Prolonged Enteral Tube Feeding in Infants With a Functional Single Ventricle Is Associated With Adverse Outcomes After Fontan Completion.

OBJECTIVES: To define the baseline characteristics of long-term tube-fed (TF) single ventricle patients, investigate associations between long-term enteral tube feeding and growth, and determine associations with long-term outcomes after Fontan procedure. STUDY DESIGN: We performed a retrospective cohort study of patients in the Australia and New Zealand Fontan Registry undergoing treatment at the Royal Children's Hospital, the Children's Hospital at Westmead, Royal Melbourne Hospital, and Royal Prince Alfred Hospital from 1981 to 2018. Patients were defined as TF or non-tube-fed (NTF) based on enteral tube feeding at the age of 90 days. Feeding groups were compared regarding body mass index (BMI) trajectory, BMI at last follow-up, and long-term incidence of severe Fontan failure. RESULTS: Of 390 patients (56 [14%] TF, 334 [86%] NTF), TF was associated with right ventricular dominance, hypoplastic left heart syndrome, Norwood procedure, increased procedures prior to Fontan, extracardiac conduit Fontan, Fontan fenestration, and atrioventricular valve repair/replacement. TF patients were less likely to be in the higher compared with lowest 0-6 month BMI trajectory (P < .01; P = .03), had lower 6 month weight-for-age z-scores (P < .01) and length-for-age z-scores (P = .01). TF were less likely to be overweight/obese at pediatric follow-up (hazard ratio [HR] = 0.31, 95% CI: 0.12-0.80; P = .02) and more likely to be underweight at adult follow-up (HR = 16.51; 5% CI: 2.70-101.10; P < .01). TF compared with NTF was associated with increased risk of severe Fontan failure (HR = 4.13; 95% CI = 1.65-10.31; P < .01). CONCLUSIONS: Prolonged infant enteral tube feeding is an independent marker of poor growth and adverse clinical outcomes extending long-term post-Fontan procedure.

Surveillance of End-Organ Damage in Fontan Patients Prior to Transition to Adult Care: Are We There Yet?

BACKGROUND: Recently published guidelines and consensus statements have outlined recommended screening practices for monitoring of end-organ dysfunction in Fontan patients. We reviewed the current approach to end-organ screening in a local population of Fontan patients at the time of transition to adult care. METHODS: Patient data from the Australia and New Zealand Fontan Registry and patient medical records were used to review investigations performed in Fontan patients transitioned from The Royal Children's Hospital Melbourne to an adult centre between 1 July 2015 and 30 June 2020. RESULTS: A total of 32 patients were referred for transition to an adult centre between 1 July 2015 and 30 June 2020 at a mean age of 18.5±0.7 years (12.7±2.5 years post-Fontan). Liver function tests were performed in 22 patients (69%) within 5 years prior to transition and were abnormal in 15 patients (68%). Liver ultrasound was performed in 13 patients (41%) within 5 years prior to the date of transition, of whom 10 (77%) had abnormal findings (features suggestive of hepatic fibrosis in seven [54%], cirrhosis in two [15%], and portal hypertension in three [23%]). Fourteen (14) patients (44%) had no record of a liver ultrasound being performed between the date of the Fontan procedure and the time of transition to adult care. Hepatocellular carcinoma was diagnosed in one patient at 18 months following transition. A total of 24 patients (75%) had a serum creatinine measured within the 5 years prior to transition, and two (8%) had an estimated glomerular filtration rate (eGFR) less than 90 mL/min/1.73 m2. No patient had a urine protein-creatinine ratio measured between the date of the Fontan procedure and the time of transition to adult care. CONCLUSIONS: In this study we have identified that the majority of patients transitioned from a tertiary paediatric centre to an adult centre within the last 5 years did not undergo routine surveillance for end-organ dysfunction. Routine screening for end-organ complications of the Fontan circulation should be incorporated into clinical practice and is an important part of Fontan patient care both pre- and post-transition to adult services.

