A Longitudinal Study Evaluating Sexual Health Outcomes and Prioritization in Patients Undergoing Chemoradiation for Human Papillomavirus-Associated Oropharyngeal Cancer.

PURPOSE: The primary objectives were to describe the longitudinal course of sexual health in people undergoing curative (chemo)radiation therapy ([C)RT) for human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPVOPSCC) and identify factors associated with higher sexual satisfaction 12 months after (C)RT. METHODS AND MATERIALS: Eligible participants from 3 sites were recruited to a prospective observational study between October 2020 and November 2021. Measures of sexual health (22-item European Organization for Research and Treatment of Cancer Sexual Health Questionnaire), treatment outcome priorities (Chicago Priorities Scale), quality of life (30-item European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire), symptom burden (MD Anderson Symptom Inventory-Head and Neck), emotional distress (Patient-Reported Outcomes Measurement Information System - Anxiety and Depression), and facial appearance and appearance distress (FACE-Q) were administered before, at the end, and 3 and 12 months after (C)RT. RESULTS: Of 128 eligible participants, 100 were recruited; sexual health measure data were available for 89 of 98 patients alive at 12 months. Mean sexual satisfaction scores were 51.8 (SD = 26.6) before (C)RT. Mixed model results indicated a clinically significant reduction in sexual satisfaction by the end of (-25.4; 95% CI, -30.7 to -20.2) and 3 months after CRT (-12.2; -17.3 to -7.0) but not 12 months after CRT (-3.8; 95% CI, -9.0 to 1.4). Of 13 treatment outcome priorities, "keeping sexual function" had a median rank of 10 and 9 before and 12 months after (C)RT, respectively; 24% and 26% identified it as a top priority at these times. Cohabiting, having a sexual partner, being sexually active, higher global health status, lower sexual health issues, lower depression, and considering sexual function a top priority were associated with higher sexual satisfaction scores 12 months after (C)RT. CONCLUSIONS: Although affected acutely by (C)RT, average sexual satisfaction returned to near pretreatment levels after 12 months. Sexual function is considered a top survivorship priority by approximately one-quarter of patients with HPVOPSCC.

Calcium and bicarbonate signaling pathways have pivotal, resonating roles in matching ATP production to demand.

Mitochondrial ATP production in ventricular cardiomyocytes must be continually adjusted to rapidly replenish the ATP consumed by the working heart. Two systems are known to be critical in this regulation: mitochondrial matrix Ca2+ ([Ca2+]m) and blood flow that is tuned by local cardiomyocyte metabolic signaling. However, these two regulatory systems do not fully account for the physiological range of ATP consumption observed. We report here on the identity, location, and signaling cascade of a third regulatory system -- CO2/bicarbonate. CO2 is generated in the mitochondrial matrix as a metabolic waste product of the oxidation of nutrients. It is a lipid soluble gas that rapidly permeates the inner mitochondrial membrane and produces bicarbonate in a reaction accelerated by carbonic anhydrase. The bicarbonate level is tracked physiologically by a bicarbonate-activated soluble adenylyl cyclase (sAC). Using structural Airyscan super-resolution imaging and functional measurements we find that sAC is primarily inside the mitochondria of ventricular cardiomyocytes where it generates cAMP when activated by bicarbonate. Our data strongly suggest that ATP production in these mitochondria is regulated by this cAMP signaling cascade operating within the inter-membrane space by activating local EPAC1 (Exchange Protein directly Activated by cAMP) which turns on Rap1 (Ras-related protein-1). Thus, mitochondrial ATP production is increased by bicarbonate-triggered sAC-signaling through Rap1. Additional evidence is presented indicating that the cAMP signaling itself does not occur directly in the matrix. We also show that this third signaling process involving bicarbonate and sAC activates the mitochondrial ATP production machinery by working independently of, yet in conjunction with, [Ca2+]m-dependent ATP production to meet the energy needs of cellular activity in both health and disease. We propose that the bicarbonate and calcium signaling arms function in a resonant or complementary manner to match mitochondrial ATP production to the full range of energy consumption in ventricular cardiomyocytes.

Treatment outcomes of standard (high dose) cisplatin and non-standard chemotherapy for locally advanced head and neck cancer.

