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1.
J Pediatr Surg ; 2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31711743

RESUMO

PURPOSE: Because of the increasing use of nephron-sparing surgery (NSS) in bilateral Wilms tumor, we sought to review the early postoperative complications associated with NSS. METHODS: A retrospective review of patients who underwent NSS at our institution from 2000 to 2017 was performed. For comparison, a cohort of patients who underwent radical nephrectomy (RN) was also reviewed. Early (30-day) postoperative complications and oncologic outcomes were assessed. RESULTS: Fifty-five patients underwent either bilateral (46) NSS or unilateral (9) NSS owing to prior resection or congenital solitary kidney. Fifty-four patients who underwent unilateral RN were also evaluated. Twenty NSS patients (36.4%) experienced 21 postoperative complications, including prolonged urine leak (9), infection (8), transient renal insufficiency (1), and intussusception (3). Seven RN patients (13.0%) experienced surgical complications, including infection (4) and intussusception (3). Average intraoperative blood loss was significantly greater in NSS as compared to RN (483.51 ± 337.92 mL and 278.15 mL ± 390.25, respectively, p < 0.001), as was the incidence of positive tumor resection margins (20 [36.4%] and 12 [22.2%], respectively, (p = 0.037). CONCLUSIONS: In our experience, prolonged urine leak, intraoperative blood loss, and positive margins were more frequent in patients undergoing NSS as compared to RN. However, the complications were successfully managed, suggesting that an aggressive approach to NSS in patients with bilateral Wilms tumor is safe and appropriate. LEVEL OF EVIDENCE: Level III TYPE OF STUDY: Treatment study.

3.
Nat Commun ; 10(1): 5031, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31695028

RESUMO

The pharmacokinetic properties of antibodies are largely dictated by the pH-dependent binding of the IgG fragment crystallizable (Fc) domain to the human neonatal Fc receptor (hFcRn). Engineered Fc domains that confer a longer circulation half-life by virtue of more favorable pH-dependent binding to hFcRn are of great therapeutic interest. Here we developed a pH Toggle switch Fc variant containing the L309D/Q311H/N434S (DHS) substitutions, which exhibits markedly improved pharmacokinetics relative to both native IgG1 and widely used half-life extension variants, both in conventional hFcRn transgenic mice and in new knock-in mouse strains. engineered specifically to recapitulate all the key processes relevant to human antibody persistence in circulation, namely: (i) physiological expression of hFcRn, (ii) the impact of hFcγRs on antibody clearance and (iii) the role of competing endogenous IgG. DHS-IgG retains intact effector functions, which are important for the clearance of target pathogenic cells and also has favorable developability.

4.
Angiogenesis ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31754927

RESUMO

Angiogenesis is largely driven by motile endothelial tip-cells capable of invading avascular tissue domains and enabling new vessel formation. Highly responsive to Vascular Endothelial Growth-Factor-A (VEGFA), endothelial tip-cells also suppress angiogenic sprouting in adjacent stalk cells, and thus have been a primary therapeutic focus in addressing neovascular pathologies. Surprisingly, however, there remains a paucity of specific endothelial tip-cell markers. Here, we employ transcriptional profiling and a lacZ reporter allele to identify Kcne3 as an early and selective endothelial tip-cell marker in multiple angiogenic contexts. In development, Kcne3 expression initiates during early phases of angiogenesis (E9) and remains specific to endothelial tip-cells, often adjacent to regions expressing VEGFA. Consistently, Kcne3 activation is highly responsive to exogenous VEGFA but maintains tip-cell specificity throughout normal retinal angiogenesis. We also demonstrate endothelial tip-cell selectivity of Kcne3 in several injury and tumor models. Together, our data show that Kcne3 is a unique marker of sprouting angiogenic tip-cells and offers new opportunities for investigating and targeting this cell type.

