Search

Background: Phase III trials with prospective biomarker validation are essential to drug development in the era of personalized oncology. However, concerns have emerged regarding the design and reporting of phase III trials with prospective biomarker validation.Methods: We searched MEDLINE for phase III oncology trials with prospective biomarker validation published in high-impact medical journals from 2011 to 2020. Information regarding trial design and reporting were extracted. Descriptive methods were used to summarize the results.Results: We identified 45 phase III trials with prospective biomarker validation. There was a trend for increasing use of biomarker validation phase III trials (from 1 trial in 2011 to 12 trials in 2020). For 39 (86.7%) trials, results in biomarker-negative population were either listed as an exploratory subgroup analysis (62.2%) or not mentioned in the methods (24.4%). Twenty-one (46.7%) trials were originally designed without biomarker validation but were then apparently modified to incorporate prospective biomarker validation after trial commencement, albeit only 15 (33.3%) trials reported this change. Treatment effect and primary outcome values in biomarker-negative patients were not reported in 24.4% and 40.0% trials, respectively. For 18 trials with statistically significant results in the overall population, only 7 trials reported a hazard ratio less than 0.8 in the biomarker-negative population.Conclusion: Although biomarker validation in phase III trials have been increasingly used in the past decade, issues regarding changes in trial design after commencement without disclosure, under-reporting of results in biomarker-negative groups and recommending treatment in biomarker negative groups despite modest effects, require substantial improvement. [ABSTRACT FROM AUTHOR]

Despite the strong prognostic stratification of circulating tumor cells (CTCs) enumeration in metastatic breast cancer (MBC), current clinical trials usually do not include a baseline CTCs in their design. This study aimed to generate a classifier for CTCs prognostic simulation in existing datasets for hypothesis generation in patients with MBC. A K-nearest neighbor machine learning algorithm was trained on a pooled dataset comprising 2436 individual MBC patients from the European Pooled Analysis Consortium and the MD Anderson Cancer Center to identify patients likely to have CTCs ≥ 5/7 mL blood (StageIVaggressive vs StageIVindolent). The model had a 65.1% accuracy and its prognostic impact resulted in a hazard ratio (HR) of 1.89 (Simulatedaggressive vs Simulatedindolent P <.001), similar to patients with actual CTCs enumeration (HR 2.76; P <.001). The classifier's performance was then tested on an independent retrospective database comprising 446 consecutive hormone receptor (HR)-positive HER2-negative MBC patients. The model further stratified clinical subgroups usually considered prognostically homogeneous such as patients with bone-only or liver metastases. Bone-only disease classified as Simulatedaggressive had a significantly worse overall survival (OS; P <.0001), while patients with liver metastases classified as Simulatedindolent had a significantly better prognosis (P <.0001). Consistent results were observed for patients who had undergone CTCs enumeration in the pooled population. The differential prognostic impact of endocrine- (ET) and chemotherapy (CT) was explored across the simulated subgroups. No significant differences were observed between ET and CT in the overall population, both in terms of progression-free survival (PFS) and OS. In contrast, a statistically significant difference, favoring CT over ET was observed among Simulatedaggressive patients (HR: 0.62; P =. 030 and HR: 0.60; P =. 037, respectively, for PFS and OS). [ABSTRACT FROM AUTHOR]

Background: Previous studies have indicated coronavirus disease 2019 (COVID-19) patients with cancer have a high fatality rate.Methods: We conducted a systematic review of studies that reported fatalities in COVID-19 patients with cancer. A comprehensive meta-analysis that assessed the overall case fatality rate and associated risk factors was performed. Using individual patient data, univariate and multivariable logistic regression analyses were used to estimate odds ratios (OR) for each variable with outcomes.Results: We included 15 studies with 3019 patients, of which 1628 were men; 41.0% were from the United Kingdom and Europe, followed by the United States and Canada (35.7%), and Asia (China, 23.3%). The overall case fatality rate of COVID-19 patients with cancer measured 22.4% (95% confidence interval [CI] = 17.3% to 28.0%). Univariate analysis revealed age (OR = 3.57, 95% CI = 1.80 to 7.06), male sex (OR = 2.10, 95% CI = 1.07 to 4.13), and comorbidity (OR = 2.00, 95% CI = 1.04 to 3.85) were associated with increased risk of severe events (defined as the individuals being admitted to the intensive care unit, or requiring invasive ventilation, or death). In multivariable analysis, only age greater than 65 years (OR = 3.16, 95% CI = 1.45 to 6.88) and being male (OR = 2.29, 95% CI = 1.07 to 4.87) were associated with increased risk of severe events.Conclusions: Our analysis demonstrated that COVID-19 patients with cancer have a higher fatality rate compared with that of COVID-19 patients without cancer. Age and sex appear to be risk factors associated with a poorer prognosis. [ABSTRACT FROM AUTHOR]

