Acceptability of extending HPV-based cervical screening intervals from 3 to 5 years: an interview study with women in England.

OBJECTIVES: The introduction of primary Human Papillomavirus (HPV) testing in the National Health Service (NHS) Cervical Screening Programme in England means the screening interval for 25-49 years can be extended from 3 to 5 years. We explored women's responses to the proposed interval extension. METHODS: We conducted semi-structured phone/video interviews with 22 women aged 25-49 years. Participants were selected to vary in age, socioeconomics and screening history. We explored attitudes to the current 3-year interval, then acceptability of a 5-year interval. Interviews were transcribed verbatim and analysed using framework analysis. RESULTS: Attitudes to the current 3-year interval varied; some wanted more frequent screening, believing cancer develops quickly. Some participants worried about the proposed change; others trusted it was evidence based. Frequent questions concerned the rationale and safety of longer intervals, speed of cancer development, the possibility of HPV being missed or cell changes occurring between screens. Many participants felt reassured when the interval change was explained alongside the move to HPV primary screening, of which most had previously been unaware. CONCLUSIONS: Communication of the interval change should be done in the context of broader information about HPV primary screening, emphasising that people who test negative for HPV are at lower risk of cell changes so can safely be screened every 5 years. The long time needed for HPV to develop into cervical cancer provides reassurance about safety, but it is important to be transparent that no screening test is perfect.

Testing key messages about extending cervical screening intervals.

OBJECTIVES: We tested the impact of different messages about the rationale for extended cervical screening intervals on acceptability of an extension. METHODS: Women in England aged 25-49 years (n = 2931) were randomised to a control group or one of 5 groups given different messages about extending cervical screening intervals from 3 to 5 years. Outcome measures were general acceptability and six components from the Theoretical Framework of Acceptability (TFA). RESULTS: The groups who saw additional messages (47-63%) were more likely to find the change acceptable than controls (43%). Messages about interval safety, test accuracy and speed of cell changes resulted in more positive affective-attitudes, higher ethicality beliefs, a better understanding of the reasons for extended intervals and greater belief in the safety of 5-year intervals. Being up-to-date with screening and previous abnormal results were associated with finding 5-yearly screening unacceptable. CONCLUSIONS: Emphasising the slow development of cell changes following an HPV negative result and the safety of longer intervals, alongside the accuracy of HPV primary screening is important. PRACTICAL IMPLICATIONS: Campaigns explaining the rationale for extended cervical screening intervals are likely to improve acceptability. Though women who feel at increased risk, may remain worried even when the rationale is explained.

Patient-reported experiences and views on the Cytosponge test: a mixed-methods analysis from the BEST3 trial.

OBJECTIVES: The BEST3 trial demonstrated the efficacy and safety of the Cytosponge-trefoil factor 3, a cell collection device coupled with the biomarker trefoil factor 3, as a tool for detecting Barrett's oesophagus, a precursor of oesophageal adenocarcinoma (OAC), in primary care. In this nested study, our aim was to understand patient experiences. DESIGN: Mixed-methods using questionnaires (including Inventory to Assess Patient Satisfaction, Spielberger State-Trait Anxiety Inventory-6 and two-item perceived risk) and interviews. OUTCOME MEASURES: Participant satisfaction, anxiety and perceived risk of developing OAC. SETTING: General practices in England. PARTICIPANTS: Patients with acid reflux enrolled in the intervention arm of the BEST3 trial and attending the Cytosponge appointment (N=1750). RESULTS: 1488 patients successfully swallowing the Cytosponge completed the follow-up questionnaires, while 30 were interviewed, including some with an unsuccessful swallow.Overall, participants were satisfied with the Cytosponge test. Several items showed positive ratings, in particular convenience and accessibility, staff's interpersonal skills and perceived technical competence. The most discomfort was reported during the Cytosponge removal, with more than 60% of participants experiencing gagging. Nevertheless, about 80% were willing to have the procedure again or to recommend it to friends; this was true even for participants experiencing discomfort, as confirmed in the interviews.Median anxiety scores were below the predefined level of clinically significant anxiety and slightly decreased between baseline and follow-up (p < 0.001). Interviews revealed concerns around the ability to swallow, participating in a clinical trial, and waiting for test results.The perceived risk of OAC increased following the Cytosponge appointment (p<0.001). Moreover, interviews suggested that some participants had trouble conceptualising risk and did not understand the relationships between test results, gastro-oesophageal reflux and risk of Barrett's oesophagus and OAC. CONCLUSIONS: When delivered during a trial in primary care, the Cytosponge is well accepted and causes little anxiety. TRIAL REGISTRATION NUMBER: ISRCTN68382401.

