A novel voxel based homogeneity index: rationale and clinical implications for whole-brain radiation therapy

A homogeneity index (HI) is an objective measure for the uniformity of a dose distribution within a given target volume in radiotherapy (RT). The calculation of conventional HIs is based on a limited number of dose volume histogram (DVH) data points which leads to assignment of the same score to RT plans with different homogeneity. This implies a fundamental drawback of DVH-based indices. A voxel-based homogeneity index (VHI) is proposed which aims to improve the sensitivity for homogeneity by utilizing the entire information present in the three-dimensional dose distribution. Properties of conventional HIs are conserved by the VHI. The score is dimensionless; its value is 0 for ideal homogeneity and increases continuously with higher inhomogeneity, therefore allowing for objective comparison of RT plans of different patients. At the same time it has novel properties like the ability to decide to which extent under- or overdosage contribute to inhomogeneity. Sensitivity of VHI was compared with conventional HIs by evaluating whole brain radiation therapy (WBRT) (n=770) RT treatment plans. A mathematical proof was formulated demonstrating the connection between VHI and tumor control probability. For clinical validation radiation underdosage as assessed by the new index was correlated with treatment outcomes of patients who underwent therapeutic WBRT (n=430). Kaplan-Meier-methods and multivariable Cox-regression analysis were used to compare overall survival (OS) and central nervous system progression free survival (CNS PFS) for different levels of underdosage (Low/Intermediate/High Underdosage). A significantly lower OS and CNS PFS were observed for higher levels of VHI_Underdosage, particularly in patients with good performance status (Karnofsky-Index > 70%). In this patient group median OS was 7.63 months in the Low Underdosage group, 7.76 months in the Intermediate Underdosage group and 3.78 months in the High Underdosage group (n=142, unadjusted HR=1.369 95%CI [1.089,1.721], Log rank test for trend P=0.007). VHI has a higher sensitivity to assess inhomogeneity than conventional HIs. First clinical implications were found in terms of compromised OS and CNS PFS for WBRT with higher levels of underdosage in the target volume as assessed by the new index.Ein Homogenitätsindex (HI) ist ein objektives Maß für die Dosishomogenität im Zielvolumen eines Bestrahlungsplans. Bei der Berechnung von konventionellen HIs werden nur wenige Datenpunkte des Dosis-Volumen-Histogramms (DVH) herangezogen, was dazu führt, dass Bestrahlungspläne mit unterschiedlicher Homogenität einen identischen Score erhalten. Dies weist auf einen fundamentalen Nachteil von DVH-basierten Indices hin. In dieser Arbeit wird ein voxel-basierter Homogenitätsindex (VHI) vorgestellt, welcher darauf abzielt, eine höhere Sensitivität bezüglich von Dosis-Inhomogenität aufzuweisen, indem die gesamte Information in der dreidimensionalen Dosisverteilung analysiert wird. Der VHI behält wesentliche Eigenschaften konventioneller HIs bei. Der Score ist eine dimensionslose Größe, hat den Wert 0 bei idealer Homogenität und steigt kontinuierlich mit höherer Inhomogenität an. Auf diese Weise wird es ermöglicht, Bestrahlungspläne verschiedener Patienten miteinander objektiv zu vergleichen. Gleichermaßen weißt er neuartige Eigenschaften auf. So kann das Ausmaß bestimmt werden, inwiefern Unter- und Überdosierungen zur Inhomogenität beitragen. Die Sensitivität des VHI wurde mit der von konventionellen HIs durch die Evaluation von Ganzhirnbestrahlungsplänen (n=770) verglichen. Es wurde ein mathematischer Beweis erbracht, der den Zusammenhang zwischen dem VHI und der Tumorkontrollwahrscheinlichkeit offenbart. Zur klinischen Validierung wurde das Outcome von Patienten mit therapeutischer Ganzhirn-Radiatio (WBRT) mit der Unterdosierung erfasst durch den VHI korreliert. Die Kaplan-Meier-Methoden und eine multivariable Cox-Regression wurden verwendet, um das Gesamtüberleben (OS) und das intrakranielle progressionsfreie Überleben (CNS PFS) von Patienten mit unterschiedlichen Leveln der Unterdosierung (niedrige/mittlere/hohe Unterdosierung) zu analysieren. Ein signifikant erniedrigtes OS und CNS PFS konnte für höhere Level von VHI_Underdosage beobachtet werden, insbesondere bei Patienten in gutem Allgemeinzustand (Karnofsky-Index > 70%). In dieser Patientengruppe lag das mediane OS bei 7.63 Monaten bei niedriger Unterdosierung, bei 7.76 Monaten bei mittlerer Unterdosierung und 3.78 Monaten bei hoher Unterdosierung (n=142, unadjustierter HR=1.369 95%CI [1.089,1.721], Log Rank Test für Trend P=0.007). Der VHI weist eine höhere Sensitivität zur Erfassung von Inhomogenitäten im Zielvolumen als konventionelle HIs auf. Eine erste klinische Relevanz konnte durch ein erniedrigtes OS und CNS PFS bei Patienten gezeigt werden, die eine therapeutische WBRT erhielten und höhere Level an Unterdosierungen im Zielvolumen aufwiesen

