bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurocognitive Development of Children After a Cerebellar Tumor in Infancy: A Longitudinal Study
Authors: Copeland Donna R. , deMoor Carl , Moore III Bartlett D. , Ater Joann L.
Published: February 2017

PURPOSE: To assess the long-term neuropsychologic effects experienced by children who have tumors in the cerebellum that are diagnosed and treated during infancy.

PATIENTS AND METHODS: Twenty-seven children with posterior fossa tumors diagnosed at less than 36 months of age were assessed prospectively with a comprehensive set of age-appropriate tests. Group means and SDs are reported for assessments conducted at diagnosis (analysis 1) and at the most recent follow-up appointment (analysis 2). Cognitive developmental growth curves were derived from the prospective data (analysis 3) using mixed model regression analyses and controlling for age at diagnosis and socioeconomic status.

RESULTS: In the first analysis, eight of 11 infants at diagnosis scored within normal limits on all neuropsychologic domains, except for motor skills, which were impaired. In the second analysis, mean scores at the most recent follow-up of 21 of 27 patients were mostly in the normal range; however, group comparisons between those who had (n = 7) and had not (n = 14) been treated with cranial radiation therapy (CRT) showed that patients in the irradiated (CRT) group scored significantly lower than those in the nonirradiated (No-CRT) group on verbal intelligence quotient (IQ) and in the motor domain. In the third analysis (growth curves of CRT and No-CRT groups), statistically significant differences in slope were found on verbal IQ, performance IQ, perceptual-motor skills, language, and attention/executive skills. Slopes on the fine-motor domain were similar; both groups declined at approximately the same rate.

CONCLUSION: Neurocognitive development and outcome of children with cerebellar tumors diagnosed in infancy is very positive among those who were treated with surgery and chemotherapy. Declines in performance across time were minimal, and scores tended to remain within normal limits. By itself, a cerebellar tumor in infancy does not seem to have a significant impact on children. However, those who received CRT as part of their treatment are likely to have neurocognitive and psychosocial deficits that require remediational interventions.
Gemcitabine and Cisplatin Versus Mitomycin, Ifosfamide, and Cisplatin in Advanced Non–Small-Cell Lung Cancer: A Randomized Phase III Study of the Italian Lung Cancer Project
Authors: Crinò L. , Scagliotti G. V. , Ricci S. , De Marinis F. , Rinaldi M. , Gridelli C. , Ceribelli A. , Bianco R. , Marangolo M. , Di Costanzo F. , Sassi M. , Barni S. , Ravaioli A. , Adamo V. , Portalone L. , Cruciani G. , Masotti A. , Ferrara G. , Gozzelino F. , Tonato M.
Published: February 2017

PURPOSE: To compare gemcitabine and cisplatin (GC) with mitomycin, ifosfamide, and cisplatin (MIC) chemotherapy in patients with stage IIIB (limited to T4 for pleural effusion and N3 for supraclavicular lymph nodes) or stage IV non–small-cell lung cancer (NSCLC). The end points were the evaluation of quality of life (QoL), response rates, survival, and toxicity.

PATIENTS AND METHODS: Three hundred seven patients were randomized to receive either gemcitabine 1,000 mg/m2 on days 1, 8, and 15 plus cisplatin 100 mg/m2 on day 2, every 28 days, or mitomycin 6 mg/m2, ifosfamide 3,000 mg/m2, and mesna on day 1 plus cisplatin 100 mg/m2 on day 2, every 28 days. The whole-blood cell count was repeated on day 1 in both arms and weekly in the GC arm before each gemcitabine administration.

RESULTS: No major differences in changes in QoL were observed between the two treatment arms. The objective response rate was 38% in the GC arm compared with 26% in the MIC arm (P = .029). The median survival time was 8.6 months in the GC arm and 9.6 months in the MIC arm (P = .877, log-rank test). Grade 3 and 4 thrombocytopenia was significantly worse in the GC arm (64% v 28%, P < .001), whereas grade 3 and 4 alopecia was reported more commonly in the MIC arm (39% v 12%, P < .001).

CONCLUSION: We report an increased response rate without changes in QoL and a similar overall survival, time to progression, and time to treatment failure for the GC when compared with the MIC regimen in the treatment of advanced NSCLC.
Multiple Courses of High-Dose Ifosfamide, Carboplatin, and Etoposide With Peripheral-Blood Progenitor Cells and Filgrastim for Small-Cell Lung Cancer: A Feasibility Study by the European Group for Blood and Marrow Transplantation
Authors: Leyvraz S. , Perey L. , Rosti G. , Lange A. , Pampallona S. , Peters R. , Humblet Y. , Bosquée L. , Pasini F. , Marangolo M.
Published: February 2017

PURPOSE: To determine the feasibility and safety of multiple sequential courses of high-dose chemotherapy and peripheral-blood progenitor cells (PBPCs) administered in a multicenter setting to patients with small-cell lung cancer.

