IFN-γ and TNF Induce Senescence and a Distinct Senescence-Associated Secretory Phenotype in Melanoma.

Immune checkpoint blockade (ICB) therapy is a central pillar of melanoma treatment leading to durable response rates. Important mechanisms of action of ICB therapy include disinhibition of CD4+ and CD8+ T cells. Stimulated CD4+ T helper 1 cells secrete the effector cytokines interferon-gamma (IFN-γ) and tumor necrosis factor alpha (TNF), which induce senescence in tumor cells. Besides being growth-arrested, senescent cells are metabolically active and secrete a large spectrum of factors, which are summarized as senescence-associated secretory phenotype (SASP). This secretome affects the tumor growth. Here, we compared the SASP of cytokine-induced senescent (CIS) cells with the SASP of therapy-induced senescent (TIS) cells. Therefore, we established in vitro models for CIS and TIS in melanoma. The human melanoma cell lines SK-MEL-28 and WM115 were treated with the cytokines IFN-γ and TNF as CIS, the chemotherapeutic agent doxorubicin, and the cell cycle inhibitor palbociclib as TIS. Then, we determined several senescence markers, i.e., growth arrest, p21 expression, and senescence-associated ß-galactosidase (SA-ß-gal) activity. For SASP analyses, we measured the regulation and secretion of several common SASP factors using qPCR arrays, protein arrays, and ELISA. Each treatment initiated a stable growth arrest, enhanced SA-ß-gal activity, and-except palbociclib-increased the expression of p21. mRNA and protein analyses revealed that gene expression and secretion of SASP factors were severalfold stronger in CIS than in TIS. Finally, we showed that treatment with the conditioned media (CM) derived from cytokine- and palbociclib-treated cells induced senescence characteristics in melanoma cells. Thus, we conclude that senescence induction via cytokines may lead to self-sustaining senescence surveillance of melanoma.

Smartglass augmented reality-assisted targeted prostate biopsy using cognitive point-of-care fusion technology.

INTRODUCTION: MRI-guided targeted biopsy has become standard of care for diagnosis of prostate cancer, with establishment of several biopsy techniques and platforms. Augmented reality smart glasses have emerged as novel technology to support image-guided interventions. We aimed to investigate its usage while prostate biopsy. METHODS: MRI with PIRADS-lesions ≥3 was uploaded to smart glasses (Vuzix BladeR ) and augmented reality smart glasses-assisted targeted biopsy (SMART-TB) of the prostate was performed using cognitive fusion technology at the point of care. Detection rates were compared to systematic biopsy. Feasibility for SMART-TB was assessed (10 domains from bad [1] to excellent [10]). RESULTS: SMART-TB was performed for four patients. Prostate cancer detection was more likely for SMART-TB (46%; 13/28) than for systematic biopsy (27%; 13/48). Feasibility scores were high [8-10] for practicality, multitasking, execution speed, comfort and device weight and low [1-4] for handling, battery and image quality. Median execution time: 28 min; Investment cost smart glass: 1017 USD. CONCLUSION: First description of SMART-TB demonstrated convenient feasibility. This novel technology might enhance diagnosis of prostate cancer in future.

The timing of initial imaging in testicular cancer: impact on radiological findings and clinical decision making.

BACKGROUND: In testicular cancer determination of clinical stage and recommendation of therapeutic strategy after inguinal orchiectomy are based on primary imaging by CT-scan of the chest and CT- or MRI-abdomen. It has not been investigated so far whether the imaging should be performed before or after primary testicular surgery. Staging before surgery means exposing all patients to CT radiation irrespective of ensured histologic malignancy while postoperative staging could pose a risk in biased clinical decision making by increased presence of unspecific lymph node enlargement caused by postsurgical effects. Therefore, we aimed to investigate the association between the timing of initial staging and occurrence of unspecific lymph node enlargement and adjuvant therapies after inguinal orchiectomy. METHODS: We retrospectively evaluated clinical and radiological data from 236 patients who had undergone inguinal orchiectomy for testicular cancer at our department. Statistical analysis was performed to determine whether the occurrence of unspecific lymph node enlargement or the rate of adjuvant therapies were influenced by timing of initial staging (preoperative vs. postoperative). RESULTS: The postoperative imaging cohort showed significant more inguinal, pelvic and retroperitoneal unspecific lymph node enlargement than the preoperative imaging cohort. Simultaneous occurrence of inguinal or pelvic lymph node enlargement together with retroperitoneal enlargements could only be found in the postoperative imaging cohort. No difference regarding adjuvant therapies could be found. CONCLUSIONS: Timing of imaging affects the detection rate of unspecific lymph node enlargements but does not show a significant effect on the rate of adjuvant therapies.

