Next Directions in the Neuroscience of Cancers Arising outside the CNS.

SUMMARY: The field of cancer neuroscience has begun to define the contributions of nerves to cancer initiation and progression; here, we highlight the future directions of basic and translational cancer neuroscience for malignancies arising outside of the central nervous system.

Primary Tumor Staging for Oral Cancer and a Proposed Modification Incorporating Perineural Invasion: An International Multicenter Study.

The objective of this study is to determine if the incorporation of perineural invasion (PNI) into the T-classification would improve the prognostic performance of TNM-8. An international, multicenter study of 1049 patients with oral cavity squamous cell carcinoma that were treated from 1994 to 2018 is performed. Various classification models are developed within each T-category and evaluated using the Harrel-concordance index (C-index), Akaike-information criterion (AIC), and visual inspection. Stratification into distinct prognostic categories, with internal validation, is performed using bootstrapping analysis (SPSS and R-software). Through multivariate analysis, PNI is significantly associated with disease-specific survival (p < 0.001). PNI integration into the staging system results in a significantly improved model compared with the current T category alone (lower AIC, p < 0.001). The PNI-integrated model is superior in predicting differential outcomes between T3 and T4 patients. A new model for T-classification of oral cavity squamous cell carcinoma is proposed, which is based on incorporating PNI into the staging system. These data can be used for future evaluations of the TNM staging system.

Beta-Blocker Use Is Associated With Worse Relapse-Free Survival in Patients With Head and Neck Cancer.

PURPOSE: Although beta-blockers (BBs) have been hypothesized to exert a beneficial effect on cancer survival through inhibition of beta-adrenergic signaling pathways, clinical data on this issue have been inconsistent. We investigated the impact of BBs on survival outcomes and efficacy of immunotherapy in patients with head and neck squamous cell carcinoma (HNSCC), non-small-cell lung cancer (NSCLC), melanoma, or squamous cell carcinoma of the skin (skin SCC), independent of comorbidity status or cancer treatment regimen. METHODS: Patients (N = 4,192) younger than 65 years with HNSCC, NSCLC, melanoma, or skin SCC treated at MD Anderson Cancer Center from 2010 to 2021 were included. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were calculated. Kaplan-Meier and multivariate analyses adjusting for age, sex, TNM staging, comorbidities, and treatment modalities were performed to assess the effect of BBs on survival outcomes. RESULTS: In patients with HNSCC (n = 682), BB use was associated with worse OS and DFS (OS: adjusted hazard ratio [aHR], 1.67; 95% CI, 1.06 to 2.62; P = .027; DFS: aHR, 1.67; 95% CI, 1.06 to 2.63; P = .027), with DSS trending to significance (DSS: aHR, 1.52; 95% CI, 0.96 to 2.41; P = .072). Negative effects of BBs were not observed in the patients with NSCLC (n = 2,037), melanoma (n = 1,331), or skin SCC (n = 123). Furthermore, decreased response to cancer treatment was observed in patients with HNSCC with BB use (aHR, 2.47; 95% CI, 1.14 to 5.38; P = .022). CONCLUSION: The effect of BBs on cancer survival outcomes is heterogeneous and varies according to cancer type and immunotherapy status. In this study, BB intake was associated with worse DSS and DFS in patients with head and neck cancer not treated with immunotherapy, but not in patients with NSCLC or skin cancer.

Middle ear effusion and newborn hearing screening.

PURPOSE: Middle ear effusion (MEE) is one of the reasons for screening failure and may require prolonged follow-up due to conductive hearing loss. We aimed to examine at 1-year follow-up, the fate of MEE. METHODS: From medical charts, computerized data were collected retrospectively of newborns born in the years 2012-2013 in Rambam Health Care Campus, Haifa city, Israel, who failed the Universal Newborn Hearing Screening (UNHS), and follow-up hearing evaluation data were extracted. RESULTS: Of 9527 newborns born in 2012-2013 in our institution, 144 [1.5%] failed the UNHS, and 46 were eventually diagnosed with conductive hearing loss caused by MEE. Spontaneous MEE clearance was recorded in 12 [26%], while 26 [57%] patients had persistent effusion that required further follow-up (10 [22%] required insertion of ventilation tubes and 16 [35%] were referred for further follow-up); 8 [17%] were lost to follow-up. CONCLUSION: Congenital MEE causing conductive hearing loss and UNHS failure is persistent and resolves at lower rates than non-congenital MEE.

Future directions in preclinical and translational cancer neuroscience research.

Recent advances in cancer neuroscience necessitate the systematic analysis of neural influences in cancer as potential therapeutic targets in oncology. Here, we outline recommendations for future preclinical and translational research in this field.

