Therapeutic cancer vaccines: are we there yet?

Enthusiasm for therapeutic cancer vaccines has been rejuvenated with the recent completion of several large, randomized phase III clinical trials that in some cases have reported an improvement in progression free or overall survival. However, an honest appraisal of their efficacy reveals modest clinical benefit and a frequent requirement for patients with relatively indolent cancers and minimal or no measurable disease. Experience with adoptive cell transfer-based immunotherapies unequivocally establishes that T cells can mediate durable complete responses, even in the setting of advanced metastatic disease. Further, these findings reveal that the successful vaccines of the future must confront: (i) a corrupted tumor microenvironment containing regulatory T cells and aberrantly matured myeloid cells, (ii) a tumor-specific T-cell repertoire that is prone to immunologic exhaustion and senescence, and (iii) highly mutable tumor targets capable of antigen loss and immune evasion. Future progress may come from innovations in the development of selective preparative regimens that eliminate or neutralize suppressive cellular populations, more effective immunologic adjuvants, and further refinement of agents capable of antagonizing immune check-point blockade pathways.     

Clinical whole-exome sequencing: are we there yet?

BackgroundClinical laboratories began offering whole-exome sequencing in 2011 at a cost between $4,500 and $9,000. Reported detection rates for deleterious mutations range from 25 to 50%. Based on the experience of our clinical genetics service, actual success rates may be lower than estimated rates. We report results from our own experience along with a survey of clinical geneticists to ascertain (i) current success rates for causal gene detection in a clinical setting; (ii) if there are insurance authorization issues; and (iii) if turnaround times quoted by the clinical laboratories are accurate; we also gauge provider opinions toward clinical whole-exome sequencing.MethodsWe reviewed our results and the results of a survey that was electronically distributed to 47 clinical genetics centers.ResultsA total of 35 exome reports were available. If all positive results are collated, we observe a success rate of 22.8%. One result incorrectly identified a known benign variant as pathogenic. Some insurers covered all testing, whereas others denied any insurance coverage. Only three (23.1%) of our reports were available within the laboratory’s quoted turnaround times. More than 50% of clinicians queried in our survey had not ordered whole-exome sequencing at the current time, many stating concerns regarding interpretation, insurance coverage, and cost.ConclusionClinical whole-exome sequencing has proven diagnostic utility; however, currently many clinicians have concerns regarding interpretation of results, insurance coverage, and cost.     

Medical informatics' promised land: are we there yet?

A decade ago, a "promised land" was envisioned in which the true potential of medical informatics would be realized. A decade later, it is time to assess academic medicine's progress in its journey into this medical informatics promised land. To that end, the author considers how our academic medical centers have been affected by changes in social, financial, and technical forces originating either "inside" or "outside" these institutions. He describes how the Internet and the World Wide Web have brought about an explosion in the availability of biomedical information, eased communication across the globe, made more information available at a lower cost, and changed the pace of everyday work. Although he argues that academic medical centers have not always kept pace with these changes, information systems are improving as the leaders in academic medicine come to appreciate the value of both information technology and the people who understand it. To reach the "promised land" envisioned a decade ago, academic medical centers must treat medical informatics as a central component of their academic mission.     

Resident duty hours reform: are we there yet?

In 2003, the Accreditation Council for Graduate Medical Education (ACGME) implemented resident duty hours restrictions to address growing concerns about medical errors and resident well-being. Many anticipated that resident duty hours restrictions would improve the quality and safety of care by minimizing the detrimental effects of fatigue on resident performance. Others were concerned that the fundamental clinical and educational principle of continuity of care would be lost or at least eroded, and that more frequent "hand-offs" might result in more clinical errors. Some lamented the loss of the total-emersion residency experience that serves as a forging process to temper the mind and body to create a finely honed clinician.The author draws from the literature to examine the effects of the ACGME resident duty hours restrictions three years after their implementation. From the perspectives of resident perceptions, attending perceptions, organizational approaches, and unintended consequences, the author concludes that far more than simple control of duty hours will be required to achieve the goals of clinical excellence, educational excellence, resident well-being, and professionalism.     

Biomarker-driven care in asthma: are we there?

Clinical asthma management is limited by the lack of straightforward and clinically applicable techniques to assess control and appropriately adjust therapy. The availability of biomarkers associated with airway caliber, responsiveness, or inflammation has prompted interest in the application of these measures as surrogate asthma end points in clinical trials. Use of a biomarker as a surrogate outcome in practice is most appropriate in settings in which the effects of therapy on clinical disease, as experienced by patients, are fully captured by that biomarker. Recent studies suggest that although asthma therapies can alter various biomarkers, the relationship between these biomarker changes and important clinical outcomes is inconsistent. Because symptom-driven titration of therapy is feasible and effective, additional data demonstrating clinically important benefits of biomarker-driven care in asthma are needed to justify the logistic and economic burdens associated with clinical dissemination of these techniques.     

Biologic immune modifiers: Trials and tribulations—are we there yet?