5.
J Clin Invest ; 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31770111

RESUMO

Omalizumab is an anti-IgE monoclonal antibody (mAb) approved for the treatment of severe asthma and chronic spontaneous urticaria. Use of Omalizumab is associated with reported side effects, ranging from local skin inflammation at the injection site to systemic anaphylaxis. To date, the mechanisms through which Omalizumab induces adverse reactions are still unknown. Here, we demonstrated that immune complexes formed between Omalizumab and IgE can induce both skin inflammation and anaphylaxis through engagement of IgG receptors (FcγRs) in FcγR-humanized mice. We further developed an Fc-engineered mutant version of Omalizumab, and demonstrated that this mAb is equally potent as Omalizumab at blocking IgE-mediated allergic reactions, but does not induce FcγR-dependent adverse reactions. Overall, our data indicate that Omalizumab can induce skin inflammation and anaphylaxis by engaging FcγRs, and demonstrate that Fc-engineered versions of the mAb could be used to reduce such adverse reactions.

6.
J Pediatr Surg ; 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31685267

RESUMO

BACKGROUND/PURPOSE: MYCN-amplification in neuroblastoma is associated with an aggressive clinical phenotype. We evaluated the association of MYCN amplification with tumor response to neoadjuvant chemotherapy. METHODS: Primary tumor response, assessed by percentage volume change on CT scan and degree of tumor resection, assessed by the operating surgeon, were retrospectively compared in 84 high-risk neuroblastoma patients. There were thirty-four (40%) with MYCN-amplified tumors and fifty (60%) with non-amplified tumors treated at our institution from 1999 to 2016. Metastatic disease response was assessed on MIBG scan by change in Curie score. RESULTS: MYCN-amplification was associated with a greater mean percentage reduction in primary tumor volume after neoadjuvant chemotherapy (72.27% versus 46.83% [non-amplified tumors], p = 0.001). The percentage of patients with a Curie score > 2 at diagnosis who then had a score ≤ 2 after neoadjuvant chemotherapy was not significantly different (8 [61.5%] and 8 [34.8%], respectively, p = 0.37). Twenty-eight (85.7%) patients with MYCN-amplification had ≥90% surgical resection compared to 45 (91.84%) patients with non-amplified tumors (p = 0.303). CONCLUSIONS: MYCN-amplification in high-risk neuroblastoma was associated with a better response of the primary tumor to neoadjuvant chemotherapy, but not metastatic sites, than in patients with non-amplified tumors. This did not significantly impact the ability to resect ≥90% of the primary tumor/locoregional disease. TYPE OF STUDY: Treatment Study LEVEL OF EVIDENCE: Level III.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31688619

RESUMO

PURPOSE: This quality improvement initiative aimed to minimize opioid prescribing after oncologic pediatric surgery. METHODS: Retrospective surgical data collected at a pediatric cancer hospital from July 2016 to June 2018 included hospitalization details, oral morphine equivalents prescribed, unplanned visits/calls because of pain, and parental/patient satisfaction with pain control. The quality improvement initiative promoted opioid prescription at discharge on the basis of prior inpatient requirements and education regarding nonopioid analgesia. Upon commencing this project in July 2018, we collected data prospectively. RESULTS: The retrospective and the prospective cohorts included 271 and 99 patients, respectively. Mean (SD) oral morphine equivalents (mg/kg) prescribed upon discharge was significantly reduced in the prospective (0.75±1.34) versus retrospective cohorts (5.48±6.94, P<0.001). The unplanned visits/calls regarding pain were 23 (retrospective, 8.5%) and 2 (prospective, 2.0%). In total, 44 patients (44.4%) received an opioid prescription at discharge in the prospective cohort, significantly fewer than retrospective cohort (251, 92.6%, P<0.001), and used a mean of 34.3 of 159.8 (21.5%) doses dispensed. Length of stay was comparable (P=0.88) between cohorts. Prospective satisfaction rate was 96.2%, leaving 3 patients (3.8%) not satisfied with their pain control regimen. CONCLUSIONS: Dramatic reduction of opioid prescriptions after oncologic surgery can be achieved without detriment to patient satisfaction or readmissions. LEVEL OF EVIDENCE: Level V.

