Characterization of Comorbidities Limiting the Recruitment of Patients in Early Phase Clinical Trials.

BACKGROUND: Early phase clinical trials evaluate the safety and efficacy of new treatments. The exclusion/inclusion criteria in these trials are usually rigorous and may exclude many patients seen in clinical practice. Our objective was to study the comorbidities limiting the participation of patients with breast, colorectal, or lung cancer in clinical trials. MATERIALS AND METHODS: We queried ClinicalTrials.gov on December 31, 2016. We reviewed the eligibility criteria of 1,103 trials. Logistic regression analyses were completed, and exclusion was studied as a binary variable. RESULTS: Out of 1,103 trials, 70 trials (6%) excluded patients >75 years of age, and 45% made no reference to age. Eighty-six percent of trials placed restrictions on patients with history of prior malignancies. Regarding central nervous system (CNS) metastasis, 416 trials (38%) excluded all patients with CNS metastasis, and 373 (34%) only allowed asymptomatic CNS metastasis. Regarding chronic viral infections, 347 trials (31%) excluded all patients with human immunodeficiency virus, and 228 trials (21%) excluded all patients with hepatitis B or C infection. On univariate analysis, chemotherapy trials were more likely to exclude patients with CNS metastasis and history of other malignancies than targeted therapy trials. Multivariate analysis demonstrated that industry-sponsored trials had higher odds of excluding patients with compromised liver function. CONCLUSION: Many clinical trials excluded large segments of the population of patients with cancer. Frequent exclusion criteria included patients with CNS metastasis, history of prior malignancies, and chronic viral infections. The criteria for participation in some clinical trials may be overly restrictive and limit enrollment. IMPLICATIONS FOR PRACTICE: The results of this study revealed that most early phase clinic trials contain strict exclusion criteria, potentially excluding the patients who may be more likely to represent the population treated in clinical settings, leaving patients susceptible to unintended harm from inappropriate generalization of trial results. Careful liberalization of the inclusion/exclusion criteria in clinical trials will allow investigators to understand the benefits and drawbacks of the experimental drug for a broader population, and possibly improve recruitment of patients with cancer into clinical trials.

Representation of Minorities and Elderly Patients in Multiple Myeloma Clinical Trials.

Multiple myeloma (MM) occurs in all races, but the incidence in non-Hispanic black patients (NHBs) is two to three times higher than in non-Hispanic white patients (NHWs). We determined the representation of minorities and elderly patients in MM clinical trials. Enrollment data from all therapeutic trials reported in ClinicalTrials.gov from 2000 to 2016 were analyzed. Enrollment fraction (EF) was defined as the number of trial enrollees divided by the 2014 MM prevalence. Participation in MM clinical trials varied significantly across racial and ethnic groups; NHWs were more likely to be enrolled in clinical trials (EF 0.18%) than NHBs (EF 0.06%, p < .0001) and Hispanic patients (EF 0.04%, p < .0001). The median age of trial participants was 62 years, with 7,956 participants (66%) being less than 65 years of age. Collaborations between investigators, sponsors, and the community are necessary to increase access to clinical trials to our minority and elderly patients.

Renal sympathetic denervation in the treatment of resistant hypertension.

Arterial hypertension (HTN) is a major health problem worldwide. Treatment-resistant hypertension (trHTN) is defined as the failure to achieve target blood pressure despite the concomitant use of maximally tolerated doses of three different antihypertensive medications, including a diuretic. trHTN is associated with considerable morbidity and mortality. Renal sympathetic denervation (RDn) is available and implemented abroad as a strategy for the treatment of trHTN and is currently under clinical investigation in the United States. Selective renal sympathectomy via an endovascular approach effectively decreases renal sympathetic nerve hyperactivity leading to a decrease in blood pressure. The Symplicity catheter, currently under investigation in the United States, is a 6-French compatible system advanced under fluoroscopic guidance via percutaneous access of the common femoral artery to the distal lumen of each of the main renal arteries. Radiofrequency (RF) energy is then applied to the endoluminal surface of the renal arteries via an electrode located at the tip of the catheter. Two clinical trials (Symplicity HTN 1 and Symplicity HTN 2) have shown the efficacy of RDn with a post-procedure decline of 27/17 mmHg at 12 months and 32/12 mmHg at 6 months, respectively, with few minor adverse events. Symplicity HTN-3 study is a, multi-center, prospective, single-blind, randomized, controlled study currently under way and will provide further insights about the safety and efficacy of renal denervation in patients with trHTN.

