Preoperative Echocardiographic Indices of Diastolic Dysfunction and Brain Natriuretic Peptide in Predicting Postoperative Atrial Fibrillation After Noncardiac Surgery.

BACKGROUND: We have shown previously that either echocardiographic indices of diastolic dysfunction or increased preoperative brain natriuretic peptide (BNP) predict postoperative atrial fibrillation (POAF). Because these 2 predictors of POAF have not been evaluated together, our goal was to further elucidate their concurrent role in patients undergoing noncardiac thoracic surgery. METHODS: We retrospectively identified 191 patients who had a preoperative transthoracic echocardiogram and serum BNP level collected as part of routine care before major lung or esophageal resection. Clinical and echocardiographic data were compared between patients who did or did not develop POAF (>5 minutes), and prognostic factors for POAF were identified. RESULTS: Univariate associations with POAF (41 of 191; 22% patients) included older age (P = .04), male sex (P = .01), hypertension (P = .03), increased body mass index (P = .01), and prolonged transmitral flow deceleration time (P < .0001), whereas BNP was not statistically significant (P = .07). Stepwise logistic regression analysis showed that both increasing transmitral flow deceleration time (continuous data log base 2 transformed; odds ratio, 16.05; 95% confidence interval, 3.74-68.96; P = .0002) and left atrial diastolic volume index (continuous data log base 2 transformed; odds ratio, 3.29; 95% confidence interval, 1.22-8.91; P = .02) were independent risk factors of POAF (area under the receiver operating characteristic curve = 0.73). There was no significant interaction between BNP and the 2 independent variables (P = .60, and P = .90), respectively. CONCLUSIONS: In a cohort of patients who had echocardiography and BNP measurements before undergoing major thoracic surgery, this study showed that when evaluated together greater preoperative left atrial diastolic volume index and transmitral flow deceleration time but not BNP levels were independent predictors for POAF.

A phase I study of D-methadone in patients with chronic pain.

D-Methadone is the d optical isomer of racemic mixture (DL-methadone) used clinically to treat pain and addiction in the United States. D-Methadone is practically devoid of opioid activity but maintains N-methyl-D-aspartate (NMDA) receptor antagonism. Evidence from extensive preclinical studies suggests that NMDA receptor antagonists attenuate neuronal plasticity, reverse opioid analgesic tolerance, and alleviate chronic pain states. The authors conducted a phase I open label study of D-methadone administered for the first time to patients with chronic pain to determine the safety and tolerability of D-methadone. In addition to their long-term regimen of opioids, the patients received 40 mg of D-methadone twice daily for 12 days. Analgesia and toxicity were recorded by the patients in a daily diary and assessed in clinic on days 1, 8, and 12. Eight patients of the 10 enrolled completed the study. Pain scores on Edmonton Symptom Assessment System (ESAS) did not change between days 1 and 12, but five of eight patients (62.5 percent) characterized D-methadone as moderately or very effective in relieving pain on the Global Assessment for pain. Five of the eight patients (62.5 percent) who completed the study requested to start treatment with commercially available methadone (DL-racemic methadone) after completing the study. D-Methadone at the dose of 40 mg PO Q 12 hours was well tolerated. Perspective: This is the first clinical study of D-methadone in patients suffering from chronic pain. Additional phase I and phase II studies are needed to confirm its safety and analgesic effects. If D-methadone is well tolerated, it is likely to become a useful adjuvant to the treatment of a wide spectrum of pain syndromes.

Methadone Use and the Risk of Hypoglycemia for Inpatients With Cancer Pain.

