A phase 2 study of AZD4635 in combination with durvalumab or oleclumab in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Inhibition of the adenosine 2A receptor (A2AR) diminishes the immunosuppressive effects of adenosine and may complement immune-targeting drugs. This phase 2 study evaluated the A2AR antagonist AZD4635 in combination with durvalumab or oleclumab in patients with metastatic castration-resistant prostate cancer. METHODS: Patients with histologically/cytologically confirmed disease progressing within 6 months on ≥ 2 therapy lines were randomly assigned to either Module 1 (AZD4635 + durvalumab) or Module 2 (AZD4635 + oleclumab). Primary endpoints were objective response rate per RECIST v1.1 and prostate-specific antigen (PSA) response rate. Secondary endpoints included radiological progression-free survival (rPFS), overall survival, safety, and pharmacokinetics. RESULTS: Fifty-nine patients were treated (Module 1, n = 29; Module 2, n = 30). Median number of prior therapies was 4. One confirmed complete response by RECIST (Module 1) and 2 confirmed PSA responses (1 per module) were observed. The most frequent adverse events (AEs) possibly related to AZD4635 were nausea (37.9%), fatigue (20.7%), and decreased appetite (17.2%) in Module 1; nausea (50%), fatigue (30%), and vomiting (23.3%) in Module 2. No dose-limiting toxicities or treatment-related serious AEs were observed. In Module 1, AZD4635 geometric mean trough concentration was 124.9 ng/mL (geometric CV% 69.84; n = 22); exposures were similar in Module 2. In Modules 1 and 2, median (95% CI) rPFS was 2.3 (1.6 -3.8) and 1.5 (1.3- 4.0) months, respectively. Median PFS was 1.7 versus 2.3 months for patients with high versus low blood-based adenosine signature. CONCLUSION: In this heavily pretreated population, AZD4635 with durvalumab or oleclumab demonstrated minimal antitumor activity with a manageable safety profile. CLINICAL TRIAL: gov identifier: NCT04089553.

Distinguishing characteristics of xanthogranulomatous cholecystitis and gallbladder adenocarcinoma: a persistent diagnostic dilemma.

BACKGROUND: Xanthogranulomatous cholecystitis (XGC) is an uncommon variant of chronic cholecystitis which can resemble gallbladder adenocarcinoma (GAC) on preoperative imaging and present technical challenges in the performance of cholecystectomy. We examined our experience with each pathology to identify distinguishing characteristics that may guide patient counseling and surgical management. METHODS: A retrospective review of all pathologically confirmed cases of XGC and GAC following cholecystectomy between 2015 and 2021 at a single institution was performed. Clinical, biochemical, radiographic, and intraoperative features were compared. RESULTS: There were 37 cases of XGC and 20 cases of GAC. Patients with GAC were older (mean 70.3 years vs 58.0, p = 0.01) and exclusively female (100% vs 45.9%, p < 0.0001). There were no significant differences in accompanying symptoms between groups (nausea/vomiting, fevers, or jaundice). The mean maximum white blood cell count was elevated for XGC compared to GAC (16.4 vs 8.6 respectively, p = 0.044); however, there were no differences in the remainder of the biochemical profile, including bilirubin, liver transaminases, CEA, and CA 19-9. The presence of an intraluminal mass (61.1% vs 9.1%, p = 0.0001) and lymphadenopathy (18.8%. vs 0.0%, p = 0.045) were associated with malignancy, whereas gallbladder wall thickening as reported on imaging (87.9% vs 38.9%, p = 0.0008) and gallstones (76.5% vs. 50.0%, p = 0.053) were more often present with XGC. Cases of XGC more often had significant adhesions/inflammation (83.8% vs 55.0%, p = 0.03). CONCLUSION: Clinical features that may favor benign chronic cholecystitis over gallbladder adenocarcinoma include younger age, male gender, current or prior leukocytosis, and the absence of an intraluminal mass or lymphadenopathy. Laparoscopic cholecystectomy is a safe surgical option for equivocal presentations. Intraoperative frozen section or intentional staging of more extensive procedures based upon final histopathology are valuable surgical strategies.

Phase 2 study of the safety and efficacy of umbralisib in patients with CLL who are intolerant to BTK or PI3Kδ inhibitor therapy.