E-Cigarette or Vaping Associated Lung Injury: Evolving Threat to Healthy Teens.

Vaping quickly rose in popularity once introduced to the market in 2003. Devices heat liquid to produce an aerosol that is inhaled by the user, an aerosol that can contain nicotine, heavy metals, volatile organic compounds, ultrafine particles, cancer-causing chemicals, and flavoring. Teenagers commonly use these products to smoke cannabinoids including delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), and butane hash oil (BHO). Liquids placed in the devices can be commercial or homemade. As popularity increased, more cases of vaping-related lung injury have been reported. We report a case of a 17-year-old female patient with delayed diagnosis of e-cigarette or vaping associated lung injury.

Multidisciplinary approach to low-dose CT screening for lung cancer in a metropolitan community.

BACKGROUND: Lung cancer is the primary cause of cancer death in men and women in the USA, led by Kentucky. In 2015, the Centers for Medicare and Medicaid Services initiated annual lung cancer screening with a low-dose computed tomography (LDCT) scan. This observational cohort study evaluated the multidisciplinary approach to this screening in our metropolitan community. METHODS: We present the prospective findings of patients who underwent a screening lung LDCT scan over a 2-year period at our institution in Kentucky. Patients who fulfilled the screening criteria were identified during an office visit with their primary care provider. RESULTS: Of the 4170 patients who underwent a screening lung LDCT scan, a total of 838 (20.9%) patients had nodules >4 mm. Of the 70 patients diagnosed with lung cancer, Stage 1 non-small cell lung cancer was most commonly detected [38 cases (54.3%)]. A follow-up lung LDCT scan (n = 897), pulmonary function test (n = 157), positron emission tomography scan (n = 12) and a lung biopsy (n = 53) were performed for certain individuals who had anomalies observed on the screening lung LDCT scan. A total of 42% of patients enrolled in group tobacco cessation classes quit smoking. CONCLUSIONS: This study provides a unique perspective of a lung LDCT scan screening program driven by primary care providers in a state plagued by cigarette smoking and lung cancer deaths and offers a valuable message into the prevention, high-risk screening and diagnosis of lung cancer.

Carcinogens and DNA damage.

Humans are variously and continuously exposed to a wide range of different DNA-damaging agents, some of which are classed as carcinogens. DNA damage can arise from exposure to exogenous agents, but damage from endogenous processes is probably far more prevalent. That said, epidemiological studies of migrant populations from regions of low cancer risk to high cancer risk countries point to a role for environmental and/or lifestyle factors playing a pivotal part in cancer aetiology. One might reasonably surmise from this that carcinogens found in our environment or diet are culpable. Exposure to carcinogens is associated with various forms of DNA damage such as single-stand breaks, double-strand breaks, covalently bound chemical DNA adducts, oxidative-induced lesions and DNA-DNA or DNA-protein cross-links. This review predominantly concentrates on DNA damage induced by the following carcinogens: polycyclic aromatic hydrocarbons, heterocyclic aromatic amines, mycotoxins, ultraviolet light, ionising radiation, aristolochic acid, nitrosamines and particulate matter. Additionally, we allude to some of the cancer types where there is molecular epidemiological evidence that these agents are aetiological risk factors. The complex role that carcinogens play in the pathophysiology of cancer development remains obscure, but DNA damage remains pivotal to this process.

