Citations

The diagnosis of ovarian torsion is challenging and relies mostly on morphologic findings. Occasionally, women or children with acute pelvic pain who have undergone an initial ultrasound (US) evaluation with results interpreted as negative for ovarian torsion will return with recurrent or increasing pain, prompting an US reevaluation. The flipped ovary sign refers to a demonstrable change in the orientation of the ovary on follow‐up US examinations, recognized by changing positions of ovarian landmarks established by follicles, cysts, or masses. This sign is valuable for identifying ovarian torsion in these patients, even in the absence of classic morphologic or Doppler features of ovarian torsion.

INTRODUCTION: As multidisciplinary treatment modalities for rectal cancer continue to evolve, neoadjuvant chemoradiation then surgical resection is a common approach. Robotic-assisted abdominoperineal resection is becoming more prevalent in part because of better visualization and instrument mobility within the pelvis. After abdominoperineal resection, postoperative perineal wound complications remain a significant risk. Pelvic reconstruction lowers this risk, and a pedicled rectus abdominis muscle flap is frequently used to achieve this. Traditional flap harvest requires laparotomy, resulting in violation of both rectus sheaths and a large midline scar. Robotic harvest of the rectus abdominis muscle for pelvic reconstruction after abdominoperineal resection is a novel approach with foreseeable benefits. TECHNIQUE: After completion of abdominoperineal resection, 2 additional trocars are inserted in the lateral abdomen, and the robot is reoriented toward the posterior abdominal wall. The peritoneum and posterior rectus sheath are incised, and dissection is carried superiorly and inferiorly in a sagittal plane to reveal the rectus abdominis muscle. The muscle body is separated from the anterior rectus sheath. Once the inferior epigastric artery is identified, the superior pole of the muscle is transected. Continued lateral dissection ensures flap mobility for placement within the pelvis. After obtaining proper reach, the robot is undocked, and the flap is sutured in place through the perineal defect. RESULTS: After trocar placement and robot repositioning, both the colorectal and plastic surgeons trade places at the console. Robotic flap harvest precludes the need for laparotomy. The anterior rectus sheath remains unviolated and the patient avoids an additional midline scar. The aforementioned benefits of robot-assisted abdominoperineal resection, namely increased visualization and maneuverability, were also found applicable when robotically harvesting this flap. CONCLUSIONS: This technique exemplifies an additional minimally invasive technique for patients pursuing abdominoperineal resection. With knowledge of this novel approach, surgeons can better tailor their operations to benefit the patient.

Senescence is a cell state defined by loss of proliferative capacity, increased metabolic activity, and importantly, resistance to apoptosis. Senescent cells can release pro‐inflammatory cytokines/chemokines, proteases, and other factors, otherwise known as the senescence‐associated secretory phenotype (SASP). The SASP can adversely affect not only neighboring cells, but also likely contributes to driving systemic aging. Senolytic compounds such as dasatinib (D), quercetin (Q), and fisetin (FIS) were recently found to target anti‐apoptotic pathways known to be upregulated in senescent cells. Several reports have found significant improvement in healthspan indices including decreased frailty, neurologic dysfunction, and bone loss in vivo following intermittent treatment with senolytic agents. Our lab routinely uses the accelerated aging model Zmpste24 −/− (Z24 −/− ) mice to investigate age‐related pathologies as they have a maximum lifespan of ~6 months. For the first time here, we examined the effects of another significantly safer senolytic compound, the flavonoid FIS, on spontaneous bone density loss associated with age using the Z24 −/− model. Z24 −/− mice begin to exhibit significant musculoskeletal decline associated with increased senescent cell burden as early as 2 months including weight loss and reduced cartilage proteoglycan and bone levels in skeletal preparations (Fig. ). Importantly, we previously found that senolytic drug treatment restored cartilage in Z24 −/− mice in a dose dependent manner. These data demonstrated for the first time the therapeutic potential for senotherapuetic drugs for the treatment of age‐associated knee OA. Fisetin, a newly characterized senolytic drug was recently demonstrated to significantly extend lifespan and healthspan, including musculoskeletal function, in progeroid mice. We thus next evaluated if FIS, a less toxic alternative to dasatinib that targets several senescence associated pathways, might better prevent bone loss in rapidly aging Z24 −/− mice. Indeed, we found that weekly dosing of FIS for weeks starting at 3 months of age could significantly attenuate bone density loss in Z24 −/− mice as evidenced by micro‐CT analysis (Fig. ). Future studies will examine if more chronic dosing of FIS at younger ages. Aging is associated with sever musculoskeletal decline including OA and osteoporosis for which there are few treatment options none of which that target shared fundamental mechanistic drivers. We previously found that the senolytic drug cocktail DQ could prevent articular cartilage degeneration. The main objective of these studies was to investigate the efficacy of senolytic drugs, principally FIS, to attenuate age‐associated loss of bone density in progeroid Z24 −/− mice. In agreement to previous reports, we found senolytic drug treatment could mitigate bone density loss in aged/progeroid mice. However, we report this for the first time using FIS, a much safer alternative to chemotherapeutic agents with similar efficacy. FIS may thus be a more clinically viable option for senotherapeutic treatment. Support or Funding Information NIA (5P01AG043376‐05). Musculoskeletal pathology in Z24−/− mice is improved with DQ treatment Figure 1 Effects of senolytic drugs on trabecular bone in Z24−/− mice Figure 2

