SDHAF2-Linked Metastatic Paraganglioma: A Case Report with Implications for Counseling and Follow-Up of Pathogenic SDHAF2 Variant Carriers.

Head and neck paragangliomas are slow growing and highly vascular neuroendocrine tumors. It is currently assumed that SDHAF2 variants exclusively cause benign and often multicentric head and neck paragangliomas. Here, we present a patient diagnosed with multiple SDHAF2-linked head and neck paragangliomas who in addition developed paraganglioma metastases to the lung and spine and a primary or metastatic paraganglioma in the head of the pancreas. During the course of the disease, a range of management strategies were deployed for the different head and neck tumors, including total resections, partial resections, and active surveillance. After identification of the paraganglioma metastases, the patient was treated with lanreotide after which the disease remained stable during the 27 months of follow-up.

Dynamic Current Focusing Compared to Monopolar Stimulation in a Take-Home Trial of Cochlear Implant Users.

OBJECTIVES: This study compared the performance of a dynamic partial tripolar cochlear implant speech encoding strategy termed dynamic current focusing (DCF) to monopolar stimulation (MP) using spectro-temporal, temporal, and speech-in-noise recognition testing. DESIGN: DCF is a strategy that utilizes tripolar or high partial tripolar stimulation at threshold level and increases loudness by slowly widening current spread towards most comfortable level. Thirteen cochlear implant users were fitted with DCF and a non-steered MP matched on pulse rate, pulse width, and active electrodes. Nine participants completed the single-blinded within-subject crossover trial. Repeated testing consisted of four sessions. Strategies were allocated in a DCF-MP-DCF-MP or MP-DCF-MP-DCF design. Three-week adaptation periods ended with a test session in which speech-in-noise recognition (matrix speech-in-noise sentence test), spectro-temporal ripple tests (SMRT and STRIPES) and a temporal amplitude modulation detection test were conducted. All participants recorded their subjective experiences with both strategies using the Speech, Spatial and Qualities of Hearing Scale questionnaire. RESULTS: Participants' SMRT thresholds improved 0.40 ripples per octave ( p = 0.02, Bonferroni-corrected: p = 0.1) with DCF over MP at 65 dB SPL. No significant differences between the strategies were found on speech-in-noise recognition at conversational (65 dB SPL) and soft (45 dB SPL) loudness levels, temporal testing, STRIPES, or the SMRT at 45 dB SPL. After Bonferroni correction, a learning effect remained on the matrix speech-in-noise sentence test at both loudness levels (65 dB SPL: p = 0.01; 45 dB SPL: p = 0.02). There was no difference in learning effects over time between DCF and MP. Similarly, no significant differences were found in subjective experience on the Speech, Spatial and Qualities of Hearing Scale questionnaire. DCF reduced average battery life by 48% (5.1 hours) ( p < 0.001) compared to MP. CONCLUSIONS: DCF may improve spectral resolution over MP at comfortable loudness (65 dB SPL) in cochlear implant users. However, the evidence collected in this study was weak and the significant result disappeared after Bonferroni correction. Also, not all spectral tests revealed this improvement. As expected, battery life was reduced for DCF. Although the current study is limited by its small sample size, considering previous studies, DCF does not consistently improve speech recognition in noise over MP strategies.

Hypofractionated radiotherapy combined with targeted therapy or immunotherapy: Dutch survey on current practice, knowledge and challenges.

