Induction of Donor-Specific Immune Hypo-Responsiveness Across Major Histocompatibility Complex Barriers in Murine Models of Solid Organ Transplant: Repurposing Extracorporeal Photochemotherapy

Recipients of solid organ transplantation (SOT) rely on life-long immunosuppression (IS), which is associated with significant side effects. Extracorporeal photochemotherapy (ECP) is a safe, existing cellular therapy used to treat transplant rejection by modulating the recipient’s own blood cells. We sought to induce donor-specific hypo-responsiveness of SOT recipients by infusing ECP-treated donor leukocytes prior to transplant. To this end, we utilized major histocompatibility complex (MHC) mismatched rodent models of allogeneic cardiac, liver, and kidney transplantation to test this novel strategy. Leukocytes isolated from donor-matched spleens for ECP treatment (ECP-DL) were infused into transplant recipients seven days prior to SOT. Pre-transplant infusion of ECP-DL without additional IS was associated with prolonged graft survival in all models. This innovative approach promoted the production of tolerogenic dendritic cells and regulatory T-cells with subsequent inhibition of T-cell priming and differentiation, along with a significant reduction of donor-specific T-cells in the spleen and grafts of treated animals. This new application of donor-type ECP-treated leukocytes provides insight into the mechanisms behind ECP-induced immunoregulation and holds significant promise in the prevention of graft rejection and reduction in need of global immune suppressive therapy in patients following SOT.

Weight Gain after Treatment of Thyroid Dysfunction and Thyroid Surgery

Thyroid surgery is generally recommended for malignant conditions and for some benign thyroid disorders. Many patients report weight gain after thyroidectomy especially during the first months following surgery. Studies on patients with Graves’ disease treated either with antithyroid drugs or radioiodine confirm that these patients frequently gain weight after restoration of thyroid function. Other studies have also shown that there is considerable weight gain after thyroidectomy for both nodular goiter and thyroid cancer. Transient hypothyroidism during the postoperative period is often thought to be associated with weight gain after thyroidectomy. The role of a number of adipocytokines and their interaction with the thyroid function has been investigated in the pathogenesis of weight changes. Levothyroxine replacement or suppressive therapy after thyroidectomy has a different impact on the metabolic parameters independent of TSH levels. The long-term effects of the impaired T3/T4 ratio are not fully understood as there are no sensitive markers to assess the biological response of target organs and tissues. Future studies are needed to identify such parameters, provide new considerations for the treatment of patients after total thyroidectomy, and help determine individual target hormone levels to ensure a sustained euthyroid state.

Leiomyomatosis Peritonealis Disseminata Following Laparoscopic Surgery With Uncontained Morcellation: 13 Cases From One Institution

Objectives: To investigate the clinical characteristics, treatment and prognosis of leiomyomatosis peritonealis disseminata (LPD) following laparoscopic surgery with uncontained morcellation and to summarize clinical features of iatrogenic LPD based on published literature together with our own experience.Methods: A cohort of 13 cases with iatrogenic LPD diagnosed and treated in Peking Union Medical College Hospital from 2011 to 2020 was reported focusing on clinical characteristics, treatment and prognosis.Results: All the patients had a history of laparoscopic myomectomy with uncontained morcellation. The average age was 35.6 (range 25–47) years. The interval between initial laparoscopic surgery and first diagnosis of LPD was 6.08 years on average (range 1–12). Most of the patients had no obvious symptoms. The accuracy of pre-operative diagnosis was low. Two patients had been treated with gonadotropin-releasing hormone agonist (GnRH-a) before surgery without obvious effect. The nodules of LPD are usually located in the lower half of the peritoneal cavity. The most commonly involved site was the pouch of Douglas. The number of nodules ranged from 3 to over 10, and they ranged in size ranged from 0.3 to 22 cm. All patients underwent surgical treatment: six patients underwent laparoscopy and seven underwent laparotomy. Pathology results confirmed LPD. The immunohistochemical profile indicated LPD tends to be positive strongly for desmin, caldesmon, ER, PR and SMA. Only one patient underwent post-operative treatment with GnRH-a. All patients were followed for an average period of 49 months without recurrence.Conclusion: Iatrogenic LPD is a relatively rare condition. Patients usually exhibit no hormonal stimulation factors. Surgery is the main method of treatment, and hormone suppressive therapy is only rarely used. The nodules are usually large and less numerous, and most involve the pelvis. The prognosis of iatrogenic LPD seems good.

