bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomised controlled trial on the effect of inhaled hypertonic saline on quality of life in primary ciliary dyskinesia
Authors: Paff Tamara , Daniels Johannes M.A. , Weersink Els J. , Lutter René , Vonk Noordegraaf Anton , Haarman Eric G.
Published: February 2017

Hypertonic saline inhalation lowers airway mucous viscosity. Increased cough transportability may improve quality of life (QoL) in primary ciliary dyskinesia (PCD).

In this randomised controlled trial (RCT), PCD patients received twice-daily inhalations of hypertonic (7%) saline or isotonic (0.9%) saline for 12 weeks, with 4 weeks washout during crossover. Primary outcome was change in QoL measured by the St George's Respiratory Questionnaire (SGRQ) total score. Secondary outcomes were SGRQ subscores, Quality of Life Questionnaire-Bronchiectasis (QoL-B) scores, lower respiratory tract infection symptoms, exacerbations, spirometry, systemic and sputum inflammatory markers, adherence, and adverse events.

There was no significant change in median (interquartile range) SGRQ total score between hypertonic saline (−2.6 (−9.0–1.5)) and isotonic saline (−0.3 (−8.1–6.1)) in 22 patients (age range 22–73 years) (p=0.38). QoL-B Health Perception scale improved with hypertonic saline (p=0.03). Adverse events occurred more frequently with hypertonic saline, but were mild.

12 weeks of inhaled hypertonic saline did not improve SGRQ total score in adult PCD patients in this RCT, but the sample size was small. On the secondary and more disease-specific end-point of the QoL-B, a significant improvement was observed in the Health Perception scale. This study found little evidence to support the hypothesis that hypertonic saline improves QoL in PCD patients. We advise the use of disease-specific outcome measures in future trials.
How Is Science Being Taught? Measuring Evidence-Based Teaching Practices across Undergraduate Science Departments
Authors: Drinkwater Michael J. , Matthews Kelly E. , Seiler Jacob
Published: February 2017

While there is a wealth of research evidencing the benefits of active-learning approaches, the extent to which these teaching practices are adopted in the sciences is not well known. The aim of this study is to establish an evidential baseline of teaching practices across a bachelor of science degree program at a large research-intensive Australian university. Our purpose is to contribute to knowledge on the adoption levels of evidence-based teaching practices by faculty within a science degree program and inform our science curriculum review in practical terms. We used the Teaching Practices Inventory (TPI) to measure the use of evidence-based teaching approaches in 129 courses (units of study) across 13 departments. We compared the results with those from a Canadian institution to identify areas in need of improvement at our institution. We applied a regression analysis to the data and found that the adoption of evidence-based teaching practices differs by discipline and is higher in first-year classes at our institution. The study demonstrates that the TPI can be used in different institutional contexts and provides data that can inform practice and policy.
Exploring professionals' understanding, interpretation and implementation of the ‘appropriate medical treatment test’ in the 2007 amendment of the Mental Health Act 1983
Authors: Perry Benjamin I. , Champaneri Nina , Griffiths Frances , Paul Moli , Islam Zoebia , Rugkåsa Jorun , Burns Tom , Tyrer Peter , Crawford Michael , Deb Shoumitro , Singh Swaran P.
Published: February 2017

Background

The appropriate medical treatment test (ATT), included in the Mental Health Act (MHA) (1983, as amended 2007), aims to ensure that detention only occurs when treatment with the purpose of alleviating a mental disorder is available.

Aims

As part of the Assessing the Impact of the Mental Health Act (AMEND) project, this qualitative study aimed to assess professionals' understanding of the ATT, and its impact on clinical practice.

Method

Forty-one professionals from a variety of mental health subspecialties were interviewed. Interviews were coded related to project aims, and themes were generated in an inductive process.

Results

We found that clinicians are often wholly relied upon for the ATT. Considered treatment varied depending on the patient's age rather than diagnosis. The ATT has had little impact on clinical practice.

Conclusions

Our findings suggest the need to review training and support for professionals involved in MHA assessments, with better-defined roles. This may enable professionals to implement the ATT as its designers intended.
Phase II trial of a 3-hour infusion of paclitaxel in previously untreated patients with advanced non-small-cell lung cancer.
Authors: Millward M J , Bishop J F , Friedlander M , Levi J A , Goldstein D , Olver I N , Smith J G , Toner G C , Rischin D , Bell D R
Published: February 2017

PURPOSE

To determine the antitumor activity and toxicity of paclitaxel administered as a 3-hour infusion in patients with advanced non-small-cell lung cancer (NSCLC).

PATIENTS AND METHODS

Fifty-one patients with advanced measurable or assessable NSCLC and performance status 0 to 2 who had not received prior chemotherapy were treated with paclitaxel 175 mg/m2 over 3 hours with premedication. Cycles were repeated every 3 weeks for a maximum of nine cycles. Most patients had prior radiotherapy (57%), extrathoracic metastatic disease (65%), and measurable disease (75%). Twenty-two percent had previously untreated stage III disease.

RESULTS

The objective response rate was five of 51 (10%; 95% confidence interval, 3% to 21%). No subgroup with a higher response rate could be identified. There were no complete responses (CRs) and all responses lasted less than 5 months. Treatment was well tolerated with brief World Health Organization (WHO) grade IV neutropenia in only 16% of patients. Grade III/IV myalgia/athralgia occurred in 22% of patients. No significant hypersensitivity reactions occurred.

