Tinnitus is defined as a perception of sound without any external sound source. Chronic tinnitus is a frequent condition that can affect the quality of life. So far, no causal cure for tinnitus has been documented, and most pharmacologic and psychosomatic treatment modalities aim to diminish tinnitus’ impact on the quality of life. Neuromodulation, a novel therapeutic modality, which aims at alternating nerve activity through a targeted delivery of a stimulus, has emerged as a potential option in tinnitus treatment. This review provides a brief overview of the current neuromodulation techniques as tinnitus treatment options. The main intention is to provide updated knowledge especially for medical professionals counselling tinnitus patients in this emerging field of medicine. Non-invasive methods such as repetitive transcranial magnetic stimulation, transcranial electrical stimulation, neurofeedback, and transcutaneous vagus nerve stimulation were included, as well as invasive methods such as implanted vagus nerve stimulation and invasive brain stimulation. Some of these neuromodulation techniques revealed promising results; nevertheless, further research is needed, especially regarding the pathophysiological principle as to how these neuromodulation techniques work and what neuronal change they induce. Various studies suggest that individually different brain states and networks are involved in the generation and perception of tinnitus. Therefore, in the future, individually tailored neuromodulation strategies could be a promising approach in tinnitus treatment for achieving a more substantial and longer lasting improvement of complaints.

Tinnitus is defined as a perception of sound without any external sound source. Chronic tinnitus is a frequent condition that can affect the quality of life. So far, no causal cure for tinnitus has been documented, and most pharmacologic and psychosomatic treatment modalities aim to diminish tinnitus' impact on the quality of life. Neuromodulation, a novel therapeutic modality, which aims at alternating nerve activity through a targeted delivery of a stimulus, has emerged as a potential option in tinnitus treatment. This review provides a brief overview of the current neuromodulation techniques as tinnitus treatment options. The main intention is to provide updated knowledge especially for medical professionals counselling tinnitus patients in this emerging field of medicine. Non-invasive methods such as repetitive transcranial magnetic stimulation, transcranial electrical stimulation, neurofeedback, and transcutaneous vagus nerve stimulation were included, as well as invasive methods such as implanted vagus nerve stimulation and invasive brain stimulation. Some of these neuromodulation techniques revealed promising results; nevertheless, further research is needed, especially regarding the pathophysiological principle as to how these neuromodulation techniques work and what neuronal change they induce. Various studies suggest that individually different brain states and networks are involved in the generation and perception of tinnitus. Therefore, in the future, individually tailored neuromodulation strategies could be a promising approach in tinnitus treatment for achieving a more substantial and longer lasting improvement of complaints.
Deep Brain Stimulation/methods* ; Humans ; Neurofeedback/methods* ; Tinnitus/therapy* ; Transcranial Direct Current Stimulation/methods* ; Transcranial Magnetic Stimulation/methods* ; Vagus Nerve Stimulation/methods*

Objective: Undifferentiated and dedifferentiated endometrial carcinoma is a rare type of uterine malignancy. This study assesses disease characteristics, treatment and survival outcomes in patients with undifferentiated and dedifferentiated endometrial carcinoma treated at BC Cancer. Methods: All patients diagnosed with undifferentiated and dedifferentiated endometrial carcinoma between 2000 and 2019 at BC Cancer were reviewed centrally. Clinical, pathologic, treatment and outcomes were reviewed retrospectively. The Kaplan-Meier method was used to evaluate overall survival (OS) and disease-free survival (DFS). Multivariable analysis was performed using Cox regression analysis. Results: Fifty-two patients were included, 33% had undifferentiated carcinoma and 67% dedifferentiated carcinoma. Sixty-nine percent of those who had mismatch repair (MMR) testing of their tumor had an abnormal profile. The 5-year DFS was 80% (95% confidence interval [CI]=71%–89%) for stage I/II, 29% (95% CI=28%–40%) for stage III and 10% (95% CI 1%–19%) for stage IV. The 5-year OS was 84% (95% CI=75%–92%) for stage I/II, 38% (95% CI=26%–50%) for stage III and 12% (95% CI=1%–24%) for stage IV. Multivariate analysis showed that receiving adjuvant chemotherapy, adjuvant radiotherapy, lower stage and better Eastern Cooperative Group performance status were associated with improved DFS (p<0.05). Conclusion Patients with stage I/II undifferentiated and dedifferentiated endometrial carcinoma had excellent survival outcomes, those with stage III/IV had worse outcomes, similar to previously reported. Adjuvant chemotherapy and radiotherapy were associated with improved DFS. MMR testing should be performed for these patients due to the high incidence of abnormal profiles.

