The role of neuromuscular ultrasound in diagnostics of peripheral neuropathies induced by cytostatic agents or immunotherapies.

A relevant number of cancer patients who receive potentially neurotoxic cytostatic agents develop a chemotherapy-induced peripheral neuropathy over time. Moreover, the increasing use of immunotherapies and targeted agents leads to a raising awareness of treatment-associated peripheral neurotoxicity, e.g., axonal and demyelinating neuropathies such as Guillain-Barré-like syndromes. To date, the differentiation of these phenomena from concurrent neurological co-morbidities or (para-)neoplastic nerve affection as well as their longitudinal monitoring remain challenging. Neuromuscular ultrasound (NMUS) is an established diagnostic tool for peripheral neuropathies. Performed by specialized neurologists, it completes clinical and neurophysiological diagnostics especially in differentiation of axonal and demyelinating neuropathies. No generally approved biomarkers of treatment-induced peripheral neurotoxicity have been established so far. NMUS might significantly extend the repertoire of diagnostic and neuromonitoring methods in this growing patient group in short term. In this article, we present enlargements of the dorsal roots both in cytostatic and in immunotherapy-induced neurotoxicity for the first time. We discuss related literature regarding new integrative applications of NMUS for cancer patients by reference to two representative case studies. Moreover, we demonstrate the integration of NMUS in a diagnostic algorithm for suspected peripheral neurotoxicity independently of a certain cancer treatment regimen emphasizing the emerging potential of NMUS for clinical routine in this interdisciplinary field and prospective clinical trials.

Evaluation of Integrated HPV DNA as Individualized Biomarkers for the Detection of Recurrent CIN2/3 during Post-Treatment Surveillance.

PURPOSE: Post-treatment follow-up in women with cervical pre-cancers (CIN3) is mandatory due to relapse in up to 10% of patients. Standard follow-up based on hrHPV-DNA/cytology co-testing has high sensitivity but limited specificity. The aim of our prospective, multicenter, observational study was to test the hypothesis that an individualized viral-cellular-junction test (vcj-PCR) combined with cytology has a lower false positive rate for the prediction of recurrence compared to standard co-testing. METHODS: Pre-surgical cervical swabs served for the identification of HPV16/18 DNA integration sites by next-generation-sequencing (NGS). Samples taken at 6, 12 and 24 months post-surgery were evaluated by cytology, hrHPV-DNA and the patients' individual HPV-integration sites (vcj-PCR on the basis of NGS). RESULTS: Integration sites were detected in 48 of 445 patients (10.8%), 39 of them had valid follow-up data. The false positive rate was 18.2% (95% CI 8.6-34.4%) for standard hrHPV/cytology at six months compared to 12.1% (95% CI 4.8-27.3%) for vcj-PCR/cytology, respectively (McNemar p = 0.50). Six patients developed recurrences (1 CIN2, 5 CIN3) during follow-up. Standard co-testing detected all, whereas vcj-PCR/cytology detected only five patients with recurrences. Data of 269 patients without evidence of HPV16/18 integration were subject to post-hoc analyses. Standard co-testing revealed a false positive rate of 15.7% (95% CI 11.7-20.7%) and predicted ten of fourteen recurrences at six months. CONCLUSIONS: Although highly specific on its own vcj-PCR could not detect all recurrent CIN2/3. Possible reasons for this unexpected result may be multifocal lesions, intratumoral heterogeneity with respect to HPV integration and/or incident CIN.

Triage of hrHPV-positive women: comparison of two commercial methylation-specific PCR assays.

AIM: High-risk human papillomavirus (hrHPV)-based screening is becoming increasingly important, either by supplementing or replacing the traditional cytology-based cervical Pap smear. However, hrHPV screening lacks specificity, because it cannot differentiate between transient virus infection and clinically relevant hrHPV-induced disease. Therefore, reliable triage methods are needed for the identification of HPV-positive women with cervical intraepithelial neoplasia (CIN) in need of treatment. Promising tools discussed for the triage of these patients are molecular diagnostic tests based on epigenetic markers. Here, we compare the performance of two commercially available DNA methylation-based diagnostic assays-GynTect® and the QIAsure Methylation Test-in physician-taken cervical scrapes from 195 subjects. FINDINGS: Both GynTect® and the QIAsure Methylation Test detected all cervical carcinoma and carcinoma in situ (CIS). The differences observed in the detection rates between both assays for the different grades of cervical lesions (QIAsure Methylation Test: CIN1 26.7%, CIN2 27.8% and CIN3 74.3%; GynTect®: CIN1 13.3%, CIN2 33.3% and CIN3 60%) were not significant. Concerning the false-positive rates, significant differences were evident. For the healthy (NILM) hrHPV-positive group, the false-positive rates were 5.7% for GynTect® and 26.4% for QIAsure Methylation Test (p = 0.003) and for the NILM hrHPV-negative group 2.2% vs. 23.9% (p = 0.006), respectively. When considering hrHPV-positive samples only for comparison (n = 149), GynTect® delivered significantly higher specificity compared to the QIAsure Methylation Test for CIN2 + (87.6% vs. 67.4% (p < 0.001)) and CIN3 + (84.1% vs. 68.2% (p = 0.002)). Overall our findings suggest that DNA methylation-based tests are suitable for the triage of hrHPV-positive women. With the goal to provide a triage test that complements the limited specificity of HPV testing in HPV-based screening, GynTect® may be preferable, due to its higher specificity for CIN2+ or CIN3+ .