Background and Aims The Organ Procurement and Transplantation Network recently approved liver transplant (LT) prioritization for patients with hepatocellular carcinoma (HCC) beyond Milan Criteria (MC) who are down‐staged (DS) with locoregional therapy (LRT). We evaluated post‐LT outcomes, predictors of down‐staging, and the impact of LRT in patients with beyond‐MC HCC from the U.S. Multicenter HCC Transplant Consortium (20 centers, 2002‐2013). Approach and Results Clinicopathologic characteristics, overall survival (OS), recurrence‐free survival (RFS), and HCC recurrence (HCC‐R) were compared between patients within MC (n = 3,570) and beyond MC (n = 789) who were down‐staged (DS, n = 465), treated with LRT and not down‐staged (LRT‐NoDS, n = 242), or untreated (NoLRT‐NoDS, n = 82). Five‐year post‐LT OS and RFS was higher in MC (71.3% and 68.2%) compared with DS (64.3% and 59.5%) and was lowest in NoDS (n = 324; 60.2% and 53.8%; overall P < 0.001). DS patients had superior RFS (60% vs. 54%, P = 0.043) and lower 5‐year HCC‐R (18% vs. 32%, P < 0.001) compared with NoDS, with further stratification by maximum radiologic tumor diameter (5‐year HCC‐R of 15.5% in DS/<5 cm and 39.1% in NoDS/>5 cm, P < 0.001). Multivariate predictors of down‐staging included alpha‐fetoprotein response to LRT, pathologic tumor number and size, and wait time >12 months. LRT‐NoDS had greater HCC‐R compared with NoLRT‐NoDS (34.1% vs. 26.1%, P < 0.001), even after controlling for clinicopathologic variables (hazard ratio [HR] = 2.33, P < 0.001) and inverse probability of treatment‐weighted propensity matching (HR = 1.82, P < 0.001). Conclusions In LT recipients with HCC presenting beyond MC, successful down‐staging is predicted by wait time, alpha‐fetoprotein response to LRT, and tumor burden and results in excellent post‐LT outcomes, justifying expansion of LT criteria. In LRT‐NoDS patients, higher HCC‐R compared with NoLRT‐NoDS cannot be explained by clinicopathologic differences, suggesting a potentially aggravating role of LRT in patients with poor tumor biology that warrants further investigation.

Objective: The aim of the study was to determine the rate, predictors, and impact of complete pathologic response (cPR) to pretransplant locoregional therapy (LRT) in a large, multicenter cohort of hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT). Background: LRT is used to mitigate waitlist dropout for patients with HCC awaiting LT. Degree of tumor necrosis found on explant has been associated with recurrence and overall survival, but has not been evaluated in a large, multicenter study. Methods: Comparisons were made among patients receiving pre-LT LRT with (n = 802) and without (n = 2637) cPR from the United States Multicenter HCC Transplant Consortium (UMHTC), and multivariable predictors of cPR were identified using logistic regression. Results: Of 3439 patients, 802 (23%) had cPR on explant. Compared with patients without cPR, cPR patients were younger; had lower Model for End-stage Liver Disease (MELD) scores, AFP levels, and neutrophil–lymphocyte ratios (NLR); were more likely to have tumors within Milan criteria and fewer LRT treatments; and had significantly lower 1-, 3-, and 5-year incidence of post-LT recurrence (1.3%, 3.5%, and 5.2% vs 6.2%, 13.5%, and 16.4%; P < 0.001) and superior overall survival (92%, 84%, and 75% vs 90%, 78%, and 68%; P < 0.001). Multivariable predictors of cPR included age, sex, liver disease diagnosis, MELD, AFP, NLR, radiographic Milan status, and number of LRT treatments (C-statistic 0.67). Conclusions: For LT recipients with HCC receiving pretransplant LRT, achieving cPR portends significantly lower posttransplant recurrence and superior survival. Factors predicting cPR are identified, which may help prioritize patients and guide LRT strategies to optimize posttransplant cancer outcomes.