Objective: To evaluate gastrointestinal (GI) patient reported outcomes (PROs) in cervical cancer patients treated with definitive radiotherapy (RT), comparing 3D conformal RT (3DCRT) vs. intensity modulated/volumetric modulated arc therapy (IMRT/VMAT). Methods: An analysis of patients treated with definitive RT between 2015–2018 was performed. GI PROs were prospectively collected at baseline, during RT (acute), ≤12 weeks after RT (subacute), and >12 weeks after RT (late). GI PROs evaluated three symptom domains: bowel problems (BPs), bowel bother (BB), and abdominal problems (APs). Multiple linear regression analysis was performed to investigate associations between mean changes of symptom scores with clinical and dosimetric variables. Results: The cohort included 167 patients. A total of 100 (60%) patients were treated with IMRT/VMAT and 67 (40%) with 3DCRT. In the subacute phase, the mean change of symptom scores from baseline in 3DCRT vs. IMRT/VMAT were +0.9 vs. −1.15 (p=0.004) for BP, +2.18 vs. −0.10 (p=0.019) for BB, and +1.41 vs. −0.38 (p=0.021) for AP. Likewise, in the late phase, mean changes were +0.72 vs. −0.82 (p=0.014) for BP, +1.98 vs. −0.03 (p=0.008) for BB, and +1.29 vs. −0.31 (p<0.001) for AP. On multiple linear regression, use of 3DCRT vs. IMRT/VMAT was associated with greater mean changes in subacute BP (p=0.023) and late phase AP (p=0.019). A higher small bowel V50Gy was associated increased symptom scores in late AP (p=0.012). Conclusion 3DCRT was associated with significantly greater worsening of GI PRO symptom scores in the subacute and late phase. These data support the ongoing use of IMRT/VMAT in routine practice.

Background: and Purpose Cerebral edema (CED) in ischemic stroke can worsen prognosis and about 70% of patients who develop severe CED die if treated conservatively. We aimed to describe incidence, risk factors and outcomes of CED in patients with extensive ischemia. Methods: Oservational study based on Safe Implementation of Treatments in Stroke-International Stroke Treatment Registry (2003–2019). Severe hemispheric syndrome (SHS) at baseline and persistent SHS (pSHS) at 24 hours were defined as National Institutes of Health Stroke Score (NIHSS) >15. Outcomes were moderate/severe CED detected by neuroimaging, functional independence (modified Rankin Scale 0–2) and death at 90 days. Results: Patients (n=8,560) presented with SHS and developed pSHS at 24 hours; 82.2% received intravenous thrombolysis (IVT), 10.5% IVT+thrombectomy, and 7.3% thrombectomy alone. Median age was 77 and NIHSS 21. Of 7,949 patients with CED data, 3,780 (47.6%) had any CED and 2,297 (28.9%) moderate/severe CED. In the multivariable analysis, age <50 years (relative risk [RR], 1.56), signs of acute infarct (RR, 1.29), hyperdense artery sign (RR, 1.39), blood glucose >128.5 mg/dL (RR, 1.21), and decreased level of consciousness (RR, 1.14) were associated with moderate/severe CED (for all P<0.05). Patients with moderate/severe CED had lower odds to achieve functional Independence (adjusted odds ratio [aOR], 0.35; 95% confidence interval [CI], 0.23 to 0.55) and higher odds of death at 90 days (aOR, 2.54; 95% CI, 2.14 to 3.02). Conclusions In patients with extensive ischemia, the most important predictors for moderate/ severe CED were age <50, high blood glucose, signs of acute infarct, hyperdense artery on baseline scans, and decreased level of consciousness. CED was associated with worse functional outcome and a higher risk of death at 3 months.

New technologies to generate, store and retrieve medical and research data are inducing a rapid change in clinical and translational research and health care. Systems medicine is the interdisciplinary approach wherein physicians and clinical investigators team up with experts from biology, biostatistics, informatics, mathematics and computational modeling to develop methods to use new and stored data to the benefit of the patient. We here provide a critical assessment of the opportunities and challenges arising out of systems approaches in medicine and from this provide a definition of what systems medicine entails. Based on our analysis of current developments in medicine and healthcare and associated research needs, we emphasize the role of systems medicine as a multilevel and multidisciplinary methodological framework for informed data acquisition and interdisciplinary data analysis to extract previously inaccessible knowledge for the benefit of patients.

