Discoveries & Impact (March 2023)

March 16, 2023

by Melanie Ho and Shin Mei Chan

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

Initiative at VA Hospital Improves Palliative Care Referrals for Heart Failure Patients

A new initiative from the VA Connecticut Healthcare System details the integration of integrating palliative care services with heart failure management teams. From October 2019 to September 2020, palliative care services were used in less than 7 percent of patients within the hospital.

The authors screened all patients admitted with heart failure from October 2020 and May 2021. Through a multi-disciplinary program, medicine teams caring for patients who met inclusion criteria were educated about palliative care. The effects were quantified via run charts, which demonstrated increased utilization of services. Through multiple iterations of the program via Plan-Do-Study-Act (PDSA) cycles, the authors identified an increase in palliative care referrals to 28 percent. Importantly, they noted a significant cultural shift whereby teams more regularly utilized palliative care for patients presenting with heart failure.

New Study Shows Appendiceal Cancer Associated w/ Better Prognosis Than Colon Cancer

Recently published in BMJ Open Gastroenterology, a team of researchers from Yale School of Medicine demonstrate patients with appendiceal cancer, a rare malignancy, is associated with greater survival rates compared to those with cecal adenocarcinoma, or colon cancer. In a population-based cohort, the Surveillance, Epidemiology, and End Results (SEER) database, the authors assessed 6491 and 99,387 patients with appendiceal and cecal adenocarcinoma, respectively. They showed that relative hazard ratios for death in the five-year period following diagnosis were higher in appendiceal cancer.

Other factors, including male sex, older age, earlier year of diagnosis, Black race, marital status, ethnicity, and histological characteristics were also associated with decreased survival rates. The authors also demonstrated that survival rates were likely associated with financial status and colorectal cancer screening rates within the individual’s counties.

This is the first study to demonstrate survival differences between appendiceal and colorectal malignancies. The authors suggest that socioeconomic factors should also be considered and further explored. To read more, read the article in BMJ Open Gastroenterology.

Chen G, Chen K, Sahyoun L, Zaman S, Protiva P. Appendiceal adenocarcinoma is associated with better prognosis than cecal adenocarcinoma: a population-based comparative survival study. BMJ Open Gastroenterol. 2023 Feb;10(1):e001045. doi: 10.1136/bmjgast-2022-001045. PMID: 36822658; PMCID: PMC9950880.

Researchers Demonstrate Altered Expression of Genes that Regulate Cerebral Spinal Fluid Production in a Preclinical Model of X-linked Hypophosphatemia

X-linked hypophosphatemia (XLH), the most common form of inherited rickets, is caused by overproduction of a hormone FGF23 that acts in the kidney to cause renal phosphate wasting and life-long hypophosphatemia that causes rickets in children and poor bone quality in adults. In addition to rickets, children with XLH frequently have cranial, spine and even spinal cord abnormalities. A team of researchers, led by Karl Insogna, MD, and Angeliki Louvi, PhD, sought to determine if altered cerebrospinal fluid (CSF) production could contribute to these debilitating complications. CSF is produced in the ventricles of the brain by the choroid plexus. The choroid plexus is called the “kidney of the brain” because many of the genes that regulate renal fluid and electrolyte transport are also expressed in the choroid plexus, including klotho, which is required for the actions of FGF23.

The authors quantified the level of expression Fgfr1c, the receptor for FGF23 and three key regulators of CSF production: Klotho, Atp1a1, and Slc12a2. They demonstrated a significant increase in expression of Klotho in the choroid plexus of the fourth compared to controls and a borderline significant reduction in the lateral ventricle. Expression of Atp1a1 was significantly suppressed in the lateral and third ventricles. Expression of Fgfr1c and Slc12a2 (the sodium/potassium/chloride cotransporter) were unchanged in all ventricles. The authors speculate that reduced ATP1a1-dependent CSF production, coupled with unaltered, or perhaps enhanced, Slc12a2 -mediated clearance, could impair CSF production in XLH. These data raise the possibility that altered CSF production occurs in XLH and contributes to the skeletal and spinal cord abnormalities mentioned above, a hypothesis that the authors contend warrants further study.

To read more about this topic, read “Altered Expression of Several Molecular Mediators of Cerebrospinal Fluid Production in Hyp Mice.”

Kaplan J, Tommasini S, Yao GQ, Zhu M, Nishimura S, Ghazarian S, Louvi A, Insogna K. Altered Expression of Several Molecular Mediators of Cerebrospinal Fluid Production in Hyp Mice. J Endocr Soc. 2023 Feb 6;7(4):bvad022. doi: 10.1210/jendso/bvad022. PMID: 36819458; PMCID: PMC9936957.

