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Wastewater-based epidemiology provides a conceptual framework for the evaluation of the prevalence of public health related biomarkers. In the context of the Coronavirus disease-2019, wastewater monitoring emerged as a complementary tool for epidemic management. In this study, we evaluated data from six wastewater treatment plants in the region of Saxony, Germany. The study period lasted from February to December 2021 and covered the third and fourth regional epidemic waves. We collected 1065 daily composite samples and analyzed SARS-CoV-2 RNA concentrations using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Regression models quantify the relation between RNA concentrations and disease prevalence. We demonstrated that the relation is site and time specific. Median loads per diagnosed case differed by a factor of 3-4 among sites during both waves and were on average 45 % higher during the third wave. In most cases, log-log-transformed data achieved better regression performance than non-transformed data and local calibration outperformed global models for all sites. The inclusion of lag/lead time, discharge and detection probability improved model performance in all cases significantly, but the importance of these components was also site and time specific. In all cases, models with lag/lead time and log-log-transformed data obtained satisfactory goodness-of-fit with adjusted coefficients of determination higher than 0.5. Back-estimation of testing efficiency from wastewater data confirmed state-wide prevalence estimation from individual testing statistics, but revealed pronounced differences throughout the epidemic waves and among the different sites., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests that could influence this study. Ethics application (BO-EK-383072021) has been confirmed by the Ethic Committee of Technische Universität Dresden, which is registered as institutional review board (IRB00001473) at the Office of Human Research Protection., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: In metastatic colorectal cancer (mCRC), there are limited data on associations between early tumor shrinkage (ETS), depth of response (DpR), and patient characteristics., Methods: Data from patients with RAS wild-type mCRC who had participated in the PRIME (NCT00364013) and PEAK (NCT00819780) studies were analyzed retrospectively. ETS and DpR were assessed by baseline Köhne category/BRAF status (PRIME) and baseline tumor load (pooled PRIME and PEAK)., Results: Analysis populations included 436 to 665 patients. Patients' chances of achieving ETS of 30% or greater were 63.8%, 50.4%, and 41.9% in the low-, medium-, and high-risk Köhne categories, and 21.7% in those with BRAF mutations. Corresponding percentages for the highest DpR classification (71%-100%) were 47.7% (low risk), 23.6% (medium risk), 10.0% (high risk), and 4.2% (BRAF mutant). No clear relationship was observed between baseline tumor load and ETS or DpR. An ETS of 30% or greater and higher DpR values were associated with statistically significant prolongation of median progression-free survival and overall survival., Conclusion: Patients with mCRC categorized at baseline by the Köhne criteria as high risk or with BRAF mutations have lower chances of achieving an ETS of 30% or greater or a high DpR. Baseline tumor load was not predictive of ETS or DpR. Favorable ETS or DpR is associated with improved progression-free and overall survival., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: There is no standardized assessment of symptomatic events in metastatic colorectal cancer (mCRC) despite disease symptoms that affect treatment decisions. Data from 3 first-line panitumumab in mCRC trials were retrospectively analyzed to assess whether early tumor shrinkage (ETS) and depth of response (DpR) were associated with time to occurrence of tumor-related symptoms., Patients and Methods: Patients with RAS wild-type mCRC from PRIME, PEAK, and Study 314 were included. ETS was defined as a reduction of ≥ 30% in the sum of the longest diameters of lesions at 8 weeks. DpR was calculated as maximum percentage change in tumor size from baseline to nadir. The proportion of patients who developed symptoms (including a composite symptomatic endpoint) during study treatment was calculated. This study was registered at ClinicalTrials.gov as PRIME (NCT00364013), PEAK (NCT00819780), and Study 314 (NCT00508404)., Results: Overall, data of 659 patients were analyzed. Onset of symptoms was delayed in patients with ETS ≥ 30% versus ETS < 30% and in patients with greater DpR. In patients with symptoms at baseline who experienced ETS ≥ 30%, overall survival was similar to that seen for patients without symptoms at baseline., Conclusion: Both ETS and DpR were associated with delayed onset of symptoms in RAS wild-type mCRC patients. Treatments with high cytoreductive potential may delay symptom development., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Approximately 20% of all Hodgkin lymphoma (HL) patients are older than 60 years and have a poor prognosis, mainly because of increased treatment-related toxicity resulting in reduced overall dose intensity and more treatment-related mortality. To possibly improve the treatment of elderly HL patients, the German Hodgkin Study Group developed a new regimen, PVAG (prednisone, vinblastine, doxorubicin, and gemcitabine). In this multicenter phase 2 study, elderly HL patients in early unfavorable and advanced stages received 6 to 8 cycles of PVAG and additional radiotherapy if they were not in complete remission (CR) after chemotherapy. Endpoints included feasibility, acute toxicity, and response rate. Fifty-nine patients 60 to 75 years of age (median, 68 years) were eligible for analysis; 93% had advanced stage disease. WHO grade 3/4 toxicities were documented in 43 patients; 46 patients responded with CR/CR uncertain (78%). Within 37 months median observation time, 15 progressions or relapses and 17 deaths were observed, of which 8 were related to HL and 1 was the result of treatment-related toxicity. The 3-year estimates for overall survival and progression-free survival were 66% (95% CI, 50%-78%) and 58% (95% CI, 43%-71%), respectively. We conclude that PVAG is safe and feasible in elderly HL patients. This trial was registered at www.clinicaltrials.gov as #NCT00147875.