Chronic obstructive pulmonary disease (COPD) significantly increases the risk of developing cancer. Biomarker studies frequently follow a case-control set-up in which patients diagnosed with a disease are compared to controls. Longitudinal cohort studies such as the COPD-centered German COPD and SYstemic consequences-COmorbidities NETwork (COSYCONET) study provide the patient and biomaterial base for discovering predictive molecular markers. We asked whether microRNA (miRNA) profiles in blood collected from COPD patients prior to a tumor diagnosis could support an early diagnosis of tumor development independent of the tumor type. From 2741 participants of COSYCONET diagnosed with COPD, we selected 534 individuals including 33 patients who developed cancer during the follow-up period of 54 months and 501 patients who did not develop cancer, but had similar age, gender and smoking history. Genome-wide miRNA profiles were generated and evaluated using machine learning techniques. For patients developing cancer we identified nine miRNAs with significantly decreased abundance (two-tailed unpaired t-test adjusted for multiple testing P < 0.05), including members of the miR-320 family. The identified miRNAs regulate different cancer-related pathways including the MAPK pathway (P = 2.3 × 10). We also observed the impact of confounding factors on the generated miRNA profiles, underlining the value of our matched analysis. For selected miRNAs, qRT-PCR analysis was applied to validate the results. In conclusion, we identified several miRNAs in blood of COPD patients, which could serve as candidates for biomarkers to help identify COPD patients at risk of developing cancer.
Aged ; Biomarkers, Tumor ; genetics ; Cohort Studies ; Female ; Gene Expression Profiling ; Genome, Human ; Humans ; Male ; MicroRNAs ; genetics ; Neoplasms ; diagnosis ; etiology ; genetics ; Prognosis ; Pulmonary Disease, Chronic Obstructive ; complications

Metastases of uveal melanoma (UM) spread predominantly to the liver. Due to low response rates to systemic therapies, liver-directed therapies (LDT) are commonly used for tumor control. The impact of LDT on the response to systemic treatment is unknown. A total of 182 patients with metastatic UM treated with immune checkpoint blockade (ICB) were included in this analysis. Patients were recruited from prospective skin cancer centers and the German national skin cancer registry (ADOReg) of the German Dermatologic Cooperative Oncology Group (DeCOG). Two cohorts were compared: patients with LDT (cohort A, n = 78) versus those without LDT (cohort B, n = 104). Data were analyzed for response to treatment, progression-free survival (PFS), and overall survival (OS). The median OS was significantly longer in cohort A than in cohort B (20.1 vs. 13.8 months; P = 0.0016) and a trend towards improved PFS was observed for cohort A (3.0 vs. 2.5 months; P = 0.054). The objective response rate to any ICB (16.7% vs. 3.8%, P = 0.0073) and combined ICB (14.1% vs. 4.5%, P = 0.017) was more favorable in cohort A. Our data suggest that the combination of LDT with ICB may be associated with a survival benefit and higher treatment response to ICB in patients with metastatic UM.
Humans ; CTLA-4 Antigen ; Immune Checkpoint Inhibitors/therapeutic use* ; Liver ; Prospective Studies ; Skin Neoplasms

Background: and Purpose Recent studies suggested an increased incidence of cerebral venous thrombosis (CVT) during the coronavirus disease 2019 (COVID-19) pandemic. We evaluated the volume of CVT hospitalization and in-hospital mortality during the 1st year of the COVID-19 pandemic compared to the preceding year. Methods: We conducted a cross-sectional retrospective study of 171 stroke centers from 49 countries. We recorded COVID-19 admission volumes, CVT hospitalization, and CVT in-hospital mortality from January 1, 2019, to May 31, 2021. CVT diagnoses were identified by International Classification of Disease-10 (ICD-10) codes or stroke databases. We additionally sought to compare the same metrics in the first 5 months of 2021 compared to the corresponding months in 2019 and 2020 (ClinicalTrials.gov Identifier: NCT04934020). Results: There were 2,313 CVT admissions across the 1-year pre-pandemic (2019) and pandemic year (2020); no differences in CVT volume or CVT mortality were observed. During the first 5 months of 2021, there was an increase in CVT volumes compared to 2019 (27.5%; 95% confidence interval [CI], 24.2 to 32.0; P<0.0001) and 2020 (41.4%; 95% CI, 37.0 to 46.0; P<0.0001). A COVID-19 diagnosis was present in 7.6% (132/1,738) of CVT hospitalizations. CVT was present in 0.04% (103/292,080) of COVID-19 hospitalizations. During the first pandemic year, CVT mortality was higher in patients who were COVID positive compared to COVID negative patients (8/53 [15.0%] vs. 41/910 [4.5%], P=0.004). There was an increase in CVT mortality during the first 5 months of pandemic years 2020 and 2021 compared to the first 5 months of the pre-pandemic year 2019 (2019 vs. 2020: 2.26% vs. 4.74%, P=0.05; 2019 vs. 2021: 2.26% vs. 4.99%, P=0.03). In the first 5 months of 2021, there were 26 cases of vaccine-induced immune thrombotic thrombocytopenia (VITT), resulting in six deaths. Conclusions During the 1st year of the COVID-19 pandemic, CVT hospitalization volume and CVT in-hospital mortality did not change compared to the prior year. COVID-19 diagnosis was associated with higher CVT in-hospital mortality. During the first 5 months of 2021, there was an increase in CVT hospitalization volume and increase in CVT-related mortality, partially attributable to VITT.