Novel Immunotherapeutic Approaches to Treating HPV-Related Head and Neck Cancer

Head and neck cancer (HNC) is the seventh most common malignancy, with oropharyngeal squamous cell carcinoma (OPSCC) accounting for a majority of cases in the western world. While HNC accounts for only 5% of all cancers in the United States, the incidence of a subset of OPSCC caused by human papillomavirus (HPV) is increasing rapidly. The treatment for OPSCC is multifaceted, with a recently emerging focus on immunotherapeutic approaches. With the increased incidence of HPV-related OPSCC and the approval of immunotherapy in the management of recurrent and metastatic HNC, there has been rising interest in exploring the role of immunotherapy in the treatment of HPV-related OPSCC specifically. The immune microenvironment in HPV-related disease is distinct from that in HPV-negative OPSCC, which has prompted further research into various immunotherapeutics. This review focuses on HPV-related OPSCC, its immune characteristics, and current challenges and future opportunities for immunotherapeutic applications in this virus-driven cancer

The Future Prospects of Immune Therapy in Gastric and Esophageal Adenocarcinoma

The prognosis of esophageal cancers is poor and novel approaches are urgently needed. Despite improvements in outcomes with transtuzumab and ramucirumab, these improvements added an average of only 2 to 3 months with a median overall survival reported to be around 1 year. Comprehensive genomic sequencing has defined some molecular alterations with potential targets, but the majority of patients still do not benefit from druggable targets. Breakthroughs in immune checkpoint blockade have provided new therapeutic options in many cancers. Programmed death ligand 1 (PDL1) overexpression, a possible biomarker predicting response to immune checkpoint inhibitors, approaches forty percent in esophageal and gastric cancers. Translational and molecular studies have shown that esophageal cancers are possible candidate malignancies for immune checkpoint inhibition. In this review, we plan to highlight the mechanisms, preclinical, and early clinical data that provide insight on the role of immune therapeutics in esophageal cancers

Trends in aortic dissection hospitalizations, interventions, and outcomes among medicare beneficiaries in the United States, 2000-2011.

To access publisher's full text version of this article click on the hyperlink at the bottom of the pageThe epidemiology of aortic dissection (AD) has not been well described among older persons in the United States. It is not known whether advancements in AD care over the last decade have been accompanied by changes in outcomes.The Inpatient Medicare data from 2000 to 2011 were used to determine trends in hospitalization rates for AD. Mortality rates were ascertained through corresponding vital status files. A total of 32 057 initial AD hospitalizations were identified. The overall hospitalization rate for AD remained unchanged at 10 per 100 000 person-years. For 30-day and 1-year mortality associated with AD, the observed rate decreased from 31.8% to 25.4% (difference, 6.4%; 95% confidence interval [CI], 6.2-6.5; adjusted, 6.4%; 95% CI, 5.7-6.9) and from 42.6% to 37.4% (difference, 5.2%; 95% CI, 5.1-5.2; adjusted, 6.2%; 95% CI, 5.3-6.7), respectively. For patients undergoing surgical repair for type A dissections, the observed 30-day mortality decreased from 30.7% to 21.4% (difference, 9.3%; 95% CI, 8.3-10.2; adjusted, 7.3%; 95% CI, 5.8-7.8) and the observed 1-year mortality decreased from 39.9% to 31.6% (difference, 8.3%; 95% CI, 7.5-9.1%; adjusted, 8.2%; 95% CI, 6.7-9.1). The 30-day mortality decreased from 24.9% to 21% (difference, 3.9%; 95% CI, 3.5-4.2; adjusted, 2.9%; 95% CI, 0.7-4.4) and 1-year decreased from 36.4% to 32.5% (difference, 3.9%; 95% CI, 3.3-4.3; adjusted, 3.9%; 95% CI, 2.5-6.3) for surgical repair of type B dissection.Although AD hospitalization rates remained stable, improvement in mortality was noted, particularly in patients undergoing surgical repair.National Heart, Lung and Blood Institute U01 HL105270-030

Occurrence and distribution of selected heavy metals and boron in groundwater of the Gulf of Khambhat region, Gujarat, India

The concentration of selected heavy metals, like As, Co, Cr, Cu, Fe, Mn, Ni, Pb, and Zn as well as B, was measured by inductively coupled plasma–optical emission spectrometry (ICP–OES) in groundwater samples from various locations in the Gulf of Khambhat (GoK), an inlet of the Arabian Sea in the state of Gujarat, India, during postmonsoon, winter, and pre-monsoon seasons in a year. Most heavy elements are characterized by low mobility under slightly alkaline and reducing conditions; concentrations in confined aquifers are smaller than the maximum permissible values for drinking water. The temporal changes indicate that a majority of metals is entering the aquifer during monsoon. Principle component analysis of the heavy metal data suggests that Co, Cu, Cd, and Zn are interrelated with each other and derived significantly from anthropogenic route, while input of Pb and Cr may be due to atmospheric deposition in the study area. Both weathering of rocks and anthropogenic input were found to be main sources of elements in the groundwater. The heavy metal levels in groundwaters of the GoK region in comparison with some of the European and Asian sites were higher; however, these metal levels were found to be comparable with few urban sites in the world