Mammalian cell response and bacterial adhesion on titanium healing abutments: effect of multiple implantation and sterilization cycles.

OBJECTIVE: Multiple implantations of the implant healing abutment (IHA) could adversely impact its surface properties in vivo. Furthermore, the effect of sterilization and reuse of the IHA on soft tissue viability and bacterial contamination has not been extensively studied. The goal of this study was to perform an in vitro analysis of mammalian cell viability and bacterial adhesion on the surfaces of retrieved IHA after single and multiple implantations and repetitive cycles of sterilization. MATERIALS AND METHODS: IHA surface morphology was studied using optical microscopy. Cell viability of gingival fibroblasts (HGF-1) and oral keratinocytes (HOKg) in indirect contact with IHAs was assessed for 3 and 7 days. Immersion in bacterial culture was performed with a polyculture of Streptococcus species for 3 days and Streptococcus species with Fusobacterium nucleatum for 7 days. RESULTS: IHAs exhibited signs of surface damage even after a single exposure to the oral cavity. Fibroblasts did not show a significant preference towards control IHAs over used IHAs, whereas keratinocytes exhibited a significant decrease in viability when exposed to IHAs after multiple implantation cycles as compared with controls. Adherent bacterial count increased with increasing number of IHA implantations for both polycultures. CONCLUSIONS: Reusing of IHAs in vivo promoted surface degradation in addition to adversely impacting host cell viability and oral bacterial attachment in vitro. These findings show IHA reuse might potentially affect its clinical performance. CLINICAL RELEVANCE: Careful consideration should be taken when reusing IHAs in patients because this practice can result in permanent surface changes that might affect soft tissue integration during the healing period and promote bacterial colonization.

Group 3 ITI Consensus Report: Patient-reported outcome measures associated with implant dentistry.

OBJECTIVES: The aim of Working Group 3 was to focus on three topics that were assessed using patient-reported outcome measures (PROMs). These topics included the following: (a) the aesthetics of tooth and implant-supported fixed dental prostheses focusing on partially edentulous patients, (b) a comparison of fixed and removable implant-retained prostheses for edentulous populations, and (c) immediate versus early/conventional loading of immediately placed implants in partially edentate patients. PROMs include ratings of satisfaction and oral health-related quality of life (QHRQoL), as well as other indicators, that is, pain, general health-related quality of life (e.g., SF-36). MATERIALS AND METHODS: The Consensus Conference Group 3 participants discussed the findings of the three systematic review manuscripts. Following comprehensive discussions, participants developed consensus statements and recommendations that were then discussed in larger plenary sessions. Following this, any necessary modifications were made and approved. RESULTS: Patients were very satisfied with the aesthetics of implant-supported fixed dental prostheses and the surrounding mucosa. Implant neck design, restorative material, or use of a provisional restoration did not influence patients' ratings. Edentulous patients highly rate both removable and fixed implant-supported prostheses. However, they rate their ability to maintain their oral hygiene significantly higher with the removable prosthesis. Both immediate provisionalization and conventional loading receive positive patient-reported outcomes. CONCLUSIONS: Patient-reported outcome measures should be gathered in every clinical study in which the outcomes of oral rehabilitation with dental implants are investigated. PROMs, such as patients' satisfaction and QHRQoL, should supplement other clinical parameters in our clinical definition of success.

The significance of Trk receptors in pancreatic cancer.