Integrated analysis of next generation sequencing minimal residual disease (MRD) and PET scan in transplant eligible myeloma patients.

Minimal residual disease (MRD) assays allow response assessment in patients with multiple myeloma (MM), and negativity is associated with improved survival outcomes. The role of highly sensitive next generation sequencing (NGS) MRD in combination with functional imaging remains to be validated. We performed a retrospective analysis on MM patients who underwent frontline autologous stem cell transplant (ASCT). Patients were evaluated at day 100 post-ASCT with NGS-MRD and positron emission tomography (PET-CT). Patients with ≥ 2 MRD measurements were included in a secondary analysis for sequential measurements. 186 patients were included. At day 100, 45 (24.2%) patients achieved MRD negativity at a sensitivity threshold of 10-6. MRD negativity was the most predictive factor for longer time to next treatment (TTNT). Negativity rates did not differ according to MM subtype, R-ISS Stage nor cytogenetic risk. PET-CT and MRD had poor agreement, with high rates of PET-CT negativity in MRD-positive patients. Patients with sustained MRD negativity had longer TTNT, regardless of baseline risk characteristics. Our results show that the ability to measure deeper and sustainable responses distinguishes patients with better outcomes. Achieving MRD negativity was the strongest prognostic marker and could help guide therapy-related decisions and serve as a response marker for clinical trials.

Methicillin-resistant Staphylococcus aureus bacteraemia and endocarditis treated with ceftaroline salvage therapy.

BACKGROUND: One of the newest methicillin-resistant Staphylococcus aureus (MRSA) antibiotics to receive FDA approval is ceftaroline fosamil, a member of a new subclass of cephalosporins with unique activity against MRSA. However, ceftaroline is currently only FDA approved for complicated skin/soft tissue infections and community-acquired pneumonia; there are currently no clinical data regarding its use in MRSA bacteraemia and endocarditis. We report a series of six patients in which ceftaroline was utilized as salvage monotherapy in persistent MRSA bacteraemia or endocarditis. METHODS: Using pharmacy records, 11 ceftaroline-treated patients were identified between January 2011 and November 2011 at University Health System and the South Texas Veterans Health Care System in San Antonio, TX, USA. All cases were reviewed and six patients received ceftaroline therapy for MRSA bacteraemia or endocarditis due to persistent or recurrent bacteraemia while on standard antibiotics (vancomycin or daptomycin). RESULTS: All six patients experienced rapid clearance of their bacteraemia after starting ceftaroline. In the case of endocarditis for which the patient subsequently developed heart failure and required valve replacement, there was no evidence of growth from cultures taken from the excised valve, suggesting sterilization within 13 days of starting ceftaroline. CONCLUSIONS: Ceftaroline exhibits potent anti-MRSA activity in both in vitro and animal studies, including rabbit endocarditis models; however, the lack of clinical data has limited its use in bacteraemia and endovascular infections in humans. We hope that this series serves as an initial stepping stone for further evaluation of this compound for more invasive infections due to MRSA.

Causes of Death After Neuroendocrine Tumors Diagnosis: A US Population-Based Analysis.

OBJECTIVE: In this study, we aimed to determine the cause of death (COD) after the diagnosis of neuroendocrine tumors (NET). METHODS: We used the Surveillance, Epidemiology and End Results (SEER) Program to review patients diagnosed with NET during 2000 to 2016. Patients were followed until death, and different CODs were determined. RESULTS: Of 94,399 patients with NETs, 40.9% died during the study period. During the first year of diagnosis, most deaths were from NETs (73%), followed by other cancers (11.2%) and cardiac diseases (4.6%). After more than 10 years, NET deaths decreased to 24.3%, whereas other cancers and cardiac disease became more common. Neuroendocrine tumors were responsible for 42.8%, 63.4%, and 81.2% of deaths in grade I, grade II, and grade III, respectively. For grade I localized NET, other cancers (22.2%) were the most common COD followed by NET (19.7%), whereas in grade 2 localized NET, NET was COD in 31.1% of cases followed by other cancers (22.4%). In metastatic disease, NET was the most common COD regardless of grade. CONCLUSIONS: For low-grade localized NET, deaths were mostly secondary to non-NET causes. In contrast, NET is responsible for most of deaths in metastatic NET regardless of grade.