Background: We examined the prognostic significance of circulating tumor cell (CTC) dynamics during treatment in metastatic breast cancer (MBC) patients receiving first-line chemotherapy.Methods: Serial CTC data from 469 patients (2202 samples) were used to build a novel latent mixture model to identify groups with similar CTC trajectory (tCTC) patterns during the course of treatment. Cox regression was used to estimate hazard ratios for progression-free survival (PFS) and overall survival (OS) in groups based on baseline CTCs, combined CTC status at baseline to the end of cycle 1, and tCTC. Akaike information criterion was used to select the model that best predicted PFS and OS.Results: Latent mixture modeling revealed 4 distinct tCTC patterns: undetectable CTCs (56.9% ), low (23.7%), intermediate (14.5%), or high (4.9%). Patients with low, intermediate, and high tCTC patterns had statistically significant inferior PFS and OS compared with those with undetectable CTCs (P < .001). Akaike Information Criterion indicated that the tCTC model best predicted PFS and OS compared with baseline CTCs and combined CTC status at baseline to the end of cycle 1 models. Validation studies in an independent cohort of 1856 MBC patients confirmed these findings. Further validation using only a single pretreatment CTC measurement confirmed prognostic performance of the tCTC model.Conclusions: We identified 4 novel prognostic groups in MBC based on similarities in tCTC patterns during chemotherapy. Prognostic groups included patients with very poor outcome (intermediate + high CTCs, 19.4%) who could benefit from more effective treatment. Our novel prognostic classification approach may be used for fine-tuning of CTC-based risk stratification strategies to guide future prospective clinical trials in MBC. [ABSTRACT FROM AUTHOR]

Background: We conducted a meta-analysis in nonmetastatic breast cancer patients treated by neoadjuvant chemotherapy (NCT) to assess the clinical validity of circulating tumor cell (CTC) detection as a prognostic marker.Methods: We collected individual patient data from 21 studies in which CTC detection by CellSearch was performed in early breast cancer patients treated with NCT. The primary end point was overall survival, analyzed according to CTC detection, using Cox regression models stratified by study. Secondary end points included distant disease-free survival, locoregional relapse-free interval, and pathological complete response. All statistical tests were two-sided.Results: Data from patients were collected before NCT (n = 1574) and before surgery (n = 1200). CTC detection revealed one or more CTCs in 25.2% of patients before NCT; this was associated with tumor size (P < .001). The number of CTCs detected had a detrimental and decremental impact on overall survival (P < .001), distant disease-free survival (P < .001), and locoregional relapse-free interval (P < .001), but not on pathological complete response. Patients with one, two, three to four, and five or more CTCs before NCT displayed hazard ratios of death of 1.09 (95% confidence interval [CI] = 0.65 to 1.69), 2.63 (95% CI = 1.42 to 4.54), 3.83 (95% CI = 2.08 to 6.66), and 6.25 (95% CI = 4.34 to 9.09), respectively. In 861 patients with full data available, adding CTC detection before NCT increased the prognostic ability of multivariable prognostic models for overall survival (P < .001), distant disease-free survival (P < .001), and locoregional relapse-free interval (P = .008).Conclusions: CTC count is an independent and quantitative prognostic factor in early breast cancer patients treated by NCT. It complements current prognostic models based on tumor characteristics and response to therapy. [ABSTRACT FROM AUTHOR]

In the article, the authors discuss the emergence of baricitinib as a treatment for coronavirus disease 2019 (COVID-19). Topics include the approved use of baricitinib as treatment of moderate to severe rheumatoid arthritis (RA), how artificial intelligence algorithms projected the effectiveness of the drug in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of cells, and the use of baricitinib and hydroxychloroquine to treat COVID-19.

While awaiting further evidence from large multinational cohort studies, as discussed in our analysis, it might be beneficial to continue curative surgical resections, chemotherapy, and other cancer treatments based on an individual patient evaluation. COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study. The overall case fatality rate of COVID19 patients with cancer measured 22.4%, which is comparable with that of the authors' report from a single institute (2) and recent meta-analysis involving similar populations from other multinational cohorts (3,4). [Extracted from the article]

Kaposi sarcoma-associated herpesvirus infection is associated with the development of 3 proliferative diseases: Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman disease. These conditions are also intimately associated with human immunodeficiency virus infection, and important synergistic interactions between these 2 viruses have been described. Despite differences in viral gene expression patterns in each condition, Kaposi sarcoma-associated herpesvirus encodes similar oncogenic proteins that promote the activation of sequential and parallel signaling pathways. Therapeutic strategies have been implemented to target these unique signaling pathways, and this sort of molecular targeting is the focus of many current research efforts. The scope of this review is to present contemporary knowledge about the epidemiology, virology, and immunology of Kaposi sarcoma-associated herpesvirus and to highlight several key oncogene products that may be targets for chemotherapy. [ABSTRACT FROM AUTHOR]

