Elevated liver enzymes at the time of deceased donor organ donation do not affect recipient or pancreas allograft survival following pancreas transplantation.

BACKGROUND: There is a lack of data on the impact of donor liver function tests (LFTs) on pancreas transplantation outcomes. Understanding their contribution could expand the donor pool. METHODS: Using the UNOS database, data from January 2010-2022 was retrospectively analyzed. Multivariable cox regressions were performed to evaluate the association between LFTs (AST, ALT and total bilirubin levels), graft failure and mortality up to three years post-transplant. RESULTS: 9138 pancreas transplants were completed. Multivariate analysis showed no association between donor AST values > 500 U/L and increased rates of graft failure (p = 0.826) or mortality (p = 0.836). Similar findings were noted for donor ALT values > 500 U/L (p = 0.522 and p = 0.997, respectively). There was no correlation with graft failure (p = 0.322) or mortality (p = 0.423) for total bilirubin levels >3 mg/dL. CONCLUSION: LFTs in the deceased pancreas donor did not increase risk of graft failure or mortality following pancreas transplantation. Elevated LFTs should not serve as absolute contraindications to transplant.

Increased CMV disease and "severe" BK viremia with belatacept vs. sirolimus three-drug maintenance immunosuppression.

OBJECTIVES: Belatacept may provide benefit in delayed graft function, but its association with infectious complications is understudied. We aim to assess the incidence of CMV and BK viremia in patients treated with sirolimus or belatacept as part of a three-drug immunosuppression regimen after kidney transplantation. MATERIALS AND METHODS: Kidney transplant recipients from 01/01/2015 to 10/01/2021 were retrospectively reviewed. Maintenance immunosuppression was either tacrolimus, mycophenolate and sirolimus (B0) or tacrolimus, mycophenolate, and belatacept (5.0 mg/kg monthly) (B1). Primary outcomes of interest were BK and CMV viremia which were followed until the end of the study period. Secondary outcomes included graft function (serum creatinine, eGFR) and acute rejection through 12 months. RESULTS: Belatacept was initiated in patients with a higher mean kidney donor profile index (B0:0.36 vs. B1:0.44, p = .02) with more delayed graft function (B0:6.1% vs. B1:26.1%, p < .001). Belatacept therapy was associated with more "severe" CMV viremia >25,000 copies/mL (B0:1.2% vs. B1:5.9%, p = .016) and CMV disease (B0:0.41% vs. B1:4.2%, p = .015). However, there was no difference in the overall incidence of CMV viremia >200 IU/mL (B0:9.4% vs. B1:13.5%, p = .28). There was no difference in the incidence of BK viremia >200 IU/mL (B0:29.7% vs. B1:31.1%, p = .78) or BK-associated nephropathy (B0:2.4% vs. B1:1.7%, p = .58), but belatacept was associated with "severe" BK viremia, defined as >10,000 IU/mL (B0:13.0% vs. B1:21.8%, p = .03). The mean serum Cr was significantly higher with belatacept therapy at 1-year follow up (B0:1.24 mg/dL vs. B1:1.43 mg/dL, p = .003). Biopsy-proven acute rejection (B0:1.2% vs. B1:2.6%, p = .35) and graft loss (B0:1.2% vs. B1:0.84%, p = .81) were comparable at 12 months. CONCLUSIONS: Belatacept therapy was associated with an increased risk of CMV disease and "severe" CMV and BK viremia. However, this regimen did not increase the overall incidence of infection and facilitated comparable acute rejection and graft loss at 12-month follow up.

Potential renal stem/progenitor cells identified by in vivo lineage tracing.