Association of Concomitant Bone Resorption Inhibitors With Overall Survival Among Patients With Metastatic Castration-Resistant Prostate Cancer and Bone Metastases Receiving Abiraterone Acetate With Prednisone as First-Line Therapy.

Importance: Bone resorption inhibitors (BRIs) are recommended by international guidelines to prevent skeletal-related events (SREs) among patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. Abiraterone acetate with prednisone is currently the most common first-line therapy for the treatment of patients with mCRPC; however, the clinical impact of the addition of BRIs to abiraterone acetate with prednisone in this disease setting is unknown. Objective: To evaluate the association of the use of concomitant BRIs with overall survival (OS) and time to first SRE among patients with mCRPC and bone metastases receiving abiraterone acetate with prednisone as first-line therapy. Design, Setting, and Participants: This retrospective cohort study collected data from 745 consecutive patients who began receiving abiraterone acetate with prednisone as first-line therapy for mCRPC with bone metastases between January 1, 2013, and December 31, 2016. Data were collected from 8 hospitals in Canada, Europe, and the US from June 15 to September 15, 2019. Exposures: Patients were classified by receipt vs nonreceipt of concomitant BRIs and subclassified by volume of disease (high volume or low volume, using definitions from the Chemohormonal Therapy Vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer [CHAARTED] E3805 study) at the initiation of abiraterone acetate with prednisone therapy. Main Outcomes and Measures: The primary end point was OS. The secondary end point was time to first SRE. The Kaplan-Meier method and Cox proportional hazards models were used. Results: Of the 745 men (median age, 77.6 years [interquartile range, 68.1-83.6 years]; 699 White individuals [93.8%]) included in the analysis, 529 men (71.0%) received abiraterone acetate with prednisone alone (abiraterone acetate cohort), and 216 men (29.0%) received abiraterone acetate with prednisone plus BRIs (BRI cohort). A total of 420 men (56.4%) had high-volume disease, and 276 men (37.0%) had low-volume disease. The median follow-up was 23.5 months (95% CI, 19.8-24.9 months). Patients in the BRI cohort experienced significantly longer OS compared with those in the abiraterone acetate cohort (31.8 vs 23.0 months; hazard ratio [HR], 0.65; 95% CI, 0.54-0.79; P < .001). The OS benefit in the BRI cohort was greater for patients with high-volume vs low-volume disease (33.6 vs 19.7 months; HR, 0.51; 95% CI, 0.38-0.68; P < .001). The BRI cohort also had a significantly shorter time to first SRE compared with the abiraterone acetate cohort (32.4 vs 42.7 months; HR, 1.27; 95% CI, 1.00-1.60; P = .04), and the risk of a first SRE was more than double in the subgroup with low-volume disease (HR, 2.29; 95% CI, 1.57-3.35; P < .001). In the multivariable analysis, concomitant BRIs use was independently associated with longer OS (HR, 0.64; 95% CI, 0.52-0.79; P < .001). Conclusions and Relevance: In this study, the addition of BRIs to abiraterone acetate with prednisone as first-line therapy for the treatment of patients with mCRPC and bone metastases was associated with longer OS, particularly in patients with high-volume disease. These results suggest that the use of BRIs in combination with abiraterone acetate with prednisone as first-line therapy for the treatment of mCRPC with bone metastases could be beneficial.

Treatment of Smoldering Multiple Myeloma: Expectant Observation Should Still Be the Standard.

Recent clinical trials have addressed the notion of early treatment of smoldering multiple myeloma (SMM). The results evidence improvement in progression-free survival and, in one study, overall survival. Although the treatment of SMM can be considered under specific circumstances, we propose here that careful interpretation of the clinical trials and the patient-specific data are needed before recommending therapy. In particular, many questions remain regarding the best regimen to be used as well as how to adapt based on the underlying disease biology. Hematologists should have a very thorough understanding of models designed to predict the progression from SMM to multiple myeloma, because their correct interpretation is paramount to establish proper care. Although there is no doubt that treatment should be started before overt end-organ damage, we do not believe that the current data support the widespread treatment of all SMM.

Limitations in Clinical Trials Leading to Anticancer Drug Approvals by the US Food and Drug Administration.