This study investigated the Trk receptor family as a therapeutic target in pancreatic ductal adenocarcinoma and assessed their prognostic significance. Global gene expression analysis was investigated in prospectively collected pancreatic ductal adenocarcinomas that had either undergone neoadjuvant chemoradiation or were treated by surgery. PANC-1 and MIA-PaCa-2 cell lines were investigated to establish whether fractionated radiation altered expression of four neuroendocrine genes and whether this resulted in subsequent changes in radiosensitivity. A specific inhibitor of TrkA, B, and C, AstraZeneca 1332, was investigated in vitro and in vivo in combination with radiation. A tissue microarray was constructed from 77 pancreatic ductal adenocarcinoma patients who had undergone neoadjuvant chemoradiation and the Trk receptor, and neurogenic differentiation 1 expression was assessed and correlated with overall survival. A total of 99 genes were identified that were differentially expressed in the chemoradiation patients with neuroendocrine genes and pathways, in particular the neurogenic differentiation 1 and Trk receptor family, being prominent. Fractionated radiation upregulated the expression of neuroendocrine genes, and AstraZeneca 1332 treatment in vitro enhanced radiosensitivity. No added effect of AstraZeneca 1332 was observed in vivo. Trk receptor expression varied between isoforms but did not correlate significantly with clinical outcome. Radiation treatment upregulated neuroendocrine gene expression but the Trk receptor family does not appear to be a promising treatment target.

Effects of decontamination solutions on the surface of titanium: investigation of surface morphology, composition, and roughness.

AIM: To investigate the impact of treatments used to detoxify dental implants on the oxide layer morphology and to infer how changes in morphology created by these treatments may impact re-osseointegration of an implant. MATERIALS AND METHODS: Pure titanium (cpTi) and the alloy Ti6Al4V were subjected to a series of chemical treatments and mechanical abrasion simulating surface decontamination of dental implants. The morphology and roughness of the surface layer before and after treatment with these solutions were investigated with optical and atomic force microscopy (OM, AFM). The solutions employed are typically used for detoxification of dental implants. These included citric acid, 15% hydrogen peroxide, chlorhexidine gluconate, tetracycline, doxycycline, sodium fluoride, peroxyacetic acid, and treatment with carbon dioxide laser. The treatments consisted of both immersions of samples in solution and rubbing with cotton swabs soaked in solution for 1, 2, and 5 min. Cotton swabs used were analyzed with energy dispersive spectroscopy (EDS). RESULTS: The microscopy investigation showed that corrosion and pitting of the samples were present in both metal grades with immersion and rubbing methods when employing more acidic solutions, which had pH <3. Mildly acidic solutions caused surface discoloration when coupled with rubbing but did not cause corrosion with immersion. Neutral or basic treatments resulted in no signs of corrosion with both methods. EDS results revealed the presence of titanium particles on all rubbing samples. CONCLUSION: It was demonstrated in this study that acidic environments coupled with rubbing are able to introduce noticeable morphological changes and corrosion on the surface of both titanium grades.

The Use and Misuse of ACE Inhibitors in Patients with Single Ventricle Physiology.

BACKGROUND: There are no clear guidelines for the use of angiotensin-converting enzyme (ACE) inhibitors in patients with single ventricle physiology, especially after the Fontan procedure. Despite this, ACE inhibitors are widely prescribed within the single ventricle population. OBJECTIVE: We decided to review the literature to better establish the efficacy of ACE inhibitors in the single ventricle population and summarise their indications. METHODS: A review of the literature was conducted to identify relevant articles describing use of ACE inhibitors in single ventricle patients both before and after the Fontan procedure. RESULTS: A search in the Ovid MEDLINE and Embase databases identified a total of 140 articles, of which 31 were deemed relevant to the review. CONCLUSIONS: There is little published evidence supporting the use of ACE inhibitors in patients with single ventricle physiology. Based on the current literature, it is possible that ACE inhibitors are overprescribed in patients with single ventricle physiology. The coordination of large, prospective studies through initiatives such as the Australia and New Zealand Fontan Registry is necessary to guide the appropriate use of ACE inhibitors in the single ventricle population.

A videoscope for use in minimally invasive periodontal surgery.

