Patients with von Hippel-Lindau (VHL) disease have a high incidence of renal cell carcinoma owing to
gene inactivation and constitutive activation of the transcription factor hypoxia-inducible factor ...2α (HIF-2α).
In this phase 2, open-label, single-group trial, we investigated the efficacy and safety of the HIF-2α inhibitor belzutifan (MK-6482, previously called PT2977), administered orally at a dose of 120 mg daily, in patients with renal cell carcinoma associated with VHL disease. The primary end point was objective response (complete or partial response) as measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1, by an independent central radiology review committee. We also assessed responses to belzutifan in patients with non-renal cell carcinoma neoplasms and the safety of belzutifan.
After a median follow-up of 21.8 months (range, 20.2 to 30.1), the percentage of patients with renal cell carcinoma who had an objective response was 49% (95% confidence interval, 36 to 62). Responses were also observed in patients with pancreatic lesions (47 of 61 patients 77%) and central nervous system hemangioblastomas (15 of 50 patients 30%). Among the 16 eyes that could be evaluated in 12 patients with retinal hemangioblastomas at baseline, all (100%) were graded as showing improvement. The most common adverse events were anemia (in 90% of the patients) and fatigue (in 66%). Seven patients discontinued treatment: four patients voluntarily discontinued, one discontinued owing to a treatment-related adverse event (grade 1 dizziness), one discontinued because of disease progression as assessed by the investigator, and one patient died (of acute toxic effects of fentanyl).
Belzutifan was associated with predominantly grade 1 and 2 adverse events and showed activity in patients with renal cell carcinomas and non-renal cell carcinoma neoplasms associated with VHL disease. (Funded by Merck Sharp and Dohme and others; MK-6482-004 ClinicalTrials.gov number, NCT03401788.).
Abstract
Aims
Vascular calcification is routinely encountered in percutaneous coronary intervention (PCI) and severe coronary calcification is a known predictor of in-stent restenosis and stent ...thrombosis. However, the histopathologic mechanisms behind such events have not been systematically described.
Methods and results
From our registry of 1211 stents, a total of 134 newer-generation drug-eluting stents (DES) (Xience, Resolute-Integrity, PROMUS-Element, and Synergy) with duration of implant ≥30 days were histologically analysed. The extent of calcification of the stented lesions was evaluated radiographically and divided into severe (SC, n = 46) and non-severely calcified lesions (NC, n = 88). The percent-uncovered struts per section {SC vs. NC; median 2.4 interquartile range (IQR) 0.0–19.0 % vs. 0.0 (IQR 0.0–4.6) %, P = 0.02} and the presence of severe medial tears (MTs) (59% vs. 44%, respectively, P = 0.03) were greater in SC than NC. In addition, SC had a higher prevalence of ≥3 consecutive struts lying directly in contact with surface calcified area (3SC) (52% vs. 8%, respectively, P < 0.0001). Multivariate analysis demonstrated that sections with duration of implantation ≤6 months odds ratio (OR): 7.7, P < 0.0001, 3SC (OR: 6.5, P < 0.0001), strut malapposition (OR: 5.0, P < 0.0001), and lack of MTs (OR: 2.5, P = 0.0005) were independent predictors of uncovered struts. Prevalence of neoatherosclerosis was significantly lower in SC than that of NC (24% vs. 44%, P = 0.02).
Conclusion
Severe calcification, especially surface calcified area is an independent predictor of uncovered struts and delayed healing after newer-generation DES implantation. These data expand of knowledge of the vascular responses of stenting of calcified arteries and suggests further understand of how best to deal with calcification in patients undergoing PCI.
Inferior outcomes in younger patients with colorectal cancer may be associated with multiple factors, including tumor biology, delayed diagnosis, disparities such as access to care, and/or treatment ...differences.
This study aims to examine age-based colorectal cancer outcomes in an equal-access health care system.
This study is a retrospective large multi-institutional database analysis.
Patients with colorectal cancer included in the Department of Defense Automated Central Tumor Registry (January 1993 to December 2008) were stratified by age <40, 40 to 49, 50 to 79, and ≥80 years to determine the effect of age on incidence, treatment, and outcomes.
The primary outcomes measured were the stage at presentation, adjuvant therapy use, 3- and 5-year disease-free survival, and overall survival.
Some 7948 patients were identified; most (77%) patients were in the 50- to 79-year age group. Overall, 25% presented with stage III disease. Compared with patients aged 50 to 79 and ≥80 years, patients aged <40 and 40 to 49 years presented more frequently with advanced disease (stage III (35% and 35% vs 28% and 26%) and stage IV (24% and 21% vs 18% and 15%); all p < 0.001). Adjuvant chemotherapy use in stage III patients was 62%; those patients ≥80 and 50 to 79 years had decreased use (p < 0.001). Overall recurrence was 8.1% at 3 years and 9.7% at 5 years, with the highest rates in patients <40 years (11.8%; p = 0.007). Overall survival was worse in patients ≥80 years, whereas the remaining cohorts were similar. For stage III disease, patients 40 to 49 years had the highest survival among all cohorts (p < 0.001).
This study was limited by the lack of specific comorbid information and the limitations inherent to large database reviews.
In an equal-access system, young age at presentation (<50 years) was associated with advanced stage and higher recurrence of colorectal cancer, but similar survival in comparison with older patients. Although increased adjuvant therapy use in younger patients may partially account for stage-specific increases in survival, the relative decreased chemotherapy use overall requires further evaluation.