CONTEXT: Methadone is an important drug in the management of both cancer-related and non-cancer-related pain and is the main pharmacologic agent used in the treatment of opioid addiction. Unexpected hypoglycemia has been observed in patients receiving methadone, prompting a more detailed investigation. OBJECTIVES: To evaluate the incidence of hypoglycemia in a cohort of inpatients receiving methadone versus other opioids including fentanyl, hydromorphone, and morphine. METHODS: Retrospective observational cohort of inpatients in a tertiary cancer center admitted for more than 48 hours from November 1, 2011 to October 30, 2013. The main outcomes were lowest measured daily blood glucose (in mg/dL) and incidence of hypoglycemia (defined as blood glucose < 70 mg/dL, equivalent to 3.9 mmol/L) with variable methadone doses compared with other non-methadone opioids. RESULTS: Of the 641 eligible patients admitted during the study period who received at least one dose of methadone during admission, multivariable logistic regression showed significant associations between methadone and hypoglycemia at doses greater than 40 mg oral equivalents per day or with patient-controlled analgesia use. A dose-response relationship was observed, with an odds ratio of 3.1 (95% confidence interval 2.5, 3.6) when doses greater than 80 mg/day were used. No evidence of increased risk of hypoglycemia or of a dose-response curve was seen for the other opioids. CONCLUSION: The risk of hypoglycemia is increased for patients taking more than 40 mg oral methadone equivalents per day. When starting methadone at or more than 40 mg/day, we recommend blood glucose monitoring.

Metabolic plasticity of metastatic breast cancer cells: adaptation to changes in the microenvironment.

Cancer cells adapt their metabolism during tumorigenesis. We studied two isogenic breast cancer cells lines (highly metastatic 4T1; nonmetastatic 67NR) to identify differences in their glucose and glutamine metabolism in response to metabolic and environmental stress. Dynamic magnetic resonance spectroscopy of (13)C-isotopomers showed that 4T1 cells have higher glycolytic and tricarboxylic acid (TCA) cycle flux than 67NR cells and readily switch between glycolysis and oxidative phosphorylation (OXPHOS) in response to different extracellular environments. OXPHOS activity increased with metastatic potential in isogenic cell lines derived from the same primary breast cancer: 4T1 > 4T07 and 168FARN (local micrometastasis only) > 67NR. We observed a restricted TCA cycle flux at the succinate dehydrogenase step in 67NR cells (but not in 4T1 cells), leading to succinate accumulation and hindering OXPHOS. In the four isogenic cell lines, environmental stresses modulated succinate dehydrogenase subunit A expression according to metastatic potential. Moreover, glucose-derived lactate production was more glutamine dependent in cell lines with higher metastatic potential. These studies show clear differences in TCA cycle metabolism between 4T1 and 67NR breast cancer cells. They indicate that metastases-forming 4T1 cells are more adept at adjusting their metabolism in response to environmental stress than isogenic, nonmetastatic 67NR cells. We suggest that the metabolic plasticity and adaptability are more important to the metastatic breast cancer phenotype than rapid cell proliferation alone, which could 1) provide a new biomarker for early detection of this phenotype, possibly at the time of diagnosis, and 2) lead to new treatment strategies of metastatic breast cancer by targeting mitochondrial metabolism.

Continuous Trastuzumab Therapy in Breast Cancer Patients With Asymptomatic Left Ventricular Dysfunction.

BACKGROUND: Adjuvant trastuzumab is a highly effective targeted treatment that improves survival for patients with HER2-positive breast cancer. However, trastuzumab interruption is recommended for patients who develop treatment-induced cardiotoxicity (i.e., decline in left ventricular ejection fraction [LVEF], with or without symptoms) and can lead to an incomplete course of treatment. We studied the cardiac safety of continuous trastuzumab therapy among patients with asymptomatic declines in LVEF. METHODS: We retrospectively evaluated patients with HER2-positive breast cancer treated with adjuvant trastuzumab at our institution between 2005 and 2010. Treatment-induced cardiotoxicity was defined by an absolute decrease in LVEF of ≥10% to below 55% or an absolute decrease of ≥16%. Logistic regression was used to determine the association between candidate risk factors and treatment-induced cardiotoxicity. RESULTS: Among 573 patients, 92 (16%) developed treatment-induced cardiotoxicity. Trastuzumab was continued without interruption in 31 of 92 patients with treatment-induced cardiotoxicity­all were asymptomatic with LVEF of ≥50% at cardiotoxicity diagnosis with median LVEF of 53% (range, 50%-63%), and none developed heart failure during follow-up. Risk factors associated with treatment-induced cardiotoxicity included age (p = .011), anthracycline chemotherapy (p = .002), and lower pretrastuzumab LVEF (p < .001). CONCLUSION: Among patients who develop asymptomatic treatment-induced cardiotoxicity with LVEF of ≥50%, continuous trastuzumab therapy appears to be safe.

Trastuzumab interruption and treatment-induced cardiotoxicity in early HER2-positive breast cancer.

