Discoveries & Impact (June 2023)

Discoveries & Impact highlights select scientific discoveries across the Department of Internal Medicine...

A Potential New Biomarker for Immune Checkpoint Inhibitor-Related Insulin-Dependent Diabetes

Immune checkpoint inhibitors (ICIs) are a type of immunotherapy that helps the body attack cancer cells. Despite the dramatic improvement in survival for patients diagnosed with cancer, ICIs can also cause severe immune-related adverse events (irAEs), including insulin-dependent diabetes. A team of researchers led by Matthew Austin, MD, assistant professor of clinical medicine (medical oncology), and Harriet Kluger, MD, Harvey and Kate Cushing Professor of Medicine (Oncology) and Dermatology, conducted a study to determine the relationship between patients who develop insulin-dependent diabetes as an irAE and recurrent somatic and germline mutations.

Based on RNA and whole exome sequencing of tumors of 13 patients that developed ICI-related diabetes, researchers determined no differences in the expression of conventional type 1 autoantigens. However, the sequencing studies showed a missense mutation in the NLRC5 gene in tumors of the majority of patients with ICI-related diabetes that was not found in tumors of control patients. This mutation was determined to be germline and was not enriched in patients with type 1 diabetes relative to the general population, suggesting ICI-induced diabetes may have a different disease mechanism than that of type 1 diabetes. The NLRC5 mutation may serve as a predictive biomarker for this immune-related complication.

Read more in “Germline Genetic Variants are Associated with Development of Insulin-Dependent Diabetes in Cancer Patients Treated with Immune Checkpoint Inhibitors.”

Caulfield JI, Aizenbud L, Perdigoto AL, Meffre E, Jilaveanu L, Michalek DA, Rich SS, Aizenbud Y, Adeniran A, Herold KC, Austin MR, Kluger H. Germline genetic variants are associated with development of insulin-dependent diabetes in cancer patients treated with immune checkpoint inhibitors. Journal for ImmunoTherapy of Cancer 2023;11:e006570. doi: 10.1136/jitc-2022-006570

How to Improve Your Point-of-Care Ultrasound Teaching Sessions

Point-of-care ultrasound (POCUS) is the use of ultrasound to gather diagnostic information directly at or near where a patient is located. During POCUS teaching sessions, teachers observe their learners during bedside encounters and provide feedback. A recent article by Yale medical educators delves into strategies to improve POCUS education.

Before a POCUS teaching session, teachers should create clear learning objectives and set aside a realistic amount of time at the bedside. Teachers should also understand the learner’s skill level and adjust the lesson by, for example, selecting a patient without pathology for early learners and saving more challenging scans for advanced learners.

POCUS teaching sessions are the ideal time to teach image optimization. Teachers should remind the learner to optimize the machine, the patient, and the operator. Finally, teachers should make time to review the images with their learners after a session and provide feedback following the I-AIM framework. The I-AIM framework organizes feedback into four categories: the learner’s understanding of indications for POCUS, ability to acquire images, interpretation of images, and medical decision-making. Learn more key strategies in Medical Science Educator.

Donroe JH, Soares S, Sofair AN. Strategies to Improve Teaching Point-of-Care Ultrasound at the Bedside. Medical Science Educator [Internet]. 2023 Mar 17 [cited 2023 May 19], Available from: https://doi.org/10.1007/s40670-023-01772-5.

Hydroxyurea Use Not Associated with Second Cancer in MPN Patients

There is controversy surrounding whether using the medication hydroxyurea is associated with an increased risk of developing a second malignancy, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) among patients with certain bone marrow or blood cancers called myeloproliferative neoplasms (MPN), including polycythemia vera, essential thrombocythemia, and primary and secondary myelofibrosis. In general, it is known that patients with these myeloproliferative neoplasms are more likely to have secondary malignancies but how hydroxyurea, a common therapy for MPN, plays into this phenomenon is unclear.