INTRODUCTION: With the introduction of tyrosine kinase inhibitors and systemic antibodies, including immune checkpoint inhibitors, the survival of advanced-stage cancer patients has improved for many tumor types. These patients are increasingly referred for radiotherapy, but it is unclear whether radiotherapy combined with these drugs is safe. No international guidelines exist on whether or how to combine these drugs with radiotherapy. Therefore, we investigated the current clinical practice in the Netherlands regarding hypofractionated radiotherapy in patients using targeted drugs and immunotherapy. MATERIALS AND METHODS: We sent a survey to all 21 Dutch radiotherapy institutes. Dedicated radiation oncologists, medical oncologists and pulmonologists were asked to fill out the survey. The questions explored their familiarity with the combination of targeted drugs and immunotherapy with radiotherapy, the encountered clinical difficulties and factors influencing treatment decisions. RESULTS: The survey was filled out by 54 respondents from 19 different institutes. The median annual number of patients per radiation oncologist referred for radiotherapy when using targeted drugs or immunotherapy was 10 and 15, respectively. Despite this high number, only 11% of the radiation oncologists stated that they had sufficient information (resources) for adequate treatment decision making. Among all physicians, 44% stated that there was insufficient knowledge within their institute regarding this topic. Only 17% stated that there was a multidisciplinary protocol available. The application of radiotherapy treatment adaptations (technique, dose, fractionation, field size) varied widely. Generally, there seemed to be no consensus regarding the expected toxicity of combined drug-radiotherapy treatments and the expected risk of tumor flare upon temporary drug discontinuation. CONCLUSION: There is no consensus amongst involved medical specialties on expected toxicity. Consequently, it is necessary to perform clinical studies examining the safety of combined drug-radiotherapy treatments, to add radiotherapy to phase I-III clinical trials for new drugs and to incorporate outcomes into multidisciplinary, evidence-based guidelines.

Aortic flow below and visceral circulation during aortic counterpulsation: Evaluation of an in vitro model.

INTRODUCTION: This study aimed to test a computer-driven cardiovascular model for the evaluation of the visceral flow during intra-aortic balloon pump (IABP) assistance. METHODS: The model includes a systemic and pulmonary circulation as well as a heart contraction model. The straight polyurethane tube aorta had a single visceral while four windkessel components mimicked resistance compliance of the brachiocephalic, renal and sub-mesenteric, pulmonary, and systemic circulation. Twelve flow probes were placed in the circuit to measure pressures and flows with the IABP on and off. RESULTS: With the balloon off, the meantime to reach the steady state was 48 ± 16 s; with the balloon on, this figure was 178 ± 20 s. The stability of pressure and flow signals was obtained after 72 ± 11 min. The number of cycles of stability of the system was 93 [86-103]. Measurements were reliable either with samples of 10 or 20 beats. Bland Altman method demonstrated the reliability of measurements. Finally, all measurements were comparable to published in vivo data. CONCLUSION: The presented mock circulation was reliable and gave values with high accuracy both at baseline and during mechanical assistance. This system allows evaluation of the mesenteric flow during IABP, under different clinical/hemodynamic conditions. Nonetheless, its translational potential needs to be further evaluated.

Unexpected toxicity of CDK4/6 inhibitor palbociclib and radiotherapy.

BACKGROUND: Cyclin-dependent kinase (CDK) 4/6 inhibitors have recently been approved for the treatment of hormone receptor-positive and HER2-negative metastatic breast cancer in association with endocrine therapy in postmenopausal women. Data on the interaction of CDK4/6 inhibition and radiotherapy are scarce, but some studies show unexpected toxicity. CASES: We report three cases of unexpected severe or prolonged soft tissue, skin, and gastrointestinal toxicity in patients treated with a combination of radiotherapy and the CDK4/6 inhibitor palbociclib. CONCLUSION: These cases indicate a possible interaction between radiotherapy and palbociclib. Therefore, we recommend using radiotherapy cautiously when combined with CDK4/6 inhibitors.

ATG12 deficiency results in intracellular glutamine depletion, abrogation of tumor hypoxia and a favorable prognosis in cancer.

