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Squamous cell carcinoma predominates as the most common malignant lesion of the oropharynx with human papilloma virus-associated disease now predominant over tobacco-related oropharynx cancer. Other rare malignant pathologies can manifest as visible neoplasms in these anatomic sites with varying degrees of symptoms such as dysphagia, odynophagia, otalgia, aspiration, hemorrhage, weight loss and dyspnea. We present a case of a rarely encountered primary oropharyngeal sarcoma managed by single-port transoral robotic resection and a selective cervical lymph node dissection followed by adjuvant radiotherapy.

To identify social, demographic, and clinical barriers for implantation with Osseointegrated Bone Conduction Devices (OBCD) in pediatric candidates.Retrospective cohort study of 94 children who met standard OBCD implantation criteria.Tertiary stand-alone children's hospital.Retrospective chart review comparing demographic (age, race, state of residence, and insurance) and clinical (severity and etiology of hearing loss, medical comorbidities, and early intervention) factors impacting implantation. Members of the existing cohort were then contacted to obtain a better understanding of qualitative factors impacting surgical decision.Of the identified 94 surgical candidates, 47 (50%) underwent OBCD implantation. State of residence significantly impacted implantation rates, with children from the District of Columbia and Virginia being less likely to receive an implant than those from Maryland. Private insurance, race, and ethnicity did not impact rate of implantation (OR 2.8 [95% CI 0.78-10]; 1.34 [95% CI 0.44-3.68]; and 1.0 [95% CI 0.42-2.43], respectively). Children with anotia or microtia and children younger than 10 years old were less likely to have an implant (OR 10.6 (95% CI 1.74-65). Thirty-nine children participated in the qualitative portion. Themes that emerged as reasons to forgo implantation included a child's young age, planned reconstruction for microtia or atresia, and overall device functionality and usage. Thirtyseven children (39%) of the cohort declined surgery and currently wear a nonsurgical bone conduction aid regularly.Despite known benefits of implantation, only one-half of children who were candidates underwent OBCD. Unlike cochlear implantation, where insurance status is a major risk factor for implantation delay and underperformance, for OBCD, implantation barriers appear to be more multifactorial and include medical, demographic, and social factors.

Site-selective oxidations of carbohydrates, employing acridinium photocatalysis and quinuclidine hydrogen atom transfer catalysis, are presented. Protocols have been developed for oxidations of all-equatorial carbohydrates as well as those containing cis-1,2-diols. Site-selectivity reflects the relative rates of hydrogen atom transfer from the carbohydrate C-H bonds, and can be enhanced using a phosphate hydrogen-bonding or boronic acid catalyst.

Platinum and taxane-based neoadjuvant chemotherapy with surgery (NAC + S) is a novel de-intensified treatment modality that is currently under investigation.All patients treated for HPV positive OPSCC with NAC + S at a single institution between 2006 and 2020 were contacted to complete the University of Washington Quality of life questionnaire (UW-QOL) at least 2 years following the completion of treatment.The UW-QOL surveys were received from 25 of 48 eligible patients (52.1%). The mean follow-up time was 4.3 years (range 2.0-7.6 years). The overall mean score for the physical subscale was 92.4 (Standard deviation, SD = 10.9), and the social-emotional subscale was 91.1 (11.8). Compared to the normative cohort, the NAC + S cohort had a worse appearance (Mean scores Normative vs. NAC + S: 93 vs. 84.0, p = 0.009).NAC + S offers favorable long-term QOL, as evidenced by near-normal scores in most QOL domains.

OBJECTIVE To evaluate 2-year follow-up swallowing function in patients with human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV+ OPSCC) who completed neoadjuvant chemotherapy and transoral robotic surgery (NAC+S). STUDY DESIGN Retrospective analysis of patients with OPSCC treated with NAC+S between 2010 and 2021. SETTING A single academic institution. METHODS This is a cross-sectional study of patient-reported swallowing function, assessed with the MD Anderson Dysphagia Inventory (MDADI) at least 2 years after completion of treatment. The inclusion criteria are patients with HPV+ OPSCC who underwent NAC+S at least 2 years ago. Those requiring adjuvant radiation or chemoradiation or experiencing relapse were excluded from the study. RESULTS Completed MDADIs were received from 37 patients at a median 3.8 years posttreatment (interquartile range, 2.0-8.6 years). Of those, 94.6% (n = 35) were male and 81.1% (n = 30) were White. The median age at OPSCC diagnosis was 59.0 years (interquartile range, 41-80 years). The most frequent primary subsite of OPSCC was the base of the tongue (n = 20, 54.1%), followed by the tonsils (n = 16, 43.2%). In addition, 75.7% (n = 28) had stage IVa disease (TNM seventh edition), and 29 (78.4%) had scores ≥80, classified as optimal function. When compared with patients who received bilateral neck dissection, patients who received unilateral neck dissection were associated with an age

Recurrent respiratory papillomatosis is a condition caused by human papilloma virus, usually sub types 6 and 11. Papillomas are benign neoplasms that are most commonly found on the larynx and can be often associated with significant airway involvement. Frequency of episodes varies among patients as do the clinical symptoms. Patients often present with symptoms such as hoarseness but there is potential for respiratory compromise and even complete airway obstruction.