INTRODUCTION: Concurrent chemoradiotherapy with high-dose (HD) cisplatin is the standard treatment for locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Due to the higher treatment-related adverse effects with standard therapy, alternative regimens (non-standard therapy), namely, lower dose weekly cisplatin, carboplatin/paclitaxel, or cetuximab are considered. There is, however, no consensus on non-standard regimens. We aimed to investigate the efficacy and safety profile of these regimens. METHODS: This single centre retrospective cohort study included all consecutive adult patients with newly diagnosed LA-HNSCC treated with either standard or non-standard regimens between January 2016 and April 2021. The primary outcome was 2-year failure-free survival (FFS). The secondary outcomes included acute toxicities, hospitalisation rates, dose modifications, treatment failure rates (TFR), and overall survival. RESULTS: About 235 patients were included in the final analysis; median age was 61 years (IQR 55-67), and 87% were male. Most had oropharyngeal tumours (85.5%) and p16-positivity was frequent (80%). About 56% received non-standard regimens: weekly cisplatin = 79 and non-cisplatin = 48. These patients had higher Charlson Comorbidity Index (CCI; p < .001) and lower European Cooperative Oncology Group (ECOG)-0 (p = .003). There was no difference in 2-year FFS (hazard ratio [HR] = 1.16; 95% confidence interval - [CI] 0.65-2.05), hospitalisation and grade-3 toxicity rates between the two regimens. Nausea and vomiting were lower in the non-standard regimen (3.0% vs. 16%, p < .001). Dose reductions, adjusted for age, sex, and CCI, were less likely in the non-standard regimen (OR = 2.36; 95%-CI: 1.01-5.49, p = .007). CONCLUSIONS: We demonstrated similar efficacy of lower dose weekly cisplatin and carboplatin/paclitaxel regimens and better safety profile of weekly cisplatin compared to standard HD cisplatin regimens for LA-HNSCC. Multicenter randomised control trials are required in HD cisplatin-ineligible patients.

The Value of In Vivo Reflectance Confocal Microscopy as an Assessment Tool in Chemotherapy-Induced Peripheral Neuropathy: A Pilot Study.

BACKGROUND: There is a lack of standardized objective and reliable assessment tools for chemotherapy-induced peripheral neuropathy (CIPN). In vivo reflectance confocal microscopy (RCM) imaging offers a non-invasive method to identify peripheral neuropathy markers, namely Meissner's corpuscles (MC). This study investigated the feasibility and value of RCM in CIPN. PATIENTS AND METHODS: Reflectance confocal microscopy was performed on the fingertip to evaluate MC density in 45 healthy controls and 9 patients with cancer (prior, during, and post-chemotherapy). Quantification was completed by 2 reviewers (one blinded), with maximum MC count/3 × 3 mm image reported. Quantitative Sensory Testing (QST; thermal and mechanical detection thresholds), Grooved pegboard test, and patient-reported outcomes measures (PROMS) were conducted for comparison. RESULTS: In controls (25 females, 20 males; 24-81 years), females exhibited greater mean MC density compared with males (49.9 ± 7.1 vs 30.9 ± 4.2 MC/3 × 3 mm; P = .03). Differences existed across age by decade (P < .0001). Meissner's corpuscle density was correlated with mechanical detection (ρ = -0.51), warm detection (ρ = -0.47), cold pain (ρ = 0.49) thresholds (P < .01); and completion time on the Grooved pegboard test in both hands (P ≤ .02). At baseline, patients had reduced MC density vs age and gender-matched controls (P = .03). Longitudinal assessment of MC density revealed significant relationships with QST and PROMS. Inter-rater reliability of MC count showed an intraclass correlation of 0.96 (P < .0001). CONCLUSIONS: The findings support the clinical utility of RCM in CIPN as it provides meaningful markers of sensory nerve dysfunction. Novel, prospective assessment demonstrated the ability to detect subclinical deficits in patients at risk of CIPN and potential to monitor neuropathy progression.

Camera-based Measurements of Intracellular [Na+] in Murine Atrial Myocytes.

Intracellular sodium concentration ([Na+]i) is an important regulator of intracellular Ca2+. Its study provides insight into the activation of the sarcolemmal Na+/Ca2+ exchanger, the behavior of voltage-gated Na+ channels and the Na+,K+-ATPase. Intracellular Ca2+ signaling is altered in atrial diseases such as atrial fibrillation. While many of the mechanisms underlying altered intracellular Ca2+ homeostasis are characterized, the role of [Na+]i and its dysregulation in atrial pathologies is poorly understood. [Na+]i in atrial myocytes increases in response to increasing stimulation rates. Responsiveness to external field stimulation is therefore crucial for [Na+]i measurements in these cells. In addition, the long preparation (dye-loading) and experiment duration (calibration) require an isolation protocol that yields atrial myocytes of exceptional quality. Due to the small size of mouse atria and the composition of the intercellular matrix, the isolation of high quality adult murine atrial myocytes is difficult. Here, we describe an optimized Langendorff-perfusion based isolation protocol that consistently delivers a high yield of high quality atrial murine myocytes. Sodium-binding benzofuran isophthalate (SBFI) is the most commonly used fluorescent Na+ indicator. SBFI can be loaded into the cardiac myocyte either in its salt form through a glass pipette or as an acetoxymethyl (AM) ester that can penetrate the myocyte's sarcolemmal membrane. Intracellularly, SBFI-AM is de-esterified by cytosolic esterases. Due to variabilities in membrane penetration and cytosolic de-esterification each cell has to be calibrated in situ. Typically, measurements of [Na+]i using SBFI whole-cell epifluorescence are performed using a photomultiplier tube (PMT). This experimental set-up allows for only one cell to be measured at one time. Due to the length of myocyte dye loading and the calibration following each experiment data yield is low. We therefore developed an EMCCD camera-based technique to measure [Na+]i. This approach permits simultaneous [Na+]i measurements in multiple myocytes thus significantly increasing experimental yield.