CONCLUSION

The antitumor activity of this dose and schedule appears inferior to that reported in previously published phase II trials in NSCLC that used higher doses of paclitaxel infused over 24 hours, although confidence intervals for response overlap. Determining the optimal dose and schedule for using paclitaxel in NSCLC requires further investigation, and these results should caution against using shorter infusions outside appropriate clinical trials.
Geographic variation in patient surveillance after colon cancer surgery.
Authors: Johnson F E , McKirgan L W , Coplin M A , Vernava A M , Longo W E , Wade T P , Virgo K S
Published: February 2017

PURPOSE

Considerable variation among surgeons exists in the current practice of patient surveillance after colon cancer treatment. We evaluated whether geographic factors are responsible for this observed variation.

METHODS

Profiles of hypothetical patients and a detailed questionnaire based on the profiles were mailed to 2,733 members of two national surgical societies. The influence of the geographic location of the respondents on practice patterns were assessed in two ways. Repeated-measures analysis of variance was used to compare the practice patterns among 19 large metropolitan statistical areas (MSAs) and chi 2 analysis was used to determine whether these patterns differed by MSA population size.

RESULTS

Seven of nine commonly used surveillance modalities were ordered significantly more frequently with increasing tumor-node-metastasis (TNM) stage and significantly less frequently with year postsurgery among the 995 respondents with assessable responses, but MSA population size and geographic location of physicians generally had no effect on documented practice variability. The remaining two modalities (bone scan and computed tomography [CT]) were used so infrequently as to preclude meaningful analysis.

CONCLUSION

Surveillance after potentially curative colon cancer surgery for otherwise healthy patients is not significantly affected by the geographic location of the surgeon who performs the surveillance testing and only modestly affected by the population size of the MSA in which he/she practices. These data should help in the design of prospective trials of this topic.
Outcome of high-dose therapy and autologous transplantation in non-Hodgkin's lymphoma based on the presence of tumor in the marrow or infused hematopoietic harvest.
Authors: Sharp J G , Kessinger A , Mann S , Crouse D A , Armitage J O , Bierman P , Weisenburger D D
Published: February 2017

PURPOSE

To evaluate the outcomes in 65 consecutive patients with non-Hodgkin's lymphoma (NHL) undergoing high-dose therapy (HDT) and autologous transplantation based on initial marrow involvement and the presence or absence of minimal disease in the hematopoietic harvests.

PATIENTS AND METHODS

Patients with any history of histologic evidence of marrow tumor underwent autologous peripheral-blood stem-cell transplantation (PSCT), whereas others underwent autologous bone marrow transplantation (ABMT). Patients who underwent ABMT were further segregated retrospectively into two groups depending on whether there was evidence by cell culture and/or Southern analysis of minimal tumor in the marrow harvest.

RESULTS

Comparable proportions (58% to 60%) of patients in each of the two groups (PSCT and ABMT) achieved a complete clinical remission (CR) at 100 days. For patients who achieve a CR, the actuarial relapse-free survival rate at 5 years for PSCT patients who received a tumor-negative apheresis harvest was 64%, compared with 57% for patients who received a tumor-negative bone marrow harvest and 17% for patients who received a histologically negative but minimally contaminated bone marrow harvest. Lymphoma grade and phenotype were not significant predictors of outcome.

CONCLUSION

The observation that survival was significantly better in the groups of patients who received tumor-negative harvests and worse for patients who received minimally contaminated harvests suggests that tumor cells, even at minimal levels, reinfused in the transplanted harvest are responsible for progression in a proportion of patients who achieve a CR following HDT, although other biologic characteristics of the tumor could also be important. A relatively good outcome can be achieved with HDT and PSCT, even in patients with a significant marrow tumor burden.
Randomized phase II trial comparing different doses of the bisphosphonate ibandronate in the treatment of hypercalcemia of malignancy.
Authors: Pecherstorfer M , Herrmann Z , Body J J , Manegold C , Degardin M , Clemens M R , Thürlimann B , Tubiana-Hulin M , Steinhauer E U , van Eijkeren M , Huss H J , Thiébaud D
Published: February 2017

PURPOSE

To evaluate the hypocalcemic effect and safety of three different doses of the bisphosphonate ibandronate in tumor-associated hypercalcemia, and to identify factors predicting response.

PATIENTS AND METHODS

One hundred seventy-four cancer patients with a serum calcium level greater than 2.7 mmol/L (10.8 mg/dL) were enrolled onto the trial. If hypercalcemia persisted after fluid repletion, patients were randomly assigned to treatment with 0.6 mg, 1.1 mg, and 2.0 mg of ibandronate. Response, defined as restoration of normocalcemia, was evaluated by an intent-to-treat analysis.

RESULTS

One hundred seventy-three (99%) patients were assessable for toxicity and 151 (87%) for efficacy. The administration of 0.6 mg (group A), 1.1 mg (group B), or 2.0 mg (group C) of ibandronate led to response rates of 44%, 52%, and 67%, respectively. Significantly more patients in group C responded than in group A (P = .0276). Of the various parameters examined, only the initial serum calcium level (P < .0001; odds ratio, 0.083) and the dose of ibandronate (P = .0162; odds ratio, 2.094) correlated with response. One hundred ninety-five adverse events (AEs) were reported, 99 classified as serious and 96 as nonserious. Three serious and sixteen nonserious AEs were considered related to ibandronate treatment. The three serious AEs were one case with thrombocytopenia, one with nausea, and one with fever.

