Citations

Liver transplantation is a complex procedure performed on critically ill patients with multiple comorbidities, which requires the anesthesiologist to be facile with complex hemodynamics and physiology, vascular access procedures, and advanced monitoring. Over the past decade, there has been a continuing debate whether or not liver transplant anesthesia is a general or specialist practice. Yet, as significant data have come out in support of dedicated liver transplant anesthesia teams, there is not a guarantee of liver transplant exposure in domestic residencies. In addition, there are no standards for what competencies are required for an individual seeking fellowship training in liver transplant anesthesia. Using the Accreditation Council for Graduate Medical Education guidelines for residency training as a model, the Society for the Advancement of Transplant Anesthesia Fellowship Committee in conjunction with the Liver Transplant Anesthesia Fellowship Task Force has developed the first proposed standardized core competencies and milestones for fellowship training in liver transplant anesthesiology.

Abstract Background: Epigenetic dysregulation is involved in the etiology and progression of various human diseases. Formalin-fixed paraffin-embedded (FFPE) samples represent the gold standard for archiving pathology samples, and thus FFPE samples are a major resource of samples in clinical research. However, chromatin-based epigenetic assays in the clinical settings are limited to fresh or frozen samples and are hampered by low chromatin yield in FFPE samples due to the lack of reliable and efficient chromatin preparation methods. Here, we introduce a new chromatin extraction method from FFPE tissues (Chrom-EX PE) for chromatin-based epigenetic assays. Results: During rehydration of FFPE tissues, applying tissue-level cross-link reversal to the deparaffinized tissue at 65°C dramatically increased chromatin yield in the soluble fraction. We found the resulting chromatin to be compatible with ChIP-qPCR and ChIP-seq analysis of histone marks (H3K4me3, H3K27me3, and H3K27Ac) and RNA polymerase II. The chromatin prepared by Chrom-EX PE showed a gradual fragmentation pattern with varying incubation temperature. At temperatures below 37°C, the majority of soluble chromatin was over 1 kb in size. The soluble chromatin prepared at 45-60°C showed a typical nucleosomal pattern shown in cell lines and frozen tissues. The majority of the chromatin prepared at 65°C is close to mononucleosomal size. These observations indicate that chromatin preparation from FFPE samples can be controlled for downstream chromatin-based epigenetic assays. Conclusions: Our method achieves efficient extraction of high-quality chromatin from FFPE samples suitable for targeted and genome-wide epigenetic assays while minimizing degradation and damages. This approach provides a new platform for developing chromatin-based assays applicable to archived FFPE samples to circumvent the over-fixed nature of FFPE tissues. This work was supported, in part, by National Institutes of Health grant P01DK068055 and the Mayo Clinic Center for Individualized Medicine Epigenomics Program. Citation Format: Jian Zhong, Zhenqing Ye, Chad Clark, Samuel Lenz, Justin Nguyen, Huihuang Yan, Keith Robertson, Gianrico Farrugia, Zhiguo Zhang, Tamas Ordog, Jeong-Heon Lee. Enhanced and controlled chromatin extraction for chromatin-based epigenetic assays in FFPE tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5180.

Introduction Upper extremity lymphedema can complicate mastectomy, lymph node dissection, and radiation. The purpose of this study is to present the outcomes of shoulder arthroplasty in patients with lymphedema. Methods The 19 shoulders with a shoulder arthroplasty and lymphedema on the surgical side (6 anatomic, 12 reverse, 1 hemiarthroplasty) were followed for four years (1–10 years). There were 2 males and 17 females; average age was 67.8 (48–86) years. Breast carcinoma was the most common reason for lymphedema (75%). A dedicated lymphedema questionnaire could be completed for 14 shoulders. Results Pain improved from moderate or severe preoperatively to no or mild in 18 shoulders. Motion improved in elevation (55° preoperatively, 107° at last follow-up), external rotation (14°, 43°), and internal rotation (sacrum, L5). Complications included an acromion stress fracture with a deep infection (1), deep infection (1), superficial infection (1), and glenoid loosening (1). Lymphedema worsened in nine cases, but worsening was permanent in only four. Currently, lymphedema treatment is being performed by 93% of survey respondents. No patients reported lymphangitis or lymphangiosarcoma. Conclusion Shoulder arthroplasty for an upper extremity with lymphedema provides substantial improvements in pain and motion; however, infection is a concerning complication. Fifty percent of the patients will experience worsening of their lymphedema and in 20% worsening may be permanent.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic cancer with limited treatment options. There is an urgent need for tools that monitor therapeutic responses in real time. Drugs such as gemcitabine and irinotecan elicit their therapeutic effect in cancer cells by producing hydrogen peroxide (H2O2). In this study, specific DNA-wrapped single-walled carbon nanotubes (SWCNT), which precisely monitor H2O2, were used to determine the therapeutic response of PDAC cells in vitro and tumors in vivo. Drug therapeutic efficacy was evaluated in vitro by monitoring H2O2 differences in situ using reversible alteration of Raman G-bands from the nanotubes. Implantation of the DNA–SWCNT probe inside the PDAC tumor resulted in approximately 50% reduction of Raman G-band intensity when treated with gemcitabine versus the pretreated tumor; the Raman G-band intensity reversed to its pretreatment level upon treatment withdrawal. In summary, using highly specific and sensitive DNA-SWCNT nanosensors, which can determine dynamic alteration of hydrogen peroxide in tumor, can evaluate the effectiveness of chemotherapeutics. Significance: A novel biosensor is used to detect intratumoral hydrogen peroxide, allowing real-time monitoring of responses to chemotherapeutic drugs.

