Head and neck cancers are a heterogeneous collection of malignancies of the upper aerodigestive tract, salivary glands and thyroid. In this Review, we primarily focus on the changing therapeutic ...landscape of head and neck squamous cell carcinomas (HNSCCs) that can arise in the oral cavity, oropharynx, hypopharynx and larynx. We highlight developments in surgical and non-surgical therapies (mainly involving the combination of radiotherapy and chemotherapy), outlining how these treatments are being used in the current era of widespread testing for the presence of human papillomavirus infection in patients with HNSCC. Finally, we describe the clinical trials that led to the approval of the first immunotherapeutic agents for HNSCC, and discuss the development of strategies to decrease the toxicity of different treatment modalities.
•Three randomized I trials have shown that PD-1 inhibitors prolong survival in R/M HNSCC.•In first-line R/M HNSCC pembrolizumab monotherapy is approved if PD-L1 positive. BULLET: Pembrolizumab is ...also approved in combination with chemotherapy in this setting.•85% of R/M HNSCC are PD-L1 positive (combined positive score ≥1).•Clinical judgment will guide selection of pembrolizumab monotherapy or plus chemotherapy.
Three randomized phase III trials have now conclusively proven that exposure to a PD-1 inhibitor prolongs survival in recurrent/metastatic (R/M) HNSCC, and it is clear that such agents should be used in the management of all patients who do not have contraindications to their use. Two of these phase III randomized trials showed that the anti-PD1 antibodies nivolumab and pembrolizumab were superior to investigators′ choice chemotherapy in second-line platinum-refractory R/M HNSCC. Recently, a third phase III randomized trial, KEYNOTE-048, showed that pembrolizumab with chemotherapy was superior to the EXTREME regimen (cis- or carboplatin, 5-fluorouracil (5-FU) and cetuximab) in all patients, and pembrolizumab monotherapy was superior in patients whose tumors express PD-L1 in first-line R/M HNSCC. Pembrolizumab is now approved as monotherapy in PD-L1 expressing disease (combined positive score ≥1) or in combination with chemotherapy for all patients with R/M HNSCC. Thus, PD-L1 biomarker testing will be routinely used in R/M HNSCC, and this employs a scoring system that incorporates immune cell staining, referred to as the combined positive score (CPS). Additionally, for the 85% of patients with PD-L1 CPS ≥1, clinical judgment will guide the choice of pembrolizumab monotherapy or pembrolizumab plus chemotherapy, until more detailed clinical data are forthcoming to better inform this decision. In this article we discuss the clinical trials leading to these therapeutic advances and we will review initial results from clinical trials in previously untreated, locally advanced disease, and those using novel combinations of checkpoint inhibitors, co-stimulatory agonists, and therapeutic vaccines.
Although autophagy controls cell death and survival, underlying mechanisms are poorly understood, and it is unknown whether autophagy affects only whether or not cells die or also controls other ...aspects of programmed cell death. MAP3K7 is a tumor suppressor gene associated with poor disease-free survival in prostate cancer. Here, we report that Map3k7 deletion in mouse prostate cells sensitizes to cell death by TRAIL (TNF-related apoptosis-inducing ligand). Surprisingly, this death occurs primarily through necroptosis, not apoptosis, due to assembly of the necrosome in association with the autophagy machinery, mediated by p62/SQSTM1 recruitment of RIPK1. The mechanism of cell death switches to apoptosis if p62-dependent recruitment of the necrosome to the autophagy machinery is blocked. These data show that the autophagy machinery can control the mechanism of programmed cell death by serving as a scaffold rather than by degrading cargo.
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•MAP3K7 loss sensitizes cells to TRAIL-induced necroptotic cell death•The necrosome associates with autophagy machinery•Autophagy inhibition promotes or inhibits cell death depending on the blocked step•Autophagy machinery can serve as a scaffold to modulate mode of programmed cell death
Goodall et al. show that in the context of Map3k7 loss, the autophagy machinery has a scaffolding role in modulating the mode of cell death between necroptosis and apoptosis. p62/SQSTM1 recruits RIPK1 and mediates necrosome assembly in association with autophagic machinery for TRAIL-induced necroptosis. Blocking this recruitment results in apoptosis.
BACKGROUND: Knowledge of biological and climatic controls in terrestrial nitrogen (N) cycling within and across ecosystems is central to understanding global patterns of key ecosystem processes. The ...ratios of ¹⁵N:¹⁴N in plants and soils have been used as indirect indices of N cycling parameters, yet our understanding of controls over N isotope ratios in plants and soils is still developing. SCOPE: In this review, we provide background on the main processes that affect plant and soil N isotope ratios. In a similar manner to partitioning the roles of state factors and interactive controls in determining ecosystem traits, we review N isotopes patterns in plants and soils across a number of proximal factors that influence ecosystem properties as well as mechanisms that affect these patterns. Lastly, some remaining questions that would improve our understanding of N isotopes in terrestrial ecosystems are highlighted. CONCLUSION: Compared to a decade ago, the global patterns of plant and soil N isotope ratios are more resolved. Additionally, we better understand how plant and soil N isotope ratios are affected by such factors as mycorrhizal fungi, climate, and microbial processing. A comprehensive understanding of the N cycle that ascribes different degrees of isotopic fractionation for each step under different conditions is closer to being realized, but a number of process-level questions still remain.