Hypoxia is a common feature of solid tumors and is associated with increased tumor progression, resistance to therapy and increased metastasis. Hence, tumor hypoxia is a prognostic factor independent of treatment modality. To survive hypoxia, cells activate macroautophagy/autophagy. Paradoxically, in several cancer types, mutations or loss of essential autophagy genes have been reported that are associated with earlier onset of tumor growth. However, to our knowledge, the phenotypic and therapeutic consequences of autophagy deficiency have remained unexplored. In this study, we determined autophagy-defects in head and neck squamous cell carcinoma (HNSCC) and observed that expression of ATG12 (autophagy related 12) was lost in 25%-40% of HNSCC. In line, ATG12 loss is associated with absence of hypoxia, as determined by pimonidazole immunohistochemistry. Hence, ATG12 loss is associated with improved prognosis after therapy in two independent HNSCC cohorts and 7 additional cancer types. In vivo, ATG12 targeting resulted in decreased hypoxia tolerance, increased necrosis and sensitivity of the tumor to therapy, but in vitro ATG12-deficient cells displayed enhanced survival in nutrient-rich culture medium. Besides oxygen, delivery of glucose was hampered in hypoxic regions in vivo, which increases the reliance of cells on other carbon sources (e.g., L-glutamine). We observed decreased intracellular L-glutamine levels in ATG12-deficient cells during hypoxia and increased cell killing after L-glutamine depletion, indicating a central role for ATG12 in maintaining L-glutamine homeostasis. Our results demonstrate that ATG12low tumors represent a phenotypically different subtype that, due to the lowered hypoxia tolerance, display a favorable outcome after therapy.Abbreviations: ARCON:accelerated radiotherapy with carbogen and nicotinamide; ATG: autophagy related; BrdUrd: bromodeoxyuridine; CA9/CAIX: carbonic anhydrase 9; HIF1A/HIF1α: hypoxia inducible factor 1 subunit alpha; HNSCC: head and neck squamous cell carcinoma; HPV: human papilloma virus; HR: hazard ratio; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MEF: mouse embryonic fibroblast; mRNA: messenger ribonucleic acid; PCR: polymerase chain reaction; SLC2A1/GLUT1: solute carrier family 2 member 1; TCGA: the Cancer Genome Atlas; TME: tumor microenvironment; UTR: untranslated region; VEGF: vascular endothelial growth factor.

Patient survival in severe low-flow, low-gradient aortic stenosis after aortic valve replacement or conservative management.

BACKGROUND AND AIM: Classical and paradoxical low-flow, low-gradient (LFLG) aortic stenosis (AS) are the most challenging subtypes of AS. The current therapeutic options are aortic valve replacement (AVR) and conservative management: AVR promotes long-term survival but is invasive, while conservative management yields a poor prognosis but is noninvasive since it uses no aortic valve replacement (noAVR). The present meta-analysis investigated the rate of survival of patients with LFLG AS undergoing either AVR or noAVR interventions. METHODS: The meta-analysis compared the outcomes of AVR with those of noAVR in terms of patient survival. In both groups, a meta-regression was conducted to investigate the impact on patient survival of the left ventricular ejection fraction (LVEF), either preserved (paradoxical LFLG AS) or reduced (classical LFLG AS). RESULTS: The relative risk of survival between the AVR and noAVR groups was 1.99 [1.40, 2.82] (p = .0001), suggesting that survival tends to be better in AVR patients than in noAVR patients. The meta-regression revealed that a reduced LVEF may be related to a higher survival in AVR patients when compared to a preserved LVEF (p = .04). Finally, the analysis indicated that LVEF seems not to be prognostic of survival in noAVR patients (p = .18). CONCLUSIONS: Patients with LFLG AS have better survival if they undergo AVR. In AVR patients, reduced LVEF rather than preserved LVEF is related to better survival, whereas there seems to be no difference in prognostic value between reduced and preserved LVEF in noAVR patients.

Intra-aortic balloon pump: Looking at the other side.

Intra-aortic balloon pump has been the most commonly employed cardiac assist device in the past, although, in recent years, its use in cardiogenic shock has been questioned. The pathophysiology of the proximal part of the balloon has been well studied, whereas, hemodynamics and flow below the distal portion of the balloon have not been fully understood yet. The distal flow contains a three-wave flow pattern during diastolic balloon expansion: a flow reduction in early diastole, a backflow in mid-diastole followed by a tele-diastolic flow. More research on this topic is warranted to better understand the physics of the distal part of the balloon and its interaction with the three components of the local regulatory system: intrinsic (local metabolic and myogenic), extrinsic (autonomic nervous system), and humoral (local or circulating vasoactive substances). These new insights will be a guide for new balloon designs that will allow enhanced performance and improved outcomes.

Stereotactic ablative body radiotherapy (SABR) combined with immunotherapy (L19-IL2) versus standard of care in stage IV NSCLC patients, ImmunoSABR: a multicentre, randomised controlled open-label phase II trial.

