Tumores en ovario en pediatría / Ovarian tumors in pediatrics

Los tumores de ovario en la edad pediátrica son raros, representan 1-5 % de los tumores infantiles, con una incidencia anual de 2,6 casos por cada 100.000 pacientes. La mayoría son benignos y se tratan de quistes funcionales, sin embargo, entre 10-20 % son malignos y generalmente se presentan en adolescentes; estos últimos, se dividen en 3 grupos: tumores epiteliales, germinales, y estromales o de células sexuales. Método: Estudio retrospectivo de tipo transversal, observacional, no experimental. Se analizaron los pacientes con diagnóstico de tumor de ovario, ingresados en el Servicio de Cirugía Pediátrica del Hospital de Niños "Dr. José Manuel de los Ríos", entre el 1 de enero de 2017 y 01 de julio de 2022. Resultados: 18 pacientes incluidos en el estudio, con edad media de 8,23 años (DE 4,77); los síntomas más frecuentes presentados al momento del ingreso fueron: aumento de volumen abdominal (52,94 %, 9 pacientes), y dolor abdominal (35,29 %, 6 pacientes), entre otros. Reporte patológico: 2 pacientes con quistes de ovario funcional (11,76 %) y 16 pacientes con tumor neoplásico (88,23 %), de los cuales 8 fueron germinales (53,33 %), 5 tumores epiteliales (33,33 %) y 2 pacientes con linfoma (13,33 %). Conclusión: Los tumores de ovario en general tienen una edad promedio de presentación de 8 años y los tumores neoplásicos se presentaron principalmente en adolescentes, siendo el tipo histológico más frecuente el tumor germinal y dentro de este grupo el teratoma quístico maduro. (AU)

Ovarian tumors in pediatric age are rare, representing 1-5 % of childhood tumors, with an annual incidence of 2.6 cases per 100,000 patients. Most of them are benign and functional cysts; however, between 10-20 % are malignant and generally occur in teenagers; the latter are divided into 3 groups: epithelial, germinal, and stromal or sex cell tumors. Methods: Retrospective, cross-sectional, observational, non-experimental study. Patients with a diagnosis of ovarian tumor, admitted to the Pediatric Surgery Service of the Children's Hospital "Dr. José Manuel de los Ríos", between January 01, 2017 and July 01, 2022, were analyzed. Results: 18 patients included in the study, with mean age 8.23 years (SD 4.77); the most frequent symptoms presented at admission were: increased abdominal volume (52.94 %, 9 patients), and abdominal pain (35.29 %, 6 patients), among others. Pathological report: 2 patients with functional ovarian cysts (11.76 %) and 16 patients with neoplastic tumor (88.23 %), of which 8 were germinal (53.33 %), 5 epithelial tumors (33.33 %) and 2 patients with lymphoma (13.33 %). Conclusion: Ovarian tumors in general have an average age of presentation of 8 years and neoplastic tumors occurred mainly in teenagers, the most common histological type being the germ cell tumor and within this group the mature cystic teratoma. (AU)

Pharmacologic Targeting of TFIIH Suppresses KRAS-Mutant Pancreatic Ductal Adenocarcinoma and Synergizes with TRAIL.

Pancreatic ductal adenocarcinoma (PDAC) typically presents as metastatic disease at diagnosis and remains refractory to treatment. Next-generation sequencing efforts have described the genomic landscape, classified molecular subtypes, and confirmed frequent alterations in major driver genes, with coexistent alterations in KRAS and TP53 correlating with the highest metastatic burden and poorest outcomes. However, translating this information to guide therapy remains a challenge. By integrating genomic analysis with an arrayed RNAi druggable genome screen and drug profiling of a KRAS/TP53 mutant PDAC cell line derived from a patient-derived xenograft (PDCL), we identified numerous targetable vulnerabilities that reveal both known and novel functional aspects of pancreatic cancer biology. A dependence on the general transcription and DNA repair factor TFIIH complex, particularly the XPB subunit and the CAK complex (CDK7/CyclinH/MAT1), was identified and further validated utilizing a panel of genomically subtyped KRAS mutant PDCLs. TFIIH function was inhibited with a covalent inhibitor of CDK7/12/13 (THZ1), a CDK7/CDK9 kinase inhibitor (SNS-032), and a covalent inhibitor of XPB (triptolide), which led to disruption of the protein stability of the RNA polymerase II subunit RPB1. Loss of RPB1 following TFIIH inhibition led to downregulation of key transcriptional effectors of KRAS-mutant signaling and negative regulators of apoptosis, including MCL1, XIAP, and CFLAR, initiating caspase-8 dependent apoptosis. All three drugs exhibited synergy in combination with a multivalent TRAIL, effectively reinforcing mitochondrial-mediated apoptosis. These findings present a novel combination therapy, with direct translational implications for current clinical trials on metastatic pancreatic cancer patients. Significance: This study utilizes functional genetic and pharmacological profiling of KRAS-mutant pancreatic adenocarcinoma to identify therapeutic strategies and finds that TFIIH inhibition synergizes with TRAIL to induce apoptosis in KRAS-driven pancreatic cancer.

