The development of immune checkpoint inhibitors has changed the treatment paradigm for advanced cancers across many tumor types. Despite encouraging and sometimes durable responses in a subset of ...patients, most patients do not respond. Tumors have adopted the PD-1/PD-L1 axis for immune escape to facilitate tumor growth, which can be leveraged as a potential target for immune checkpoint inhibitors. On this basis, PD-L1 protein expression on tumor or immune cells emerged as the first potential predictive biomarker for sensitivity to immune checkpoint blockade. The goal of our study was to evaluate PD-L1 as a predictive biomarker based on all US Food and Drug Administration (FDA) drug approvals of immune checkpoint inhibitors. We evaluated the primary studies associated with 45 FDA drug approvals from 2011 until April 2019. In total, there were approvals across 15 tumor types. Across all approvals, PD-L1 was predictive in only 28.9% of cases, and was either not predictive (53.3%) or not tested (17.8%) in the remaining cases. There were 9 FDA approvals linked to a specific PD-L1 threshold and companion diagnostic: bladder cancer (N = 3), non-small cell lung cancer (N = 3), triple-negative breast cancer (N = 1), cervical cancer (N = 1), and gastric/gastroesophageal junction cancer (N = 1) with 8 of 9 (88.9%) with immune checkpoint inhibitor monotherapy. The PD-L1 thresholds were variable both within and across tumor types using several different assays, including approvals at the following PD-L1 thresholds: 1, 5, and 50%. PD-L1 expression was also measured in a variable fashion either on tumor cells, tumor-infiltrating immune cells, or both. In conclusion, our findings indicate that PD-L1 expression as a predictive biomarker has limitations and that the decision to pursue testing must be carefully implemented for clinical decision-making.
This work presents an examination of the wire electric discharge machining (WEDM) in processing Inconel 625. The major WEDM variables (pulse-on time, pulse-off time, servo voltage, wire feed rate) ...were experimentally investigated to address multiple aspects of this process, namely to reduce the gap current and surface roughness and increase the cutting speed. After testing the statistical significance of the major WEDM parameters for the three responses, an advanced statistical procedure was utilized for tackling correlations among outputs and their integration into the WEDM output performance in a fully objective manner. The Bayesian regularized neural network established a highly accurate process model that was engaged as the objective function for the evolutionary algorithms to identify the optimal machining conditions. The following algorithms were employed: particle swarm optimization, teaching-learning based optimization, grey wolf optimization and Jaya algorithm. Their results were thoroughly analyzed in terms of accuracy, i.e., repeatability of the resulting solutions, convergence speed and computational time, including assessment of the hyperparameter effects. The obtained optimal solution was highly convincing and it was successfully validated in a confirmation run. Therefore, the benefits of these findings are twofold, offering: (i) a thorough analysis of the four metaheuristics effectiveness in dealing with a real industrial problem, (ii) useful insights for controlling WEDM variables to enhance the technological, environmental and economic aspects at the same time.
Purpose of Review
The objectives of this article are to review the major changes in the staging of head and neck cancers and the rationale for the modifications.
Recent Findings
Information gathered ...from various institutional reports lead to a better understanding of the clinical and biological behavior of head and neck tumors, resulting in distinct outcomes, which were used to update the staging system.
Summary
This article reviews the changes in the staging of head and neck cancers published in the 8th edition of the AJCC/UICC TNM staging system.
•2082 patients with OSCC operated at a tertiary cancer care center from 1985 to 2015 were studied.•Age, comorbidity, margin, vascular and perineural invasion, T, N were independent predictors of ...OS.•Alcohol use, margin, vascular and perineural invasion, T, and N were independent predictors of DSS.•pN was the single most powerful and consistent predictor of outcome in patients with OSCC.
To present treatment results of oral squamous cell carcinoma (OSCC) at a tertiary cancer care center from 1985 to 2015.
A total of 2082 patients were eligible for this study. Main outcomes measured were overall survival (OS) and disease specific survival (DSS). Prognostic variables were identified with bivariate analyses using Kaplan-Meier curves and log-rank testing for comparison. A p-value < 0.05 was considered statistically significant and significant factors were entered into multivariate analysis. Median age was 62 years (16–100), 56% were men, 66% reported a history of tobacco use and 71% of alcohol consumption. The most common subsite was tongue (51%). Seventy-three percent of patients had cT1-2 and 71% had clinically negative necks (cN0). Surgery alone was performed in 1348 patients (65%), adjuvant postoperative radiotherapy in 608 patients (29%) and postoperative chemoradiation in 126 patients (6%). Neck dissection was performed in 920 patients with cN0, and in 585 patients with a clinically involved neck. The median follow-up was 37.6 months (range 1–382).
The 5-year OS and DSS were 64.4% and 79.3%, respectively. Age, comorbidities, margin status, vascular invasion, perineural invasion, AJCC 8th edition pT, and pN were independent prognostic factors of OS (p < 0.05). History of alcohol consumption, margin status, vascular invasion, perineural invasion, pT, and pN were independent prognostic factors of DSS (p < 0.05).
pN stage is the most powerful and consistent predictor of outcome in patients with OSCC treated with primary surgery and appropriate adjuvant therapy.
