bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized comparison of progenitor-cell mobilization using chemotherapy, stem-cell factor, and filgrastim or chemotherapy plus filgrastim alone in patients with ovarian cancer.
Authors: Weaver A , Chang J , Wrigley E , de Wynter E , Woll P J , Lind M , Jenkins B , Gill C , Wilkinson P M , Pettengell R , Radford J A , Collins C D , Dexter T M , Testa N G , Crowther D
Published: February 2017

PURPOSE

This was the first randomized study to investigate the efficacy of peripheral-blood progenitor cell (PBPC) mobilization using stem-cell factor (SCF) in combination with filgrastim (G-CSF) following chemotherapy compared with filgrastim alone following chemotherapy.

PATIENTS AND METHODS

Forty-eight patients with ovarian cancer were treated with cyclophosphamide and randomized to receive filgrastim 5 microg/kg alone or filgrastim 5 microg/kg plus SCF. The dose of SCF was cohort-dependent (5, 10, 15, and 20 microg/kg), with 12 patients in each cohort, nine of whom received SCF plus filgrastim and the remaining three patients who received filgrastim alone. On recovery from the WBC nadir, patients underwent a single apheresis.

RESULTS

SCF in combination with filgrastim following chemotherapy enhanced the mobilization of progenitor cells compared with that produced by filgrastim alone following chemotherapy. This enhancement was dose-dependent for colony-forming unit-granulocyte-macrophage (CFU-GM), burst-forming unit-erythrocyte (BFU-E), and CD34+ cells in both the peripheral blood and apheresis product. In the apheresis product, threefold to fivefold increases in median CD34+ and progenitor cell yields were obtained in patients treated with SCF 20 microg/kg plus filgrastim compared with yields obtained in patients treated with filgrastim alone. Peripheral blood values of CFU-GM, BFU-E, and CD34+ cells per milliliter remained above defined threshold levels longer with higher doses of SCF. The higher doses of SCF offer a greater window of opportunity in which to perform the apheresis to achieve high yields.

CONCLUSION

SCF (15 or 20 microg/kg) in combination with filgrastim following chemotherapy is an effective way of increasing progenitor cell yields compared with filgrastim alone following chemotherapy.
Enzyme-linked immunoabsorbent assay-detected p53 protein accumulation: a prognostic factor in a large breast cancer cohort.
Authors: Levesque M A , Yu H , Clark G M , Diamandis E P
Published: February 2017

PURPOSE

This study was designed to evaluate whether patients with an unfavorable breast cancer prognosis could be identified by p53 protein overexpression detected by a quantitative enzyme-linked immunoabsorbent assay (ELISA).

PATIENTS AND METHODS

Extracts from 998 breast carcinomas were assayed for p53 protein by an ELISA that used both DO-1 monoclonal and CM-1 polyclonal antibodies. Relative risks (RRs) for cancer relapse and death after 6 years of follow-up for patients with p53-positive tumors based on different dichotomization criteria were determined by multivariate Cox regression, adjusted for patient age, tumor size, S-phase fraction, estrogen (ER) and progesterone (PR) receptor concentrations, DNA ploidy, and lymph node metastases. Disease-free (DFS) and overall (OS) survival probabilities of p53-positive and p53-negative groups, using a median cutoff, were also estimated by the Kaplan-Meier method and the log-rank test. These analyses were performed for all patients and for subgroups defined by ER status, node status, and primary postoperative treatment.

RESULTS

Univariate analysis showed that p53 concentrations that exceeded the median indicated significantly increased risks for relapse (P < .01) and death (P = .02). Multivariate analyses confirmed these observations (RR = 1.40; P = .02 for DFS and RR = 1.50; P < .01 for OS) and showed trends for increasing risks for relapse (P = .02) and death (P = .06) when p53 was considered as a four-level categoric variable, and identified p53 positivity as a significant predictor of outcome in node-positive patients (RR = 1.67; P < .01 and RR = 2.10; P < .01 for DFS and OS, respectively), ER-positive patients (RR = 1.45; P = .02 and RR = 1.50; P = .01 for DFS and OS, respectively), and in patients treated with chemotherapy (RR = 1.73; P = .04 for relapse and RR = 2.04; P = .03 for death).

CONCLUSION

Assessment of p53 overexpression by ELISA, easily incorporated into the routine biochemical work-up of breast tumors, may be an independent predictor of reduced survival of breast cancer patients.
Programs for adult survivors of childhood cancer.
Authors: Oeffinger K C , Eshelman D A , Tomlinson G E , Buchanan G R
Published: February 2017

PURPOSE

The potential for late effects of treatment necessitates long-term monitoring of adult survivors of childhood cancer. The purpose of this study was to determine how institutions follow up young adult survivors of pediatric malignancy. Specifically, we were interested in the types of health care providers who follow up these patients, how the follow-up is administered, and what barriers to follow-up have been encountered.

METHODS

A 16-item questionnaire was mailed to the 219 members of the Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG). The survey consisted of four categories of questions that asked for information regarding the existence of a program to follow up young adults, the setting of the program, routine activities of the program, and commonly encountered barriers to care.

RESULTS

One hundred eighty-two members returned the survey (83% response rate). Fifty-three percent of the respondents have a long-term follow-up clinic at their institution. Whereas 44% have a mechanism for following up adult survivors, only 15% of the programs have established a formal database for adults. Nearly all the programs (93%) use a pediatric oncologist. Although an adult oncologist assists in 13% of the programs, primary care physicians are uncommonly (8%) involved.