Trastuzumab improves outcomes among patients with HER2-positive breast cancer but is associated with a risk of treatment-induced cardiotoxicity (TIC). It is unclear how frequently TIC leads to trastuzumab interruption outside of prospective trials, and how TIC is managed in clinical practice. Patients with HER2-postive breast cancer receiving adjuvant trastuzumab from 2005 to 2010 were identified (n = 608). We evaluated the incidence, risk factors, and management of trastuzumab interruption due to TIC. In total, 488 (80 %) patients were treated with anthracycline prior to trastuzumab. Trastuzumab was interrupted in 108 (18 %) patients. Cumulative trastuzumab dose was lower in the interrupted group (median 86 vs. 108 mg/kg, p < 0.0001). The most common reason for interruption was TIC (66 of 108 patients): 20 had symptomatic heart failure and 46 had asymptomatic left ventricular ejection fraction (LVEF) decline. Patients with trastuzumab interruption for TIC were older (54 vs. 50 years, p = 0.014) with lower LVEF before anthracycline (63 vs. 67 %, p < 0.0001) and trastuzumab (62 vs. 67 %, p < 0.0001) therapy. Mean LVEF at baseline, TIC diagnosis, and follow-up after trastuzumab interruption was 63, 45, and 55 %, respectively. Thirty-three of 66 patients with TIC were re-challenged with trastuzumab, and five patients had recurrent LVEF decline. In clinical practice, trastuzumab interruption is common and most often due to TIC, with most patients receiving anthracycline prior to trastuzumab. Cardiac dysfunction improves after trastuzumab interruption but may not fully recover to baseline. Strategies to minimize cardiotoxicity and treatment interruption should be investigated to prevent persistent left ventricular dysfunction in affected patients.

Beneficial effects of perioperative statins for major pulmonary resection.

OBJECTIVES: Statins improve overall outcomes after noncardiac surgery. The primary aim of the study was to determine whether use of perioperative atorvastatin reduced the rate of postoperative complications in patients undergoing pulmonary resection. METHODS: This was a prospective, randomized, placebo-controlled, double-blind trial of patients undergoing elective pulmonary resection who received atorvastatin (40 mg daily) or placebo beginning 1 week before surgery and continued for 1 week postoperatively. Patient characteristics and postoperative complications were recorded. Plasma inflammatory markers were sampled at baseline, in the post-anesthesia care unit, and on postoperative day 3. Because of difficulty enrolling statin-naive patients, the study was stopped at the interim analysis. RESULTS: Postoperative complications occurred in 16 of 72 patients (22%) receiving placebo and in 8 of 65 patients (12%) receiving atorvastatin (P = .13). For patients undergoing major anatomic resection, there were 24 complications in 15 of 45 placebo-treated patients and 8 complications in 7 of 43 atorvastatin-treated patients (P = .04). Plasma levels of C-reactive protein, tumor necrosis factor-α, and myeloperoxidase did not differ between the 2 treatment arms during the study. CONCLUSIONS: After a 2-week perioperative course of atorvastatin (40 mg) in statin-naïve patients undergoing major pulmonary resection, we found evidence of a reduction in the number of clinically important cardiovascular and pulmonary complications compared with placebo. These promising results merit evaluation in a larger, perhaps multicenter study.

External validation of the number of risk factors score in a palliative care outpatient clinic at a comprehensive cancer center.

BACKGROUND: Prognostic tools are available to predict if terminally ill cancer patients have days or weeks to live. Tools for predicting the prognosis in ambulatory patients at an earlier stage are lacking. The Number of Risk Factors (NRF) score developed in ambulatory cancer patients receiving palliative radiation therapy may be suitable for this purpose but has not been tested in a palliative care setting. OBJECTIVE: Our aim was to evaluate the prognostic accuracy of the NRF score in patients referred to a palliative care outpatient clinic at a comprehensive cancer center. METHODS: We conducted a retrospective chart review of NRF scores and survival in 300 consecutive, newly referred patients. Measurements included primary cancer type, extent of disease, Karnofsky Performance Scale (KPS) score, and survival duration after first visit. One point was allocated each for cancer other than breast cancer, metastases other than bone, and low KPS score. RESULTS: Of 300 patients, 236 (79%) had advanced disease. Of those 236, 212 (90%) had a cancer other than breast cancer, 180 (76%) had metastatic disease in sites other than bone, and 64 (27%) had a KPS score <70%. During the 2-year follow-up, 221 (94%) patients died, with overall median survival of 4.9 months (95% confidence interval, 3.9-6.1 months). NRF scores of 0 to 1, 2, and 3 split the sample into subgroups with highly significantly different survival among the groups, with medians 9.0, 4.6, and 2.1 months, respectively (Wilcoxon test χ(2)=43.9, degrees of freedom [df] 2, p<0.0001). A simple parametric model was fit to determine the probability of subgroup members surviving to a certain number of months. CONCLUSIONS: In cancer patients referred to palliative care earlier in their disease trajectory, the NRF score may be a useful prognostic tool. Further validation in other palliative care populations is needed.

