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.
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.
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.
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.
Objective
The coronavirus 2019 (COVID‐19) pandemic has had widespread implications on clinical practice at U.S. hospitals. These changes are particularly relevant to otolaryngology–head and neck ...surgery (OHNS) residents because reports suggest an increased risk of contracting COVID‐19 for otolaryngologists. The objectives of this study were to evaluate OHNS residency program practice changes and characterize resident perceptions during the initial phase of the pandemic.
Study Design
A cross‐sectional survey of U.S. OHNS residents at 81 programs was conducted between March 23, 2020, and March 29, 2020.
Results
Eighty‐two residents from 51 institutions (63% of invited programs) responded. At the time of survey, 98% of programs had enacted policy changes to minimize COVID‐19 spread. These included filtered respirator use for aerosol‐generating procedures even in COVID‐19‐negative patients (85%), decreased resident staffing of surgeries (70%), and reduced frequency of tracheotomy care (61%). The majority of residents (66%) perceived that residents were at higher risk of contracting COVID‐19 compared to attendings. Residents were most concerned about protective equipment shortage (93%) and transmitting COVID‐19 to patients (90%). The majority of residents (73%) were satisfied with their department's COVID‐19 response. Resident satisfaction correlated with comfort level in discussing concerns with attendings (r = 0.72, P < .00001) and inversely correlated with perceptions of increased risk compared to attendings (r = −0.52, P < .00001).
Conclusion
U.S. OHNS residency programs implemented policy changes quickly in response to the COVID‐19 pandemic. Sources of resident anxieties demonstrate the importance of open communication and an integrated team approach to facilitate optimal patient and provider care during this unprecedented crisis.
Level of Evidence
4. Laryngoscope, 130:2550–2557, 2020
Complications following head and neck microvascular free tissue transfer (MFTT) are common. Less is known about when they occur.
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.
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).
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.
Understanding patient-specific risk of adverse histopathologic findings after primary surgery for human papillomavirus (HPV)-positive oropharynx squamous cell carcinoma (OPSCC) may help guide patient ...consultations.
To determine the likelihood of adverse histopathologic features that may indicate adjuvant radiotherapy or chemoradiotherapy after primary surgery for HPV-positive OPSCC according to 2021 National Comprehensive Cancer Network guidelines.
This retrospective cohort study was performed at a single academic tertiary care center. Of 258 patients who underwent transoral robotic surgery (TORS) from March 1, 2012, to March 1, 2021, 136 consecutive, treatment-naive patients with HPV-positive OPSCC without obvious clinical extranodal extension (ENE) who underwent definitive TORS and neck dissection were included in the analysis. Indications for surgical treatment included non-deeply infiltrative oropharynx tumors, minimal soft palate involvement, and low suspicion for pathologic ENE.
Primary site TORS with neck dissection.
The primary outcomes were the adverse histopathologic features of pathologic ENE and positive surgical margins (PSM) that are indications for possible adjuvant chemoradiotherapy. Outcomes were compared among varying American Joint Committee on Cancer 7th edition (AJCC-7) T and N categories and patient clinical characteristics.
Of the 136 patients included in the analysis (113 men 83.1%; median age, 63 interquartile range, 55-70 years), 109 (80.1%) had at least 1 indication for possible adjuvant radiotherapy. Twenty-seven patients (19.9%) had pathologic ENE and 10 (7.3%) had PSM. Thirty-four patients (25.0%) had pathologic ENE and/or PSM, whereas 3 (2.2%) had both. Age, smoking history, history of alcohol consumption, and clinical T category were not associated with pathologic ENE, PSM, lymphovascular invasion, perineural invasion, or pN2 category or greater. The proportion of pathologic ENE varied by clinical N category: 0 of 16 for cN0, 8 of 48 (16.7%) for cN1, 3 of 23 (13.0%) for cN2a, and 16 of 45 (35.6%) for cN2b. Compared with patients with cN1-cN2a disease, patients with cN2b disease had higher odds of pathologic ENE (odds ratio, 3.01; 95% CI, 1.14-8.10). Clinical and pathologic N category were concordant in 77 patients (56.6%), whereas 42 (30.9%) were upstaged and 17 (12.5%) were downstaged.
In this cohort study, approximately one-quarter of carefully selected patients with HPV-positive OPSCC without obvious clinical ENE undergoing primary surgery had pathologic ENE and/or PSM. Patients with AJCC-7 cT0-cT2 cN0-cN2b disease, especially cN0-cN2a, without signs of clinical ENE may represent appropriate candidates for primary surgery when avoidance of adjuvant chemotherapy and/or reduction of adjuvant radiotherapy dose/extent are the goals.
Human papillomavirus-related (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is a relatively new clinical entity that is dramatically on the rise globally. HPV+ OPSCC is thought to be a separate ...clinical entity compared to HPV- OPSCC with a distinct tumor biology. Patients with HPV associated disease have been shown to have a substantially better prognosis and overall survival than those patients with the HPV negative (HPV-) counterpart. The standard of care for OPSCC is definitive radiation therapy (RT) and concurrent chemoradiation therapy (CRT), for lower and higher stage disease, respectively. However, traditional CRT is also associated with severe acute and late toxicities affecting patient quality of life, such as severe mucositis, dry mouth and dysphagia. Considering that HPV+ OPSCC is on the rise in a younger, healthier patient population and the good prognosis of HPV-related disease, there has been a focus on reducing treatment toxicities and optimizing quality of life while maintaining favorable oncologic outcomes. A variety of such de-escalation regimens are currently being explored in recently completed and ongoing clinical trials. Alterations to the standard chemotherapy, radiation and surgical regimens are being explored. This review will provide an overview of the rationale for and available results of the major de-intensification strategies in the treatment of locally advanced HPV+ OPSCC.
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.
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.
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