Mammalian kidneys consist of more than 30 different types of cells. A challenging task is to identify and characterize the stem/progenitor subpopulations that establish the lineage relationships among these cellular elements during nephrogenesis in the embryonic and neonate kidneys and during tissue homeostasis and/or injury repair in the mature kidney. Moreover, the potential clinical utility of stem/progenitor cells holds promise for the development of new regenerative medicine approaches for the treatment of renal diseases. Stem cells are defined by unlimited self-renewal capacity and pluripotentiality. Progenitor cells have pluripotentiality but no or limited self-renewal potential. Cre-LoxP-based in vivo genetic lineage tracing is a powerful tool to identify stem/progenitor cells in their native environment. Hypothetically, this technique enables investigators to accurately track the progeny of a single cell or a group of cells. The Cre/LoxP system has been widely used to uncover the function of genes in various mammalian tissues and to identify stem/progenitor cells through in vivo lineage tracing analyses. In this review, we summarize the recent advances in the development and characterization of various Cre drivers and their use in identifying potential renal stem/progenitor cells in both developing and mature mouse kidneys.

Targeting myeloid-derived suppressor cells using a novel adenosine monophosphate-activated protein kinase (AMPK) activator.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of early myeloid cells that accumulate in the blood and tumors of patients with cancer. MDSC play a critical role during tumor evasion and promote immune suppression through variety of mechanisms, such as the generation of reactive oxygen and nitrogen species (ROS and RNS) and cytokines. AMPactivated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that regulates energy homeostasis and metabolic stress. However, the role of AMPK in the regulation of MDSC function remains largely unexplored. This study was designed to investigate whether treatment of MDSC with OSU-53, a PPAR-inactive derivative that stimulates AMPK kinase, can modulate MDSC function. Our results demonstrate that OSU-53 treatment increases the phosphorylation of AMPK, significantly reduces nitric oxide production, inhibits MDSC migration, and reduces the levels of IL-6 in murine MDSC cell line (MSC2 cells). OSU53 treatment mitigated the immune suppressive functions of murine MDSC, promoting T-cell proliferation. Although OSU-53 had a modest effect on tumor growth in mice inoculated with EMT-6 cells, importantly, administration of OSU53 significantly (p < 0.05) reduced the levels of MDSC in the spleens and tumors. Furthermore, mouse MDSC from EMT-6 tumor-bearing mice and human MDSC isolated from melanoma patients treated with OSU-53 showed a significant reduction in the expression of immune suppressive genes iNOS and arginase. In summary, these results demonstrate a novel role of AMPK in the regulation of MDSC functions and provide a rationale of combining OSU-53 with immune checkpoint inhibitors to augment their response in cancer patients.

A case of a pseudo colonic mass causing gastrointestinal bleeding in a patient with a left ventricular assist device.

There are many complications associated with the left ventricular assist devices (LVADs), including gastrointestinal bleeding (GIB). We present a case of a pseudo colonic mass visualized on colonoscopy during workup for GIB in an LVAD patient necessitating a right colectomy with final pathology negative for malignancy. A review of the literature in regards to the pathology, diagnosis, and treatment of this interesting condition is included.

A novel dual AMPK activator/mTOR inhibitor inhibits thyroid cancer cell growth.

CONTEXT: Activated AMP protein kinase (AMPK) is a key regulator of intracellular energy homeostasis and may also function as a tumor suppressor by inhibiting cell growth through suppression of mammalian target of rapamycin (mTOR)/p70S6K signaling. AMPK activating agents, such as metformin and 5-aminoimidazole-4-carboxamide-ribonucleoside, have been demonstrated to inhibit thyroid cancer cell growth in in vitro and in vivo models. OSU-53, a recently developed AMPK activator, was previously shown to exhibit both in vitro and in vivo antitumor activity against aggressive breast cancer cell lines and their xenografts in nude mice. OBJECTIVE: The objective of the study was to assess the in vitro effects of OSU-53 treatment in a panel of thyroid cancer cells. DESIGN: Experiments were performed to determine the effects of OSU-53 on cell growth, oncogenic signaling, apoptosis, autophagy, and cell rescue after selective knockdown of AMPK. RESULTS: OSU-53 inhibited in vitro cell growth of all seven thyroid cancer cells tested and induced activation of AMPK. Cell lines with activating mutations in RAS or BRAF, compared with cells with phosphatase and tensin homolog deleted from chromosome 10 null and RET/papillary thyroid carcinoma mutations, were more sensitive to drug treatment and demonstrated a more robust AMPK activation, inhibition of mTOR signaling, and autophagy stimulation. After selective knockdown of AMPK, cell rescue from OSU-53 treatment was not observed. We demonstrated an off-target effect of direct mTOR inhibition by OSU-53. Increased autophagy was observed in cells with activation RAS or BRAF mutations. CONCLUSIONS: OSU-53, a novel dual-AMPK activator/mTOR inhibitor, effectively inhibits growth in a variety of thyroid cancer cell lines and is most potent in cells with activating mutations in RAS or BRAF.