The need for liver transplantation (LT) among older patients is increasing, but the role of LT in the elderly (≥70 years) is not well defined. We retrospectively reviewed all primary LTs from 1998 through 2016 at our center. Survival and associated risk factors were analyzed with Cox regression and Kaplan‐Meier methods for LT recipients in 3 age groups: <60, 60‐69, and ≥70 years. Among 2281 LT recipients, the median age was 56 years (range, 15‐80 years), and 162 were aged ≥70 years. The estimated 5‐ and 10‐year patient survival probabilities for elderly LT recipients were lower (70.8% and 43.6%) than for recipients aged 60‐69 years (77.2% and 64.6%) and <60 years (80.7% and 67.6%). Patient and graft survival rates associated with LT improved over time from the pre–Model for End‐Stage Liver Disease era to Share 15, pre–Share 35, and Share 35 for the cohort overall (P < 0.001), but rates remained relatively stable in septuagenarians throughout the study periods (all P > 0.45). There was no incremental negative effect of age at LT among elderly patients aged 70‐75 years (log‐rank P = 0.32). Among elderly LT recipients, greater requirement for packed red blood cells and longer warm ischemia times were significantly associated with decreased survival (P < 0.05). Survival of LT recipients, regardless of age, markedly surpassed that of patients who were denied LT, but it was persistently 20%‐30% lower than the expected survival of the general US population (P < 0.001). With the aging of the population, select older patients with end‐stage liver diseases can benefit from LT, which largely restores their expected life spans.

Background:IBER is a novel cereblon E3 ligase modulator (CELMoD) with enhanced tumoricidal and immunostimulatory activities. Preclinically, IBER overcomes immunomodulatory drug (IMiD) resistance and has synergy with daratumumab (DARA), bortezomib (BORT), and dexamethasone (DEX).Aims:This phase 1b/2a multicenter, open‐label, dose‐escalation study (NCT02773030) was conducted to evaluate the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety and preliminary efficacy of IBER in combination with DEX, in patients with relapsed/refractory multiple myeloma (RRMM).Methods:Eligible patients had RRMM and must have received ≥2 prior regimens including lenalidomide (LEN) and/or pomalidomide (POM), and a proteasome inhibitor (PI). All patients had progressed on or within 60 days of last MM therapy. Escalating doses of IBER were given on days 1–21, in combination with DEX 40 mg (20 mg in patients aged >75 years) on days 1, 8, 15, and 22, of each 28‐day cycle. Dose escalation was reviewed by a dose escalation committee.Results:As of January 2019, 58 patients had received IBER + DEX. Median age was 64.5 years (range 33–79), and median number of prior regimens was 5 (2–12). Prior therapies included autologous stem cell transplantation (79%), LEN (100%), POM (69%), PIs (100%), and DARA (66%). IBER dose ranged from 0.3 to 1.2 mg; MTD/RP2D was not reached. Median duration of therapy was 12+ weeks (range 4–109). Grade 3–4 adverse events (AEs) were reported in 41 (72%) patients and were not related to dose. Grade 3–4 neutropenia, thrombocytopenia, neuropathy, and fatigue occurred in 26%, 11%, 2%, and 0% patients, respectively. Three patients discontinued treatment due to AEs. Clinical activity occurred early and was observed across all dose levels (Table 1); 20 of 51 patients remain on treatment (2–27+ cycles).Summary/Conclusion:IBER + DEX showed favorable efficacy and safety in heavily pretreated patients with RRMM who failed multiple prior therapies. This study is ongoing, including combinations of IBER with DARA or BORT.image