68 Ga-prostate-specific membrane antigen (PSMA) PET/CT as a clinical decision-making tool in biochemically recurrent prostate cancer.

OBJECTIVE: PSMA PET/CT has demonstrated superior sensitivity over conventional imaging in the detection of local and distant recurrence in biochemically relapsed (BCR) prostate cancer. We prospectively investigated the management impact of 68 Ga-PSMA PET/CT imaging in men with BCR, with the aim of identifying baseline clinicopathological predictors for management change. PATIENTS AND METHODS: Men with BCR who met eligibility criteria underwent 68 Ga-PSMA-11 PET/CT at Monash Health (Melbourne, Australia). Intended management plans were prospectively documented before and after 68 Ga-PSMA PET/CT imaging. Binary logistic regression analysis was performed to identify potential clinicopathological predictors of management change. Descriptive statistics were used to characterize the nature of these changes. RESULTS: Seventy men underwent 68 Ga-PSMA-11 PET/CT imaging. Median age was 67 years (IQR 63-72) and median PSA was 0.48 ng/ml (IQR 0.21-1.9). PSMA-avid disease was observed in 56% (39/70) of patients. Pre-scan management plan was altered following scanning in 43% (30/70) of patients. Management changes were significantly more common in patients with higher baseline PSA levels (PSA≥2 ng/ml, p = 0.01). 18/36 (50%) of the patients initially planned for watchful waiting had their management changed, including the use of salvage pelvic radiotherapy (n = 7) and stereotactic ablative body radiotherapy to oligometastatic disease (n = 6). CONCLUSION: Management change after 68 Ga-PSMA PET/CT for BCR is common and typically resulted in treatment intensification strategies in those planned for a watchful waiting approach. This study adds to the growing pool of evidence supporting the clinical utility of PSMA PET/CT imaging in the care of patients with BCR after definitive therapy.

Symptom burden, quality of life, functioning and emotional distress in survivors of human papillomavirus associated oropharyngeal cancer: An Australian cohort.

BACKGROUND: This cross-sectional study examines patient-reported outcomes and functioning-based subgroups in human papillomavirus-associated oropharyngeal cancer survivors treated with chemoradiotherapy ≥12 months prior. METHOD: Survivors completed EORTC QLQ-C30, MDASI-HN and PROMIS-Emotional distress questionnaires. Subgroups were identified via two-step clustering of QLQ-C30 functioning scales. RESULTS: 136 patients were enrolled. Clinicians' graded 19/136 (14%) patients as having at least one severe (Grade 3 CTCAE) toxicity, whereas 68/136 (50%) patients self-reported at least one toxicity in the severe range (MDASI-HN ≥ 7). QLQ-C30 Global health status score (mean 76, SD = 20) was comparable to population norms. Rates of moderate/severe anxiety (10%/1%) and depression (4%/1%) were low. Two functioning-based subgroups were formed based on auto-clustering statistics: high- (n = 93) and low-functioning (n = 41). Differences on all functioning scales were large (d: 1.57-2.29), as were differences on the remaining QLQ-C30 scales/items, most MDASI-HN symptom severity/interference scales, and PROMIS scales (d: 0.80-2.03). Differences and associations with patient/clinical characteristics were not significant. CONCLUSION: In this Australian cohort of HPV-OPC survivors there was significant discordance between clinician- and patient-reported toxicity. We observed population comparable global quality of life and low rates of emotional distress. However, we identified a low-functioning subgroup reporting significantly worse outcomes on a range of patient-reported measures who may benefit from targeted support.

Fear of Cancer Recurrence in Survivors of Human Papillomavirus-Associated Oropharyngeal Carcinoma.

