Factors associated with successful electrolarynx use after total laryngectomy, a multi-institutional study.

Objective: To identify characteristics associated with successful electrolarynx (EL) use after total laryngectomy (TL). Methods: Records of 196 adults who underwent TL from 03/15/2012 to 03/15/2022 at the University of Washington and Puget Sound Veterans Affairs were reviewed. Characteristics included age, Charlson Comorbidity Index, social support, pre-operative radiation (RT) and chemoradiation (CRT), and 6-month post-TL swallow status. EL success was evaluated using pre-defined criteria of intelligibility, reliability, and independence with use. Poisson regressions and robust standard error estimates were used to estimate unadjusted risk ratios for each characteristic. Statistically significant characteristics were included in multivariate analysis (MVA) to estimate adjusted risk ratios. Results: Median age was 64, median Charlson Comorbidity Index was 5, 170 (87%) were male, 159 (81%) had high social support, and 159 (81%) attained post-TL full-oral diet. Pre-operatively, 110 (56%) had RT, including 55 (28%) with CRT. Ninety-three (47%) met our criteria for EL success. Characteristics significantly associated with EL success included social support (p = .037) and post-TL full-oral diet (p = .037); both approached significance on MVA. EL success varied by pre-operative treatment on univariate (p = .005) and MVA (p = .014). Compared to no prior RT or CRT, the probability of EL success was 29% higher with prior RT and 29% lower with prior CRT in MVA, although these associations did not reach significance. Conclusions: In this retrospective review, EL success correlated with high social support, post-TL full-oral diet, and pre-operative treatment history. These results warrant validation in a larger prospective study to help guide the choice of voice rehabilitation modalities or intensified speech therapy. Level of Evidence: 4.

Peripheral lymphocytes and lactate dehydrogenase correlate with response and survival in head and neck cancers treated with immune checkpoint inhibitors.

BACKGROUND: Little is known regarding associations between peripheral blood biomarkers (PBBMs) and survival, response, and toxicity in recurrent/metastatic head and neck squamous cell carcinomas (R/M HNSCC) treated with immune checkpoint inhibitors (ICIs). METHODS: In this single-institution retrospective cohort study, a dataset of patients with R/M HNSCC treated with ICIs between 08/2012-03/2021 was established, including demographic and clinicopathologic characteristics. Pretreatment PBBMs were collected and evaluated for associations with grade ≥3 adverse events (G ≥ 3AE) by CTCAEv5, objective response (ORR) by RECIST 1.1, overall survival (OS), and progression-free survival (PFS). Multivariable models for each outcome were created using elastic net variable selection. RESULTS: Our study included 186 patients, with 51 (27%) demonstrating complete or partial response to immunotherapy. Multivariable models adjusted for ECOG performance status (PS), p16, and smoking demonstrated that pretreatment higher LDH and absolute neutrophils, as well as lower percent lymphocytes correlated with worse OS and PFS. Higher LDH and lower % lymphocytes also correlated with worse ORR. CONCLUSIONS: In the largest study to date examining PBBMs in ICI-treated R/M HNSCCs, our variable selection method revealed PBBMs prognostic for survival and response to immunotherapy. These biomarkers warrant further investigation in a prospective study along with validation with CPS biomarker.

Neutrophil to lymphocyte ratio and peripheral blood biomarkers correlate with survival outcomes but not response among head and neck and salivary cancer treated with pembrolizumab and vorinostat.

BACKGROUND: Associations between peripheral blood biomarkers and oncologic outcomes were explored in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HN) and salivary gland cancer (SGC) treated with pembrolizumab and vorinostat on a phase II trial (NCT02538510). EXPERIMENTAL DESIGN: Twenty-five HN and 25 SGCs were treated with pembrolizumab and vorinostat. Baseline peripheral blood was available in 21 HN and 20 SGCs and evaluated for associations with grade ≥3 adverse events (G ≥ 3AE) by CTCAEv4, objective response rate (ORR), overall survival (OS), and progression-free survival (PFS). RESULTS: Higher pretreatment neutrophil-to-lymphocyte ratio (NLR) and neutrophils, as well as lower pretreatment lymphocytes and T helper cells correlated with worse OS and PFS. Higher NLR further predicted increased rates of G ≥ 3AEs. No correlations with ORR were observed. CONCLUSIONS: In a prospectively evaluated cohort of HN and SGCs treated with pembrolizumab and vorinostat, we observed novel associations between peripheral blood biomarkers and oncologic outcomes and toxicities.

Oral Cancer: What the General Surgeon Should Know.