Importance: While there have been multiple assessments of clinical trials leading to anticancer drug approvals by the US Food and Drug Administration (FDA), the cumulative percentage of approvals based on trials with a limitation remains uncertain. Objective: To assess the percentage of clinical trials with limitations in 4 domains-lack of randomization, lack of significant overall survival advantage, inappropriate use of crossover, and use of suboptimal control arms-that led to FDA approvals from June 30, 2014, to July 31, 2019. Design, Setting, and Participants: This observational analysis included all anticancer drug indications approved by the FDA from June 30, 2014, through July 31, 2019. All indications were investigated, and each clinical trial was evaluated for design, enrollment period, primary end points, and presence of a limitation in the domains of interest. The standard-of-care therapy was determined by evaluating the literature and published guidelines 1 year prior to the start of clinical trial enrollment. Crossover was examined and evaluated for optimal use. The percentage of approvals based on clinical trials with any or all limitations of interest was then calculated. Main Outcomes and Measures: Estimated percentage of clinical trials with limitations of interest that led to an anticancer drug marketing authorization by the FDA. Results: A total of 187 trials leading to 176 approvals for 75 distinct novel anticancer drugs by the FDA were evaluated. Sixty-four (34%) were single-arm clinical trials, and 123 (63%) were randomized clinical trials. A total of 125 (67%) had at least 1 limitation in the domains of interest; 60 of the 125 trials (48%) were randomized clinical trials. Of all 123 randomized clinical trials, 37 (30%) lacked overall survival benefit, 31 (25%) had a suboptimal control, and 17 (14%) used crossover inappropriately. Conclusions and Relevance: Two-thirds of cancer drugs are approved based on clinical trials with limitations in at least 1 of 4 essential domains. Efforts to minimize these limitations at the time of clinical trial design are essential to ensure that new anticancer drugs truly improve patient outcomes over current standards.

Racial/ethnic differences in patients with anemia and folate deficiency.

OBJECTIVE: To determine the presence of racial/ethnic differences in patients with anemia and serum folate deficiency. METHODS: We performed a retrospective analysis of data from patient samples collected from January 2010 to October 2018. Reference laboratory ranges were determined by Mayo Clinic Reference Laboratories. Race and ethnicity were classified according to National Institutes of Health categories. RESULTS: The analysis comprised 197 974 samples. Hemoglobin, hematocrit, and SF results were available for 173 337, 173 056, and 129 760 samples, respectively. Of the samples, 46 505 (26.8%) showed anemia, with a higher prevalence among American Indian/Alaskan Natives (AI/AN) 42.9% and African Americans (AA) 47.2% (P < .001). SF deficiency was present in 897 (0.7%), with a higher prevalence among AI/AN (9, [1.4%]) and AA (78, [1.2%]) and a lower prevalence in non-Hispanic whites (NHW) (758, [0.7%]), Hispanics (40, [0.6%]), and Asians (8, [0.3%]). In multivariable analysis, the prevalence of anemia was higher in all non-NHW racial/ethnic groups: AA (OR, 3.67, [95%CI: 3.47-3.88, P < .001]), AI/AN (OR, 3.25, [95%CI: 2.71-3.90, P < .001]), Asians (OR, 1.62, [95%CI: 1.47-1.77, P < .001]), and Hispanics (OR, 1.41, [95%CI: 1.32-1.50, P < .001]). SF deficiency was more common in AA (OR, 1.48, [95%CI: 1.17-1.88, P.001]) and less common in Asians (OR, 0.35, [95%CI: 0.17-0.70, P = .003]), compared with NHW. CONCLUSIONS: We showed significant racial/ethnic differences in anemia and SF deficiency. Differences were observed especially among NHW, AA, and Asians. We believe that these differences may be explained by social determinants of health. More research is needed regarding the causes of these differences and their clinical implications at a population level.

Evaluating Unconscious Bias: Speaker Introductions at an International Oncology Conference.