Abstract When unrepaired, alkylated DNA can induce cell death or trigger mutagenesis. Cellular capacity for repair of these lesions by O6-methylguanine methyltransferase (MGMT) dictates the equilibrium between cell viability and genetic diversity. Treatment of glioblastoma cells with temozolomide (TMZ) induced ATM- and Rad3-related (ATR) kinase dependent polyribonucleotide nucleotidyltransferase 1 (PNPT1) degradation of miR-181d. miR-181d suppresses MGMT expression; its degradation increases the mean MGMT expression of the cell population. miR-181d degradation also magnifies the cell-to-cell variability in MGMT expression, expanding the genetic heterogeneity of the population. This expanded heterogeneity enhances the “fitness” of the population and constitutes a novel form of chemotherapeutic resistance. These effects can be suppressed by overexpression of miR-181d, suggesting miRNA delivery as a strategy for glioblastoma therapy. To characterize the mechanism of acquired resistance, we profiled the expression of 2400 miRNAs before and after TMZ treatment. In independent patient-derived neurosphere lines, the majority of miRNAs remained unchanged after treatment. However, miR-181d was consistently suppressed after TMZ treatment. Our previous work demonstrated miR-181d as the master regulator of MGMT. We confirmed TMZ-induced suppression of miR-181d using independent in vitro and in vivo models as well as matched pre- and post-TMZ treated clinical specimens. TMZ-induced miR-181d suppression persisted after transcriptional inhibition, suggesting degradation as the primary mechanism. We performed an siRNA screen and identified polyribonucleotide nucleotidyltransferase 1 (PNPT1) as the gene responsible for miR-181d degradation. CRISPR inactivation of PNPT1 eliminated TMZ-induced suppression of miR-181d; this was rescued by wild-type PNPT1 but not by PNPT1 harboring RNAse-inactivating mutations. TMZ-induced degradation of miR-181d requires ATR kinase. Silencing or inhibition of ATR eliminated binding of PNPT1 to miR-181d and prevented degradation of miR-181d. TMZ-sensitizing effects of ATR inhibition were reversed by anti-miR-181d, suggesting miR-181d is essential in this process. In addition to elevating the mean MGMT expression of the population, single-cell analysis revealed that miR-181d degradation broadened the cell-to-cell variability in MGMT expression in vitro. In matched clinical pre- and post-TMZ treated specimens, variability in MGMT expression was significantly elevated in post-TMZ samples. This was recapitulated using The Cancer Genome Atlas (TCGA) database. We propose that miR-181d degradation-mediated expansion of genetic heterogeneity enhances the “fitness” of the population, constituting a novel form of chemotherapeutic resistance. These effects are suppressed by miR-181d overexpression, suggesting miRNA delivery as a strategy for glioblastoma therapy. Citation Format: Valya Ramakrishnan, Johnny Akers, Thien Nguyen, Aaron Wang, Bandita Adhikari, Brian Hirshman, Jie Li, Jann Sarkaria, Wei Hua, Mao Ying, Masayuki Nitta, Tao Jiang, Bob Carter, Clark C. Chen. miR-181d degradation mediated genetic heterogeneity and acquired resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1956.

Colovaginal and/or rectovaginal fistulas cause significant and distressing symptoms, including vaginitis, passage of flatus/feces through the vagina, and painful skin excoriation. These fistulas can be a challenging condition to treat. Although most fistulas can be treated with surgical repair, for those patients who are not operative candidates, limited options remain. As minimally-invasive interventional techniques have evolved, the possibility of fistula occlusion has enriched the therapeutic armamentarium for the treatment of these complex patients. In order to offer optimal treatment options to these patients, it is important to understand the imaging and anatomical features which may appropriately guide the surgeon and/or interventional radiologist during pre-procedural planning.

Objectives Our primary objective was to describe the prevalence of pelvic floor disorders (PFDs), pelvic girdle pain (PGP), and the female athlete triad (disordered eating, menstrual irregularities, and osteoporosis) in a female triathlete population. We also evaluated for an association between these conditions. Methods We administered an online survey to women who self-identified as female triathletes. Using validated questionnaires, Epidemiology of Prolapse and Incontinence Questionnaire and Pelvic Girdle Questionnaire, along with the female athlete triad questionnaire, we identified the prevalence of PFDs, PGP, and female athlete triad in this specific population. Demographic and exercise intensity were also queried to characterize these female triathletes. Results Three hundred eleven female triathletes responded to the Internet survey. There was a significant prevalence of PFDs with stress urinary incontinence and anal incontinence symptoms being most common (37.4% and 28%, respectively). Urgency urinary incontinence and pelvic organ prolapse were less common (16% and 5%, respectively). Stress urinary incontinence and pelvic organ prolapse were more common in parous triathletes (P = 0.001, P = 0.05). Pelvic girdle pain was noted in 18% of these triathletes but was not disabling. Twenty-four percent of participants screened positive for at least 1 arm of the female athlete triad. No association was found between the female athlete triad and PFDs. Conclusions Pelvic floor disorders are common and bothersome in female triathletes. Pelvic girdle pain, while present, does not limit these athletes from their training. These female triathletes may be at risk for the female athlete triad. Female triathletes may be at risk for both metabolic and PFDs and should be screened when identified.