Background The incidence of thyroid cancer has more than doubled in recent decades. Debate continues on whether the increasing incidence is a result of an increased detection of small neoplasms or ...other factors. Methods Using the Surveillance, Epidemiology and End Results database, we examined the overall incidence of thyroid cancer with variations based on tumor pathology, size, and stage, as well as the current surgical and adjuvant therapy of thyroid carcinoma. Results Thyroid cancer incidence increased 2.6-fold from 1973 to 2006. This change can be attributed primarily to an increase in papillary thyroid carcinoma, which increased 3.2-fold ( P < .0001). The increase in papillary thyroid carcinoma also was examined based on tumor size. Tumors ≤1 cm increased the most at a total of 441% between 1983 and 2006 or by 19.2% per year, the incidence of papillary thyroid carcinoma also increased at 12.3%/year in 1.1–2-cm tumors, 10.3%/year in 2.1–5-cm tumors, and 12.0%/year for >5-cm tumors (all P < .0001 by Cochran–Armitage trend test). We also demonstrated a positive correlation between papillary thyroid carcinoma tumor size and stage of disease (Spearman, r = 0.285, P < .0001). Operative treatment for thyroid cancer also has shifted with total thyroidectomy replacing partial thyroidectomy as the most common surgical procedure. Conclusion Contrary to other studies, our data indicate that the increasing incidence of thyroid cancer cannot be accounted for fully by an increased detection of small neoplasms. Other possible explanations for the increase in clinically significant (>1 cm) well-differentiated thyroid carcinomas should be explored.
Objectives
Sentinel lymph node biopsy (SLNB) has been shown to be an accurate technique for staging the neck in early‐stage oral cavity squamous cell carcinoma (OCSCC) and has been incorporated in ...treatment guidelines as an option instead of elective neck dissection (END). However, utilization of SLNB in the United States remains unclear, and existing prospective studies did not directly compare survival between SLNB and END.
Methods
We conducted a retrospective cohort study of patients with stage I to II OCSCC (cT1‐2cN0cM0) who underwent staging of the neck in the National Cancer Data Base from 2012 to 2015. We compared the practice patterns and outcomes of patients who underwent SLNB versus END.
Results
We identified 8,328 eligible patients with a median follow‐up of 35.4 months. SLNB was used for 240 patients, or 2.9% of stage I to II OCSCC. Completion neck dissection was avoided in 63.8% of patients undergoing SLNB. SLNB was associated with reduced perioperative morbidity, with median length of hospital stay of 1.0 days versus 3.0 days after END (P < 0.001). Perioperative 30‐day mortality was 0% after SLNB versus 0.7% after END (P = 0.42). Overall 3‐year survival was 82.0% after SLNB and 77.5% after END (P = 0.40). After adjustment, overall survival was equivalent between patients who underwent SLNB versus END (adjusted hazard ratio 1.03, confidence interval 0.67–1.59).
Conclusions
SLNB for stage I to II OCSCC is associated with reduced length of hospital stay and equivalent overall survival compared with END. Despite these attributes, SLNB remains rarely used in the United States.
Level of Evidence
NA Laryngoscope, 129:162–169, 2019
Long and irregular menstrual cycles, a hallmark of polycystic ovary syndrome (PCOS), have been associated with higher androgen and lower sex hormone binding globulin levels and this altered hormonal ...environment may increase the risk of specific histologic subtypes of ovarian cancer. We investigated whether menstrual cycle characteristics and self‐reported PCOS were associated with ovarian cancer risk among 2,041 women with epithelial ovarian cancer and 2,100 controls in the New England Case‐Control Study (1992–2008). Menstrual cycle irregularity, menstrual cycle length, and PCOS were collected through in‐person interview. Unconditional logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (95% CIs) for ovarian cancer risk overall, and polytomous logistic regression to evaluate whether risk differed between histologic subtypes. Overall, we observed no elevation in ovarian cancer risk for women who reported periods that were never regular or for those reporting a menstrual cycle length of >35 days with ORs of 0.87 (95% CI = 0.69–1.10) and 0.83 (95% CI = 0.44–1.54), respectively. We observed no overall association between self‐reported PCOS and ovarian cancer (OR = 0.97; 95% CI = 0.61–1.56). However, we observed significant differences in the association with menstrual cycle irregularity and risk of ovarian cancer subtypes (pheterogeneity = 0.03) as well as by BMI and OC use (pinteraction < 0.01). Most notable, menstrual cycle irregularity was associated with a decreased risk of high grade serous tumors but an increased risk of serous borderline tumors among women who had never used OCs and those who were overweight. Future research in a large collaborative consortium may help clarify these associations.
What's new?
Do menstrual cycle irregularities portend ovarian cancer? Not necessarily, but they could indicate increased risk of certain cancer subtypes. The long and irregular menstrual cycles that accompany polycystic ovary syndrome (PCOS) indicate altered hormone levels, which can spur ovarian cancer. These authors questioned ovarian cancer cases and controls for menstrual cycle information. Overall, they found, menstrual irregularities did not boost ovarian cancer risk; however, separating cases by subtype did reveal associations. In overweight women who never used oral contraceptives, for instance, irregular cycle was associated with increased risk of serous borderline tumors, and decreased risk of high grade serous tumors.
To test whether N regulates transpiration, Phaseolus vulgaris was grown with N placed at one of six distances behind a root-impenetrable mesh whilst control plants intercepted the N-source. ...N-availability regulated transpiration-driven mass-flow of nutrients from soil zones that were inaccessible
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