Higher risk tumor features are not associated with higher nodal stage in patients with estrogen receptor-positive, node-positive breast cancer.

INTRODUCTION: Studies support omission of axillary lymph node dissection (ALND) for patients with sentinel node-positive disease, with ALND recommended for patients who present with clinically positive nodes. Here, we evaluate patient and tumor characteristics and pathologic nodal stage of patients with estrogen receptor-positive (ER +) breast cancer who undergo ALND to determine if differences exist based on nodal presentation. MATERIALS AND METHODS: Retrospective chart review from 2010 to 2019 defined three groups of patients with ER + breast cancer who underwent ALND for positive nodes: SLN + (positive node identified at SLN biopsy), cNUS (abnormal preoperative US and biopsy), and cNpalp (palpable adenopathy). Patients who received neoadjuvant chemotherapy or presented with axillary recurrence were excluded. RESULTS: Of 191 patients, 94 were SLN + , 40 were cNUS, and 57 were cNpalp. Patients with SLN + compared with cNpalp were younger (56 vs 64 years, p < 0.01), more often pre-menopausal (41% vs 14%, p < 0.01), and White (65% vs 39%, p = 0.01) with more tumors that were low-grade (36% vs 8%, p < 0.01). Rates of PR + (p = 0.16), levels of Ki67 expression (p = 0.07) and LVI (p = 0.06) did not differ significantly among groups. Of patients with SLN + disease, 64% had pN1 disease compared to 38% of cNUS (p = 0.1) and 40% of cNpalp (p = 0.01). On univariable analysis, tumor size (p = 0.01) and histology (p = 0.04) were significantly associated with pN1 disease, with size remaining an independent predictor on multivariable analysis (p = 0.02). CONCLUSION: Historically, higher risk features have been attributed to patients with clinically positive nodes precluding omission of ALND, but when restricting evaluation to patients with ER + breast cancer, only tumor size is associated with higher nodal stage.

Upstaging of Fibroepithelial Lesions: A Single-Institution Experience.

INTRODUCTION: Fibroepithelial lesions of the breast (FEL) are heterogeneous lesions ranging from fibroadenomas (FA) to phyllodes tumors (PT). FEL with cellular stroma are diagnostic challenges on core needle biopsy (CNB) as it is difficult to distinguish cellular FA from PT. The purpose of this study was to determine the features of FEL on CNB that may be predictive of PT, the upstage rate to PT after excision, and the outcomes of those who did not undergo excision. METHODS: Overall, 305 patients with FEL on CNB between 2009 and 2019 were identified from a prospectively maintained institutional database. Presentation, imaging, and pathology were evaluated. RESULTS: Mean age at diagnosis was 43.8 years. Pathology on CNB included 97 cases of FEL favoring FA, 19 cases of FEL favoring PT, 3 cases of FEL versus pseudoangiomatous stromal hyperplasia, and 186 cases of FEL not otherwise specified. Following CNB, 96 (31.5%) patients were observed, 158 (51.8%) patients had an excisional biopsy, 48 (15.7%) patients underwent segmental mastectomy, and 3 (1.0%) patients underwent a mastectomy. The upgrade rate from FEL on CNB to PT upon excision was 25.8%. PT on final pathology was more commonly seen when the CNB identified stromal overgrowth, necrosis, and diagnosis of FEL favoring PT. On multivariable analysis, a final diagnosis of PT was associated with age >50 years, larger tumor size >2 cm, stromal overgrowth, and ≥1 mitoses/10 high power fields (HPF) on CNB. Patients who were observed had smaller tumors compared with those who underwent excision. CONCLUSION: In this 10-year single-institution experience of FEL, the upstage rate to PT was 25.8%. Excision of FEL is recommended. Furthermore, the observation of lesions appeared to be safe in select cases, specifically in patients with smaller tumor size.

Commission on Cancer CP3R Compliance Rates for Treatment of Patients With Triple Negative and HER2+ Breast Cancer: A National Cancer Database Analysis.