Oral cavity cancer represents a heterogeneous group of cancers with unique etiologic, diagnostic, and treatment considerations based on the subsite. While decreases in smoking have resulted in the development of fewer oral cavity cancers, the incidence remains high in certain geographic areas. History and physical examination, as well as tissue biopsy, are key to diagnosis. Although surgical resection is the primary treatment modality for oral cavity cancer, the optimal treatment plan for a patient is an individualized approach accounting for comorbidities, goals of care, and functional outcomes related to speech and swallowing.

NSD1 mutations by HPV status in head and neck cancer: differences in survival and response to DNA-damaging agents.

BACKGROUND: Compared to HPV-negative head and neck squamous cell carcinomas (HNSCCs), HPV-positive HNSCCs are associated with a favorable prognosis in part due to their improved treatment sensitivity. Inactivating mutations in NSD1 were shown to be a favorable prognostic biomarker in laryngeal cancers. Here, we characterize NSD1 mutations from the expanded The Cancer Genome Atlas (TCGA) HNSCC cohort (n = 522) and examine their prognostic implications based on HPV status of the tumor. We also begin to examine if NSD1 regulates response to platinum-based drugs and other DNA-damaging agents. METHODS: TCGA HNSCC samples were segregated by HPV and NSD1 mutations using cBioPortal and patient survival was determined. Pathogenicity of mutations was predicted using UMD-Predictor. NSD1-depleted cell lines were established by transfection with control or shRNAs against NSD1, followed by puromycin selection, and confirmed by qRT-PCR. Cell sensitivity to DNA damaging agents was assessed using short-term proliferation and long-term clonogenic survival assays. RESULTS: Among 457 HPV(-) tumors, 13% contained alterations in the NSD1 gene. The majority (61.3%) of NSD1 gene alterations in HPV(-) specimens were truncating mutations within or before the enzymatic SET domain. The remaining alterations included homozygous gene deletions (6.7%), missense point mutations (30.7%) and inframe deletions (1.3%). UMD-Predictor categorized 18 of 23 missense point mutations as pathogenic. For HPV(+) HNSCC (n = 65), 6 NSD1 mutations, comprised of two truncating (33%) and 4 missense point (66%) mutations, were identified. Three of the 4 missense point mutations were predicted to be pathogenic or probably pathogenic by UMD-Predictor. Kaplan-Meier survival analysis determined significantly improved survival of HPV(-) HNSCC patients whose tumors harbored NSD1 gene alterations, as compared to patients with wild-type NSD1 tumors. Interestingly, the survival effect of NSD1 mutations observed in HPV-negative HNSCC was reversed in HPV(+) tumors. Proliferation and clonogenic survival of two HPV(-) cell lines stably expressing control or NSD1 shRNAs showed that NSD1-depleted cells were more sensitive to cisplatin and carboplatin, but not to other DNA damaging drugs. CONCLUSIONS: Genetic alterations in NSD1 hold potential as novel prognostic biomarkers in HPV(-) head and neck cancers. NSD1 mutations in HPV(+) cancers may also play a prognostic role, although this effect must be examined in a larger cohort. NSD1 downregulation results in improved sensitivity to cisplatin and carboplatin, but not to other DNA-damaging agents, in epithelial cells. Increased sensitivity to platinum-based chemotherapy agents associated with NSD1 depletion may contribute to improved survival in HPV(-) HNSCCs. Further studies are needed to determine mechanisms through which NSD1 protects HPV(-) HNSCC cells from platinum-based therapy, as well as confirmation of NSD1 effect in HPV(+) HNSCC.

Endoscope-assisted resection of intravestibular Schwannoma: A video case report.

Intravestibular schwannomas are a rare cause of unilateral sensorineural hearing loss. Management of these tumors involves translabyrinthine resection, for which complete visualization around the angles of the vestibule may be limited under an operating microscope. We present the first reported case of an endoscope-assisted resection of an intravestibular schwannoma, along with the operative video recording. Using additional information gained from endoscopic examination of the tumor and its resection site, we also propose a mechanism by which this patient's intravestibular schwannoma caused hearing loss. Use of the endoscope in resection of intravestibular schwannomas may have advantages over the traditional operating microscope in improving visualization of the narrow and angled vestibule, confirming the integrity of surrounding structures, and ensuring complete tumor removal. Laryngoscope, 129:986-988, 2019.

HPV-driven oropharyngeal cancer: current knowledge of molecular biology and mechanisms of carcinogenesis.

Understanding of oropharyngeal squamous cell carcinoma has significantly progressed over the last decades, and the concept that this disease can be subdivided into two distinct entities based on human papilloma virus (HPV) status has gained acceptance. To combat the constantly growing epidemic of HPV+ oropharyngeal cancer, further investigation and characterization the unique features of the disease, along with the development and implementation of new, targeted therapies, is crucial. In this review, we summarize the etiology, pathogenesis, diagnosis, treatment, and molecular characteristics of HPV-associated oropharyngeal squamous cell carcinoma.

