Totality of evidence of the effectiveness of repurposed therapies for COVID-19: Can we use real-world studies alongside randomized controlled trials?

Rapid and robust strategies to evaluate the efficacy and effectiveness of novel and existing pharmacotherapeutic interventions (repurposed treatments) in future pandemics are required. Observational "real-world studies" (RWS) can report more quickly than randomized controlled trials (RCTs) and would have value were they to yield reliable results. Both RCTs and RWS were deployed during the coronavirus disease 2019 (COVID-19) pandemic. Comparing results between them offers a unique opportunity to determine the potential value and contribution of each. A learning review of these parallel evidence channels in COVID-19, based on quantitative modeling, can help improve speed and reliability in the evaluation of repurposed therapeutics in a future pandemic. Analysis of all-cause mortality data from 249 observational RWS and RCTs across eight treatment regimens for COVID-19 showed that RWS yield more heterogeneous results, and generally overestimate the effect size subsequently seen in RCTs. This is explained in part by a few study factors: the presence of RWS that are imbalanced for age, gender, and disease severity, and those reporting mortality at 2 weeks or less. Smaller studies of either type contributed negligibly. Analysis of evidence generated sequentially during the pandemic indicated that larger RCTs drive our ability to make conclusive decisions regarding clinical benefit of each treatment, with limited inference drawn from RWS. These results suggest that when evaluating therapies in future pandemics, (1) large RCTs, especially platform studies, be deployed early; (2) any RWS should be large and should have adequate matching of known confounders and long follow-up; (3) reporting standards and data standards for primary endpoints, explanatory factors, and key subgroups should be improved; in addition, (4) appropriate incentives should be in place to enable access to patient-level data; and (5) an overall aggregate view of all available results should be available at any given time.

Artificial Intelligence Applied to in vitro Gene Expression Testing (IVIGET) to Predict Trivalent Inactivated Influenza Vaccine Immunogenicity in HIV Infected Children.

The number of patients affected by chronic diseases with special vaccination needs is burgeoning. In this scenario, predictive markers of immunogenicity, as well as signatures of immune responses are typically missing even though it would especially improve the identification of personalized immunization practices in these populations. We aimed to develop a predictive score of immunogenicity to Influenza Trivalent Inactivated Vaccination (TIV) by applying deep machine learning algorithms using transcriptional data from sort-purified lymphocyte subsets after in vitro stimulation. Peripheral blood mononuclear cells (PBMCs) collected before TIV from 23 vertically HIV infected children under ART and virally controlled were stimulated in vitro with p09/H1N1 peptides (stim) or left unstimulated (med). A multiplexed-qPCR for 96 genes was made on fixed numbers of 3 B cell subsets, 3 T cell subsets and total PBMCs. The ability to respond to TIV was assessed through hemagglutination Inhibition Assay (HIV) and ELIspot and patients were classified as Responders (R) and Non Responders (NR). A predictive modeling framework was applied to the data set in order to define genes and conditions with the higher predicted probability able to inform the final score. Twelve NR and 11 R were analyzed for gene expression differences in all subsets and 3 conditions [med, stim or Δ (stim-med)]. Differentially expressed genes between R and NR were selected and tested with the Adaptive Boosting Model to build a prediction score. The score obtained from subsets revealed the best prediction score from 46 genes from 5 different subsets and conditions. Calculating a combined score based on these 5 categories, we achieved a model accuracy of 95.6% and only one misclassified patient. These data show how a predictive bioinformatic model applied to transcriptional analysis deriving from in-vitro stimulated lymphocytes subsets may predict poor or protective vaccination immune response in vulnerable populations, such as HIV-infected individuals. Future studies on larger cohorts are needed to validate such strategy in the context of vaccination trials.

Open science: The open clinical trials data journey.

Open data sharing and access has the potential to promote transparency and reproducibility in research, contribute to education and training, and prompt innovative secondary research. Yet, there are many reasons why researchers don't share their data. These include, among others, time and resource constraints, patient data privacy issues, lack of access to appropriate funding, insufficient recognition of the data originators' contribution, and the concern that commercial or academic competitors may benefit from analyses based on shared data. Nevertheless, there is a positive interest within and across the research and patient communities to create shared data resources. In this perspective, we will try to highlight the spectrum of "openness" and "data access" that exists at present and highlight the strengths and weakness of current data access platforms, present current examples of data sharing platforms, and propose guidelines to revise current data sharing practices going forward.

Lung nodules: improved detection with software that suppresses the rib and clavicle on chest radiographs.

