Citations

Purpose A pressing need exists for agents active against anthracycline- or taxane-refractory metastatic breast cancer (MBC), or both. Previous clinical trials suggested that irinotecan might have such activity. We conducted this multicenter phase II study to assess efficacy and tolerability of two irinotecan schedules. Patients and Methods MBC patients who experienced disease progression after one to three chemotherapy regimens, including at least one anthracycline- or taxane-based regimen, were randomly assigned to irinotecan in 6-week cycles comprising 100 mg/m2 weekly for 4 weeks, then a 2-week rest (weekly) or 240 mg/m2 every 3 weeks. Results The weekly arm had 52 assessable patients; the every-3-weeks arm had 51 assessable patients. In the weekly arm, the objective response (complete regression [CR] + partial regression [PR]) rate was 23% (one CR, 11 PR; 95% CI, 13% to 37%). Median response duration was 4.9 months (range, 1.9 to 15.9 months), and median overall survival was 9.7 months (95% CI, 8.0 to 14.2 months). In the every-3-weeks arm, the objective response rate was 14% (nine PR; 95% CI, 6% to 26%), median response duration was 4.2 months (range, 3.1 to 13.9 months), and median overall survival was 8.6 months (95% CI, 7.0 to 12.3 months). Treatment generally was well tolerated, especially in the weekly arm. Grade 3 to 4 adverse events with ≥ 10% incidence included neutropenia (29%) and diarrhea (17%) in the weekly arm and neutropenia (36%), vomiting (20%), dyspnea (18%), nausea (16%), and diarrhea (12%) in the every-3-weeks arm. Conclusion Irinotecan is active with good tolerability in refractory MBC. Irinotecan (especially weekly) warrants additional study as monotherapy and in combination regimens in this setting.

Purpose To update and expand on previously published clinical practice guidelines for the treatment of cancer treatment-induced diarrhea. Methods An expert multidisciplinary panel was convened to review the recent literature and discuss recommendations for updating the practice guidelines previously published by this group in the Journal of Clinical Oncology in 1998. MEDLINE searches were performed and the relevant literature published since 1998 was reviewed by all panel members. The treatment recommendations and algorithm were revised by panel consensus. Results A recent review of early toxic deaths occurring in two National Cancer Institute-sponsored cooperative group trials of irinotecan plus high-dose fluorouracil and leucovorin for advanced colorectal cancer has led to the recognition of a life-threatening gastrointestinal syndrome and highlighted the need for vigilant monitoring and aggressive therapy for this serious complication. Loperamide remains the standard therapy for uncomplicated cases. However, the revised guidelines reflect the need for recognition of the early warning signs of complicated cases of diarrhea and the need for early and aggressive management, including the addition of antibiotics. Management of radiation-induced diarrhea is similar but may not require hospitalization, and chronic low- to intermediate-grade symptoms can be managed with continued loperamide. Conclusion With vigilant monitoring and aggressive therapy for cancer treatment-induced diarrhea, particularly in patients with early warning signs of severe complications, morbidity and mortality may be reduced.

Purpose Some patients with colon cancer have a high risk of local recurrence postoperatively. This trial was undertaken to determine whether radiation therapy added to an adjuvant chemotherapy regimen improves outcome in high-risk patients. Patients and Methods Patients with resected colon cancer with tumor adherence or invasion of surrounding structures, or with T3N1 or T3N2 tumors of the ascending or descending colon were randomly assigned to receive fluorouracil and levamisole therapy with or without radiation therapy. Patients who received chemotherapy and radiation therapy (chemoRT) received 45 to 50.4 Gy in 25 to 28 fractions beginning 28 days after starting chemotherapy. Patient enrollment was terminated because of slow accrual after 222 patients enrolled (original goal was 700 patients); 187 patients were assessable. Results Overall 5-year survival was 62% for chemotherapy patients and 58% for chemoRT patients (P > .50); 5-year disease-free survival was 51% for both groups (P > .50). Toxicity (≥ grade 3) occurred in 42% of chemotherapy patients and 54% of chemoRT patients (P = .04). Leukopenia (≥ grade 3) occurred in 10% of chemotherapy patients and 22% of chemoRT patients (P = .02). No significant difference in nonhematologic toxicity (≥ grade 3) was observed between chemoRT and chemotherapy patients (35% v 44%; P = .26). Conclusion Patients who received chemotherapy or chemoRT had similar overall survival and disease-free survival. Toxicity was higher among chemoRT patients. These results must be interpreted with caution because of the high number of ineligible patients and the limited power of the study to detect potentially meaningful differences.

