Reliable Long-Term Serial Evaluation of Cochlear Function Using Pulsed Distortion-Product Otoacoustic Emissions: Analyzing Levels and Pressure Time Courses.

OBJECTIVES: To date, there is no international standard on how to use distortion-product otoacoustic emissions (DPOAEs) in serial measurements to accurately detect changes in the function of the cochlear amplifier due, for example, to ototoxic therapies, occupational noise, or the development of regenerative therapies. The use of clinically established standard DPOAE protocols for serial monitoring programs appears to be hampered by multiple factors, including probe placement and calibration effects, signal-processing complexities associated with multiple sites of emission generation as well as suboptimal selection of stimulus parameters. DESIGN: Pulsed DPOAEs were measured seven times within 3 months for f2 = 1 to 14 kHz and L2 = 25 to 80 dB SPL in 20 ears of 10 healthy participants with normal hearing (mean age = 32.1 ± 9.7 years). L1 values were computed from individual optimal-path parameters derived from the corresponding individual DPOAE level map in the first test session. Three different DPOAE metrics for evaluating the functional state of the cochlear amplifier were investigated with respect to their test-retest reliability: (1) the interference-free, nonlinear-distortion component level (LOD), (2) the time course of the DPOAE-envelope levels, LDP(t), and (3) the squared, zero-lag correlation coefficient () between the time courses of the DPOAE-envelope pressures, pDP(t), measured in two sessions. The latter two metrics include the two main DPOAE components and their state of interference. RESULTS: Collated over all sessions and frequencies, the median absolute difference for LOD was 1.93 dB and for LDP(t) was 2.52 dB; the median of was 0.988. For the low (f2 = 1 to 3 kHz), mid (f2 = 4 to 9 kHz), and high (f2 = 10 to 14 kHz) frequency ranges, the test-retest reliability of LOD increased with increasing signal to noise ratio (SNR). CONCLUSIONS: On the basis of the knowledge gained from this study on the test-retest reliability of pulsed DPOAE signals and the current literature, we propose a DPOAE protocol for future serial monitoring applications that takes into account the following factors: (1) separation of DPOAE components, (2) use of individually optimal stimulus parameters, (3) SNR of at least 15 dB, (4) accurate pressure calibration, (5) consideration of frequency- and level-dependent test-retest reliabilities and corresponding reference ranges, and (6) stimulus levels L2 that are as low as possible with sufficient SNR to capture the nonlinear functional state of the cochlear amplifier operating at its highest gain.

Test-retest reliability of distortion-product thresholds compared to behavioral auditory thresholds.

When referred to baseline measures, serial monitoring of pure-tone behavioral thresholds and distortion-product otoacoustic emissions (DPOAEs) can be used to detect the progression of cochlear damage. Semi-logarithmic DPOAE input-output (I/O) functions enable the computation of estimated distortion-product thresholds (EDPTs) by means of linear regression, a metric that provides a quantitative estimate of hearing loss due to cochlear-amplifier degradation. DPOAE wave interference and a suboptimal choice of stimulus levels limit the accuracy of EDPTs. This work identifies the test-retest reliability of EDPTs derived from short-pulse DPOAE level maps (EDPTLM), a method that circumvents limitations associated with both wave interference and suboptimal choice of stimulus levels. The test-retest reliability was compared to that of EDPTs derived from semi-logarithmic I/O functions (EDPTI/O) and that of behavioral thresholds acquired with pure-tone audiometry (PTA) and modified Békésy tracking audiometry (TA) to provide a foundation for identifying and interpreting significant threshold shifts. The DPOAE-based auditory thresholds (EDPTLM and EDPTI/O) and behavioral thresholds (PTA and TA) were recorded seven times within three months at 14 frequencies with f2 = 1-14 kHz in 20 ears from ten subjects with normal hearing (4PTA0.5-4kHz < 20 dB HL). To obtain EDPTLM, short-pulse DPOAEs were recorded using 21 L1,L2 pairs. Reconstruction of DPOAE growth behavior as a function of L1 and L2 using nonlinear curve fitting enabled the derivation of EDPTLM for each frequency. Test-retest reliability was determined using three different approaches: 1) centered thresholds, 2) average threshold differences, and 3) average absolute threshold differences, between each possible test session (N = 21). Test-retest reliability based on centered thresholds and average threshold differences showed no statistically significant difference between EDPTLM, EDPTI/O, PTA, and TA for the pooled analysis incorporating all stimulus frequencies. Average absolute threshold differences presented small but significant differences in test-retest reliability with median values of 3.00 dB for PTA, 3.20 dB for TA, 3.34 dB for EDPTLM, and 3.51 dB for EDPTI/O. A considerable frequency dependence of test-retest reliability was found; namely, the highest test-retest reliability was for EDPTLM at f2 = 11 - 14 kHz. Otherwise, at lower frequencies, the highest test-retest reliability was for TA at f2 =1 - 2 kHz. Overall, the test-retest reliability of EDPTLM was better than that of EDPTI/O and was similar to that for behavioral thresholds. Hence, deriving EDPTLM from individual level maps is a promising and sensitive method for objectively monitoring the state of the cochlea. Furthermore, the detection of an equidirectional threshold change at a single frequency in both EDPTLM and TA might allow reducing the threshold shift as indication of a follow-up examination from the clinical standard of 10 dB down to 5 dB. This stricter indicator might be beneficial when monitoring cochlear damage, for example ototoxicity, in the presence of (remnant) cochlear amplification at baseline.