CONCLUSION

Ibandronate therapy led to a dose-dependent reduction in serum calcium levels. The response to ibandronate treatment correlated negatively with the initial serum calcium level and positively with the dose administered. A dose of 2 mg was necessary to achieve a response rate comparable to that in previous studies with the bisphosphonates pamidronate and clodronate. Because the incidence of drug-associated AEs was low, a dose escalation of ibandronate can be recommended for further clinical trials.
New statistical strategy for monitoring safety and efficacy in single-arm clinical trials.
Authors: Thall P F , Simon R M , Estey E H
Published: February 2017

PURPOSE

Efficacy and toxicity are both important outcomes in cancer clinical trials. Nonetheless, most statistical designs for phase II trials only provide rules for evaluating treatment efficacy, and moreover only allow early stopping after fixed cohorts of patients have been treated. We illustrate a new statistical design strategy for monitoring both adverse and efficacy outcomes on a patient-by-patient basis in phase II and other single-arm clinical trials.

DESIGN

The new strategy is used to design a phase II trial of the experimental regimen idarubicin plus cytarabine (ara-C) plus cyclosporine for treatment of patients with intermediate-prognosis acute myelogenous leukemia (AML). The design requires a maximum of 56 patients and provides continuous monitoring boundaries to terminate the trial if the toxicity rate is unacceptably high or the complete remission (CR) rate is unacceptably low compared with the rates of these events with the standard regimen of anthracycline plus ara-C.

RESULTS

The design has an 88% to 91% probability of stopping the trial early with a median of 15 to 18 patients if the toxicity rate of the experimental regimen is .05 to .10 above that of the standard and there is no improvement in the CR rate. If there is a .15 improvement in the CR rate and the toxicity rate is no more than .05 above that of the standard, then there is at least an 83% probability that the trial will run to completion.

CONCLUSION

The proposed monitoring strategy provides a flexible, practical means to continuously monitor both safety and efficacy in single-arm cancer clinical trials. The design strategy can be implemented easily using a freely available menu-driven computer program, and provides a scientifically sound alternative to the use of ad hoc safety monitoring rules.
Phase II and pharmacologic study of docetaxel as initial chemotherapy for metastatic breast cancer.
Authors: Hudis C A , Seidman A D , Crown J P , Balmaceda C , Freilich R , Gilewski T A , Hakes T B , Currie V , Lebwohl D E , Baselga J , Raptis G , Gollub M , Robles M , Bruno R , Norton L
Published: February 2017

PURPOSE

Because docetaxel (Taxotere, RP 56976; Rhone-Poulenc Rorer, Antony, France) appeared to be active against breast cancer in phase I trials, we performed this phase II study.

PATIENTS AND METHODS

Thirty-seven patients with measurable disease were enrolled. Only prior hormone therapy was allowed, as was adjuvant chemotherapy completed > or = 12 months earlier. Docetaxel 100 mg/m2 was administered over 1 hour every 21 days. Diphenhydramine hydrochloride and/or corticosteroid premedication was added after hypersensitivity-like reactions (HSRs) were seen in two of the first six patients. Pharmacokinetic studies were performed during cycle 1 for correlation with toxicity.

RESULTS

Thirty-seven patients were assessable. Nineteen (51%) required dose reductions, usually for neutropenic fever. The median nadir WBC count was 1.4 x 10(3)/microL. HSRs were noted in 20 patients (54%). At a median cumulative dose of 297 mg/m2 (range, 99.6 to 424.5 mg/m2), 30 patients (81%) developed fluid retention, for which 11 (30%) subsequently stopped treatment. The first-cycle plasma area under the concentration-time curve (AUC) did not correlate with toxicity, although an ineligible patient with hepatic metastases (pretreatment bilirubin level 1.8 mg/dL) had an elevated AUC and died of toxicity. Responses were seen at all sites. On an intent-to-treat basis, there were two (5%) complete responses (CRs) and 18 (49%) partial responses (PRs). The overall response proportion (CRs plus PRs) was 54% (95% confidence interval, 37% to 71%). The median time to response was 12 weeks (range, 3 to 15) and the median duration was 26 weeks (range, 10 to 58+).

CONCLUSION

Docetaxel is active for metastatic breast cancer. Neutropenia and fluid retention are dose-limiting. The AUC did not predict toxicity, but caution is warranted when treating patients with liver dysfunction. An understanding of the pathophysiology of the fluid retention may facilitate prevention. Frequent HSR may warrant prophylactic premedication.
Outcome of extensive evaluation before adjuvant therapy in women with breast cancer and 10 or more positive axillary lymph nodes.
Authors: Crump M , Goss P E , Prince M , Girouard C
Published: February 2017

PURPOSE

To evaluate the effect of extensive screening of women with high-risk, node-positive breast cancer on the detection of occult metastatic disease and patient eligibility for a randomized trial of the addition of high-dose chemotherapy and autologous bone marrow support (ABMT) to standard adjuvant therapy.

PATIENTS AND METHODS

Women with resected T1-3N1,2 primary breast cancer and > or = 10 positive axillary lymph nodes referred for possible trial participation were evaluated for this report. All had normal chest x-ray, bone scan, and liver ultrasound performed by the referring physician. Those who provided informed consent for the randomized trial were further evaluated according to protocol with computed tomographic (CT) scans of the head, chest, abdomen, and pelvis and bilateral bone marrow biopsies; those with metastatic disease detected by any of these tests were excluded from study registration.

RESULTS

Forty-four women were evaluated between February 1993 and April 1995. Fourteen did not undergo further protocol staging because of refusal to participate or the presence of metastatic disease on clinical assessment or review of outside radiologic studies. The remaining 30 underwent additional investigations, and seven (23%; 95% confidence interval [CI], 12% to 41%) had metastases detected by CT scanning (four patients) or bone marrow biopsy (three patients) not detected by routine screening.