CONCLUSION

Few programs focus on the long-term health care needs of adult survivors of childhood cancer. The majority of existing programs are in pediatric institutions, without significant input from adult-oriented, generalist health care providers.
Detection of K-ras point mutations in sputum from patients with adenocarcinoma of the lung by point-EXACCT.
Authors: Somers V A , Pietersen A M , Theunissen P H , Thunnissen F B
Published: February 2017

PURPOSE

Kirsten ras (K-ras) point mutations are found in 30% to 56% of pulmonary adenocarcinomas by means of highly sensitive techniques. Recently, the Point-EXACCT (point mutation detection using exonuclease amplification coupled capture technique) method was described, which detected one cell with a mutation in 15,000 normal cells. The aim of this study was to examine whether K-ras point mutations could be found with this rapid method in the sputum of patients with adenocarcinoma of the lung.

PATIENTS AND METHODS

DNA from paraffin-embedded adenocarcinoma and corresponding sputum samples were analyzed for mutations of the K-ras gene. Twenty-eight biopsy specimens and 54 sputum samples of 22 patients were used for amplification and K-ras codon 12 point mutation detection.

RESULTS

In 11 of 22 patients (50%), a mutation in K-ras codon 12 was shown in the tumor sample. In five of 11 patients (45%) with a K-ras mutation in the tumor, the same type of mutation was identified in at least one sputum sample. A mutation could not be detected in any of the sputum samples from patients with a K-ras-negative tumor. Time between K-ras point mutation detection in sputum and clinical diagnosis of lung cancer varied from 1 month to almost 4 years. In two of the five patients with K-ras-positive sputum specimens, malignant cells were found with cytologic examination.

CONCLUSION

Point-EXACCT is suitable for the detection of K-ras point mutations in sputum samples of patients with adenocarcinoma of the lung. This approach may be an important adjunct to cytology in the early diagnosis of lung cancer.
Vascular endothelial growth factor is of high prognostic value in node-negative breast carcinoma.
Authors: Linderholm B , Tavelin B , Grankvist K , Henriksson R
Published: February 2017

PURPOSE

The prognostic value of vascular endothelial growth factor (VEGF) protein, known to stimulate endothelial growth and angiogenesis, was evaluated in node-negative breast carcinoma (NNBC) and compared with established prognostic factors.

PATIENTS AND METHODS

In 525 consecutive patients with primary invasive NNBC (T1-2N0M0; tumor, node, metastasis stage), of whom 500 patients did not receive any systemic therapy, the cytosolic levels of VEGF165 were measured by using a quantitative enzyme-linked immunosorbent assay. The median follow-up was 46 months. Univariate and multivariate analyses were performed.

RESULTS

VEGF level was significantly inversely correlated with estrogen receptor (ER) positivity but positively associated with tumor size and histologic grade. Patients with VEGF levels above the median value (2.40 pg/microg of DNA) showed a significantly shorter survival time (P=.0012) than patients with levels less than the median value, also when analyzed as a continuous variable (P=.0277). Tumor size, grade, and ER expression were all statistically significant for overall survival in univariate analyses (P=.0069, P=.014, and P < .001, respectively). Multivariate analysis showed that VEGF level was the strongest predictor of overall survival (P=.0199). Histologic grade was also an independent predictor of survival (P=.0477). Among the 381 patients with ER-positive tumors, a group in general considered to have a good prognosis, we found a significant reduction in survival for those with levels of VEGF greater than the median value (P=.0009).

CONCLUSION

The results suggest that the level of VEGF165 protein is an independent, strong prognostic factor for survival in patients with NNBC, especially in the subgroup of patients with ER positivity. Thus, cytosolic VEGF165 might be useful to select patients for adjuvant systemic therapy.
A single scale for comparing dose-intensity of all chemotherapy regimens in breast cancer: summation dose-intensity.
Authors: Hryniuk W , Frei E , Wright F A
Published: February 2017

PURPOSE

To construct a single scale for comparing the dose-intensity of all chemotherapy regimens in breast cancer.

MATERIALS AND METHODS

First-line single-agent trials in metastatic disease were reviewed. The unit dose-intensity (UDI) that was required to produce a 30% complete response plus partial response (CR + PR) rate was determined for each drug. Randomized trials were then analyzed that prospectively tested dose-intensity. The dose-intensities of the drugs in each arm were expressed as fractions of their UDIs and added together. This yielded each arm's summation dose-intensity (SDI), which was then correlated with treatment outcomes.

RESULTS

In the single-agent trials, dose-response relationships were linear when the studies covered a range of dose-intensities. In the randomized trials that tested dose-intensity in metastatic disease, response rates and median survival correlated linearly with the SDIs of the treatment arms. An increment of one SDI unit increased CR + PR rate by approximately 30%, CR rate by 10%, and median survival by 3.75 months. Metastatic disease trials were negative if the difference between the arms was less than 0.54 SDI units. Adjuvant trials that tested a dose-intensity difference of less than 0.65 SDI units were also negative.

CONCLUSION

A single-agent dose-response database can be derived from historic literature that enables comparison of the dose-intensity of all combination regimens on one scale. The dose-intensity increase required to improve outcome can then be identified in earlier trials that tested that variable. SDI methodology should be tested prospectively in contemporary patients, and may be useful in guiding dosage increases beyond the conventional range.
Hodgkin's Disease Survivors More Fatigued Than the General Population
Authors: Loge Jon Håvard , Abrahamsen Arne Foss , Ekeberg Øivind , Kaasa Stein
Published: February 2017

PURPOSE: To estimate the level of fatigue and frequency of fatigue cases among Hodgkin's disease survivors (HDS) and compare them with normative data from the general population.