Cost-effectiveness analysis of robotically assisted laparoscopy for newly diagnosed uterine cancers.

OBJECTIVE: To assess the direct costs of three surgical approaches in uterine cancer and the cost-effectiveness of incorporating robot-assisted surgery. METHODS: A cost system that allocates the actual cost of resources used to treat each patient, as opposed to borrowing cost data from a billing system, was used to determine direct costs for patients who underwent surgery for uterine cancer from 2009 to 2010. These costs included all aspects of surgical care up to 6 months after discharge. Total amortized direct costs included the capital cost of three dual-console robotic platforms with 5 years of service contracts. Nonamortized costs were also calculated (excluded capital costs). Modeling was performed to estimate the mean cost of surgical care for patients presenting with endometrial cancer from 2007 to 2010. RESULTS: Of 436 cases (132 laparoscopic, 262 robotic, 42 laparotomy), total mean amortized direct costs per case were $20,489 (laparoscopy), $23,646 (robot), and $24,642 (laparotomy) (P<.05 [robot compared with laparoscopy]; P=.6 [robot compared with laparotomy]). Total nonamortized costs per case were $20,289, $20,467, and $24,433, respectively (P=.9 [robot compared with laparoscopy]; P=.03 [robot compared with laparotomy]). The planned surgical approach in 2007 was laparoscopy, 68%; robot, 8%; and laparotomy, 24% compared with 26%, 64%, and 9%, respectively, in 2010 (P<.001). The modeled mean amortized direct costs per case were $21,738 in 2007 and $22,678 in 2010 (+$940). Nonamortized costs were $21,298 in 2007 and $20,573 in 2010 (-$725). CONCLUSION: Laparoscopy is least expensive when including capital acquisition costs. Laparoscopy and robotic surgery are comparable if upfront costs are excluded. There is cost neutralization with the robot when it helps decrease laparotomy rates.

Imaging the norepinephrine transporter in neuroblastoma: a comparison of [18F]-MFBG and 123I-MIBG.

PURPOSE: The norepinephrine transporter (NET) is a critical regulator of catecholamine uptake in normal physiology and is expressed in neuroendocrine tumors like neuroblastoma. Although the norepinephrine analog, meta-iodobenzylguanidine (MIBG), is an established substrate for NET, (123)I/(131)I-MIBG has several clinical limitations for diagnostic imaging. In the current studies, we evaluated meta-[(18)F]-fluorobenzylguanidine ([(18)F]-MFBG) and compared it with (123)I-MIBG for imaging NET-expressing neuroblastomas. EXPERIMENTAL DESIGN: NET expression levels in neuroblastoma cell lines were determined by Western blot and (123)I-MIBG uptake assays. Five neuroblastoma cell lines and two xenografts (SK-N-BE(2)C and LAN1) expressing different levels of NET were used for comparative in vitro and in vivo uptake studies. RESULTS: The uptake of [(18)F]-MFBG in cells was specific and proportional to the expression level of NET. Although [(18)F]-MFBG had a 3-fold lower affinity for NET and an approximately 2-fold lower cell uptake in vitro compared with that of (123)I-MIBG, the in vivo imaging and tissue radioactivity concentration measurements demonstrated higher [(18)F]-MFBG xenograft uptake and tumor-to-normal organ ratios at 1 and 4 hours after injection. A comparison of 4 hours [(18)F]-MFBG PET (positron emission tomography) imaging with 24 hours (123)I-MIBG SPECT (single-photon emission computed tomography) imaging showed an approximately 3-fold higher tumor uptake of [(18)F]-MFBG, but slightly lower tumor-to-background ratios in mice. CONCLUSIONS: [(18)F]-MFBG is a promising radiopharmaceutical for specifically imaging NET-expressing neuroblastomas, with fast pharmacokinetics and whole-body clearance. [(18)F]-MFBG PET imaging shows higher sensitivity, better detection of small lesions with low NET expression, allows same day scintigraphy with a shorter image acquisition time, and has the potential for lower patient radiation exposure compared with (131)I/(123)I-MIBG.