Synthetic lethal kinases in Ras/p53 mutant squamous cell carcinoma.

The oncogene Ras and the tumor suppressor gene p53 are frequently co-mutated in human cancer and mutations in Ras and p53 can cooperate to generate a more malignant cell state. To discover novel druggable targets for cancers carrying co-mutations in Ras and p53, we performed arrayed, kinome focused siRNA and oncology drug phenotypic screening utilizing a set of syngeneic Ras mutant squamous cell carcinoma (SCC) cell lines that also carried co-mutations in selected p53 pathway genes. These cell lines were derived from SCCs from carcinogen-treated inbred mice which harbored germline deletions or mutations in Trp53, p19Arf, Atm, or Prkdc. Both siRNA and drug phenotypic screening converge to implicate the phosphoinositol kinases, receptor tyrosine kinases, MAP kinases, as well as cell cycle and DNA damage response genes as targetable dependencies in SCC. Differences in functional kinome profiles between Ras mutant cell lines reflect incomplete penetrance of Ras synthetic lethal kinases and indicate that co-mutations cause a rewiring of survival pathways in Ras mutant tumors. This study describes the functional kinomic landscape of Ras/p53 mutant chemically-induced squamous cell carcinoma in both the baseline unperturbed state and following DNA damage and nominates candidate therapeutic targets, including the Nek4 kinase, for further development.

Impact of HPV status on immune responses in head and neck squamous cell carcinoma.

The main objective of our study was to understand the impact of immune cell composition and the tumor-reactivity of tumor infiltrating lymphocytes (TIL) in HPV-positive (HPV+) and HPV-negative (HPV-) head and neck squamous cell carcinoma (HNSCC). TIL cultures were established from primary HNSCC tumors, the T cell subsets were phenotypically characterized using flow cytometry, and Interferon (IFN)-γ ELISA assay was used to determine TIL function. NanoString Immune Profiler was used to determine an immune signature by HPV-status, and multiplex immunohistochemistry (MIHC) was used to quantify immune cell distributions and their spatial relationships. Results showed that HPV+ and HPV- HNSCC had similar capacity to expand IFN-γ reactive TIL populations, and these TIL populations had similar characteristics. NanoString analysis revealed increased differential expression of genes related to B cell functions in HPV+ HNSCC, which were significant at a Benjamini-Yekutieli adjusted p-value of < 0.001. MIHC also displayed increased CD8+ T cell and CD19/CD20+ B cell densities in the tumor region of HPV+ HNSCC as opposed to HPV- HNSCC (p < 0.01). Increases in a combined metric of tumor B cell content and stromal plasma cell content was associated with increased progression-free survival in HPV- HNSCC patients treated with immune checkpoint inhibitor therapy (p = 0.03). In summary, TIL populations expanded from HPV+ and HPV- HNSCC displayed similar IFN-γ reactivity. However, we identified a strong B-cell signature present within HPV+ HNSCC, and higher B and plasma cell content associated with improved PFS in HPV- HNSCC patients treated with immune checkpoint inhibitors.

Phase II Randomized Trial of Transoral Surgery and Low-Dose Intensity Modulated Radiation Therapy in Resectable p16+ Locally Advanced Oropharynx Cancer: An ECOG-ACRIN Cancer Research Group Trial (E3311).