CONCLUSION

Although the number of patients evaluated is small, these data suggest that some of the improvement in outcome of women with > or = 10 positive axillary lymph nodes who receive ABMT as part of adjuvant chemotherapy in phase II trials may be from the exclusion of patients with occult metastatic disease. The importance of these exclusions can only be determined by ongoing, randomized controlled trials.
Phase I study of paclitaxel in combination with cyclophosphamide and granulocyte colony-stimulating factor in metastatic breast cancer patients.
Authors: Tolcher A W , Cowan K H , Noone M H , Denicoff A M , Kohler D R , Goldspiel B R , Barnes C S , McCabe M , Gossard M R , Zujewski J , O'Shaughnessy J A
Published: February 2017

PURPOSE

In vitro data suggest that prolonged exposure to paclitaxel enhances breast cancer cytotoxicity. Our objective in this phase I study was to determine the tolerability of paclitaxel administered by 72-hour continuous intravenous (i.v.) infusion (CIVI) in combination with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) in the ambulatory setting to metastatic breast cancer patients.

PATIENTS AND METHODS

Paclitaxel was administered over 72 hours by CIVI and cyclophosphamide was given daily by i.v. bolus on days 1, 2, and 3, followed by G-CSF every 21 days. The availability of ambulatory infusion pumps and paclitaxel-compatible tubing permitted outpatient administration.

RESULTS

Fifty-five patients with metastatic breast cancer who had been previously treated with a median of two prior chemotherapy regimens were entered onto the study. Dose-limiting toxicity of grade 4 neutropenia for longer than 5 days and grade 4 thrombocytopenia occurred in three of five patients treated with paclitaxel 160 mg/m2 CIVI and cyclophosphamide 3,300 mg/m2 followed by G-CSF. The maximum-tolerated dose (MTD) was paclitaxel 160 mg/m2 CIVI and cyclophosphamide 2,700 mg/m2 in divided doses with G-CSF. Nonhematologic toxicities were moderate and included diarrhea, mucositis, and arthalgias. Although hemorrhagic cystitis developed in six patients, recurrence was prevented with i.v. and oral mesna, which permitted continued outpatient delivery. One hundred seventy-four cycles were safely administered in the ambulatory setting using infusional pumps and tubing. Objective responses occurred in 23 (one complete and 22 partial) of 42 patients with bidimensionally measurable disease (55%; 95% confidence interval, 38% to 70%), with a response rate of 73% (11 of 15) seen at the highest dose levels.

CONCLUSION

Paclitaxel by 72-hour CIVI with daily cyclophosphamide followed by G-CSF can be administered safely in the ambulatory setting, has acceptable toxicity, and is an active regimen in the treatment of metastatic breast cancer.
In vivo purging of bone marrow in children with poor-risk neuroblastoma for marrow collection and autologous bone marrow transplantation.
Authors: Saarinen U M , Wikström S , Mäkipernaa A , Lanning M , Perkkiö M , Hovi L , Rapola J , Sariola H
Published: February 2017

PURPOSE

To evaluate the following prospectively in poor-risk neuroblastoma (NBL) patients: (1) the feasibility and efficacy of in vivo purging of bone marrow; and (2) the outcome after autologous bone marrow transplantation (ABMT) when immunologically tumor-free, unpurged autografts were used.

PATIENTS AND METHODS

Twenty-three children with poor-risk NBL were evaluated during induction chemotherapy by repeat bone marrow examinations, including aspirate, biopsy, and an immunofluorescence method using the anti-GD2 monoclonal antibody 3A7. Nineteen patients completed the program with surgery with or without local irradiation followed by ABMT.

RESULTS

Autologous bone marrow grafts, both immunologically and cytologically clean, were obtained and used in 19 of 23 children. The overall 4-year disease-free survival of the 19 grafted children was 53%, with a toxic death rate of 16% and a posttransplant relapse rate of 37%. According to the in vivo purging efficacy of the 18 children with initial marrow disease, the following three groups were formed: patients with (1) perfect in vivo purging (n = 5); (2) eventually successful in vivo purging (n = 8); and (3) unsuccesful in vivo purging (n = 5). The 4-year DFS was 100%, 67%, and 0%, respectively (P < 0.001). The five patients with unsuccessful in vivo purging failed because of resistant/progressive bulky disease.

CONCLUSION

In patients with poor-risk NBL, in vivo purging of bone marrow by conventional chemotherapy is feasible, can be monitored, and the purging efficacy during the first 3 months after diagnosis is a strong prognostic factor reflecting tumor responsiveness to therapy. Autografting with immunologically clean, unpurged marrows gives a DFS well comparable to previous studies using ex vivo purging.
Biweekly intensified ambulatory chronomodulated chemotherapy with oxaliplatin, fluorouracil, and leucovorin in patients with metastatic colorectal cancer.
Authors: Bertheault-Cvitkovic F , Jami A , Ithzaki M , Brummer P D , Brienza S , Adam R , Kunstlinger F , Bismuth H , Misset J L , Lévi F
Published: February 2017

PURPOSE

This study sought to determine the feasibility and antitumor efficacy of an intensified three-drug chronomodulated regimen with maximum delivery at 4:00 AM for fluorouracil (5-FU)-leucovorin (folinic acid [FA]) and at 4:00 PM for oxaliplatin (I-OHP).

PATIENTS AND METHODS

Fifty patients with metastatic colorectal cancer were enrolled in the trial. The first treatment course consisted of daily administration of 5-FU (700 mg/m2/d), FA (300 mg/m2/d), and L-OHP (25 mg/m2/d) for 4 days with a multichannel programmable pump. Courses were repeated every 14 days, with 5-FU escalation by 100 mg/m2/d if toxicity was less than grade 2.