Abstract Background: Transthyretin-associated hereditary amyloidosis (ATTR) is an inherited disease in which variants in the primary structure of transthyretin (TTR; prealbumin) lead to the extracellular polymerization of insoluble protein fibrils, causing organ failure and ultimately death when major organs are involved. We have developed an integrated approach to molecular diagnosis with initial analysis of intact plasma TTR by electrospray ionization mass spectrometry (MS) and referral of positive samples for DNA sequence analysis and real-time PCR to confirm the common Gly6Ser polymorphism. Methods: Samples from 6 patients previously diagnosed with ATTR and from 25 controls with (n = 15) or without (n = 10) polyneuropathy were analyzed in a blinded fashion for the presence of variant TTR. TTR protein was extracted with an immunoaffinity resin from 20 μL of archived plasma samples. The purified TTR was reduced with tris(2-carboxyethyl)phosphine and analyzed by MS. The appearance of two peaks (or a single peak shifted in mass indicative of a homozygous variant), including the wild-type mass of 13 761 Da, was indicative of the presence of a variant, and the individual was referred for DNA sequence analysis. Results: MS analysis of intact reduced TTR correctly identified each of six samples known to contain variant TTR. These results were corroborated by subsequent DNA sequence analysis. Additionally, all Gly6Ser polymorphisms were correctly called based on the +30 mass shift and an equal relative abundance of the +30 polymorphism relative to wild-type TTR. No false-positive results were seen. Conclusions: This referral method eliminates the necessity of sequencing most samples and allows screening for the familial forms of amyloidosis in a broad patient population in a timely fashion. This method correctly identified all previously known variants and also identified a novel variant, Val94Ala.

PurposeTo describe the predictive value of liver function tests (LFTs), chest x-ray, and diagnostic imaging for detecting melanoma metastasis during routine follow-up after treatment for choroidal melanoma.Materials and MethodsProspective longitudinal follow-up of patients enrolled onto two randomized trials was conducted by the Collaborative Ocular Melanoma Study (COMS) Group. Baseline and annual or semiannual systemic and laboratory evaluations were performed according to a standard protocol for 2,320 patients enrolled on the COMS.ResultsCOMS patients were screened annually for metastasis and new cancers using LFTs (alkaline phosphatase, AST, ALT, or bilirubin). Elevated findings (1.5 to 2 times upper limit of normal) on LFT prompted a diagnostic or imaging test to confirm or rule out cancer recurrence. Of 714 patients with clinical reports of metastasis, 675 patients died. Of these 675 patients, all but four had either histopathologically confirmed or clinically suspected metastatic melanoma present at the time of death. Among all patients, the 5-year cumulative diagnosis rate of metastatic melanoma was 24% (95% CI, 22% to 27%). Based on all patients with reported metastasis, the sensitivity, specificity, positive predictive value and negative predictive value associated with at least one abnormal LFT before first diagnosis of metastasis at any site was 14.7%, 92.3%, 45.7% and 71.0%, respectively.ConclusionUse of LFTs results followed by diagnostic tests has high specificity and predictive values but low sensitivity. Better tests are needed to identify earlier metastatic disease associated with choroidal melanoma.

Purpose Studies suggest eicosapentaenoic acid (EPA), an omega-3 fatty acid, augments weight, appetite, and survival in cancer-associated wasting. This study determined whether an EPA supplement—administered alone or with megestrol acetate (MA)—was more effective than MA. Patients and Methods Four hundred twenty-one assessable patients with cancer-associated wasting were randomly assigned to an EPA supplement 1.09 g administered bid plus placebo; MA liquid suspension 600 mg/d plus an isocaloric, isonitrogenous supplement administered twice a day; or both. Eligible patients reported a 5-lb, 2-month weight loss and/or intake of less than 20 calories/kg/d. Results A smaller percentage taking the EPA supplement gained ≥ 10% of baseline weight compared with those taking MA: 6% v 18%, respectively (P = .004). Combination therapy resulted in weight gain of ≥ 10% in 11% of patients (P = .17 across all arms). The percentage of patients with appetite improvement (North Central Cancer Treatment Group Questionnaire) was not statistically different: 63%, 69%, and 66%, in EPA-, MA-, and combination-treated arms, respectively (P = .69). In contrast, 4-week Functional Assessment of Anorexia/Cachexia Therapy scores suggested MA-containing arms experienced superior appetite stimulation compared with the EPA arm, with scores of 40, 55, and 55 in EPA-, MA-, and combination-treated arms, respectively (P = .004). Survival was not significantly different among arms. Global quality of life was not significantly different among groups. With the exception of increased impotence in MA-treated patients, toxicity was comparable. Conclusion This EPA supplement, either alone or in combination with MA, does not improve weight or appetite better than MA alone.