Risk adapted dose-intensified postoperative radiation therapy in prostate cancer patients using a simultaneous integrated boost technique applied with helical Tomotherapy

Background Postoperative adjuvant radiation therapy (ART) in T3 and R1 prostate cancer as well as salvage radiation therapy (SRT) in case of postoperative biochemical failure (BF) are established treatments. Dose- intensified postoperative radiation therapy (RT) schemes have shown superior biochemical control accompanied by increased toxicity rates. In our study we evaluate a novel risk adapted dose-intensified postoperative RT scheme. Methods A consecutive series of prostate cancer patients receiving postoperative RT after radical prostatectomy using helical Tomotherapy between 04/2012 and 04/2015 was analyzed retrospectively. RT was administered using a simultaneous integrated boost (SIB) to the area at risk (37 fractions of 1.9 Gy, total dose: 70.3 Gy) being defined based on histopathological findings (T3/R1 region) and in few cases according to additional diagnostic imaging. The whole prostate bed was treated with a dose of 66.6 Gy (37 fractions of 1.8 Gy). Primary endpoints were acute and late genitourinary (GU) and gastrointestinal (GI) toxicities. Secondary endpoints included patient reported outcome as assessed by the International Prostate Symptom Score (IPSS), the International Consultation on Incontinence questionnaire (ICIQ) and prostate cancer specific Quality of Life questionnaire QLQ-PR25, as well as rates of BF. Results A total of 69 patients were analyzed. Sixteen patients underwent ART and 53 patients SRT, respectively. The median follow-up was 20 months (range, 8–41 months). Seven (10.1%) and four (5.8%) patients experienced acute grade 2 GU and GI toxicity. Two patients (2.9%) had late grade 2 GU toxicity, whereas no late grade 2 GI nor any grade 3 acute or late GU or GI events were observed. When compared to the baseline IPSS scores (p = 1.0) and ICIQ scores (p = 0.87) were not significantly different at the end of follow-up. Patient reported Quality of life (QoL) showed also no significant difference. A total of seven patients (10.1%) experienced a biochemical recurrence with the 2-year biochemical progression-free survival (bPFS) being 91%. Conclusions Postoperative RT for prostate cancer patients with a risk adapted dose-intensified SIB using helical tomotherapy is feasible and associated with favorable acute and late GU and GI toxicity rates, no significant change of IPSS-, ICIQ scores and patient reported QoL and results in promising bPFS rates

Efficacy and Toxicity of Different Chemotherapy Protocols for Concurrent Chemoradiation in Non-Small Cell Lung Cancer—A Secondary Analysis of the PET Plan Trial

(1) Background: The optimal chemotherapy (CHT) regimen for concurrent chemoradiation (cCRT) is not well defined. In this secondary analysis of the international randomized PET-Plan trial, we evaluate the efficacy of different CHT. (2) Methods: Patients with inoperable NSCLC were randomized at a 1:1 ratio regarding the target volume definition and received isotoxically dose-escalated cCRT using cisplatin 80 mg/m2 (day 1, 22) and vinorelbin 15 mg/m2 (day 1, 8, 22, 29) (P1) or cisplatin 20 mg/m2 (day 1–5, 29–33) and vinorelbin 12.5 mg/m2 (day 1, 8, 15, 29, 36, 43) (P2) or carboplatin AUC1 (day 1–5, 29–33) and vinorelbin 12.5 mg/m2 (day 1, 8, 15, 29, 36, 43) (P3) or other CHT at the treating physician’s discretion. (3) Results: Between 05/2009 and 11/2016, 205 patients were randomized and 172 included in the per-protocol analysis. Patients treated in P1 or P2 had a better overall survival (OS) compared to P3 (p = 0.015, p = 0.01, respectively). Patients treated with carboplatin had a worse OS compared to cisplatin (HR 1.78, p = 0.03), but the difference did not remain significant after adjusting for age, ECOG, cardiac function creatinine and completeness of CHT. (4) Conclusions: Carboplatin doublets show no significant difference compared to cisplatin, after adjusting for possibly relevant factors, probably due to existing selection bias

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Clinical evaluation of a web-based personalized recommendation system with electronic health record interface to optimize healthcare resources during SARS-CoV-2 surges

Abstract During the SARS-CoV-2 pandemic, the German healthcare system faced challenges of efficiently allocating testing resources. To address this, we developed an open-source personalized recommendation system (PRS) called “CovApp”. The PRS utilized a questionnaire to estimate the risk of infection, provided personalized recommendations such as testing, self-isolation, or quarantine, and featured QR code data transmission to electronic health records. The PRS served up to 2.5 million monthly users and received 67,000 backlinks from 1800 domains. We clinically evaluated the PRS at the SARS-CoV-2 testing facility at Charité and observed a 21.7% increase in patient throughput per hour and a 22.5% increase in patients per day. Patients using the PRS were twice as likely to belong to the High Risk group eligible for testing (18.6% vs. 8.9%, p < 0.0001), indicating successful compliance with CovApp’s recommendations. CovApp served as a digital bridge between the population and medical staff and significantly improved testing efficiency. As an open-source platform, CovApp can be readily customized to address emerging public health crises. Further, given the EHR interface, the app is of great utility for other applications in clinical settings