BACKGROUND: About 50% of non-small cell lung cancer (NSCLC) patients have metastatic disease at initial diagnosis, which limits their treatment options and, consequently, the 5-year survival rate (15%). Immune checkpoint inhibitors (ICI), either alone or in combination with chemotherapy, have become standard of care (SOC) for most good performance status patients. However, most patients will not obtain long-term benefit and new treatment strategies are therefore needed. We previously demonstrated clinical safety of the tumour-selective immunocytokine L19-IL2, consisting of the anti-ED-B scFv L19 antibody coupled to IL2, combined with stereotactic ablative radiotherapy (SABR). METHODS: This investigator-initiated, multicentric, randomised controlled open-label phase II clinical trial will test the hypothesis that the combination of SABR and L19-IL2 increases progression free survival (PFS) in patients with limited metastatic NSCLC. One hundred twenty-six patients will be stratified according to their metastatic load (oligo-metastatic: ≤5 or poly-metastatic: 6 to 10) and randomised to the experimental-arm (E-arm) or the control-arm (C-arm). The C-arm will receive SOC, according to the local protocol. E-arm oligo-metastatic patients will receive SABR to all lesions followed by L19-IL2 therapy; radiotherapy for poly-metastatic patients consists of irradiation of one (symptomatic) to a maximum of 5 lesions (including ICI in both arms if this is the SOC). The accrual period will be 2.5-years, starting after the first centre is initiated and active. Primary endpoint is PFS at 1.5-years based on blinded radiological review, and secondary endpoints are overall survival, toxicity, quality of life and abscopal response. Associative biomarker studies, immune monitoring, CT-based radiomics, stool collection, iRECIST and tumour growth rate will be performed. DISCUSSION: The combination of SABR with or without ICI and the immunocytokine L19-IL2 will be tested as 1st, 2nd or 3rd line treatment in stage IV NSCLC patients in 14 centres located in 6 countries. This bimodal and trimodal treatment approach is based on the direct cytotoxic effect of radiotherapy, the tumour selective immunocytokine L19-IL2, the abscopal effect observed distant from the irradiated metastatic site(s) and the memory effect. The first results are expected end 2023. TRIAL REGISTRATION: ImmunoSABR Protocol Code: NL67629.068.18; EudraCT: 2018-002583-11; Clinicaltrials.gov: NCT03705403; ISRCTN ID: ISRCTN49817477; Date of registration: 03-April-2019.

Synergizing systemic responses by combining immunotherapy with radiotherapy in metastatic non-small cell lung cancer: The potential of the abscopal effect.

Immunotherapy has obtained a secure place in the treatment of metastatic non-small cell lung cancer (NSCLC) and has made a great impact on prognosis of responders. Unfortunately, not all NSCLC patients derive benefit from this treatment. Several immune escape mechanisms have been postulated, explaining failure of tumor immune attack. A better understanding of these mechanisms helps us to seek treatment strategies to overcome resistance to immunotherapy. Radiotherapy has immunomodulatory qualities capable of enhancing the anti-cancer immune response by tackling a number of these tumor escape mechanisms. In this review, we focus on mechanisms of off-target effects of radiotherapy, the so-called abscopal effect, by describing the current role of immune checkpoint inhibitors (ICIs) in NSCLC, the possible reasons for its failures and evidence on how radiotherapy may be able to counteract these mechanisms. An oversight of pre-clinical and clinical data supporting augmentation of abscopal events by radiotherapy when combined with ICIs is presented. As much remains unclear regarding optimal dose, fractionation, target volume or timing of radiation therapy, future research will need to focus on implementing data from pre-clinical and translational findings in the development of new clinical trials in order to help optimizing the potential of the combination of immunotherapy with radiotherapy.

Are recurrence of ischemic mitral regurgitation and left ventricular reverse remodeling after restrictive annuloplasty ring dependent?