8.
Circulation ; 140(14): 1170-1184, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31567014

RESUMO

BACKGROUND: Despite robust cholesterol lowering, cardiovascular disease risk remains increased in patients with diabetes mellitus. Consistent with this, diabetes mellitus impairs atherosclerosis regression after cholesterol lowering in humans and mice. In mice, this is attributed in part to hyperglycemia-induced monocytosis, which increases monocyte entry into plaques despite cholesterol lowering. In addition, diabetes mellitus skews plaque macrophages toward an atherogenic inflammatory M1 phenotype instead of toward the atherosclerosis-resolving M2 state typical with cholesterol lowering. Functional high-density lipoprotein (HDL), typically low in patients with diabetes mellitus, reduces monocyte precursor proliferation in murine bone marrow and has anti-inflammatory effects on human and murine macrophages. Our study aimed to test whether raising functional HDL levels in diabetic mice prevents monocytosis, reduces the quantity and inflammation of plaque macrophages, and enhances atherosclerosis regression after cholesterol lowering. METHODS: Aortic arches containing plaques developed in Ldlr-/- mice were transplanted into either wild-type, diabetic wild-type, or diabetic mice transgenic for human apolipoprotein AI, which have elevated functional HDL. Recipient mice all had low levels of low-density lipoprotein cholesterol to promote plaque regression. After 2 weeks, plaques in recipient mouse aortic grafts were examined. RESULTS: Diabetic wild-type mice had impaired atherosclerosis regression, which was normalized by raising HDL levels. This benefit was linked to suppressed hyperglycemia-driven myelopoiesis, monocytosis, and neutrophilia. Increased HDL improved cholesterol efflux from bone marrow progenitors, suppressing their proliferation and monocyte and neutrophil production capacity. In addition to reducing circulating monocytes available for recruitment into plaques, in the diabetic milieu, HDL suppressed the general recruitability of monocytes to inflammatory sites and promoted plaque macrophage polarization to the M2, atherosclerosis-resolving state. There was also a decrease in plaque neutrophil extracellular traps, which are atherogenic and increased by diabetes mellitus. CONCLUSIONS: Raising apolipoprotein AI and functional levels of HDL promotes multiple favorable changes in the production of monocytes and neutrophils and in the inflammatory environment of atherosclerotic plaques of diabetic mice after cholesterol lowering and may represent a novel approach to reduce cardiovascular disease risk in people with diabetes mellitus.

9.
J Clin Invest ; 129(10): 4239-4244, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31483287

RESUMO

Macrophage activation in response to LPS is coupled to profound metabolic changes, typified by accumulation of the TCA cycle intermediates citrate, itaconate, and succinate. We have identified that endogenous type I IFN controls the cellular citrate/α-ketoglutarate ratio and inhibits expression and activity of isocitrate dehydrogenase (IDH); and, via 13C-labeling studies, demonstrated that autocrine type I IFN controls carbon flow through IDH in LPS-activated macrophages. We also found that type I IFN-driven IL-10 contributes to inhibition of IDH activity and itaconate synthesis in LPS-stimulated macrophages. Our findings have identified the autocrine type I IFN pathway as being responsible for the inhibition of IDH in LPS-stimulated macrophages.

10.
J Lipid Res ; 2019 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-31471447

RESUMO

Lipid rafts are highly ordered regions of the plasma membrane that are enriched in cholesterol and sphingolipids and play important roles in many cells. In hematopoietic stem and progenitor cells, lipid rafts house receptors critical for normal hematopoiesis. Lipid rafts also can bind and sequester kinases that induce negative feedback pathways to limit proliferative cytokine receptor cycling back to the cell membrane. Modulation of lipid rafts occurs through an array of mechanisms, with optimal cholesterol efflux one of the major regulators. As such, cholesterol homeostasis also regulates hematopoiesis. Increased lipid raft content, which occurs in response to changes in cholesterol efflux in the membrane, can result in prolonged receptor occupancy in the cell membrane and enhanced signaling. In addition, certain diseases, like diabetes, may contribute to lipid raft formation and affect cholesterol retention in rafts. In this review, we explore the role of lipid raft-related mechanisms in hematopoiesis and cardiovascular disease (specifically, atherosclerosis) and discuss how defective cholesterol efflux pathways in hematopoietic stem and progenitor cells contribute to expansion of lipid rafts, thereby promoting myelopoiesis and thrombopoiesis. We also discuss the utility of cholesterol acceptors in contributing to lipid raft regulation and disruption, and highlight the potential to manipulate these pathways for therapeutic gain in cardiovascular disease as well as other disorders with aberrant hematopoiesis.