Long-Term Quality of Life after Endoscopic Pituitary Adenoma Surgery with Nasoseptal Flap Reconstruction.

INTRODUCTION: Endoscopic endonasal transsphenoidal surgery (EETS) on the pituitary gland is considered safe and efficacious. The nasoseptal flap (NSF) is sometimes used to prevent or repair postoperative cerebrospinal fluid (CSF) leaks. Few investigators have quantified long-term quality-of-life (QOL) outcomes regarding sinonasal measures after EETS, with or without involvement of the NSF. This study assesses whether the septal flap affects sinonasal QOL outcomes for patients receiving EETS for pituitary adenoma. METHODS AND MATERIALS: This is a retrospective study of patients who underwent EETS between 2013 and 2018. A total of 62 adults completed the Sinonasal Outcome Test-22 (SNOT-22) at least one year after the surgery. Outcome measures were compared between patients who underwent EETS with and without septal flap reconstruction. RESULTS: For the entire cohort, there were 14 patients (22.6%) who had septal flap reconstruction and 48 patients (77.4%) who did not. Patient demographics, tumor characteristics, surgical outcomes, and duration between surgery and completion of the questionnaire were similar for both groups. The mean SNOT-22 scores in the no reconstruction (NR) group and the nasoseptal flap reconstruction (NSFR) group were similar (P=0.9). In terms of SNOT-22 subdomains (rhinologic symptoms, extranasal rhinologic symptoms, ear/facial symptoms, psychological dysfunction, and sleep dysfunction), no significant differences were found when comparing the groups. CONCLUSION: As compared with no reconstructive involvement, NSF utilization does not affect the QOL and nasal symptoms of patients undergoing EETS.

Can Tonsillectomy Be Safely Performed by Residents? A Comparative Retrospective Study.

OBJECTIVE: To assess whether a surgeon's level of training is associated with outcomes in pediatric tonsillectomy. DESIGN: A retrospective cohort study of the outcomes of pediatric tonsillectomies performed between 2006 and 2016 by senior surgeons versus resident surgeons under the supervision of senior surgeons. SETTING: An otolaryngology department in a tertiary academic hospital. PATIENTS: Children younger than 18 years who underwent bilateral tonsillectomy with or without adenoidectomy. MAIN OUTCOME MEASURES: Intraoperative bleeding, initiation of oral intake, and intraoperative and postoperative complications. RESULTS: Of 785 children, 397 (50.5%) were operated on by a resident surgeon and 388 (49.5%) by a senior surgeon. Patient demographics and surgical techniques were similar between the groups. The mean surgical time was 33.2 minutes in the residents' group and 27.1 minutes in the seniors' group (P = .032). The groups were similar in intraoperative bleeding, while same-day initiation of oral intake was 71% for children in the residents' group versus 61% in the seniors' group (P = .28). Reports of postoperative bleeding necessitating readmission and revised operations were similar for both groups (3.0% and 0.7%, respectively, in the residents' group; and 2.5% and 1.0%, respectively, in the seniors' group). CONCLUSION: Children undergoing tonsillectomy showed similar short-term outcomes, whether the operations were performed by a senior surgeon or a resident surgeon supervised by an attending surgeon. This study demonstrates the safety of pediatric tonsillectomy performed by resident surgeons supervised by attending physicians.

Psychometric testing of the Skull Base Inventory health-related quality of life questionnaire in a multi-institutional study of patients undergoing open and endoscopic surgery.

PURPOSE: The skull base inventory (SBI) was developed to better assess health-related quality of life (HR-QOL) in patients with anterior and central skull base neoplasms treated by endoscopic and open approaches. The primary objective of this study was to prospectively assess the psychometric properties of the SBI. METHODS: This study is part of a multi-center study of patients undergoing endoscopic and open procedures completed between 2012 and 2018. Participants were eligible if they were over 18 years of age; had benign or malignant anterior, antero-lateral, or central skull base tumors; and required either an open or endoscopic skull base surgical approach. In order to assess the psychometric properties of the SBI, patients completed the instrument at six time points (preoperative, 2 weeks, 3 months, 6 months, 12 months postoperative). Patients also completed the Anterior Skull Base (ASB) questionnaire and the Sinonasal Outcome Test (SNOT-22) to allow comparison to the SBI. RESULTS: One hundred and eighty-seven patients were included across five centers, with 121 having an endoscopic procedure. Internal consistency (Cronbach's alpha = 0.95) and test-retest at 12 months and 12 months plus 2 weeks (intraclass correlation > 0.90) were excellent. Concurrent validity was demonstrated by very strong correlation between total SBI scores and ASB scores (r = 0.810 to 0.869, p < 0.001) and moderate correlation between nasal domain SBI scores and SNOT-22 scores (r = - 0.616 to - 0.738, p < 0.001). Convergent validity was demonstrated by moderate correlation between change in SBI scores and global QOL change (rs = 0.4942, p < 0.001). The minimally important clinical difference (global HR-QOL change of "a little better" or "a little worse") was 6.0. CONCLUSION: The SBI questionnaire is reliable and valid for patients treated by both endoscopic and open approaches and can be used for assessment of HR-QOL in these settings.

