Citations

Three multicenter studies have shown that the addition of mycophenolate mofetil (MMF) to an immunosuppressive regime consisting of cyclosporin A (CSA) and prednisone (PRED) decreases the incidence of acute rejection episodes when compared with azathioprine (AZA) or placebo (1–3). In those patients receiving 3 g/d of MMF, the highest dose used in the studies, there was a trend towards an increased incidence of cytomegaloviral sepsis (CMV). We postulated therefore that MMF may represent an independent risk factor for the development of CMV infection in patients receiving renal allografts and MMF at our institution. Having altered the triple drug regime from CSA, AZA (2‐2.5 mg/kg/d) and PRED to CSA. MMF (2 g/d) and PRED in July 1995, we elected to study all patients undergoing kidney transplantation for the 33‐month period January 1994‐September 1996, by undertaking a case control analysis to determine independent risk factors for the development of CMV infection, as defined by CMV viremia or tissue‐invasive CMV. Three CMV disease‐free control patients were matched to each case, these patients having been randomly selected from the entire pool of patients in the observation period. There were 31 CMV case patients and 102 control patients. Univariate analysis indicated that gender, a concomitant pancreas transplant, acute rejection and CMV seropositivity in the donor were risk factors. However, multivariate analysis indicated that only acute rejection and donor CMV seropositivity were independently linked (p<0.05) to CMV disease in this sample. Specifically, the odds ratio (OR) for CMV disease between MMF and AZA was 1.0 (95% confidence interval (CI): 0.46‐2.18). Therefore, in this case control study we find no evidence that MMF at a dose of 2 g/d is an independent risk factor for primary CMV viremia or tissue invasion in renal allograft recipients.

AbstractBackgroundIgA Nephropathy (IgA N) is one of the most common glomerulopathies and may lead to renal failure in 10–20% of cases. After renal transplantation, IgA N has a strong tendency to recur in the graft. Initially considered a benign condition, graft losses from recurrent IgA N have been reported over the last 20 yr, casting doubt on the initial premise. Since large single‐center studies of the fate of renal allografts in IgA N are rare and the Mayo Clinic transplant experience for IgA N is extensive (dating back to 1970), a review of these issues appeared worthwhile.MethodsA retrospective study was done of all renal transplant patients who had had biopsy‐proven IgA N as underlying disorder. We extracted data on the underlying disease, history leading to renal transplantation, factors affecting transplant outcome, and on the course after transplantation with special attention to rejection activity and recurrence of the primary disease. Standard statistical methods were employed.Results53 renal allografts were transplanted to 51 biopsy‐proven IgA N patients: 12 were cadaveric (CAD) grafts, 3 HLA‐mismatched living related donor (LRD) kidneys, 29 one haplotype‐matched LRD and 9 HLA‐identical LRD organs. Five‐year actuarial graft survival was 100% in HLA‐ identical LRD, 88% in one haplotype‐matched LRD, and 74% in CAD grafts. All three HLA‐mismatched LRD kidneys were functioning up to 1.6 yr (longest follow‐up). Only one patient died after acute rejection of the CAD graft. There were 3 early graft losses from acute rejection and 4 late losses. IgA N recurred in 26% of allografts and led to significant loss of graft function in 10 of the 14 patients (71%) over a long period of observation. Three of four late graft losses were in patients with recurrent IgA N. Recurrence was not related to the type of graft, i.e. CAD vs. LRD, nor to the extent of HLA‐matching in LRD transplantation.ConclusionRenal transplantation in patients with IgA N has excellent patient and graft survival. There is a high rate of recurrence of the primary glomerulopathy in the renal allograft, and this event is by no means inconsequential. Loss of renal function and even graft loss occur over prolonged periods of time. There is no disadvantage getting a well matched LRD in regard to incidence of recurrent IgA N. Thus, we encourage LRD transplantation in IgA N.

We examined the value of thallium‐201 myocardial perfusion scintigraphy in noninvasive assessment of cardiac risk in 36 insulin‐dependent (type 1) diabetic patients being evaluated for pancreas or combined pancreas/kidney transplantation. An extensive cardiovascular evaluation including electrocardiogram was performed in all patients, and most patients were also evaluated by two‐dimensional and Doppler echocardiography. Exercise thallium studies were performed in 31 patients. Five patients were unable to exercise and underwent dipyridamole‐thallium study. The thallium images were abnormal in 12 patients, 10 of whom underwent coronary arteriography. Significant coronary artery disease was found in 7 of these patients. Nineteen patients underwent pancreatic (3 patients) or pancreato‐renal (16) transplantation without any occurrence of cardiac death or nonfatal myocardial infarction peri‐operatively or on follow‐up ranging from 7 months to 21 months. In contrast, 3 cardiac events occurred in 12 patients not approved for transplantation, each of whom had an abnormal thallium study exhibiting significant ischemia. Resting left ventricular global and regional function was not helpful in determining perioperative risk. Thus, thallium‐201 myocardial perfusion scintigraphy may be useful in identifying diabetic patients at low risk for pancreas transplantation and may obviate the need for routine coronary angiography in these patients.