INTRODUCTION: Minimally invasive periodontal procedures have been reported to produce excellent clinical results. Visualization during minimally invasive procedures has traditionally been obtained by the use of surgical telescopes, surgical microscopes, glass fibre endoscopes or a combination of these devices. All of these methods for visualization are less than fully satisfactory due to problems with access, magnification and blurred imaging. CLINICAL INNOVATION: A videoscope for use with minimally invasive periodontal procedures has been developed to overcome some of the difficulties that exist with current visualization approaches. This videoscope incorporates a gas shielding technology that eliminates the problems of fogging and fouling of the optics of the videoscope that has previously prevented the successful application of endoscopic visualization to periodontal surgery. In addition, as part of the gas shielding technology the videoscope also includes a moveable retractor specifically adapted for minimally invasive surgery. DISCUSSION: The clinical use of the videoscope during minimally invasive periodontal surgery is demonstrated and discussed. CONCLUSION: The videoscope with gas shielding alleviates many of the difficulties associated with visualization during minimally invasive periodontal surgery.

The Use of Enamel Matrix Derivative during Surgical Therapy for Peri-Implantitis: A Case Series.

Peri-implantitis is a growing concern and currently, there is no agreement on the best method for treating this condition. This study looked at surgical intervention with the use of enamel matrix derivative (EMD) for treating this condition. A cohort of 25 (34 implants) consecutive patients treated with EMD for peri-implantitis was followed for up to 6.4 years. The survival of the implants as well as changes in clinical parameters are reported. Statistical analysis was performed using paired t tests and general estimating equations. The mean length of time implants were followed post-surgery was 3.05 ± 1.53 years. All but two of the treated implants survived in function (94%). Both failed implants were lost in the same patient, who was a heavy smoker. The changes in mean probing depth (1.94 ± 1.18 mm), change in deepest probing depth (3.12 ± 1.45 mm), and reduction in bleeding on probing (73.6 ± 43.9%) according to patient means were all highly significant (p < 0.001 for all changes). When EMD is used during surgical treatment of peri-implantitis, there is a high survival rate of implants and significant improvements in clinical parameters.

Characterization of miR-335-5p and miR-335-3p in human osteoarthritic tissues.

OBJECTIVE: We aimed to characterize the expression patterns, gene targets, and functional effects of miR-335-5p and miR-335-3p among seven primary human knee and hip osteoarthritic tissue types. METHODS: We collected synovial fluid, subchondral bone, articular cartilage, synovium, meniscus/labrum, infrapatellar/acetabular fat, anterior cruciate ligament/ligamentum teres, and vastus medialis oblique/quadratus femoris muscle (n = 7-20) from surgical patients with early- or late-stage osteoarthritis (OA) and quantified miR-335-5p and miR-335-3p expression by real-time PCR. Predicted gene targets were measured in knee OA infrapatellar fat following miRNA inhibitor transfection (n = 3), and prioritized gene targets were validated following miRNA inhibitor and mimic transfection (n = 6). Following pathway analyses, we performed Oil-Red-O staining to assess changes in total lipid content in infrapatellar fat. RESULTS: Showing a 227-fold increase in knee OA infrapatellar fat (the highest expressing tissue) versus meniscus (the lowest expressing tissue), miR-335-5p was more abundant than miR-335-3p (92-fold increase). MiR-335-5p showed higher expression across knee tissues versus hip tissues, and in late-stage versus early-stage knee OA fat. Exploring candidate genes, VCAM1 and MMP13 were identified as putative direct targets of miR-335-5p and miR-335-3p, respectively, showing downregulation with miRNA mimic transfection. Exploring candidate pathways, predicted miR-335-5p gene targets were enriched in a canonical adipogenesis network (p = 2.1e - 5). Modulation of miR-335-5p in late-stage knee OA fat showed an inverse relationship to total lipid content. CONCLUSION: Our data suggest both miR-335-5p and miR-335-3p regulate gene targets in late-stage knee OA infrapatellar fat, though miR-335-5p appears to be more prominent, with tissue-, joint-, and stage-specific effects.

Liver Cirrhosis After the Fontan Procedure: Impact of Atrioventricular Valve Failure.