RESULTS

World Health Organization (WHO)-modified grade 3 or 4 diarrhea (40% of patients and 7% of courses) or stomatitis (28% of patients and 4% of courses) or grade 2 cumulative peripheral sensitive neuropathy (28% of patients) were dose-limiting. Median 5-FU and L-OHP dose-intensities (DIs), were increased by 32% and 18%, respectively, as compared with our previous 5 days on-16 days off schedule. The overall objective response rate was 48% (95% confidence limits [CL], 34% to 62%), being 40% (24% to 57%) in 37 previously treated patients and 69% (48% to 90%) in 13 chemotherapy-naive patients. A 5-FU DI > 1,400 mg/m2/wk over four courses was associated with a near doubling of the response rate. Residual metastases were surgically removed in 13 patients (26%). Median progression-free survival and survival durations were 9.3 months (95% CL, 6.6 to 11.2) and 17.8 months (95% CL, 14.1 to 21.4), respectively.

CONCLUSION

This highly effective fully ambulatory outpatient regimen deserves further testing in randomized trials both in chemotherapy-naive patients and before surgery to remove metastases.
Survival from locally invasive or widespread neuroblastoma without cytotoxic therapy.
Authors: Kushner B H , Cheung N K , LaQuaglia M P , Ambros P F , Ambros I M , Bonilla M A , Gerald W L , Ladanyi M , Gilbert F , Rosenfield N S , Yeh S D
Published: February 2017

PURPOSE

To test the hypothesis that cytotoxic therapy is not needed at diagnosis to assure the survival of most patients with non-stage 4 neuroblastoma.

METHODS

Patients with non-stage 4 disease received no cytotoxic therapy in the absence of N-myc amplification. The International Neuroblastoma Staging System (INSS) was used.

RESULTS

Of 84 consecutive patients with previously untreated, newly diagnosed neuroblastoma, 31 (37%) had non-stage 4 disease. All 31 patients initially received no cytotoxic therapy because none of them had N-myc amplification. Nine stage 1 patients are relapse-free. This report focuses on the 22 patients with locally invasive or distant disease: two stage 2A with gross residual tumor postsurgery, 11 stage 2B with ipsilateral or midline lymph node involvement, four stage 3, and five stage 4S. Eight of the 22 patients were older than 1 year. Postsurgery, 13 patients had visible residual disease, and two others had markedly increased urinary catecholamine levels for more than 1 year. Recurrent or enlarging tumors regressed spontaneously (n = 2) or were excised 5 to 39 months after diagnosis (n = 4). One of the latter had chromosome 1p deletions (common in poor-risk neuroblastoma) that were not detected in the patient's original tumor resected 23 months earlier--findings consistent with clonal evolution or multifocal disease. The patient received chemotherapy. All 22 patients are alive 24 to 98 months (median, 64) from diagnosis.

CONCLUSION

Our results suggest that non-stage 4 patients without N-myc amplification can be spared cytotoxic therapy because (1) residual postsurgical or recurrent biologically favorable neuroblastoma rarely evolves into lethal stage 4 disease; and (2) neuroblastoma in lymph nodes has no prognostic significance. These findings are remarkable because no other cancer includes subtypes that are curable without therapy to ablate residual disease.
Cytoreduction and prognosis in acute lymphoblastic leukemia--the importance of early marrow response: report from the Childrens Cancer Group.
Authors: Steinherz P G , Gaynon P S , Breneman J C , Cherlow J M , Grossman N J , Kersey J H , Johnstone H S , Sather H N , Trigg M E , Chappell R , Hammond D , Bleyer W A
Published: February 2017

PURPOSE

To quantify the residual marrow lymphoblast fraction that best defines patients at high risk for relapse, and the optimal time for assessment during remission induction.

PATIENTS AND METHODS

The residual lymphoblast percentage was evaluated on day 7 (n = 220) and day 14 (n = 205) during a four- or five-drug induction in patients with poor prognostic factors. The rate of cytoreduction was related to event-free survival (EFS) and other factors.

RESULTS

On the New York (NY) regimen, 68%, 14%, and 18%, and on the Berlin-Frankfurt-Munster (BFM) regimen, 56%, 15%, and 29% of patients had M1 (< 5% blasts), M2 (5-25%), or M3 (> 25%) responses on day 7 (P = .075). On day 14, the corresponding values were 87%, 6%, 7% on NY and 84%, 8%, 8% on BFM. For patients who achieved remission by day 28 and a day-7 marrow rating of M1, M2, or M3, the 6-year EFS rate was 78%, 61%, and 49% (P < .001). The day-14 ratings predicted for a 72%, 32%, or 40% EFS (P < .001). Patients with 5% to 10% blasts day 7 had three times as many events as those with less than 5% and had no better EFS than those with 11% to 25% blasts. Patients with a WBC count more than 200,000/microL at diagnosis and an M1 day 7 marrow had an EFS rate of 69%, while for those with M2 or M3, the EFS rate was 41%. Day-7 marrow had greater prognostic significance than the day-14 evaluation. For slow responders on day 7, the day-14 marrow provided additional information. EFS for patients who achieved M1 by day 14 was 65%. EFS decreased to 20% for those still M2 or M3 on day 14. Day-7 and -14 evaluations had significance for patients of all ages and WBC levels.

CONCLUSION

Marrow aspiration on day 7 of therapy provided more useful information than that on day 14. However, day-14 marrow provided additional information for patients with a poor day-7 response. The rate of cytoreduction is a powerful, independent prognostic factor that can identify patients with a slow early response who are at risk for a short remission duration.
Docetaxel in patients with metastatic breast cancer: a phase II study of the National Cancer Institute of Canada-Clinical Trials Group.
Authors: Trudeau M E , Eisenhauer E A , Higgins B P , Letendre F , Lofters W S , Norris B D , Vandenberg T A , Delorme F , Muldal A M
Published: February 2017

PURPOSE

The National Cancer Institute of Canada-Clinical Trials Group (NCIC-CTG) conducted a phase II study to assess the efficacy and toxicity of docetaxel as first-line chemotherapy in metastatic breast cancer (MBC).

