Saint Agnes Hospital

BACKGROUND: Ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2, has clinically significant activity in myelofibrosis. METHODS: In this double-blind trial, we randomly assigned patients with intermediate-2 or high-risk myelofibrosis to twice-daily oral ruxolitinib (155 patients) or placebo (154 patients). The primary end point was the proportion of patients with a reduction in spleen volume of 35% or more at 24 weeks, assessed by means of magnetic resonance imaging. Secondary end points included the durability of response, changes in symptom burden (assessed by the total symptom score), and overall survival. RESULTS: The primary end point was reached in 41.9% of patients in the ruxolitinib group as compared with 0.7% in the placebo group (P<0.001). A reduction in spleen volume was maintained in patients who received ruxolitinib; 67.0% of the patients with a response had the response for 48 weeks or more. There was an improvement of 50% or more in the total symptom score at 24 weeks in 45.9% of patients who received ruxolitinib as compared with 5.3% of patients who received placebo (P<0.001). Thirteen deaths occurred in the ruxolitinib group as compared with 24 deaths in the placebo group (hazard ratio, 0.50; 95% confidence interval, 0.25 to 0.98; P=0.04). The rate of discontinuation of the study drug because of adverse events was 11.0% in the ruxolitinib group and 10.6% in the placebo group. Among patients who received ruxolitinib, anemia and thrombocytopenia were the most common adverse events, but they rarely led to discontinuation of the drug (in one patient for each event). Two patients had transformation to acute myeloid leukemia; both were in the ruxolitinib group. CONCLUSIONS: Ruxolitinib, as compared with placebo, provided significant clinical benefits in patients with myelofibrosis by reducing spleen size, ameliorating debilitating myelofibrosis-related symptoms, and improving overall survival. These benefits came at the cost of more frequent anemia and thrombocytopenia in the early part of the treatment period. (Funded by Incyte; COMFORT-I ClinicalTrials.gov number, NCT00952289.).

Between 1963 and 1980, one or more posterior-lateral foraminotomies were performed for simple cervical radiculopathy as the sole operative procedure for 736 patients. One hundred three patients (14%) required a second posterior procedure, but only 24 (3%) cases represented true recurrent radiculopathy. There were 13 minor complications (1.5%) and no deaths or detectable incidence of air embolism. All operations were done with the patient in the sitting position. Central venous pressure monitoring was used only infrequently. There was a 96% incidence of relief of significant arm pain and/or paresthesia and a 98% incidence of resolution of preoperatively present motor deficit. Eight hundred twenty-eight procedures (98%) were preceded by Pantopaque cervical myelography. There was a 71.5% incidence of correlation between preoperative clinical findings (both sensory and motor) and operative findings. In 13% of the cases, two spaces were thought by the operating surgeon to be equally involved by the spondylotic process. Most (91.5%) of the patients describe themselves as either "good or excellent" postoperatively. There was no significant difference postoperatively regarding results or recurrence between patients with suspected soft or hard disc protrusions and those with strictly spondylotic radiculopathy. Nor was there any statistical difference in results among the three patient population groups ("private" vs. compensation vs. liability). The mean length of time to return to work or other "normal" activities was 9.4 weeks. The mean length of follow-up time was 146 weeks (2.8 years). There was an associated incidence of significant lumbar disc and/or foraminal disease requiring operation of 33.4%.