PURPOSE: Definitive or postoperative chemoradiation (CRT) is curative for human papillomavirus-associated (HPV+) oropharynx cancer (OPC) but induces significant toxicity. As a deintensification strategy, we studied primary transoral surgery (TOS) and reduced postoperative radiation therapy (RT) in intermediate-risk HPV+ OPC. METHODS: E3311 is a phase II randomized trial of reduced- or standard-dose postoperative RT for resected stage III-IVa (American Joint Committee on Cancer-seventh edition) HPV+ OPC, determined by pathologic parameters. Primary goals were feasibility of prospective multi-institutional study of TOS for HPV+ OPC, and oncologic efficacy (2-year progression-free survival) of TOS and adjuvant therapy in intermediate-risk patients after resection. TOS plus 50 Gy was considered promising if the lower limit of the exact 90% binomial confidence intervals exceeded 85%. Quality of life and swallowing were measured by functional assessment of cancer therapy-head and neck and MD Anderson Dysphagia Index. RESULTS: Credentialed surgeons performed TOS for 495 patients. Eligible and treated patients were assigned as follows: arm A (low risk, n = 38) enrolled 11%, intermediate risk arms B (50 Gy, n = 100) or C (60 Gy, n = 108) randomly allocated 58%, and arm D (high risk, n = 113) enrolled 31%. With a median 35.2-month follow-up for 359 evaluable (eligible and treated) patients, 2-year progression-free survival Kaplan-Meier estimate is 96.9% (90% CI, 91.9 to 100) for arm A (observation), 94.9% (90% CI, 91.3 to 98.6]) for arm B (50 Gy), 96.0% (90% CI, 92.8 to 99.3) for arm C (60 Gy), and 90.7% (90% CI, 86.2 to 95.4) for arm D (66 Gy plus weekly cisplatin). Treatment arm distribution and oncologic outcome for ineligible or step 2 untreated patients (n = 136) mirrored the 359 evaluable patients. Exploratory comparison of functional assessment of cancer therapy-head and neck total scores between arms B and C is presented. CONCLUSION: Primary TOS and reduced postoperative RT result in outstanding oncologic outcome and favorable functional outcomes in intermediate-risk HPV+ OPC.

Recurrent Human Papillomavirus-Related Head and Neck Cancer Undergoes Metabolic Reprogramming and Is Driven by Oxidative Phosphorylation.

PURPOSE: Human papillomavirus (HPV) infection drives the development of some head and neck squamous cell carcinomas (HNSCC). This disease is rapidly increasing in incidence worldwide. Although these tumors are sensitive to treatment, approximately 10% of patients fail therapy. However, the mechanisms that underlie treatment failure remain unclear. EXPERIMENTAL DESIGN: We performed RNA sequencing (RNA-seq) on tissues from matched primary- (pHNSCC) and metachronous-recurrent cancers (rHNSCC) to identify transcriptional differences to gain mechanistic insight into the evolutionary adaptations of metachronous-recurrent tumors. We used HPV-related HNSCC cells lines to investigate the effect of (i) NRF2 overexpression on growth in vitro and in vivo, (ii) oxidative phosphorylation (OXPHOS) inhibition using IACS-010759 on NRF2-dependent cells, and (iii) combination of cisplatin and OXPHOS inhibition. RESULTS: The OXPHOS pathway is enriched in recurrent HPV-associated HNSCC and may contribute to treatment failure. NRF2-enriched HNSCC samples from The Cancer Genome Atlas (TCGA) with enrichment in OXPHOS, fatty-acid metabolism, Myc, Mtor, reactive oxygen species (ROS), and glycolytic signaling networks exhibited worse survival. HPV-positive HNSCC cells demonstrated sensitivity to the OXPHOS inhibitor, in a NRF2-dependent manner. Further, using murine xenograft models, we identified NRF2 as a driver of tumor growth. Mechanistically, NRF2 drives ROS and mitochondrial respiration, and NRF2 is a critical regulator of redox homeostasis that can be crippled by disruption of OXPHOS. NRF2 also mediated cisplatin sensitivity in endogenously overexpressing primary HPV-related HNSCC cells. CONCLUSIONS: These results unveil a paradigm-shifting translational target harnessing NRF2-mediated metabolic reprogramming in HPV-related HNSCC.

FOXM1 drives HPV+ HNSCC sensitivity to WEE1 inhibition.

Head and neck squamous cell carcinoma (HNSCC) associated with high-risk human papilloma virus (HPV) infection is a growing clinical problem. The WEE1 kinase inhibitor AZD1775 (WEE1i) overrides cell cycle checkpoints and is being studied in HNSCC regimens. We show that the HPV16 E6/E7 oncoproteins sensitize HNSCC cells to single-agent WEE1i treatment through activation of a FOXM1-CDK1 circuit that drives mitotic gene expression and DNA damage. An isogenic cell system indicated that E6 largely accounts for these phenotypes in ways that extend beyond p53 inactivation. A targeted genomic analysis implicated FOXM1 signaling downstream of E6/E7 expression and analyses of primary tumors and The Cancer Genome Atlas (TCGA) data revealed an activated FOXM1-directed promitotic transcriptional signature in HPV+ versus HPV- HNSCCs. Finally, we demonstrate the causality of FOXM1 in driving WEE1i sensitivity. These data suggest that elevated basal FOXM1 activity predisposes HPV+ HNSCC to WEE1i-induced toxicity and provide mechanistic insights into WEE1i and HPV+ HNSCC therapies.