PATIENTS AND METHODS: A cross-sectional follow-up study was done of 557 HDS (age range, 19 to 74 years) treated at the Norwegian Radium Hospital from 1971 to 1991. The sample was approached by mail, and their data were compared with normative data from 2,214 controls (age range, 19 to 74 years) representative of the general Norwegian population. Of the 557 HDS, 459 (82%) responded. The mean age (± SD) at the time of study was 44 ± 12 years, and the mean observation time was 12 ± 6 years. The Fatigue Questionnaire (11 items) measures physical and mental fatigue. Two systems of scoring were used, dichotomized (0, 0, 1, and 1) and Likert (0, 1, 2, and 3). Total fatigue (TF) constitutes the sum of all the Likert scores. Caseness was defined as a total dichotomized score of ≥4 and fatigue that lasted 6 months or longer.

RESULTS: The HDS had significantly higher levels of TF than the controls (14.3 v 12.2) (P < .001). Fatigue among the HDS equaled that of the controls in poorest health. More HDS (61%) than controls (31%) reported fatigue symptoms lasting 6 months or longer (P < .001). Fatigue cases were more frequent among HDS (men, 24%; women, 27%) than among the controls (men, 9%; women, 12%) (P < .001). Disease stage/substage IB/IIB predicted fatigue caseness (P = .03). No significant associations were found between treatment characteristics and fatigue.

CONCLUSION: Hodgkin's disease survivors are considerably more fatigued than the general population and report fatigue of a substantially longer duration.
Polymerase Chain Reaction-Based Detection of Circulating Melanoma Cells as an Effective Marker of Tumor Progression
Authors: Palmieri Giuseppe , Strazzullo Maria , Ascierto Paolo A. , Satriano Sabrina M.R. , Daponte Antonio , Castello for the Melanoma Cooperative Group Giuseppe
Published: February 2017

PURPOSE: Reverse transcriptase (RT) polymerase chain reaction (PCR) with multiple markers has been demonstrated to be highly sensitive in detecting circulating cells from patients with malignant melanoma (MM). We evaluated the clinical significance of the presence in peripheral blood of specific PCR-positive mRNA markers as an expression of circulating melanoma cells.

PATIENTS AND METHODS: Total cellular RNA was obtained from the peripheral blood of 235 patients with either localized (n = 154) or metastatic (n = 81) melanoma. We performed RT-PCR using tyrosinase, p97, MUC18, and MelanA/MART1 as gene markers. The PCR products were analyzed by gel electrophoresis and Southern blot hybridization. In addition, 20 healthy subjects and 21 patients with nonmelanoma cancer were used as negative controls.

RESULTS: Although detected at various levels among assessable patients, each mRNA marker was significantly correlated with disease stage. A significant correlation with disease stage was demonstrated for patients who were positive to all four markers (P < .0001) or to at least three markers (P < .001). Univariate analysis showed a significant correlation between risk of recurrence (evaluated in stage I, II, and III patients) and increasing number of PCR-positive markers (P = .0002). Logistic regression multivariate analysis indicated that each single marker (except tyrosinase) and, more especially, the presence of four PCR-positive markers remained statistically independent prognostic factors for tumor progression.

CONCLUSION: Our data establish the existence of a significant correlation among clinical stages, tumor progression, and presence of circulating melanoma-associated antigens in peripheral blood of MM patients. Preliminary assessment of a subset of patients with a higher risk of recurrence needs longer follow-up and further studies to define the role of RT-PCR in monitoring MM patients.
Clinical Relevance of Expression of the CIP/KIP Cell-Cycle Inhibitors p21 and p27 in Laryngeal Cancer
Authors: Pruneri Giancarlo , Pignataro Lorenzo , Carboni Nadia , Buffa Roberto , Di Finizio Devrim , Cesana Bruno Mario , Neri Antonino
Published: February 2017

PURPOSE: To investigate the prognostic relevance of p21 and p27 protein expression in laryngeal squamous cell carcinoma (LSCC).

PATIENTS AND METHODS: We have analyzed by immunohistochemistry p21 and p27 expression in a series of 132 patients who underwent surgical resection of their LSCC and who had previously been investigated for p53 gene mutations and cyclin D1 expression. The tumors were considered low expressors when they had ≤ 10% of p21 and ≤ 50% of p27 immunoreactive neoplastic cells.

RESULTS: In 41 cases (31.1%), p21 was expressed in ≤ 10% of neoplastic cells; in 91 cases (68.9%), it was expressed in more than 10% of neoplastic cells. In 11 cases (8.3%), p27 was expressed in less than 5% of neoplastic cells; in 39 cases (29.6%), it was expressed in 5% to 50% of neoplastic cells; and in 82 cases (62.1%), it was expressed in more than 50% of the neoplastic cells. Low levels of p21 expression were associated with poor histologic differentiation and lymph node metastases. Low levels of p27 expression were associated with tumor extension and advanced clinical stage. Expression of p21 and p27 was not correlated with p53 gene status, and low p27 expression was more frequently detected in the cyclin D1–positive cases, with a borderline level of statistical significance. At univariate analysis, anatomic site, tumor extension, clinical stage, high cyclin D1 expression, and low p27 expression were significantly associated with reduced disease-free and overall survival rates. At multivariate analysis, high cyclin D1 expression and low p27 expression were the only significant covariates. The patients with a cyclin D1+/p27− phenotype had the poorest disease-free and overall survival rates.