BACKGROUND: The randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial evaluated the JAK1/JAK2 inhibitor ruxolitinib in patients with intermediate-2/high-risk myelofibrosis. The primary and planned 3-year analyses of COMFORT-I data demonstrated that ruxolitinib-the first myelofibrosis-approved therapy-reduced splenomegaly and prolonged overall survival versus placebo. Here, we present the final 5-year results. METHODS: Patients managed in Australia, Canada, and the USA were randomized centrally (interactive voice response system) 1:1 to oral ruxolitinib twice daily (15 or 20 mg per baseline platelet counts) or placebo. Investigators and patients were blinded to treatment. The secondary endpoints evaluated in this analysis were durability of a ≥35% reduction from baseline in spleen volume (spleen response) and overall survival, evaluated in the intent-to-treat population. Safety was evaluated in patients who received study treatment. RESULTS: Patients were randomized (September 2009-April 2010) to ruxolitinib (n = 155) or placebo (n = 154). At termination, 27.7% of ruxolitinib-randomized patients and 25.2% (28/111) who crossed over from placebo were on treatment; no patients remained on placebo. Patients randomized to ruxolitinib had a median spleen response duration of 168.3 weeks and prolonged median overall survival versus placebo (ruxolitinib group, not reached; placebo group, 200 weeks; HR, 0.69; 95% CI, 0.50-0.96; P = 0.025) despite the crossover to ruxolitinib. The ruxolitinib safety profile remained consistent with previous analyses. The most common new-onset all-grade nonhematologic adverse events starting <12 versus ≥48 months after ruxolitinib initiation were fatigue (29.0 vs 33.3%) and diarrhea (27.8 vs 14.6%). New-onset grade 3 or 4 anemia and thrombocytopenia both primarily occurred within the first 6 months, with no cases after 42 months. The most common treatment-emergent adverse event-related deaths in the ruxolitinib-randomized group were sepsis (2.6%), disease progression (1.9%), and pneumonia (1.9%). CONCLUSION: The final COMFORT-I results continue to support ruxolitinib as an effective treatment for patients with intermediate-2/high-risk MF. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00952289.

In the phase III COMFORT-I study, the Janus kinase 1 (JAK1)/JAK2 inhibitor ruxolitinib provided significant improvements in splenomegaly, key symptoms, and quality-of-life measures and was associated with an overall survival benefit relative to placebo in patients with intermediate-2 or high-risk myelofibrosis. This planned analysis assessed the long-term efficacy and safety of ruxolitinib at a median follow-up of 149 weeks. At data cutoff, approximately 50% of patients originally randomized to ruxolitinib remained on treatment whereas all patients originally assigned to placebo had discontinued or crossed over to ruxolitinib. At week 144, mean spleen volume reduction was 34% with ruxolitinib. Previously observed improvements in quality-of-life measures were sustained with longer-term ruxolitinib therapy. Overall survival continued to favor ruxolitinib despite the majority of placebo patients crossing over to ruxolitinib [hazard ratio 0.69 (95% confidence interval: 0.46-1.03); P = 0.067]. Exploratory analyses suggest that crossover may have contributed to an underestimation of the true survival difference between the treatment groups. Ruxolitinib continued to be generally well tolerated; there was no pattern of worsening grade ≥ 3 anemia or thrombocytopenia with longer-term ruxolitinib exposure. These longer-term data continue to support the efficacy and safety of ruxolitinib in patients with myelofibrosis. The study is registered at clinicaltrials.gov: NCT00952289.

BACKGROUND: St John's Wort is a widely used herbal product. Information regarding its potential for drug interactions is required for responsible treatment of patients using St John's Wort. CYP3A4 is a metabolic enzyme implicated in most clinically significant drug-drug interactions. OBJECTIVE: To determine the in vivo effect of reagent-grade St John's Wort extract on CYP3A4 activity through evaluation of urinary 6-beta-hydroxycortisol/cortisol ratios. METHODS: Thirteen subjects ranging in age from 18 to 25 years participated in this unblinded, multiple-dose, single-treatment before-after trial conducted in a university-based pharmacokinetics and biopharmaceutics laboratory. Each subject ingested a 300-mg tablet of reagent-grade St John's Wort extract standardized to 0.3% hypericin three times a day for 14 days. Baseline and posttreatment CYP3A4 activity was assessed with the urinary 6-beta-hydroxycortisol/cortisol ratio after a 24-hour urine collection. RESULTS: The mean +/- SD urinary 6-beta-hydroxycortisol/cortisol ratio significantly increased (P = .003) from a baseline value of 7.1 +/- 4.5 to 13 +/- 4.9. The mean +/- SD percentage increase was 114% +/- 95%, with a range from -25% to 259%. All but one subject had an increase in the ratio. CONCLUSIONS: Treatment with St John's Wort for 14 days resulted in significant increases in the urinary 6-beta-hydroxycortisol/cortisol ratio. This finding suggests that St John's Wort is an inducer of CYP3A4.