Endoscopic Management of Early Esophageal Cancer.

The absolute incidence of esophageal adenocarcinoma has increased 7-fold over the past 5 decades, and esophageal adenocarcinoma is the most rapidly increasing epithelial malignancy in the United States. The incidence of early esophageal cancer has also increased proportionately. In the past decade, radiofrequency ablation has become the standard first-line therapy for high-grade dysplasia when found in the precursor lesion to esophageal adenocarcinoma, Barrett's esophagus. Success in the endoscopic management of high-grade dysplasia has furthered efforts to treat early esophageal cancers endoscopically. Although surgery remains the mainstay of treatment for more advanced tumors, national guidelines now recommend endoscopic mucosal resection followed by radiofrequency ablation for intramucosal carcinomas and T1a cancers. T1b cancers represent a more challenging group-very good results have been reported in highly selected subsets of patients with T1b tumors; however, many recommendations favor individualization or a surgical approach for this stage. This review examines the current data and recommendations regarding the endoscopic management of early esophageal adenocarcinomas.

Specific uptake of 99mTc-NC100692, an αvß3-targeted imaging probe, in subcutaneous and orthotopic tumors.

INTRODUCTION: The αvß3 integrin, which is expressed by angiogenic epithelium and some tumor cells, is an attractive target for the development of both imaging agents and therapeutics. While optimal implementation of αvß3-targeted therapeutics will require a priori identification of the presence of the target, the clinical evaluation of these compounds has typically not included parallel studies with αvß3-targeted diagnostics. This is at least partly due to the relatively limited availability of PET radiopharmaceuticals in comparison to those labeled with (99m)Tc. In an effort to begin to address this limitation, we evaluated the tumor uptake of (99m)Tc-NC100692, a cyclic RGD peptide that binds to αvß3 with ~1-nM affinity, in an αvß3-positive tumor model as well as its in vivo specificity. METHODS: MicroSPECT imaging was used to assess the ability of cilengitide, a therapeutic with high affinity for αvß3, to block and displace (99m)Tc-NC100692 in an orthotopic U87 glioma tumor. The specificity of (99m)Tc-NC100692 was quantitatively evaluated in mice bearing subcutaneous U87MG tumors, by comparison of the biodistribution of (99m)Tc-NC100692 with that of the non-specific structural analogue (99m)Tc-AH-111744 and by blocking uptake of (99m)Tc-NC100692 with excess unlabeled NC100692. RESULTS: MicroSPECT imaging studies demonstrated that uptake of (99m)Tc-NC100692 in the intracranial tumor model was both blocked and displaced by the αvß3-targeted therapeutic cilengitide. Biodistribution studies provided quantitative confirmation of these imaging results. Tumor uptake of (99m)Tc-NC100692 at 1h post-injection was 2.8 ± 0.7% ID/g compared to 0.38 ± 0.1% ID/g for (99m)Tc-AH-111744 (p < 0.001). Blocking (99m)Tc-NC100692 uptake by pre-injecting the mice with excess unlabeled NC100692 reduced tumor uptake by approximately five-fold, to 0.68 ± 0.3% ID/g (p = 0.01). CONCLUSION: These results confirm that (99m)Tc-NC100692 does, in fact, target the αvß3 integrin and may, therefore, be useful in identifying patients prior to anti-αvß3 therapy as well as monitoring the response of these patients to therapy.

A small-molecule IAP inhibitor overcomes resistance to cytotoxic therapies in malignant gliomas in vitro and in vivo.