Background:Iberdomide (IBER) is a novel cereblon (CRBN) E3 ligase modulatory compound (CELMoD) that is being investigated as monotherapy, in combination with dexamethasone (DEX), and in combination with DEX and daratumumab or bortezomib in a phase 1b/2a dose‐escalation study in relapsed/refractory multiple myeloma (RRMM). IBER modulates CRBN, which induces ubiquitination of Aiolos, Ikaros and ZFP91, increases their proteasome‐dependent degradation, and thereby inhibits myeloma cell growth. IBER binds more potently to CRBN and is more efficient at degrading Aiolos and Ikaros than the immunomodulatory agents (IMiDs) lenalidomide (LEN) and pomalidomide (POM) and it can overcome IMiD drug resistance in pre‐clinical models.Aims:To determine if IBER is pharmacodynamically (PD) active in multiple myeloma patients refractory to POM and/or LEN, and to establish pharmacokinetic (PK)/PD and PD/dose relationships.Methods:As of Jan 11, 2019, 83 patients received IBER as monotherapy or in combination with DEX; 61 (74%) were LEN refractory and 47 (57%) were POM refractory. Longitudinal immunohistochemistry (IHC) data on CRBN, Aiolos, Ikaros and ZFP91 expression was obtained from bone marrow samples from 14 patients dosed with 0.3–0.9 mg IBER daily ± DEX. PD analysis of immune activity by TruCulture® (n = 45) and by peripheral blood flow cytometry (n = 60) was completed on a subset of patients dosed up to 1.0 mg IBER ± DEX. A population PK approach was used to estimate exposure (area under the concentration curve over the 24 hr dosing interval [AUCτ]) on 59 patients dosed up to 1.0 mg IBER ± DEX.Results:IBER AUCτ increased in a dose‐proportional manner in RRMM patients over the dose range 0.3–1.0 mg (22.4–65.31 ng∗hr/mL, respectively). In patient biopsies analyzed to date, CRBN expression was observed in all tumors by IHC at baseline and did not significantly change while on‐treatment. Furthermore, no significant decrease in baseline CRBN expression was observed in patients refractory to POM. In MM cells, significant decreases in Aiolos (median 37% decrease, P < 0.001), Ikaros (median 12% decrease, P = 0.006), and ZFP91 (median 47% decrease, P < 0.001) protein expression were observed on‐treatment across all dose levels; these decreases were unrelated to levels of CRBN expression at screening or prior LEN or POM refractoriness. In TruCulture® samples, dose‐dependent increases were observed in IL‐2 and IFN‐γ, with median increases of 78% and 66%, respectively, 5 hours post 0.9 mg dose of IBER. A dose‐ and exposure‐dependent decrease in B‐cells was detected (median 74% decrease at cycle 2 day 15, IBER 0.9 mg). These observations are consistent with the proposed IBER mechanism of action. Immunoprofiling showed significant increases in total and proliferating NK cells in RRMM patients treated with IBER, and a dose‐dependent increase in proliferating, activated, and effector memory T‐cells. These trends were consistent in RRMM patients treated with IBER monotherapy and in combination with DEX.Summary/Conclusion:These translational analyses from IBER treated RRMM patients indicate it is pharmacodynamically active at the lowest dose (0.3 mg) and exhibits dose‐ and exposure‐dependent immunostimulatory activity, supporting further dose‐escalation beyond 1.0 mg, which is currently ongoing. These results also suggest that prior refractoriness to LEN or POM is not associated with significant loss of CRBN or IBER PD activity, supporting continued investigation of IBER in RRMM patients refractory to IMiD drugs.

Abstract Trichoblastic carcinoma is an uncommon malignant neoplasm arising from follicular germinative cells. The high-grade trichoblastic carcinoma has been reported with lymphatic and hematogenous dissemination. The authors present a 59-year-old man with gluteal cleft trichoblastic carcinoma and highlight the useful role of serial 18F-FDG PET/CT examinations in the demonstration of initial and subsequent nodal metastasis in the inguina and pelvis.