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Cervical cancer is still the fourth most common cancer in women throughout the world; an estimated 604,000 new cases were observed in 2020. Better knowledge of its pathogenesis, gained in recent years, has introduced new preventive and diagnostic approaches. Knowledge of its pathogenesis has made it possible to provide individualized surgical and drug treatment. In industrialized countries, cervical cancer has become a less frequent tumor entity due to the accessibility of the human papilloma virus vaccination, systematic preventive programs/early detection programs, health care infrastructure and the availability of effective therapy options. Nevertheless, globally, neither mortality nor morbidity has been significantly reduced over the past 10 years, and therapy approaches differ widely. The aim of this review is to address recent advances in the prevention, diagnostic investigation and treatment of cervical cancer globally, focusing on advances in Germany, with a view toward providing an updated overview for clinicians. The following aspects are addressed in detail: (a) the prevalence and causes of cervical cancer, (b) diagnostic tools using imaging techniques, cytology and pathology, (c) pathomechanisms and clinical symptoms of cervical cancer and (d) different treatment approaches (pharmacological, surgical and others) and their impact on outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Stereotactic body radiation therapy (SBRT) is widely applied for treatment of early stage lung cancer and pulmonary metastases. Modern immune checkpoint blockade (ICB) is progressively used in cancer treatment. Pneumonitis is a relevant side effect of both thoracic SBRT and ICB. Currently, it remains unclear whether we can presume the same radiation dose–volume–effect correlations and dose constraints for safe application of SBRT + ICB. We present a dose–volume–effect correlation analysis method using pneumonitis contours and dose–volume histograms (DVH). We showed dosimetric differences for pneumonitis volumes between SBRT + ICB and SBRT alone. We found a large extent of pneumonitis, even bilateral and apart from the radiation field for combined SBRT + ICB. We noticed a shift in pneumonitis DVHs towards lower doses and a trend towards decreased areas under the curve (AUC) for SBRT + ICB. This provides a direction for re-evaluation and potential adaptation of lung dose constraints for combined SBRT and ICB. Thoracic stereotactic body radiation therapy (SBRT) is extensively used in combination with immune checkpoint blockade (ICB). While current evidence suggests that the occurrence of pneumonitis as a side effect of both treatments is not enhanced for the combination, the dose–volume correlation remains unclear. We investigate dose–volume–effect correlations for pneumonitis after combined SBRT + ICB. We analyzed patient clinical characteristics and dosimetric data for 42 data sets for thoracic SBRT with ICB treatment (13) and without (29). Dose volumes were converted into 2 Gy equivalent doses (EQD2), allowing for dosimetric comparison of different fractionation regimes. Pneumonitis volumes were delineated and corresponding DVHs were analyzed. We noticed a shift towards lower doses for combined SBRT + ICB treatment, supported by a trend of smaller areas under the curve (AUC) for SBRT+ ICB (median AUC 1337.37 vs. 5799.10, p = 0.317). We present a DVH-based dose–volume–effect correlation method and observed large pneumonitis volumes, even with bilateral extent in the SBRT + ICB group. We conclude that further studies using this method with enhanced statistical power are needed to clarify whether adjustments of the radiation dose constraints are required to better estimate risks of pneumonitis after the combination of SBRT and ICB. [ABSTRACT FROM AUTHOR]