A novel surgeon credentialing and quality assurance process using transoral surgery for oropharyngeal cancer in ECOG-ACRIN Cancer Research Group Trial E3311.

PURPOSE: Understanding the role of transoral surgery in oropharyngeal cancer (OPC) requires prospective, randomized multi-institutional data. Meticulous evaluation of surgeon expertise and surgical quality assurance (QA) will be critical to the validity of such trials. We describe a novel surgeon credentialing and QA process developed to support the ECOG-ACRIN Cancer Research Group E3311 (E3311) and report outcomes related to QA. PATIENTS AND METHODS: E3311 was a phase II randomized clinical trial of transoral surgery followed by low- or standard-dose, risk-adjusted post-operative therapy with stage III-IVa (AJCC 7th edition) HPV-associated OPC. In order to be credentialed to accrue to this trial, surgeons were required to demonstrate active hospital credentials and technique-specific surgical expertise with ≥20 cases of transoral resection for OPC. In addition, 10 paired operative and surgical pathology reports from the preceding 24 months were reviewed by an expert panel. Ongoing QA required <10% rate of positive margins, low oropharyngeal bleeding rates, and accrual of at least one patient per 12 months. Otherwise surgeons were placed on hold and not permitted to accrue until re-credentialed using a new series of transoral resections. RESULTS: 120 surgeons trained in transoral minimally invasive surgery applied for credentialing for E3311 and after peer-review, 87 (73%) were approved from 59 centers. During QA on E3311, positive final pathologic margins were reported in 19 (3.8%) patients. Grade III/IV and grade V oropharyngeal bleeding was reported in 29 (5.9%) and 1 (0.2%) of patients. CONCLUSIONS: We provide proof of concept that a comprehensive credentialing process can support multicenter transoral head and neck surgical oncology trials, with low incidence of positive margins and *grade III/V oropharyngeal bleeding.

Aplicación de la ley de Zipf-Mandelbrot al diagnóstico de la dinámica cardíaca normal y aguda / Application of the law of Zipf-Mandelbrot to the diagnosis of normal and acute cardiac dynamics

Introducción: Es conocida la capacidad de los fractales estadísticos en la evaluación de la complejidad de diferentes sistemas cuya dinámica pueda ser evaluada a partir de las frecuencias de una variable; para esto, se utiliza la medida de la dimensión fractal estadística, la cual puede ser calculada con la ley de Zipf-Mandelbrot. Esta ley matemática ha sido aplicada en cardiología para evaluar el grado de complejidad de la dinámica cardíaca. En el presente trabajo se aplicó la ley de Zipf-Mandelbrot junto con la metodología diagnóstica desarrollada previamente para evaluar dinámicas cardíacas normales y con enfermedad aguda. Materiales y métodos: Se tomaron 15 registros Holter; 10 con diagnóstico normal y 5 con patologías agudas de pacientes de la Unidad de Cuidados Intensivos. Se organizaron jerárquicamente las frecuencias de aparición de las frecuencias cardíacas de cada dinámica en rangos de a 15 lat/min, en busca del comportamiento hiperbólico necesario para la aplicación de la ley de Zipf-Mandelbrot. Posteriormente se realizó una linealización y se obtuvo la dimensión fractal estadística para cada dinámica. Resultados: Los valores de la dimensión fractal estadística para una dinámica cardíaca aguda variaron entre 0.4925 y 0.6061, mientras que para una dinámica normal variaron entre 0.7134 y 0.9749, evidenciando la diferenciación entre ambos grupos. Conclusiones: El comportamiento fractal estadístico de la dinámica cardíaca fue corroborado, de igual forma la pérdida de complejidad para las dinámicas agudas respecto a las dinámicas normales