11.
Front Immunol ; 10: 2054, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31555280

RESUMO

Monocytes in humans consist of 3 subsets; CD14+CD16- (classical), CD14+CD16+ (intermediate) and CD14dimCD16+ (non-classical), which exhibit distinct and heterogeneous responses to activation. During acute inflammation CD14+CD16- monocytes are significantly elevated and migrate to the sites of injury via the adhesion cascade. The field of immunometabolism has begun to elucidate the importance of the engagement of specific metabolic pathways in immune cell function. Yet, little is known about monocyte metabolism and the role of metabolism in mediating monocyte activation and adherence to vessels. Accordingly, we aimed to determine whether manipulating the metabolism of CD14+CD16- monocytes alters their ability to become activated and adhere. We discovered that LPS stimulation increased the rate of glycolysis in human CD14+CD16- monocytes. Inhibition of glycolysis with 2-deoxy-D-glucose blunted LPS-induced activation and adhesion of monocytes. Mechanistically, we found that increased glycolysis was regulated by mTOR-induced glucose transporter (GLUT)-1. Furthermore, enhanced glycolysis increased accumulation of reactive oxygen species (ROS) and activation of p38 MAPK, which lead to activation and adhesion of monocytes. These findings reveal that glycolytic metabolism is critical for the activation of CD14+CD16- monocytes and contributes to our understanding of the interplay between metabolic substrate preference and immune cell function.

12.
Artigo em Inglês | MEDLINE | ID: mdl-31562870

RESUMO

BACKGROUND: Severe inflammatory airway diseases are associated with inflammation that does not resolve, leading to structural changes and an overall environment primed for exacerbations. OBJECTIVE: We sought to identify and inhibit pathways that perpetuate this heightened inflammatory state because this could lead to therapies that allow for a more quiescent lung that is less predisposed to symptoms and exacerbations. METHODS: Using prolonged exposure to house dust mite in mice, we developed a mouse model of persistent and exacerbating airway disease characterized by a mixed inflammatory phenotype. RESULTS: We show that lung IL-33 drives inflammation and remodeling beyond the type 2 response classically associated with IL-33 signaling. IL-33 blockade with an IL-33 neutralizing antibody normalized established inflammation and improved remodeling of both the lung epithelium and lung parenchyma. Specifically, IL-33 blockade normalized persisting and exacerbating inflammatory end points, including eosinophilic, neutrophilic, and ST2+CD4+ T-cell infiltration. Importantly, we identified a key role for IL-33 in driving lung remodeling because anti-IL-33 also re-established the presence of ciliated cells over mucus-producing cells and decreased myofibroblast numbers, even in the context of continuous allergen exposure, resulting in improved lung function. CONCLUSION: Overall, this study shows that increased IL-33 levels drive a self-perpetuating amplification loop that maintains the lung in a state of lasting inflammation and remodeled tissue primed for exacerbations. Thus IL-33 blockade might ameliorate symptoms and prevent exacerbations by quelling persistent inflammation and airway remodeling.