Endoscopic Septoplasty Versus Traditional Septoplasty for Treating Deviated Nasal Septum: A Prospective, Randomized Controlled Trial.

IMPORTANCE: This is the first randomized study to compare the quality of life of patients undergoing endoscopic septoplasty compared to traditional trans-nasal trans-speculum (TNTS) septoplasty. OBJECTIVE: To assess the clinical outcomes and quality of life results of endoscopic versus TNTS septoplasty in patients with septal deviation and nasal obstruction. DESIGN: A prospective, randomized controlled trial comparing 2 approaches of septoplasty: endoscopic and TNTS septoplasty performed in a single institution during the years 2016 to2017. The follow-up time was 3 months. SETTING: A single institution study in a tertiary health-care referral center. PARTICIPANTS: Patients who underwent primary surgery for repairing deviated nasal septum due to nasal obstruction, were older than 18 years old, and were eligible for study inclusion. Sixty-five patients were enrolled in this study, 34 in the endoscopic arm and 31 in the TNTS septoplasty arm. The overall follow-up rate was 94% at the first visit (2 weeks) and 92% at the last visit (12 weeks). Thus, the final cohort consisted of 60 patients, 30 in each study arm. The patients ranged in age from 18 to 71 years (mean 27 years) old. MAIN OUTCOMES AND MEASURES: The primary outcome was the Sino-Nasal Outcome Test-22 (SNOT-22) score. Secondary outcomes were the Short Form 36 (SF36) QOL score and complication rates. Both questionnaires were administered at 2 weeks and 3 months following surgery. RESULTS: Sixty patients completed this study, 30 in each study arm. Sino-Nasal Outcome Test-22 scores were improved after 3 months, with no difference between the study arms. There were no cases of septal perforation or profound bleeding requiring repeated surgery. CONCLUSIONS AND RELEVANCE: Endoscopic septoplasty and TNTS show similar results for treatment of nasal septum deviation. Trial Registration: Traditional Septoplasty versus Endoscopic Septoplasty for Treating Deviated Nasal Septum, NCT02653950. https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0005ZOR&selectaction=Edit&uid=U00021YC&ts=2&cx=-2w7hot.

Clinically Actionable Strategies for Studying Neural Influences in Cancer.

Neuro-glial activation is a recently identified hallmark of growing cancers. Targeting tumor hyperinnervation in preclinical and small clinical trials has yielded promising antitumor effects, highlighting the need of systematic analysis of neural influences in cancer (NIC). Here, we outline the strategies translating these findings from bench to the clinic.

Cold versus hot adenoidectomy: A prospective, randomized controlled trial.

OBJECTIVE: Adenoidectomy can be performed using the cold method (mainly adenoid curettes) or the hot method (suction diathermy). Both techniques have similar intra and postoperative outcomes. However, the long-term clinical outcome of improving sleep disorder symptoms has not been well established. The objective of this study was to compare outcomes of hot method and cold method adenoidectomy one year following the surgery. STUDY DESIGN: A prospective, randomized, single-blinded study of children under age 16 years who underwent adenoidectomy during the years 2014-2017. Patients were randomized to hot or cold adenoidectomy techniques. SETTING: A tertiary health care referral center. SUBJECTS AND METHODS: The final analysis included 58 children, mean age 5.9 years (range 1.2-15). The primary outcome was change in the Pediatric Sleep Questionnaire (PSQ) scores one month and one year after surgery. The secondary outcome was complication rate. RESULTS: Clinical and demographic parameters were similar between the patients in the hot method group (n = 30) and the cold method group (n = 28). Adenoid size and estimated bleeding were similar between the groups. At one month after surgery, PSQ score was improved by a mean + 0.31 in the hot method group compared to +0.32 in the cold method group (p = 0.54). Improvement in PSQ scores was greater following hot than cold adenoidectomy at one year after surgery (+0.31 points vs. +0.22 points, p = 0.009). CONCLUSION: Hot adenoidectomy is associated with better outcome than the cold technique, as reflected by PSQ scores one year after the surgery.