Background: The capacity of statistical fractals in the evaluation of the complexity of different systems whose dynamics can be evaluated from the frequencies of a variable is known. This is why the measure of the statistical fractal dimension is used, which can be calculated with the Zipf-Mandelbrot law, this mathematical law has been applied in cardiology evaluating the degree of complexity of cardiac dynamics. In the present work, the Zipf-Mandelbrot law was applied together with the diagnostic methodology previously developed to evaluate normal cardiac dynamics and acute disease. Material and methods: 15 Holter records were taken; 10 with normal diagnosis and 5 with acute pathologies of patients of the Intensive Care Unit. The frequencies of occurrence of the heart frequencies of each dynamics were organized hierarchically in ranges of 15 lat/min, in search of the hyperbolic behavior required for the application of the law of Zipf-Mandelbrot. Subsequently, a linearization was performed and the statistical fractal dimension was obtained for each dynamics. Results: The values of the statistical fractal dimension for acute cardiac dynamics varied between 0.4925 and 0.6061, whereas for normal dynamics they varied between 0.7134 and 0.9749, evidencing the differentiation between both groups. Conclusions: The statistical fractal behavior of the cardiac dynamics was corroborated, as well as the loss of complexity for the acute dynamics with respect to the normal dynamics

Choosing the adequate thermodynamic reference state: The evolution of pyrophosphate bioenergetics as an example.

The use of the thermodynamic formalism in the investigation of biochemical reactions constitutes one of the key analysis in bioenergetics, and the first step in such analysis is the selection of the adequate reference state. For biochemistry majors, thermodynamic analysis based on the chemical reference state is used in Physical Chemistry courses, while the biological and biochemical reference states are used in Biochemistry courses. As these definitions are introduced in different courses, it is difficult that students can understand the need to select a reference state as a first step in the energy analysis of a system. The lack of suitable examples in textbooks to illustrate the importance of the adequate selection of the reference state in a thermodynamic analysis, promoted the present analysis of the energetic role of pyrophosphate (PPi) in comparison with adenosine-triphosphate in different ambient conditions, namely, the early PPi world (better described by the chemical reference state), the enclosed systems like the cells (better described by the biological reference state), and the actual thioester world (better described by the biochemical reference state). This example not only provides a new interesting point of view on the evolution of two biochemical fuels but also represents a biochemical example in which the use of different reference states can illustrate a single process from different points of views.

Wound Complications in Head and Neck Squamous Cell Carcinomas After Anti-PD-1 Therapy.

Immune checkpoint inhibitors have demonstrated activity in recurrent/metastatic head and neck squamous cell cancer, but less is known regarding their long-term sequelae. We describe four patients who, after complete responses to anti-PD-1 therapy, developed complications requiring surgical intervention. Patient 1 is a 57-year-old female whose marked tumor regression exposed some mandibular hardware. Patient 2 is a 39-year-old male who developed an ulcerated buccal lesion with exposed mandible. Patient 3 is a 66-year-old male with craniofacial osteoradionecrosis. Patient 4 is a 71-year-old male who developed an exposed and fractured mandible. All patients successfully underwent surgical intervention and remain disease free. Laryngoscope, 129:E428-E433, 2019.

Multiple Defects Sensitize p53-Deficient Head and Neck Cancer Cells to the WEE1 Kinase Inhibition.

The p53 gene is the most commonly mutated gene in solid tumors, but leveraging p53 status in therapy remains a challenge. Previously, we determined that p53 deficiency sensitizes head and neck cancer cells to AZD1775, a WEE1 kinase inhibitor, and translated our findings into a phase I clinical trial. Here, we investigate how p53 affects cellular responses to AZD1775 at the molecular level. We found that p53 modulates both replication stress and mitotic deregulation triggered by WEE1 inhibition. Without p53, slowing of replication forks due to replication stress is exacerbated. Abnormal, γH2AX-positive mitoses become more common and can proceed with damaged or underreplicated DNA. p53-deficient cells fail to properly recover from WEE1 inhibition and exhibit fewer 53BP1 nuclear bodies despite evidence of unresolved damage. A faulty G1-S checkpoint propagates this damage into the next division. Together, these deficiencies can intensify damages in each consecutive cell cycle in the drug. IMPLICATIONS: The data encourage the use of AZD1775 in combination with genotoxic modalities against p53-deficient head and neck squamous cell carcinoma.

Patterns of cervical node positivity, regional failure rates, and fistula rates for HPV+ oropharyngeal squamous cell carcinoma treated with transoral robotic surgery (TORS).