Homeward bound: an analysis of patients discharged home from an oncologic intensive care unit.

PURPOSE: The objectives of our study were to evaluate the characteristics and outcomes of patients discharged home directly from an oncologic intensive care unit (ICU) and their 30-day hospital readmission patterns. MATERIALS AND METHODS: We retrospectively reviewed ICU discharges over 3 years (2008-2010) and identified patients who were discharged directly home. Demographic, clinical, ICU discharge, and 30-day hospital readmission and mortality rates were analyzed. RESULTS: Ninety-five patients (3.6%) were discharged home directly from the ICU (average annual rate of 3.9%). ICU diagnoses primarily included respiratory insufficiency, sepsis, cardiac syndromes, and gastrointestinal bleeding. Home discharge occurred most commonly between Thursday and Saturday. Five (5.3%) patients, including 2 hospice patients, died within 30 days of ICU home discharge. Thirty (31.6%) patients were readmitted within 30 days of discharge. The unplanned 30-day readmission rate was 23.2% (22/95) with a median time to hospital readmission of 13 (8-18) days. Most (64%) of the unplanned readmissions were related to the initial ICU admission. CONCLUSIONS: Home discharge of ICU patients at our institution is infrequent but consistent. Almost one third of these patients were readmitted to the hospital within 30 days. Enhancements to the ICU home discharge process may be required to ensure optimal post-ICU care.

Brain natriuretic peptide and risk of atrial fibrillation after thoracic surgery.

OBJECTIVES: Postoperative atrial fibrillation (POAF) complicating general thoracic surgery is a marker of increased morbidity and stroke risk. Our goal was to determine whether increased preoperative brain natriuretic peptide (BNP) levels are able to stratify patients by the risk of POAF. METHODS: Using a prospective database of 415 patients aged 60 years or older, who had undergone lung or esophageal surgery during a 1-year period, the preoperative clinical data, including BNP levels, were compared between patients who developed POAF lasting longer than 5 minutes during hospitalization and those who did not. RESULTS: POAF occurred in 65 (16%) of the 415 patients and was more frequent among patients who had undergone esophagectomy or anatomic lung resection (22% or 58 of 269) compared with those who did not (5% or 7 of 146; P < .0001). After esophagectomy or anatomic lung resection, 46 (34%) of the 135 patients with BNP levels greater than the median (≥ 30 pg/mL) developed POAF compared with only 12 (9%) of 134 patients with BNP levels less than 30 pg/mL (P < .0001). The rates of POAF in patients undergoing other thoracic procedures were low and not associated with the BNP levels. Multivariate logistic regression analysis showed that in patients undergoing esophagectomy or anatomic lung resection, older age (5-year increments, odds ratio [OR], 1.28; 95% confidence interval [CI], 1.01-1.61; P = .04), male gender (OR, 2.61; 95% CI, 1.12-4.17; P = .02), and BNP level 30 pg/mL or greater (OR, 4.52; 95% CI, 2.19-9.32; P < .0001) were independent risk factors for POAF. The length of hospital stay was significantly increased in patients who developed POAF compared with those who did not (P < .0001). CONCLUSIONS: Among patients undergoing anatomic lung resection or esophagectomy, increased age, male gender, and preoperative BNP level of 30 pg/mL or greater were significant risk factors for the development of POAF. The identification of patients who are more likely to develop POAF will allow the development of trials assessing prevention strategies aimed at reducing this complication.

Dynamic contrast-enhanced magnetic resonance imaging as a predictor of outcome in head-and-neck squamous cell carcinoma patients with nodal metastases.