OBJECTIVE: This meta-analysis investigates MR recurrence and degree of left ventricular reverse remodeling (LVRR) in CIMR patients in mitral annuloplasty employing different ring designs. BACKGROUND: The deeper understanding of complex changes caused by chronic ischemic mitral regurgitation (CIMR) have led to new generations of rings that, by maintaining normal 3D annular geometry are supposed to enhance long-term repair durability. METHODS: A meta-analysis of all available reports in literature of MV repair through different ring design was conducted. Meta-regression was performed to investigate the impact of mitral ring characteristics related to flexibility, planarity, symmetry and single type utilized. Twenty studies encompassing a total of 1876 patients were included at the end of the selection process. RESULTS: At meta-regression recurrence of MR was not influenced by the ring employed. Nonetheless, the event rate of MR recurrence in planar rings was 19%. Vs. 11% observed with non-planar rings. Recurrence rate in patients implanted with symmetric rings was 14% whereas it was 7% in asymmetric rings. The non-planar asymmetric IMR-ETlogix showed the lowest recurrence rate (6%). Furthermore, in planar group the reduction of pre- and post-operative LVEDD was - 4%. In the non-planar group, the LVEDD was reduced by 8.6%. In patients implanted with symmetric rings LVEDD reduction was 10.8%. LVRR in the asymmetric group was -5.8%. CONCLUSION: MR recurrence occurred the least with asymmetric rings with less disproportionate asymmetry. In contrast, LVRR occurred at a greater extent in symmetric rings.

Papillary muscle intervention vs mitral ring annuloplasty in ischemic mitral regurgitation.

BACKGROUND AND AIMS: The main pathophysiological factor of chronic ischemic mitral regurgitation (MR) is the outward displacement of the papillary muscles (PMs) leading to leaflet tethering. For this reason, papillary muscle intervention (PMI) in combination with mitral ring annuloplasty (MRA) has recently been introduced into clinical practice to correct this displacement, and to reduce the recurrence of regurgitation. METHODS: A meta-analysis was conducted comparing the outcomes of PMI and MRA performed in combination vs MRA performed alone, in terms of MR recurrence and left ventricular reverse remodeling (LVRR). A meta-regression was carried out to investigate the impact of the type of PMI procedure on the outcomes. RESULTS: MR recurrence in patients undergoing both PMI and MRA was lower than in those who only had MRA (log incidence rate ratio, -0.66; lower-upper limits, -1.13 to 0.20; I2 = 0.0%; p = .44; Egger's test: intercept 0.35 [-0.78 to 1.51]; p = .42). The group with both PMI and MRA and that with only MRA showed a slightly higher reduction in left ventricular diameters (-5.94%; -8.75% to 3.13%,). However, in both groups, LVRR was <10%. No difference was detected between PM relocation/repositioning and papillary muscle approximation in terms of LVRR (p = .33). CONCLUSIONS: Using PMI and MRA together has a lower MR recurrence than using MRA alone. No significant LVRR was observed between the two groups nor between the PMI techniques employed.

Effectiveness of Phantom Stimulation in Shifting the Pitch Percept in Cochlear Implant Users.