Global change of surgical and oncological clinical practice in urology during early COVID-19 pandemic.

OBJECTIVES: While the coronavirus disease 2019 (COVID-19) pandemic captures healthcare resources worldwide, data on the impact of prioritization strategies in urology during pandemic are absent. We aimed to quantitatively assess the global change in surgical and oncological clinical practice in the early COVID-19 pandemic. METHODS: In this cross-sectional observational study, we designed a 12-item online survey on the global effects of the COVID-19 pandemic on clinical practice in urology. Demographic survey data, change of clinical practice, current performance of procedures, and current commencement of treatment for 5 conditions in medical urological oncology were evaluated. RESULTS: 235 urologists from 44 countries responded. Out of them, 93% indicated a change of clinical practice due to COVID-19. In a 4-tiered surgery down-escalation scheme, 44% reported to make first cancellations, 23% secondary cancellations, 20% last cancellations and 13% emergency cases only. Oncological surgeries had low cancellation rates (%): transurethral resection of bladder tumor (27%), radical cystectomy (21-24%), nephroureterectomy (21%), radical nephrectomy (18%), and radical orchiectomy (8%). (Neo)adjuvant/palliative treatment is currently not started by more than half of the urologists. COVID-19 high-risk-countries had higher total cancellation rates for non-oncological procedures (78% vs. 68%, p = 0.01) and were performing oncological treatment for metastatic diseases at a lower rate (35% vs. 48%, p = 0.02). CONCLUSION: The COVID-19 pandemic has affected clinical practice of 93% of urologists worldwide. The impact of implementing surgical prioritization protocols with moderate cancellation rates for oncological surgeries and delay or reduction in (neo)adjuvant/palliative treatment will have to be evaluated after the pandemic.

Cancer immune control needs senescence induction by interferon-dependent cell cycle regulator pathways in tumours.

Immune checkpoint blockade (ICB)-based or natural cancer immune responses largely eliminate tumours. Yet, they require additional mechanisms to arrest those cancer cells that are not rejected. Cytokine-induced senescence (CIS) can stably arrest cancer cells, suggesting that interferon-dependent induction of senescence-inducing cell cycle regulators is needed to control those cancer cells that escape from killing. Here we report in two different cancers sensitive to T cell-mediated rejection, that deletion of the senescence-inducing cell cycle regulators p16Ink4a/p19Arf (Cdkn2a) or p21Cip1 (Cdkn1a) in the tumour cells abrogates both the natural and the ICB-induced cancer immune control. Also in humans, melanoma metastases that progressed rapidly during ICB have losses of senescence-inducing genes and amplifications of senescence inhibitors. Metastatic cells also resist CIS. Such genetic and functional alterations are infrequent in metastatic melanomas regressing during ICB. Thus, activation of tumour-intrinsic, senescence-inducing cell cycle regulators is required to stably arrest cancer cells that escape from eradication.

Prognostic significance of PD-1 and PD-L1 positive tumor-infiltrating immune cells in ovarian carcinoma.

INTRODUCTION: Ovarian carcinoma is associated with the highest mortality of all gynecologic malignancies. Even after optimal treatment, prognosis remains poor. There is no established biomarker to predict individual patient outcome. OBJECTIVE: To evaluate the prognostic significance of PD-1 and PD-L1 expression in tumor tissues from patients with ovarian cancer. METHODS: Tissue micro-arrays were prepared from routinely formalin-fixed, paraffin-embedded tumor tissues and examined immunohistochemically for the expression of programed cell death protein 1 (PD-1) and one of its ligands (PD-L1) on epithelial tumor cells, as well as on tumor- and stroma-infiltrating immune cells. RESULTS: The presence of PD-1 positive tumor-infiltrating immune cells was significantly associated with prolonged overall survival. PD-1 and PD-L1 positive tumor-infiltrating immune cells were associated with the presence of lymph node metastases and higher tumor grade. Interestingly, the amount of PD-1/PD-L1 positive tumor- and stroma-infiltrating immune cells independent of PD-1 or PD-L1 expression did not show any significant correlation with prognostic variables. CONCLUSION: Our results highlight the prognostic value of PD-1 and PD-L1 positive tumor-infiltrating immune cells in ovarian carcinoma. Their association with favorable prognosis supports the hypothesis that the expression of PD-1 and PD-L1 on tumor-infiltrating immune cells represents a strong immune response.