CONCLUSION: Our study provides evidence that the immunohistochemical evaluation of p27 expression is a significant independent predictor of prognosis in laryngeal carcinoma.
Prognostic Importance of the Standardized Uptake Value on 18F-Fluoro-2-Deoxy-Glucose–Positron Emission Tomography Scan in Non–Small-Cell Lung Cancer: An Analysis of 125 Cases
Authors: Vansteenkiste Johan F. , Stroobants Sigrid G. , Dupont Patrick J. , De Leyn Paul R. , Verbeken Erik K. , Deneffe Georges J. , Mortelmans Luc A. , Demedts Maurits G.
Published: February 2017

PURPOSE: The amount of radio-labeled 18F-fluoro-2-deoxy-glucose (FDG) uptake, a measurement of the increased glucose metabolism of non–small-cell lung cancer (NSCLC) cells, has recently been correlated with proliferation capacity. The Standardized Uptake Value (SUV), a semi-quantitative measurement of FDG uptake on positron emission tomography (PET) scan, could thus be of prognostic significance.

PATIENTS AND METHODS: We analyzed the follow-up of 125 potentially operable NSCLC patients, previously included in three of our prospective PET protocols. Performance status, maximal tumor diameter, tumor-cell type, SUV, and final staging were analyzed for their possible association with survival.

RESULTS: Sixty-five patients had stage I or II NSCLC, 37 had stage IIIA, and 23 had stage IIIB. Treatment was complete resection in 91 cases. In a univariate analysis, performance status (P = .002), stage (P = .001), tumor diameter (P = .06), tumor-cell type (P = .03), and SUV greater than 7 (P = .001) were correlated with survival. For SUV, group dichotomy with a cut-off SUV of 7 had the best discriminative value for prognosis, both in the total and surgical cohort. A multivariate Cox analysis identified performance status (P = .02), stage (P = .01), and SUV (P = .007) as important for the prognosis. In the surgical group, patients with a resected tumor less than 3 cm had an expected 2-year survival of 86%, if the SUV was below 7, and 60%, if above 7. Nearly all resected tumors larger than 3 cm had SUV's greater than 7 and an expected 2-year survival of 43%.

CONCLUSION: We conclude that the FDG uptake in primary NSCLC on PET has an important prognostic value and could be complementary to other well-known factors in the decision on adjuvant treatment protocols.
Acute Myelogenous Leukemia After Treatment for Malignant Germ Cell Tumors in Children
Authors: Schneider Dominik T. , Hilgenfeld Elisabeth , Schwabe Dirk , Behnisch Wolfgang , Zoubek Andreas , Wessalowski Rüdiger , Göbel Ulrich
Published: February 2017

PURPOSE: To identify the long-term sequelae of therapy for malignant germ cell tumors (GCTs).

PATIENTS AND METHODS: Between 1980 and 1998, 1,132 patients were prospectively enrolled onto the German nontesticular GCT studies. A total of 442 patients received chemotherapy using combinations of the drugs cisplatin, ifosfamide, etoposide, vinblastine, and bleomycin, and 174 patients were treated with a combination of chemotherapy and radiotherapy. Median follow-up duration was 38 months (range, 6 to 199 months).

RESULTS: Six patients developed therapy-related acute myelogenous leukemia (t-AML). There was no t-AML among patients treated with surgery (n = 392) or radiotherapy only (n = 124). The Kaplan-Meier estimates of the cumulative incidence (at 10 years) of t-AML were 1.0% for patients treated with chemotherapy (three of 442) and 4.2% for patients treated with combined chemotherapy and radiotherapy (three of 174). Notably, four of these six patients had been treated according to a standard protocol with modest cumulative chemotherapy doses. Five patients had received less than 2 g/m2 epipodophyllotoxins, and four patients had received less than 20 g/m2 ifosfamide. Four patients presented with AML, two with myelodysplasia in transformation to AML. In five patients, cytogenetic aberrations were found, four of which were considered characteristic for t-AML. Four patients died despite antileukemic therapy. One patient is alive but suffered a relapse of his GCT, and one patient is alive and well. No secondary solid neoplasm was observed.

CONCLUSION: In patients with AML after treatment for GCT, several pathogenetic mechanisms must be considered. AML might evolve from a malignant transformation of GCT components without any influence of the chemotherapy. On the other hand, the use of alkylators and topoisomerase II inhibitors is associated with an increased risk of t-AML. Future studies will show if the reduction of treatment intensity in the current protocol reduces the risk of secondary leukemia in these patients.
Phase II Trial of Weekly Irinotecan Plus Cisplatin in Advanced Esophageal Cancer
Authors: Ilson David H. , Saltz Leonard , Enzinger Peter , Huang Ying , Kornblith Alice , Gollub Marc , O'Reilly Eileen , Schwartz Gary , DeGroff Julia , Gonzalez Gladys , Kelsen David P.
Published: February 2017

PURPOSE: To evaluate the response, toxicity, survival, and quality of life in patients with unresectable or metastatic esophageal cancer treated with weekly irinotecan and cisplatin.

PATIENTS AND METHODS: Thirty-five patients with metastatic or unresectable esophageal adenocarcinoma (23 patients) or squamous cell carcinoma (12 patients) were treated. No prior chemotherapy was allowed. The majority of patients had metastatic and bidimensionally measurable disease (34 patients each [97%]). Patients were treated with cisplatin 30 mg/m2 and irinotecan 65 mg/m2, repeated weekly for 4 weeks, followed by a 2-week rest period. Treatment was recycled every 6 weeks. Degree of dysphagia relief was monitored, and quality of life was measured prospectively using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C-30 and Functional Assessment of Cancer Therapy–General instruments.