OBJECTIVES: Phantom electrode stimulation was developed for cochlear implant (CI) systems to provide a lower pitch percept by stimulating more apical regions of the cochlea, without inserting the electrode array deeper into the cochlea. Phantom stimulation involves simultaneously stimulating a primary and a compensating electrode with opposite polarity, thereby shifting the electrical field toward the apex and eliciting a lower pitch percept. The current study compared the effect sizes (in shifts of place of excitation) of multiple phantom configurations by matching the perceived pitch with phantom stimulation to that perceived with monopolar stimulation. Additionally, the effects of electrode location, type of electrode array, and stimulus level on the perceived pitch were investigated. DESIGN: Fifteen adult advanced bionics CI users participated in this study, which included four experiments to eventually measure the shifts in place of excitation with five different phantom configurations. The proportions of current delivered to the compensating electrode, expressed as σ, were 0.5, 0.6, 0.7, and 0.8 for the symmetrical biphasic pulses (SBC0.5, SBC0.6, SBC0.7, and SBC0.8) and 0.75 for the pseudomonophasic pulse shape (PSA0.75). A pitch discrimination experiment was first completed to determine which basal and apical electrode contacts should be used for the subsequent experiments. An extensive loudness balancing experiment followed where both the threshold level (T-level) and most comfortable level (M-level) were determined to enable testing at multiple levels of the dynamic range. A pitch matching experiment was then performed to estimate the shift in place of excitation at the chosen electrode contacts. These rough shifts were then used in the subsequent experiment, where the shifts in place of excitation were determined more accurately. RESULTS: Reliable data were obtained from 20 electrode contacts. The average shifts were 0.39, 0.53, 0.64, 0.76, and 0.53 electrode contacts toward the apex for SBC0.5, SBC0.6, SBC0.7, SBC0.8, and PSA0.75, respectively. When only the best configurations per electrode contact were included, the average shift in place of excitation was 0.92 electrode contacts (range: 0.25 to 2.0). While PSA0.75 leads to equal results as the SBC configurations in the apex, it did not result in a significant shift at the base. The shift in place of excitation was significantly larger at the apex and with lateral wall electrode contacts. The stimulus level did not affect the shift. CONCLUSIONS: Phantom stimulation results in significant shifts in place of excitation, especially at the apical part of the electrode array. The phantom configuration that leads to the largest shift in place of excitation differs between subjects. Therefore, the settings of the phantom electrode should be individualized so that the phantom stimulation is optimized for each CI user. The real added value to the sound quality needs to be established in a take-home trial.

Superior mesenteric flow pattern during counterpulsation: is simply a shorter balloon the solution for visceral hypoperfusion?

OBJECTIVES: We studied the flow pattern in the superior mesenteric artery (SMA) during intra-aortic balloon pump support, comparing 2 intra-aortic balloons of 2 different lengths. METHODS: Sixteen Landrace pigs (mean weight 84.0 kg ± 6.0) were used in this study. The animals were randomly assigned to 2 groups: group 1 received an 8-Fr, 40-ml standard balloon; group 2 received an 8-Fr, 40-ml short balloon. SMA flow was measured during early, mid- and telediastole. RESULTS: The standard balloon led to a reduction in SMA flow in early diastole (P < 0.001), a negative flow in mid-diastole (P < 0.001) and a reincrease in telediastole (P < 0.001). In contrast, in early diastole a significant reduction was observed with the short balloon (P < 0.001), followed by another drop in mid-diastole (P < 0.001), without reaching negative values and by a telediastolic increase (P < 0.001). SMA flows were comparable between balloons during early diastole (P = 0.66), whereas they were higher with the short balloon during mid (P < 0.001) and telediastole (P = 0.02). Overall, the diastolic area was significantly larger when the short balloon was used (P < 0.001). Finally, during counterpulsation, mesenteric resistances increased significantly (P < 0.001), although, with the short balloon, they were lower than with the standard balloon (P = 0.01). CONCLUSIONS: Despite better overall mean mesenteric diastolic flow, the short balloon leads to early- and mid-diastolic flow reduction, although to a lesser extent than the standard intra-aortic balloon pump balloon. Our data are a call for improvement in the design of the short balloon.

ACLY (ATP Citrate Lyase) Mediates Radioresistance in Head and Neck Squamous Cell Carcinomas and is a Novel Predictive Radiotherapy Biomarker.

Radiotherapy is an important treatment modality of head and neck squamous cell carcinomas (HNSCC). Multiple links have been described between the metabolic activity of tumors and their clinical outcome. Here we test the hypothesis that metabolic features determine radiosensitivity, explaining the relationship between metabolism and clinical outcome. Radiosensitivity of 14 human HNSCC cell lines was determined using colony forming assays and the expression profile of approximately 200 metabolic and cancer-related genes was generated using targeted RNA sequencing by single molecule molecular inversion probes. Results: Correlation between radiosensitivity data and expression profiles yielded 18 genes associated with radiosensitivity or radioresistance, of which adenosine triphosphate (ATP) citrate lyase (ACLY) was of particular interest. Pharmacological inhibition of ACLY caused an impairment of DNA damage repair, specifically homologous recombination, and lead to radiosensitization in HNSCC cell lines. Examination of a The Cancer Genome Atlas (TCGA) cohort of HNSCC patients revealed that high expression of ACLY was predictive for radiotherapy failure, as it was only associated with poor overall survival in patients who received radiotherapy (hazard ratio of 2.00, 95% CI: 1.12-3.55; p = 0.0184). These data were further validated in an independent cohort of HNSCC patients treated with chemoradiation. Furthermore, patients with poor locoregional control after radiotherapy have significantly higher nuclear ACLY protein levels. Together, we here show that ACLY affects DNA damage repair, and is a predictive factor for radiotherapy outcome in HNSCC.