Background— In this study we evaluate the diastolic deformation of ischemic/reperfused myocardium and relate this deformation to tissue elastic properties. Methods and Results— Farm pigs were subjected to left anterior descending coronary artery occlusion followed by reperfusion to create either stunning (n=12) or transmural myocardial infarction (n=12). Ultrasound-derived radial strain rates (SR) and strain were measured in the ischemic and remote walls. Myocardial stiffness was estimated from diastolic pressure–wall thickness relationship obtained from preload alterations. At reperfusion, end-systolic strain (ε sys ) was significantly reduced in both stunned and infarcted walls compared with their remote walls (3±3% versus 26±2% and 1±0% versus 33±5%, respectively; P <0.0001) or baseline values. Diastolic passive deformation (ε A ) and rates of deformation during early (E SR ) and late (A SR ) diastole were comparable between stunned and remote walls (ε A : 7.3±1.6% versus 7.9±1.9%; E SR : −2.7±0.4 s −1 versus −2.6±0.5 s −1 ; A SR : −1.8±0.2 s −1 versus −1.9±0.3 s −1 ; P =NS for all) but were of significantly lower magnitude in infarcted walls versus remote walls (ε A : 1.1±0.2% versus 11.4±1.9%; E SR : −0.3±0.1 s −1 versus −2.4±0.4 s −1 ; A SR : −0.3±0.1 s −1 versus −2.5±0.4 s −1 ; P <0.0001 for all). Stiffness coefficient of exponential diastolic pressure–wall thickness relation was higher for infarcted ( P <0.05) but not for stunned walls ( P =NS) compared with their remote walls. Conclusions— Early after postischemic reperfusion and in the presence of severely reduced systolic deformation, diastolic passive deformation (and rates of deformation) can distinguish stiff, noncompliant, transmurally infarcted myocardial walls from those more compliant walls containing viable but stunned myocardium.

Background— Restenosis prediction from published studies is hampered by inadequate sample size and incomplete angiographic follow-up. The prediction of restenosis with the existing variables is poor. The aim of the present study was to include the clinical and angiographic variables commonly associated with angiographic restenosis and develop a prediction model for restenosis from the PRESTO database. Methods and Results— This study included 1312 patients with a single lesion enrolled in the angiographic substudy of the PRESTO trial. We constructed 2 risk scores. The first used preprocedural variables (female gender, vessel size [≤2.5 mm, 2.5 to 3 mm, 3 to 3.5 mm, 3.5 to 4 mm, >4 mm], lesion length >20 mm, diabetes, smoking status, type C lesion, any previous percutaneous coronary intervention [PCI], and unstable angina) derived from previous studies. Estimated restenosis rates and corresponding variability for each possible level of the resultant risk score were obtained via bootstrapping techniques. The area under the receiver-operator characteristic (ROC) curve was 0.63, indicating modest discriminatory ability to predict restenosis. The second approach constructed a multiple logistic regression model considering significant univariate clinical and angiographic predictors of restenosis identified from the PRESTO database (treated diabetes mellitus, nonsmoker, vessel size, lesion length, American College of Cardiology/American Heart Association type C lesion, ostial location, and previous PCI). The area under the ROC curve for this risk score was also 0.63. Conclusions— The preprocedural clinical and angiographic variables from available studies and from the PRESTO trial have only modest predictive ability for restenosis after PCI.

The propagation speed of shear waves is related to frequency and the complex stiffness (shear elasticity and viscosity) of the medium. A method is presented to solve for shear elasticity and viscosity of a homogeneous medium by measuring shear wave speed dispersion. Harmonic radiation force, introduced by modulating the energy density of incident ultrasound, is used to generate cylindrical shear waves of various frequencies in a homogeneous medium. The speed of shear waves is measured from phase shift detected over the distance propagated. Measurements of shear wave speed at multiple frequencies are fit with the theoretical model to solve for the complex stiffness of the medium. Experiments in gelatin phantoms show promising results validated by an independent method. Practical considerations and challenges in possible medical applications are discussed.