We tested the use of the small-molecule Inhibitor of Apoptosis Protein (IAP) inhibitor LBW242 in combination with the standard-of-care therapies of irradiation and temozolomide for malignant gliomas. In vitro assays demonstrated that LBW242 enhanced the cytotoxic activity of radiotherapy, and clonogenic assays showed that the combination therapy led to a synergistic anti-glioma effect in multiple cell lines. Neurosphere assays revealed that the combination of radiation and LBW242 led to a pro-apoptotic effect in these glioma-initiating cell-enriched assays, with a corresponding inhibition of primary tumor cell growth. Athymic mice bearing established human malignant glioma tumor xenografts treated with LBW242 plus radiation and temozolomide demonstrated a synergistic suppression of tumor growth. Taken together, these experiments show that the pro-apoptotic and anti-glioma effects of radiotherapy and chemotherapy can be enhanced by the addition of a small-molecule IAP inhibitor. These results are readily translatable to clinical trial and offer the potential for improved treatment outcomes for patients with glioma.

Lonafarnib (SCH66336) improves the activity of temozolomide and radiation for orthotopic malignant gliomas.

Malignant gliomas are highly lethal tumors resistant to current therapies. The standard treatment modality for these tumors, surgical resection followed by radiation therapy and concurrent temozolomide, has demonstrated activity, but development of resistance and disease progression is common. Although oncogenic Ras mutations are uncommon in gliomas, Ras has been found to be constitutively activated through the action of upstream signaling pathways, suggesting that farnesyltransferase inhibitors may show activity against these tumors. We now report the in vitro and orthotopic in vivo results of combination therapy using radiation, temozolomide and lonafarnib (SCH66336), an oral farnesyl transferase inhibitor, in a murine model of glioblastoma. We examined the viability, proliferation, farnesylation of H-Ras, and activation of downstream signaling of combination-treated U87 cells in vitro. Lonafarnib alone or in combination with radiation and temozolomide had limited tumor cell cytotoxicity in vitro although it did demonstrate significant inhibition in tumor cell proliferation. In vivo, lonafarnib alone had a modest ability to inhibit orthotopic U87 tumors, radiation and temozolomide demonstrated better inhibition, while significant anti-tumor activity was found with concurrent lonafarnib, radiation, and temozolomide, with the majority of animals demonstrating a decrease in tumor volume. The use of tumor neurospheres derived from freshly resected adult human glioblastoma tissue was relatively resistant to both temozolomide and radiation therapy. Lonafarnib had a significant inhibitory activity against these neurospheres and could potentate the activity of temozolomide and radiation. These data support the continued research of high grade glioma treatment combinations of farnesyl transferase inhibitors, temozolomide, and radiation therapy.

Efficacy of the HSP90 inhibitor 17-AAG in human glioma cell lines and tumorigenic glioma stem cells.

Glioblastoma multiforme (GBM) arises from genetic and signaling abnormalities in components of signal transduction pathways involved in proliferation, survival, and the cell cycle axis. Studies to date with single-agent targeted molecular therapy have revealed only modest effects in attenuating the growth of these tumors, suggesting that targeting multiple aberrant pathways may be more beneficial. Heat-shock protein 90 (HSP90) is a molecular chaperone that is involved in the conformational maturation of a defined group of client proteins, many of which are deregulated in GBM. 17-allylamino-17-demethoxygeldanamycin (17-AAG) is a well-characterized HSP90 inhibitor that should be able to target many of the aberrant signal transduction pathways in GBM. We assessed the ability of 17-AAG to inhibit the growth of glioma cell lines and glioma stem cells both in vitro and in vivo and assessed its ability to synergize with radiation and/or temozolomide, the standard therapies for GBM. Our results reveal that 17-AAG is able to inhibit the growth of both human glioma cell lines and glioma stem cells in vitro and is able to target the appropriate proteins within these cells. In addition, 17-AAG can inhibit the growth of intracranial tumors and can synergize with radiation both in tissue culture and in intracranial tumors. This compound was not found to synergize with temozolomide in any of our models of gliomas. Our results suggest that HSP90 inhibitors like 17-AAG may have therapeutic potential in GBM, either as a single agent or in combination with radiation.