13.
Cell Stem Cell ; 25(2): 258-272.e9, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374198

RESUMO

Tumors are composed of phenotypically heterogeneous cancer cells that often resemble various differentiation states of their lineage of origin. Within this hierarchy, it is thought that an immature subpopulation of tumor-propagating cancer stem cells (CSCs) differentiates into non-tumorigenic progeny, providing a rationale for therapeutic strategies that specifically eradicate CSCs or induce their differentiation. The clinical success of these approaches depends on CSC differentiation being unidirectional rather than reversible, yet this question remains unresolved even in prototypically hierarchical malignancies, such as acute myeloid leukemia (AML). Here, we show in murine and human models of AML that, upon perturbation of endogenous expression of the lineage-determining transcription factor PU.1 or withdrawal of established differentiation therapies, some mature leukemia cells can de-differentiate and reacquire clonogenic and leukemogenic properties. Our results reveal plasticity of CSC maturation in AML, highlighting the need to therapeutically eradicate cancer cells across a range of differentiation states.

14.
Sci Rep ; 9(1): 12031, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31427700

RESUMO

Harnessing complement-mediated cytotoxicity by therapeutic antibodies has been limited because of dependency on size and density of antigen, structural constraints resulting from orientation of antibody binding, and blockade of complement activation by inhibitors expressed on target cells. We developed a modular bispecific antibody platform that directs the complement-initiating protein C1q to target cells, increases local complement deposition and induces cytotoxicity against target antigens with a wide-range of expression. The broad utility of this approach to eliminate both prokaryotic and eukaryotic cells was demonstrated by pairing a unique C1q-recruiting arm with multiple targeting arms specific for Staphylococcus aureus, Pseudomonas aeruginosa, B-cells and T-cells, indicating applicability for diverse indications ranging from infectious diseases to cancer. Generation of C1q humanized mice allowed for demonstration of the efficacy of this approach to clear disease-inducing cells in vivo. In summary, we present a novel, broadly applicable, and versatile therapeutic modality for targeted cell depletion.

15.
Biol Blood Marrow Transplant ; 25(11): 2181-2185, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31255742

RESUMO

Hematopoietic stem cell transplantation (HSCT) in the pediatric population is associated with pulmonary complications in 25% of recipients. The role of surgical lung biopsy (SLB) remains unclear because of concerns about both the therapeutic impact and morbidity associated with the procedure. A retrospective review of consecutive allogeneic HSCT recipients at Dana-Farber and Boston Children's Hospital Cancer and Blood Disorders Center between 2006 and 2016 was performed. All recipients who underwent SLB during the study period were identified and charts reviewed for perioperative complications, histopathologic findings, and changes in therapy delivered. Pearson's chi-square test and Student's t-test (or appropriate nonparametric test) were used to evaluate the associations between perioperative complication and categorical and continuous variables, respectively. Five hundred fifty-five HSCTs were included, among which 48 SLBs (8.6%) were identified. Median follow-up time was 24 months (range, 0 to 139). Thirty-day postoperative morbidity was 16.7% and 30-day postoperative mortality 10.4% (n = 5). The overall 30-day postoperative complication rate (including mortality) was 20.8% (n = 10). No mortalities were directly attributable to SLB. Definitive diagnoses were identified in 70.8% of SLBs (n = 34), and therapeutic changes occurred in 79.2% (n = 38). Overall, 83.3% of SLBs (n = 40) either provided a diagnosis or led to a change in therapy. SLB has an acceptable risk of perioperative complications in this medically complicated and often severely ill population. In most HSCT patients, SLB aids in defining the etiology of pulmonary infiltrates and can inform therapeutic decisions in patients where noninvasive diagnostic modalities have failed to provide a definitive diagnosis.