Discrepancy Between Patient Health Literacy Levels and Readability of Patient Education Materials from an Electronic Health Record.

Limited health literacy is associated with worse health outcomes. It is standard practice in many primary care clinics to provide patients with written patient education materials (PEM), which often come directly from an electronic health record (EHR). We compared the health literacy of patients in a primary care residency clinic with EHR PEM readability by grade level. We assessed health literacy using the Rapid Estimate of Adult Literacy in Medicine-Short Form (REALM-SF), and determined grade level readability for the PEM distributed for the five most common clinical diagnoses using the Simple Measure of Gobbledygook (SMOG) and Flesch-Kincaid metrics. Among 175 participants, health literacy was ≥9th grade for 76 patients (43.4%), 7th to 8th grade for 66 patients (37.7%), and ≤6th grade for 30 patients (17.1%). Average standard PEM readability by SMOG was grade 9.2 and easy-to-read PEM readability was grade 6.8. These findings suggest a discrepancy between the health literacy of most patients who were surveyed and standard PEM readability. Despite national guidelines encouraging clinicians to provide PEM at an appropriate reading level, our results indicate that PEM from EHR may not be readable for many patients. [Health Literacy Research and Practice. 2017;1(4):e203-e207.].

Flexible binding of PNP pincer ligands to monomeric iron complexes.

Transition metal complexes supported by pincer ligands have many important applications. Here, the syntheses of five-coordinate PNP pincer-supported Fe complexes of the type (PNP)FeCl2 (PNP = HN{CH2CH2(PR2)}2, R = iPr ((iPr)PNP), tBu ((tBu)PNP), or cyclohexyl ((Cy)PNP)) are reported. In the solid state, ((iPr)PNP)FeCl2 was characterized in two different geometries by X-ray crystallography. In one form, the (iPr)PNP ligand binds to the Fe center in the typical meridional geometry for a pincer ligand, whereas in the other form, the (iPr)PNP ligand binds in a facial geometry. The electronic structures and geometries of all of the (PNP)FeCl2 complexes were further explored using (57)Fe Mössbauer and magnetic circular dichroism spectroscopy. These measurements show that in some cases two isomers of the (PNP)FeCl2 complexes are present in solution and conclusively demonstrate that binding of the PNP ligand is flexible, which may have implications for the reactivity of this important class of compounds.

Synthesis and structure of six-coordinate iron borohydride complexes supported by PNP ligands.

The preparation of a number of iron complexes supported by ligands of the type HN{CH2CH2(PR2)}2 [R = isopropyl (((i)Pr)PNP) or cyclohexyl ((Cy)PNP)] is reported. This is the first time this important bifunctional ligand has been coordinated to iron. The iron(II) complexes (((i)Pr)PNP)FeCl2(CO) (1a) and ((Cy)PNP)FeCl2(CO) (1b) were synthesized through the reaction of the appropriate free ligand and FeCl2 in the presence of CO. The iron(0) complex (((i)Pr)PNP)Fe(CO)2 (2a) was prepared through the reaction of Fe(CO)5 with ((i)Pr)PNP, while irradiating with UV light. Compound 2a is unstable in CH2Cl2 and is oxidized to 1a via the intermediate iron(II) complex [(((i)Pr)PNP)FeCl(CO)2]Cl (3a). The reaction of 2a with HCl generated the related complex [(((i)Pr)PNP)FeH(CO)2]Cl (4a), while the neutral iron hydrides (((i)Pr)PNP)FeHCl(CO) (5a) and ((Cy)PNP)FeHCl(CO) (5b) were synthesized through the reaction of 1a or 1b with 1 equiv of (n)Bu4NBH4. The related reaction between 1a and excess NaBH4 generated the unusual η(1)-HBH3 complex (((i)Pr)PNP)FeH(η(1)-HBH3)(CO) (6a). This complex features a bifurcated intramolecular dihydrogen bond between two of the hydrogen atoms associated with the η(1)-HBH3 ligand and the N-H proton of the pincer ligand, as well as intermolecular dihydrogen bonding. The protonation of 6a with 2,6-lutidinium tetraphenylborate resulted in the formation of the dimeric complex [{(((i)Pr)PNP)FeH(CO)}2(µ2,η(1):η(1)-H2BH2)][BPh4] (7a), which features a rare example of a µ2,η(1):η(1)-H2BH2 ligand. Unlike all previous examples of complexes with a µ2,η(1):η(1)-H2BH2 ligand, there is no metal-metal bond and additional bridging ligand supporting the borohydride ligand in 7a; however, it is proposed that two dihydrogen-bonding interactions stabilize the complex. Complexes 1a, 2a, 3a, 4a, 5a, 6a, and 7a were characterized by X-ray crystallography.