RESULTS: Thirty-five patients were assessable for response and toxicity. Major objective responses were observed in 20 patients (57%; 95% confidence interval, 41% to 73%), including two complete responses (6%). Similar response rates were observed for adenocarcinoma (12 of 23 patients; 52%) and squamous carcinoma (eight of 12 patients; 66%). The median duration of response was 4.2 months (range, 1 to 8.8+ months). Median actuarial survival was 14.6 months (range, 1 to 15.2+ months). In 20 patients with dysphagia assessable at baseline, 18 (90%) noted either improvement or resolution of dysphagia on chemotherapy. Global quality of life improved in responding patients, primarily because of improvements in pain, emotional state, and relationships with family and friends. Toxicity was relatively mild and included only three patients (9%) with grade 4 neutropenia and four (11%) with grade 3 diarrhea. There were no treatment-related deaths.

CONCLUSION: The combination of weekly cisplatin plus irinotecan had significant activity in metastatic esophageal carcinoma and resulted in significant relief of dysphagia. The regimen was well tolerated, with acceptable myelosuppression and rare treatment-related diarrhea. Further evaluation of the combination of weekly irinotecan and cisplatin, including the addition of other agents to this regimen, is indicated.
Dietary Fat and Carbohydrates Are Independently Associated With Circulating Insulin-Like Growth Factor 1 and Insulin-Like Growth Factor–Binding Protein 3 Concentrations in Healthy Adults
Authors: Kaklamani Virginia G. , Linos Athena , Kaklamani Evangelia , Markaki Ioanna , Koumantaki Yvonni , Mantzoros Christos S.
Published: February 2017

PURPOSE: To evaluate and quantify the association between consumption of specific food groups/macronutrients and concentrations of serum insulin-like growth factor 1 (IGF-1) and insulin-like growth factor–binding protein 3 (IGFBP-3).

SUBJECTS AND METHODS: Data from a comprehensive food-frequency questionnaire administered to 115 healthy subjects were used to study cross-sectionally the relationship between nutritional factors and circulating IGF-1 and IGFBP-3 concentrations. Adjustment for the effect of total energy intake and a series of epidemiologic parameters (age, sex, height, body mass index, smoking, alcohol consumption, and coffee drinking) was implemented through multivariate linear regression.

RESULTS: We observed that serum levels of IGF-1 are positively associated with consumption of redmeats, fats, and oils. In addition, serum levels of IGF-1 are independently and positively associated with energy intake from lipids and negatively associated with energy intake from carbohydrates. Finally, serum levels of IGFBP-3 are independently and negatively associated with energy intake from saturated fat.

CONCLUSION: Serum IGF-1 and/or IGFBP-3 concentrations are associated with red meat, carbohydrate intake, and fat intake and, thus, may mediate the effect of these dietary factors on the pathogenesis of several disease states. Additional studies are needed to further quantify these associations and elucidate the underlying mechanisms.
Prospective Evaluation of Paclitaxel Versus Combination Chemotherapy With Fluorouracil, Doxorubicin, and Cyclophosphamide as Neoadjuvant Therapy in Patients With Operable Breast Cancer
Authors: Buzdar Aman U. , Singletary S. Eva , Theriault Richard L. , Booser Daniel J. , Valero Vicente , Ibrahim Nuhad , Smith Terry L. , Asmar Lina , Frye Debra , Manuel Nikki , Kau Shu-Wan , McNeese Marsha , Strom Eric , Hunt Kelly , Ames Frederick , Hortobagyi Gabriel N.
Published: February 2017

PURPOSE: To compare prospectively the antitumor activity of single-agent paclitaxel to the three-drug combination of fluorouracil, doxorubicin, and cyclophosphamide (FAC) as neoadjuvant therapy in patients with operable breast cancer.

PATIENTS AND METHODS: Patients with T1-3N0-1M0 disease were randomized to receive either paclitaxel (250 mg/m2) as 24-hour infusion or FAC in standard doses at every-3-week intervals. Each patient was treated with four cycles of preoperative chemotherapy. Clinical response and extent of residual disease in the breast and lymph nodes was assessed after four cycles of induction chemotherapy.

RESULTS: A total of 174 patients were registered, and 87 were randomized to each arm of the study. Clinical response, ie, complete and partial responses, was similar in both arms of the study. Three patients in the FAC arm and one patient in the paclitaxel subgroup had progressive disease. The extent of residual disease by intent-to-treat analysis at the time of surgery was similar between the two arms of the study.

CONCLUSION: The results of this prospective study demonstrated that single-agent paclitaxel as neoadjuvant therapy has significant antitumor activity, and this was clinically comparable to FAC. Similar fractions of patients had clinical complete and partial responses, and very few patients had no response to either therapy. The value of alternate non–cross-resistant therapies as used in this protocol on the clinical course of this disease would require longer follow-up.
Galectin-3 and CD44v6 Isoforms in the Preoperative Evaluation of Thyroid Nodules
Authors: Gasbarri Alessandra , Martegani Marco Paolo , Del Prete Fabrizio , Lucante Teresa , Natali Pier Giorgio , Bartolazzi Armando
Published: February 2017

PURPOSE: Thyroid cancer is the most frequently occurring endocrine malignancy; however, preoperative diagnosis of some lesions, in particular those with follicular histology, is difficult, and a consistent number of nototherwise-specified “follicular nodules” are surgically resected more for diagnosis than therapeutic purposes. In this study, we investigated whether the lectin-related molecules CD44v6 and galectin-3, the expression of which is altered during deregulated cell growth and malignant transformation, could be potential markers for improving the diagnostic accuracy of conventional cytology.

MATERIALS AND METHODS: A comparative immuno-chemical and molecular analysis was performed on 157 thyroid specimens representative of normal, benign, and malignant tissues, and on 36 cytologic samples obtained preoperatively by fine-needle aspiration biopsy from nonselected patients with palpable thyroid nodules.