PURPOSE: Indolent non-Hodgkin lymphoma (iNHL) remains largely incurable and often requires multiple lines of treatment after becoming refractory to standard therapies. Duvelisib was approved by the Food and Drug Administration for relapsed or refractory (RR) chronic lymphocytic leukemia or small lymphocytic lymphoma (SLL) and RR follicular lymphoma (FL) after two or more prior systemic therapies. On the basis of the activity of duvelisib, a first-in-class oral dual inhibitor of phosphoinositide 3-kinase-δ,-γ, in RR iNHL in a phase I study, the safety and efficacy of duvelisib monotherapy was evaluated in iNHL refractory to rituximab and either chemotherapy or radioimmunotherapy. PATIENTS AND METHODS: Eligible patients had measurable iNHL (FL, SLL, or marginal zone B-cell lymphoma) double refractory to rituximab (monotherapy or in combination) and to either chemotherapy or radioimmunotherapy. All were treated with duvelisib 25 mg orally twice daily in 28-day cycles until progression, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) using the revised International Working Group criteria for malignant lymphoma. RESULTS: This open-label, global phase II trial enrolled 129 patients (median age, 65 years; median of three prior lines of therapy) with an ORR of 47.3% (SLL, 67.9%; FL, 42.2%; MZL, 38.9%). The estimated median duration of response was 10 months, and the estimated median progression-free survival was 9.5 months. The most frequent any-grade treatment-emergent adverse events (TEAEs) were diarrhea (48.8%), nausea (29.5%), neutropenia (28.7%), fatigue (27.9%), and cough (27.1%). Among the 88.4% of patients with at least one grade 3 or greater TEAE, the most common TEAEs were neutropenia (24.8%), diarrhea (14.7%), anemia (14.7%), and thrombocytopenia (11.6%). CONCLUSION: In the DYNAMO study, oral duvelisib monotherapy demonstrated clinically meaningful activity and a manageable safety profile in heavily pretreated, double-refractory iNHL, consistent with previous observations. Duvelisib may provide a new oral treatment option for this patient population of which many are elderly and in need of additional therapies.

Venous air embolism (VAE) can be a lethal complication of surgical procedures, during which (1) venous pressure at the site of surgery is subatmospheric or (2) gas is forced under pressure into a body cavity. Though classically associated with neurosurgery, VAE is also a potential complication of laparoscopic, pelvic, and orthopedic procedures. It is, therefore, essential for the practicing anesthesiologist to recognize and treat venous air entrainment. An in-depth review of the pathophysiology, clinical presentation, detection, prevention, and treatment of VAE is presented.

OBJECTIVE: To determine whether and to what extent preexisting medical comorbidities influence mortality risk and length of hospitalization in patients with acute burn injury. SUMMARY BACKGROUND DATA: The effects on mortality and length of stay of a number of important medical comorbidities have not been examined in acute burn injury. Existing studies that have investigated the effects of medical comorbidities on outcomes in acute burn injury have produced inconsistent results, chiefly due to the use of relatively small samples from single burn centers. METHODS: Records of 31,338 adults who were admitted with acute burn injury to 70 burn centers from the American Burn Association National Burn Repository, were reviewed. A burn-specific list of medical comorbidities was derived from diagnoses included in the Charlson Index of Comorbidities and the Elixhauser method of comorbidity measurement. Logistic regression was used to assess the effects of preexisting medical conditions on mortality, controlling for demographic and burn injury characteristics. Ordinal least squares regression with a logarithmic transformation of the dependent variable was used to assess the relationship of comorbidities with length of stay. RESULTS: In-hospital mortality was significantly predicted by HIV/AIDS (odds ratio [OR] = 10.2), renal disease (OR = 5.1), liver disease (OR = 4.8), metastatic cancer (OR = 4.6), pulmonary circulation disorders (OR = 2.9), congestive heart failure (OR = 2.4), obesity (OR = 2.1), non-metastatic malignancies (OR = 2.1), peripheral vascular disorders (OR = 1.8), alcohol abuse (OR = 1.8), neurological disorders (OR = 1.6), and cardiac arrhythmias (OR = 1.5). Increased length of hospital stay among survivors was significantly predicted by paralysis (90% increase), dementia (60%), peptic ulcer disease (53%), other neurological disorders (52%), HIV/AIDS (49%), renal disease (44%), a psychiatric diagnosis (42%), cerebrovascular disease (41%), cardiac arrhythmias (40%), peripheral vascular disorders (39%), alcohol abuse (36%), valvular disease (32%), liver disease (30%), diabetes (26%), congestive heart failure (23%), drug abuse (20%), and hypertension (17%). CONCLUSIONS: A number of preexisting medical conditions influence outcomes in acute burn injury. Patients with preburn HIV/AIDS, metastatic cancer, liver disease, and renal disease have particularly poor prognoses.