Intolerance is the most common reason for kinase inhibitor (KI) discontinuation in chronic lymphocytic leukemia (CLL). Umbralisib, a novel highly selective phosphatidylinositol 3-kinase Î´ (PI3Kδ)/CK1ε inhibitor, is active and well tolerated in CLL patients. In this phase 2 trial (NCT02742090), umbralisib was initiated at 800 mg/d in CLL patients requiring therapy, who were intolerant to prior BTK inhibitor (BTKi) or PI3K inhibitor (PI3Ki) therapy, until progression or toxicity. Primary end point was progression-free survival (PFS). Secondary end points included time to treatment failure and safety. DNA was genotyped for CYP3A4, CYP3A5, and CYP2D6 polymorphisms. Fifty-one patients were enrolled (44 BTKi intolerant and 7 PI3Kδi intolerant); median age was 70 years (range, 48-96), with a median of 2 prior lines of therapy (range, 1-7), 24% had del17p and/or TP53 mutation, and 65% had unmutated IGHV. Most common adverse events (AEs) leading to prior KI discontinuation were rash (27%), arthralgia (18%), and atrial fibrillation (16%). Median PFS was 23.5 months (95% CI, 13.1-not estimable), with 58% of patients on umbralisib for a longer duration than prior KI. Most common (≥5%) grade ≥3 AEs on umbralisib (all causality) were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea (8%). Six patients (12%) discontinued umbralisib because of an AE. Eight patients (16%) had dose reductions and were successfully rechallenged. These are the first prospective data to confirm that switching from a BTKi or alternate PI3Ki to umbralisib in this BTKi- and PI3Ki-intolerant CLL population can result in durable well-tolerated responses.

Randomized Phase II Trial of Sapanisertib ± TAK-117 vs. Everolimus in Patients With Advanced Renal Cell Carcinoma After VEGF-Targeted Therapy.

BACKGROUND: Sapanisertib, a dual mTORC1/2 inhibitor, may offer more complete inhibition of the PI3K/AKT/mTOR pathway than mTORC1 inhibitors, such as everolimus. This phase II study evaluated the efficacy and safety of single-agent sapanisertib and sapanisertib plus the PI3Kα inhibitor TAK-117, vs. everolimus in patients with advanced clear cell renal cell carcinoma (ccRCC) that had progressed on or after VEGF-targeted therapy. MATERIALS AND METHODS: Patients with histologically confirmed, advanced ccRCC were randomized 1:1:1 to receive single-agent everolimus 10 mg once daily, single-agent sapanisertib 30 mg once weekly, or sapanisertib 4 mg plus TAK-117 200 mg, both once daily for 3 days/week, in 28-day cycles. The primary endpoint was progression-free survival (PFS). RESULTS: Ninety-five patients were treated with everolimus or sapanisertib (n = 32 each), or sapanisertib plus TAK-117 (n = 31). There were no significant differences in PFS among the 3 groups or across any subgroups. Median PFS was 3.8 months with everolimus vs. 3.6 months with sapanisertib (HR, 1.33; 95% CI, 0.75-2.36), and 3.1 months with sapanisertib plus TAK-117 (HR, 1.37; 95% CI, 0.75-2.52). No significant differences in overall survival were seen among groups. Overall response rate was 16.7%, 0%, and 7.1%, respectively. Discontinuations due to treatment-emergent adverse events were 15.6%, 28.1%, and 29.0%. CONCLUSION: Sapanisertib with or without TAK-117 was less tolerable and did not improve efficacy vs. everolimus in patients with advanced ccRCC who had relapsed after or were refractory to VEGF-targeted therapies. Dual mTORC1/2 inhibition may not be an effective therapeutic approach for these patients.

Obesity and unanticipated hospital admission following outpatient laparoscopic cholecystectomy.

INTRODUCTION: Compared to other common outpatient operations, laparoscopic cholecystectomy has higher rates of unanticipated hospital admission with reports ranging from 1.0 to 39.5%. Identification of simple preoperative risk factors for admission can aid appropriate patient selection. The aim of this study was to evaluate the association of obesity with need for hospital admission and day of surgery postoperative complications. METHODS: The ACS NSQIP database from 2007 to 2016 was used to evaluate patients ≥ 18 years old who had undergone outpatient laparoscopic cholecystectomy. The primary outcome was hospital admission, defined as hospital length of stay ≥ 24 h. The secondary endpoint was postoperative complications on day of surgery. A multivariable logistic regression was used to evaluate the association of body mass index (BMI) and the outcomes of interest. Odds ratio (OR) and their 95% confidence interval (CI) were reported. RESULTS: 192,750 patients underwent laparoscopic cholecystectomy in the outpatient setting. 38,945 (20.20%) required hospital admission. 89 (0.05%) had postoperative complications on the day of surgery. On multivariable logistic regression analysis, when compared to the baseline cohort of BMI ≥ 30 and < 40 kg/m2, patients with a BMI ≥ 50 kg/m2 had a 10% increased odds of hospital admission (OR 1.10, CI 1.02-1.19, p < 0.001). BMI ≥ 40 kg/m2 and < 50 kg/m2 was not associated with increased odds of hospital admission (OR 0.99, CI 0.95-1.03, p 0.725). There was no increased odds of postoperative complications for patients with higher BMI (OR 1.35, CI 0.32-3.89, p < 0.623). CONCLUSION: Patients with super obesity have a 10% increased odds of hospital admission following laparoscopic cholecystectomy. Obesity is not associated with increased odds of same-day postoperative complications. Ambulatory laparoscopic cholecystectomy for the morbidly obese is safe; however, those with BMI > 50 kg/m2 should be considered on a case-by-case basis.