The team, led by Nikolai Podoltsev, MD, PhD, retrospectively assessed a cohort of 4023 older patients with MPN and demonstrated that 489 of these patients had developed a secondary cancer. However, there were no significant differences in the incidence of solid or hematologic secondary malignancies between patients treated with hydroxyurea and those that were not treated with hydroxyurea.

Learn more about this study in Blood Advances.

Wang R, Shallis RM, Stempel JM, Huntington SF, Zeidan AM, Gore SD, Ma X, Podoltsev NA. Second malignancies among older patients with classical myeloproliferative neoplasms treated with hydroxyurea. Blood Adv. 2023 Mar 14;7(5):734-743. doi: 10.1182/bloodadvances.2022008259. PMID: 35917456; PMCID: PMC9989521.

Using Ideal Body Weight for LAmB Dosing in Pregnancy

Liposomal amphotericin B (LAmB) is a medication used to treat fungal and parasitic infections, such as leishmaniasis, and is considered safe for pregnant patients. However, there is a lack of clear guidelines on the best dosage for LAmB during pregnancy. In the Journal of Human Pharmacology and Drug Therapy, Yale researchers review the literature and describe their use of ideal body weight for dosing LAmB in the case of a pregnant patient with mucocutaneous leishmaniasis (MCL.)

This work builds on the efforts of a previous publication, “Mucocutaneous Leishmaniasis in a Pregnant Immigrant” which focused on the clinical and immunological aspects to the case. This sister paper provides the thoughtful insight into the broader dosing and monitoring of the medication during pregnancy.

The patient, in her third trimester of pregnancy, presented to the emergency department with skin lesions on the nose, forehead, and arm. Clinicians administered 5 mg/kg/day for the first seven days based on ideal body weight, followed by 4 mg/kg weekly using adjusted body weight. On day eight, the patient gave birth to a healthy male infant and treatment continued postpartum. The patient's skin lesions improved over the course of treatment, and no new lesions formed. This is the first case to report the treatment of MCL during pregnancy with LAmB.

Their findings suggest that using ideal body weight in LAmB dosing during pregnancy may reduce the risk of adverse effects on the fetus while effectively treating leishmaniasis. Read more in “Dosing implications for liposomal amphotericin B in pregnancy.”

O'Grady N, McManus D, Briggs N, Azar MM, Topal J, Davis MW. Dosing implications for liposomal amphotericin B in pregnancy. Pharmacotherapy. 2023 May;43(5):452-462. doi: 10.1002/phar.2784. Epub 2023 Mar 16. PMID: 36862037.

Left-ventricular Global Longitudinal Strain: Imaging to Predict Mortality in Systemic Sclerosis

A multidisciplinary group of physicians at Yale School of Medicine uncovered an association between impaired left-ventricular global longitudinal strain, as measured by cardiac magnetic resonance (CMR) imaging, and mortality in patients with systemic sclerosis. This study, led by Attila Feher, MD, PhD and Lauren A. Baldassarre, MD, in collaboration with Monique Hinchcliff, MD, MS, builds on previous knowledge that impaired cardiac strain can be seen in the autoimmune disease systemic sclerosis.

However, until this study, it was unknown whether abnormal strain was a negative prognostic factor for patient outcomes. In this retrospective review, consisting of 42 patients with systemic sclerosis, the authors demonstrate that patients within the highest quartile of impaired left ventricular global longitudinal strain by CMR had worse survival compared with those who had preserved strain, even when controlling for other risk factors. Mortality was further potentiated in those with both impaired left ventricular longitudinal strain and late gadolinium enhancement by CMR, compared to patients with only one of those imaging risk factors alone.

To learn more about this study, read in Rheumatology International.

Feher A, Miller EJ, Peters DC, Mojibian HR, Sinusas AJ, Hinchcliff M, Baldassarre LA. Impaired left-ventricular global longitudinal strain by feature-tracking cardiac MRI predicts mortality in systemic sclerosis. Rheumatol Int. 2023 May;43(5):849-858. doi: 10.1007/s00296-023-05294-6. Epub 2023 Mar 10. PMID: 36894756.