Background: The incidence of renal cell carcinoma (RCC), one of the most common malignant tumors in Germany, continues to increase. Medical treatment is indicated in relapsed or metastatic disease., Materials and Methods: The article is based on the content of the recent guidelines and a selective literature search., Results: The use of the introduction of immune checkpoint inhibitors (ICI) and their combination with tyrosine kinase inhibitors (TKI) in particularly vulnerable patients has fundamentally changed the therapeutic landscape. The median overall survival was thus extended to > 40 months. However, until recently neither targeted nor conventional therapy could be established in (neo)adjuvant therapy. New data show survival benefit for patients at high risk of recurrence on adjuvant therapy with pembrolizumab., Conclusions: Currently only pembrolizumab is approved in adjuvant therapy in Germany. Further studies and a longer follow-up will help us in the future in the classification of therapy with ICI and its combination with TKI in localized RCC., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Introduction: Pembrolizumab is a highly effective standard of care in PD-L1 overexpressing (≥ 50%) non-small-cell lung cancer. However, a substantial share of patients from everyday clinical practice is treated without clear evidence from clinical trials., Patients and Methods: We performed a retrospective multicentric study including all consecutive patients from 6 certified lung cancer centers in Berlin, Germany, having received pembrolizumab as first-line palliative therapy from January 1 until December 31, 2017. Aims were to validate published clinical trials with a special focus on efficacy and outcome in patients with reduced performance status (PS), brain metastases, and steroids., Results: A total of 153 patients were included (median age 69 years, 58% men, 69% adenocarcinoma). Rates for PS ≥ 2, brain metastases, and steroids were 24.8%, 20.9%, and 24.2%, respectively. Median objective response rate, progression-free and overall survival were 48.5%, 8.2 and 22.0 months for all patients and 52.4%, 8.8 and 29.2 months in patients fulfilling the inclusion criteria for the KEYNOTE-024 trial. Patients with a comorbidity-defined PS ≥ 2, symptomatic brain metastases requiring upfront radiotherapy, or baseline steroids had significantly reduced survival. In contrast, durable responses occurred with a tumor-related PS ≥ 2 or asymptomatic brain metastases. Grade 3/4 and 5 immune-related adverse events affected 13.7% and 2.0% of patients., Conclusion: Real-world and clinical trial efficacy with upfront pembrolizumab correspond well. Pembrolizumab may sufficiently control asymptomatic brain metastases and may improve a cancer-related reduced PS. However, the frail share of patients with a comorbidity-defined PS ≥ 2, symptomatic brain metastases, or baseline steroids derives no relevant benefit., (Copyright © 2021. Published by Elsevier Inc.)

Immune-related adverse events (irAEs) are a class-effect of checkpoint inhibitors (CIs). The development of a Bullous pemphigoid (BP)-like blistering disease, driven by autoantibodies against the hemidesmosomal protein BP180, is a potentially serious irAE whose incidence seems to be increasing. We therefore set out to characterize the clinical and (immuno)histopathological features and treatment responses of cases of BP which developed during or after CI therapy collated in six German tertiary referral centers between 2014 and 2018. We identified twelve cases of BP which emerged during and/or after CI therapy. The time interval between the initiation of CI therapy and the diagnosis of BP was 3-74 weeks (median: 23 weeks). Age at the time of diagnosis of BP varied between 62 and 80 years (median: 76 years). The clinical presentation of the patients was diverse but the severity was relatively mild when compared to that seen in most cases of spontaneous BP. Only four patients met all of the immunopathological criteria recommended in the European guidelines for the diagnosis of BP. Topical corticosteroid treatment was sufficient to achieve disease control in most patients. CI therapy could be continued in 8 out of 12 patients. In summary, our study indicates that cases of BP during or after CI therapy bear several peculiarities distinguishing them from spontaneous BP. Given the diversity of the clinical presentation of CI-induced BP the application of existing diagnostic algorithms developed for spontaneous BP can be utilized to uncover the frequency and features of CI-induced BP and to develop and optimize management algorithms., Competing Interests: DG reports personal fees and other from Pierre Fabre Pharma Gmbh, personal fees and other from Roche Pharma AG, personal fees and other from Bristol-Myers Squibb GmbH & Co. KGaA, personal fees and other from Novartis Pharma GmbH, personal fees and other from Sanofi-Aventis GmbH, during the conduct of the study; other from Amgen GmbH, other from Janssen-Cilag GmbH, other from Galderma Laberatorium GmbH, outside the submitted work. RG reports personal fees and non-financial support from BristolMyersSquibb, personal fees and non-financial support from Roche Pharma, grants, personal fees and non-financial support from Merck Serono, grants, personal fees and non-financial support from Amgen, personal fees and non-financial support from Pierre Fabre, grants, personal fees and non-financial support from Sanofi Regeneron, personal fees from MerckSharpDohme, grants, personal fees and non-financial support from Novartis, personal fees from Almirall Hermal, grants and personal fees from Pfizer, personal fees from SUN Pharma, personal fees from 4SC, grants from Johnson&Johnson outside the submitted work. RH reports personal fees from ROCHE, personal fees from BMS, personal fees from MSD, personal fees from Novartis, personal fees from Pierre-Fabre, outside the submitted work. EL reports personal fees and non-financial support from BristolMyersSquibb, personal fees and non-financial support from Novartis, Meeting and travel support from Curevac and advisory board fees from Sun Pharma. CL reports personal fees from BMS, personal fees from MSD, personal fees from Sanofi, personal fees from Novartis, personal fees from Roche, personal fees from Pierre Fabre, personal fees from Amgen, personal fees from Kyowa Kirin, personal fees from Biontech, personal fees from Almiral Hermal, personal fees from Sun Pharma, personal fees from Merck, outside the submitted work. PT: speaker´s honoraria from BMS, Novartis, MSD, Pierre-Fabre, CureVac and Roche, consultant´s honoraria from BMS, Novartis, Pierre-Fabre, Merck Serono, Sanofi und Roche and travel support fom BMS, Pierre-Fabre and Roche. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sadik, Langan, Gutzmer, Fleischer, Loquai, Reinhardt, Meier, Göppner, Herbst, Zillikens and Terheyden.)

More than 250 million people worldwide suffer from chronic infection with hepatitis B virus (CHB). Chronic infection is associated with an increased risk of developing liver fibrosis/cirrhosis and hepatocellular carcinoma. Approximately 0.8-1 million people die annually as a result of CHB. One difficulty in the treatment of CHB is that the viral genome can persist for a very long time in the form of a minichromosome, and viral sequences can insert themselves into the host genome. Chronic infections are often characterized by functional defects of the cellular immune response, especially the T‑cell response, which prevents the elimination of HBV-infected cells.Immunotherapies aiming to cure CHB therefore aim to restore the antiviral function of the cellular immune response. In this review, various current approaches to immunotherapy of CHB are described, in particular the use of genetically modified autologous T cells as a possible tool for therapy. Furthermore, the modulation of checkpoint inhibitors of the immune response, metabolic T cell therapies, and therapeutic vaccination to stimulate the T‑cell response are summarized as immunotherapeutic strategies for treating CHB.

Combination therapies of different drugs are an integral part of medicine. However, there is a scientific and regulatory need to understand the contribution of each drug to the overall effect, i.e., nonclinical and clinical development programs have to consider these aspects and need to be designed accordingly. Many drugs are currently under development that attempt to control malignant diseases in the long term by using and activating components of the patient's own immune system. The term immuno-oncology is often used in this context. Medicines that are developed and used for immuno-oncology can be assigned to completely different classes of medicines.This article provides an analysis of combination therapies in immuno-oncology with medicinal products produced by biotechnological manufacturing. This encompasses checkpoint inhibitors, genetically modified cell therapies, tumor vaccines, and oncolytic viruses. The challenges in clinical development are demonstrated on the basis of this heterogenous group of approved immuno-oncological drugs that have been investigated in combination therapies. Due to the different characteristics and number of combination partners, an individually tailored program must be designed for each development program and there is no standard solution.

In the German healthcare system, immunotherapies have been well established for years. Currently there are over 100 registrations of monoclonal antibodies (MABs). In recent years, new immunotherapeutic approaches became available, amongst them checkpoint inhibitors and CAR‑T cells in oncology. Increasing expenditures of the German statutory health insurance (SHI) system are regarded with concerns. This article presents an overview of the development and status of prescriptions and sales of selected immunotherapeutics in Germany. Data from 2015-2019 were analyzed, primarily from the GKV-Arzneimittel-Schnellinformation (GAmSi) and the consultancy IQVIA.In the group of older MABs, such as immunosuppressive and antineoplastic agents, biosimilars led to a (temporary) increase of applications, but reimbursement amounts are decreasing. Instruments of the SHI system like drug agreements, reference prices, and individual discount contracts intervene as expenditure control. Checkpoint inhibitors clearly show increasing prescriptions and expenditures. Finally, the CAR‑T cells are indeed very expensive treatments, but are currently not that important due to the limited number of applications. In addition, the exemption from VAT of 19% and the signed discount agreements between suppliers and sickness funds reduce the burden. In 2015 and 2019, the net expenditures on drugs and surgical dressings accounted for 17.2% of the total expenditures on benefits of the SHI system. Should the expenditures on drugs increase overproportionately in the future, the German SHI system will be able to counteract with already available or new instruments, supported by the legislator. Manufacturers and the SHI system should develop joint actions to achieve solutions for new treatment approaches.

Background: Great advances have been made for the treatment of urothelial carcinoma by the introduction of checkpoint inhibitors (CPI). Single-agent immunotherapy with CPIs has been approved for patients with metastatic or locally advanced inoperable urothelial carcinoma who have either progressed during or after platinum-based chemotherapy or who are cisplatin-ineligible. For cisplatin-ineligible patients, approval is restricted to patients with high programmed cell death ligand 1 (PD-L1) expression. For patients with nonmuscle invasive bladder cancer (NMIBC) or patients with muscle invasive bladder cancer (MIBC) who receive curative therapy, no CPIs have received approval in Germany., Objectives: To provide an overview of the current landscape of immunotherapy in patients with urothelial carcinoma., Methods: Summary of the therapeutic landscape and resulting challenges based on currently published data using a PubMed search., Results: In the treatment of metastatic or inoperable urothelial carcinoma, CPIs represent standard treatment. Depending on the results of currently performed trials, an extension of its use to the perioperative setting (neoadjuvant/adjuvant) and to patients with Bacillus Calmette Guérin (BCG) unresponsive NMIBC in the near future is currently being discussed., Conclusions: Immuno-oncologic treatment using CPIs has become an integral part of the management of patients with advanced bladder cancer. For biomarker-based patient selection and combination therapies, there is an urgent need for further investigations within clinical trial protocols.

Cholangiocellular carcinoma (CCA) is one of the primary liver tumors and overall represents a rare malignancy; however, in recent years the incidence, particularly of intrahepatic CCA (iCCA) has increased worldwide. Due to the high mortality, CCAs cause a significant proportion of cancer-related deaths also in Germany. Because the diagnosis is often made in advanced stages of the disease, in many cases a surgical approach with curative intention is not possible. For locally advanced or metastatic CCA the combination of gemcitabine and cisplatin currently remains the only approved systemic treatment. As the average survival time is only approximately 12 months even under first-line treatment with gemcitabine/cisplatin, research is focused on developing new molecularly targeted and immunological treatment options. Various studies are currently being carried out to investigate approval options for targeted treatment, which could be considered for genetically altered tumors, e.g. in fibroblast growth factor receptor (FGFR) fusion and isocitrate dehydrogenase (IDH) mutations. Additionally, initial clinical data on immune checkpoint inhibitors are available for CCA. Due to the complex selection and partially limited applicability of current treatment options in patients with CCA, an early collaboration with a gastroenterology and oncology center with the possibility of supervision by a tumor board consisting of gastroenterological oncologists, surgeons, radiologists and radio-oncologists or in advanced stages by a molecular tumor board is essential.