Biliary tract complications are a significant risk following orthotopic liver transplantation (OLT). We reviewed the biliary tract complications of the first 50 liver transplants in 44 recipients performed in our institution. The mean follow‐up was 8 months (range 1 to 16 months). Biliary tract complications that required surgical or instrumental intervention developed in 17 of the 50 (34%) transplants. No deaths were attributable to biliary tract complications. Hepatic artery thrombosis caused the biliary tract complication in 3 transplants (1 stenosis, 2 anastomotic leaks) and a cystocele of the cystic duct remnant caused 1 common bile duct obstruction. The other 13 complications were associated either with the type of anastomosis performed or type of stent used. An end‐to‐end choledochocholedochostomy was performed in 31 transplants and 2 developed biliary tract complications (6.5%). One developed a biliary leak and the other developed a stenosis at the anastomosis. Nineteen of these choledochocholedochostomies were stented with a straight tube and 6 developed stent‐related complications. Twelve were stented with a T‐tube and only 1 stent complication occurred. An end‐to‐side choledochojejunostomy with a Roux‐en‐Y loop was performed in 19 patients. Only 1 early biliary complication occurred (5%), which was an anastomotic leak. However, 2 developed a stenosis of the entire donor extra‐hepatic duct, 12 and 13 months following transplantation. All anastomoses were stented with a straight tube and only 1 leak developed at the entrance site of the stent into the Roux‐Y. We conclude that the choledochocholedochostomy and the choledochojejunostomy with a Roux‐en‐Y loop are safe methods of biliary reconstruction following OLT. We recommend that a T‐tube be used for stenting the choledochocholedochostomy, and a hepatic artery thrombosis must be excluded when biliary tract complications develop.

Abstract Objective The presence of comorbidities can substantially affect patients’ quality of life, but data regarding their impact on idiopathic inflammatory myopathies (IIMs) are limited. Methods We examined the prevalence of comorbidities in IIM patients, other autoimmune rheumatic diseases (oAIRDs) and healthy controls (HCs), using data from the self-reported COVAD-2 survey. We defined basic multimorbidity (BM) as the presence of ≥2 non-rheumatic chronic conditions and complex multimorbidity (CM) as the presence of ≥3 non-rheumatic chronic conditions affecting ≥3 organ systems. Hierarchical clustering on principal components was performed for grouping. Results Among the COVAD respondents, 1558 IIMs, 4591 oAIRDs and 3652 HCs were analysed. IIMs exhibited a high burden of comorbidities (odds ratio [OR]: 1.62 vs oAIRDs and 2.95 vs HCs, P &lt; 0.01), BM (OR: 1.66 vs oAIRDs and 3.52 vs HCs, P &lt; 0.01), CM (OR: 1.69 vs AIRDs and 6.23 vs HCs, P &lt; 0.01) and mental health disorders (MHDs) (OR: 1.33 vs oAIRDs and 2.63 vs HCs, P &lt; 0.01). Among the IIM patients, those with comorbidities or MHDs had lower PROMIS Global Physical (PGP), PROMIS Global Mental (PGM), and PROMIS Physical Function (SF10) scores, and higher fatigue (F4a) scores (all P &lt; 0.001). PGP, PGM, SF10a and F4a were influenced by age, active disease, BM and MHDs. Four distinct clusters were identified among the IIMs according to comorbidities and PROMIS scores. Conclusion Patients with IIMs have a higher burden of comorbidities that influence physical and mental health, identifiable as clinical clusters for optimized and holistic management approaches.

AbstractINTRODUCTIONWe investigated longitudinal associations between self‐reported exercise and Alzheimer's disease (AD)‐related biomarkers in individuals with autosomal dominant AD (ADAD) mutations.METHODSParticipants were 308 ADAD mutation carriers aged 39.7 ± 10.8 years from the Dominantly Inherited Alzheimer's Network. Weekly exercise volume was measured via questionnaire and associations with brain volume (magnetic resonance imaging), cerebrospinal fluid biomarkers, and brain amyloid beta (Aβ) measured by positron emission tomography were investigated.RESULTSGreater volume of weekly exercise at baseline was associated with slower accumulation of brain Aβ at preclinical disease stages β = –0.16 [–0.23 to –0.08], and a slower decline in multiple brain regions including hippocampal volume β = 0.06 [0.03 to 0.08].DISCUSSIONExercise is associated with more favorable profiles of AD‐related biomarkers in individuals with ADAD mutations. Exercise may have therapeutic potential for delaying the onset of AD; however, randomized controlled trials are vital to determine a causal relationship before a clinical recommendation of exercise is implemented.Highlights Greater self‐reported weekly exercise predicts slower declines in brain volume in autosomal dominant Alzheimer's disease (ADAD). Greater self‐reported weekly exercise predicts slower accumulation of brain amyloid beta in ADAD. Associations varied depending on closeness to estimated symptom onset.