Electronic cigarette (ECIG) use continues to be highly prevalent, especially among youth and young adults. Potential exposure from secondhand ECIG particulate matter (PM) places bystanders in danger ...of inhaling harmful substances, especially in confined spaces. This study was conducted to measure the potential exposure from secondhand ECIG PM exposure in vehicles, with participants completing a 30-min ECIG use session in their own vehicle with their preferred ECIG device. Sessions included a 5-min, 10-puff directed bout (30-s interpuff interval), followed by a 25-min ad libitum bout in which participants could take as many puffs as desired. Real-time PM1, PM2.5, and PM10 (the 50% efficiency mass cut-off of that passes through a size-selective inlet at 1 μm, 2.5 μm, and 10 μm aerodynamic diameters, respectively) measurements were captured during the sessions using portable PM monitors (MiniWRAS, pDR, SidePak, and GeoAir2 low-cost monitors). A total of 56 participants with valid measurements were included in the study, with a total of 13 unique ECIG device brands, including Vuse Alto, Box Air Bar, ElfBar, Esco Bar, Aegis Legend, Hyde Edge, JUUL, Kang Onee Stick, Kang Onee Stick Plus, Nord X, Nord 2, Nord 3, and Vaporesso. During the 5-min directed bout, the highest real-time PM2.5 mean concentrations were 175 μg/m3 for the MiniWRAS, 1050 μg/m3 for pDR and 3314 μg/m3 for SidePak. The filter measurements were not detectable in most experiments, except for two participants, with one taking 205 puffs and the other taking 285 puffs, approximately 10 times the mean (30) puffs of all participants. The evaluation of GeoAir2 with the MiniWRAS showed a wide range of Pearson correlation coefficient (r) values, ranging from −0.03 to 1.00, for the 13 ECIG brands. The mass median diameter (0.31 μm–3.42 μm) and geometric standard deviation (2.47–8.21) were different based on the participants for the same ECIG brand.
Display omitted
•Particulate matter (PM) measurements varied among aerosol monitors.•Discrete filter measurements were not detectable for most experiments.•The low-cost monitor showed potential for detecting PM measurements once calibrated.•The mass median diameter differed among participants for the same exposure.
We show here that cyclin-dependent kinase 5 (CDK5), a known regulator of migration in neuronal development, plays an important role in prostate cancer motility and metastasis. P35, an activator of ...CDK5 that is indicative of its activity, is expressed in a panel of human and rat prostate cancer cell lines, and is also expressed in 87.5% of the human metastatic prostate cancers we examined. Blocking of CDK5 activity with a dominant-negative CDK5 construct, small interfering RNA, or roscovitine resulted in changes in the microtubule cytoskeleton, loss of cellular polarity, and loss of motility. Expression of a dominant-negative CDK5 in the highly metastatic Dunning AT6.3 prostate cancer cell line also greatly impaired invasive capacity. CDK5 activity was important for spontaneous metastasis in vivo; xenografts of AT6.3 cells expressing dominant-negative CDK5 had less than one-fourth the number of lung metastases exhibited by AT6.3 cells expressing the empty vector. These results show that CDK5 activity controls cell motility and metastatic potential in prostate cancer.
Nutcracker syndrome, caused by mesoaortic compression of the left renal vein leading to symptoms related to venous hypertension, is an uncommon entity that may require operative intervention. ...Traditional open transposition of the left renal vein to the vena cava has been shown to have a reintervention rate of up to 30%, while also having additional morbidity associated with laparotomy. More recently, endovascular stenting has been described in several small series but have reported stent fracture, thrombosis, and migration.
We report the case of a 26-year-old woman with 4 months of intermittent flank pain and hematuria, diagnosed with nutcracker syndrome by both duplex ultrasound and axial based imaging.
The patient underwent catheter venography confirming left renal vein compression, which also demonstrated a dilated gonadal vein measuring 11 mm leading to significant pelvic varices. Through a left lower quadrant retroperitoneal exposure, the gonadal vein was transposed to the left common iliac vein with completion venography demonstrating relief of renal venous congestion. The patient was discharged uneventfully with immediate resolution of symptoms and remains symptom-free at 6-month follow-up.
Gonadal vein transposition is an effective alternative surgical treatment for nutcracker syndrome.
To evaluate the relative diagnostic value of nonmydriatic fundus photography (nFP) among patients screened for diabetic retinopathy in remote rural medical clinics and an urban academic medical ...center for nonadherence to recommended annual dilated eye examination.
A retrospective cross-sectional study was performed among diabetic patients seen in primary outpatient clinics between 2006 and 2011 who were screened for diabetic retinopathy with nFP for history of nonadherence to recommended annual dilated eye examination. A single nonstereoscopic, 45°, 10-megapixel digital image of the disc and macula of both eyes was obtained locally and transmitted electronically to a retinal specialist for remote review. The results from remote rural Native American Indian reservations were compared with those from an urban academic family practice clinic. The proportion of subjects diagnosed with diabetic retinopathy and the quality of fundus images were compared.
Among 872 patients (1,744 eyes) screened from rural sites and 517 subjects (1,034 eyes) screened from an urban site, images were of good quality for evaluation in 82.4% and 85.7% of subjects, respectively. Diabetic retinopathy was noted in 12.6% of rural subjects and 29.6% of urban subjects (p<0.001).
nFP can be a useful tool in both rural and urban settings to screen for diabetic retinopathy in patients who are nonadherent to the recommended dilated annual eye exam. In our study population, a surprisingly higher percentage of diabetic subjects screened from the urban clinic had retinopathy compared with subjects screened in rural clinics.
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