BACKGROUND: Cancer Program Practice Profile Reports (CP3R) metrics were released by the Commission on Cancer to provide standards for high-quality care. One metric is the recommendation of combination chemotherapy or chemo-immunotherapy (CIT) within 120 days of diagnosis for women under 70 with AJCC T1cN0M0 or Stage IB-III HER2+ or hormone receptor negative breast cancer ([Multi-agent chemotherapy] MAC). Our study assesses national concordance rates for MAC and CIT. METHODS: The National Cancer Database was queried from 2004-2014. RESULTS: 122,045 patients met criteria, of whom treatment for 101,800 (83.4%) patients was concordant with MAC and CIT. Treatment concordance increased from 75.7% in 2004 to 89.5% in 2014. For HER2+ patients, use of CIT treatment downtrended with progression of pathological stage, from 70.1% (stage I) to 58.1% (stage III). Mean overall survival of patients whose treatment was concordant with MAC and CIT was longer than that of patients who were non-concordant (146.6 vs 143.8 months, P <.01). On Cox regression, there was a survival benefit for concordant patients who were treated at academic hospitals (HR .89, 95% CI 0.802-.976) and had private insurance (HR .76, 95% CI 0.65-.89). CONCLUSION: Compliance with MAC and CIT has improved over the past decade and is associated with a significant improvement in overall survival.

Clinicopathologic Characteristics and Patient Outcomes of Phyllodes Tumors: A Single Institution Experience.

Phyllodes tumors (PT) are rare fibroepithelial neoplasms that are classified as benign, borderline, or malignant. Patients with PT diagnosed between 2009 and 2019 were identified from a prospectively maintained single institutional database. 76 patients with PT were included; 47 (61.8%) were benign, 9 (11.8%) were borderline, and 20 (26.3%) were malignant. The mean age at diagnosis was 52. Surgical treatment of benign PT included excisional biopsy in 31 (66.0%) patients, segmental mastectomy in 15 (31.9%), and mastectomy in 1 (2.1%). Among patients with borderline PT, operative management was excisional biopsy in 4 (44.4%) and segmental mastectomy in 5 (55.6%). Of those with malignant PT, 7 (35.0%) were treated with excisional biopsy alone, 9 (45.0%) had lumpectomy (segmental mastectomy), and 4 (20.0%) underwent mastectomy. Malignant PT had a higher rate of necrosis compared to borderline or benign PT (25.0% vs 0% vs 4.3%, P = .016). Four patients had recurrent PT. Final positive margins were associated with recurrence (P = .044). The median overall follow-up time was 86.3 months (range 1.5-1414.1 months), and no deaths occurred among patients with malignant PT. Overall, recurrence rates of PT are low but may be increased by presence of positive margins.

Comparison of multiple oncotype DX® from the same patient.

For women with breast cancer in whom multiple Oncotype DX® Recurrence Scores (RS) are obtained, RS concordance utilizing current NCCN recommendations has not been evaluated. Patients with two or more RS were identified. RS were stratified by NCCN guidelines and compared for concordance. Twenty-four patients were evaluated. RS concordance varied by tumor type: 100% in the same tumor, 91.7% in multiple ipsilateral tumors, 71.4% in contralateral tumors, and 66.7% in in-breast recurrent tumors. RS concordance for multiple assays in the same patient is not high enough to omit Oncotype DX® testing for each tumor.

Assessing the Burden of Nodal Disease for Breast Cancer Patients with Clinically Positive Nodes: Hope for More Limited Axillary Surgery.

BACKGROUND: Omission of axillary lymph node dissection (ALND) is accepted for patients with one or two positive sentinel nodes, and studies are focusing on clinically node-positive patients who have been downstaged with neoadjuvant chemotherapy (NAC). Evidence is lacking for patients with positive nodes who undergo surgery upfront. These patients are assumed to have a higher burden of nodal disease such that ALND remains the standard of care. METHODS: Patients who underwent ALND for breast cancer between 2010 and 2019 at the authors' institution were retrospectively identified. Those with clinical N1 disease were included in the study. Patients who received NAC and those who had surgery for sentinel node positive disease or axillary recurrence were excluded. Clinical and pathologic factors associated with nodal stage were evaluated. RESULTS: Of 111 patients who met the inclusion criteria, 61.3% had a palpable node on exam, and 41.4% ultimately had pN1 disease. Most of the tumors were estrogen receptor (ER)-positive (91.5%), and 21.7% of the tumors were invasive lobular cancers. Lobular histology, tumor size, and metastasis size were associated with higher nodal stage. In the multivariable analysis, the patients with nodal metastasis larger than 10 mm had significantly lower odds of having pN1 disease (odds ratio 0.12; 95% confidence interval 0.02-0.69; p = 0.02). In a subset analysis of patients with palpable nodes, tumor size and histology remained significantly associated with nodal stage. CONCLUSION: More than 40% of breast cancer patients with clinically positive nodes had minimal nodal disease (pN1) at surgery. Additionally, palpable nodes on exam did not predict higher nodal stage. A subset of patients with clinically positive nodes may be identified who can potentially be spared the morbidity of ALND.