Medical management with combinations of cytotoxic chemotherapy, and/or biological agents, has resulted in an unprecedented median survival >20 months in patients with Stage IV colorectal cancer. The management of disease limited to the peritoneal cavity has been controversial and at the present time, there is no published data that outlines the impact of these new therapeutic regimens when given to patients with colorectal cancer with metastatic disease confined to the peritoneum. Over the last 5 years, an increasing number of international treatment centers have published their prospective results using cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of peritoneal surface malignancies of colorectal origin and have shown that good long-term results can be achieved with a complete cytoreduction and HIPEC. However, most of the surgical data comes from Phase II studies from single institutions and there is a wide range on inclusion/exclusion criteria, drugs, temperatures and methods of delivering the heated chemotherapy. This manuscript will analyze and discuss the results of a group of health care providers trying to achieve a consensus statement in the management of this group of patients.

BACKGROUND: Evaluation of peritoneal metastases by computed tomography (CT) scans is challenging and has been reported to be inaccurate. METHODS: A multi-institutional prospective observational registry study of patients with peritoneal carcinomatosis from colorectal cancer was conducted and a subset analysis was performed to examine peritoneal cancer index (PCI) based on CT and intraoperative exploration. RESULTS: Fifty-two patients (mean age 52.6 ± 12.4 years) from 16 institutions were included in this study. Inaccuracies of CT-based assessment of lesion sizes were observed in the RUQ (P = 0.004), LLQ (P < 0.0005), RLQ (P = 0.003), distal jejunum (P = 0.004), and distal ileum (P < 0.0005). When CT-PCI was classified based on the extent of carcinomatosis, 17 cases (33%) were underestimations, of which, 11 cases (21%) were upstaged from low to moderate, 4 cases (8%) were upstaged from low to severe, and 2 cases (4%) were upstaged from moderate to severe. Relevant clinical discordance where an upstage occurred to severe carcinomatosis constituted a true inaccuracy and was observed in six cases (12%). CONCLUSIONS: The actual clinical impact of inaccuracies of CT-PCI was modest. CT-PCI will remain as a mandatory imaging tool and may be supplemented with other tools including positron emission tomography scan or diagnostic laparoscopy, in the patient selection for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

STUDY DESIGN: A prospective, randomized trial comparing Proceed, a gelatin-based hemostatic sealant (treatment), with Gelfoam-thrombin (control) in stopping intraoperative bleeding during spinal surgery. OBJECTIVES: To determine the effectiveness and safety of Proceed. SUMMARY OF BACKGROUND DATA: Proceed has been tested in animal models to determine its safety and effectiveness as a hemostatic agent. The current study was conducted under a Food and Drug Administration-approved Investigational Device Exemption to evaluate the effectiveness and safety of Proceed in humans. METHODS: For this study, 127 patients undergoing spinal surgery were randomized into either the treatment or control group after standard surgical means to control bleeding had failed. The bleeding site was evaluated at 1, 2, 3, 6, and 10 minutes after the hemostatic agent was applied. The application was considered successful if the bleeding stopped within 10 minutes. Follow-up evaluation was performed at 12 to 36 hours, then at 6 to 8 weeks after surgery. RESULTS: Proceed stopped bleeding in 98% of the patients (first bleeding site only) within 10 minutes, as compared with 90% of the control patients (P = 0.001). At 3 minutes, successful hemostasis had been achieved in 97% of the Proceed group, as compared with 71% of the control group (P = 0.0001). There was no difference in the adverse event profile between the two groups. CONCLUSIONS: A significantly larger number of bleeding sites had achieved hemostasis with Proceed than with Gelfoam-thrombin at 1, 2, and 3 minutes after application. Proceed was as safe as Gelfoam-thrombin when used for hemostasis during spinal surgery procedures.