OBJECTIVES: (1) Report the patterns of cervical node positivity for HPV + oropharyngeal squamous cell carcinoma (OPSCC) treated with transoral robotic surgery (TORS) and a unilateral level II-IV node dissection. (2) Investigate the regional failure rate following this operation. (3) Report the rate of pharyngocutaneous fistula (PCF) formation intraoperatively and postoperatively following TORS/neck dissection. METHODS: Retrospective case series of 88 patients with HPV+ OPSCC treated with TORS and simultaneous neck dissection levels II-IV at the University of Washington from 2010 to 2016. Primary endpoints were PCF, regional recurrence, disease-free survival (DFS), and overall survival (OS). RESULTS: The overall frequency of cervical node positivity was 93%, with 84% in level IIa, 7% in IIb, 23% in III, and 13% in IV. Two patients developed PCF intraoperatively, repaired with a local digastric flap, and no postoperative PCF occurred. Sixteen patients (18%) received surgery alone, 49 patients (56%) received adjuvant radiation, and 23 patients (26%) underwent adjuvant chemoradiation. DFS at 2 years was 95% and OS at 2 years was 100%. No concerning level Ib nodes were identified preoperatively or during surgery, and no regional failures occurred in this location. CONCLUSION: Our data suggests, in TORS for HPV+ OPSCC, neck dissection of levels II-IV accurately stages the neck pathologically and prevents regional recurrences, with adjuvant therapy when indicated, and survival outcomes are excellent. Single-staged operations did not result in any postoperative PCF. Avoiding dissection of level Ib with TORS oropharyngectomy limits morbidity to the marginal mandibular nerve and salivary function, and resulted in no postoperative fistulas with minimal reconstruction interventions.

The mutational landscape of recurrent versus nonrecurrent human papillomavirus-related oropharyngeal cancer.

BACKGROUND: Human papillomavirus-related (HPV-related) oropharyngeal squamous cell carcinomas (OPSCCs) have an excellent response rate to platinum-based chemoradiotherapy. Genomic differences between primary HPV-related OPSCCs that do or do not recur are unknown. Furthermore, it is unclear if HPV-related OPSCCs that recur share a genomic landscape with HPV-negative head and neck cancers (HNCs). METHODS: We utilized whole exome sequencing to analyze somatic nucleotide (SNVs) and copy number variants (CNVs) among a unique set of 51 primary HPV-related OPSCCs, including 35 that did not recur and 16 that recurred. We evaluated 12 metachronous recurrent OPSCCs (7 with paired primary OPSCCs) and 33 primary HPV-unrelated oral cavity and OPSCCs. RESULTS: KMT2D was the most frequently mutated gene among primary HPV-related OPSCCs (n = 51; 14%) and among metachronous recurrent OPSCCs (n = 12; 42%). Primary HPV-related OPSCCs that recurred shared a genomic landscape with primary HPV-related OPSCCs that did not recur. However, TSC2, BRIP1, NBN, and NFE2L2 mutations occurred in primary OPSCCs that recurred but not in those that did not recur. Moreover, primary HPV-related OPSCCs that recur harbor features of HPV-unrelated HNCs, notably including MAPK, JAK/STAT, and differentiation signaling pathway aberrations. Metachronous recurrent OPSCCs shared a genomic landscape with HPV-unrelated HNCs, including a high frequency of TP53, CASP8, FAT1, HLA-A, AJUBA, and NSD1 genomic alterations. CONCLUSION: Overall, primary HPV-related OPSCCs that recur share a genomic landscape with nonrecurrent OPSCCs. Metachronous recurrent OPSCCs share genomic features with HPV-negative HNCs. These data aim to guide future deescalation endeavors and functional experiments. FUNDING: This study is supported by the American Cancer Society (RSG TBG-123653), funding support for RAH (T32DC00018, Research Training in Otolaryngology, University of Washington), funds to EM from Seattle Translational Tumor Research (Fred Hutchinson Cancer Research Center), and center funds from the Fred Hutchinson Cancer Research Center to EM. UD is supported by the Department of Veterans Affairs, Biomedical Laboratory Research and Development (BLR&D), grant IO1-oo23456, and funds from the Pittsburgh Foundation and PNC Foundation.

A Phase I Clinical Trial of AZD1775 in Combination with Neoadjuvant Weekly Docetaxel and Cisplatin before Definitive Therapy in Head and Neck Squamous Cell Carcinoma.