The Philips Recall: Advocating for Improved Medical Device Surveillance

A new editorial published in JAMA Internal Medicine outlines one of the largest medical device recalls in history, the contentious recall of more than 10 million invasive ventilators and positive airway pressure machines manufactured by Philips Respironics (Philips). These devices, most commonly used for obstructive sleep apnea and respiratory insufficiency, are ubiquitous and are used both in home and hospital settings.

The editorial details the chronological timeline of recall, beginning with initial clearance dating back to 2009. The U.S. Food and Drug Administration (FDA) did not require premarket or postmarket clinical studies for these devices. In 2021, following complaints of black particles within air circuits of devices using polyester-based polyurethane sound abatement foam, the recall was initiated amidst the COVID-19 pandemic. The story details until October 2022, following involvement of the FDA.

The authors detail recommendations for both physicians and the FDA, including calling on Philips to make amends for devices. Additionally, the authors call for more oversight and surveillance from the FDA. Further systemic reform to medical device regulation is necessary.

Read the editorial in JAMA Internal Medicine.

Kadakia KT, Ross JS, Rathi VK. The Philips Respironics Recall of Ventilators and Positive Airway Pressure Machines—Breakdowns in Medical Device Surveillance. JAMA Intern Med. 2023;183(1):5–8. doi:10.1001/jamainternmed.2022.5141

Age-associated Differences in Platelet Response

Platelets are best known for their roles in blood coagulation, and are not typically thought of as mediators of immunity; however, these cells express a full range of immune receptors and secrete cytokines, chemokines, antimicrobial peptides and numerous inflammatory mediators. With a lifespan of only 7-10 days, platelets have not been well studied for changes in function associated with age. In a new paper published in Aging Cell, researchers reported age-associated alterations in human platelet function at baseline and following influenza vaccination.

The team found markedly higher expression of RNAs associated with activation and signal transduction in platelets from community-dwelling older, versus young adults; even higher levels of such activation RNAs were found in platelets from older residents of skilled nursing facilities (SNFs), compared to community-dwelling older adults. The older adult SNF residents were highly enriched for the geriatric syndrome of frailty, while the community-dwelling older individuals were almost all non-frail. Distinct trajectories of RNA expression were found following influenza vaccination in the young, community-dwelling and SNF-resident older groups.

These findings are particularly notable since platelets develop from megakaryocytes and lack nuclei, and except for their mitochondria do not undergo transcription. These results implicate platelets in the chronic inflammation seen with aging that may also contribute to the increased incidence of thrombotic diseases in older adults. Read more in “Platelet response to influenza vaccination reflects effects of aging.”

Konstorum A, Mohanty S, Zhao Y, Melillo A, Vander Wyk B, Nelson A, Tsang S, Blevins TP, Belshe RB, Chawla DG, Rondina MT, Gill TM, Montgomery RR, Allore HG, Kleinstein SH, Shaw AC. Platelet response to influenza vaccination reflects effects of aging. Aging Cell. 2023 Feb;22(2):e13749. doi: 10.1111/acel.13749. Epub 2023 Jan 19. PMID: 36656789; PMCID: PMC9924941.

In BRCA-like Metastatic Breast Cancer, Addition of Veliparib Increases Progression-free Survival

A new randomized, double-blind, placebo-controlled phase 2 study published in Lancet Oncology reveals the addition of veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor to cisplatin chemotherapy significantly improves progression-free survival in patients with BRCA-like metastatic triple-negative breast cancer. This effect was not seen in non-BRCA-like cancers.

This multi-site multi-investigator trial was conducted by the SWOG clinical trial network Breast Cancer Research Committee that is chaired by Lajos Pusztai, MD, professor of medicine (medical oncology). It demonstrated in a cohort of 335 patients that patients with BRCA-like molecular features treated with cisplatin plus veliparib had median progression-free survival 5.9 months (95% CI 4.2-7.8), significantly higher than the cisplatin plus placebo group (HR = 0.79, 95% CI 0.38-1.67). This study indicates that PARP inhibitors may have benefit in a broader group of triple negative breast cancers not only in those with germline BRCA mutations. Read more about this study here.

Rodler E, Sharma P, Barlow WE, Gralow JR, Puhalla SL, Anders CK, Goldstein L, Tripathy D, Brown-Glaberman UA, Huynh TT, Szyarto CS, Godwin AK, Pathak HB, Swisher EM, Radke MR, Timms KM, Lew DL, Miao J, Pusztai L, Hayes DF, Hortobagyi GN. Cisplatin with veliparib or placebo in metastatic triple-negative breast cancer and BRCA mutation-associated breast cancer (S1416): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2023 Feb;24(2):162-174. doi: 10.1016/S1470-2045(22)00739-2. Epub 2023 Jan 6. PMID: 36623515; PMCID: PMC9924094. https://pubmed.ncbi.nlm.nih.gov/36623515/