PURPOSE: Dynamic contrast-enhanced MRI (DCE-MRI) can provide information regarding tumor perfusion and permeability and has shown prognostic value in certain tumors types. The goal of this study was to assess the prognostic value of pretreatment DCE-MRI in head and neck squamous cell carcinoma (HNSCC) patients with nodal disease undergoing chemoradiation therapy or surgery. METHODS AND MATERIALS: Seventy-four patients with histologically proven squamous cell carcinoma and neck nodal metastases were eligible for the study. Pretreatment DCE-MRI was performed on a 1.5T MRI. Clinical follow-up was a minimum of 12 months. DCE-MRI data were analyzed using the Tofts model. DCE-MRI parameters were related to treatment outcome (progression-free survival [PFS] and overall survival [OS]). Patients were grouped as no evidence of disease (NED), alive with disease (AWD), dead with disease (DOD), or dead of other causes (DOC). Prognostic significance was assessed using the log-rank test for single variables and Cox proportional hazards regression for combinations of variables. RESULTS: At last clinical follow-up, for Stage III, all 12 patients were NED. For Stage IV, 43 patients were NED, 4 were AWD, 11 were DOD, and 4 were DOC. K(trans) is volume transfer constant. In a stepwise Cox regression, skewness of K(trans) (volume transfer constant) was the strongest predictor for Stage IV patients (PFS and OS: p <0.001). CONCLUSION: Our study shows that skewness of K(trans) was the strongest predictor of PFS and OS in Stage IV HNSCC patients with nodal disease. This study suggests an important role for pretreatment DCE-MRI parameter K(trans) as a predictor of outcome in these patients.

Preoperative left atrial dysfunction and risk of postoperative atrial fibrillation complicating thoracic surgery.

OBJECTIVE: Postoperative atrial fibrillation complicating general thoracic surgery increases morbidity and stroke risk. We aimed to determine whether preoperative atrial dysfunction or other echocardiographic markers are associated with postoperative atrial fibrillation. METHODS: In 191 patients who had undergone anatomic lung or esophageal resection, preoperative clinical and echocardiographic data were compared between patients with and without postoperative atrial fibrillation. Presence of postoperative atrial fibrillation lasting more than 5 minutes during hospitalization was detected using continuous telemetry or 12-lead electrocardiography. Maximal left atrial volume and indices of left atrial function were assessed. RESULTS: Patients with postoperative atrial fibrillation (33/191, 17%) were older (71 ± 5 years vs 64 ± 12 years, P < .0001), were taking ß-blockers more often, had greater left atrial volume, had decreased left atrial emptying fraction, and had lower E' and A' septal velocities compared with patients without postoperative atrial fibrillation. The incidence of postoperative atrial fibrillation in patients with left atrial volume 32 mL/m(2) or greater was 37% (11/30) and greater than in those with left atrial volume less than 32 mL/m(2) (14%, 22/160, P = .002). Length of hospital stay was significantly increased in patients with postoperative atrial fibrillation compared with patients without (P = .04). Older age was significantly associated with greater ß-blocker use and left atrial volume and lower left atrial emptying fraction. On multivariate analysis, lower left atrial emptying fraction (odds ratio, 1.03 per unit decrement; 95% confidence interval, 1.002-1.065; P = .04) and preoperative use of ß-blockers (odds ratio, 2.82; 95% confidence interval, 1.18-6.77; P = .02) were the only independent risk factors associated with postoperative atrial fibrillation. CONCLUSIONS: These data show that an echocardiogram before major thoracic surgery, increased use of preoperative ß-blockers, and decreased left atrial emptying fraction were associated with postoperative atrial fibrillation. Echocardiographic predictors of left atrial mechanical dysfunction may prove clinically useful in risk stratifying patients in whom postoperative atrial fibrillation is more likely to develop and to benefit from prevention strategies aimed at mitigating atrial function before surgery.

Cognitive functions in primary CNS lymphoma after single or combined modality regimens.