A phase II study of addition of pracinostat to a hypomethylating agent in patients with myelodysplastic syndromes who have not responded to previous hypomethylating agent therapy.

Hypomethylating agents (HMAs) are standard of care for higher-risk myelodysplastic syndromes (MDS). However, less than half of patients achieve objective responses and most eventually lose their response. Pracinostat is a pan-histone deacetylase inhibitor with demonstrated activity in advanced myeloid malignancies. This phase II study explored the benefit of adding pracinostat to HMAs in MDS patients who did not respond to single-agent HMA treatment. The goal was to estimate the clinical improvement rate [complete remission (CR), marrow CR, partial response (PR) and haematological improvement]. Group 1 included patients with primary/secondary HMA failures; Group 2 included those who did not achieve response but had stable disease (SD) after single-agent HMAs. Forty-five patients (39 Group 1, 6 Group 2) received a median of 3 cycles. Among all patients, 1 (2%) had CR, 7 (16%) had marrow CR and 18 (40%) had SD; disease progression occurred in 3 (7%). Median overall survival was 5·7/5·6 months for Group 1/2. Grade ≥3 adverse events occurred in 38 patients (84%) leading to treatment discontinuation in 12 (33%). Adding pracinostat to HMAs did not improve outcomes in patients previously treated with HMAs. Frequent dose modifications/early discontinuation resulted in suboptimal drug exposure. A reduced pracinostat dose may improve tolerability and efficacy.

Phase II Randomized Trial of Sequential or Concurrent FOLFOXIRI-Bevacizumab Versus FOLFOX-Bevacizumab for Metastatic Colorectal Cancer (STEAM).

BACKGROUND: First-line treatment for metastatic colorectal cancer (mCRC) typically entails a biologic such as bevacizumab (BEV) with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) or 5-fluorouracil/leucovorin/irinotecan (FOLFIRI). STEAM (NCT01765582) assessed the efficacy of BEV plus FOLFOX/FOLFIRI (FOLFOXIRI), administered concurrently (cFOLFOXIRI-BEV) or sequentially (sFOLFOXIRI-BEV, FOLFOX-BEV alternating with FOLFIRI-BEV), versus FOLFOX-BEV for mCRC. PATIENTS AND METHODS: Patients with previously untreated mCRC (n = 280) were randomized 1:1:1 to cFOLFOXIRI-BEV, sFOLFOXIRI-BEV, or FOLFOX-BEV and treated with 4-6-month induction followed by maintenance. Coprimary objectives were overall response rate (ORR; first-line cFOLFOXIRI-BEV vs. FOLFOX-BEV) and progression-free survival (PFS; pooled first-line cFOLFOXIRI-BEV and sFOLFOXIRI-BEV vs. FOLFOX-BEV). Secondary/exploratory objectives included overall survival (OS), liver resection rates, biomarker analyses, and safety. RESULTS: ORR was 72.0%, 72.8%, and 62.1% and median PFS was 11.9, 11.4, and 9.5 months with cFOLFOXIRI-BEV, sFOLFOXIRI-BEV, and FOLFOX-BEV, respectively. OS was similar between arms. ORR between cFOLFOXIRI-BEV and FOLFOX-BEV did not significantly differ (p = .132); thus, the primary ORR endpoint was not met. cFOLFOXIRI-BEV and sFOLFOXIRI-BEV numerically improved ORR and PFS, regardless of RAS status. Median PFS was higher with pooled concurrent and sequential FOLFOXIRI-BEV versus FOLFOX-BEV (11.7 vs. 9.5 months; hazard ratio, 0.7; 90% confidence interval, 0.5-0.9; p < .01). Liver resection rates were 17.2% (cFOLFOXIRI-BEV), 9.8% (sFOLFOXIRI-BEV), and 8.4% (FOLFOX-BEV). Grade ≥ 3 treatment-emergent adverse events (TEAEs) were observed in 91.2% (cFOLFOXIRI-BEV), 86.7% (sFOLFOXIRI-BEV), and 85.6% (FOLFOX-BEV) of patients, with no increase in serious chemotherapy-associated TEAEs. CONCLUSION: cFOLFOXIRI-BEV and sFOLFOXIRI-BEV were well tolerated with numerically improved ORR, PFS, and liver resection rates versus FOLFOX-BEV, supporting triplet chemotherapy plus BEV as a first-line treatment option for mCRC. IMPLICATIONS FOR PRACTICE: The combination of first-line FOLFIRI with FOLFOX and bevacizumab (concurrent FOLFOXIRI-BEV) improves clinical outcomes in patients with metastatic colorectal cancer (mCRC) relative to FOLFIRI-BEV or FOLFOX-BEV, but it is thought to be associated with increased toxicity. Alternating treatment of FOLFOX and FOLFIRI (sequential FOLFOXIRI-BEV) could improve tolerability. In the phase II STEAM trial, which is the largest study of FOLFOXIRI-BEV in patients in the U.S., it was found that both concurrent and sequential FOLFOXIRI-BEV are active and well tolerated in patients with previously untreated mCRC, supporting the use of these regimens as potential first-line treatment options for this population.