The L74V and K65R mutations confer resistance to several nucleoside analogues, and the impact on subsequent regimens is unclear. The risk of developing L74V or K65R mutation in the era of highly active antiretroviral therapy (HAART) was 4.5 and 2.8 cases per 100 person-years, respectively; concomitant receipt of boosted protease inhibitors protected against K65R. High rates of virologic suppression in the presence of either mutation were observed if the next regimen contained at least 2 active agents. If suboptimal HAART was used, patients with K65R experienced significantly higher rates of virologic suppression than did those with L74V (P = .01). [ABSTRACT FROM AUTHOR]

Generally physicians have a legal and ethical obligation of keeping confidentiality regarding their communication with patients and it is clear that we all have rights. The application of rights theorem, which usually refers to the recognition of individual human rights, to the deceased offers possible answers to the problematic question of patient confidentiality after death. Philosophical considerations broadly support utilitarian ideals concerning the `common good'. However, it may be possible to rank rights according to a hierarchy of need and thus preserve individual rights where they do not impinge upon the publics' right to protection from harm and the physician's right to tell the truth. This has broad implications for confidentiality, anonymity and health care information in general for patients, their families and healthcare workers. We discuss these issues, with specific reference to an individual case. [ABSTRACT FROM AUTHOR]

From a cohort of 9621 human immunodeficiency virus type 1-infected individuals, we identified 61 patients with primary central nervous system lymphoma (PCL) who had a median survival of 1.3 months. We compared clinicopathologic variables of patients who were treated in the pre-highly active antiretroviral therapy (HAART) and HAART eras and investigated whether exposure to antiretroviral agents with differing cerebrospinal fluid penetrations was associated with risk for PCL. All statistical tests were two-sided. Incidence of PCL was lower in the HAART era (1.2 cases per 1000 patient-years, 95% confidence interval [CI] = 0.8 to 1.9) than in the pre-HAART era (three cases per 1000 years, 95% Cl = 2.1 to 4.0; P<.001), and overall survival was longer (median survival = 32 days, range = 5-315 days, versus 48 days, range = 15-1136 days; log rank P = .03). In the HAART era, fewer patients had prior acquired immunodeficiency syndrome-defining illnesses than in the pre-HAART era (64% versus 90%; P = .013), and patients were more likely to have the diagnosis of PCL confirmed histologically or by polymerase chain reaction (77% versus 26%; P<.001). Exposure to specific antiretroviral agents was not associated with risk for PCL. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus type 1 (HIV-1) appears to adversely affect hepatitis C, but whether hepatitis C virus (HCV) has a reciprocal effect on HIV-1 infection remains a point of controversy. In a multivariate analysis of a cohort of 5832 individuals, we found that individuals coinfected with HCV and HIV-1 (prevalence of coinfection, 5.8%) had a CD4+ cell count that decreased at a rate similar to that for individuals infected with HIV-1 alone. However, coinfection was associated with a statistically significant increased likelihood of onset of an acquired immunodeficiency syndrome- defining illness or developing a CD4+ cell count of <200 cells/ mm³, compared with infection with HIV-1 alone (hazard ratio, 1.52; 95% confidence interval, 1.07-2.17). Patients who were naive to highly active antiretroviral therapy were significantly less likely to progress to either end point, because of their higher CD4+ cell counts. In conclusion, there was an increased number of adverse events in coinfected individuals, compared with individuals infected with HIV-1 alone. [ABSTRACT FROM AUTHOR]

The author reflects on the role of cell free deoxyribonucleic acid (DNA) in detecting the malignancy. He informs about the Epstein-Barr virus (EBV) which is a viral nuclear antigen and acts as an anticancer agent in the myelodysplastic syndrome. He further discusses the Kaposi sarcoma herpesvirus (KSHV) in which the proposed viral oncogenic porducts are lytic genes.

CCR5 antagonists may provide a well-tolerated switch option for patients experiencing tolerability or toxicity of their antiretroviral regimen. We analyzed stored samples from patients undergoing planned treatment interruptions for reasons other than virological failure, in order to analyze tropism evolution during fully suppressive antiretroviral therapy (ART). Two of 37 patients showed evidence of switching. Tropism switching after suppressive ART was uncommon in this cohort. Pretreatment human immunodeficiency virus (HIV) RNA tropism testing may help guide the switch to CCR5 antagonists in patients with undetectable HIV RNA. [ABSTRACT FROM AUTHOR]

The article focuses on the importance of the host control of lytic and latent infection in human herpesvirus-8 (HHV-8). Poorly controlled and lytic HHV-8 infection, as assessed by the detection of antibodies to the lytic K8.1 antigen, and latent HHV-8 infection, as assessed by the detection of antibodies to latent nuclear antigen, were associated with an overrepresentation of a 3 locus haplotype, interleukin-4, and the functional promoter variant of interleukin-6, as well as interleukin-12A, respectively.