Prognostic models for breast cancer developed from Western countries performed less accurately in the Asian population. We aimed to develop a survival prediction model for overall survival (OS) and disease-free survival (DFS) for Thai patients with breast cancer. We conducted a prognostic model research using a multicenter hospital-based cancer clinical registry from the Network of National Cancer Institutes of Thailand. All women diagnosed with breast cancer who underwent surgery between 1 January 2010 and 31 December 2011 were included in the analysis. A flexible parametric survival model was used for developing the prognostic model for OS and DFS prediction. During the study period, 2021 patients were included. Of these, 1386 patients with 590 events were available for a complete-case analysis. The newly derived individualized prediction of breast cancer survival or the IPBS model consists of twelve routinely available predictors. The C-statistics from the OS and the DFS model were 0.72 and 0.70, respectively. The model showed good calibration for the prediction of five-year OS and DFS. The IPBS model provides good performance for the prediction of OS and PFS for breast cancer patients. A further external validation study is required before clinical implementation. Full article

Multi-gene assays often include UGT1A1 and, in certain instances, may report associated toxicity risks for irinotecan, belinostat, pazopanib, and nilotinib. However, guidance for incorporating UGT1A1 results into therapeutic decision-making is mostly lacking for these anticancer drugs. We summarized meta-analyses, genome-wide association studies, clinical trials, drug labels, and guidelines relating to the impact of UGT1A1 polymorphisms on irinotecan, belinostat, pazopanib, or nilotinib toxicities. For irinotecan, UGT1A1*28 was significantly associated with neutropenia and diarrhea, particularly with doses ≥ 180 mg/m², supporting the use of UGT1A1 to guide irinotecan prescribing. The drug label for belinostat recommends a reduced starting dose of 750 mg/m² for UGT1A1*28 homozygotes, though published studies supporting this recommendation are sparse. There was a correlation between UGT1A1 polymorphisms and pazopanib-induced hepatotoxicity, though further studies are needed to elucidate the role of UGT1A1-guided pazopanib dose adjustments. Limited studies have investigated the association between UGT1A1 polymorphisms and nilotinib-induced hepatotoxicity, with data currently insufficient for UGT1A1-guided nilotinib dose adjustments. Full article

In the last two decades, surgical methods for axillary staging in breast cancer patients have become less extensive, and full axillary lymph node dissection (ALND) is confined to selected patients. In initially node-positive patients undergoing neoadjuvant chemotherapy, however, the optimal management remains unclear. Current guidelines vary widely, endorsing different strategies. We performed a literature review on axillary staging strategies and their place in international recommendations. This overview defines knowledge gaps associated with specific procedures, summarizes currently ongoing clinical trials that address these unsolved issues, and provides the rationale for further research. While some guidelines have already implemented surgical de-escalation, replacing ALND with, e.g., sentinel lymph node biopsy (SLNB) or targeted axillary dissection (TAD) in cN+ patients converting to clinical node negativity, others recommend ALND. Numerous techniques are in use for tagging lymph node metastasis, but many questions regarding the marking technique, i.e., the optimal time for marker placement and the number of marked nodes, remain unanswered. The optimal number of SLNs to be excised also remains a matter of debate. Data on oncological safety and quality of life following different staging procedures are lacking. These results provide the rationale for the multinational prospective cohort study AXSANA initiated by EUBREAST, which started enrollment in June 2020 and aims at recruiting 3000 patients in 20 countries (NCT04373655; Funded by AGO-B, Claudia von Schilling Foundation for Breast Cancer Research, AWOgyn, EndoMag, Mammotome, and MeritMedical). Full article