Custirsen in combination with docetaxel and prednisone for patients with metastatic castration-resistant prostate cancer (SYNERGY trial): a phase 3, multicentre, open-label, randomised trial.

BACKGROUND: Clusterin is a chaperone protein associated with treatment resistance and upregulated by apoptotic stressors such as chemotherapy. Custirsen is a second-generation antisense oligonucleotide that inhibits clusterin production. The aim of the SYNERGY trial was to investigate the effect of custirsen in combination with docetaxel and prednisone on overall survival in patients with metastatic castration-resistant prostate cancer. METHODS: SYNERGY was a phase 3, multicentre, open-label, randomised trial set at 134 study centres in 12 countries. Patients were eligible for participation if they had: metastatic castration-resistant prostate cancer and had received no previous chemotherapy; prostate-specific antigen greater than 5 ng/mL; and a Karnofsky performance score of 70% or higher. Patients were randomly assigned 1:1 centrally to either the docetaxel, prednisone, and custirsen combination or docetaxel and prednisone alone. Patients were not masked to treatment allocation. Randomisation was stratified by opioid use for cancer-related pain and radiographic evidence of progression. All patients received docetaxel 75 mg/m2 intravenously with 5 mg of prednisone orally twice daily. Patients assigned docetaxel, prednisone, and custirsen received weekly doses of custirsen 640 mg intravenously after three loading doses of 640 mg. The primary endpoint was overall survival analysed in the intention-to-treat population. Patients who received at least one study dose were included in the safety analysis set. This trial is registered with ClinicalTrials.gov, number NCT01188187. The trial is completed and final analyses are reported here. FINDINGS: Between Dec 10, 2010, and Nov 7, 2012, 1022 patients were enrolled to the trial, of whom 510 were assigned docetaxel, prednisone, and custirsen and 512 were allocated docetaxel and prednisone. No difference in overall survival was recorded between the two groups (median survival 23·4 months [95% CI 20·9-24·8] with docetaxel, prednisone, and custirsen vs 22·0 months [19·5-24·0] with docetaxel and prednisone; hazard ratio [HR] 0·93, 95% CI 0·79-1·10; p=0·415). The most common adverse events of grade 3 or worse in the docetaxel, prednisone and custirsen group (n=501) compared with the docetaxel and prednisone alone group (n=499) were neutropenia (grade 3, 63 [13%] vs 28 [6%]; grade 4, 98 [20%] vs 77 [15%]), febrile neutropenia (grade 3, 52 [10%] vs 31 [6%]; grade 4, four [1%] vs two [<1%]), and fatigue (grade 3, 53 [11%] vs 41 [8%]; grade 4, three [1%] vs one [<1%]). One or more serious adverse events were reported for 214 (43%) of 501 patients treated with docetaxel, prednisone, and custirsen and 181 (36%) of 499 receiving docetaxel and prednisone alone. Adverse events were attributable to 23 (5%) deaths in the docetaxel, prednisone, and custirsen group and 24 (5%) deaths in the docetaxel and prednisone alone group. INTERPRETATION: Addition of custirsen to first-line docetaxel and prednisone was reasonably well tolerated, but overall survival was not significantly longer for patients with metastatic castration-resistant prostate cancer treated with this combination, compared with patients treated with docetaxel and prednisone alone. FUNDING: OncoGenex Technologies.

A phase 2 study of the sphingosine-1-phosphate antibody sonepcizumab in patients with metastatic renal cell carcinoma.