BACKGROUND: The Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) negatively affect patient quality of life (QoL) and are associated with increased risk of mortality. METHODS: The MPN Landmark survey was conducted from May to July 2014 in patients with MF, PV, or ET under active management in the United States. The survey assessed respondent perceptions of disease burden and treatment management and included questions on overall disease burden, QoL, activities of daily living, and work productivity. Outcomes were further analyzed by calculated (ie, not respondent-reported) prognostic risk score and symptom severity quartile. RESULTS: The survey was completed by 813 respondents (MF, n = 207; PV, n = 380; ET, n = 226). The median respondent age in each of the 3 MPN subtypes ranged from 62 to 66 years; median disease duration was 4 to 7 years. Many respondents reported that they had experienced MPN-related symptoms ≥1 year before diagnosis (MF, 49 %; PV, 61 %; ET, 58 %). Respondents also reported that MPN-related symptoms reduced their QoL, including respondents with low prognostic risk scores (MF, 67 %; PV, 62 %; ET, 57 %) and low symptom severity (MF, 51 %; PV, 33 %; ET, 15 %). Many respondents, including those with a low prognostic risk score, reported that their MPN had caused them to cancel planned activities or call in sick to work at least once in the preceding 30 days (cancel planned activities: MF, 56 %; PV, 35 %; ET, 35 %; call in sick: MF, 40 %; PV, 21 %; ET, 23 %). CONCLUSIONS: These findings of the MPN Landmark survey support previous research about the symptom burden experienced by patients with MPNs and are the first to detail the challenges that patients with MPNs experience related to reductions in activities of daily living and work productivity.

INTRODUCTION: Extubation failure has been associated with poor intensive care unit (ICU) and hospital outcomes in tertiary care medical centers. Given the large proportion of critical care delivered in the community setting, our purpose was to determine the impact of extubation failure on patient outcomes in a community hospital ICU. METHODS: A retrospective cohort study was performed using data gathered in a 16-bed medical/surgical ICU in a community hospital. During 30 months, all patients with acute respiratory failure admitted to the ICU were included in the source population if they were mechanically ventilated by endotracheal tube for more than 12 hours. Extubation failure was defined as reinstitution of mechanical ventilation within 72 hours (n = 60), and the control cohort included patients who were successfully extubated at 72 hours (n = 93). RESULTS: The primary outcome was total ICU length of stay after the initial extubation. Secondary outcomes were total hospital length of stay after the initial extubation, ICU mortality, hospital mortality, and total hospital cost. Patient groups were similar in terms of age, sex, and severity of illness, as assessed using admission Acute Physiology and Chronic Health Evaluation II score (P > 0.05). Both ICU (1.0 versus 10 days; P < 0.01) and hospital length of stay (6.0 versus 17 days; P < 0.01) after initial extubation were significantly longer in reintubated patients. ICU mortality was significantly higher in patients who failed extubation (odds ratio = 12.2, 95% confidence interval [CI] = 1.5-101; P < 0.05), but there was no significant difference in hospital mortality (odds ratio = 2.1, 95% CI = 0.8-5.4; P < 0.15). Total hospital costs (estimated from direct and indirect charges) were significantly increased by a mean of 33,926 US dollars (95% CI = 22,573 US dollars - 45,280 US dollars; P < 0.01). CONCLUSION: Extubation failure in a community hospital is univariately associated with prolonged inpatient care and significantly increased cost. Corroborating data from tertiary care centers, these adverse outcomes highlight the importance of accurate predictors of extubation outcome.