Background: Few studies have evaluated long-term medical monetary cost in patients with prostate cancer (PC) receiving open radical prostatectomy (ORP), laparoscopic radical prostatectomy (LRP), or robot-assisted radical prostatectomy (RARP). To the best of our knowledge, this is the largest and longest follow-up study to examine medical monetary cost in patients with PC undergoing ORP, LRP, or RARP. After adjustment for confounders, the medical monetary cost in the RARP group was the least compared with that in the ORP and LRP groups. Purpose: To estimate long-term medical resource consumption among patients with prostate cancer (PC) receiving open radical prostatectomy (ORP), laparoscopic radical prostatectomy (LRP), or robot-assisted radical prostatectomy (RARP). Patients and Methods: Participants were men enrolled in the Taiwan Cancer Registry with localized PC diagnosis who received radical prostatectomy. After adjustment for confounders, a generalized linear mixed model was used to determine significant differences in the number of urology outpatient clinic visits required, proportion of patients being hospitalized for urinary diseases or surgical complications, and medical reimbursement for urinary diseases or surgical complications following ORP, LRP, or RARP in the first, second, and third years. Results: No differences were observed in the median number of urology outpatient clinic visits between the three types of surgical modalities up to the second year after ORP, LRP, and RARP (median: 15, 10, and seven visits, respectively; p < 0.001), but significant differences were observed in the third year. Similarly, with RARP (10.9% versus 18.7% in ORP and 9.8% in LRP; p = 0.0014), the rate of hospitalization for urinary diseases or surgical complications decreased in the third year. Medical reimbursement for urinary diseases or surgical complications reduced after RARP compared with that for ORP and LRP, with approximately 22% reduction in the first year (p = 0.0052) and 20–40% reduction in the third year (p value = 0.0024). Conclusions: Medical resource consumption in the RARP group was less compared with those in the ORP and LRP groups. Full article

The tumor microenvironment plays a major role in tumor growth, invasion and resistance to chemotherapy, however understanding how all actors from microenvironment interact together remains a complex issue. The tumor microenvironment is classically represented as three closely connected components including the stromal cells such as immune cells, fibroblasts, adipocytes and endothelial cells, the extracellular matrix (ECM) and the cytokine/growth factors. Within this space, proteins of the adamalysin family (ADAM for a disintegrin and metalloproteinase; ADAMTS for ADAM with thrombospondin motifs; ADAMTSL for ADAMTS-like) play critical roles by modulating cell–cell and cell–ECM communication. During last decade, the implication of adamalysins in the development of hepatocellular carcinoma (HCC) has been supported by numerous studies however the functional characterization of most of them remain unsettled. In the present review we propose both an overview of the literature and a meta-analysis of adamalysins expression in HCC using data generated by The Cancer Genome Atlas (TCGA) Research Network. Full article

There is a paucity of biomarkers for the prediction of intracranial (IC) outcome in immune checkpoint inhibitor (ICI)-treated non-small cell lung cancer (NSCLC) patients (pts) with brain metastases (BM). We identified 280 NSCLC pts treated with ICIs at Karolinska University Hospital, Sweden, and University Hospital of Heraklion, Greece. The inclusion criteria for response assessment were brain metastases (BM) prior to ICI administration, radiological evaluation with CT or MRI for IC response assessment, PD-1/PD-L1 inhibitors as monotherapy, and no local central nervous system (CNS) treatment modalities for ≥3 months before ICI initiation. In the IC response analysis, 33 pts were included. Non-primary (BM not present at diagnosis) BM, odds ratio (OR): 13.33 (95% CI: 1.424–124.880, p = 0.023); no previous brain radiation therapy (RT), OR: 5.49 (95% CI: 1.210–25.000, p = 0.027); and age ≥70 years, OR: 6.19 (95% CI: 1.27–30.170, p = 0.024) were associated with increased probability of IC disease progression. Two prognostic groups (immunotherapy (I-O) CNS score) were created based on the abovementioned parameters. The I-O CNS poor prognostic group B exhibited a higher probability for IC disease progression, OR: 27.50 (95% CI: 2.88–262.34, p = 0.004). Age, CNS radiotherapy before the start of ICI treatment, and primary brain metastatic disease can potentially affect the IC outcome of NSCLC pts with BM. Full article