PATIENTS AND METHODS

Fifty-one patients with measurable MBC were studied. Three patients were ineligible and were excluded from analysis. The planned dose of docetaxel was 100 mg/m2 intravenously (i.v.) every 3 weeks. Prior adjuvant chemotherapy was allowed if at least 12 months had elapsed from completion of treatment to recurrence.

RESULTS

The most severe toxicity was granulocytopenia. Ten patients (20.8%) were hospitalized for febrile neutropenia. The protocol was amended to a starting dose of 75 mg/m2 for the last 16 patients. Sixty percent of patients experienced hypersensitivity reactions (HSRs). After two protocol amendments, the use of a premedication regimen of oral dexamethasone and i.v. H1 and H2 blockers prevented significant HSRs. Edema developed in 62% of patients and was cumulative, was present in 50% who received greater than 400 mg/m2, and was not improved by premedication regimens. Following an independent radiology review, 22 partial remissions and four complete responses in 47 assessable patients were confirmed (response rate, 55%; 95% confidence interval [CI], 40% to 69%). The response rate for 15 assessable patients registered at 75 mg/m2 was 40% (95% CI, 16% to 67%); for 32 assessable patients registered at 100 mg/m2, the response rate was 63%, (95% CI, 43% to 78%).

CONCLUSION

Docetaxel is an active agent in MBC. Its activity as a single agent is comparable to many combination chemotherapy regimens and is not affected by prior adjuvant chemotherapy. Studies are ongoing to improve its therapeutic index and to incorporate docetaxel in combination chemotherapy regimens.
Treatment of patients with melanoma of the extremity using hyperthermic isolated limb perfusion with melphalan, tumor necrosis factor, and interferon gamma: results of a tumor necrosis factor dose-escalation study.
Authors: Fraker D L , Alexander H R , Andrich M , Rosenberg S A
Published: February 2017

PURPOSE

To evaluate response rates and systemic and regional toxicity of hyperthermic isolated limb perfusion (ILP) for treatment of in-transit metastases of extremity melanoma using escalating-dose tumor necrosis factor (TNF) in conjunction with melphalan and interferon gamma (IFN).

PATIENTS AND METHODS

All patients received IFN 0.2 mg2 for 2 days followed by a 90-minute ILP with TNF and IFN (0.2 mg) given at time 0 and melphalan (10 mg/L limb volume) given at 30 minutes. Twenty-six patients were treated with 4 mg of TNF and 12 patients received 6 mg of TNF. All patients had assessable disease in the perfusion field and all but two patients were assessable for response at 1 month after treatment.

RESULTS

Mean peak perfusate TNF levels in the 4-mg group were 4.8 micrograms/mL, compared with 7.4 micrograms/mL for the 6-mg group (P = .03). The complete response rate in the 4-mg TNF group was 76%, with an overall objective response rate of 92%, compared with 36% and 100% for the 6-mg group. Subgroup analyses showed that the lower complete response rate in the 6-mg TNF group was not explained by differences in disease burden or prior regional therapy. Systemic drug toxicity was short-lived, easily managed, and related to perfusate leak more than to TNF perfusate dose. Regional toxicity, particularly painful myopathy and neuropathy, was greater with the 6-mg dose level and was considered dose-limiting.

CONCLUSION

ILP with 4 mg TNF, IFN, and melphalan can lead to complete local responses in the majority of patients with extremity melanoma. Escalating the TNF dose to 6 mg did not increase the complete response rate and increased regional toxicity.
No effect of 96-hour paclitaxel infusion in patients with relapsed non-Hodgkin's lymphoma refractory to a 3-hour infusion schedule.
Authors: Younes A , Ayoub J P , Hagemeister F B , McLaughlin P , Sarris A , Rodriguez M A , Swan F , Romaguera J E , Martin J , Cabanillas F
Published: February 2017

PURPOSE

Preclinical data suggest that the efficacy of paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ) is schedule-dependent. Schedule dependency is currently under investigation in ongoing randomized trials.

PATIENTS AND METHODS

Twelve patients with relapsed non-Hodgkin's lymphoma (NHL) refractory to a 3-hour infusion of 200 mg/m2 Taxol were crossed over to receive a 96-hour infusion of 140 mg/m2 Taxol every 3 weeks in an outpatient setting. Premedication with corticosteroids and antihistamines was not used. Patients who did not achieve at least a partial remission (PR) after two courses or whose disease progressed after one course were removed from the study.

RESULTS

All 12 patients were assessable for response. Eleven patients received at least two courses and one patient received one course of 96-hour Taxol infusion. None of the 12 patients crossed over to receive 96-hour Taxol infusion achieved a PR or complete response (CR). Eight patients (67%) developed progressive lymphoma, three (25%) had stable disease, and only one (8%) had a minor response. No major hypersensitivity reactions or life-threatening toxicities were observed.