The first mAb (OKT3) was approved for the treatment of allograft rejection in 1986, and was all mouse protein. Now virtually all new mAbs are humanized. However, most of the growing numbers of mAbs entering clinical trials are completely human. Two technological advances have made it possible to design all human mAb for the treatment of disease: phage display technology and transgenic mice that express human immunoglobulin genes. For example, adalimumab is a human anti–TNF-α mAb derived from phage-display technology for the treatment of rheumatoid arthritis and psoriatic arthritis. A key advantage of mAb and recombinant protein conjugates is that their properties can be modified, even endowing them with new activities through advances in molecular biology. Even in 1 year, there have been many advances in the use of biologics as therapeutic modalities, especially in autoimmune disease and in the treatment of cancers. More than 150 mAbs are currently in clinical development. Over the next 5 years, we will see the development of designer mAbs for the treatment of a variety of disease processes.So, “are we there yet?” Omalizumab is an effective and safe biologic immune modifier for patients with severe allergic asthma. As discussed in this article, there are other mAb and fusion proteins that are in phase II studies (Table I). However, asthma is a complex immunologic and inflammatory disease. Even in those patients who are atopic, a variety of triggers can worsen the disease. As we have seen with mAb to IL-5 and soluble IL-4 receptor, clinical results have been limited. Thus, targeting a single cytokine may not work well in the treatment of a complex inflammatory process like asthma, but may require a cocktail of mAbs.⁵⁰ However, TNF-α blockade does look promising in patients with severe asthma.^{29, 30 and 31} Over the next 5 years, as we learn from other inflammatory and autoimmune diseases how to modulate the inflammatory and immune pathways with mAb and fusion proteins, these new treatment approaches will be extrapolated for the treatment of asthma and other allergic diseases, and ideally will be both effective and safe.     

Personalized medicine – the promised land: are we there yet?

The delivery of personalized genomic medicine (refer Table 1 for a comparison of genomic vs genetic medicine and box 1 for glossary) hinges on obtaining personal genomic data through genome-wide association studies (GWAS) or whole-genome sequencing. After the completion of the human genome project (see box 2 for human genome projects and its derivative projects) in 2003, there appeared to be a period of euphoric optimism that as soon as the cost of sequencing the whole human genome could be brought down to an affordable range, the promise of personalized medicine would become a reality. However, inasmuch as the miraculous technological advancements are making whole-genome data acquisition an inexpensive reality, we are also starting to appreciate that making sense of the enormous amount of genomic data is a far bigger hurdle. Issues, both scientific and ethico-legal, will have to be addressed as genomic data are been pushed for clinical and direct-to-consumer utilization. [Table: see text].     

Live-attenuated Salmonella as a prototype vaccine vector for passenger immunogens in humans: are we there yet?

It has been nearly 20 years since the first Phase I clinical trial of a live-attenuated bacterial vaccine was created by recombinant DNA methods, opening the door to the use of these organisms as mucosal delivery vehicles for passenger antigens. Over this time, a number of animal studies have indicated the feasibility of this approach. These include studies showing that bacteria can deliver antigens expressed by the bacterium itself and that bacteria can deliver DNA vaccines to be expressed in target eukaryotic cells. Concomitant studies have identified a number of attenuating mutations that render the bacterial vectors both safe and immunogenic in humans. Both avenues of research indicate the significant promise of this approach to mucosal vaccine development; however, this promise remains largely unrealized at the level of human clinical trials. This review sketches the history of this problem and points toward possible solutions using Salmonella vaccine vectors as the prototypes.     

Why are there defaulters in eye health projects?

PURPOSE:

To identify barriers to attendance for eye examination of schoolchildren.

METHODS:

Cross-sectional study. Students in grades 1-4 in elementary school in Guarulhos (Brazil) were screened and referred for ophthalmic examination in 2006. Facilities offered in this project were: examination arranged during weekends, free transportation, spectacle donation and two different opportunities for exam. A questionnaire was applied, by interview, to a sample consisted of students'' parents attended in a community project who missed the first call and attended the recall, to identify the reasons for non-attendance.

RESULTS:

The sample consisted of 767 parents or guardians, corresponding to an equal number of schoolchildren. Personal characteristics of the students: 49.2% male and 50.8% female, 60.2% of them had never received previous ophthalmologic evaluation. Reported reasons for no-show to the project: parents had not received appropriate orientation (35.6%), loss of working day (20.6%), illness (12.4%), had another appointment (10.0%). The need for eyeglasses was higher in the recall.

CONCLUSIONS:

A significant number of parents did not take their children for ophthalmological exams, even when a second opportunity was offered in projects with transportation facilities, free exams performed during weekends and spectacle donation. The main causes of absenteeism were lack of awareness and work. For 87.1% of the absenteeism cases, the difficulties could be overcome via improved structuring of the first call. A recall increases attendance coverage of target population by only 15.2% (59.3 to 74.5%). Notably, the eye exam campaign was the first exam for most of the absent students.