OBJECTIVE: We investigated the safety and efficacy of stereotactic radiotherapy as an alternative therapy to surgical resection for optic nerve sheath meningiomas (ONSMs). METHODS: Thirty patients and 33 optic nerves with ONSMs were treated with conventional fractionated stereotactic radiotherapy treatment (CF-SRT) between July 1996 and May 2001 with the use of a 6-MeV LINAC designed for and dedicated to radiosurgery. The LINAC technique involved daily CF-SRT involving a relocatable frame, an average of three isocenters, and high-radiation dose conformality established by noncoplanar arc beam shaping and differential beam weighting. The patients who were treated with CF-SRT were followed clinically with serial visual fields and radiographically with both magnetic resonance imaging and functional (111)In-octreotide single-photon emission computed tomography. The results of treatment were compared with a historical control group of ONSM patients who were either observed or treated surgically and then observed. RESULTS: Our study population comprised 18 women and 12 men with a median age of 44 years (age range, 20-76 yr). The median isosurface radiation dose was 51 Gy (dose range, 50-54.0 Gy), and the median clinical follow-up time was 89 weeks (range, 9-284 wk). Of 22 optic nerves with vision before CF-SRT, 20 nerves (92%) demonstrated preserved vision, and 42% manifested improvement in visual acuity and/or visual field at follow-up. Comparison of our patients with a historical control group revealed preserved vision in only 16% of patients in a comparable period of observation, along with a 150% greater probability of visual improvement. Four patients (13%) had posttreatment morbidities, including visual loss (two patients), optic neuritis (one patient), and transient orbital pain (one patient). On magnetic resonance imaging studies, there was no evidence of tumor progression or recurrence in all patients, including tumor volume reductions noted in four patients. All six patients monitored with (111)In-octreotide scintigraphy demonstrated significant decreases in tumor activity after CF-SRT. CONCLUSION: To date, this article describes the largest reported series of ONSMs. Although longer follow-up is necessary, we think that CF-SRT represents a safe alternative to surgery and offers a higher likelihood of preserved or improved vision in patients with ONSM. Our analysis suggests that CF-SRT is also preferable to observation. Functional (111)In-octreotide single-photon emission computed tomographic scintigraphy provides a useful technique for the assessment of tumor control that complements serial posttreatment magnetic resonance imaging in patients with ONSMs.

OBJECTIVE: To evaluate the role of preoperative lymphoscintigraphy in sentinel lymph node (SLN) biopsy for breast cancer. SUMMARY BACKGROUND DATA: Numerous studies have demonstrated that SLN biopsy can be used to stage axillary lymph nodes for breast cancer. SLN biopsy is performed using injection of radioactive colloid, blue dye, or both. When radioactive colloid is used, a preoperative lymphoscintigram (nuclear medicine scan) is often obtained to ease SLN identification. Whether a preoperative lymphoscintigram adds diagnostic accuracy to offset the additional time and cost required is not clear. METHODS: After informed consent was obtained, 805 patients were enrolled in the University of Louisville Breast Cancer Sentinel Lymph Node Study, a multiinstitutional study involving 99 surgeons. Patients with clinical stage T1-2, N0 breast cancer were eligible for the study. All patients underwent SLN biopsy, followed by level I/II axillary dissection. Preoperative lymphoscintigraphy was performed at the discretion of the individual surgeon. Biopsy of nonaxillary SLNs was not required in the protocol. Chi-square analysis and analysis of variance were used for statistical comparison. RESULTS: Radioactive colloid injection was performed in 588 patients. In 560, peritumoral injection of isosulfan blue dye was also performed. A preoperative lymphoscintigram was obtained in 348 of the 588 patients (59%). The SLN was identified in 221 of 240 patients (92.1%) who did not undergo a preoperative lymphoscintigram, with a false-negative rate of 1.6%. In the 348 patients who underwent a preoperative lymphoscintigram, the SLN was identified in 310 (89.1%), with a false-negative rate of 8.7%. A mean of 2.2 and 2. 0 SLNs per patient were removed in the groups without and with a preoperative lymphoscintigram, respectively. There was no statistically significant difference in the SLN identification rate, false-negative rate, or number of SLNs removed when a preoperative lymphoscintigram was obtained. CONCLUSIONS: Preoperative lymphoscintigraphy does not improve the ability to identify axillary SLN during surgery, nor does it decrease the false-negative rate. Routine preoperative lymphoscintigraphy is not necessary for the identification of axillary SLNs in breast cancer.