Intraoperative scintigraphy using a large field-of-view portable gamma camera for primary hyperparathyroidism: initial experience.

BACKGROUND: We investigated a novel technique, intraoperative (99 m)Tc-Sestamibi (MIBI) imaging (neck and excised specimen (ES)), using a large field-of-view portable gamma camera (LFOVGC), for expediting confirmation of MIBI-avid parathyroid adenoma removal. METHODS: Twenty patients with MIBI-avid parathyroid adenomas were preoperatively administered MIBI and intraoperatively imaged prior to incision (neck) and immediately following resection (neck and/or ES). Preoperative and intraoperative serum parathyroid hormone monitoring (IOPTH) and pathology (path) were also performed. RESULTS: MIBI neck activity was absent and specimen activity was present in 13/20 with imaging after initial ES removal. In the remaining 7/20 cases, residual neck activity and/or absent ES activity prompted excision of additional tissue, ultimately leading to complete hyperfunctioning tissue excision. Postexcision LFOVGC ES imaging confirmed parathyroid adenoma resection 100% when postresection imaging qualitatively had activity (ES) and/or no activity (neck). The mean ± SEM time saving using intraoperative LFOVGC data to confirm resection versus first IOPTH or path result would have been 22.0 ± 2 minutes (specimen imaging) and 26.0 ± 3 minutes (neck imaging). CONCLUSION: Utilization of a novel real-time intraoperative LFOVGC imaging approach can provide confirmation of MIBI-avid parathyroid adenoma removal appreciably faster than IOPTH and/or path and may provide a valuable adjunct to parathyroid surgery.

Factors affecting lymph node yield in patients undergoing axillary node dissection for primary breast cancer: a single-institution review.

BACKGROUND: A minimum of 10 level I/II axillary nodes is recommended for accurate breast cancer staging. The goal of this study was to assess the effect of neoadjuvant chemotherapy on lymph node yield at axillary lymph node dissection. METHODS: A single-institution National Comprehensive Cancer Network (NCCN) breast cancer database was queried for cases with axillary node dissection from 2000 to 2008. All dissections were performed at the same institution. Demographic, chemotherapy, and clinicopathologic data were collected. Age and body mass index at diagnosis were calculated for subset analyses. Statistical analyses used Student's t-test or analysis of variance with Tukey multiple comparison and Fisher's exact test. RESULTS: Two hundred forty patients had axillary node dissection after neoadjuvant chemotherapy; an additional 903 women with primary lymph node dissection were identified as contemporaneous control subjects. There was a far lower nodal yield in patients undergoing axillary dissection after neoadjuvant chemotherapy than those undergoing primary surgery. Patients with pathologic stage II or III disease undergoing primary surgery had more lymph nodes at axillary dissection than stage I disease. CONCLUSIONS: Age, type of breast surgery, body mass index, and clinical stage have no effect on yield of lymph nodes at axillary lymph node dissection. Neoadjuvant chemotherapy, however, is associated with a far fewer nodes at axillary dissection, and alteration of the guidelines should be considered for this population of patients.