RESULTS: Normal thyrocytes did not express galectin-3 nor CD44v6. Although the expression of CD44v6 isnegligible in thyroiditis, these molecules are variably detected in benign and malignant proliferative lesions. Interestingly, galectin-3 is never expressed in benign lesions, but it is invariably detected in cancers. A comparative evaluation of CD44v6 and galectin-3 expression in thyroid malignancies demonstrated that these molecules are coexpressed at the messenger RNA and protein level in almost all lesions.

CONCLUSION: Our findings suggest that CD44v6 and galectin-3 could be potential markers to preoperatively identify malignant transformed thyrocytes. Immunodetection of these molecules on cytologic specimens obtained by fine-needle aspiration biopsy is an accurate and improved method for selecting, on a molecular basis, those nodular lesions of the thyroid gland that need to be surgically resected.
Multicenter Phase II Study of Bimonthly High-Dose Leucovorin, Fluorouracil Infusion, and Oxaliplatin for Metastatic Colorectal Cancer Resistant to the Same Leucovorin and Fluorouracil Regimen
Authors: André Thierry , Bensmaine Mohamed A. , Louvet Christophe , François Eric , Lucas Virginie , Desseigne Françoise , Beerblock Karine , Bouché Olivier , Carola Elisabeth , Merrouche Yacine , Morvan François , Dupont-André Ghislaine , de Gramont Aimery
Published: February 2017

PURPOSE: To evaluate the objective tumor response rates and toxicities of leucovorin (LV) plus fluorouracil (5-FU) cancer regimen combined with oxaliplatin (85 mg/m2) every 2 weeks on metastatic colorectal cancer patients with documented proof of progression while on bimonthly LV and 5-FU alone.

PATIENTS AND METHODS: One hundred patients were enrolled onto this study and 97 received the study drugs between October 1995 and December 1996. Eighty-nine patients were eligible for per-protocol efficacy analysis with documented proof of progression on one of the following two treatments: LV 500 mg/m2 and continuous 5-FU infusion 1.5 to 2 g/m2/22 hours, days 1 through 2 every 2 weeks (FOLFUHD); or LV 200 mg/m2, bolus 5-FU 400 mg/m2, and continuous 5-FU infusion 600 mg/m2/22 hours, days 1 through 2 every 2 weeks (LV5FU2). In our study, 40 patients received FOLFUHD + 85 mg/m2 of oxaliplatin day 1 (FOLFOX3) and 57 patients received LV5FU2 + 85 mg/m2 of oxaliplatin day 1 (FOLFOX4).

RESULTS: Of the 97 patients treated, 20 partial responses were observed (FOLFOX3/4: response rate, 20.6%; 95% confidence interval, 13% to 31.1%; FOLFOX3: response rate,18.4%; FOLFOX4: response rate, 23.5%). For patients treated with FOLFOX3/4, the median response duration for was 7.5 months, and the major toxicities were peripheral neuropathy and neutropenia. The incidence of grade 3 (National Cancer Institute common toxicity criteria) peripheral neuropathy was 20.6%; whereas the overall incidence of grade 3 to 4 neutropenia was 27.8%, 15%, and 36.9% for FOLFOX3/4, FOLFOX3, and FOLFOX4, respectively (P = .02). From the start of treatment, median progression-free survival was 4.7, 4.6, and 5.1 months for FOLFOX3/4, FOLFOX3, FOLFOX4, respectively, and median overall survival was 10.8, 10.6, and 11.1 months, respectively.

CONCLUSION: This phase II study of oxaliplatin at 85 mg/m2 in combination with bimonthly LV plus 5-FU in patients with colorectal cancer resistant to LV plus 5-FU alone confirms the enhanced antitumor activity of oxaliplatin in combination with 5-FU.
Treatment Outcome and Prognostic Factors for Infants With Acute Lymphoblastic Leukemia Treated on Two Consecutive Trials of the Children's Cancer Group
Authors: Reaman Gregory H. , Sposto Richard , Sensel Martha G. , Lange Beverly J. , Feusner James H. , Heerema Nyla A. , Leonard Marcia , Holmes Emiko J. , Sather Harland N. , Pendergrass Thomas W. , Johnstone Helen S. , O'Brien Richard T. , Steinherz Peter G. , Zeltzer Paul M. , Gaynon Paul S. , Trigg Michael E. , Uckun Fatih M.
Published: February 2017

PURPOSE: Infants represent a very poor risk group for acute lymphoblastic leukemia (ALL). We report treatment outcome for such patients treated with intensive therapy on consecutive Children's Cancer Group (CCG) protocols.

PATIENTS AND METHODS: Between 1984 and 1993, infants with newly diagnosed ALL were enrolled onto CCG-107 (n = 99) and CCG-1883 (n = 135) protocols. Postconsolidation therapy was more intensive on CCG-1883. On both studies, prophylactic treatment of the CNS included both high-dose systemic chemotherapy and intrathecal therapy, in contrast to whole-brain radiotherapy, which was used in earlier studies.

RESULTS: Most patients (> 95%) achieved remission with induction therapy. The most frequent event was a marrow relapse (46 patients on CCG-107 and 66 patients on CCG-1883). Four-year event-free survival was 33% (SE = 4.7%) on CCG-107 and 39% (SE = 4.2%) on CCG-1883. Both studies represent an improvement compared with a 22% (SE = 5.1%) event-free survival for historical controls. Four-year cumulative probabilities of any marrow relapse or an isolated CNS relapse were, respectively, 49% (SE = 5%) and 9% (SE = 3%) on CCG-107 and 50% (SE = 5%) and 3% (SE = 2%) on CCG-1883, compared with 63% (SE = 6%) and 5% (SE = 3%) for the historical controls. Independent adverse prognostic factors were age less than 3 months, WBC count of more than 50,000/μL, CD10 negativity, slow response to induction therapy, and presence of the translocation t(4;11).