16.
Cancer ; 125(21): 3873-3881, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31322729

RESUMO

BACKGROUND: The prevalence and associated psychosocial morbidity of late-onset anorectal disease after surgery and radiotherapy for the treatment of childhood cancer are not known. METHODS: A total of 25,530 survivors diagnosed between 1970 and 1999 (median age at cancer diagnosis, 6.1 years; age at survey, 30.2 years) and 5036 siblings were evaluated for late-onset anorectal disease, which was defined as a self-reported fistula-in-ano, self-reported anorectal stricture, or pathology- or medical record-confirmed anorectal subsequent malignant neoplasm (SMN) 5 or more years after the primary cancer diagnosis. Piecewise exponential models compared the survivors and siblings and examined associations between cancer treatments and late-onset anorectal disease. Multiple logistic regression with generalized estimating equations was used to evaluate associations between late-onset anorectal disease and emotional distress, as defined by the Brief Symptom Inventory 18 (BSI-18), and health-related quality of life, as defined by the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). RESULTS: By 45 years after the diagnosis, 394 survivors (fistula, n = 291; stricture, n = 116; anorectal SMN, n = 26) and 84 siblings (fistula, n = 73; stricture, n = 23; anorectal neoplasm, n = 1) had developed late-onset anorectal disease (adjusted rate ratio [RR] for survivors vs siblings, 1.2; 95% confidence interval [CI], 1.0-1.5). Among survivors, pelvic radiotherapy with ≥30 Gy within 5 years of the cancer diagnosis was associated with late-onset anorectal disease (adjusted RR for 30-49.9 Gy vs none, 1.6; 95% CI, 1.1-2.3; adjusted RR for ≥50 Gy vs none, 5.4; 95% CI, 3.1-9.2). Late-onset anorectal disease was associated with psychosocial impairment in all BSI-18 and SF-36 domains. CONCLUSIONS: Late-onset anorectal disease was more common among childhood cancer survivors who received higher doses of pelvic radiotherapy and was associated with substantial psychosocial morbidity.

17.
J Laparoendosc Adv Surg Tech A ; 29(8): 1046-1051, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31241404

RESUMO

Background: Despite the lack of randomized or controlled trials for minimally invasive surgery (MIS) in pediatric surgical oncology, the integration of MIS into the surgical practice of pediatric oncology has become increasingly popular. The aim of this study was to evaluate the implementation of MIS in a pediatric tertiary cancer center and compare present use of MIS to that in a previous analysis at our center. Methods: We retrospectively reviewed the medical records of patients with pediatric cancer treated with MIS at a single institution between 2000 and 2014. Results: A total of 252 MIS procedures were performed: 73 laparoscopic (29%) and 179 thoracoscopic (71%). MIS was used for diagnostic purposes in 59% (146 thoracoscopic and 34 laparoscopic) and the therapeutic resection in 24% (39 laparoscopic cases and 33 thoracoscopic cases). Conversion to an open procedure occurred in 18 tumor resections (6%) and in 22 diagnostic biopsies (7%), mostly due to technical challenges in identifying or mobilizing tumors. Complications occurred in seven tumor resections (2%) and included three pneumothoraces, two bleeding complications, one bowel injury, and one wound infection. Complications occurred in 10 diagnostic biopsies (3%), mostly pneumothoraces. No tumor upstaging or trocar site recurrences occurred (follow-up time, 1-15 years). Conclusions: Over the last decade, we demonstrate the evolution of MIS in the management of solid tumors in children. We encourage surgeons and oncologists to join the call to arms to establish prospective trials evaluating MIS in pediatric surgical oncology.


Assuntos
Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Neoplasias/cirurgia , Pediatria/métodos , Oncologia Cirúrgica/métodos , Biópsia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Laparoscopia , Masculino , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Toracoscopia
18.
Methods ; 164-165: 91-99, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31039396

RESUMO

The engineering of conditional alleles has evolved from simple floxing of regions of genes to more elaborate methods. Previously, we developed Conditional by Inversion (COIN), an allele design that utilizes an exon-splitting intron and an invertible genetrap-like module (COIN module) to create null alleles upon Cre-mediated inversion. Here we build upon COINs by generating a new Multifunctional Allele (MFA), that utilizes a single gene-targeting step and three site-specific recombination systems, to generate four allelic states: 1. The initial MFA (generated upon targeting) functions as a null with reporter (plus drug selection cassette) allele, wherein the gene of interest is inactivated by both inversion of a critical region of its coding sequence and simultaneous insertion of a reporter gene. MFAs can also be used as 'reverse-conditional' alleles as they are functionally wild type when they are converted to COIN alleles. 2. Null with reporter (minus drug selection cassette), wherein the selection cassette, the inverted critical region, and the COIN module are removed. 3. COIN-based conditional-null via removal of the selection cassette and reporter and simultaneous re-inversion of the critical region of the target. 4. Inverted COIN allele, wherein the COIN allele in turn is reconverted to a null allele by taking advantage of the COIN module's gene trap while simultaneously deleting the critical region.