Simultaneous Coexistence of Thyrotropin-Prolactin-Secreting Adenoma and Papillary Thyroid Carcinoma

Background. The thyrotropin-secreting adenomas are very rare and even more rare when they simultaneously coexist with thyroid carcinoma. So far, only sixteen cases have been reported in the literature. Here, we present a unique case of successful management of a concurrent case of thyrotropin-prolactinoma with papillary thyroid carcinoma. Case Presentation. A 50-year-old Moroccan woman underwent a total thyroidectomy and complementary totalization by iratherapy for papillary thyroid carcinoma, who presented persistence of an inappropriate secretion of the thyroid-stimulating hormone (TSH > 4 mUI/L) despite of levothyroxine suppressive therapy (300 μg/d). After eliminating noncompliance, interfering medicines, and thyroid malabsorption, a pituitary adenoma (12 mm) was documented at magnetic resonance imaging. The patient has had transsphenoidal pituitary adenomectomy with histology confirming a thyrotropin-prolactin-secreting adenoma. After surgery and lanreotide treatment failures, we noted a complete response (TSH < 0.5) with cabergoline treatment (3 mg/week). Conclusion. The unusual association of thyroid adenocarcinoma and TSHoma enriches the hypothesis of a potential link between thyrotropic hypersecretion and thyroid carcinogenesis. Our case also illustrates the difficulty of monitoring thyroid carcinoma in nonremission of a TSHoma.

HIV-1 persistence in lymph node T follicular helper cells (TFH) is mitigated by functional virus-specific T cell responses during hyperacute-treated HIV-1 infection

HIV persistence in tissue sites despite ART is a major barrier to HIV cure. Detailed studies of HIV infected cells and immune responses in native lymph node (LN) tissue environment is critical for gaining insight into immune mechanisms impacting HIV persistence and clearance in tissue sanctuary sites. We compared HIV persistence and HIV-specific T cell responses in LN biopsies obtained from 14 individuals who initiated therapy in Fiebig stages I/II, 5 persons treated (Tx) in Fiebig stages III-V and 17 late Tx individuals who initiated ART in Fiebig VI and beyond. Using multicolor immunofluorescence staining and in situ hybridization, HIV RNA and/or protein was detected in 12 of 14 Fiebig I/II Tx persons who were on suppressive therapy for 1 to 55 months, while all late Tx persons had persistent antigens. CXCR3+T follicular helper T cells harbored the greatest amounts of gag mRNA transcripts. Notably, HIV-specific CD8+ T cells responses associated with lower HIV antigen burden in LNs, suggesting that these responses may contribute to HIV suppression in LNs during therapy. These results reveal HIV persistence despite the initiation of ART in hyperacute infection and highlight the contribution of virus-specific responses to HIV suppression in tissue sanctuaries during suppressive ART.

Effects of TSH Suppressive Therapy On Bone Mineral Density (BMD) and Bone Turnover Markers (BTMs) in Patients with Differentiated Thyroid Cancer in Northeast China: A Prospective Controlled Cohort Study

Purpose This study aimed to evaluate the effects of thyroid-stimulating hormone (TSH) suppressive therapy on bone mineral density (BMD) and bone turnover markers (BTMs) in differentiated thyroid cancer (DTC) patients after postoperative 1-2 years in Northeast China. Methods Five male, sixteen premenopausal, and eight postmenopausal female DTC patients receiving TSH suppressive therapy after thyroidectomy were enrolled. Patients were matched with healthy controls in a ratio of 1:2. All participants completed postoperative 1-year follow-up, and postmenopausal women completed 2-year follow-up. We measured BMD of the lumbar spine (LS), femoral neck (FN), and total hip (TH) using dual-energy X-ray absorptiometry (DXA). Bone formation marker P1NP and bone resorption marker β-CTX were also evaluated. Fracture risks were assessed by FRAX. Results There was no difference in BMD and BTMs between DTC patients and controls in the male group at 1-year follow-up. In the premenopausal women, the LS-BMD, FN-BMD, and TH-BMD in DTC patients were all higher than those in controls, but only FN-BMD showed a significant difference. The change rate of P1NP showed a significant difference between DTC patients and controls, while no difference was found in the β-CTX level. In the postmenopausal women, no difference in BMD and BTMs were observed between DTC patients and controls at the 1-year and 2-year follow-up. Conclusion Our study indicated that postoperative 1-year TSH suppressive therapy did not show detrimental effects on BMD and BTMs in men, premenopausal, and postmenopausal DTC patients. The 2-year postoperative TSH suppressive therapy did not lead to additional loss of bone mass in postmenopausal DTC patients.

The Effect of TSH-Suppressive Dose of Levothyroxine On Skeletal Muscle In Ovariectomized Rats

Hyperthyroidism is often observed in postmenopausal women due to conditions such as thyroiditis and toxic nodular goiter, Grave’s disease or thyroid stimulating hormone suppressive therapy for treating differentiated thyroid carcinoma (DTC). However, the effect of such hormonal changes on skeletal muscles in females remain unclear. Therefore, this study aimed to observe the effects of hyperthyroidism on the skeletal muscle of ovariectomized rats. We randomly divided female Sprague-Dawley rats into sham-operated (Sham), ovariectomized (OVX), and levothyroxine-treated ovariectomized groups (OVX+LT4). Levothyroxine was administered intraperitoneally at 0.3 mg/kg, daily for six weeks. Protein synthesis was increased after ovariectomy whereas protein synthesis was suppressed and protein degradation was increased in response to levothyroxine treatment. However, there was no difference in lean mass between the two groups. Collagen I levels were similar between the Sham and OVX groups, but were significantly decreased in the OVX+LT4 group. The mRNA levels of matrix metalloproteinase (MMP) ‐2 and ‐9 were similar between the Sham and OVX groups but were upregulated in the OVX+LT4 group. After ovariectomy, mitochondrial biogenesis and dynamics were changed; these changes were exacerbated in hyperthyroidism. Our findings indicate that in postmenopausal rats with hyperthyroidism, the progression of muscle weakness occurs through impaired regulation of signaling pathways related to extracellular matrix homeostasis, protein turnover, and mitochondrial quality.