(1) Inactivation of the tumor suppressor NF2 is believed to play a major role in the pathogenesis of malignant pleural mesothelioma (MPM) by deregulating the Hippo-YAP signaling pathway. However, NF2 has functions beyond regulation of the Hippo pathway, raising the possibility that NF2 contributes to MPM via Hippo-independent mechanisms. (2) We performed weighted gene co-expression analysis (WGCNA) in transcriptomic and proteomic datasets obtained from The Cancer Gene Atlas (TCGA) MPM cohort to identify clusters of co-expressed genes highly correlated with NF2 and phospho (p)-YAP protein, surrogate markers of active Hippo signaling and YAP inactivation. The potential targets are experimentally validated using a cell viability assay. (3) MPM tumors with NF2 loss-of-function are not associated with changes in p-YAP level nor YAP/TAZ activity score, but are characterized by a deficient B-cell receptor (BCR) signaling pathway. Conversely, MPM tumors with YAP activation display exhausted CD8 T-cell-mediated immunity together with significantly upregulated PD-L1, which is validated in an independent MPM cohort, suggesting a potential benefit of immune-checkpoint inhibitors (ICI) in this patient subset. In support of this, mutations in core Hippo signaling components including LATS2, but not NF2, are independently associated with better overall survival in response to ICI in patients. Additionally, based on cancer cell line models, we show that MPM cells with a high Hippo-YAP activity are particularly sensitive to inhibitors of BCR-ABL/SRC, stratifying a unique MPM patient subset that may benefit from BCR-ABL/SRC therapies. Furthermore, we observe that NF2 physically interacts with a considerable number of proteins that are not involved in the canonical Hippo-YAP pathway, providing a possible explanation for its Hippo-independent role in MPM. Finally, survival analyses show that YAP/TAZ scores together with p-YAP protein level, but not NF2, predict the prognosis of MPM patients. (4) NF2 loss-of-function and dysregulated Hippo-YAP pathway define distinct MPM subsets that differ in their molecular features and prognosis, which has important clinical implications for precision oncology in MPM patients. Full article

With a dismally low median survival of less than two years after diagnosis, Glioblastoma (GBM) is the most lethal type of brain cancer. The standard-of-care of surgical resection, followed by DNA-damaging chemo-/radiotherapy, is often non-curative. In part, this is because individual cells close to the resection border remain alive and eventually undergo renewed proliferation. These residual, therapy-resistant cells lead to rapid recurrence, against which no effective treatment exists to date. Thus, new experimental approaches need to be developed against residual disease to prevent GBM survival and recurrence. Cellular senescence is an attractive area for the development of such new approaches. Senescence can occur in healthy cells when they are irreparably damaged. Senescent cells develop a chronic secretory phenotype that is generally considered pro-tumorigenic and pro-migratory. Age is a negative prognostic factor for GBM stage, and, with age, senescence steadily increases. Moreover, chemo-/radiotherapy can provide an additional increase in senescence close to the tumor. In light of this, we will review the importance of senescence in the tumor-supportive brain parenchyma, focusing on the invasion and growth of GBM in residual disease. We will propose a future direction on the application of anti-senescence therapies against recurrent GBM. Full article

Background: Optimal recurrent thymoma management remains arguable because of limited patient numbers, and relatively late and variable recurrence patterns. Given the absence of high-quality evidence and relatively small study cohorts, we performed a quantitative meta-analysis to determine the outcome of surgical and non-surgical approaches assessing the five-year overall survival (5y overall survival (OS)) in patients with recurrent thymoma. Methods: We performed a comprehensive literature search and analysis according to PRISMA guidelines of studies published from 1 January 1980 until 18 June 2020 from PubMed/MEDLINE, EMBASE, and Scopus. We included studies with the cohorts’ superior to 30 patients describing recurrent thymoma treatment, comparing surgical and non-surgical approaches reporting survival data. Results: Literature search revealed 3017 articles. Nine studies met all inclusion criteria and were selected for the meta-analysis. The recurrences were local/regional in 73–98% of cases and multiple in 49–72%. After treatment, 5y OS ranged from 48–77% and 10y OS from 37–51%. The quantitative meta-analysis showed a better outcome comparing surgical vs other treatments. Two studies showed statistically significant risk differences in the 5y OS favoring complete resection. After pooling results of seven studies using the random model, the combined 5y OS risk difference was 0.39, with lower and upper limits of 0.16 and 0.62, respectively (p = 0.001), and a moderate heterogeneity among studies (p = 0.098, I2 = 43.9%). Definitive conclusions could not be drawn regarding the prognostic impact of myasthenia gravis, histology, and patterns of relapse reported in literature. Conclusions: Surgical treatment after thymoma recurrence is associated with a significant better 5y OS; therefore, surgical resection should be preferred in all technically feasible cases. Full article

