grade malignancies. CONCLUSION: SGTs exhibit significant immunologic diversity. High-grade malignancies tended to have greater infiltration of exhausted CD8+ T cells and Tregs, which may guide future studies for immunotherapy strategies.

Postoperative inpatient surgical complications following head and neck microvascular free tissue transfer.

BACKGROUND: Complications following head and neck microvascular free tissue transfer (MFTT) are common. Less is known about when they occur. METHOD: Retrospective study of patients with primary or recurrent head and neck cancer undergoing MFTT reconstruction at a tertiary care institution. MFTT reconstructions with inpatient postoperative complications were included. The Kruskal-Wallis test was used to compare median postoperative day (POD) onset of complication by flap type. RESULTS: Of 1090 patients undergoing MFTT reconstruction, 126 (11.6%) patients experienced inpatient complications including fibula (n = 35), anterolateral thigh (n = 60), or radial forearm (n = 31) MFTTs. POD onset was shortest for surgical site hematoma (median = 1 [IQR 1-5]), and longest for donor site infection (median = 11.5 [IQR 8-15]). There was no significant difference between flap types and POD onset of complications (p > 0.05). CONCLUSION: Hematoma formation and flap failure occur earliest during hospitalization, while dehiscence, infection, and fistula occur later. There is no difference in complication timing between flap types.

The neutrophil-to-lymphocyte ratio in salivary gland cancers treated with pembrolizumab.

BACKGROUND: A minority of patients with recurrent/metastatic (R/M) salivary gland cancers (SGCs) benefit from immune checkpoint inhibitors (ICIs), necessitating reliable biomarkers for ICI response prediction. METHODS: Retrospective observational study of R/M SGC patients treated with pembrolizumab between 2016 and 2022, with a primary outcome of 6-month progression-free survival (PFS) and secondary outcome of 2-year overall survival (OS). Univariate and multivariable Cox proportional hazards models were employed. RESULTS: Twenty R/M SGC patients were included. After adjustment, NLR as a continuous variable was independently associated with 6-month PFS (HR 1.30, 95% CI 1.10-1.54, p = 0.002) and 2-year OS (HR 1.33, 95% CI 1.07-1.66, p = 0.010). Similarly, NLR ≥ 5 was associated with higher hazards of progression at 6 months (HR 12.85, 95% CI 2.17-76.16, p = 0.005) and death at 2 years (HR 11.25, 95% CI 1.67-75.77, p = 0.013). CONCLUSIONS: Higher pretreatment NLR was independently associated with inferior 6-month PFS and 2-year OS in pembrolizumab-treated R/M SGC patients.

Is the clinical head impulse test helpful in cochlear implantation candidacy evaluation?

Objective: Vestibular dysfunction is a known risk of cochlear implantation (CI). However, the utility of the physical exam to screen CI candidates for vestibular dysfunction is not well-studied. The objective of this study is to evaluate the preoperative role of the clinical head impulse test (cHIT) in subjects undergoing CI surgery evaluation. Study Design Setting and Subjects: We conducted a retrospective review of 64 adult CI candidacy cases between 2017 and 2020 at a tertiary health care center. Methods: All patients underwent audiometric testing and evaluation by the senior author. Patients with an abnormal catch-up saccade contralateral to their worse hearing ear during cHIT were referred for formal vestibular testing. Outcomes included clinical and formal vestibular results, operated ear with regard to audiometric and vestibular results, and postoperative vertigo. Results: Among all CI candidates, 44% (n = 28) reported preoperative disequilibrium symptoms. Overall, 62% (n = 40) of the cHITs were normal, 33% (n = 21) were abnormal, and 5% (n = 3) were inconclusive. There was one patient who presented with a false positive cHIT. Among the patients who endorsed disequilibrium, 43% had a positive preoperative cHIT. Fourteen percent of the subjects (n = 9) without disequilibrium had an abnormal cHIT. In this cohort, bilateral vestibular impairment (71%) was more common than unilateral vestibular impairment (29%). In 3% of the cases (n = 2), surgical management was revisited or altered due to cHIT findings. Conclusion: There is a high prevalence of vestibular hypofunction in the CI candidate population. Self-reported assessments of vestibular function are often not congruent with cHIT results. Clinicians should consider incorporating cHITs as part of the preoperative physical exam to potentially avoid bilateral vestibular dysfunction in a minority of patients.

Patterns of Postoperative Trismus Following Mandibulectomy and Fibula Free Flap Reconstruction.

The factors that contribute to postoperative trismus after mandibulectomy and fibula free flap reconstruction (FFFR) are undefined. We retrospectively assessed postoperative trismus (defined as a maximum interincisal opening ≤35 mm) in 106 patients undergoing mandibulectomy with FFFR, employing logistic regression to identify risk factors associated with this sequela. The surgical indication was primary ablation in 64%, salvage for recurrence in 24%, and osteonecrosis in 12%. Forty-five percent of patients had existing preoperative trismus, and 58% of patients received adjuvant radiation/chemoradiation following surgery. The overall rates of postoperative trismus were 76% in the early postoperative period (≤3 months after surgery) and 67% in the late postoperative period (>6 months after surgery). Late postoperative trismus occurred more frequently in patients with ramus-involving vs. ramus-preserving posterior mandibulotomies (82% vs. 46%, p = 0.004). A ramus-involving mandibulotomy was the only variable significantly associated with trismus >6 months postoperatively on multivariable logistic regression (OR, 7.94; 95% CI, 1.85−33.97; p = 0.005). This work demonstrates that trismus is common after mandibulectomy and FFFR, and suggests that posterior mandibulotomies that involve or remove the ramus may predispose to a higher risk of persistent postoperative trismus.