PURPOSE: In a professional setting, the introduction of female speakers without their professional title may have an impact on the public's perception of the female speaker. We examined how professional titles were used during speakers' introductions at the ASCO Annual Meeting. METHODS: We conducted a retrospective, observational study of video-archived speaker introductions at the 2017 and 2018 ASCO Annual Meetings. A "professional address" was defined as the professional title followed by the speaker's full name or last name. Multivariable logistic regressions were used to identify factors associated with the form of address. RESULTS: Of 2,511 videos reviewed, 781 met inclusion criteria. Female speakers were addressed less often by their professional title compared with male speakers (62% v 81%; P < .001). Males were less likely to use a professional address when introducing female speakers compared with females when introducing male speakers (53% v 80%; P < .01). When women performed speaker introductions, no gender differences in professional address were observed (75% v 82%; P = .13). Female speakers were more likely to be introduced by first name only (17% v 3%; P < .001). Male introducers were more likely to address female speakers by first name only compared with female introducers (24% v 7%; P < .01). In a multivariable regression including gender, degree, academic rank, and geographic location of the speaker's institution, male speakers were more likely to receive a professional address compared with female speakers (odds ratio, 2.43; 95% CI, 1.71 to 3.47; P < .01). CONCLUSION: When introduced by men, female speakers were less likely to receive a professional address and more likely to be introduced by first name only compared with their male peers.

Representation of Minorities and Women in Oncology Clinical Trials: Review of the Past 14 Years.

PURPOSE: Many cancer clinical trials lack appropriate representation of specific patient populations, limiting their generalizability. Therefore, we determined the representation of ethnic minorities and women in cancer clinical trials. METHODS: Enrollment data from all therapeutic trials reported as completed in ClinicalTrials.gov from 2003 to 2016 were analyzed. We calculated enrollment fractions (EFs) for each group, defined as the number of enrollees divided by the 2013 Surveillance, Epidemiology, and End Results (SEER) database cancer prevalence. RESULTS: Of 1,012 clinical trials, 310 (31%) reported ethnicity with a total of 55,689 enrollees. Participation varied significantly across ethnic groups. Non-Hispanic whites were more likely to be enrolled in clinical trials (EF, 1.2%) than African Americans (EF, 0.7%; P < .001) and Hispanics (EF, 0.4%; P < .001). A decrease in African American (6% v 9.2%) and Hispanic (2.6% v 3.1%) enrollment was observed when compared with historical data from 1996 to 2002. Younger patients (age younger than 65 years) were more likely to be enrolled in clinical trials than the elderly (64% v 36%; P < .001). Low recruitment of female patients was observed in clinical trials for melanoma (35%), lung cancer (39%), and pancreatic cancer (40%). CONCLUSION: We observed a decrease in recruitment of minorities over the past 14 years compared with historical data. African Americans, Hispanics, and women were less likely to be enrolled in cancer clinical trials. Future trials should take extra measures to recruit participants that adequately represent the US cancer population.

Sir William Osler. Desde el nacimientode los hospitales universitarioshasta la satisfacción por lamedicina moderna / Sir William Osler. From the beginning of the university hospitals, to the satisfaction for modern medicine

William Osler es uno de los médicos con más influencia e importancia en la historia de la medicina. Su influencia abarca varios campos: el clínico, el educativo, el literario, elinvestigativo, e incluso el filosófico. Muchos de sus métodos de estudio son aun utilizados en muchasescuelas de medicina, y también sus enseñanzas son aplicables a la práctica de la medicina actual.Biólogo, patólogo, internista, profesor, observador clínico, autor, bibliófilo, historiador y amante de su profesión, Sir William Osler revolucionó el sistema de enseñanza de la medicina y creó el primer hospital universitarioen Estados Unidos hace más de 100 años. La grandeza del pensamiento de Osler, su reverencia por losestudiantes y los pacientes, lo convierte en un personajedigno del recuerdo. Osler, a pesar de los pocos tratamientosefectivos que poseía (lo que su época tenía), creía que los médicos podían encontrar satisfacción en su practicade la medicina y podían ayudar a los pacientes a curar, oal menos a tener una mejor calidad de vida, teniendo la mente abierta, siendo creativos y artistas científicos, másque intercambiadores de servicios.

William Osler is one of the most influent and important physicians in the history of medicine.His influence covers many fields, as clinical practice, education, literature, research, even philosophy. Many of his teachings are still used in many medical schools over the world, as theyare still practiced in actual medicine. Biologist, pathologist, internist, teacher, clinical observer,author, bibliophile, historian, and a lover of his profession, Sir William Osler revolved the teachingof medicine in the United States, and createdthe first university hospital more than 100 years ago. The greatness of his thoughts, his reverencefor the students and patients, convertshim in a person worth remembering. Besides the few effective treatments of time, Osler believedthat physicians could find satisfaction in their practice, and that they could cure patients, and helps them have a better quality of life, by beingopen minded, creative and scientific artists, more than exchangers of services.