CONCLUSION: Outcome for infants on CCG-107 and CCG-1883 improved, compared with historical controls. Marrow relapse remains the primary mode of failure. Isolated CNS relapse rates are low, indicating that intrathecal chemotherapy combined with very-high-dose systemic therapy provides adequate protection of the CNS. The overall unsatisfactory outcome observed for the infant ALL population warrants the future use of novel alternative therapies.
Comparison of Standard and CA-125 Response Criteria in Patients With Epithelial Ovarian Cancer Treated With Platinum or Paclitaxel
Authors: Bridgewater John A. , Nelstrop Ann E. , Rustin Gordon J.S. , Gore Martin E. , McGuire William P. , Hoskins William J.
Published: February 2017

PURPOSE: To assess CA-125 as a measure of response in patients treated with paclitaxel.

PATIENTS AND METHODS: One hundred forty-four patients treated with paclitaxel derived from four different trials and 625 patients treated with platinum from two trials were analyzed using precisely defined 50% and 75% reductions in CA-125. The standard and CA-125 response rates to paclitaxel and platinum were compared. In addition, we analyzed individual patient groups in which there was a difference in response according to the two response criteria.

RESULTS: Patients with stable disease as determined by standard criteria who were treated with platinum and responded according to CA-125 criteria have an improved median progression-free survival compared with patients with stable disease who did not respond according to CA-125 criteria (10.6 v 4.8 months; P < .001). Standard and CA-125 response rates for patients treated with platinum (58.93% v 61.31%, respectively) and paclitaxel (30.65% v 31.67%, respectively) were very similar, as were rates of false-positive prediction of response by CA-125 (platinum 2.2% and paclitaxel 2.9%). Responders to paclitaxel had a significantly improved progression-free survival compared with nonresponders by both standard criteria (median progression-free survival, 6.8 v 2.5 months; P < .001) and CA-125 criteria (median progression-free survival, 6.8 v 3.4 months; P < .001).

CONCLUSION: For assessing activity of therapy for ovarian cancer, these data show that precise 50% or 75% CA-125 response criteria are as sensitive as standard response criteria. We propose that they may be used as a measure of response in lieu of or in addition to standard response criteria in clinical trials involving epithelial ovarian cancer. Sensitivity is maintained whether patients are treated with platinum or paclitaxel.
Value of Combined Approach With Thallium-201 Single-Photon Emission Computed Tomography and Epstein-Barr Virus DNA Polymerase Chain Reaction in CSF for the Diagnosis of AIDS-Related Primary CNS Lymphoma
Authors: Antinori A. , De Rossi G. , Ammassari A. , Cingolani A. , Murri R. , Di Giuda D. , De Luca A. , Pierconti F. , Tartaglione T. , Scerrati M. , Larocca L. M. , Ortona L.
Published: February 2017

PURPOSE: To determine the diagnostic capability of thallium-201 (201Tl) single-photon emission computed tomography (SPECT) combined with Epstein-Barr virus DNA (EBV-DNA) in CSF for the diagnosis of AIDS-related primary CNS lymphoma (PCNSL).

PATIENTS AND METHODS: All human immunodeficiency virus (HIV)–infected patients with focal brain lesions observed between June 1996 and March 1998 underwent lumbar puncture and 201Tl SPECT. Each CSF sample was tested with polymerase chain reaction (PCR) for EBV-DNA.

RESULTS: Thirty-one patients were included, 13 with PCNSL and 18 with nontumor disorders. In 11 PCNSL patients, EBV-DNA was positive. Thallium-201 uptake ranged from 1.90 to 4.07 in PCNSL cases (mean, 2.77; 95% confidence interval [CI], 2.35 to 3.19) and from 0.91 to 3.38 in nontumor patients (mean, 1.62; 95% CI, 1.30 to 1.94) (P < .0002). Using a lesion/background ratio of 1.95 as cutoff, a negative SPECT was found in one PCNSL case and 16 nonneoplastic cases. A cryptococcoma and a tuberculoma showed highly increased 201Tl uptake. Epstein-Barr virus DNA was never detected in nonneoplastic patients. For PCNSL diagnosis, hyperactive lesions showed 92% sensitivity and 94% negative predictive value (NPV), whereas positive EBV-DNA had 100% specificity and 100% positive predictive value. The presence of increased uptake and/or positive EBV-DNA had 100% sensitivity and 100% NPV.

CONCLUSION: Combined SPECT and EBV-DNA showed a very high diagnostic accuracy for AIDS-related PCNSL. Because PCNSL likelihood is extremely high in patients with hyperactive lesions and positive EBV-DNA, brain biopsy could be avoided, and patients could promptly undergo radiotherapy or multimodal therapy. On the contrary, in patients showing hypoactive lesions with negative EBV-DNA, empiric anti-Toxoplasma therapy is indicated. In patients with discordant SPECT/PCR results, brain biopsy seems to be advisable.
K-ras Mutations in DNA Extracted From the Plasma of Patients With Pancreatic Carcinoma: Diagnostic Utility and Prognostic Significance
Authors: Castells Antoni , Puig Pere , Móra Josefina , Boadas Jaume , Boix Loreto , Urgell Eulàlia , Solé Manel , Capellà Gabriel , Lluís Fèlix , Fernández-Cruz Laureano , Navarro Salvador , Farré Antoni
Published: February 2017

PURPOSE: Previous studies have demonstrated the presence of K-ras mutations in the plasma of patients with pancreatic carcinoma. However, the diagnostic utility and the prognostic significance of this finding have never been addressed.