Quantitative Measure of Intestinal Permeability Using Blue Food Coloring.

BACKGROUND: Loss of intestinal barrier integrity plays a fundamental role in the pathogenesis of various gastrointestinal diseases and is implicated in the onset of sepsis and multiple organ failure. An array of methods to assess different aspects of intestinal barrier function suffers from lack of sensitivity, prolonged periods of specimen collection, or high expense. We have developed a technique to measure the concentration of the food dye FD&C Blue #1 from blood and sought to assess its utility in measuring intestinal barrier function in humans. MATERIALS AND METHODS: Four healthy volunteers and 10 critically ill subjects in the intensive care unit were recruited in accordance with an institutional review board approved protocol. Subjects were given 0.5 mg/kg Blue #1 enterally as an aqueous solution of diluted food coloring. Five blood specimens were drawn per subject: 0 h (before dose), 1, 2, 4, and 8 h. After plasma isolation, organic extracts were analyzed by high-performance liquid chromatography/mass spectrometry detecting the presence of unmodified dye. RESULTS: We found no baseline detectable absorption in healthy volunteers. After including the subjects in the intensive care unit, we compared dye absorption in the six subjects who met criteria for septic shock with the eight who did not. Septic patients demonstrated significantly greater absorption of Blue #1 after 2 h. CONCLUSIONS: We have developed a novel, easy-to-use method to measure intestinal barrier integrity using a food grade dye detectable by mass spectrometry analysis of patient blood following oral administration.

Human hepatocyte transplantation corrects the inherited metabolic liver disorder arginase deficiency in mice.

The transplantation, engraftment, and expansion of primary hepatocytes have the potential to be an effective therapy for metabolic disorders of the liver including those of nitrogen metabolism. To date, such methods for the treatment of urea cycle disorders in murine models has only been minimally explored. Arginase deficiency, an inherited disorder of nitrogen metabolism that presents in the first two years of life, has the potential to be treated by such methods. To explore the potential of this approach, we mated the conditional arginase deficient mouse with a mouse model deficient in fumarylacetoacetate hydrolase (FAH) and with Rag2 and IL2-Rγ mutations to give a selective advantage to transplanted (normal) human hepatocytes. On day -1, a uroplasminogen-expressing adenoviral vector was administered intravenously followed the next day with the transplantation of 1 × 106 human hepatocytes (or vehicle alone) by intrasplenic injection. As the initial number of administered hepatocytes would be too low to prevent hepatotoxicity-induced mortality, NTBC cycling was performed to allow for hepatocyte expansion and repopulation. While all control mice died, all except one human hepatocyte transplanted mice survived. Four months after hepatocyte transplantation, 2 × 1011 genome copies of AAV-TBG-Cre recombinase was administered IV to disrupt endogenous hepatic arginase expression. While all control mice died within the first month, human hepatocyte transplanted mice did well. Ammonia and amino acids, analyzed in both groups before and after disruption of endogenous arginase expression, while well-controlled in the transplanted group, were markedly abnormal in the controls. Ammonium challenging further demonstrated the durability and functionality of the human repopulated liver. In conclusion, these studies demonstrate that human hepatocyte repopulation in the murine liver can result in effective treatment of arginase deficiency.

Noninvasive Imaging of Drug-Induced Liver Injury with 18F-DFA PET.