Novel Immunotherapeutic Approaches to Treating HPV-Related Head and Neck Cancer

Head and neck cancer (HNC) is the seventh most common malignancy, with oropharyngeal squamous cell carcinoma (OPSCC) accounting for a majority of cases in the western world. While HNC accounts for only 5% of all cancers in the United States, the incidence of a subset of OPSCC caused by human papillomavirus (HPV) is increasing rapidly. The treatment for OPSCC is multifaceted, with a recently emerging focus on immunotherapeutic approaches. With the increased incidence of HPV-related OPSCC and the approval of immunotherapy in the management of recurrent and metastatic HNC, there has been rising interest in exploring the role of immunotherapy in the treatment of HPV-related OPSCC specifically. The immune microenvironment in HPV-related disease is distinct from that in HPV-negative OPSCC, which has prompted further research into various immunotherapeutics. This review focuses on HPV-related OPSCC, its immune characteristics, and current challenges and future opportunities for immunotherapeutic applications in this virus-driven cancer

The role of ERK1, 2, and 5 in dopamine neuron survival during aging

The extracellular signal-regulated kinases (ERKs) 1, 2, and 5 have been shown to play distinct roles in proliferation, differentiation, and neuronal viability. In this study, we examined ERK1, 2, and 5 expression and activation in the substantia nigra (SN), striatum (STR), and ventral tegmental area (VTA) during aging. An age-related decrease in phosphorylated ERK5 was observed in the SN and STR, whereas an increase in total ERK1 was observed in all three regions. In primary cultures of the SN and VTA, inhibition of ERK5 but not ERK1 and 2 significantly decreased DA neuronal viability. These data suggest that ERK5 is essential for the basal survival of SN and VTA dopaminergic neurons. These are the first studies to examine ERK1, 2, and 5 expression and activation in the SN, STR, and VTA during aging and the relative roles of ERK1, 2, and 5 in basal survival of SN and VTA dopaminergic neurons. These data raise the possibility that a decline ERK5 signaling may play a role in age-related impairments in dopaminergic function

Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma (LEAP-002): a randomised, double-blind, phase 3 trial

Summary Background Systemic therapies have improved the management of hepatocellular carcinoma, but there is still a need to further enhance overall survival in first-line advanced stages. This study aimed to evaluate the addition of pembrolizumab to lenvatinib versus lenvatinib plus placebo in the first-line setting for unresectable hepatocellular carcinoma. Methods In this global, randomised, double-blind, phase 3 study (LEAP-002), patients aged 18 years or older with unresectable hepatocellular carcinoma, Child Pugh class A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no previous systemic treatment were enrolled at 172 global sites. Patients were randomly assigned (1:1) with a central interactive voice-response system (block size of 4) to receive lenvatinib (bodyweight <60 kg, 8 mg/day; bodyweight ≥60 kg, 12 mg/day) plus pembrolizumab (200 mg every 3 weeks) or lenvatinib plus placebo. Randomisation was stratified by geographical region, macrovascular portal vein invasion or extrahepatic spread or both, α-fetoprotein concentration, and Eastern Cooperative Oncology Group performance status. Dual primary endpoints were overall survival (superiority threshold at final overall survival analysis, one-sided p=0·019; final analysis to occur after 532 events) and progression-free survival (superiority threshold one-sided p=0·002; final analysis to occur after 571 events) in the intention-to-treat population. Results from the final analysis are reported. This study is registered with ClinicalTrials.gov, NCT03713593, and is active but not recruiting. Findings Between Jan 17, 2019, and April 28, 2020, of 1309 patients assessed, 794 were randomly assigned to lenvatinib plus pembrolizumab (n=395) or lenvatinib plus placebo (n=399). Median age was 66·0 years (IQR 57·0–72·0), 644 (81%) of 794 were male, 150 (19%) were female, 345 (43%) were Asian, 345 (43%) were White, 22 (3%) were multiple races, 21 (3%) were American Indian or Alaska Native, 21 (3%) were Native Hawaiian or other Pacific Islander, 13 (2%) were Black or African American, and 46 (6%) did not have available race data. Median follow up as of data cutoff for the final analysis (June 21, 2022) was 32·1 months (IQR 29·4–35·3). Median overall survival was 21·2 months (95% CI 19·0–23·6; 252 [64%] of 395 died) with lenvatinib plus pembrolizumab versus 19·0 months (17·2–21·7; 282 [71%] of 399 died) with lenvatinib plus placebo (hazard ratio [HR] 0·84; 95% CI 0·71–1·00; stratified log-rank p=0·023). As of data cutoff for the progression-free survival final analysis (April 5, 2021), median progression-free survival was 8·2 months (95% CI 6·4–8·4; 270 events occurred [42 deaths; 228 progressions]) with lenvatinib plus pembrolizumab versus 8·0 months (6·3–8·2; 301 events occurred [36 deaths; 265 progressions]) with lenvatinib plus placebo (HR 0·87; 95% CI 0·73–1·02; stratified log-rank p=0·047). The most common treatment-related grade 3–4 adverse events were hypertension (69 [17%] of 395 patients in the lenvatinib plus pembrolizumab group vs 68 [17%] of 395 patients) in the lenvatinib plus placebo group), increased aspartate aminotransferase (27 [7%] vs 17 [4%]), and diarrhoea (25 [6%] vs 15 [4%]). Treatment-related deaths occurred in four (1%) patients in the lenvatinib plus pembrolizumab group (due to gastrointestinal haemorrhage and hepatorenal syndrome [n=1 each] and hepatic encephalopathy [n=2]) and in three (1%) patients in the lenvatinib plus placebo group (due to gastrointestinal haemorrhage, hepatorenal syndrome, and cerebrovascular accident [n=1 each]). Interpretation In earlier studies, the addition of pembrolizumab to lenvatinib as first-line therapy for advanced hepatocellular carcinoma has shown promising clinical activity; however, lenvatinib plus pembrolizumab did not meet prespecified significance for improved overall survival and progression-free survival versus lenvatinib plus placebo. Our findings do not support a change in clinical practice. Funding Eisai US, and Merck Sharp & Dohme, a subsidiary of Merck