Microfluidic devices can be used to explore a vast range of phenomena in biophysics and soft-matter physics. While the popularity of these devices is in part driven by the ease of soft-lithography, most research labs still depend upon expensive, clean-room fabrication of photoresist molds, which can make this technique inaccessible to the undergraduate laboratory. However, there are much simpler, if coarser, approaches to designing molds that are capable of producing surprisingly complicated devices. Here, we detail the fabrication and characterization of a microfluidic device for flow cytometry or particle sorting on a chip. Our device is a layered polydimethylsiloxane chip that uses a series of Quake valves to sort. The molds were fabricated on equipment accessible to most undergraduate labs. The techniques and physics we discuss in this manuscript can be employed to create an almost endless variety of devices for learning about complex fluid mechanics, mesoscopic, soft-matter, and biological physics.Microfluidic devices can be used to explore a vast range of phenomena in biophysics and soft-matter physics. While the popularity of these devices is in part driven by the ease of soft-lithography, most research labs still depend upon expensive, clean-room fabrication of photoresist molds, which can make this technique inaccessible to the undergraduate laboratory. However, there are much simpler, if coarser, approaches to designing molds that are capable of producing surprisingly complicated devices. Here, we detail the fabrication and characterization of a microfluidic device for flow cytometry or particle sorting on a chip. Our device is a layered polydimethylsiloxane chip that uses a series of Quake valves to sort. The molds were fabricated on equipment accessible to most undergraduate labs. The techniques and physics we discuss in this manuscript can be employed to create an almost endless variety of devices for learning about complex fluid mechanics, mesoscopic, soft-matter, and biological physics.

Diorganotin dihalides act as cocatalysts for site-selective and stereoselective couplings of diol-containing carbohydrates with electron-deficient alkenes in the presence of an Ir(III) photoredox catalyst and quinuclidine, a hydrogen atom transfer mediator. Quantum-chemical calculations support a proposed mechanism involving the formation of a cyclic stannylene acetal intermediate that shows enhanced reactivity toward hydrogen atom abstraction by the quinuclidinium radical cation. Addition of the carbon-centered radical to the alkene partner results in C-alkylation of the carbohydrate substrate.

The objective of this systematic review and meta-analysis was to evaluate the diagnostic performance of the second-generation molecular tests in the diagnosis of thyroid nodules with indeterminate fine-needle aspiration biopsy results.We searched PubMed, Google Scholar, Scopus, and Cochrane Library for studies published between January 2017 and March 2021. Inclusion criteria were indeterminate thyroid results from fine-needle aspiration (FNA) that included Bethesda categories III and IV, use of Afirma GSC, Thyroseq v3, and ThyGeNext as an index test, and conclusive histopathological results. Studies with no post-surgical diagnoses were excluded. For each included study, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were obtained. Sensitivity and specificity were pooled jointly using a bivariate binomial random-effects model. Statistical significance was indicated at p-value less than 0.05.Our search yielded 431 non-duplicate articles, of which 15 were included in the study (7 GSC, 6 Thyroseq v3, and 2 ThyGeNext). ThyGeNext studies were excluded from the meta-analysis due to the small sample size. Pooled data for GSC studies on 472 thyroid nodules showed a sensitivity of 96.6 (95% confidence interval: 89.7-98.9%), specificity of 52.9% (23.4-80.5%), PPV of 63% (51-74%), and NPV of 96% (94-98%). Pooled data for ThyroSeq studies on 530 thyroid nodules showed a sensitivity of 95.1% (91.1-97.4%), specificity of 49.6% (29.3-70.1%), PPV of 70% (55-83%), and NPV of 92% (86-97%). There was no statistically significant difference in diagnostic performances of the two tests (p-values for sensitivity = 0.89, specificity = 0.82, PPV = 0.43, NPV = 0.17).High sensitivity and high NPV in GSC and Thyroseq v3 have potential to help rule out malignancy among thyroid nodules with indeterminate cytology results. There was no difference in diagnostic performances between the two molecular tests indicating that either test is appropriate to determine the malignancy of thyroid nodules. Further long-term outcome data are warranted to make a clear recommendation.