Despite the introduction of newer chemotherapeutic agents such as irinotecan, capecitabine and oxaliplatin, patients with metastatic colorectal cancer (mCRC) still have a poor prognosis. More effective and better-tolerated treatment strategies are needed to improve patient outcomes, particularly in subsequent lines of treatment following chemotherapy failure. The favourable efficacy and acceptable safety profiles of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) have led to the approval of panitumumab and cetuximab monotherapy for the treatment of patients with EGFR-expressing mCRC whose tumours express non-mutated (wildtype) KRAS, after failure of standard chemotherapy. Cetuximab is also approved in combination with chemotherapy for the treatment of mCRC in this patient population. In phase III monotherapy studies, panitumumab and cetuximab demonstrated significant improvements in progression-free survival when administered with best supportive care (BSC) vs. BSC alone in chemotherapy-refractory mCRC patients. A planned retrospective analysis of the panitumumab monotherapy trial was the first large-scale clinical demonstration that efficacy was confined to patients with tumours expressing wild-type KRAS. It is now recognised that anti-EGFR mAb therapy should only be used in patients whose tumours express wild-type KRAS. While generally well tolerated, anti-EGFR mAb monotherapy is associated with skin toxicity, and severity of the skin rash has been proposed as an early marker of response to treatment. BRAF, PTEN, and PI3K are also emerging as future potential predictive markers of response; however, further clinical studies are warranted to define the role of these biomarkers.

Background/aims: Local ablation methods are an effective treatment for hepatocellular carcinoma (HCC). The rate of recurrence or development of intra-hepatic metastases may be lowered by antitumoral immune responses. Since HCCs are in general only weakly immunogenic, cell injury induced by local tumor ablation (PEI/RFTA) may increase HCC immunogenicity and may release endogenous adjuvants that activate dendritic cells (DC). The aim of the study, therefore, was the analysis whether PEI or RFTA induced injury results in an adjuvant effect for immune responses to HCCs., Methods: Eight HCC patients were treated with PEI or RFTA and serially analyzed for 4 weeks. Plasmocytoid (PDC) and myeloid dendritic cells (MDC) were analyzed directly ex vivo and in vitro using FACS and proliferation assays., Results: HCC ablation induced a functional transient activation of MDC but not of PDC associated with increased serum levels of TNF-alpha and IL-1beta., Conclusions: These findings suggest that the combination of PEI or RFTA and active antigen specific immunotherapeutic approaches using DCs is a promising approach for the induction of sustained antitumoral immune responses aiming at the reduction of tumor recurrence and metastases in HCC patients.

Background/aims: Novel immunotherapeutic and other strategies are being explored for the treatment of hepatocellular carcinoma (HCC). Alpha-fetoprotein (AFP) may be a target antigen for immunotherapy. Little is known, however, about the immunobiology of AFP. Therefore, the impact of AFP on dendritic cells (DC), CD4+ and CD8+ T cells was studied in detail., Methods: Immune cells from peripheral blood of 27 HCC patients were studied using FACS, ELISPOT, and proliferation assays., Results: The in vitro generation, maturation, and T cell stimulatory capacity of DCs were not altered by AFP up to concentrations of 20 microg/ml. Higher AFP concentrations (> 20 microg/ml) resulted in phenotypic changes on DCs without impairing their capacity to stimulate CD4+ T cells. Frequencies and function of DCs and AFP specific T cells were not reduced in HCC patients independent on serum AFP levels. Finally, T lymphocytic infiltrations in the liver were not dependent on AFP serum levels., Conclusions: These studies clearly demonstrate that (i) DC-based immunotherapeutic approaches are a promising approach for HCC treatment and (ii) AFP-reactive T cell clones have not been deleted from the human T cell repertoire establishing AFP as a potential target for T cell based immunotherapy of HCC.