BACKGROUND: Upregulation of sphingosine-1-phosphate (S1P) may mediate resistance to vascular endothelial growth factor (VEGF)-directed therapies and inhibit antitumor immunity. Antagonism of S1P in preclinical models appears to overcome this resistance. In this phase 2 study, the authors assessed the activity of sonepcizumab, a first-in-class inhibitor of S1P, in patients with metastatic renal cell carcinoma (mRCC) with a history of prior VEGF-directed therapy. METHODS: Patients were required to have clear cell mRCC and to have received treatment with at least 1 prior VEGF-directed agent. Prior treatment with immunotherapeutic agents and ≤1 mammalian target of rapamycin inhibitors was permitted. The primary endpoint of the study was progression-free survival. Additional endpoints included response rate and safety, and overall survival (OS) performed post hoc. RESULTS: A total of 40 patients were enrolled with a median of 3 prior therapies (range, 1-5 prior therapies), 78% of whom had intermediate-risk disease by second-line International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. Although the current study did not achieve its primary endpoint based on the 2-month progression-free survival, a median OS of 21.7 months was observed. Four patients (10%) demonstrated a partial response, with a median duration of response of 5.9 months. No grade 3/4 treatment-related adverse events were observed in >5% of patients (adverse events were graded and recorded for each patient using Common Terminology Criteria for Adverse Events [version 4.0]); the most frequent grade 1/2 treatment-related adverse events were fatigue (30%), weight gain (18%), constipation (15%), and nausea (15%). Biomarker studies demonstrated an increase in S1P concentrations with therapy. Comprehensive genomic profiling of 3 patients with a clinical benefit of >24 months indicated von Hippel-Lindau (VHL) and polybromo-1 (PBRM1) alterations. CONCLUSIONS: The encouraging OS and favorable safety profile observed with sonepcizumab should prompt further investigation of the agent in combination with VEGF-directed agents or checkpoint inhibitors. Cancer 2017;123:576-582. © 2016 American Cancer Society.

Phase 2, randomized, double-blind study of pracinostat in combination with azacitidine in patients with untreated, higher-risk myelodysplastic syndromes.

BACKGROUND: The prognosis of patients with higher-risk myelodysplastic syndromes (MDS) remains poor despite available therapies. Histone deacetylase inhibitors have demonstrated activity in patients with MDS and in vitro synergy with azacitidine. METHODS: A phase 2 randomized, placebo-controlled clinical trial of azacitidine and pracinostat was conducted in patients who had International Prognostic Scoring System intermediate-2-risk or high-risk MDS. The primary endpoint was the complete response (CR) rate by cycle 6 of therapy. RESULTS: Of 102 randomized patients, there were 51 in the pracinostat group and 51 in the placebo group. The median age was 69 years. The CR rate by cycle 6 of therapy was 18% and 33% (P = .07) in the pracinostat and placebo groups, respectively. No significant differences in overall survival (median, 16 vs 19 months, respectively; hazard ratio, 1.21; 95% confidence interval, 0.66-2.23) or progression-free survival (11 vs 9 months, respectively; hazard ratio, 0.82; 95% confidence interval, 0.546-1.46) were observed between groups. Grade ≥3 adverse events occurred more frequently in the pracinostat group (98% vs 74%), leading to more treatment discontinuations (20% vs 10%). CONCLUSIONS: The combination of azacitidine with pracinostat did not improve outcomes in patients with higher-risk MDS. Higher rates of treatment discontinuation may partially explain these results, suggesting alternative dosing and schedules to improve tolerability may be required to determine the potential of the combination. Cancer 2017;123:994-1002. © 2016 American Cancer Society.

Phase II study of bendamustine, bortezomib and dexamethasone (BBD) in the first-line treatment of patients with multiple myeloma who are not candidates for high dose chemotherapy.

The combination of bendamustine, bortezomib and dexamethasone (BBD) was evaluated as a first-line therapy for multiple myeloma. The original treatment regimen of bendamustine 80 mg/m2 , days 1, 4; bortezomib 1·3 mg/m2 , days 1, 4, 8, 11; dexamethasone 40 mg, days 1, 2, 3, 4 on a 28-day cycle (up to 8 cycles) was efficacious but determined relatively toxic in an interim analysis. The regimen was amended to bendamustine 80 mg/m2 , days 1, 2; bortezomib 1·3 mg/m2 , days 1, 8, 15; dexamethasone 20 mg, days 1, 2, 8, 9, 15, 16 every 28 days (up to 8 cycles), then maintenance 1·3 mg/m2 IV bortezomib every 2 weeks. Fifty-nine patients were enrolled. Primary endpoint was complete response (CR) rate. The original schema was given for a median of 7 cycles (range 1-8); modified schema was given for a median of 8 cycles (range 1-8) plus maintenance. Overall response was 91%, CR was 9%. Median follow-up was 19·1 months; median progression-free survival was 11·1 months and 18·9 months on the original and modified regimens, respectively. The most common Grade 3/4 adverse events were fatigue and neuropathy. The combination of BBD is tolerable and efficacious in this patient population. Modifications to decrease intensity but increase duration translated to better outcomes.