Contemporary Multidisciplinary Management of Sinonasal Mucosal Melanoma.

Sinonasal mucosal melanoma (SNMM) is a rare tumor, comprising less than 10% of sinonasal malignancies. SNMM most frequently occurs in the nasal cavity (70%) and maxillary sinus (14%), typically as black patches. Overall, SNMM harbors a very poor prognosis; 5-year survival is less than 30%. Nasal cavity tumors confer a better prognosis than sinus melanoma. The primary management for SNMM is surgery, when feasible, followed by adjuvant radiotherapy. Recent studies suggest that immunotherapy may confer survival benefit to patients with advanced disease. The multidisciplinary team approach has been shown to optimize treatment, reduce costs, and minimize adverse events, while maximizing the chances for cure.

Foreign Body Aspiration in Infants and Older Children: A Comparative Study.

BACKGROUND: Foreign body aspiration (FBA) is a major cause of morbidity and mortality in children. It is a preventable event that predominates in preschool age. The signs and symptoms mimic respiratory diseases common in the same age-group. We compared FBA in infants to FBA in older children. METHODS: Retrospective analysis of all the cases of suspected FBA of children under the age of 18 years hospitalized at one medical center during 2002 to 2016. We analyzed the data according to age: up to 1 year (infants) and 1 to 18 years. RESULTS: One hundred seventy-five children with suspected FBA were admitted; of whom, 27 (15%) were infants and 148 (85%) were older children (age 1-18 years). For the 2 age groups, adults witnessed 85% and 73%, respectively, of the incidents (P = .4). In the neonate group, 48% presented with normal X-ray findings compared to only 20% in the older group; 15% of the older group had a positive chest X-ray for a foreign body, while none had such in the infants' group (P = .01). For the 2 age groups, the majority of the FBs found were from organic origin. About half of the patients were diagnosed and managed within 24 hours of the aspiration event. In 10%, repeated bronchoscopy was performed due to a retained FB remnant. In a multivariate analysis, signs and symptoms (P < .05), location of the FB (P < .001), and witnessed aspiration (P < .001) were independent prognostic factors for the length of hospitalization. CONCLUSION: Foreign body aspiration is not uncommon in young infants; the management is challenging due to small airways, the need to use smaller bronchoscopes, and the lack of working channel forces in pediatric bronchoscopes.

Radioiodine-Refractory Thyroid Cancer: Molecular Basis of Redifferentiation Therapies, Management, and Novel Therapies.

Recurrent, metastatic disease represents the most frequent cause of death for patients with thyroid cancer, and radioactive iodine (RAI) remains a mainstay of therapy for these patients. Unfortunately, many thyroid cancer patients have tumors that no longer trap iodine, and hence are refractory to RAI, heralding a poor prognosis. RAI-refractory (RAI-R) cancer cells result from the loss of thyroid differentiation features, such as iodide uptake and organification. This loss of differentiation features correlates with the degree of mitogen-activated protein kinase (MAPK) activation, which is higher in tumors with BRAF (B-Raf proto-oncogene) mutations than in those with RTK (receptor tyrosine kinase) or RAS (rat sarcoma) mutations. Hence, inhibition of the mitogen-activated protein kinase kinase-1 and -2 (MEK-1 and -2) downstream of RAF (rapidly accelerated fibrosarcoma) could sensitize RAI refractivity in thyroid cancer. However, a significant hurdle is the development of secondary tumor resistance (escape mechanisms) to these drugs through upregulation of tyrosine kinase receptors or another alternative signaling pathway. The sodium iodide symporter (NIS) is a plasma membrane glycoprotein, a member of solute carrier family 5A (SLC5A5), located on the basolateral surfaces of the thyroid follicular epithelial cells, which mediates active iodide transport into thyroid follicular cells. The mechanisms responsible for NIS loss of function in RAI-R thyroid cancer remains unclear. In a study of patients with recurrent thyroid cancer, expression levels of specific ribosomal machinery-namely PIGU (phosphatidylinositol glycan anchor biosynthesis class U), a subunit of the GPI (glycosylphosphatidylinositol transamidase complex-correlated with RAI avidity in radioiodine scanning, NIS levels, and biochemical response to RAI treatment. Here, we review the proposed mechanisms for RAI refractivity and the management of RAI-refractive metastatic, recurrent thyroid cancer. We also describe novel targeted systemic agents that are in use or under investigation for RAI-refractory disease, their mechanisms of action, and their adverse events.

Efficacy of posttreatment radioiodine scanning in patients with differentiated thyroid cancer.