Hairy cell leukemia (HCL) is a purine analog-responsive B-cell malignancy containing the BRAF V600E mutation, expressing CD22, CD11c, CD103, tartrate resistant acid phosphatase (TRAP) CD25, CD123, and annexin 1A. BRAF V600E and the latter 4 markers are usually absent in the more aggressive and chemoresistant variant HCLv. To evaluate differences between HCL and HCLv, expression microarrays comparing HCL with HCLv were performed for 24694 genes using 47323 probes. Microarray data from 35 HCL and 27 HCLv purified samples showed the greatest HCL-HCLv difference in the muscle-associated gene MYF6, expressed by its 2 probes 18.5- and 10.8-fold higher in HCL than HCLv (p

Sulfated carbohydrates have been implicated in diverse biological processes, with the position and extent of sulfation of a glycoside often playing important roles in determining the affinity and specificity of its binding to a biomolecular partner. Methods for the site-selective introduction of sulfate groups to carbohydrates are thus of interest. Here, we describe the development of a diarylborinic acid-catalyzed protocol for selective sulfation of pyranoside derivatives at the equatorial position of a cis-1,2-diol group. This method, which employs the sulfur trioxide-trimethylamine complex as the electrophile, has been employed for installation of a sulfate group at the 3-position of a range of galacto- and mannopyranosides, including substrates having a free primary OH group. By using a full equivalent of the diarylborinic acid, selective syntheses of more complex monosulfated glycosides, namely, a 3'-sulfolactose derivative and 3'-sulfo-β-galactosylceramide, have been accomplished. Preliminary kinetics experiments suggested that the catalyst resting state is a tetracoordinate diarylborinic ester that reacts with the SO

An approach to the synthesis of libraries of chiral phosphine ligands is described, using condensations of 2-formylarylboronic acids, diols or related compounds, and aminophosphines. The three-component nature of this condensation, along with the ready availability of the building blocks, enables the rapid generation of diverse structures. From a library of iminoboronate-derived phosphines, three ligands that gave 90% ee or greater in a benchmark palladium-catalyzed allylic substitution reaction were identified. Significant variation of selectivity as a function of the structure of each component was observed. 11B NMR spectroscopy was used to evaluate the existence of B–N interactions in the free ligands as well as their Pd-derived complexes. A bidentate P,N-coordination mode was inferred for ligands that gave high enantioselectivity in the allylic substitution reaction. Abbreviation: BINOL: 1,1'-bi-2-naphthol; BSA: N,O-bis(trimethylsilyl)acetamide; DIOP: (2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane; HPLC: high-performance liquid chromatography; NMR: nuclear magnetic resonance; THF: tetrahydrofuran

Recombinant immunotoxins are composed of fragments of monoclonal antibodies (Mabs) and protein toxins, enabling the toxin to bind to a target cell recognized by the antibody, and the toxin to kill the cell after internalization. Recombinant immunotoxins are similar to but distinct from growth-factor fusions toxins like denileukin diftitox and Tagraxofusp, FDA-approved in 1999 and 2018, respectively. Unlike chemical conjugates, Recombinant immunotoxins have a peptide that links the cell-binding to the toxin domains. After proteolytic cleavage, the toxin separates from the binding domain, undergoes intracellular trafficking and enters the cytosol, resulting in apoptotic cell death. Recombinant immunotoxins containing Pseudomonas exotoxin A contain an Fv or Fab fragment of a Mab replacing the native cell-binding toxin domain. The first recombinant immunotoxin we made contained an anti-CD25 single-chain Fv fused to a 38 kDa fragment of Pseudomonas exotoxin called PE38. Anti-CD25 recombinant immunotoxin LMB-2 was active in several hematologic malignancies, notably hairy cell leukemia (HCL) and adult T-cell leukemia (ATL). LMB-2 achieved a high complete remission (CR) rate in ATL when combined with chemotherapy to reduce immunogenicity and progression between cycles. Improved targeting of HCL was achieved with anti-CD22 recombinant immunotoxin Moxetumomab Pasudotox (Moxe) that was stabilized with a disulfide bond in the Fv and has a high affinity for CD22. Moxe achieved investigator-assessed CR rates of 51-64% in relapsed/refractory HCL in Phase 1 and 3 trials, leading to FDA-approval in 2018. Minimal residual disease (MRD) was negative in most CRs. On the phase I trial, which had adequate follow-up, MRD eradication by the most sensitive standard assay, flow cytometry of the bone marrow aspirate (BMA), was associated with longer CR duration. Extra or ‘consolidation’ cycles past documentation of CR was also associated with longer CR duration. To detect MRD with higher sensitivity, patient specific immunoglobulin heavy chain (IgH) rearrangements were cloned and real-time quantitative PCR (RQ-PCR) performed. Using patient-specific primers and probe, 1 HCL cell could be detected in 106 normal cells. We found that phase 1-3 patients achieving MRD-free CR by blood RQ-PCR had significantly prolonged CR duration (p Citation Format: Robert Kreitman, Daniel Gorelik, Maryalice Stetler-Stevenson, Constance M Yuan, Hao-Wei Wang, Hong Zhou, Katherine Potocka, Erin Fykes, Evgeny Arons, Ira Pastan. Recombinant immunotoxins for hematologic malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr CN07-03. doi:10.1158/1535-7163.TARG-19-CN07-03