PURPOSE: To estimate the prevalence of and characteristics associated with fear of cancer recurrence (FCR) among human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) survivors. METHODS AND MATERIALS: We conducted a cross-sectional study in HPV-OPC survivors ≥12 months from completion of definitive (chemo)radiation therapy (RT/CRT). Eligible patients completed the Fear of Cancer Recurrence Inventory short-form (FCRI-SF), the European Organisation for research and Treatment of Cancer QLQ-C30, MD Anderson Symptom Inventory-Head and Neck, and PROMIS Anxiety and Depression short forms. Associations between FCRI-SF scores and other variables were investigated using linear regression models. RESULTS: A total of 136 HPV-OPC survivors were enrolled; the median age was 61 years (range, 42-87 years), 84% were male, 72% were currently partnered, 83% were current nonsmokers, 67% were regular alcohol consumers, and the median time since treatment was 2.8 years (range, 1.0-5.5 years). Clinical levels of FCR (≥13) were observed in 72 of 135 patients (53%; 95% confidence interval [CI], 45%-62%). Characteristics significantly associated with increasing FCR scores were younger age (-0.9/5 years; 95% CI, -1.7 to -0.01; P = .031), lower global quality of life (-0.8/10 unit increase; 95% CI, -1.4 to -0.2; P = .012), higher symptom interference (0.8/unit increase; 95% CI, 0.1-1.5; P = .017), and a higher burden of anxiety (0.4/unit; 95% CI, 0.3-0.5; P <.001) and depression (0.3/unit; 95% CI, 0.1-0.4; P <.001). Other sociodemographic tumor- and treatment-related characteristics were not statistically significant. Compared with patients reporting nonclinical levels of FCR, significantly more patients reporting clinical levels of FCR than expected believed professional psychological assistance would have been beneficial (60% vs 33%; P = .002). CONCLUSIONS: Clinical levels of FCR were observed in approximately half of the HPV-OPC survivors. Survivors reporting higher FCR were younger with worse self-reported global quality of life and higher symptom interference and emotional distress. No other patient, tumor, or treatment factors were associated with higher FCR.

Sexual Health and Interpersonal Relationships After Chemoradiation Therapy for Human Papillomavirus-Associated Oropharyngeal Cancer: A Cross-sectional Study.

PURPOSE: To examine sexual health, including sexual satisfaction, and perceived changes in relationships and sexual relationships of human papillomavirus (HPV) oropharyngeal cancer (OPC) survivors ≥12 months after (chemo)radiation therapy. METHODS AND MATERIALS: We undertook a cross-sectional study of HPV-OPC survivors who had completed treatment ≥12 months prior. Eligible patients completed the EORTC QLQ-SHQ22, a customized relationship questionnaire, the EORTC QLQ-C30, MDASI-HN, and PROMIS Anxiety and Depression scales. RESULTS: We enrolled 136 survivors (median age, 61 years [range, 42-87 years]; male, 84%; currently partnered, 72%). The median time from (chemo)radiation therapy completion was 2.8 years (range, 1.0-5.5 years). Most patients (71/131; 60%) reported an active sex life as important; however, only 20% (26/133) reported significant recent sexual activity ("quite a bit"/"very much"). The mean sexual satisfaction score was 47/100 (interquartile range, 27-67; standard deviation 28). On univariable analysis, greater sexual satisfaction was positively associated with greater importance of sexual activity, stronger libido, greater relationship security, and more erection confidence (males). Lower sexual satisfaction was significantly associated with female sex (P = .04), more medical comorbidities (P = .008), and more time since treatment completion (P = .006). Only a few patients reported a change in their marital status (10/136; 7%). The majority (62/109; 57%) of patients partnered at diagnosis reported no change in their precancer relationship. Among those reporting a change, it was more frequently perceived as positive (29/109; 27%) than negative (16/109; 15%). Regarding their sexual relationship, 54 of 107 (50%) reported no change, 40 of 107 (37%) reported a negative change, and 8 of 107 (7%) reported a positive change. CONCLUSIONS: Although an active sex life is important to many HPV-OPC survivors, fewer reported significant recent sexual activity. Sexual satisfaction scores were moderate in this cohort. Although recall bias was possible, most patients reported either no change or a positive change in their interpersonal relationship. Prospective studies evaluating sexual health outcomes and addressing informational needs in HPV-OPC survivors are needed.

Ethylene-independent functions of the ethylene precursor ACC in Marchantia polymorpha.

The plant hormone ethylene has many roles in growth and development1. In seed plants, the ethylene precursor 1-aminocyclopropane-1-carboxylic acid (ACC) is converted into ethylene by ACC oxidase (ACO), and treatment with ACC induces ethylene responses2. However, non-seed plants lack ACO homologues3-8, which led us to examine the relationship between ACC and ethylene in the liverwort Marchantia polymorpha. Here, we demonstrate that ACC and ethylene can induce divergent growth responses in Marchantia. Ethylene increases plant and gemma size, induces more gemma cups and promotes gemmae dormancy. As predicted, Mpctr1-knockout mutants display constitutive ethylene responses, whereas Mpein3-knockout mutants exhibit ethylene insensitivity. Compared with the wild type, Mpctr1 gemmae have more and larger epidermal cells, whereas Mpein3 gemmae have fewer and smaller epidermal cells, suggesting that ethylene promotes cell division and growth in developing gemmae. By contrast, ACC treatment inhibits gemma growth and development by suppressing cell division, even in the Mpein3-knockout alleles. Knockout mutants of one or both ACC SYNTHASE (ACS) gene homologues produce negligible levels of ACC, have more and larger gemma cups, and have more-expanded thallus branches. Mpacs2 and Mpacs1 Mpacs2 gemmae also display a high frequency of abnormal apical notches (meristems) that are not observed in ethylene mutants. These findings reveal that ethylene and ACC have distinct functions, and suggest that ACC is a signalling molecule in Marchantia. ACC may be an evolutionarily conserved signal that predates its efficient conversion to ethylene in higher plants.