CONCLUSION

Ninety-six-hour Taxol infusion does not produce significant responses in patients with NHL refractory to 3-hour Taxol infusion. Until the results of an ongoing multicenter trial comparing a 3- with a 96-hour infusion are published, the use of 96-hour Taxol infusion in NHL patients should be restricted to investigational programs. Because 48- to 72-hour infusions can produce higher plasma concentrations of Taxol than a 96-hour infusion, these schedules should be investigated to determine if they can induce better clinical responses.
Phase III Randomized Study of Two Fluorouracil Combinations With Either Interferon Alfa-2a or Leucovorin for Advanced Colorectal Cancer
Authors:   Corfu-A Study Group
Published: February 2017

The name of a Corfu-A Study Group member listed in the Appendix of the report entitled, "Phase III Randomized Study of Two Fluorouracil Combinations With Either Interferon Alfa-2a or Leucovorin for Advanced Colorectal Cancer" by the Corfu-A Study Group (J Clin Oncol 13:921–928, 1995) appeared incorrectly. The third name listed should have appeared as "R. Bell."
Improved local control and disease-free survival after perioperative chemotherapy for early-stage breast cancer. A European Organization for Research and Treatment of Cancer Breast Cancer Cooperative Group Study.
Authors: Clahsen P C , van de Velde C J , Julien J P , Floiras J L , Delozier T , Mignolet F Y , Sahmoud T M
Published: February 2017

PURPOSE

To investigate whether a short intensive course of perioperative polychemotherapy can change the course of early breast cancer.

PATIENTS AND METHODS

A total of 2,795 women with early breast cancer, stage I to IIIA, were randomized onto a trial (European Organization for Research and Treatment of Cancer [EORTC] 10854) to compare surgery followed by one course of perioperative chemotherapy versus surgery alone. Patients assigned to the chemotherapy arm received one course of fluorouracil 600 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 600 mg/m2 (FAC) intravenously, within 24 hours after surgery. In both randomized treatment arms, a recommendation was made for premenopausal women with positive axillary nodes to receive prolonged courses of cyclophosphamide, methotrexate, and fluorouracil (CMF), according to the standard treatment for this subgroup.

RESULTS

At a median follow-up time of 41 months, local control was significantly better in the perioperative treatment arm as compared with the observation arm (hazards ratio, 0.60; 95% confidence interval, 0.44 to 0.83; P < .01). Disease-free survival was significantly prolonged in the chemotherapy arm (hazards ratio, 0.84; 95% confidence interval, 0.70 to 0.99; P = .04). Premenopausal node-negative patients especially showed an advantage for the perioperative chemotherapy arm. No advantage for perioperative chemotherapy was observed in premenopausal node-positive women who also had received prolonged chemotherapy.

CONCLUSION

We conclude that one course of perioperative FAC is able to improve local control and can prolong disease-free survival in women with early breast cancer. However, our results also suggest that a perioperative timing cannot improve the results of standard prolonged chemotherapy in premenopausal women with positive axillary nodes.
Fifteen-year results of breast-conserving surgery and definitive breast irradiation for the treatment of ductal carcinoma in situ of the breast.
Authors: Solin L J , Kurtz J , Fourquet A , Amalric R , Recht A , Bornstein B A , Kuske R , Taylor M , Barrett W , Fowble B , Haffty B , Schultz D J , Yeh I T , McCormick B , McNeese M
Published: February 2017

PURPOSE

To determine the 15-year outcome for women with ductal carcinoma in situ (DCIS, intraductal carcinoma) of the breast treated with breast-conserving surgery followed by definitive breast irradiation.

PATIENTS AND METHODS

An analysis was performed of 270 intraductal breast carcinomas in 268 women from 10 institutions in Europe and the United States. In all patients, breast-conserving surgery included complete gross excision of the primary tumor followed by definitive breast irradiation. When performed, pathologic axillary lymph node staging was node-negative (n=86). The median follow-up time was 10.3 years (range, 0.9 to 26.8).

RESULTS

The 15-year actuarial overall survival rate was 87%, and the 15-year actuarial cause-specific survival rate was 96%. The 15-year actuarial rate of freedom from distant metastases was 96%. There were 45 local recurrences in the treated breast, and the 15-year actuarial rate of local failure was 19%. The median time to local failure was 5.2 years (range, 1.4 to 16.8). A number of clinical and pathologic parameters were evaluated for correlation with local failure, and none were predictive for local failure (all P > or = .15).

CONCLUSION

The results from the present study demonstrate high rates of overall survival, cause-specific survival, and freedom from distant metastases following the treatment of DCIS of the breast using breast-conserving surgery and definitive breast irradiation. These results support the use of breast-conserving surgery and definitive breast irradiation for the treatment of DCIS of the breast.
Tumor size and prognosis in aggressively treated osteosarcoma.
Authors: Bieling P , Rehan N , Winkler P , Helmke K , Maas R , Fuchs N , Bielack S , Heise U , Jurgens H , Treuner J , Romanowski R , Exner U , Kotz R , Winkler K
Published: February 2017

PURPOSE

The aim of this retrospective analysis was to investigate the prognostic significance and optimal measures of tumor size in osteosarcoma treated with intensive neoadjuvant chemotherapy.

PATIENTS AND METHODS

Initial anterior-posterior (AP) and lateral x-ray films of 128 patients treated within the trials Cooperative Osteosarcoma Study (COSS)-80, -82, and -86, were evaluated for the following three tumor diameters: length, width, and depth. Metastasis-free survival (MFS) analyses were performed in univariate and multivariate models with one, two, and three dimensions of the tumor as absolute or relative measures (tumor length, referred to bone length, plane and volume to body-surface area).

RESULTS

Univariate analyses of MFS showed a high prognostic significance of all absolute measures. Relative measures, at best, showed a comparable predictive value. Cox regression analysis indicated the high prognostic significance of absolute tumor volume (ATV; P < .0001) and histologic response (P < .0001). None of 19 patients with an ATV < or = 70 cm3 and only four of 53 with an ATV < or = 150 cm3 relapsed, while in patients with an ATV more than 150 cm3, the relapse rate remained 40% to 60%, irrespective of further increase in volume.