BACKGROUND: Liver cirrhosis is now well recognized as a potential complication after the Fontan procedure, although associated risk factors and optimal timing of liver screening remain unclear. METHODS: All patients who underwent an extracardiac conduit Fontan procedure at The Royal Children's Hospital, Melbourne, were identified using the Australia and New Zealand Fontan Registry. Cirrhosis was diagnosed based on liver biopsy, or a combination of imaging findings and clinical evaluation by a hepatologist. RESULTS: Between 1997 and 2020, 398 patients underwent an extracardiac conduit Fontan procedure at our center, and 276 had ongoing follow-up in Victoria. Ninety-five patients (34%) underwent liver assessment at a mean age of 18.2 ± 6.7 years (11.8 ± 5.5 years post-Fontan). Fifteen patients (16%) were diagnosed with cirrhosis at a mean age of 22.7 ± 5.9 years (14.0 ± 5.2 years post-Fontan). The need for prior or concomitant atrioventricular valve repair or replacement was associated with an increased risk of cirrhosis (univariable hazard ratio [HR] 7.09, 95% confidence interval [CI] 2.13-23.61, P = .001). By multivariable analysis, factors associated with development of cirrhosis were atrioventricular valve failure prior to Fontan (HR 3.27, 95% CI 1.15-9.31, P = .026) and older age at Fontan operation (HR 1.13 per year increase, 95% CI 1.01-1.26, P = .034). The proportion of patients alive, nontransplanted, and without cirrhosis at 10, 15, and 20 years was 93.4% (95% CI 88.4%-98.7%), 79.6% (95% CI 69.7%-90.8%), and 64.6% (95% CI 51.0%-81.9%), respectively. CONCLUSIONS: Early commencement of liver screening should be considered for patients with a history of atrioventricular failure during Fontan palliation.

Prevalence of irritable bowel syndrome and functional abdominal pain disorders in children with inflammatory bowel disease in remission.

Despite evidence of an increased prevalence of irritable bowel syndrome (IBS) in adults with inflammatory bowel disease (IBD) compared with the general population, the prevalence of IBS in children with IBD is unclear. In this review, we aimed to identify the reported prevalence of IBS or functional abdominal pain disorders (FAPDs) in children with IBD in remission. A search of three databases (MEDLINE, Embase, and PubMed) was performed to identify studies reporting the prevalence of IBS or FAPDs in pediatric patients with IBD in remission. A total of 60 studies were identified, with four eligible studies remaining following abstract screening. In children with IBD in remission, the overall prevalence of IBS ranged between 3.9 and 16.1%, and the overall prevalence of FAPDs ranged between 9.6 and 29.5%. The prevalence of FAPDs in patients in biomarker-based remission was generally higher than those in clinical remission (range 16-22.5% vs 9.6-16.7%, respectively). There is a paucity of literature reporting on the prevalence of IBS or FAPDs in children with IBD in remission. Despite the differences in criteria used to define IBD remission in the included articles, there seems to be an increased overall prevalence of IBS or FAPDs in children with IBD.

The Potential Role of Titanium Allergy in Implant Failure.

Implant bone loss and implant failure are growing concerns. In some cases, a possible factor leading to bone loss may be an allergy to titanium (Ti). In this report, the existing literature on Ti allergy as a factor in implant loss is reviewed, and the current views on its potential role in implant bone loss are discussed. A case report of implant loss and retreatment in a patient with a potential Ti allergy or intolerance is presented and clinically analyzed. The subsequent success of a ceramic implant may support the finding of a Ti allergy or intolerance. Unfortunately, the lack of prospective clinical trials and lack of a reliable test for Ti allergy makes it impossible to clinically verify whether Ti allergy plays a part in implant bone loss.

Body Mass Index Trajectory and Outcome Post Fontan Procedure.