Clinical outcomes of automated anastomotic devices: A metanalysis.

BACKGROUND AND AIMS: We investigated neurological events, graft patency, major adverse cardiovascular events (MACEs), and mortality at 1 year following coronary artery bypass grafting (CABG) surgery using automated proximal anastomotic devices (APADs) and compared the overall rates with the current literature. METHODS: A systematic review of all available reports of APADs use in the literature was conducted. Cumulative incidence and 95% confidence interval (CI) were the main statistical indexes. Nine observational studies encompassing a total of 718 patients were included at the end of the selection process. RESULTS: The cumulative event rate of neurological complications was 4.8% (lower-upper limits: 2.8-8.0, P < .001; I2 = 72.907%, P = .002; Egger's test: intercept = -2.47, P = 0.16; Begg and Mazumdar test: τ = -0.20, p = 0.57). Graft patency was 90.5% (80.4 to 95.7, P < .001; I2 = 76.823%, P = .005; Egger's test: intercept = -3.04, P = .10; Begg and Mazumdar test: τ = -0.67, P = .17). Furthermore, the overall incidence of MACEs was 3.7% (1.3-10.4, P < .001; I2 = 51.556%, P = .103; Egger's test: intercept = -1.98, P = < .11; Begg and Mazumdar test: τ = -0.67, P = .17). Finally, mortality within 1 year was 5% (3.5-7, P < .001; I2 = 29.675%, P = .202; Egger's test: intercept = -0.91, P = .62; Begg and Mazumdar test: τ = -0.04, P = .88). CONCLUSIONS: APADs do not seem to be correlated with a reduction of either neurological events or mortality. By contrast, these tools showed satisfactory one-year graft patency and a low incidence of MACEs. Further research on this topic is warranted.

Acute Hypoxia Profile is a Stronger Prognostic Factor than Chronic Hypoxia in Advanced Stage Head and Neck Cancer Patients.

Hypoxic head and neck tumors respond poorly to radiotherapy and can be identified using gene expression profiles. However, it is unknown whether treatment outcome is driven by acute or chronic hypoxia. Gene expression data of 398 head and neck cancers was collected. Four clinical hypoxia profiles were compared to in vitro acute and chronic hypoxia profiles. Chronic and acute hypoxia profiles were tested for their association to outcome using Cox proportional hazard analyses. In an initial set of 224 patients, scores of the four clinical hypoxia profiles correlated with each other and with chronic hypoxia. However, the acute hypoxia profile showed a stronger association with local recurrence after chemoradiotherapy (p = 0.02; HR = 3.1) than the four clinical (chronic hypoxia) profiles (p = 0.2; HR = 0.9). An independent set of 174 patients confirmed that acute hypoxia is a stronger prognostic factor than chronic hypoxia for overall survival, progression-free survival, local and locoregional control. Multivariable analyses accounting for known prognostic factors substantiate this finding (p = 0.045; p = 0.042; p = 0.018 and p = 0.003, respectively). In conclusion, the four clinical hypoxia profiles are related to chronic hypoxia and not acute hypoxia. The acute hypoxia profile shows a stronger association with patient outcome and should be incorporated into existing prediction models.

Dynamic current focusing for loudness encoding in cochlear implants: a take-home trial.