PURPOSE: To demonstrate possible superiority in the performance of a radiologist who is tasked with detecting actionable nodules and aided by the bone suppression and soft-tissue visualization algorithm of a new software program that produces a modified image by suppressing the ribs and clavicles, filtering noise, and equalizing the contrast in the area of the lungs. MATERIALS AND METHODS: The study and use of anonymized and deidentified data received approval from the MedStar-Georgetown University Oncology Institutional Review Board. Informed consent was obtained from 15 study radiologists. The study radiologists participated as observers in a reader study of 368 patients in an approximately 2:1 cancer-free-to-cancer ratio. The localized receiver operating characteristic (LROC) method was used for analyses. Images were rerandomized for each radiologist. Each patient image was sequentially read, first with the standard radiograph and then with the software-aided image. Normal studies were confirmed with computed tomography (CT), follow-up, and/or panel consensus. RESULTS: Each reader and the combined scores of the 15 readers showed improvement. The area under the combined LROC curve increased significantly from 0.460 unaided to 0.558 aided by visualization software (P = .0001). When measured according to the reader's indication that a case should be sent or not sent for CT or biopsy, sensitivity for cancer detection increased from 49.5% unaided to 66.3% aided by software (P < .0001); specificity decreased from 96.1% to 91.8% (P = .004). Seventy-four percent of the aided detections occurred in cancers with 70% or greater overlap of the bone and the nodule. CONCLUSION: The radiologists using visualization software significantly increased their detection of lung cancers and benign nodules.

Developing the evidence base for applying pharmacogenomics: proceeds from DIA Workshop IV--Breakout Session 1.

The 4th Drug Information Association Workshop in a series of workshops on Pharmacogenomics: 'Biomarkers and Pharmacogenomics in Drug Development and Regulatory Decision Making' took place on December 10-12, 2007 in Bethesda, MD, USA. A number of breakout sessions were conducted to focus on different aspects of the development of biomarkers. Breakout Session 1 considered the evidence base for the development of pharmacogenomic markers from both safety and efficacy perspectives, with a view to understanding the challenges in the design of appropriate clinical studies during drug development. Case studies based on data generated during all stages of drug development were used to stimulate discussion and refine considerations for what constitutes a sufficient evidence base to support the effective use of novel, pharmacogenomic biomarkers. The discussions were open and lively, and some broad principles were drawn from the discussion. In this article, we summarize the case studies presented and develop key discussion points that arose out of the meeting. These case studies help to illustrate the current state of the art in the application of pharmacogenomics in drug development and the challenges being faced in the development of pharmacogenomics from interesting, exploratory associations into predictive biomarkers with clinical utility. We hope that this will serve as a stimulus to consideration of the critical issues facing the implementation of pharmacogenomics into drug development.

Outpatient genetic risk assessment in women with breast cancer: one center's experience.

A chart audit at one cancer center, of 193 women with breast cancer, was completed to assess whether a complete family history that may indicate genetic predisposition was obtained and if that information led a provider to suggest risk reduction strategies. A risk management tool, which included a pedigree template, was used. Of the 193 charts reviewed, 88.6% had family history information recorded; 41.5% reported three generations of family history. Risk management was undocumented in 21.8% of the charts reviewed and, for those that were reported (78.2%), 7.25% were referred for genetic counseling. These results suggest that a more detailed assessment of hereditary breast cancer risk incorporating three generations of family history and additional types of cancer need to be integrated into medical oncology practice. An algorithm was developed as a guide to improve the process of evaluation and referral for genetic risk assessment.

Computed tomographic characterization of malignant peritoneal mesothelioma.

AIMS AND BACKGROUND: Peritoneal mesothelioma is a rare disease with a universally fatal outcome when managed in a traditional palliative manner. New approaches to treatment using cytoreductive surgery and intraperitoneal chemotherapy suggest that long-term survival is possible in selected patients. Early recognition of this disease process with an orderly surgical approach will begin to optimize treatment. METHODS: Thirty-three patients with malignant peritoneal mesothelioma had CT scans available for review. A Z-score was used to evaluate the incidence of cancer at a particular anatomic site as compared to a general incidence of disease at all sites. CT was analyzed by abdominopelvic anatomic sites (16), abdominopelvic regions (9), and for presence versus absence of disease in the chest. Interpretative CT findings (class 0-III) were determined for these 33 patients. RESULTS: Eight of 33 patients had pleural abnormalities. In an analysis of 16 abdominopelvic anatomic sites, the vesical or rectal uterine pouch was involved in 97% and the greater omentum in 91%. These anatomic sites were the only ones with a positive Z-score of >1. In the analysis of 9 abdominopelvic regions, the central and pelvic regions had Z-scores >2 for large volume disease >5 cm. For CT interpretative findings class I, class II and class III was determined in approximately one-third in each category. Sixty-six percent of the patients had ascites by CT. CONCLUSIONS: Malignant peritoneal mesothelioma by CT evaluation predominates in tumor mass within the central and pelvic portions of the abdomen. Minimal, moderate, and extensive small bowel enlargements were seen in roughly one-third of the patients. With the use of the Z-score and interpretative small bowel findings a radiologic characterization of this disease for primary radiologic diagnosis is possible.

