Trends in Swallowing Outcomes Following Deintensified Treatment in Selected p16+ Oropharyngeal Carcinoma

OBJECTIVE: Identify trends in swallowing outcomes in p16+ oropharyngeal squamous cell carcinoma following neoadjuvant chemotherapy+surgery (NAC+S) versus neoadjuvant chemotherapy+surgery+radiation (NAC+S+R). STUDY DESIGN: Cohort study. SETTING: Single academic institution. METHODS: Swallowing outcome was measured using a validated questionnaire, MD Anderson Dysphagia Inventory (MDADI). MDADI scores were compared between NAC+S and NAC+S+R groups in short-term (\u3c1 year), middle-term (1-3 years), and long-term (\u3e3 years). Clinical factors associated with MDADI scores were explored using a linear mixed model. Statistical significance was established at  \u3c .05. RESULTS: Sixty-seven patients met the inclusion criteria and were divided into 2 groups: NAC+S (57 [85.1%]) and NAC+S+R (10 [14.9%]). All patients had improved MDADI scores in the middle-term compared to short-term (NAC+S: score increase = 3.43,  = .002; NAC+S+R: score increase = 11.18,  = .044), long-term compared to short-term (NAC+S: score increase = 6.97,  \u3c .001; NAC+S+R: score increase = 20.35,  \u3c .001), and long-term compared to middle-term (NAC+S: score increase = 3.54,  = .043; NAC+S+R: score increase = 9.18,  = .026). NAC+S patients had better MDADI scores than NAC+S+R patients at short-term (83.80 vs 71.26,  = .001). There was no significant difference in swallowing function in the middle-term or long-term. CONCLUSION: Regardless of treatment type, swallowing will likely be improved in the middle-term and long-term compared to the short-term. Patients treated with NAC+S+R will have worse short-term swallowing function. However, in the middle-term and long-term, there is no significant difference in swallowing function between patients treated with NAC+S and NAC+S+R

Comparison of quality of life outcomes in a de-intensification treatment regimen for p16 + oropharyngeal cancer

BACKGROUND: Platinum and taxane-based neoadjuvant chemotherapy with surgery (NAC + S) is a novel de-intensified treatment modality that is currently under investigation. METHODS: 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. RESULTS: 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). CONCLUSION: NAC + S offers favorable long-term QOL, as evidenced by near-normal scores in most QOL domains

Swallowing Function Following Neoadjuvant Chemotherapy and Transoral Robotic Surgery for Oropharyngeal Carcinoma: A 2-Year Follow-up

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 \u3c65 years old ( = .036) and lower clinical TNM stage ( = .04), as well as higher composite, emotional, functional, and physical MDADI scores ( = .017, .046, .013, and .05, respectively). CONCLUSION: Patients with OPSCC who were treated with NAC+S achieved satisfactory long-term swallowing outcomes. Unilateral neck dissection was significantly associated with higher MDADI scores in this patient cohort

The Ins(1,3,4)P(3) 5/6-kinase/Ins(3,4,5,6)P(4) 1-kinase is not a protein kinase

Among inositol phosphate kinases, Ins(3,4,5,6)P(4) 1-kinase has been considered to be an outsider with disparate sequence, a proclaimed capacity to also phosphorylate proteins and apparent 1-phosphatase activity. Such multifunctionality, coupled with ignorance of its operational domains, complicates any mechanistic rationale behind literature reports that Ins(3,4,5,6)P(4) 1-kinase regulates apoptosis, salt and fluid secretion, and transcription. We have expressed poly(His)-tagged human Ins(3,4,5,6)P(4) 1-kinase in Sf9 insect cells and purified the enzyme using Ni–agarose chromatography. Protein kinase activity was eluted from the Ni–agarose column, but this did not co-elute with the Ins(3,4,5,6)P(4) 1-kinase, indicating that the protein kinase and inositol kinase activities belong to separate proteins. To pursue this conclusion, we prepared catalytically inactive mutants of the Ins(3,4,5,6)P(4) 1-kinase by identifying and targeting the ATP-binding site. Our strategy was based on sequence alignments suggesting homology of the Ins(3,4,5,6)P(4) 1-kinase with ATP-grasp metabolic enzymes. Individual mutation of four candidate MgATP-binding participants, Lys(157), Asp(281), Asp(295) and Asn(297), severely compromised Ins(3,4,5,6)P(4) 1-kinase activity. Yet, these mutations did not affect the protein kinase activity. We conclude that the Ins(3,4,5,6)P(4) 1-kinase is not a protein kinase, contrary to earlier reports [e.g. Wilson, Sun, Cao and Majerus (2001) J. Biol. Chem. 276, 40998–41004]. Elimination of protein kinase activity from the enzyme's repertoire and recognition of its ATP-grasp homology together indicate that structural, functional and catalytic relationships between Ins(3,4,5,6)P(4) 1-kinase and other inositol phosphate kinases are closer than previously thought [Gonzalez, Schell, Letcher, Veprintsev, Irvine and Williams (2004) Mol. Cell 15, 689–701]

\u3ci\u3eDrosophila\u3c/i\u3e Muller F Elements Maintain a Distinct Set of Genomic Properties Over 40 Million Years of Evolution

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu