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Background: Recently, enormous progress in cancer therapy has been achieved by the use of immune checkpoint inhibitors. Activating the body's own immune system has added a novel and powerful therapeutic option for the treatment of melanoma and lung cancer. Furthermore, the potential use of immunotherapy is being extensively explored also in other malignancies. Objective of review: This review summarises current clinical studies using immune checkpoint modulators for the treatment of head and neck cancer (HNSCC). Type of review: Systematic review. Search strategy: A PubMed search from 2010 onwards was performed for the use of immune checkpoint inhibitors in clinical trials of HNSCC. An equivalent search was performed at clinicaltrials.gov. Additionally, the abstracts from the annual meetings of the ASCO, ESMO and AACR were screened. Results: A total of 45 relevant studies using immune checkpoint inhibitors in HNSCC were identified. In the majority of these studies, antagonistic antibodies targeting the immune checkpoint receptors PD‐1 are used either solely or combined, mostly with other immunomodulatory antibodies, such as inhibitors of CTLA‐4. Most studies are still recruiting patients (26/45). In the primary setting, we identified 16 studies using checkpoint inhibition as neoadjuvant/adjuvant modality for treatment with curative intent. The response rate upon treatment with PD‐1 antagonists in relation to the PD‐L1 status is being investigated in 12 trials. Novel immune checkpoint modulators combined with the inhibition of the PD‐1/PD‐L1 axis or CTLA‐4 have been set up in six trials. So far, only four studies that use immune checkpoint inhibition in HNSCC have presented results and all of these explored the inhibition of the PD‐1/PD‐L1 axis. The studies demonstrated overall response rates (ORR) in the range of 20%. These preliminary data suggest that a PD‐L1 expression ≥1% is associated with a higher response rate compared to a PD‐L1 expression ≤1%. The anti‐PD‐1‐antibody pembrolizumab extended the duration of response in recurrent and/or metastatic (R/M) HNSCC (by approximately 53 weeks) in a phase Ib study. Therefore, pembrolizumab was granted accelerated approval for the treatment of platinum refractory R/M HNSCC by the FDA. Conclusion: Numerous clinical trials are addressing the suitability and efficacy of immune checkpoint modulators in HNSCC with the predominant targets being the established immune checkpoint receptors PD‐1/PD‐L1 and CTLA‐4. Recently, presented results have shown a survival benefit, a favourable safety profile and an extended duration of response in favour of using immune checkpoint modulation in R/M HNSCC. [ABSTRACT FROM AUTHOR]

Inhibition of homologous recombination (HR) is believed to be a transactivation-independent function of p53 that protects from genetic instability. Misrepair by HR can lead to genetic alterations such as translocations, duplications, insertions and loss of heterozygosity, which all bear the risk of driving oncogenic transformation. Regulation of HR by wild-type p53 (wtp53) should prevent these genomic rearrangements. Mutation of p53 is a frequent event during carcinogenesis. In particular, dominant-negative mutants inhibiting wtp53 expressed from the unperturbed allel can drive oncogenic transformation by disrupting the p53-dependent anticancer barrier. Here, we asked whether the hot spot mutants R175H and R273H relax HR control in p53-proficient cells. Utilizing an I-SceI-based reporter assay, we observed a moderate (1.5 × ) stimulation of HR upon expression of the mutant proteins in p53-proficient CV-1, but not in p53-deficient H1299 cells. Importantly, the stimulatory effect was exactly paralleled by an increase in the number of HR competent S- and G2-phase cells, which can well explain the enhanced recombination frequencies. Furthermore, the impact on HR exerted by the transactivation domain double-mutant L22Q/W23S and mutant R273P, both of which were reported to regulate HR independently of G1-arrest execution, is also exactly mirrored by cell-cycle behavior. These results are in contrast to previous concepts stating that the transactivation-independent impact of p53 on HR is a general phenomenon valid for replication-associated and also for directly induced double-strand break. Our data strongly suggest that the latter is largely mediated by cell-cycle regulation, a classical transactivation-dependent function of p53. [ABSTRACT FROM AUTHOR]

Process Improvement (PI) is an approach for helping organizations to identify and resolve inefficient and ineffective processes through problem solving and pilot testing change. Use of PI in improving client access, retention and outcomes in addiction treatment is on the rise through the teaching of the Network for the Improvement of Addiction Treatments (NIATx) Model for Improvement. Emphasizing five phases of change, five key principles for change, and four revolving aims, NIATx has taught hundreds of addiction treatment administrative and clinical staff to lead successful process improvement initiatives. This paper draws on experience from NIATx and offers methods and concepts to consider in the teaching of core process improvement tools and techniques. [ABSTRACT FROM AUTHOR]

A review of United States based two-year (82), four-year (38), and graduate (68) addictions professional preparation programs indicated that the discipline lacks consistency regarding name, whether preparation has a science or arts academic foundation, whether preparation has an academic or technical base, and in what department or academic unit hosts the program. Educators, researchers and providers working in the substance abuse field who participated in informal discussions of the results of this study found this variation understandable and believed the emerging nature of the discipline, institutional politics, the variation in terminology used by state and local agencies, and the interdisciplinary nature of the field create these inconsistencies. These variations indicate that the addictions profession has not yet developed consensus on what terminology best describes the discipline, nor the curricular framework that leads to most consistent academic preparation. Further, this variation provides insights about the influence the discipline has on public policy and the perceptions of addictions studies held by the public, consumers, and other related health professionals. Moving to full recognition as a profession will require attention to the preparation of professionals, standards for credentialing, and expectations for professional conduct and continuing professional development. [ABSTRACT FROM AUTHOR]