PATIENTS AND METHODS: Forty-four consecutive patients with histologically confirmed primary pancreatic ductal adenocarcinoma were included. A control group of 37 patients with chronic pancreatitis, 10 patients with other tumors of the pancreatic area, nine patients with acute pancreatitis, and four healthy volunteers was also included. Plasma DNA was isolated and K-ras codon-12 mutations were analyzed by means of restriction fragment length polymorphism-polymerase chain reaction and single-strand conformation polymorphism techniques. Patients were followed up to establish their clinical outcome.

RESULTS: The mutant-type K-ras gene was found in plasma DNA samples of 12 (27%) of 44 patients with pancreatic ductal adenocarcinoma; this finding was related to the tumor stage (P = .05), mainly in the presence of distant metastases (P = .02). In addition, K-ras mutations were detected in the plasma DNA of two (5%) of 37 patients with chronic pancreatitis. In the subset of patients with pancreatic masses, the sensitivity and specificity of plasma K-ras analysis for pancreatic adenocarcinoma were 27% and 100%, respectively. Finally, pancreatic carcinoma patients with the mutant-type K-ras gene in plasma DNA exhibited a shorter survival time than patients with the wild-type gene (P < .005), and plasma K-ras mutations were identified as the only independent prognostic factor (odds ratio, 1.51; 95% confidence interval, 1.02 to 2.23).

CONCLUSION: Plasma K-ras analysis is a highly specific, low-sensitivity approach that has diagnostic and prognostic clinical implications in patients with pancreatic carcinoma.
Combination of Chemotherapy With Interleukin-2 and Interferon Alfa for the Treatment of Metastatic Melanoma
Authors: Richards Jon M. , Gale Danielle , Mehta Nilesh , Lestingi Timothy
Published: February 2017

PURPOSE: The primary objective of this clinical study was to assess the feasibility of administering recombinant interleukin-2 and recombinant interferon alfa-2a before and after combination cytotoxic chemotherapy. After encouraging initial responses, the study was expanded to further evaluate the therapeutic potential, clarify the toxicities of this regimen, and explore any associated immunologic changes.

PATIENTS AND METHODS: Eighty-four patients with metastatic melanoma, including patients with brain metastases, were treated on this 6-week protocol. Patients received combination cisplatin (25 mg/m2/d) and dacarbazine (220 mg/m2/d) on days 1 through 3 and 22 through 24 plus carmustine (150 mg/m2) on day 1. Interleukin 2 (13.5 million IU/m2/d) and interferon alfa (6 MU/m2/d) were administered on days 4 through 8 and 17 through 21.

RESULTS: Among 83 patients assessable for response, 12 complete and 34 partial responses were documented (55% response rate). The median time to disease progression was 7 months, the median survival from study entry was 12.2 months, and the median survival from diagnosis of metastatic disease was 15.5 months. Although patients were hospitalized to receive treatment, intensive care unit support generally was not needed. Dose-limiting toxicities were related to elevations in serum bilirubin and serum creatinine levels. No patient developed a grade 4 clinical toxicity. Treatment produced a skin depigmentation, which was associated with prolonged survival.

CONCLUSION: A plateau in both the survival and time to progression curves beyond 2 years (15% of the patients) and a greater than 10% disease-free survival beyond 4 years indicate that there may be a long-term benefit for some patients. The limited toxicity of this regimen should permit its use in most oncology settings. A randomized trial of chemoimmunotherapy versus chemotherapy should be performed to establish the value of chemoimmunotherapy for melanoma.
Impact of Preoperative Bimodality Induction Including Twice-Daily Radiation on Tumor Regression and Survival in Stage III Non–Small-Cell Lung Cancer
Authors: Thomas Michael , Rübe Christian , Semik Michael , von Eiff Michael , Freitag Lutz , Macha Hans N. , Wagner Wolfgang , Klinke Folker , Scheld Hans H. , Willich Norman , Berdel Wolfgang E. , Junker Klaus
Published: February 2017

PURPOSE: The objective of this prospective study was to assess the feasibility, toxicity, and efficacy of an intensive trimodality approach in stage III non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Fifty-four patients with NSCLC and biopsy-proven N2 nodes (IIIA; n = 25) or N3 nodes or T4 lesions (IIIB; n = 29) were administered two initial cycles of ifosfamide, carboplatin, and etoposide; subsequent radiotherapy (45 Gy, twice-daily 1.5 Gy) with concurrent carboplatin and vindesine; and surgery if the patient's disease was resectable or conventional radiotherapy (16 Gy, 2 Gy/d) if the patient's disease was not resectable or incompletely resectable.

RESULTS: Thirty-seven patients (69%) responded to preoperative induction. Forty of 54 patients (74%) had disease that was resectable, with 34 (63%) complete resections (R0). A substantial pathologic response (tumor regression [TR] > 90%) was achieved in 27 of 54 patients (50%) and is revealed as an independent predictor for long-term survival after surgery. Five treatment-related deaths (9%) occurred. With a median follow-up period of 44 months, calculated survival rates at 3 years were 35% for patients with stage IIIA disease, 26% for patients with stage IIIB disease, and 56% for patients with R0 disease and TR > 90%.

CONCLUSION: This trimodality approach is feasible and results in encouraging 3-year survival rates in prognostically unfavorable patients with stage III NSCLC. Patients experiencing a 90% degree of pathologic TR were most likely to achieve long-term survival.