Drug-induced liver failure is a significant indication for a liver transplant, and unexpected liver toxicity is a major reason that otherwise effective therapies are removed from the market. Various methods exist for monitoring liver injury but are often inadequate to predict liver failure. New diagnostic tools are needed. Methods: We evaluate in a preclinical model whether 18F-2-deoxy-2-fluoroarabinose (18F-DFA), a PET radiotracer that measures the ribose salvage pathway, can be used to monitor acetaminophen-induced liver injury and failure. Mice treated with vehicle, 100, 300, or 500 mg/kg acetaminophen for 7 or 21 h were imaged with 18F-FDG and 18F-DFA PET. Hepatic radiotracer accumulation was correlated to survival and percentage of nonnecrotic tissue in the liver. Mice treated with acetaminophen and vehicle or N-acetylcysteine were imaged with 18F-DFA PET. 18F-DFA accumulation was evaluated in human hepatocytes engrafted into the mouse liver. Results: We show that hepatic 18F-DFA accumulation is 49%-52% lower in mice treated with high-dose acetaminophen than in mice treated with low-dose acetaminophen or vehicle. Under these same conditions, hepatic 18F-FDG accumulation was unaffected. At 21 h after acetaminophen treatment, hepatic 18F-DFA accumulation can distinguish mice that will succumb to the liver injury from those that will survive it (6.2 vs. 9.7 signal to background, respectively). Hepatic 18F-DFA accumulation in this model provides a tomographic representation of hepatocyte density in the liver, with a R2 between hepatic 18F-DFA accumulation and percentage of nonnecrotic tissue of 0.70. PET imaging with 18F-DFA can be used to distinguish effective from ineffective resolution of acetaminophen-induced liver injury with N-acetylcysteine (15.6 vs. 6.2 signal to background, respectively). Human hepatocytes, in culture or engrafted into a mouse liver, have levels of ribose salvage activity similar to those of mouse hepatocytes. Conclusion: Our findings suggest that PET imaging with 18F-DFA can be used to visualize and quantify drug-induced acute liver injury and may provide information on the progression from liver injury to hepatic failure.

Rescue Diverting Loop Ileostomy: An Alternative to Emergent Colectomy in the Setting of Severe Acute Refractory IBD-Colitis.

BACKGROUND: Severe acute refractory colitis has traditionally been an indication for emergent colectomy in IBD, yet under these circumstances patients are at elevated risk for complications because of their heightened inflammatory state, nutritional deficiencies, and immunocompromised state. OBJECTIVE: We hypothesized that rescue diverting loop ileostomy may be a viable alternative to emergent colectomy, providing the opportunity for colonic healing and patient optimization before more definitive surgery. DESIGN: This was a retrospective case series. SETTINGS: The study was conducted at a single academic center. PATIENTS: Patients with severe acute medically refractory IBD-related colitis were included. INTERVENTION: Rescue diverting loop ileostomy was the intervening procedure. MAIN OUTCOME MEASURES: The primary outcome was avoidance of urgent/emergent colectomy. The secondary outcome was efficacy, defined by 3 clinical aims: 1) reduced steroid dependence or opportunity for bridge to medical rescue, 2) improved nutritional status, and 3) ability to undergo an elective laparoscopic definitive procedure or ileostomy reversal with colon salvage. RESULTS: Among 33 patients, 14 had Crohn's disease and 19 had ulcerative colitis. Three patients required urgent/emergent colectomy, 2 with ulcerative colitis and 1 with Crohn's disease. Across both disease cohorts, >80% of patients achieved each clinical aim for efficacy: 88% reduced their steroid dependence or were able to bridge to medical rescue, 87% improved their nutritional status, and 82% underwent an elective laparoscopic definitive procedure or ileostomy reversal. A total of 4 patients (11.7%) experienced a postoperative complication following diversion, including 3 surgical site infections and 1 episode of acute kidney injury. LIMITATIONS: The study was limited by being a single-center, retrospective series. CONCLUSIONS: Rescue diverting loop ileostomy in the setting of severe, refractory IBD-colitis is a safe and effective alternative to emergent colectomy. This procedure has acceptably low complication rates and affords patients time for medical and nutritional optimization before definitive surgical intervention. See Video Abstract at http://links.lww.com/DCR/A520.

Pneumonia after liver transplantation.