Background: Hepatocellular carcinoma (HCC) still represents a human tumor entity with very limited therapeutic options, especially for advanced stages. Here, immune checkpoint modulating drugs alone or in combination with local ablative techniques could open a new and attractive therapeutic “door” to improve outcome and response rate for patients with HCC. Methods: Published data on HCC experimental to pre-(clinical) treatment strategies from standard of care to novel immunomodulatory concepts were summarized and discussed in detail. Results: Overall, our knowledge of the role of immune checkpoints in HCC is dramatically increased in the last years. Experimental and pre-clinical findings could be translated to phase 1 and 2 clinical trials and became standard of care. Local ablative techniques of HCC could improve the effectivity of immune checkpoint inhibitors in situ. Conclusions: This review demonstrates the importance of immunomodulatory treatment strategies of HCC, whereby the “best treatment code” of immune checkpoint drugs, combination with ablative techniques and of timing must be evaluated in coming clinical trials. Full article

Noncoding RNAs (ncRNAs) have emerged as a novel class of genomic regulators, ushering in a new era in molecular biology. With the advent of advanced genetic sequencing technology, several different classes of ncRNAs have been uncovered, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and piwi-interacting RNAs (piRNAs), which have been linked to many important developmental and disease processes and are being pursued as clinical and therapeutic targets. Molecular phenotyping studies of glioblastoma (GBM), the most common and lethal cancer of the adult brain, revealed that several ncRNAs are frequently dysregulated in its pathogenesis. Additionally, ncRNAs regulate many important aspects of glioma biology including tumour cell proliferation, migration, invasion, apoptosis, angiogenesis, and self-renewal. Here, we present an overview of the biogenesis of the different classes of ncRNAs, discuss their biological roles, as well as their relevance to gliomagenesis. We conclude by discussing potential approaches to therapeutically target the ncRNAs in clinic. Full article

Bone metastasis in clear-cell renal cell carcinoma (ccRCC) leads to substantial morbidity through skeletal related adverse events and implicates worse clinical outcomes. MicroRNAs (miRNA) are small non-protein coding RNA molecules with important regulatory functions in cancer development and metastasis. In this retrospective analysis we present dysregulated miRNA in ccRCC, which are associated with bone metastasis. In particular, miR-23a-3p, miR-27a-3p, miR-20a-5p, and miR-335-3p specifically correlated with the earlier appearance of bone metastasis, compared to metastasis in other organs. In contrast, miR-30b-3p and miR-139-3p were correlated with less occurrence of bone metastasis. These miRNAs are potential biomarkers and attractive targets for miRNA inhibitors or mimics, which could lead to novel therapeutic possibilities for bone targeted treatment in metastatic ccRCC. Full article

Although organized, low-dose, computed-tomography (CT) scan lung-cancer screening has been shown to lower all-cause and lung-cancer-specific mortality, the primary cause of death for subjects eligible for such screening remains cardiovascular (CV) mortality. This meta-analysis study was undertaken to evaluate the impact of screening-scan-detected coronary artery calcifications (CACs) on CV and all-cause mortality. We conducted a systematic review and meta-analysis of studies reporting CV mortality according to the Agatson CAC score for participants in a lung-cancer screening program of randomized clinical or cohort studies. PubMed, Embase, and Cochrane databases were screened in June 2020. Two authors independently selected articles and extracted data. Six studies, including 20,175 subjects, were retained. CV and all-cause mortality rates were higher for subjects with CAC scores >0, with respective relative risks of 2.02 [95% CI 1.23–3.32] and 2.29 [95% CI 1.00–5.21]. Both mortality rates were even higher for those with high CAC scores (>400 or >1000). CACs are more common in men than in women, with an odds ratio of 1.49 [95% CI 1.40–1.59]. The presence of CAC is associated with CV mortality with an RR of 2.05 [95% CI 1.20–3.57] in men and 2.37 [CI 95% 1.29–5.09] in women, respectively. Analysis of lung-cancer-screening scans for CACs is a tool able to predict CV mortality. Prospective studies within those programs are needed to assess the benefit of primary CV prevention based on CAC detection. Full article