Comparative assessment of docetaxel for safety and efficacy between hormone-sensitive and castration-resistant metastatic prostate cancer.

OBJECTIVE: To compare toxicity and response of docetaxel chemotherapy between metastatic hormone-sensitive prostate cancer (mHSPC) and castration-resistant metastatic prostate cancer (mCRPC) patients of the same therapeutic era for assessing of upfront docetaxel against the benchmark of docetaxel in the castrate resistant stage in the setting outside of clinical trials. METHODS: A prospectively collected database of real-world prostate cancer patients receiving docetaxel was divided in mHSPC and mCRPC cases and retrospectively analyzed. Principal objectives were toxicity measured by the common criteria of adverse events terminology and response characterized by Prostate specific antigen decline and radiographic progression-free disease at restaging. The prognostic value of suspected variables for grade 3 to 5 toxicity and response was investigated by logistic regression analysis. RESULTS: Of 72 patients 34 (47%) were treated for mHSPC and 38 (53%) for mCRPC. Patients with mCRPC were older and had worse performance status (P< 0.01). In mHSPC total number of grade 3 to 5 adverse events (24, median 0, interquartile range 0-1) was significantly less than in mCRPC (46, median 1, interquartile range 1-2) (P = 0.01). Multivariable analysis revealed age as independent predictive variable for grade 3 to 5 toxicity (P = 0.03) but not disease stage, Prostate specific antigen predocetaxel, volume of disease, and Eastern Cooperative Oncology Group performance status (P > 0.05). Objective response was significantly higher in mHSPC compared to mCRPC patients (P < 0.01). Multivariable analysis confirmed mHSPC stage as independent prognostic factor for radiographic progression free disease at restaging (P < 0.01). CONCLUSIONS: The association of age with toxicity and of mHSPC stage with response resulted in significantly fewer grade 3 to 5 adverse events but higher response rates for upfront docetaxel in mHSPC compared with docetaxel in the later mCRPC stage.

Cost-effectiveness analysis of a vaccination program for the prevention of herpes zoster and post-herpetic neuralgia in adults aged 50 and over in Germany.

Herpes zoster (HZ; shingles) is a common viral disease that affects the nerves and surrounding skin causing a painful dermatomal rash and leading to debilitating complications such as, mainly, post-herpetic neuralgia (PHN). Currently, there is no effective treatment for HZ and PHN. The objective of this study was to assess the cost-effectiveness of a HZ vaccination program in Germany. An existing Markov Model was adapted to the German healthcare setting to compare a vaccination policy to no vaccination on a lifetime time-horizon, considering 2 scenarios: vaccinating people starting at the age of 50 or at the age of 60 years, from the perspective of the statutory health insurance (SHI) and the societal perspective. According to the perspective, vaccinating 20% of the 60+ German population resulted in 162,713 to 186,732 HZ and 31,657 to 35,793 PHN cases avoided. Corresponding incremental cost-effectiveness ratios (ICER) were 39,306 €/QALY from the SHI perspective and 37,417 €/QALY from a societal perspective. Results for the 50+ German population ranged from 336,468 to 394,575 HZ and from 48,637 to 56,087 PHN cases avoided from the societal perspective. Corresponding ICER were 39,782 €/QALY from a SHI perspective and 32,848 €/QALY from a societal perspective. Sensitivity analyses showed that results are mainly impacted by discount rates, utility values and use of alternative epidemiological data.The model indicated that a HZ vaccination policy in Germany leads to significant public health benefits and could be a cost-effective intervention. The results were robust and consistent with local and international existing literature.