Hyperkalemia and cardiac arrest associated with glucose replacement in a patient on spironolactone.

We present a case of hypoglycemia, which after intravenous glucose replacement, led to cardiac arrest secondary to a profound extracellular potassium shift. The patient was on spironolactone therapy which is known to cause aldosterone resistance (which inhibits the body's ability to prevent potassium shifts) [1]. Physicians typically review medications that cause hypoglycemia, but other medications may interfere with potassium homeostasis with administration of glucose. Knowledge of this case may prompt further monitoring, repeat lab testing, and careful medication reconciliation before discharging a patient with risk for aldosterone resistance. On our literature review, we have not found additional reports where this particular physiology led to cardiac arrest.

Pazopanib versus sunitinib in metastatic renal-cell carcinoma.

BACKGROUND: Pazopanib and sunitinib provided a progression-free survival benefit, as compared with placebo or interferon, in previous phase 3 studies involving patients with metastatic renal-cell carcinoma. This phase 3, randomized trial compared the efficacy and safety of pazopanib and sunitinib as first-line therapy. METHODS: We randomly assigned 1110 patients with clear-cell, metastatic renal-cell carcinoma, in a 1:1 ratio, to receive a continuous dose of pazopanib (800 mg once daily; 557 patients) or sunitinib in 6-week cycles (50 mg once daily for 4 weeks, followed by 2 weeks without treatment; 553 patients). The primary end point was progression-free survival as assessed by independent review, and the study was powered to show the noninferiority of pazopanib versus sunitinib. Secondary end points included overall survival, safety, and quality of life. RESULTS: Pazopanib was noninferior to sunitinib with respect to progression-free survival (hazard ratio for progression of disease or death from any cause, 1.05; 95% confidence interval [CI], 0.90 to 1.22), meeting the predefined noninferiority margin (upper bound of the 95% confidence interval, <1.25). Overall survival was similar (hazard ratio for death with pazopanib, 0.91; 95% CI, 0.76 to 1.08). Patients treated with sunitinib, as compared with those treated with pazopanib, had a higher incidence of fatigue (63% vs. 55%), the hand-foot syndrome (50% vs. 29%), and thrombocytopenia (78% vs. 41%); patients treated with pazopanib had a higher incidence of increased levels of alanine aminotransferase (60%, vs. 43% with sunitinib). The mean change from baseline in 11 of 14 health-related quality-of-life domains, particularly those related to fatigue or soreness in the mouth, throat, hands, or feet, during the first 6 months of treatment favored pazopanib (P<0.05 for all 11 comparisons). CONCLUSIONS: Pazopanib and sunitinib have similar efficacy, but the safety and quality-of-life profiles favor pazopanib. (Funded by GlaxoSmithKline Pharmaceuticals; COMPARZ ClinicalTrials.gov number, NCT00720941.).

Early outcomes and perioperative risk assessment in elective open thoracoabdominal aortic aneurysm repair: An analysis of national data over a five-year period.

Open surgical repair of thoracoabdominal aortic aneurysms remains associated with significant morbidity and mortality. We sought to analyse multicentre national data on early outcomes of open surgical thoracoabdominal aortic aneurysm repair. Patients who underwent open repair of thoracoabdominal aortic aneurysm from 2005 to 2010 were identified from the National Surgical Quality Improvement Program database. The primary endpoint was mortality at 30 days. Patient demographics, clinical variables, and intraoperative parameters were analysed by univariate and multivariate logistic regression methods to identify risk factors for mortality. Of the 682 elective repairs, 30-day outcomes of elective repairs were: 10.0% mortality, 21.6% surgical complications, 42.2% pulmonary complications, 17.2% renal complications, 12.9% cardiovascular complications, 19.2% septic complications, and 6.6% wound complications. Multivariate logistic regression analysis showed that age, ASA-class IV, dependent functional status prior to surgery, and operation time are independent risk factors for mortality. Our study found a higher rate of mortality nationwide, as compared to several previous single center studies.

Carotid duplex criteria for patients with contralateral occlusion.