Purpose: The WEE1 tyrosine kinase regulates G2-M transition and maintains genomic stability, particularly in p53-deficient tumors which require DNA repair after genotoxic therapy. Thus, a need arises to exploit the role of WEE1 inhibition in head and neck squamous cell carcinoma (HNSCC) mostly driven by tumor-suppressor loss. This completed phase I clinical trial represents the first published clinical experience using the WEE1 inhibitor, AZD1775, with cisplatin and docetaxel.Patients and Methods: We implemented an open-label phase I clinical trial using a 3+3 dose-escalation design for patients with stage III/IVB HNSCC with borderline-resectable or -unresectable disease, but who were candidates for definitive chemoradiation. Escalating AZD1775 was administered orally twice a day over 2.5 days on the first week, then in combination with fixed cisplatin (25 mg/m2) and docetaxel (35 mg/m2) for 3 additional weeks. The primary outcome measure was adverse events to establish MTD. Secondary measures included response rates, pharmacokinetics (PK), pharmacodynamics, and genomic data.Results: The MTD for AZD1775 was established at 150 mg orally twice per day for 2.5 days. RECISTv1.1 responses were seen in 5 of 10 patients; histologic adjustment revealed three additional responders. The only drug-limiting toxicity was grade 3 diarrhea. The PK C8hr target of 240 nmol/L was achieved on day 4 at all three doses tested. Pharmacodynamic analysis revealed a reduction in pY15-Cdk, and increases in γH2AX, CC3, and RPA32/RPA2 were noted in responders versus nonresponders.Conclusions: The triplet combination of AZD1775, cisplatin, and docetaxel is safe and tolerable. Preliminary results show promising antitumor efficacy in advanced HNSCC, meriting further investigation at the recommended phase II dose. Clin Cancer Res; 24(12); 2740-8. ©2018 AACR.

Role of Psychosocial Factors on Communicative Participation among Survivors of Head and Neck Cancer.

Objective The purpose of this study was to examine the unique contribution of psychosocial factors, including perceived social support, depression, and resilience to communicative participation, among adult survivors of head and neck cancer (HNC). Study Design Cross-sectional. Setting University-based laboratory and speech clinic. Subjects and Methods Adult survivors of HNC who were at least 2 years posttreatment for HNC completed patient-reported outcome measures, including those related to communicative participation and psychosocial function. Multiple linear regression analysis was conducted to predict communicative participation. Self-rated speech severity, cognitive function, laryngectomy status, and time since diagnosis were entered first as a block of variables (block 1), and psychosocial factors were entered second (block 2). Results Eighty-eight adults who were on average 12.2 years post-HNC diagnosis participated. The final regression model predicted 58.2% of the variance in communicative participation (full model R2 = 0.58, P < .001). Self-rated speech severity, cognitive function, laryngectomy status, and time since diagnosis together significantly predicted 46.1% of the variance in block 1. Perceived social support, depression, resilience, and interactions significantly and uniquely predicted 12.1% of the additional variance in block 2. Conclusion For clinicians, psychosocial factors such as perceived depression warrant consideration when counseling patients with HNC about communication outcomes and when designing future studies related to rehabilitation.

Functional Precision Medicine Identifies Novel Druggable Targets and Therapeutic Options in Head and Neck Cancer.

Purpose: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with high mortality and a lack of targeted therapies. To identify and prioritize druggable targets, we performed genome analysis together with genome-scale siRNA and oncology drug profiling using low-passage tumor cells derived from a patient with treatment-resistant HPV-negative HNSCC.Experimental Design: A tumor cell culture was established and subjected to whole-exome sequencing, RNA sequencing, comparative genome hybridization, and high-throughput phenotyping with a siRNA library covering the druggable genome and an oncology drug library. Secondary screens of candidate target genes were performed on the primary tumor cells and two nontumorigenic keratinocyte cell cultures for validation and to assess cancer specificity. siRNA screens of the kinome on two isogenic pairs of p53-mutated HNSCC cell lines were used to determine generalizability. Clinical utility was addressed by performing drug screens on two additional HNSCC cell cultures derived from patients enrolled in a clinical trial.Results: Many of the identified copy number aberrations and somatic mutations in the primary tumor were typical of HPV(-) HNSCC, but none pointed to obvious therapeutic choices. In contrast, siRNA profiling identified 391 candidate target genes, 35 of which were preferentially lethal to cancer cells, most of which were not genomically altered. Chemotherapies and targeted agents with strong tumor-specific activities corroborated the siRNA profiling results and included drugs that targeted the mitotic spindle, the proteasome, and G2-M kinases WEE1 and CHK1 We also show the feasibility of ex vivo drug profiling for patients enrolled in a clinical trial.Conclusions: High-throughput phenotyping with siRNA and drug libraries using patient-derived tumor cells prioritizes mutated driver genes and identifies novel drug targets not revealed by genomic profiling. Functional profiling is a promising adjunct to DNA sequencing for precision oncology. Clin Cancer Res; 24(12); 2828-43. ©2018 AACR.