Patient-reported quality of life and toxicity in unilateral and bilateral radiotherapy for early-stage human papillomavirus associated tonsillar carcinoma.

PURPOSE: The purpose of this study was to compare self-reported health-related quality of life (QoL) and symptom burden in early stage tonsillar carcinoma patients treated with unilateral (URT) and bilateral radiotherapy (BRT). METHODS AND MATERIALS: This is a secondary analysis of a larger study assessing patient reported outcomes in human papillomavirus (HPV) oropharyngeal cancer (OPC) patients. Recruited patients were ≥12 months from completion of radiotherapy. This analysis included only patients with T1-2, N1-2b tonsil cancer and excluded patients with base of tongue involvement or recurrent disease. QoL and patient reported toxicity was measured using the EORTC QLQ-C30 module and the MDASI-HN. RESULTS: Patients were enrolled from November 2018 to May 2019. Of the 136 patients recruited to the main study, 43 were eligible for this substudy (22 URT, 21 BRT), with a median age and follow up of 58.2 and 3.0 years respectively. The two groups were balanced with respect to patient, tumor and treatment factors with the exception of higher rates of T2 disease (27% v 71%, p = 0.006) and more extensive GTV nodal volumes (11.0 v 25.5cc, p = 0.006) in the BRT group.BRT patients had lower global health status/QoL (84 v 69, p = 0.0005) and social functioning scores (93 vs 78, p = 0.033) on the EORTC QLQ-C30, and higher symptom severity (0.6 vs. 2.0, p = 0.001) and symptom interference scores (0.8 vs. 2.0, p = 0.010) on the MDASI-HN. Four of the six largest differences observed on MDASI-HN items were attributable to radiotherapy technique (dry mouth, mucous, difficulty swallowing/chewing and taste), with corresponding dose differences to the respective organs (contralateral parotid, oral cavity and pharyngeal constrictors). In every instance, severity of symptoms was worse on average for patients treated with BRT. CONCLUSIONS: In the highly conformal radiotherapy era, BRT in early HPV tonsillar cancer survivors has an enduring impact on long-term QoL and toxicity.

Dynamics of the mitochondrial permeability transition pore: Transient and permanent opening events.

A gentle optical examination of the mitochondrial permeability transition pore (mPTP) opening events was carried out in isolated quiescent ventricular myocytes by tracking the inner membrane potential (ΔΨM) using TMRM (tetramethylrhodamine methyl ester). Zeiss Airyscan 880 ″super-resolution" or "high-resolution" imaging was done with very low levels of illumination (0.009% laser power). In cellular areas imaged every 9 s (ROI or regions of interest), transient depolarizations of variable amplitudes occurred at increasing rates for the first 30 min. The time to first depolarization events was 8.4 min (±1.1 SEM n = 21 cells). At longer times, essentially permanent and irreversible depolarizations occurred at an increasing fraction of all events. In other cellular areas surrounding the ROI, mitochondria were rarely illuminated (once per 5 min) and virtually no permanent depolarization events occurred for over 1 h of imaging. These findings suggest that photon stress due to the imaging itself plays an important role in the generation of both the transient mPTP opening events as well as the permanent mPTP opening events. Consistent with the evidence that photon "stress" in mitochondria loaded with virtually any photon absorbing substance, generates reactive oxygen species (ROS) [1-5], we show that cyclosporine-A (CsA, 10 µM) and the antioxidant n-acetyl cysteine (NAC, 10 mM), reduced the number of events by 80% and 93% respectively. Furthermore, CsA and NAC treatment led to the virtual disappearance of permanent depolarization events. Nevertheless, all transient depolarization events in any condition (control, CsA and NAC) appeared to repolarize with a similar half-time of 30 ±â€¯6 s (n = 478) at 37 °C. Further experiments showed quantitatively similar results in cerebral vascular smooth muscle cells, using a different confocal system, and different photon absorbing reagent (TMRE; tetramethylrhodamine ethyl ester). In these experiments, using modest power (1% laser power) transient depolarization events were seen in only 8 out of 23 cells while with higher power (8%), all cells showed transient events, which align with the level of photon stress being the driver of the effect. Together, our findings suggest that photon-induced ROS is sufficient to cause depolarization events of individual mitochondria in quiescent cells; without electrical or mechanical activity to stimulates mitochondrial metabolism, and without raising the mitochondrial matrix Ca2+. In a broad context, these findings neither support nor deny the relevance or occurrence of ΔΨM depolarization events in specific putatively physiologic mitochondrial behaviors such as MitoFlashes [6,7] or MitoWinks [8]. Instead, our findings raise a caution with regards to the physiological and pathophysiological functions attributed to singular ΔΨM depolarization events when those functions are investigated using photon absorbing substances. Nevertheless, using photon stress as a tool ("Optical Stress-Probe"), we can extract information on the activation, reversibility, permanency and kinetics of mitochondrial depolarization. These data may provide new information on mPTP, help identify the mPTP protein complex, and establish the physiological function of the mPTP protein complex and their links to MitoFlashes and MitoWinks.