19.
J Surg Res ; 242: 336-341, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31129243

RESUMO

BACKGROUND: Individuals with sickle cell disease (SCD) are at high risk of developing life-threatening complications, particularly acute chest syndrome (ACS) postoperatively. The perioperative factors associated with the development of ACS in children with SCD after splenectomy have not been clearly identified. MATERIALS AND METHODS: We retrospectively reviewed medical records of all children who underwent splenectomy at our institution between 1997 and 2017 with the goal of identifying perioperative factors associated with postoperative ACS. Categorical and noncategorical variables were compared using Fisher's exact test and Student's two-tailed t-test, respectively. RESULTS: Sixty-five patients with SCD underwent splenectomy at a median of 4.0 (interquartile range [IQR] 2.0-8.0) years of age. A laparoscopic approach was used for 64 (98.5%) patients. Fifty-six (86.2%) underwent laparoscopic total splenectomy, and eight (12.3%) underwent laparoscopic partial splenectomy, of which two were converted to open. One had an open partial splenectomy (1.5%). Of the 65 patients, 10 (15.4%) developed ACS with a mean time to diagnosis of 49.0 ± 34.5 h. Children who developed ACS had a higher postoperative median pain score of 6.8 (IQR 5.1-9.1) versus 2.7 (IQR 1.6-4.2), P < 0.001, higher median pain score area under the curve 111.5 (IQR 76.9-169.1) versus 47.3 (IQR 30.5-78.3), P = 0.01, and received more total morphine equivalents (median 1.4 [IQR 0.4-2.7] versus 0.5 [IQR 0.3-0.9] mg/kg, respectively; P = 0.003), compared with children who did not develop ACS. CONCLUSIONS: Significant postoperative pain may be an early sign of ACS that could be worsened by opioid use, supporting the investigation of nonopioid pain control options in this patient population.

20.
Ann Surg Oncol ; 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30963398

RESUMO

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare intra-abdominal soft tissue sarcoma affecting adolescents and young adults. Cytoreduction, hyperthermic intraperitoneal chemotherapy (CRS/HIPEC), and adjuvant radiotherapy may improve local control. We review our experience with patients who undergo CRS/HIPEC and adjuvant radiotherapy for DSRCT. METHODS: A retrospective review was performed for patients with DSRCT from 2013 to 2017 who underwent CRS/HIPEC. Clinicopathologic, operative, and outcome data were reviewed. RESULTS: Ten CRS/HIPEC procedures were performed for nine patients (7 males, 6 Caucasian, median age 19 years (range 10-24)). Four patients presented with extra-abdominal disease; five had liver involvement. The median peritoneal cancer index was 16 (range 5-20). All received neoadjuvant chemotherapy. CCR 0/1 resection was possible in nine patients. Major complications occurred in four with no operative mortalities. All received adjuvant chemotherapy, seven received radiation therapy, and three received stem-cell transplant. All but one patient recurred after treatment. The median recurrence-free and overall survival (OS) were 12 and 45 months (95% confidence interval 35.1-54.9) respectively, with a 3-year OS of 55%. Long-term parenteral nutrition was required in eight for a median of 261 days (range 37-997). Clinically significant long-term complications requiring further surgery included gastroparesis (N = 1), small bowel obstruction (N = 3) and hemorrhagic cystitis (N = 2). CONCLUSIONS: Multimodal therapy for DSRCT consisting of multiagent neoadjuvant chemotherapy, CRS/HIPEC, adjuvant chemotherapy, and radiation therapy is associated with potential cumulative toxicity. Recurrence after resection is common. Prolonged parenteral nutrition may be necessary, and late gastrointestinal and genitourinary complications may require additional treatment.

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