COMFORT-I is a randomized, double-blind, placebo-controlled trial of the Janus kinase 1/Janus kinase 2 inhibitor ruxolitinib in 309 patients with intermediate-2 or high-risk myelofibrosis. This analysis of COMFORT-I describes the long-term efficacy and safety of ruxolitinib (median follow-up, 2 years). Spleen volume was measured by magnetic resonance imaging, and quality of life was evaluated using the EORTC QLQ-C30. Overall survival was determined according to randomized treatment group. At the time of this analysis, 100 of 155 patients randomized to ruxolitinib were still receiving treatment. All patients randomized to placebo crossed over to ruxolitinib or discontinued within 3 months of the primary analysis (median time to crossover, 41 weeks). Mean spleen volume reductions in the ruxolitinib group were 31.6% at week 24 and 34.9% at week 96; improvements in quality of life measures were also maintained. Improved survival was observed for ruxolitinib (n=27 deaths) versus placebo (n=41 deaths) (hazard ratio=0.58; 95% confidence interval: 0.36, 0.95; P=0.03). The incidence of new-onset grade 3 or 4 anemia and thrombocytopenia decreased over time to levels observed in patients receiving placebo. These data indicate that ruxolitinib treatment provides durable reductions in spleen volume and improvements in quality of life and suggest a continued survival advantage for ruxolitinib over placebo.

INTRODUCTION: Systemic therapy and cytoreduction (CRS) with hyperthermic intra-peritoneal chemotherapy (HIPEC) may benefit selected patients with carcinomatosis from colon cancer (PC). This study presents the results of a consecutive series of patients evaluated under a single strategy. PATIENTS AND METHODS: Forty patients with PC referred for CRS were evaluated. Evaluation of their treatment was determined according to disease severity scored on a 3-point scale including: (1) symptoms, (2) extent of peritoneal dissemination (PCI), and (3) primary tumor histology. Overall survival (OS) was analyzed using Kaplan-Meier product-limit method and log rank testing according to four tiers of estimated disease severity based on the above parameters. RESULTS: For patients with disease severity score I, II, III, and IV, 2-year OS following treatment was 100%, 80%, 80%, and 0%, respectively. Median OS with most advanced disease (IV: n = 20) was 5 months versus 36 months for disease of lesser severity (I-III: n = 20; P < 0.001; RR = 0.2; 95%CI 0.1-0.5). Advanced disease (IV) was an independent predictor of adverse outcome on multivariate analysis with 2.6-fold increased likelihood of mortality. CONCLUSION: A treatment strategy based on disease severity determined at time of diagnosis, stratifies patients into prognostic groups and may improve selection of patients for appropriate therapy.

Background: Although acute kidney injury (AKI) is a frequent complication in patients receiving extracorporeal membrane oxygenation (ECMO), the incidence and impact of AKI on mortality among patients on ECMO remain unclear. We conducted this systematic review to summarize the incidence and impact of AKI on mortality risk among adult patients on ECMO. Methods: A literature search was performed using EMBASE, Ovid MEDLINE, and Cochrane Databases from inception until March 2019 to identify studies assessing the incidence of AKI (using a standard AKI definition), severe AKI requiring renal replacement therapy (RRT), and the impact of AKI among adult patients on ECMO. Effect estimates from the individual studies were obtained and combined utilizing random-effects, generic inverse variance method of DerSimonian-Laird. The protocol for this systematic review is registered with PROSPERO (no. CRD42018103527). Results: 41 cohort studies with a total of 10,282 adult patients receiving ECMO were enrolled. Overall, the pooled estimated incidence of AKI and severe AKI requiring RRT were 62.8% (95%CI: 52.1%–72.4%) and 44.9% (95%CI: 40.8%–49.0%), respectively. Meta-regression showed that the year of study did not significantly affect the incidence of AKI (p = 0.67) or AKI requiring RRT (p = 0.83). The pooled odds ratio (OR) of hospital mortality among patients receiving ECMO with AKI on RRT was 3.73 (95% CI, 2.87–4.85). When the analysis was limited to studies with confounder-adjusted analysis, increased hospital mortality remained significant among patients receiving ECMO with AKI requiring RRT with pooled OR of 3.32 (95% CI, 2.21–4.99). There was no publication bias as evaluated by the funnel plot and Egger’s regression asymmetry test with p = 0.62 and p = 0.17 for the incidence of AKI and severe AKI requiring RRT, respectively. Conclusion: Among patients receiving ECMO, the incidence rates of AKI and severe AKI requiring RRT are high, which has not changed over time. Patients who develop AKI requiring RRT while on ECMO carry 3.7-fold higher hospital mortality.