Patient-specific 3D Printing: A Novel Technique for Complex Pediatric Renal Transplantation.

OBJECTIVE: The authors investigated a novel application of patient-specific three-dimensional (3D) printing, to enhance preoperative, multidisciplinary planning in complex, living-donor pediatric renal transplantation. SUMMARY BACKGROUND DATA: For children with end-stage kidney disease, the transplantation of adult-sized, living-donor kidneys into small recipients (<20 kg) with increasingly complex structural anomalies can be difficult. Establishing the operative feasibility in such cases demands a surgical understanding of anatomy to be derived from medical imaging. However, this is hampered by the representation of complex structures in 2D, the inherent interpretive expertise this demands, and the challenge of conveying this appreciation to others. METHODS: We report the novel use of patient-specific 3D printed models to achieve personalized management for 3 children who underwent living-donor renal transplantation. Each presented a unique surgical challenge that would otherwise prevent preoperative determination of transplantation feasibility. Patient-specific geometries were segmented from imaging data and fabricated using polyjet, 3D printing technology. Models were verified by an expert radiologist and presented during multidisciplinary discussion and surgical simulation. RESULTS: 3D printed models enhanced preoperative deliberation and surgical simulation and allowed on-table exploration of a small child to be avoided. We have critically determined specific clinical indications, technical insights, limitations, and outcomes of this approach. At latest follow-up (>16 mo) all patients remain well with functioning renal allografts. CONCLUSIONS: We report the new and safe integration of patient-specific 3D printing into complex pediatric renal transplantation. This technique enhances surgical planning and can inform operative feasibility in those cases which would otherwise be uncertain.

Evaluating the Diagnostic Accuracy of Reflectance Confocal Microscopy to Diagnose Skin Cancer: Protocol for a Prospective, Multicenter Study.

BACKGROUND: In the United Kingdom, 350,000 patients per year are referred to hospital clinics with suspicious moles, and approximately half undergo a biopsy to identify the 5%-10% who require further treatment. If cancer cannot be ruled out clinically and on the basis of biopsy results, the lesion is surgically removed. One type of precancerous mole, called lentigo maligna, is particularly challenging to delineate and treat. Reflectance confocal microscopy (VivaScope, Caliber Imaging & Diagnostics) is an imaging technique that can supplement dermoscopy in identifying whether a clinically suspicious mole is malignant and can better assess lentigo maligna margins for excision. It allows clinicians to visualize the skin lesion to a depth of 200 microns with subcellular resolution, described as quasi-histological, and therefore better guide more accurate diagnoses. OBJECTIVE: The aim of this paper is to describe a prospective, single blinded, multicenter study to examine patients with clinically suspicious moles or lentigo maligna to determine whether confocal microscopy can both reduce the number of unnecessary biopsies of moles and more accurately guide the surgical excision margins of lentigo maligna. METHODS: This study will prospectively recruit adults into the following two cohorts: diagnostic accuracy and margin delineation. The diagnostic accuracy cohort will assess people with clinically suspicious lesions suspected of being diagnosed with melanoma and having an equivocal finding on dermoscopy or persistent clinical suspicion despite normal dermoscopy. Diagnostic accuracy will include the sensitivity and specificity of VivaScope in comparison with the histological diagnosis as the gold standard for patients. The margin delineation cohort will assess the ability of VivaScope to accurately delineate the margins of lentigo maligna compared with that of dermoscopy alone using margins taken during Mohs micrographic surgery as the gold standard. The primary study outcomes will be the diagnostic accuracy of VivaScope for the first cohort of patients and margin agreement between VivaScope and the final pathology report for the second cohort of patients. RESULTS: Funding for this proposed research is being secured. CONCLUSIONS: The outcomes of the proposed study will indicate how many biopsies of nonmelanoma lesions, which are potentially unnecessary, could be prevented. This would reduce patient anxiety and cost to the National Health Service (NHS) in the United Kingdom. Improved margin delineation of lentigo maligna could also improve the surgical clearance rates and decrease overall cost. The results would demonstrate whether the adoption of VivaScope would potentially benefit patients and the NHS. REGISTERED REPORT IDENTIFIER: RR1-10.2196/9296.