BACKGROUND: Contralateral occlusion (CLO) occurs in approximately 8% of patients undergoing intervention for carotid artery stenosis. Patients with CLO have increased stroke risk compared with patients without CLO, but standard carotid duplex ultrasonography (CDUS) criteria are not a reliable manner to screen or follow patients with CLO. Because appropriate duplex criteria for these patients are not well understood, this article defines CDUS parameters that accurately predict carotid artery stenosis at our institution. METHODS: Sixty-five patients with ipsilateral carotid stenosis and CLO were identified from our institutional database. Fifteen of sixty-five patients had arteriography, computed tomography angiography, or magnetic resonance angiography within 6 mo of CDUS. We determined accuracy of our laboratory's criteria for determining stenosis category compared with three-dimensional imaging. Receiver operating characteristic curves were used to determine optimal peak systolic velocity (PSV), end diastolic velocity (EDV), and systolic ratio (SR) cutoff values for diagnosing ≥50% stenosis in this pilot cohort. Finally, the revised criteria were prospectively applied to a validation cohort (n = 8) from the same institution. RESULTS: Categorization of stenosis by standard PSV, EDV, and SR criteria saw similar accuracy trends in both pilot (46.7, 53.3, and 66.7%) and validation (25, 25, and 62.5%) cohorts. Receiver operating characteristic curve analysis in the pilot cohort identified optimized PSV, EDV, and SR cutoffs (≥250, ≥90, and ≥2.3 cm/s, respectively) for diagnosing ≥50% stenosis. In the pilot cohort, new PSV criteria increased specificity (60%-100%) with minimal decreased sensitivity (90%-80%), whereas new EDV criteria increased specificity (40%-71.4%) and maintained 100% sensitivity. New SR criteria failed to improve sensitivity or specificity above 80%. Similar trends for the new CDUS velocity criteria were observed in the validation cohort. CONCLUSIONS: Increasingly stringent ultrasound parameters can provide reliable criteria for determining ≥50% carotid stenosis in patients with CLO. Further prospective validation that includes more patients with high-grade ipsilateral stenosis will help identify the role of SR in segregating high-grade versus moderate stenosis in CLO patients.

Influence of the hostile neck on restenosis after carotid stenting.

BACKGROUND: Carotid artery stenting (CAS) for carotid stenosis is favored over carotid endarterectomy (CEA) in patients with a hostile neck from prior CEA or cervical irradiation (XRT). However, the restenosis rate after CAS in patients with hostile necks is variable in the literature. The objective of this study was to quantify differences in the in-stent restenosis (ISR)/occlusion and reintervention rates after CAS in patients with and without a hostile neck. Here we hypothesize that patients with hostile necks have an increased ISR, and that this increase may add morbidity to these patients. MATERIALS AND METHODS: All patients undergoing CAS from 2007 to 2013 for carotid artery stenosis with follow-up imaging at our institution were queried from our carotid database (n = 236). Patients with hostile necks, including both CAS after prior CEA (n = 65) and prior XRT (n = 37), were compared with patients who underwent CAS for other reasons including both anatomical (n = 46) and medical comorbidities (n = 88). The primary end points were ISR, repeat intervention, and stent occlusion. Secondary end points of the study were stroke/myocardial infarction (MI)/death at 30 days, perioperative cardiovascular accident, transient ischemic attack, MI, groin access complications, hyperperfusion syndrome, and periprocedural hypotension or bradycardia. RESULTS: Despite the hostile neck cohort being younger and having lower incidence of chronic obstructive pulmonary disease, coronary artery disease, and renal insufficiency, they had a greater incidence of ISR (11% vs. 4%; P = .03) and required more reinterventions (8% vs. 2%; P = .04). Stent occlusion and periprocedural morbidity/mortality were not different between groups. CONCLUSIONS: Patients with hostile necks have increased risk of restenosis and need for reinterventions after CAS compared with patients without a hostile neck. However, they do not appear to have higher rates of stent occlusion or per-procedural events.

Mechanical thromboembolic prophylaxis with risk stratification in total knee arthroplasty.

The purpose of this study was to determine the rate of thromboembolic and bleeding complications when using mechanical prophylaxis with preoperative risk stratification following total knee arthroplasty (TKA). Between 1994 and 2007, 4037 TKAs were performed on 3144 patients at our institution. Mechanical VTE prophylaxis was used for standard risk patients, which included AV impulse foot pumps, thigh high stockings, and early mobilization. Chemoprophylaxis was only given to patients who were at increased thromboembolic risk. The incidence of DVT identified by ultrasound following TKA was 2.1%. A retrospective review showed 1 patient had a fatal pulmonary embolism, and 5 patients had bleeding complications in the knee. We conclude that mechanical thromboembolic prophylaxis using risk stratification is safe and effective following TKA.