BACKGROUND: Hairy cell leukemia (HCL) is an indolent B-cell malignancy strongly expressing CD22, with high sensitivity to purine analog chemotherapy, but relapses frequently occur, associated with minimal residual disease (MRD). Targeted non-chemotherapeutic approaches have shown efficacy but leave MRD. Moxetumomab pasudotox is an anti-CD22 recombinant immunotoxin recently reported in relapsed/refractory HCL to achieve 57% and 51% complete remission (CR) rates in phase 1 and 3 testing, respectively. Eradication of MRD by bone marrow flow cytometry or immunohistochemistry was associated with improved CR duration. We have previously reported that Taqman real-time quantitative PCR (RQPCR), which amplifies patient- and HCL-specific B-cell immunoglobulin rearrangements (IGHV), can detect one HCL cell in 106 normal cells. In the present study we determined whether MRD eradication measured by RQPCR is associated with improved CR duration. METHODS: A total of 28 patients achieving CR to moxetumomab pasudotox in phase 1 (n=18) and phase 3 (n=10) trials were studied at the National Institutes of Health by multicolor flow cytometry of the bone marrow aspirate (BMA) and blood. Patients received moxetumomab pasudotox at 40-50 mcg/Kg on days 1, 3 and 5 of 2-7 cycles (median 5) at 4-week intervals. Blood and bone marrow samples were obtained to determine CR. In addition to end of treatment, bone marrow samples for MRD were generally obtained every 6-12 months for 2.5 years, then every other year. Blood flow cytometry was obtained every 6 months for 2.5 years, then yearly. Follow-up (time since treatment initiation) was 26.9-121.8 (median 84) months. For this analysis, CR for each bone marrow time point was determined by standard criteria for all patients independent of specific data-reporting requirements and data cut-off time points. RQPCR testing for each patient required cloning the immunoglobulin heavy chain variable regions and designing sequence-specific primers and probes. RNA samples were made from PAXgene tubes of blood and sodium-heparin tubes of BMA. RESULTS: We found that BMA RQPCR was most sensitive, followed by BMA flow cytometry, blood RQPCR, and blood flow cytometry. Of the 28 patients studied, 12 (43%) achieved MRD-free CR by all 4 tests and 2 of 12 patients (17%) relapsed. Seven (25%) were MRD+ by BMA RQPCR but negative by the other 3 studies, and none relapsed. One patient RQPCR+ and flow-negative in both blood and BMA relapsed. Seven patients flow-negative but RQPCR+ in blood, flow+ in BMA, and either BMA RQPCR+ or RQPCR not done, all relapsed. One patient with BMA RQPCR not done and the other 3 studies positive relapsed. With respect to RQPCR of blood as a single test, 3 of 20 negative vs 8 of 8 positive patients relapsed (p CONCLUSIONS: RQPCR negativity of blood is strongly associated with prolonged CR duration after moxetumomab pasudotox and may be a useful measure of MRD when bone marrow studies cannot be done. Additional testing will be needed to determine if blood RQPCR can be used to determine the optimal number of cycles of immunotoxin to administer. BMA RQPCR, though more sensitive than blood RQPCR, was not as useful due to fewer patients being evaluable and more time needed for BMA-RQPCR+ patients to relapse. Additional testing and follow-up may determine if BMA RQPCR negativity will correlate significantly with CR duration. Figure. Figure. Disclosures Yao: MedImmune: Employment. Marshall:MedImmume: Employment. Pastan:NIH: Patents & Royalties: Co-inventor on the NIH patent for Moxetumomab Pasudotox. Kreitman:NIH: Patents & Royalties: Co-inventor on the NIH patent for Moxetumomab Pasudotox.