183. Management of Left Ventricular Assist Device Infections at a Large Academic Medical Center

Background Left ventricular assist device infections (LVADIs) contribute significantly to morbidity and mortality. The lack of evidenced-based treatment recommendations results in substantial variability in clinical practice. The purpose of this study was to evaluate the management of LVADIs at our institution to better assess practice patterns and standardize treatment decisions. Methods This was a retrospective study including adults diagnosed with an initial LVADI from January 1, 2013 to July 1, 2019. Exclusion criteria included concomitant non-LVADI, patients with other mechanical circulatory systems, or pregnancy. Pertinent patient, LVAD, infection, management, and clinical outcome data was collected and described with descriptive statistics. Results A total of 49 patients were included, 37 of which had at least one recurrence, resulting in 57 recurrent and 106 total LVADIs. The majority of LVADIs were driveline infections (DLIs) (92%). There was an increase in the incidence of deep DLIs (35% vs. 10%) and bloodstream infections (26% vs. 4%) amongst recurrent vs. initial LVADIs. Staphylococcus aureus (51%) and nosocomial gram-negatives (20%) were the most common causative pathogens. Surgical interventions were common (55%). LVADIs treated predominately with oral antibiotics (54%) or IV antibiotics (46%) received a median duration of therapy of 31 and 35 days, respectively. Antibiotic regimens included anti-methicillin-resistant S.aureus coverage and anti-pseudomonal coverage in 49% and 22% of total cases, respectively. Suppressive antibiotics were commonly prescribed (54%). LVADI-related readmission (69%) and recurrence (76%) within one year of initial LVADI was frequent. Recurrent LVADI occurred regardless of receiving suppressive therapy in 60% of total recurrent cases. Conclusion This study offers unique insight into initial vs. recurrent LVADIs as well as infection characteristics and clinical outcomes at a large academic medical center. Future studies with additional focus on risk factors for recurrence would be beneficial for drawing conclusions on the efficacy of current practices and shaping future treatment guidelines. Disclosures All Authors: No reported disclosures

Anti Thymocyte Globulin-Based Treatment for Acquired Bone Marrow Failure in Adults

Idiopathic acquired aplastic anemia can be successfully treated with Anti Thymocyte Globulin (ATG)-based immune suppressive therapy and is therefore considered a T cell-mediated auto immune disease. Based on this finding, several other forms of idiopathic acquired bone marrow failure are treated with ATG as well. For this review, we extensively searched the present literature for evidence that ATG can lead to enduring remissions in different forms of acquired multi- or single-lineage bone marrow failure. We conclude that ATG-based therapy can lead to an enduring hematopoietic response and increased overall survival (OS) in patients with acquired aplastic aplasia. In patients with hypocellular myelodysplastic syndrome, ATG can lead to a hematological improvement without changing the OS. ATG seems less effective in acquired single-lineage failure diseases like Pure Red Cell Aplasia, Amegakaryocytic Thrombocytopenia and Pure White Cell Aplasia, suggesting a different pathogenesis in these bone marrow failure states compared to aplastic anemia. T cell depletion is hypothesized to play an important role in the beneficial effect of ATG but, as ATG is a mixture of polyclonal antibodies binding to different antigens, other anti-inflammatory or immunomodulatory effects could play a role as well.

Aplastic anemia secondary to dual cancer immunotherapies a physician nightmare: case report and literature review

Background Treatment with immune checkpoint inhibitors has revolutionized cancer treatment over the past several years. Despite their clinical benefits, a wide range of immune-mediated toxicities can be observed including hematological toxicities. Although, the majority can easily be managed, immune-mediated adverse events rarely can be severe and difficult to approach. Herein, we are reporting a case of very severe aplastic anemia secondary to ipilimumab (I) and nivolumab (N) treatment that failed various treatment including intensive immune suppressive therapy. Case presentation We described a case of a 45-year old white male, heavy smoker presented to the clinic complaining of left flank pain. He was found to have a metastatic renal cell carcinoma for which he was treated with dual immunotherapy and later complicated by severe immune related adverse events. The patient later died after failing intensive immune suppressive therapy. Conclusion Immunotherapy has become an established pillar of cancer treatment improving the prognosis of many patients with variant malignancies. Yet, lethal adverse events can occur in rare cases. It is our duty, as physicians, to remain alert and cautious.