Background Patients with a single ventricle who experience early life growth failure suffer high morbidity and mortality in the perisurgical period. However, long-term implications of poor infant growth, as well as associations between body mass index (BMI) and outcome in adulthood, remain unclear. We aimed to model BMI trajectories of patients with a single ventricle undergoing a Fontan procedure to determine trajectory-based differences in baseline characteristics and long-term clinical outcomes. Methods and Results We performed a retrospective analysis of medical records from patients in the Australia and New Zealand Fontan Registry receiving treatment at the Royal Children's Hospital, The Children's Hospital at Westmead, Royal Melbourne Hospital, and Royal Prince Alfred Hospital from 1981 to 2018. BMI trajectories were modeled in 496 patients using latent class growth analysis from 0 to 6 months, 6 to 60 months, and 5 to 16 years. Trajectories were compared regarding long-term incidence of severe Fontan failure (defined as mortality, heart transplantation, Fontan takedown, or New York Heart Association class III/IV heart failure). Three trajectories were found for male and female subjects at each age group-lower, middle, higher. Subjects in the lower trajectory at 0 to 6 months were more likely to have an atriopulmonary Fontan and experienced increased mortality long term. No association was found between higher BMI trajectory, current BMI, and long-term outcome. Conclusions Poor growth in early life correlates with increased long-term severe Fontan failure. Delineation of distinct BMI trajectories can be used in larger and older cohorts to find optimal BMI targets for patient outcome.

Minimum criteria for immediate provisionalization of single-tooth dental implants in extraction sites: a 1-year retrospective study of 100 consecutive cases.

PURPOSE: Minimum criteria were used in the placement of 100 consecutive provisional restorations on single-tooth dental implants placed into extraction sites within 3 days of surgery. MATERIALS AND METHODS: Provisional restorations were placed on 4.1- and 4.8-mm diameter standard ITI (Straumann, Waltham, MA) implants in the anterior mandible and maxilla in 100 treatment sites over a 3-year period. Provisionals were placed despite low insertion torque values of 15 N-cm or 50 implant stability quotient using radiofrequency analysis. Implants had final impressions for definitive restorations done 8 to 12 weeks after implant placement. All patients were recalled 1 year after restoration and evaluated according to parameters suggested by Albrektsson et al (Int J Oral Maxillofac Implants 1:11, 1986). RESULTS: One implant was not osseointegrated. The remaining implants were judged successful at the 1-year recall appointment. CONCLUSION: Immediate provisionalization of implants placed into fresh extraction sites can be effective even when minimal provisionalization criteria are met.

Bone loss around implants-is it metallosis?

Most would agree that the etiology of dental implant failure is related to oral biofilm. At present one group of scientists and clinicians feel that biofilm is solely responsible for bone loss around the devices. However, there is strong evidence that particles and ions of titanium released into the surrounding tissues by the action of biofilm and/or mechanical forces, a process termed metallosis, can be responsible for bone loss around some dental implants. These findings are reinforced by similar responses found around failed metal on metal joint prostheses. Both possible etiologies are discussed in detail in this commentary.

Treating brain metastases in melanoma: What is the optimal CNS-directed and systemic management?

Treatments for melanoma have significantly advanced with the approval of targeted treatments against the BRAF/MEK pathway and immunotherapy in the form of checkpoint inhibitors. Studies have shown the effectiveness of these treatments against brain metastases. However, the optimum treatment strategy utilising CNS-directed treatments such as stereotactic radiosurgery (SRS) and neurosurgical resection is less clear. Over six years, 70 patients with metastatic melanoma were treated for brain metastases at a tertiary treatment centre. The median overall survival (OS) for all patients was 10.2 months. 51 patients received localised treatment; 7 resection (median OS 10 months), 11 resection and SRS (median OS 17.3 months) and 33 SRS alone (median OS 17.4 months). For patients treated with SRS those who had <2 cm3 treated had a better median OS (20.5 months) compared to those who had >2 cm3 treated (12 months). 69 Patients received systemic treatment. The median OS of patients who did not have CNS-directed treatment was poor (median OS 1.2 months). Patients treated with first line dual immunotherapy had the best median OS (26.7 months), compared to anti-PD-1 (14.1 months), ipilimumab (14.3 months) and kinase inhibitors (10.9 months). Despite advancements in treatment, the development of brain metastases in melanoma is associated with worse outcomes. A combination of CNS-directed and systemic treatment is important to improve survival. Dual immunotherapy appears to be the most effective systemic treatment and the use of SRS improved outcomes. As metastatic melanoma treatments evolve there need to be an ongoing focus to ensure these strategies adequately treat intracranial disease.