Diffuse Reflectance Spectroscopy as a Reliable Means of Comparing Ultraviolet Radiation-induced Erythema in Extreme Skin Colors.

Erythema is widely considered an indicator of skin cancer susceptibility, but assessments are challenging in black skin because melanin can mask erythema under traditional visual and advanced objective Commission Internationale de l'Eclairage (CIE) L*a*b* assessments. Using spectral measurements (400-700 nm) from a spectrophotometer, an algorithm was developed to measure erythema in white Caucasians (n = 9) and black West Africans (n = 11) 19-24 h postsolar simulated radiation (SSR) exposures to the volar forearm. The derived spectrum achieved showed a strong maximum peak for hemoglobin at 580 nm and a linear slope between 650 and 700 nm for melanin absorption, as reported by other authors. Absorption by hemoglobin at 580 nm was used as a proxy for erythema, and melanin was quantified between 650 and 700 nm. Our algorithm corrected the erythema measurements for stray specular (mirror-like) reflection and the melanin-masking effect. A linear relationship between SSR exposure and erythema was evident (p < 0.0001 for white and black skin), and white skin is 8.4 times more responsive to SSR compared to black skin. The prediction of ultraviolet radiation sensitivity is vital in both clinical and investigative dermatology especially in the determination of starting phototherapy doses. Our methodology allows for the accurate assessment of erythema independent of constitutive pigmentation.

Unilateral radiotherapy treatment for p16/human papillomavirus-positive squamous cell carcinoma of unknown primary in the head and neck.

OBJECTIVES/HYPOTHESIS: The outcomes of unilateral radiotherapy treatment for patients with p16/HPV-positive squamous cell carcinomas of unknown primary (SCCUP) affecting cervical lymph nodes are under-reported. Compared to radiating large volumes of the pharyngeal axis (the more common approach), this is potentially a much less toxic treatment for a good prognosis group. STUDY DESIGN: Retrospective cohort study. METHODS: We identified patients with SCCUP who were treated radically at our center and did not have parotid or isolated level IV or V nodal involvement. Failure-free and overall survivals were calculated using Kaplan-Meier methods. RESULTS: From 2004 to 2012, there were 49 radically treated patients with SCCUP. Fourteen patients had bilateral neck treatment (they had bilateral nodal disease or suspected lesions in the base of tongue, though not proven with biopsy), two had surgery alone, whereas 33 had unilateral radiotherapy (after neck dissection, excisional biopsy, or definitively with concurrent chemotherapy). Of the 33 patients, 21 tested positive to p16/HPV and had median follow-up of 57 months. In this group, no isolated contralateral neck failures or putative primaries emerged. There was 1/21 (4.3%) ipsilateral neck failure, 1/21 (4.3%) concurrent contralateral neck and distant failure, and 1/21 (4.3%) patient with distant failure. The 5-year freedom from failure was 78% (95% confidence interval [CI]: 56%-100%) and overall survival was 90% (95% CI: 79%-100%). CONCLUSIONS: With no emergence of putative primaries and no isolated contralateral neck failures, this single-institution experience in p16/HPV-positive SCCUP patients suggests that unilateral radiotherapy may be an underutilized management strategy. LEVELS OF EVIDENCE: 4 Laryngoscope, 128:2076-2083, 2018.

Safety and effectiveness of endovascular embolization or stent-graft reconstruction for treatment of acute carotid blowout syndrome in patients with head and neck cancer: Case series and systematic review of observational studies.

BACKGROUND: Indications for treatment and outcomes after endovascular management of carotid blowout syndrome for patients with head and neck cancer are not well defined. We investigated the safety and effectiveness of endovascular embolization and stent-graft reconstruction. METHODS: A literature review was performed for studies published between 2001 and 2015 with relevance to treatment outcomes. Our institutional database was examined to identify patients treated with endovascular techniques. RESULTS: A total of 266 patients were included. Rates of procedural stroke were higher after embolization of internal carotid artery (ICA)/common carotid artery (CCA) compared to stent graft (embolization 10.3%; stent graft 2.5%; P < .02). Stent graft of ICA/CCA was associated with higher rates of recurrent bleeding (embolization 9.1%; stent graft 31.9%; P < .01). CONCLUSION: Both embolization and stent grafts are safe therapeutic options for acute carotid blowout syndrome. Embolization for ICA/CCA carotid blowout syndrome was associated with higher risks of procedural stroke and lower recurrent bleeding compared to stent grafts.

Weekly cisplatin and radiotherapy for low risk, locoregionally advanced human papillomavirus-positive oropharyngeal squamous cell carcinoma.