Endometriosis is a common cause of pelvic pain and affects up to 10% of women of reproductive age. Aberrant progesterone signaling in the endometrium plays a significant role in impaired ...decidualization and establishment of ectopic endometrial implants. Eutopic endometrial cells from women with endometriosis fail to downregulate genes needed for decidualization, such as those involved in cell cycle regulation, leading to unbridled proliferation. Several causes of progesterone resistance in the endometrium have been postulated, including congenital “preconditioning”, whereby the in utero environment renders infants susceptible to neonatal uterine bleeding and endometriosis. Progesterone action is crucial to decreasing inflammation in the endometrium, and deviant progesterone signaling results in a proinflammatory phenotype. Conversely, chronic inflammation can induce a progesterone‐resistant state. Repetitive retrograde endometrial shedding begets chronic peritoneal inflammation, which further exacerbates progesterone resistance. Genetic causes of progesterone resistance include progesterone receptor gene polymorphisms, altered microRNA expression, and epigenetic modifications to progesterone receptors and their targets. Environmental toxins such as dioxin play a possible role in the genesis of endometriosis by permitting an inflammatory milieu. A consequence of impaired progesterone action is that hormonal therapy is rendered ineffective for a subset of women with endometriosis. Synthetic progestins, such as dienogest, may overcome this phenomenon by increasing progesterone receptor expression and decreasing proinflammatory cytokines. Other modalities include high dose depot formulations of progestins, medicated intrauterine devices and the likely advent of oral GnRH antagonists. Unearthing root causes of progesterone inaction in endometriosis will aid in the development of novel therapeutics geared toward prevention and treatment.
The incidence of early-onset colorectal cnacer-ie, colorectal cancer diagnosed in patients under the age of 50 years- has been increasing around the world. This Series paper provides a comprehensive ...review on the topic of early-onset colorectal cancer, including examining the epidemiology of early-onset colorectal cancer around the world, clinical and pathological features, genetic and epigenetic landscapes, and emerging data on the clinical risk factors associated with this malignancy. Evidence-based approaches to prevention and early detection are also presented.
Cancer of the oral cavity Montero, Pablo H; Patel, Snehal G
Surgical oncology clinics of North America,
07/2015, Letnik:
24, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Cancer of the oral cavity is one of the most common malignancies worldwide. Although early diagnosis is relatively easy, presentation with advanced disease is not uncommon. The standard of care is ...primary surgical resection with or without postoperative adjuvant therapy. Improvements in surgical techniques combined with the routine use of postoperative radiation or chemoradiation therapy have resulted in improved survival. Successful treatment is predicated on multidisciplinary treatment strategies to maximize oncologic control and minimize impact of therapy on form and function. Prevention of oral cancer requires better education about lifestyle-related risk factors, and improved awareness and tools for early diagnosis.
Stellar kinematics provide insights into the masses and formation histories of galaxies. At high redshifts, spatially resolving the stellar kinematics of quiescent galaxies is challenging due to ...their compact sizes. Using deep near-infrared spectroscopy, we have measured the resolved stellar kinematics of four quiescent galaxies at z = 1.95-2.64, introduced in Paper I, that are gravitationally lensed by galaxy clusters. Analyses of two of these have previously been reported individually by Newman et al. and Toft et al., and for the latter, we present new observations. All four galaxies show significant rotation and can be classified as "fast rotators." In the three systems for which the lensing constraints permit a reconstruction of the source, we find that all are likely to be highly flattened (intrinsic ellipticities of 0.75-0.85) disk-dominated galaxies with rapid rotation speeds of Vmax = 290-352 km s−1 and predominantly rotational support, as indicated by the ratio Compared to coeval star-forming galaxies of similar mass, the quiescent galaxies have smaller V/ . Given their high masses, , we argue that these galaxies are likely to evolve into "slow rotator" elliptical galaxies whose specific angular momentum is reduced by a factor of 5-10. This provides strong evidence for merger-driven evolution of massive galaxies after quenching. Consistent with indirect evidence from earlier morphological studies, our small but unique sample suggests that the kinematic transformations that produced round, dispersion-supported elliptical galaxies were not generally coincident with quenching. Such galaxies probably emerged later via mergers that increased their masses and sizes while also eroding their rotational support.
Lymph node density (LND) has previously been reported to reliably predict recurrence risk and survival in oral cavity squamous cell carcinoma (OSCC). This multicenter international study was designed ...to validate the concept of LND in OSCC.
The study included 4254 patients diagnosed as having OSCC. The median follow-up was 41 months. Five-year overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), locoregional control and distant metastasis rates were calculated using the Kaplan-Meier method. Lymph node density (number of positive lymph nodes/total number of excised lymph nodes) was subjected to multivariate analysis.
The OS was 49% for patients with LND0.07 compared with 35% for patients with LND>0.07 (P<0.001). Similarly, the DSS was 60% for patients with LND0.07 compared with 41% for those with LND>0.07 (P<0.001). Lymph node density reliably stratified patients according to their risk of failure within the individual N subgroups (P=0.03). A modified TNM staging system based on LND ratio was consistently superior to the traditional system in estimating survival measures.
This multi-institutional study validates the reliability and applicability of LND as a predictor of outcomes in OSCC. Lymph node density can potentially assist in identifying patients with poor outcomes and therefore for whom more aggressive adjuvant treatment is needed.
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