RESPONSE is an open-label phase 3 study evaluating the Janus kinase 1/Janus kinase 2 inhibitor ruxolitinib versus best available therapy for efficacy/safety in hydroxyurea-resistant or intolerant patients with polycythemia vera. This preplanned analysis occurred when all patients completed the Week 80 visit or discontinued. Objectives included evaluating the durability of the primary response (Week 32 phlebotomy-independent hematocrit control plus ≥35% spleen volume reduction), its components, and that of complete hematologic remission; and long-term safety. Median exposure was 111 weeks; 91/110 (82.7%) patients randomized to ruxolitinib remained on treatment. No patients continued best available therapy (98/112 [87.5%] crossed over to ruxolitinib, most at/soon after Week 32). At Week 32, primary response was achieved by 22.7% vs. 0.9% of patients randomized to ruxolitinib and best available therapy, respectively (hematocrit control, 60.0% vs. 18.8%; spleen response, 40.0% vs. 0.9%). The probability of maintaining primary and hematocrit responses for ≥80 weeks was 92% and 89%, respectively; 43/44 spleen responses were maintained until Week 80. Complete hematologic remission at Week 32 was achieved in 23.6% of ruxolitinib-randomized patients; the probability of maintaining complete hematologic remission for ≥80 weeks was 69%. Among ruxolitinib crossover patients, 79.2% were not phlebotomized, and 18.8% achieved a ≥35% reduction from baseline in spleen volume after 32 weeks of treatment. New or worsening hematologic laboratory abnormalities in ruxolitinib-treated patients were primarily grade 1/2 decreases in hemoglobin, lymphocytes, and platelets. The thromboembolic event rate per 100 patient-years was 1.8 with randomized ruxolitinib treatment vs. 8.2 with best available therapy. These data support ruxolitinib as an effective long-term treatment option for hydroxyurea-resistant or intolerant patients with polycythemia vera. This trial was registered at clinicaltrials.gov identifier: 01243944.

OBJECTIVE: The choice of coronary artery bypass grafting (CABG) as an intervention for coronary artery disease has been clouded by concerns about postoperative cognitive decline. Long-term cognitive decline after CABG has been reported, but without appropriate control subjects, it is not known whether this decline is specific to CABG or related to other factors such as cerebrovascular disease. METHODS: This prospective, observational study of patients with diagnosed coronary artery disease included 152 CABG and 92 nonsurgical cardiac comparison patients from one institution. The main outcome measure was within-patient change in cognitive performance for eight cognitive domains from baseline to 12- and 72-month follow-up. RESULTS: Mild late cognitive decline was observed for both study groups, but despite greater than 80% power to detect a 0.2 standard deviation difference, there were no statistically significant differences between the surgical and nonsurgical patients in the degree of change from 12 to 72 months for any cognitive domain. There was also no difference between groups in the degree of change from baseline to 72 months or in the number of patients with a Mini-Mental State Examination score in the clinically impaired range at 72 months. INTERPRETATION: Late cognitive decline does occur in patients who have undergone CABG surgery, but the degree of this decline does not differ from that observed in patients of similar age with coronary artery disease who have not undergone CABG. Therefore, late cognitive decline after CABG is not specific to the use of cardiopulmonary bypass.