BACKGROUND: Differentiated thyroid cancers often require radioiodine treatment followed by posttreatment scan. We aimed in this study to assess the utility of the posttreatment radioiodine scan in this population. METHODS: An analysis of patients who received radioiodine treatment at Rambam Campus, during 2006-2013. Scans showing remnant normal thyroid tissue were considered as normal. Positive uptake was defined as uptake in the lateral neck or distant sites. RESULTS: A total of 455 patients were analyzed, 68% had T1-T2 and 28% had positive lymph nodes. Positive uptake in the lateral neck was recorded in 52 (11.4%) and in distant sites in 41 (9%) patients. Tracheal invasion, esophageal invasion, nerve invasion, and N1b classification were associated with a positive scan (P < .05). A positive radioactive iodine scan was not related to poor prognosis. CONCLUSIONS: Posttreatment scans are positive in only 20% of patients. Locally invasive tumor and positive nodes are associated with positive scans.

L1CAM induces perineural invasion of pancreas cancer cells by upregulation of metalloproteinase expression.

Pancreas cancer cells have a tendency to invade along nerves. Such cancerous nerve invasion (CNI) is associated with poor outcome; however, the exact mechanism that drives cancer cells to disseminate along nerves is unknown. Immunohistochemical analysis of human pancreatic ductal adenocarcinoma (PDAC) specimens showed overexpression of the L1 cell adhesion molecule (L1CAM) in cancer cells and in adjacent Schwann cells (SC) in invaded nerves. By modeling the neural microenvironment, we found that L1CAM secreted from SCs acts as a strong chemoattractant to cancer cells, through activation of MAP kinase signaling. L1CAM also upregulated expression of metalloproteinase-2 (MMP-2) and MMP-9 by PDAC cells, through STAT3 activation. Using a transgenic Pdx-1-Cre/KrasG12D /p53R172H (KPC) mouse model, we show that treatment with anti-L1CAM Ab significantly reduces CNI in vivo. We provide evidence of a paracrine response between SCs and cancer cells in the neural niche, which promotes cancer invasion via L1CAM secretion.

RET, a targetable driver of pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) remains a deadly disease, affecting about 40,000 individuals in the United States annually. We aimed to characterize the role of RET as a co-driver of pancreas tumorigenesis. To assess the role of RET as a co-driver of PDA, we generated a novel triple mutant transgenic mouse based on the cre-activated p53R172H gene and a constitutively active RET M919T mutant (PRC). Survival analysis was performed using Kaplan-Meier analysis. Study of human PDA specimens and Pdx-1-Cre/KrasG12D /p53R172H (KPC) mice revealed that RET is upregulated during pancreas tumorigenesis, from inception through precursor lesions, to invasive cancer. We demonstrated that activation of RET is capable of inducing invasive pancreatic carcinomas in the background of the P53 inactivation mutation. Compared to KPC mice, PRC animals had distinct phenotypes, including longer latency to tumor progression, longer survival, and the presence of multiple macrometastases. Enhanced activation of the MAPK pathway was observed as early as the PanIN 2 stage. Sequencing of the exonic regions of KRAS in PRC-derived PDA cells revealed no evidence of KRAS mutations. RET can be an essential co-driver of pancreatic tumorigenesis in conjugation with KRAS activity. These data suggest that RET may be a potential target in the treatment of PDA.

The role of adjuvant treatment in early-stage oral cavity squamous cell carcinoma: An international collaborative study.

BACKGROUND: Up to half of patients with oral cavity squamous cell carcinoma (OCSCC) have stage I to II disease. When adequate resection is attained, no further treatment is needed; however, re-resection or radiotherapy may be indicated for patients with positive or close margins. This multicenter study evaluated the outcomes and role of adjuvant treatment in patients with stage I to II OCSCC. METHODS: Overall survival (OS), disease-specific survival, local-free survival, and disease-free survival rates were calculated with Kaplan-Meier analysis. RESULTS: Of 1257 patients with T1-2N0M0 disease, 33 (2.6%) had positive margins, and 205 (16.3%) had close margins. The 5-year OS rate was 80% for patients with clear margins, 52% for patients with close margins, and 63% for patients with positive margins (P < .0001). In a multivariate analysis, age, depth of invasion, and margins were independent predictors of outcome. Close margins were associated with a >2-fold increase in the risk of recurrence (P < .0001). The multivariate analysis revealed that adjuvant treatment significantly improved the outcomes of patients with close/positive margins (P = .002 to .03). CONCLUSIONS: Patients with stage I to II OCSCC and positive/close margins have poor long-term outcomes. For this population, adjuvant treatment may be associated with improved survival. Cancer 2018;124:2948-55. © 2018 American Cancer Society.