Objective: This study aimed to evaluate a more energy-efficient dynamic current focussing (DCF) speech-processing strategy after long-term listening experience. In DCF, tripolar stimulation is used near the threshold and loudness is controlled by the compensation coefficient σ. A recent acute pilot study showed improved spectral-temporally modulated ripple test (SMRT) scores at low loudness levels, but battery life was reduced to 1.5-4 hours. Design: Within-subject comparisons were made for the clinical versus. DCF strategy after 5 weeks of at-home usage. Speech intelligibility in noise, spectral ripple discrimination, temporal modulation detection, loudness growth, and subjective ratings were assessed. Study sample: Twenty HiRes90K (Advanced Bionics, Valencia, USA) cochlear implant (CI) users. Results: Average battery life was 9 hours with the newly implemented DCF compared to 13.4 hours with the clinical strategy. Compared with measurements made at the beginning of the study, SMRT-scores and speech intelligibility in noise were significantly improved with DCF. However, both measures suffered from unexpected learning effects over time. The improvement disappeared and speech intelligibility in noise declined significantly relative to the final control measurement with the clinical strategy. Conclusion: Most CI users can adapt to the DCF strategy in a take-home setting. Although DCF has the potential to improve performance on the SMRT test, learning effects complicate the interpretation of the current results.

Continuous monitoring of membrane lung carbon dioxide removal during ECMO: experimental testing of a new volumetric capnometer.

BACKGROUND: Extracorporeal membrane oxygenation constitutes a complex support modality, and accurate monitoring is required. An ideal monitoring system should promptly detect ECMO malfunctions and provide real-time information to optimize the patient-machine interactions. We tested a new volumetric capnometer which enables continuous monitoring of membrane lung carbon dioxide removal (V'CO2ML), to help in estimating the oxygenator performance, in terms of CO2 removal and oxygenator dead space (VDsML). METHODS: This study was conducted on nine pigs undergoing veno-arterial ECMO due to cardiogenic shock after induced acute myocardial infarction. The accuracy and reliability of the prototype of the volumetric capnometer (CO2RESET™, by Eurosets srl, Medolla, Italy) device was evaluated for V'CO2ML and VDsML measurements by comparing the obtained measurements from the new device to a control capnometer with the sweep gas values. Measurements were taken at five different levels of gas flow/blood flow ratio (0.5-1.5). Agreement between the corresponding measurements was taken with the two methods. We expected that 95% of differences were between d - 1.96s and d + 1.96s. RESULTS: In all, 120 coupled measurements from each device were obtained for the V'CO2ML calculation and 40 for the VDsML. The new capnometer mean percentage bias (95% confidence interval limits of agreement) was 3.86% (12.07-4.35%) for V'CO2ML and 2.62% (8.96-14.20%) for VDsML. A negative proportional bias for V'CO2ML estimation with the new device was observed with a mean of 3.86% (12.07-4.35%). No correlations were found between differences in the coupled V'CO2ML and VDsML measurements and the gas flow/blood flow ratio or temperature. Coupled measurements for V'CO2ML showed strong correlation (rs = 0.991; p = 0.0005), as did VDsML calculations (rs = 0.973; p = 0.0005). CONCLUSION: The volumetric capnometer is reliable for continuous monitoring of CO2 removal by membrane lung and VDsML calculations. Further studies are necessary to confirm these data.

Channel discrimination along all contacts of the cochlear implant electrode array and its relation to speech perception.

OBJECTIVE: To test the channel discrimination of cochlear implant (CI) users along all contacts of the electrode array and assess whether this is related to speech perception. DESIGN: CI recipients were tested with a custom-made channel discrimination test. They were asked to distinguish a target stimulus from two reference stimuli in a three-alternative forced choice (3AFC) task. The target stimulus was evoked using current steering, with current steering coefficients (α) of 1, 0.5 and 0.25. The test provided a discrimination score (Dα) for each electrode contact along the array. STUDY SAMPLE: Thirty adults implanted with a CI from Advanced Bionics. RESULTS: Large variations in Dα scores were observed, both across the electrode array and between subjects. Statistical analysis revealed a significant channel-to-channel variability in Dα score (p < 0.01). Further, there was a significant relationship between subjects' Dα scores and their speech perception in quiet (p < 0.001). CONCLUSIONS: The large variations in Dα score emphasise the importance of testing pitch discrimination across the complete electrode array. The relationship between Dα score and speech perception indicates that pitch discrimination might be a contributing factor to the performance of individual implant users.