The standard treatment for primary CNS lymphoma (PCNSL) involves high-dose methotrexate-based chemotherapy (HD-MTX) alone or in combination with whole brain radiotherapy (WBRT). The combined modality regimen carries a substantial risk for cognitive impairment, and HD-MTX alone has been used more often recently in part to reduce neurotoxicity. In this study, we assessed cognitive functioning and quality of life in PCNSL survivors treated with WBRT + HD-MTX or HD-MTX alone. Fifty PCNSL patients in disease remission underwent a posttreatment baseline neuropsychological evaluation, and a subset of patients completed a follow-up evaluation. Quality of life and extent of white matter disease and atrophy on MRI were assessed. Comparisons according to treatment type after controlling for age and time since treatment completion showed that patients treated with HD-MTX alone had significantly higher scores on tests of selective attention and memory than patients treated with the combined modality regimen. Patients treated with WBRT + HD-MTX had impairments across most cognitive domains, and these were of sufficient severity to interfere with quality of life, as over 50% were not working due to their illness. Patients treated with HD-MTX alone did not meet criteria for cognitive impairment but scored within 1 SD below the normative sample on most tests. Patients with more extensive white matter disease had lower scores on tests of set-shifting and memory. Cognitive dysfunction was more prevalent in PCNSL survivors treated with WBRT + HD-MTX compared with patients treated with HD-MTX alone.

Thrombolytic therapy is effective in paroxysmal nocturnal hemoglobinuria: a series of nine patients and a review of the literature.

BACKGROUND: Thrombosis is the major risk factor for death in patients with paroxysmal nocturnal hemoglobinuria. Previous case reports indicate that venous thrombosis in patients with paroxysmal nocturnal hemoglobinuria is amenable to thrombolysis. DESIGN AND METHODS: We reviewed the outcome of thrombolytic therapy for patients with paroxysmal nocturnal hemoglobinuria who had thromboses refractory to anticoagulation at our institutions. RESULTS: In this study of 41 patients who had at least one thrombotic event, we confirmed a very high incidence of recurrence despite anticoagulation. Nine patients with thrombosis were regarded as eligible for administration of intravenous tissue plasminogen activator, which was effective in reversing thrombi in all of 15 occasions in which it was given. Serious hemorrhagic complications developed in three cases. At last follow-up visit, of the nine patients treated, three had died, and six were in very good to excellent condition in terms of clinical outcome and radiological findings. The only patient in whom thrombolysis may have contributed to a fatal outcome also had complications of "heparin induced thrombocytopenia with thrombosis", which we diagnosed in three additional patients. In our review of the literature, nine out of 15 patients treated with thrombolysis have had a good outcome. CONCLUSIONS: Although it is associated with a significant but manageable risk of bleeding, systemic thrombolysis is a highly effective treatment for reversing venous thromboses in patients with paroxysmal nocturnal hemoglobinuria.

Identifying clinical improvement in consolidation single-arm phase 2 trials in patients with ovarian cancer in second or greater clinical remission.

OBJECTIVE: Estimates of progression-free survival (PFS) from single-arm phase 2 consolidation/maintenance trials for recurrent ovarian cancer are usually interpreted in the context of historical controls. We illustrate how the duration of second-line therapy (SLT), the time on the investigational therapy (IT), and patient enrollment plan can affect efficacy measures from maintenance trials and might result in underpowered studies. METHODS: Efficacy data from 3 published single-arm consolidation therapies in second remission in ovarian cancer were used for illustration. The studies were designed to show an increase in estimated median PFS from 9 to 13.5 months. We partitioned PFS as the sum of the duration of SLT, treatment-free interval, and duration of IT. We calculated the statistical power when IT is given concurrently with SLT or after SLT by varying the start of IT. We compared the sample sizes required when PFS includes the time on SLT versus PFS that starts after SLT at initiation of IT. RESULTS: Required sample sizes varied with duration of SLT. If IT starts with initiation of SLT, only 34 patients are needed to provide 80% power to detect a 33% hazard reduction. In contrast, 104 patients are required for a single-arm study for 80% power, if IT begins 7.5 months after SLT initiation. CONCLUSIONS: Designs of nonrandomized consolidation trials that aim to prolong PFS must consider the effect of the duration of SLT on the end point definition and on required sample size. If IT is given concurrently with SLT, and after SLT, then SLT duration must be restricted per protocol eligibility, so that a comparison with historical data from other single-arm phase 2 studies is unbiased. If IT is given after SLT, the duration of SLT should be taken into account in the design stage because it will affect statistical power and sample size.

CA125 regression in ovarian cancer patients treated with intravenous versus intraperitoneal platinum-based chemotherapy: a gynecologic oncology group study.