[Is Sexual Identity Optional? A Study of The Genetics of Transsexuality]. / ¿La Identidad Sexual Es una Opción? Un Estudio Sobre la Base Genética de la Transexualidad.

Transsexualism in the ICD-10 (International Classification of Diseases, Tenth Revision), Gender Dysphoria in adolescents and adults in the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition), is characterized by a marked incongruence between one's experienced gender and biological sex. The etiology is complex, but some hypotheses suggest that Gender Dysphoria (GD) arises from discrepant cerebral and biological sexual differentiation. Increasing evidence supports the idea of genetic vulnerability. Henningsson et al, (2004) found significant differences when they examined estrogen receptor ß (ERß) in a male-to- female (MtF) population. They suggested that a long ERß polymorphism is more common in MtFs. Hare et al, (2009) also examined an MtF population and found a significant association between the androgen receptor (AR) and GD. Our group analyzed the same polymorphisms and found an association between ERα, ERß and AR in GD. Our results suggest a genetic basis of GD in MtF and FtM populations. Our data corroborate the implication of the two estrogen receptors, ERα and ß, and the androgen receptor in the genetic basis of GD, and advise the importance of estrogens and androgens in cerebral masculinization. Our data also confirm that sexual identity is not optional, but is determined prenatally by the genes, although it has a very important hormonal component. Therefore, its substrate is cerebral, not ideological.

Post-operative therapy following transoral robotic surgery for unknown primary cancers of the head and neck.

OBJECTIVES: Our primary objective is to describe the post- operative management in patients with an unknown primary squamous cell carcinoma of the head and neck (HNSCC) treated with trans-oral robotic surgery (TORS). MATERIALS & METHODS: We conducted a retrospective multi-institutional case series including all patients diagnosed with an unknown primary HNSCC who underwent TORS to identify the primary site from January 1, 2010 to June 30, 2016. We excluded those with recurrent disease, ≤6months of follow up from TORS, previous history of radiation therapy (RT) to the head and neck, or evidence of primary tumor site based on previous biopsies. Our main outcome measure was receipt of post-operative therapy. RESULTS: The tumor was identified in 26/35 (74.3%) subjects. Post-TORS, 2 subjects did not receive adjuvant therapy due to favorable pathology. Volume reduction of RT mucosal site coverage was achieved in 12/26 (46.1%) subjects who had lateralizing tumors, ie. those confined to the palatine tonsil or glossotonsillar sulcus. In addition, for 8/26 (30.1%), the contralateral neck RT was also avoided. In 9 subjects, no primary was identified (pT0); four of these received RT to the involved ipsilateral neck nodal basin only without pharyngeal mucosal irradiation. CONCLUSION: Surgical management of an unknown primary with TORS can lead to deintensification of adjuvant therapy including avoidance of chemotherapy and reduction in RT doses and volume. There was no increase in short term treatment failures. Treatment after TORS can vary significantly, thus we advocate adherence to NCCN guideline therapy post-TORS to avoid treatment-associated variability.

Methods to reduce postoperative surgical site infections after head and neck oncology surgery.

Head and neck cancer surgery is often a complex multi-step procedure that includes major resections, vascularised tissue reconstruction, and extensive neck dissection. The upper aerodigestive tract mucosal lining is often disrupted during surgery, which requires the management of a clean-contaminated field and the need to reconstruct the mucosal lining. With bacterial contamination, surgical site infections (SSI) are a serious complication that can result in delayed wound healing, wound breakdown, fistula formation, and compromised tissue reconstruction. Methods to reduce SSI in patients with head and neck cancer have been intensely researched, yielding evolving and varied practice patterns. In this Review, we outline the data supporting perioperative antibiotic prophylaxis for clean-contaminated surgeries, which suggest that clindamycin is an inadequate prophylactic antibiotic therapy in the reduction of SSI, and that prolonged antibiotic courses have no established benefit. For salvage laryngectomy after radiotherapy with or without chemotherapy, reconstruction with vascularised tissue reduces the frequency and severity of pharyngocutaneous fistula formation. These evidence-based recommendations have been shown to reduce the chance of SSI after head and neck surgery.