Vascular disrupting agents (VDAs), or endothelial disrupting agents, attempt to exploit the vascular endothelium that supplies rapidly dividing neoplasms. Unlike antiangiogenesis agents (e.g. the ...monoclonal antibody bevacizumab; and tyrosine kinase inhibitors sorafenib and sunitinib) that disrupt endothelial cell survival mechanisms and the development of a new tumor blood supply, VDAs are designed to disrupt the already established abnormal vasculature that supports tumors, by targeting their dysmorphic endothelial cells. Tumor vascular endothelium is characterized by its increased permeability, abnormal morphology, disorganized vascular networks, and variable density. VDAs induce rapid shutdown of tumor blood supply, causing subsequent tumor death from hypoxia and nutrient deprivation. The safety profile of this class of compounds is more indicative of agents that are indeed 'vascularly' active. For example, VDAs can cause: acute coronary and other thrombophlebitic syndromes; alterations in blood pressure, heart rate, and ventricular conduction; transient flush and hot flashes; neuropathy; and tumor pain. Despite these cardiovascular concerns some patients have benefited from VDAs in early clinical trials. Further drug development of VDAs must include the combination of these agents with other novel biological agents, cytotoxic chemotherapy, and radiotherapy. Close monitoring of patients receiving VDAs for any cardiovascular toxicity is imperative.
Oesophageal cancer is the seventh most common cancer and the sixth leading cause of cancer death worldwide, and its incidence varies globally. In Uganda, the incidence and trend are on the increase. ...However, there is a paucity of published data regarding this population's oesophageal cancer clinicopathologic characterisation and treatment outcomes.
To study the patients' clinicopathologic characteristics and treatment outcomes of oesophageal cancer over 10 years at the Uganda Cancer Institute.
Patients' charts with histologically confirmed diagnoses of oesophageal cancer for 2009-2019 were identified. Case information, which included patient demographics, history of alcohol use or smoking, tumour location, histological type, tumour grade, clinical TNM (Tumour, Node, Metastasis) staging treatment exposure and treatment outcomes, was evaluated retrospectively. The median survival time was estimated with the Kaplan-Meier method and the median follow-up period was estimated using the reverse Kaplan-Meier.
1,965 oesophageal cancer patients were identified; 1,380(70.23%) were males and 585(29.77 %) females, their mean age was 60.20 years (±12.66). Most males had a history of both alcohol consumption and smoking 640(46.38%). The lower third of the oesophagus was the most common anatomical location 771(39.24%). The majority had squamous cell carcinoma histological type 1,783(90.74%) followed by adenocarcinomas 182(9.26%) in the distal oesophagus. Poorly differentiated tumour grade 743(37.81%) was predominant. The majority of the patients were in stage IVB, 733(37.30%), and most patients were planned for the best supportive care, 731(37.20%). Radiation alone was offered to 621(31.60%) and feeding gastrostomy to 249(12.70%). Treatment outcomes: at the time of the current analysis, 58.68% had died, 1.48% were alive and 39.84% were lost to follow-up. The median follow-up period was 65 months (IQR:35.83-83.30) with a median survival time of 4.47 months (95% CI: 4.17-4.80).
Treatment outcomes of Ugandan oesophageal cancer patients seeking care are poor as most patients present with advanced disease. There is a significant loss of follow-up after treatment initiation. Therefore, reduction in exposure to known modifiable risk factors, early detection and timely referral for treatment strategies are needed to improve outcomes of these patients in our population. Designing interventions to improve treatment adherence is necessary.
Purpose: The purpose of our study was to review and determine the cardiovascular safety profile of combretastatin A4 phosphate (CA4P)
in a Phase I study in 25 patients with advanced solid tumors.
...Experimental Design: CA4P was administered in a dose-escalating fashion starting at 18 mg/m 2 i.v. every 21 days, and the maximal dosage was 90 mg/m 2 . Continuous evaluation included bedside blood pressure and pulse monitoring, 12-lead electrocardiogram (ECG) at fixed time
points for measured QT interval determination, determination of the corrected QT interval (QTc) using Bazett’s formula QTc
= QT/(R-R interval) 1/2 , and chart review. Pharmacodynamic correlations of CA4P dose, CA4P/CA4 area under the curve, and C max versus heart rate (HR), blood pressure, QT, and QTc intervals, over the first 4 h postdosing were analyzed.
Results: After CA4P administration, there were significant increases in QTc interval at the 3-h and 4-h time points 27.2 ms ( P < 0.0001) and 30.8 ms ( P < 0.0001), respectively and HR at the 3- and 4-h time points 13.2 beats per minute (bpm; P < 0.01) and 15.1 bpm ( P < 0.001), respectively. Three of 25 patients had prolonged QTc intervals at baseline, whereas 15 (60%) of 25 and 18 (75%)
of 24 patients had prolonged QTc intervals at 3 and 4 h. The slope of HR and QTc increasing as a function of time during the
first 4 h was correlated to dose (in milligrams) of CA4P ( P = 0.01 and r = 0.49 for HR, P = 0.005 and r = 0.55 for QTc) and to CA4 area under the curve ( P = 0.04 and r = 0.41 for HR, P = 0.02 and r = 0.44 for QTc); blood pressure and uncorrected QTc interval dose-response correlations were not significant. Two patients
had ECG changes consistent with an acute coronary syndrome within 24 h of CA4P infusion.
Conclusions: CA4P prolongs the QTc interval. There was a temporal relationship with the CA4P infusion and with ECG changes consistent
with an acute coronary syndrome in two patients. It is advisable that future trials with CA4P have eligibility guidelines
limiting patients with known coronary artery disease or those with multiple coronary artery disease risk factors until more
experience is gained regarding potential cardiovascular toxicity with this agent.