The Role of ECM Remodeling, EMT, and Adhesion Molecules in Cancerous Neural Invasion: Changing Perspectives.

Perineural invasion (PNI) refers to the cancerous invasion of nerves. It provides an alternative route for metastatic invasion and can exist independently in the absence of lymphatic or vascular invasion. It is a prominent characteristic of specific aggressive malignancies where it correlates with poor prognosis. The clinical significance of PNI is widely recognized despite a lack of understanding of the molecular mechanisms underlying its pathogenesis. The interaction between the nerve and the cancer cells is the most pivotal PNI step which is mediated by the activation or inhibition of multiple signaling pathways that include chemokines, interleukins, nerve growth factors, and matrix metalloproteinases, to name a few. The nerve-cancer cell interaction brings about specific changes in the perineural niche, which not only affects the regular nerve functions, but also enhances the migratory, invasive, and adherent properties of the tumor cells. This review aims to elucidate the vital role of adhesion molecules, extracellular matrix, and epithelial-mesenchymal proteins that promote PNI, which may serve as therapeutic targets in the future.

Approaches to the Management of Metastatic Adenoid Cystic Carcinoma.

High rates of recurrence and distant metastasis are a foremost challenge in the management of adenoid cystic carcinoma (ACC), occurring in approximately 40% of all ACC patients. Despite the morbidity and mortality resulting from recurrent/metastatic (R/M) disease, there are no FDA-approved systemic agents for these patients. In this review, we summarize pertinent ACC pathophysiology and its implications for different systemic treatment regimens in R/M ACC. We review the evidence for the most widely used systemic agents - cytotoxic chemotherapy and tyrosine kinase inhibitors (TKIs) targeting VEGFR - in addition to immune checkpoint inhibitors and non-TKI biologic agents. Exciting emerging targets for R/M ACC, including inhibitors of Notch signaling, stemness, PRMT5, and Axl, are also discussed. Lastly, we review local therapies for small-volume lung disease in patients with oligometastatic ACC, specifically pulmonary metastasectomy and stereotactic body radiation therapy (SBRT). Future development of targeted molecular agents which exploit the underlying biology of this disease may yield novel therapeutic options to improve clinical outcomes in patients with R/M ACC.

Feasibility of accelerated image-guided high-dose-rate interstitial brachytherapy with inverse planning simulated annealing (IPSA-HDRBT) for post-operative treatment of pathologically node-negative squamous cell carcinomas of the oral tongue.

PURPOSE: Inverse planning simulated annealing (IPSA) produces highly conformal dose distributions and quick optimizations for high-dose-rate interstitial brachytherapy (HDRBT). We report our dosimetry and overall outcomes using this approach for the accelerated post-operative treatment of pathologically node-negative squamous cell carcinomas of the oral tongue (OTSCC) with high risk of local recurrence. METHODS: Patients with newly diagnosed pN0 OTSCC treated with partial glossectomy, neck dissection, and post-operative HDRBT alone from 2007 to 2021 were retrospectively reviewed. Patients received 30 Gy in 5 fractions over 2.5 days. Target volume and mandible dosimetry are reported. Actuarial rates of local control, regional control, disease-specific survival, and overall survival were estimated using the Kaplan-Meier method. Toxicity was categorized using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: 19 consecutive patients were reviewed. Median follow-up was 3.2 years (IQR 1.4-8.2 years) with a 3-year estimated local control rate of 81%. Target volumes were generally small, as the median volume was 12.66 cc. Median V150% and V200% were 52% and 24%, respectively. D1cc and D2cc to the mandible were 17.31 Gy and 14.42 Gy, respectively. CONCLUSIONS: IPSA-HDRBT is feasible and highly efficient for post-operative treatment of the primary tumor bed in patients with pathologically node-negative squamous cell carcinomas of the oral tongue. Further technical optimization and prospective clinical evaluation in a larger patient cohort are planned.

Development of a Community-Based Network to Promote Anti-Drug Messaging and Identify Hidden Drug Abusers in Hong Kong.

Developing a community-based network by training peers as anti-drug ambassadors (ADAs) is a feasible strategy to identify hidden drug abusers. The Ask, Warn, Advise, Refer and Do-it-again (AWARD) model of smoking cessation is useful for enhancing people's confidence in making referrals to anti-drug services. This study evaluated the effectiveness of such a network by examining the change in knowledge, attitudes and practices (KAP) of 198 ADAs aged 13-18 before and after six months of our training. A one-group pre-test and repeated post-test design was used. One-way repeated-measures analysis of variance was applied to assess the changes in KAP, with p-values adjusted by Bonferroni correction. The results showed that the ADAs statistically significantly improved their KAP regarding drug abuse at the six-month follow-up compared to baseline. All ADAs who knew drug abusers (n = 3) had referred them to services based on the AWARD model. A total of 154 anti-drug abuse activities were conducted, reaching 4561 people. Based on the results, we concluded that the community-based network was effective in improving the KAP of ADAs regarding drug abuse, as well as referring hidden drug abusers. Future studies should consider implementing the network on a larger scale, thus maximizing its anti-drug capacity.

Molecular Markers that Matter in Salivary Malignancy.

Despite aggressive initial interventions, recurrent/metastatic salivary gland cancer is not uncommon. Standard chemotherapy has not been shown to have durable clinical benefits. Several potential molecular markers have been identified in different histologic subtypes of salivary cancers. The objective of this review is to highlight the molecular markers that have been targeted in clinical trials for salivary gland cancers.