Activities of daily living is a critical factor in predicting outcome after carotid endarterectomy in asymptomatic patients.

BACKGROUND AND PURPOSE: Ability to perform basic daily activity represented by functional status (FNS) before surgery can be assessed in the clinic for determining health status of the patient. We sought to study the effect of FNS on postoperative outcomes after carotid endarterectomy (CEA) in a national data set. METHODS: National Surgical Quality Improvement Project is a national data set, which includes data from >300 hospitals. Patients who underwent CEA were identified by Current Procedural Terminology code and divided into 3 categories based on FNS: independent, partially dependent, and dependent. Thirty-day postoperative stroke, death, and other postoperative complications were identified as the study end point. We used multivariate logistic regression to estimate odds ratio for outcomes while controlling for sex, race, diabetes mellitus, cardiovascular disease, smoking, and other confounders. RESULTS: Of 19 748 CEAs, 19 348 (97.97%) were functionally independent, 377 (1.99%) were functionally partially dependent, and 23 (0.12%) were functionallydependent. In functionally independent group, there were 196 (1.01%) strokes, 84 (0.43%) deaths, and 1416 (7.17%) other complications, whereas in the functionally partially dependent group, there were 14 (3.71%) strokes, 10 (2.65%) deaths, and 80 (21.22%) other complications. In multivariable risk-adjusted model, using functionally independent as reference, functionally partially dependent was associated with death (odds ratio, 3.3; 95% confidence interval, 1.6-6.8; P<0.001), stroke (odds ratio, 3; 95% confidence interval, 1.7-5.4; P<0.001), and other complications (odds ratio, 2.5; 95% confidence interval, 1.9-3.2; P<0.001). CONCLUSIONS: In this national data set, patient's inability to perform basic activities of independent living is associated with adverse postoperative outcomes after CEA. Hence, FNS should be vigilantly assessed in clinic for risk stratification along with other objective factors for gauging risk of adverse outcomes after CEA.

Latent mycobacterium avium infection causing a mycotic suprarenal aortic aneurysm in a human immunodeficiency virus-positive patient.

Mycobacterium avium complex (MAC) infection occurs in up to 50% of advanced-stage human immunodeficiency 1 (HIV-1) infections when the CD4 counts is <50/mm³. We report the case of a 52-year-old HIV-positive patient who presented with a symptomatic, rapidly growing suprarenal abdominal aortic aneurysm. He had been diagnosed and treated for disseminated MAC infection 3 years earlier. He was treated with antiretroviral medications and had a CD4 count >250 cells/mm³ and an undetectable viral load. Open repair was performed using cryopreserved homograft. Microbiologic cultures from the specimen revealed infection with mycobacterium avium. This is the first case to report a mycotic suprarenal aortic aneurysm caused by an active conversion of a latent MAC infection.

Anatomic characteristics of aortic transection: centerline analysis to facilitate graft selection.

BACKGROUND: Traumatic transection of the thoracic aorta is a life-threatening complication that most commonly occurs after high-speed motor vehicle collisions. Although such injuries were previously treated with open surgical reconstruction, they are now more commonly being treated with endovascularly placed stent grafts. Unfortunately, most stent grafts are designed for treating aortic aneurysmal disease instead of traumatic injury. Further refinements in stent graft technology depend on a thorough anatomic understanding of the transection injury process. METHODS: All patients with computed tomography (CT) evidence of blunt aortic injury (BAI) between 2006 and 2012 at a Level 1 trauma center were queried. Their initial CT scans were imported into the Intuition (Terarecon, Inc.) viewing program, and off-line centerline reconstruction was performed. Standard demographic data were collected in addition to anatomic characteristics, including aortic diameters and the relationship of the injury to the arch vessels. RESULTS: Thirty-five patients were identified. Three patients were injured proximal to the left subclavian artery. The average length from the left subclavian artery to the proximal site of injury was 16.2 mm (range 2-31 mm). Most patients had >15 mm of landing zone beyond the left subclavian artery. The range of proximal diameters ranged from 17 to 32 mm, with an average aortic diameter of 23.9 mm. The average length of injured aortic segment was 27 mm. CONCLUSIONS: In this contemporary series from a large trauma center, 91% of patients are anatomically able to be treated with a stent graft that does not require coverage of the left common carotid artery. Most patients have an aortic diameter that falls between 21 and 26 mm in diameter, as well as a short segment of injured artery. Centers interested in emergently treating aortic transections are able to do so while maintaining a limited stock of stent grafts that can be used to treat the majority of the population.