Heterogeneity of risk for melanoma and pancreatic and digestive malignancies: a melanoma case-control study.

BACKGROUND: Data addressing the interfamilial heterogeneity of melanoma are limited. In the current study, the authors assessed melanoma risk according to family history of melanoma and other melanoma-associated malignancies and evaluated the familial heterogeneity of melanomas, pancreatic malignancies, and gastrointestinal malignancies. METHODS: The authors obtained patient histories of malignancy in first-degree relatives as part of a clinic-based case-control study. The case group included 737 newly diagnosed patients with invasive melanoma, and the control group included 1021 outpatients from clinics at the same medical centers. To assess heterogeneity of risk among families affected by melanoma, a nonparametric method was used to detect extrabinomial variation. In addition, selected patients with melanoma (n=133) were tested for germline mutations in CDKN2A. RESULTS: The adjusted odds ratio associated with a family history of melanoma was 1.7 (95% confidence interval, 1.1-2.7). Family histories of pancreatic, gastrointestinal, brain, breast, or lymphoproliferative disease did not increase the risk of melanoma significantly. Among case families, significant evidence of familial heterogeneity was found for melanomas, but not for pancreatic or gastrointestinal malignancies. Two mutations in CDKN2A previously associated with melanoma risk were identified among the 133 patients tested in the case group; mutation detection did not differ between families with low and high heterogeneity scores. CONCLUSIONS: Familial heterogeneity testing in the study population did not improve the selection of high-risk families for genetic study. Even in a large case-control study, few families that had multiple members with melanoma were identified, and family members with pancreatic malignancies were rare.

Clinical presentation of peritoneal mesothelioma.

AIM: To describe the clinical presentation of peritoneal mesothelioma and its impact on survival. METHODS: Data was collected from 51 patients with peritoneal mesothelioma treated at the Washington Cancer Institute. The demographic, clinical and pathologic information were analyzed. RESULTS: Pain was the most common symptom (recorded in 33% of patients); increased abdominal girth occurred in 31%, increased abdominal girth and pain in 5%, and a new onset hernia in 12%. In an additional 14% of patients, a variety of other clinical findings led to the diagnosis. There was a statistically significant difference in survival by gender, weight loss and volume of disease. CONCLUSIONS: Pain was the most common initial presenting symptom, with increased abdominal girth as a second. A more favorable prognosis occurred in women with a small disease volume.

Intraperitoneal cancer dissemination: mechanisms of the patterns of spread.

BACKGROUND: Well known patterns govern the distribution of hematogenous and lymphatic metastasis of cancer. In the past the distribution of cancer cells free within abdominal cavity received little attention and was thought to be a random event. However, surgical observation led the authors to generate and test hypotheses regarding patterns of spread that vary with tumor type, with the intraperitoneal environment, and with the physiology of the peritoneal surface tissues. METHODS: The distribution and volume of peritoneal surface malignancy was prospectively recorded in 129 patients with 5 different types of tumors at the time of cytoreductive surgery. The malignancies studied included pseudomyxoma peritonei (PMP) of appendiceal origin, colonic mucinous adenocarcinoma (MA), nonmucinous colonic adenocarcinoma (NMA), ovarian carcinoma (OV) and sarcoma (SA). The abdominal and pelvic cavity was divided into 3 horizontal sectors, 9 regions and 25 sites. The incidences of tumor implants in these designated areas were statistically analyzed for each tumor type and comparisons between tumor types studied. RESULTS: The magnitude of intraperitoneal cancer dissemination was similar for mucinous tumors, including PMP and MA and significantly higher than for non-mucinous tumors. Also the mucinous cancers were more likely to be present in the upper horizontal sector than were non-mucinous. When NMA was compared to PMP and MA the epigastric region was significantly less likely to contain tumor. For all cancer diagnoses the colon, greater omentum and cul-de-sac of Douglas were most often affected. The ileocecal valve region was more likely to have large tumor masses on its surface than small bowel surface or small bowel mesentery. CONCLUSIONS: Peritoneal carcinomatosis had a wider distribution when mucinous fluid was present; this cancer distribution by intraperitoneal fluid hydrodynamics occurred regardless of histologic aggressiveness. The organs that have peritoneal fluid resorption (omentum and omental appendages) have a high incidence of implants. Small bowel and its mesentery free to move by peristalsis had a reduced incidence of implants as compared to the ileocecal area, which is fixed to the retroperitoneum. These observations may facilitate efforts to treat peritoneal surface malignancy.