Impact of functional electrical stimulation on nerve-damaged muscles by quantifying fat infiltration using deep learning.

Quantitative imaging in life sciences has evolved into a powerful approach combining advanced microscopy acquisition and automated analysis of image data. The focus of the present study is on the imaging-based evaluation of the posterior cricoarytenoid muscle (PCA) influenced by long-term functional electrical stimulation (FES), which may assist the inspiration of patients with bilateral vocal fold paresis. To this end, muscle cross-sections of the PCA of sheep were examined by quantitative image analysis. Previous investigations of the muscle fibers and the collagen amount have not revealed signs of atrophy and fibrosis due to FES by a laryngeal pacemaker. It was therefore hypothesized that regardless of the stimulation parameters the fat in the muscle cross-sections would not be significantly altered. We here extending our previous investigations using quantitative imaging of intramuscular fat in cross-sections. In order to perform this analysis both reliably and faster than a qualitative evaluation and time-consuming manual annotation, the selection of the automated method was of crucial importance. To this end, our recently established deep neural network IMFSegNet, which provides more accurate results compared to standard machine learning approaches, was applied to more than 300 H&E stained muscle cross-sections from 22 sheep. It was found that there were no significant differences in the amount of intramuscular fat between the PCA with and without long-term FES, nor were any significant differences found between the low and high duty cycle stimulated groups. This study on a human-like animal model not only confirms the hypothesis that FES with the selected parameters has no negative impact on the PCA, but also demonstrates that objective and automated deep learning-based quantitative imaging is a powerful tool for such a challenging analysis.

Long-term stimulation by implanted pacemaker enables non-atrophic treatment of bilateral vocal fold paresis in a human-like animal model.

A wide variety of treatments have been developed to improve respiratory function and quality of life in patients with bilateral vocal fold paresis (BVFP). One experimental method is the electrical activation of the posterior cricoarytenoid (PCA) muscle with a laryngeal pacemaker (LP) to open the vocal folds. We used an ovine (sheep) model of unilateral VFP to study the long-term effects of functional electrical stimulation on the PCA muscles. The left recurrent laryngeal nerve was cryo-damaged in all animals and an LP was implanted except for the controls. After a reinnervation phase of six months, animals were pooled into groups that received either no treatment, implantation of an LP only, or implantation of an LP and six months of stimulation with different duty cycles. Automated image analysis of fluorescently stained PCA cross-sections was performed to assess relevant muscle characteristics. We observed a fast-to-slow fibre type shift in response to nerve damage and stimulation, but no complete conversion to a slow-twitch-muscle. Fibre size, proportion of hybrid fibres, and intramuscular collagen content were not substantially altered by the stimulation. These results demonstrate that 30 Hz burst stimulation with duty cycles of 40% and 70% did not induce PCA atrophy or fibrosis. Thus, long-term stimulation with an LP is a promising approach for treating BVFP in humans without compromising muscle conditions.

Factors Impacting Survival After Transarterial Radioembolization in Patients with Unresectable Intrahepatic Cholangiocarcinoma: A Combined Analysis of the Prospective CIRT Studies.

PURPOSE: Transarterial radioembolization (TARE) with Yttrium-90 resin microspheres is a treatment option for patients with intrahepatic cholangiocarcinoma (ICC). However, optimising the timing of TARE in relation to systemic therapies and patient selection remains challenging. We report here on the effectiveness, safety, and prognostic factors associated with TARE for ICC in a combined analysis of the prospective observational CIRT studies (NCT02305459 and NCT03256994). METHODS: A combined analysis of 174 unresectable ICC patients enrolled between 2015 and 2020 was performed. Patient characteristics and treatment-related data were collected at baseline; adverse events and time-to-event data (overall survival [OS], progression-free survival [PFS] and hepatic PFS) were collected at every follow-up visit. Log-rank tests and a multivariable Cox proportional hazard model were used to identify prognostic factors. RESULTS: Patients receiving a first-line strategy of TARE in addition to any systemic treatment had a median OS and PFS of 32.5 months and 11.3 months. Patients selected for first-line TARE alone showed a median OS and PFS of 16.2 months and 7.4 months, whereas TARE as 2nd or further treatment-line resulted in a median OS and PFS of 12 and 9.3 months (p = 0.0028), and 5.1 and 3.5 months (p = 0.0012), respectively. Partition model dosimetry was an independent predictor for better OS (HR 0.59 [95% CI 0.37-0.94], p = 0.0259). No extrahepatic disease, no ascites, and < 6.1 months from diagnosis to treatment were independent predictors for longer PFS. CONCLUSION: This combined analysis indicates that in unresectable ICC, TARE in combination with any systemic treatment is a promising treatment option. LEVEL OF EVIDENCE: level 3, Prospective observational.

Standardizing data collection in adjuvant colon cancer trials: A consensus project from the IDEA and ACCENT international consortia and national experts.