Acute and Chronic Kidney Disease Following Congenital Heart Surgery: A Review.

BACKGROUND: There is an increasing prevalence of chronic kidney disease in the population of adults currently living with congenital heart disease. A considerable proportion of children who undergo congenital heart surgery experience postoperative acute kidney injury. Whether there is an association between acute kidney injury after cardiac surgery in childhood and development of chronic kidney disease is unclear. METHODS: Three electronic databases were searched to capture relevant studies exploring the relationship between acute kidney injury after congenital heart surgery in children and progression to chronic kidney disease. RESULTS: A literature search identified a total of 212 research articles, 7 of which were selected for in-depth review. CONCLUSIONS: There is a likely association between acute kidney injury in children undergoing congenital heart surgery and progression to chronic kidney disease. Research should be developed to mitigate factors contributing to postoperative acute kidney injury in neonates, infants, and children undergoing cardiac surgery. Better targeted follow-up protocols to monitor renal function in children undergoing cardiac surgery should be implemented. A universal definition for acute kidney injury and chronic kidney disease is needed to improve detection and research in this field.

Correlation between tumor voxel dose response matrix and tumor biomarker profile in patients with head and neck squamous cell carcinoma.

BACKGROUND: We have developed a novel imaging analysis procedure that is highly predictive of local failure after chemoradiation in head and neck cancer. In this study we investigated whether any pretreatment biomarkers correlated with key imaging parameters. METHODS: Pretreatment biopsy material was available for 28 patients entered into an institutional trial of adaptive radiotherapy in which FDG-PET images were collected weekly during treatment. The biopsies were immunohistochemically stained for CD44, EGFR, GLUT1, ALDH1, Ki-67 and p53 and quantified using image analysis. Expression levels were correlated with previously derived imaging parameters, the pretreatment SUVmax and the dose response matrix (DRM). RESULTS: The different parameters of the SUVmax and DRM did not correlate with each other. We observed a positive and highly significant (p = 0.0088) correlation between CD44 expression and volume of tumor with a DRM greater than 0.8. We found no correlation between any DRM parameter and GLUT1, p53, Ki-67 and EGFR or ALDH1. GLUT1 expression did correlate with the maximum SUV0 and the volume of tumor with an SUV0 greater than 20. CONCLUSIONS: The pretreatment SUVmax and DRM are independent imaging parameters that combine to predict local recurrence. The significant correlation between CD44 expression, a known cancer stem cell (CSC) marker, and volume of tumor with a DRM greater than 0.8 is consistent with concept that specific foci of cells are responsible for tumor recurrence and that CSCs may be randomly distributed in tumors in specific niches. Dose painting these small areas may lead to improved tumor control.

Dacomitinib and gedatolisib in combination with fractionated radiation in head and neck cancer.

BACKGROUND AND PURPOSE: There has been little success targeting individual genes in combination with radiation in head and neck cancer. In this study we investigated whether targeting two key pathways simultaneously might be more effective. MATERIALS AND METHODS: We studied the effect of combining dacomitinib (pan-HER, irreversible inhibitor) and gedatolisib (dual PI3K/MTOR inhibitor) with radiation in well characterized, low passage xenograft models of HNSCC in vitro and in vivo. RESULTS: Dacomitinib showed differential growth inhibition in vitro that correlated to EGFR expression whilst gedatolisib was effective in both cell lines. Neither agent radiosensitized the cell lines in vitro. In vivo studies demonstrated that dacomitinib was an effective agent alone and in combination with radiation whilst the addition of gedatolisib did not enhance the effect of these two modalities despite inhibiting phosphorylation of key genes in the PI3K/MTOR pathway. CONCLUSIONS: Our results showed that combining two drugs with radiation provided no added benefit compared to the single most active drug. Dacomitinib deserves more investigation as a radiation sensitizing agent in HNSCC.