BACKGROUND: There is interest in different treatment strategies, including deintensification in good prognosis human papillomavirus-positive (HPV(+)) oropharyngeal squamous cell carcinoma (SCC). We reviewed our experience with weekly cisplatin in low-risk, locoregionally advanced HPV(+) oropharyngeal SCC since late 2009. METHODS: Data from patients with low-risk HPV(+) oropharyngeal SCC treated with weekly cisplatin (40 mg/m(2) ) and 70 Gy radiotherapy were collected. Low risk was defined as stage III to IV oropharyngeal SCC excluding T1-2N1, T4 or N3 disease, or N2b to N2c disease in patients with >10 pack-year smoking history. RESULTS: Of 31 patients, the median age was 56 years (range, 41-69 years). All patients completed 70 Gy radiotherapy within 51 days and 84% completed at least 5 cycles of cisplatin. Grade 3 mucositis occurred in 22 patients (71%) and grade 3 febrile neutropenia in 6 patients (19%). No patients required enteral feeding at 12 months. The median follow-up was 30 months (range, 21-57 months) with no recurrences or deaths. CONCLUSION: Concurrent weekly cisplatin is relatively well-tolerated and associated with excellent disease control in low-risk, locoregionally advanced HPV(+) oropharyngeal SCC. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1117-E1121, 2016.

Safety and cost analysis of an (18)FDG-PET-CT response based follow-up strategy for head and neck cancers treated with primary radiation or chemoradiation.

BACKGROUND: Prognostic information can rationalise clinical follow-up after radical cancer treatment. This retrospective cohort study of radical head and neck (chemo)radiotherapy patients examines the clinical safety and cost implications of stratifying follow-up intensity by post-treatment (18)FDG-PET-CT response. METHODS: In 2008 clinical review after radical head and neck radiotherapy was reduced from 3- to 6-monthly for patients with complete (18)FDG-PET-CT response at 3months. 184 patients treated after this change ("PET Stratified", 2009-11) were compared to 178 patients treated before ("Standard", 2005-7). Clinical safety was assessed by the time to detection of recurrence, overall survival and potential for radical treatment of recurrence. A hospital cost analysis was performed using individual patient data. RESULTS: 127 of 178 Standard and 148 of 184 PET Stratified patients achieved complete response on post-treatment imaging. Baseline clinical characteristics were comparable. Median follow-up from response assessment was 4.8years in the Standard cohort and 2.1years for PET Stratified. PET Stratified patients had a mean 4.4 outpatient visits in 2years, compared to 7.0 among Standard patients. Over 90% of patients remained free of recurrence at 2years in both cohorts. Time to detection of recurrence was similar between two cohorts (HR1.05, 95%CI 0.45-2.52), as was overall survival (HR0.91, 95%CI 0.36-2.29). The proportion of radically treatable recurrences was also similar (42% Standard vs. 47% PET Stratified). The hospital cost savings per patient from reduced review were AUD$2606 over 2years, AUD$5012 over five. CONCLUSION: (18)FDG-PET-CT to stratify follow-up intensity after radical radiotherapy for head and neck cancer reduces costs with no apparent clinical detriment.

A phase II study of induction carboplatin and gemcitabine followed by chemoradiotherapy for the treatment of locally advanced nasopharyngeal carcinoma.

OBJECTIVES: To investigate the tolerability and feasibility of induction gemcitabine and carboplatin chemotherapy followed by radiotherapy with concurrent cisplatin in patients with locally advanced nasopharyngeal carcinoma. PATIENTS AND METHODS: Twenty-eight patients with previously untreated non-keratinising nasopharyngeal carcinoma, with stage IIb to IV disease were enroled to receive three cycles of carboplatin AUC 5 and gemcitabine 1 g/m(2) day 1 and 8 every 21-days, followed by 70 Gy of radiotherapy with concurrent cisplatin 20 mg/m(2)/day for 5 days of weeks 1, 4 and 7. RESULTS: 26/28 (93.0%) patients received all three cycles of induction chemotherapy. All 27 patients who commenced chemoradiotherapy received 70 Gy in 35 fractions of radiotherapy with at least two cycles of concurrent cisplatin. The three-year time to locoregional failure rate was 92.9% (95% CI: 75.5-98.2%) and the three-year overall survival rate was 89.3% (95% CI: 71.6-96.5%). Induction chemotherapy was well tolerated with 5/28 (17.9%) patients experiencing grade 3 non-haematological toxicities and no reported episodes of febrile neutropenia or grade 4 toxicity. For the 27 patients who received radiotherapy, no acute grade 4 radiation toxicities and only 2/27 (7.4%) late grade 4 radiation adverse events were observed. CONCLUSION: The use of induction carboplatin and gemcitabine followed by chemoradiotherapy is feasible, with acceptable toxicity, and is a promising regimen for the treatment of locally advanced nasopharyngeal carcinoma.