Objectives: The microvasculature of the human meniscus has been previously described by Arnoczky and Warren. However, to date the qualitative and quantitative extra-articular vascular anatomy of the medial meniscus has not yet been characterized. Therefore, the purpose of our study was to perform a qualitative and quantitative anatomic study of the extra-articular medial meniscal vasculature and to introduce the novel “medial meniscal artery” (MMA), potentially providing future guidelines for the treatment of meniscal pathology. Methods: Thirty-three unpaired frozen human cadaveric knees were dissected. The popliteal artery was identified and cannulated with an angiocatheter. The arteries were perfused with a red acrylic paint solution allowing for improved visualization. Artery dimensions and distances were measured using a digital caliper. Perfused specimens were imaged with Computed Tomography scanning and segmented using software to identify vessels and repeat artery measurements. Results: The MMA was consistently identified in all specimens. In 26 of 33 (82%) specimens, the MMA branched directly from the popliteal artery, while in 6, the MMA shared a common trunk with the inferior medial genicular artery (IMGA). The MMA was easily distinguishable from the superior MGA, inferior MGA, and MGA, given its direct course to the medial joint line with terminal branches to the posterior horn of the medial meniscus and deep to the semimembranosus tendon. The MMA exhibited a consistently smaller vessel diameter relative to the genicular arteries. Conclusions: This is the first study identifying and quantitively describing the MMA in the human knee. The MMA can be identified consistently on gross anatomic dissection in patients of varying demographics. The findings of this study will provide future avenues of study toward understanding the medial meniscus vascularization and the genesis of potential degenerative changes when vascularization is poor. This will help to further refine diagnostic and treatment options for meniscus revascularization and compartment preservation. Additionally, this study may help define safe zones in the knee during posterior approaches, as well as furthering the base of knowledge for emerging vascular procedures such as genicular artery embolization. Further research is needed to identify and characterize the artery in vivo and to determine the MMA’s role in meniscus preservation.

Abstract Introduction Pancreatic adenocarcinoma (PDA) will be the second leading cause of cancer related death by 2030 and patient response to chemotherapy is poor with a strong likelihood of cancer recurrence. While past studies have investigated pre- and post-chemotherapy patient samples, there is a paucity of studies looking at fresh, patient matched samples which allow us to observe interpatient heterogeneity in chemotherapy response. Methods Here, we study the effects of chemotherapy on five different patients using sc-RNA sequencing of matched treatment naïve and post treatment tissue biopsies to compare the effects of chemotherapy, not only on the tumor cells, but also on the tumor microenvironment – a key contributor to tumor survival and proliferation. We utilized the Seurat v4 pipeline and CellChat v2 to observe transcriptomic differences in epithelial cells, myeloid cells, t-Cells, and fibroblasts and their corresponding putative interactions in pre- and post- treatment states. Results Unsurprisingly, we found insufficient tumor epithelial cells post-treatment to perform further analysis on due to the intended cytotoxic effects of chemotherapy. Therefore, we turned our focus to the tumor microenvironment, where we had sufficient numbers of stromal and immune cells, to investigate the effects of chemotherapy. We identified that fibroblasts changed the most consistently across all patients in response to chemotherapy. The fibroblasts clustered into three distinct groups: an immunomodulatory group, a myofibroblastic and neurotropic group, as well as a mixed group expressing genes from all three categories. Interestingly, the neurotropic fibroblast signature was universally enriched after chemotherapy in all five patients, despite having a small and clinically heterogeneous cohort. Conclusions Through an analysis of each fibroblast group in the treatment naïve and post treatment categories, we observed that a specific set of fibroblasts become less myofibroblastic and increasingly neurotropic following treatment, leading us to posit that fibroblasts altered by exposure to chemotherapy may potentially contribute to a ‘pro-tumor’ environment that supports recurrence. To test this in vitro, we treated patient derived fibroblasts with Gemcitabine and used RTPCR to analyze their relative changes in gene expression. We specifically probed for genes that were definitive of myofibroblasts and neurotropic fibroblasts and saw that post-chemotherapy exposure, neurotropic genes such as NEGR1 and NFIA were upregulated. This validated our scRNA conclusions that fibroblasts become increasingly neurotropic following treatment and then differentially interact with their surrounding environment. In future studies, we will further analyze the role these neurotropic fibroblasts play in chemoresponse and tumor recurrence. Matched samples are critical to studies of chemotherapy effects on PDA due to the fact that they allow us to deconvolute one aspect of PDA heterogenity - interpatient heterogeneity - which is a large limitation in studies of this disease. Citation Format: Aylin Z Henstridge, Padma Kadiyala, Ahmed M Elhossiny, Jianhua Liu, Vaibhav Sahai, Nicole Peterson, Jorge Machicado, Richard Kwon, Allison Schulman, Erik Wamsteker, George Philips, Martin Fernandez-Zapico, Mark Truty, Costas Lyssiotis, Timothy Frankel, Filip Bednar, Marina Pasca di Magliano, Eileen S Carpenter. Neurotropic fibroblast population increases following exposure to chemotherapy in pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A062.