OBJECTIVE: CA125 is a non-specific marker of peritoneal irritation which has the potential for false elevation during intraperitoneal treatment. The purpose of this study is to identify the rate of CA125 regression during intraperitoneal (IP) versus intravenous (IV) chemotherapy for ovarian cancer. METHODS: GOG 114, a randomized control trial evaluating IP and IV treatment, includes an intensive CA125 measurement schema with weekly CA125 levels until ≤ 35 units/ml for both IP- and IV-treated patients. Rate of CA125 normalization, median CA125 values for each treatment cycle, as well as clinical and pathologic features were compared between the treatment groups. Baseline CA125 levels and rate of CA125 decline were evaluated with respect to overall survival. RESULTS: CA125 data were available for 223 patients who received IV cisplatin/paclitaxel and for 231 patients who received IV carboplatin followed by IP cisplatin/paclitaxel. Standard prognostic criteria and baseline CA125 values were similar between the treatment groups. For treatment cycles in which IP-treatment was administered, there was no statistically significant difference in CA125 levels between IV- and IP-treated patients. The rate of CA125 normalization was similar between IV- and IP-treated patients (p=0.55). Patients with low pre-chemotherapy CA125 levels which rapidly declined during treatment demonstrated a survival advantage (p<0.0001). CONCLUSIONS: No difference in CA125 decline was identified between IP- and IV-treated patients undergoing a weekly CA125 monitoring schedule. This data supports the utilization of standard CA125 response criteria in the therapeutic monitoring for patients receiving IP treatment.

Advance directives in an oncologic intensive care unit: a contemporary analysis of their frequency, type, and impact.

BACKGROUND: Our objective was to provide a contemporary analysis of the prevalence, types, and impact of advance health care directives in critically ill cancer patients. METHODS: We retrospectively reviewed all intensive care unit (ICU) admissions (January 1, 2006 to April 25, 2008) at an oncologic center and identified all patients who completed a living will (LW), or health care proxy (HCP), or neither prior to ICU admission. Demographics, clinical data, end-of-life (EOL) parameters and outcomes were compared among three groups: LWs, HCPs, and no LW or HCP. RESULTS: Of 1,333 ICU admissions, 1,121 patients (84%) were included for analysis: 176 patients (15.7%) had LW, 534 (47.6%) had HCP and 411 (36.7%) had no LW or HCP. Patients with LW were significantly more likely to be older and white as compared to patients with HCP alone, or no LW or HCP. There were no significant demographic differences between patients with HCP or no LW or HCP. Patients with HCP alone, or no LW or HCP, were significantly more likely to have Medicaid than patients with LW. There were no differences noted in ICU care, EOL management, or outcomes among the three groups. CONCLUSIONS: The prevalence of LWs in patients admitted to our oncologic ICU is low. More than half of the remaining patients had designated HCPs. Older age and white race were associated with the presence of LWs. However, the presence of LWs or HCPs did not influence ICU care, EOL management or outcomes at our institution.

Cognitive functions in long-term survivors of ovarian cancer.

BACKGROUND: Women diagnosed with ovarian cancer often undergo chemotherapy involving multiple agents. However, little is known about the incidence of cognitive adverse effects of chemotherapy in survivors of this disease. This cross-sectional study assessed neuropsychological functions in long-term survivors of ovarian cancer who were either in complete remission or with evidence of recurrent disease. METHODS: Forty-eight women diagnosed with ovarian cancer 5 to 10 years prior to study enrollment underwent a brief neuropsychological evaluation; 22 patients were disease free and without history of recurrence (Group 1), and 26 patients had recurrent disease and were receiving treatment with chemotherapy or hormonal therapy (Group 2). RESULTS: There were no statistically significant differences between the two patient groups on tests of attention, memory, and executive functions. Group mean cognitive test scores were within the average range on all tests; however 28% of patients met criteria for cognitive impairment, a significantly higher frequency (p=0.03) than reported in healthy populations. CONCLUSIONS: In this study, neuropsychological test performance did not differ significantly between ovarian cancer survivors who were in remission and patients with recurrent disease and receiving treatment. Cognitive impairment was evident in a subset of patients, although group means test scores were within the average range. Additional research using prospective longitudinal designs is needed to clarify the contribution of disease, chemotherapy, hormonal therapy, and other risk factors to cognitive outcome in this clinical population.