Neutrophil-to-Lymphocyte Ratio in Rectal Cancer-Novel Biomarker of Tumor Immunogenicity During Radiotherapy or Confounding Variable?

The aim of this study was to investigate the predictive value of blood-derived makers of local and systemic inflammatory responses on early and long-term oncological outcomes. A retrospective analysis of patients with locally advanced rectal cancer treated with preoperative long-course 5-fluorouracil-based radiochemotherapy was performed. Differential blood counts before neoadjuvant treatment were extracted from the patients' electronic charts. Optimal cut-off values for neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) were determined. Potential clinical and hematological prognostic factors for disease-free survival (DFS) were studied using uni- and multivariate analysis. A total of 220 patients were included in the analysis. Median follow-up was 67 months. Five-year DFS and overall survival (OS) were 70% and 85%, respectively. NLR with a cut-off value of 4.06 was identified as optimal to predict DFS events. In multivariate analysis, only tumor volume (HR 0.33, 95% CI (0.14-0.83), p = 0.017) and NLR (HR 0.3, 95% CI (0.11-0.81), p = 0.017) remained significant predictors of DFS. Patients with a good histological response (Dworak 3 and 4) to radiotherapy also had a lower NLR than patients with less pronounced tumor regression (3.0 vs. 4.2, p = 0.015). A strong correlation between primary tumor volume and NLR was seen (Pearson's r = 0.64, p < 0.001). Moreover, patients with T4 tumors had a significantly higher NLR than patients with T1-T3 tumors (6.6 vs. 3.3, p < 0.001). An elevated pretherapeutic NLR was associated with higher T stage, inferior DFS, and poor pathological response to neoadjuvant radiochemotherapy. A strong correlation between NLR and primary tumor volume was seen. This association is important for the interpretation of study results and for the design of translational studies which are warranted.

Resolution of atelectasis during radiochemotherapy of lung cancer with serious implications for further treatment. A case report.

Local failure is a major cause for low overall survival rates in advanced non small cell lung cancer (NSCLC). Among others, radioresistant tumor clones as well as geographical miss can explain these high local failure rates. One reason for geographical miss is a change of tumor related atelectasis in the course of radiotherapy. We present the case of a patient with UICC Stage IIIb NSCLC who presented with a large tumor related atelectasis. During definitive radiochemotherapy, the atelectasis resolved, which resulted in a massive tumor shift out of the planning target volume within 2 days. Without close monitoring by cone beam CTs and prompt replanning, this would have led to a geographical miss and relevant underdosage of the tumor. Furthermore, changes in anatomy and pulmonary function during treatment had implications for organs at risk and opened windows for dose escalation. We suggest at least biweekly CBCTs in patients with poststenotic atelectasis to ensure the rapid detection of geographical changes of the target and subsequent intervention if necessary.

Radiotherapy and hyperthermia with curative intent in recurrent high risk soft tissue sarcomas.

PURPOSE: Radiotherapy before or after resection is one of the pillars of treatment for localised high risk soft tissue sarcomas. Treatment intensification has been described with concurrent chemotherapy and hyperthermia. The aim of this study is to assess local control after multimodal treatment, focussing on the treatment of local recurrences after surgery only. PATIENTS AND METHODS: Of 42 patients treated in a prospective protocol with radiotherapy and hyperthermia, nine were treated for isolated local recurrences without metastatic spread. Most patients were treated with trimodal therapy including chemotherapy with ifosfamide and underwent resection whenever possible. Median follow-up was 1.4 years. RESULTS: The treatment was well tolerated. Estimated disease free survival, distant metastases free survival and local control for the whole cohort after 1.5 years were 66, 73 and 88%, respectively. Neoadjuvant vs. adjuvant treatment influenced local control with a trend to statistical significance. Resection status did not influence local control. The cohort of patients treated for local recurrence after surgery alone had a significantly impaired local control compared to multimodal treatment at primary diagnosis (100 vs. 52%, p < 0.001). CONCLUSIONS: With multimodal therapy including radiotherapy and hyperthermia local tumour control is achievable even in locally recurrent tumours. The clear-cut difference of the treatment of local recurrence in contrast to primary diagnosis might either reflect difficulties in diagnosis and treatment of local recurrences or biological aggressiveness of recurrent tumours. However, we recommend to consider multimodal treatment at primary diagnosis of high risk soft tissue sarcomas.