PURPOSE OF REVIEW: Pneumonia occurs in 8-23% of patients after liver transplantation and contributes considerably to their morbidity and mortality. With the increasing acuity of liver transplantation patients in the current era, pneumonias, particularly ventilator-associated pneumonias, and multidrug-resistant pathogens, are of growing concern. RECENT FINDINGS: Postliver transplantation pneumonia cause varies with the timing of infection. In the early period (<1 month postliver transplantation), nosocomial pneumonias, including ventilator-associated pneumonias and multidrug-resistant species are most common. During the intermediate period (1-6 months postliver transplantation), opportunistic infections predominate as intensive immunosuppression persists. In the late period (>6 months postliver transplantation), community-acquired bacterial and viral pneumonias arise, as immunosuppression is reduced. Numerous risk factors have been implicated in postliver transplantation pneumonias. Prevention is aimed at reducing bacterial colonization, preventing aspiration events, and utilizing surveillance and targeted antibiotics. Novel studies have also shown reduced risk of infection with personalized immunosuppression regimens guided by an immune function assay. SUMMARY: The etiologic patterns, risk factors, and preventive measures for postliver transplantation pneumonia must be understood to minimize patient exposure to modifiable risks and optimize recipient status in the perioperative period. Prevention is multifaceted and may be enhanced by personalization of immune therapy based on predisposition to infection and graft rejection.

Optimizing the Management of Abnormal Liver Function Tests after Orthotopic Liver Transplant: A Systems-Based Analysis of Health Care Utilization.

Elevated liver function tests (eLFTs) are a major cause of unplanned readmissions (UR) after orthotopic liver transplantation. Diagnostic workup for eLFTs requires multiple invasive and noninvasive procedures, often done in the inpatient setting to expedite diagnosis, yet consequently resulting in increased costs. In this study, we evaluated eLFT readmissions at a single institution with respect to resource utilization. From 3/2013 to 12/2015, 388 patients underwent orthotopic liver transplantation, resulting in 463 UR totaling 5833 bed days; 87 (18.8%) UR and 929 (15.9%) bed days were for eLFTs. During eLFT-UR all patients underwent repeat laboratory testing, 75 (86.2%) liver ultrasound, 66 (75.8%) liver biopsy, and 17 (19.5%) endoscopic retrograde cholangiopancreatography. Discharge diagnoses were acute cellular rejection (40.2%), transaminitis not otherwise specified (17.2%), biliary complications (16.1%), recurrent hepatitis (11.5%), vascular complications (5.8%), viral hepatitis (5.8%), and steatohepatitis (3.5%). The greatest bed-day utilization was secondary to acute cellular rejection (60.8%) and biliary complications (13.7%). More than 35 per cent of eLFT-UR were due to transaminitis not otherwise specified, steatohepatitis, recurrent or viral hepatitis, none of which necessitate inpatient treatment. In addition, >25 per cent of eLFT-UR bed days were attributed to diagnostic workup. Identifying patients who can undergo expedited outpatient workup and require only outpatient management will result in significantly decreased readmissions, bed days, and hospital costs.

Restoring Ureagenesis in Hepatocytes by CRISPR/Cas9-mediated Genomic Addition to Arginase-deficient Induced Pluripotent Stem Cells.

Urea cycle disorders are incurable enzymopathies that affect nitrogen metabolism and typically lead to hyperammonemia. Arginase deficiency results from a mutation in Arg1, the enzyme regulating the final step of ureagenesis and typically results in developmental disabilities, seizures, spastic diplegia, and sometimes death. Current medical treatments for urea cycle disorders are only marginally effective, and for proximal disorders, liver transplantation is effective but limited by graft availability. Advances in human induced pluripotent stem cell research has allowed for the genetic modification of stem cells for potential cellular replacement therapies. In this study, we demonstrate a universally-applicable CRISPR/Cas9-based strategy utilizing exon 1 of the hypoxanthine-guanine phosphoribosyltransferase locus to genetically modify and restore arginase activity, and thus ureagenesis, in genetically distinct patient-specific human induced pluripotent stem cells and hepatocyte-like derivatives. Successful strategies restoring gene function in patient-specific human induced pluripotent stem cells may advance applications of genetically modified cell therapy to treat urea cycle and other inborn errors of metabolism.