CONCLUSION

Initial tumor size is an important and easily obtainable prognostic factor in osteosarcoma and may serve as a basis for risk-adapted therapy. It is best represented by the absolute three-dimensional measure ATV. There is a cut-off point regarding the incidence of metastases at a tumor volume of approximately 150 cm3 as calculated from two-plane x-ray films.
Predicting the risk of bacteremia in childen with fever and neutropenia.
Authors: Rackoff W R , Gonin R , Robinson C , Kreissman S G , Breitfeld P B
Published: February 2017

PURPOSE

We sought to identify factors assessable at the time of admission for fever and neutropenia that predict bacteremia in children with cancer.

PATIENTS AND METHODS

One hundred fifteen consecutive episodes of fever and absolute neutrophil count (ANC) less than 500/microliter in 72 children with cancer were studied prospectively to determine the risk of bacteremia using data assessable at the time of presentation. After exploratory analysis identified admission temperature and absolute monocyte count (AMoC) as the strongest predictive factors, recursive partitioning was used to determine cutpoints for these variables that resulted in discrimination between episodes associated with a lower or higher risk of bacteremia.

RESULTS

There were 24 episodes of bacteremia (21% of episodes). Episodes were grouped using the cutpoints for AMoC and temperature: 17% were classified as low risk for bacteremia (AMoC > or = 100/microliter), 65% as intermediate risk (AMoC < 100/microliter and temperature < 39.0 degrees C), and 18% as high risk (AMoC < 100/microliter and temperature > or = 39.0 degrees C). No episodes classified as low risk were associated with bacteremia; 19% of intermediate-risk and 48% of high-risk episodes were associated with bacteremia. The odds ratio of bacteremia for the high-risk versus the intermediate-risk group is 4.4 (95% confidence interval, 1.6 to 12.9). The risk classification was validated using data from 57 different episodes of fever and neutropenia treated in the same hospital.

CONCLUSION

Three levels of risk for bacteremia are defined using the AMoC and temperature at the time of admission for fever and neutropenia. Trials now should be conducted to test whether these factors may be used to assign some children to less intensive or outpatient antibiotic therapy at the time of presentation with fever and neutropenia.
Minimal toxicity and mortality in high-risk breast cancer patients receiving high-dose cyclophosphamide, thiotepa, and carboplatin plus autologous marrow/stem-cell transplantation and comprehensive supportive care.
Authors: Holland H K , Dix S P , Geller R B , Devine S M , Heffner L T , Connaghan D G , Hillyer C D , Hughes L L , Miller R L , Moore M R , Winton E F , Wingard J R
Published: February 2017

PURPOSE

To assess the clinical toxicity and outcome associated with a comprehensive supportive care approach in poor-risk breast cancer (BrCA) patients with high-dose chemotherapy (HDC).

PATIENTS AND METHODS

One hundred twenty-five consecutive patients with stages II, III or metastatic breast cancer received HDC between February 1992 and June 1994. Recipients received 4 days of continuous infusion of cyclophosphamide 1.5 g/m2/d, thiotepa 125 mg/m2/d, and carboplatin 200 mg/m2/d followed by infusion of bone marrow or peripheral-blood stem cells (PBSC) and recombinant human growth factor (rhu-GF) support. Patients received similar supportive care that included administration of prophylactic antibiotics, management of neutropenic fevers, and transfusion support.

RESULTS

There were 38 women with stage II or III (27 patients with > or = 10 lymph nodes), four with stage IIIB, and 83 with metastatic breast cancer. The median age was 44 years (range, 27 to 61). Grade II or greater nonhematologic toxicities included diarrhea (66%), stomatitis (33%), hepatic venoocclusive disease (VOD) (5%), and pulmonary toxicity (4%). Myeloid and platelet engraftment was comparable between bone marrow and PBSC recipients (P > .1). Infectious complications were rare and consisted of gram-negative bacteremia (1.6%), gram-positive bacteremia (1.6%), fungemia (1.6%), and documented or suspected aspergillosis infection (3%). There was one treatment-related death secondary to severe VOD.

CONCLUSION

A comprehensive supportive care approach was associated with a low treatment-related mortality rate of less than 1%. With the observed reduction in treatment-related mortality, it is reasonable to evaluate the efficacy of HDC in women with less than 10 positive nodes and stage II disease in well-designed clinical trials.
Interobserver variability on the histopathologic diagnosis of cutaneous melanoma and other pigmented skin lesions.
Authors: Corona R , Mele A , Amini M , De Rosa G , Coppola G , Piccardi P , Fucci M , Pasquini P , Faraggiana T
Published: February 2017

PURPOSE

To assess the interobserver agreement on the diagnosis and classification of cutaneous melanoma.

MATERIALS AND METHODS

A set of 140 slides of cutaneous melanoma, including a small subset of benign pigmented skin lesions, were circulated to four experienced histopathologists. The kappa statistic for multiple ratings per subject was calculated using the method described by Fleiss.

RESULTS

The kappa value on the diagnosis of cutaneous melanoma versus benign lesions was 0.61. There was some discordance on the diagnosis in 37 of 140 cases (26%). For the histopathologic classification of cutaneous melanoma, the highest kappa values were attained for Breslow thickness (kappa = 0.76) and presence of ulceration (kappa = 0.87). The agreement was generally poor for other histologic features, such as level of dermal invasion (kappa = 0.38), presence of regression (kappa = 0.27), and lymphocytic infiltration (kappa = 0.27).

CONCLUSION

Our study suggests considerable disagreement among pathologists on the diagnosis of melanoma versus other pigmented lesions. Tumor thickness and presence of ulceration are the most reproducible histologic features of cutaneous melanoma.