BACKGROUND: Despite contributions provided by the recent clinical trials, several issues and challenges still remain unsolved in adjuvant colon cancer (CC). Hence, further studies should be planned to better refine risk assessment as well as to establish the optimal treatment strategy in the adjuvant setting. However, it is necessary to request adequate, contemporary and relevant variables and report them homogeneously in order to bring maximal information when analyzing their prognostic value. MATERIAL AND METHODS: The project was devised to gain a consensus from experts engaged in the planning, accrual and analyses of stage II and III CC clinical trials, to identify mandatory and recommended baseline variables in order to i) harmonize future data collection worldwide in clinical trials dedicated to adjuvant treatment of CC; ii) propose guidance for Case Report Forms to be used for clinical trials in this setting. A total of 72 questions related to variables that should be reported and how to report them in adjuvant clinical trials were approved and then voted to reach a final consensus from panelists. RESULTS: Data items on patient-related factors, histopathological features, molecular profile, circulating biomarkers and blood analyses were analyzed and discussed by the whole expert panel. For each item, we report data supporting the acquired consensus and the relevant issues that were discussed. Nineteen items were deemed to be mandatory for resected stage III patients and 24 for resected stage II disease. In addition, 9 and 4 items were judged as recommended for stage III and II, respectively. CONCLUSION: In our opinion, these 28 variables should be used and uniformly reported in more comprehensive CRFs as research groups design future clinical trials in the field of adjuvant colon cancer.

Prediction of resistance to bevacizumab plus FOLFOX in metastatic colorectal cancer-Results of the prospective multicenter PERMAD trial.

BACKGROUND: Anti-vascular endothelial growth factor (VEGF) monoclonal antibodies (mAbs) are widely used for tumor treatment, including metastatic colorectal cancer (mCRC). So far, there are no biomarkers that reliably predict resistance to anti-VEGF mAbs like bevacizumab. A biomarker-guided strategy for early and accurate assessment of resistance could avoid the use of non-effective treatment and improve patient outcomes. We hypothesized that repeated analysis of multiple cytokines and angiogenic growth factors (CAFs) before and during treatment using machine learning could provide an accurate and earlier, i.e., 100 days before conventional radiologic staging, prediction of resistance to first-line mCRC treatment with FOLFOX plus bevacizumab. PATIENTS AND METHODS: 15 German and Austrian centers prospectively recruited 50 mCRC patients receiving FOLFOX plus bevacizumab as first-line treatment. Plasma samples were collected every two weeks until radiologic progression (RECIST 1.1) as determined by CT scans performed every 2 months. 102 pre-selected CAFs were centrally analyzed using a cytokine multiplex assay (Luminex, Myriad RBM). RESULTS: Using random forests, we developed a predictive machine learning model that discriminated between the situations of "no progress within 100 days before radiological progress" and "progress within 100 days before radiological progress". We could further identify a combination of ten out of the 102 CAF markers, which fulfilled this task with 78.2% accuracy, 71.8% sensitivity, and 82.5% specificity. CONCLUSIONS: We identified a CAF marker combination that indicates treatment resistance to FOLFOX plus bevacizumab in patients with mCRC within 100 days prior to radiologic progress.

Prognostic value of liver metastases in colorectal cancer treated by systemic therapy: An ARCAD pooled analysis.

BACKGROUND: The liver is the most frequent site of metastases in colorectal cancer (CRC). This study aimed to assess the response rate and survival outcomes in metastatic CRC patients with non-liver metastases (NLM) compared to those with liver metastases (LM) across different lines of treatment. METHODS: A total of 17,924 mCRC patients included in 26 trials from the ARCAD CRC database were analyzed. The analysis was conducted based on the presence or absence of LM across different treatment groups: chemotherapy (CT) alone, CT + anti-VEGF, CT + anti-EGFR in KRAS wild-type tumors, within the first-line (1 L) and second-line (2 L), and patients enrolled in third-line (≥3 L) trials treated with trifluridine/tipiracil or regorafenib or placebo. The endpoints were overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). RESULTS: Out of the 17,924 patients, 14,066 had LM (30.6 % with only liver involvement and 69.4 % with liver and other metastatic sites), while 3858 patients had NLM. In the CT alone and CT + anti-VEGF subgroups, NLM patients showed better OS and PFS in the 1 L and 2 L settings. However, in the CT + anti-EGFR 1 L and 2 L subgroups, there was no significant difference in OS and PFS between NLM and LM patients. In the ≥ 3 L subgroups, better OS and PFS were observed in NLM patients. ORRs were higher in LM patients than in NLM patients across all cohorts treated in the 1 L and only in the anti-EGFR cohort in the 2 L. CONCLUSION: LM is a poor prognostic factor for mCRC increasing from 1 L to ≥ 3 L except for patients in 1 L and 2 L receiving CT+anti-EGFR. These data justify using LM as a stratification factor in future trials for patients with unresectable mCRC.