Interleukin-15-armored GPC3-CAR T cells for patients with solid cancers.

Interleukin-15 (IL15) promotes the survival of T lymphocytes and enhances the antitumor properties of CAR T cells in preclinical models of solid neoplasms in which CAR T cells have limited efficacy1-4. Glypican-3 (GPC3) is expressed in a group of solid cancers5-10, and here we report the first evaluation in humans of the effects of IL15 co-expression on GPC3-CAR T cells. Cohort 1 patients (NCT02905188/NCT02932956) received GPC3-CAR T cells, which were safe but produced no objective antitumor responses and reached peak expansion at two weeks. Cohort 2 patients (NCT05103631/NCT04377932) received GPC3-CAR T cells that co-expressed IL15 (15.CAR), which mediated significantly increased cell expansion and induced a disease control rate of 66% and antitumor response rate of 33%. Infusion of 15.CAR T cells was associated with increased incidence of cytokine release syndrome, which was rapidly ameliorated by activation of the inducible caspase 9 safety switch. Compared to non-responders, tumor-infiltrating 15.CAR T cells from responders showed repression of SWI/SNF epigenetic regulators and upregulation of FOS and JUN family members as well as genes related to type I interferon signaling. Collectively, these results demonstrate that IL15 increases the expansion, intratumoral survival, and antitumor activity of GPC3-CAR T cells in patients.

Positive Yet Unequal Trends.

The American Cancer Society recently reported a second consecutive year of very positive data regarding cancer survival. Although the latest data may have been affected by pandemic-associated delays, the trend in the data indicates that the overall death rate from cancer in the United States continues to decline. The death rate from cancer has fallen 31% from 1991 to 2018, with an estimated 2.9 million fewer cancer deaths during that interval than would have occurred if death rates had remained at their peak level (based on five-year age-specific, sex-specific, and population-based data). Multiple factors have contributed to this improvement in cancer survival. For example, notable improvements in treatments for childhood cancers have resulted in overall survival increasing from 30% in the 1960s to greater than 80% in most high-income countries in 2020. In addition, vaccines against human papillomavirus are reducing cervical cancer risk, enhancement in breast cancer diagnosis and treatment have led to marked survival gains, and targeted therapies (e.g., immune checkpoint inhibitors) for malignant melanoma have increased long-term survival by 50% in some cases. However, other cancer types, such as pancreatic and brain, have seen lower levels of improvement.

Grommets and glue guns: standardization of a pfannenstiel model for low-fidelity obstetrics-gynecology education.

OBJECTIVE: To validate standardized instructions for the creation, implementation, and performance assessment of a low-fidelity model for Pfannenstiel incision. STUDY DESIGN: The Pfannenstiel model used at the University of Florida-Jacksonville was broken down into composite steps and constructed by obstetrics-gynecology faculty from across the country. The model was then utilized at participants' home institutions and evaluated with respect to realism of the model, ability to replicate the simulation, appropriateness of the skills checklists, and perceived utility of a publication of similarly catalogued simulation modules for use in obstetrics-gynecology training programs. RESULTS: The model was correctly constructed by 94.7% (18 of 19) participants and 72.2% (13 of 18) completed a post construction/post simulation survey indicating a high degree of perceived educational utility, feasibility of construction, and desire for additional catalogued modules. CONCLUSIONS: A low-fidelity simulation model was developed, successfully reproduced using inexpensive materials, and implemented across multiple training programs. This model can serve as a template for developing, standardizing and cataloging other low-fidelity simulations for use in resident education. As discussions among medical educators continue regarding further restrictions on duty hours, it is highly likely that more programs will be looking for guidance in establishing quick, inexpensive, and reliable means of developing and assessing surgical skills in their learners. Furthermore, the Accreditation Council for Graduate Medical Education (ACGME) has well-defined goals of programs developing better and more reproducible tools for all of their assessments. For programs with limited resources, preparing and disseminating reproducible, validated tools could be invaluable in complying with future ACGME mandates.

Medical education and indigent patient care.

The 20th century model of medical education has focused on a network of urban medical centers serving primarily indigent patients in an unspoken contract of medical services in exchange for student and resident education. The improvement in federal and state reimbursement for indigent care services, along with the decline in reimbursement rates from the private sector, has led to competition for these patients from nonacademic providers. As numbers of patients seeking care at urban teaching centers have steadily declined, concerns about adequate teaching volume and revenue generation have led to very creative problem-solving. Bringing marketing concerns into the indigent care environment is not a straightforward undertaking, but the rewards might far exceed the simple goal of "getting our numbers back up."

Graduate education in women's health care: where have all the young men gone?

The trend toward female gender-dominance in women's health care carries enormous implications for the specialty, patients, and the practice of medicine as a whole. It is unclear what "gates," if any, should be created/maintained to control gender dominance, but it is certain that a continued shift in specialty constituency will change the way health care is provided to women. It is doubtful that even the most thorough prognosticators will be able to identify these changes prospectively, but several concerns arise regarding the security of the specialty when current literature is reviewed.