There is a paucity of published data regarding upper gastrointestinal diseases in Ugandans with upper gastrointestinal symptoms referred for endoscopy.
To study the presenting complaints, pathology ...and Helicobacter pylori prevalence among patients with upper gastrointestinal symptoms in South-Western Uganda.
Patients presenting with upper gastrointestinal symptoms underwent upper endoscopy and a urease test for Helicobacter Pylori, all suspicious lesions were biopsied for histopathology review as appropriate.
The most common presenting complaints were epigastric pain (51.6%), dysphagia (13.6%) and odynophagia (7.1%). The most common endoscopy finding was gastritis (40.2%), followed by normal examination (15.2%), oesophageal cancer (13.6%), gastric ulcer (7.6%) and gastric cancer (7.1%). Patients older than 40 years (n=110) had significant findings including gastritis (50.9%), oesophageal cancer (22.7%) and gastric cancer (11.8%). However in younger patients, with the age range of 18-40 years (n=74), most examinations were normal (92.9%). Of the 176 patients able to undergo Helicobacter pylori testing 75.6% were positive. Helicobacter pylori infection was associated with statistically significant increase in gastritis, oesophageal cancer, gastric ulcer, gastric cancer, and duodenal ulcers (p-values< 0.05).
Gastritis, ulcerative disease, and upper gastrointestinal malignancies are common in South-Western Ugandans and are associated with a high prevalence of Helicobacter pylori.
To identify retrospectively hypercoagulable events that occurred over time in patients who underwent image-guided percutaneous renal cryoablation and compare the incidence with a cohort of patients ...who underwent surgical partial nephrectomy (PN) during the same time period.
An electronic medical record database was queried for patients who underwent percutaneous image-guided renal mass cryoablation or PN between September 2006 and June 2012. Records were examined for thrombotic events during the year following the procedure in each group. Incidence rates, Kaplan-Meier estimates, and patient demographic variables were compared using the stratified log-rank test and t test for independent samples.
The study comprised 114 cryoablation cases. The cumulative incidence of thrombotic events after 1 year was 4.39%. The incidence per 100 person-years was 4.84. There were 105 PN cases. The cumulative incidence of thrombotic events after 1 year was 1.0%. The incidence per 100 person-years was 1.14. The person-time incidence rate difference for these two groups did not reach statistical significance (P = .0894).
The incidence of thrombotic events in patients who underwent percutaneous renal cryoablation in this study was not significantly different than a comparable cohort who underwent surgical PN during the same time period.
There are numerous barriers to enrollment in oncology biomarker-driven studies.
The ELAINE 2 study (ClinicalTrials.gov identifier: NCT04432454) is an open-label phase 2 study of lasofoxifene combined ...with abemaciclib in patients with advanced or metastatic estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer with an
mutation. ELAINE 2 opened clinical sites by using a Traditional approach, which activated a site before patient identification, and the Tempus TIME Trial network, which opened a site only after identifying an eligible patient. This manuscript presents the operational metrics comparing the Traditional and TIME Trial site data.
The study enrolled patients over 34 weeks and 16 sites (six Traditional and 10 TIME Trial) participated. Duration for full clinical trial agreement execution for Traditional sites and TIME Trial sites averaged 200.5 (range, 142-257) and 7.6 days (range, 2-14), respectively. Institutional review board approval time for Traditional sites and TIME Trial sites was 27.5 (range, 12-71) and 3.0 days (range, 1-12), respectively. Duration from study activation to first consent was 33.3 (range, 18-58) and 8.8 days (range, 1-35) for Traditional and TIME Trial sites, respectively. The first patient on study was at a TIME Trial site 115 days before a Traditional site and the first seven patients enrolled were at TIME Trial sites. Traditional sites consented 23 and enrolled 16 patients, while TIME Trial sites consented 16 and enrolled 13. The trial enrolled 29 patients in 8.5 months with the anticipated enrollment duration being 12-18 months.
The TIME Trial network opened earlier and enrolled the first study patients. These results demonstrate that the Just-in-TIME model, along with a Traditional model, can improve enrollment in biomarker-driven studies.
Objective To assess national trends in the usage of local ablative therapy for small renal masses (SRMs) in a cohort of young patients. Ablation of SRMs has been shown to offer cancer control with ...limited follow-up. Although ablation is considered effective for patients with limited life expectancy, its use among younger patients may be considered controversial. Methods We used the National Cancer Data Base to identify patients between the ages of 40 and 65 years who were diagnosed with SRMs from 2004 to 2011. The primary outcome was the use of local ablative therapy. Multivariable logistic regression analysis was used to identify patient and hospital factors associated with ablation therapies in this cohort. Results During the study period, we identified 49,441 patients with SRMs, of which 2789 (5.6%) were treated with ablative therapies. The proportion of patients undergoing ablation gradually rose from 2.2% in 2004 to 6.2% in 2011 ( P < .001). On multivariable analysis, patients were more likely to receive local ablation at academic hospitals (odds ratio OR: 1.5; P < .001) compared with community hospitals, or primarily insured by Medicaid (OR: 1.4; P < .001) or Medicare (OR: 1.3; P < .001) compared with private insurance. Conclusion The use of local ablative therapies is gradually rising but has so far been limited to a small fraction of young patients with SRMs. Patients treated at high-volume, academic hospitals or insured with Medicaid or Medicare were treated to a greater degree with ablation. These results have important implications for the adoption of ablation and the need for long-term surveillance.
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