PATIENTS AND METHODS: Sixty-nine patients (limited disease, n = 30; extensive disease, n = 39) treated at 15 European centers were scheduled to receive three courses of high-dose chemotherapy with ifosfamide 10 g/m2, carboplatin 1200 mg/m2, and etoposide 1200 mg/m2 (ICE) divided over 4 days at 28-day intervals. PBPCs were harvested before treatment and mobilized with epirubicin 150 mg/m2 administered via an intravenous bolus divided over 2 days and filgrastim 5 μg/kg/d administered subcutaneously.

RESULTS: The performed leukaphereses (one to five per patient) yielded a median of 16.6 × 106/kg (range, 1.0 to 96.6 × 106/kg) CD34+ cells, which was sufficient for three reinfusions. Fifty patients (72%) completed the treatment according to schedule. Nine patients completed two courses, and six patients completed one course of treatment. The increase in dose-intensity was 290% that of a standard ICE regimen. The median duration of myelosuppression was similar between courses, namely 4 days (range, 1 to 12 days) for leukocytes less than 0.5 × 109/L and 4 days (range, 0 to 22 days) for thrombocytes less than 20 × 109/L. Febrile neutropenia developed in 66% of courses, severe diarrhea in 14%, mucositis in 10%, and nausea and vomiting in 21% of courses. There were six cases of toxic death (9%), most of which occurred in the first year of accrual and thus were attributable to the learning curve. The antitumor effect of the regimen was reflected in an 86% remission rate (95% confidence interval [CI], 74% to 93%), with 51% of patients achieving a complete response (95% CI, 38% to 63%). Median overall survival was 18 months for patients with limited disease and 11 months for patients with extensive disease.

CONCLUSION: This multiple sequential high-dose ICE regimen could be safely administered on a multicenter basis to patients with small-cell lung cancer. The dose-intensity could be increased to 290% that of standard ICE regimen. The benefit of this approach is currently being tested in a randomized trial that aims to double the long-term rate of survival for patients with small-cell lung cancer.
Decision Analysis on Alternative Treatment Strategies for Favorable-Prognosis, Early-Stage Hodgkin's Disease
Authors: Ng Andrea K. , Weeks Jane C. , Mauch Peter M. , Kuntz Karen M.
Published: February 2017

PURPOSE: To compare the therapeutic outcomes of various treatment strategies in early-stage, favorable-prognosis Hodgkin's disease (HD) using methods of decision analysis.

METHODS: We constructed a decision-analytic model to determine the life expectancy and quality-adjusted life expectancy for a hypothetical cohort of clinically or pathologically staged 25-year-old patients with early-stage, favorable-prognosis HD treated with varying degrees of initial therapy. Markov models were used to simulate the lifetime clinical course of patients, and baseline probability estimates were derived from published study results.

RESULTS: Among patients with pathologic stage (PS) I to II, mantle and para-aortic (MPA) radiotherapy was favored over combined-modality therapy (CMT), mantle radiotherapy, and chemotherapy by 1.18, 1.33, and 1.55 years, respectively. For patients with clinical stage (CS) I to II, the treatment options of MPA-splenic radiotherapy, CMT, and chemotherapy yielded similar survival outcomes. Sensitivity analysis showed that the decision between CMT and MPA-splenic radiotherapy was highly influenced by the precise values of the estimates of treatment efficacy and long-term morbidity, the quality-of-life value assigned to the postsplenic irradiation state, and the time discount value used in the model. Probabilistic sensitivity analysis demonstrated that even if future studies doubled the precision of the estimates of the treatment-related variables, it would be impossible to demonstrate the superiority of one treatment over the other.

CONCLUSION: Our model predicted that on average, MPA radiotherapy was clearly the preferred treatment for PS I to II patients. For CS I to II patients the treatment decision is a toss-up between MPA-splenic radiotherapy and CMT, emphasizing the importance of patient preference exploration and shared decision making between patient and physician when choosing between treatments.
Cardiotoxicity of Epirubicin/Paclitaxel–Containing Regimens: Role of Cardiac Risk Factors
Authors: Gennari Alessandra , Salvadori Barbara , Donati Sara , Bengala Carmelo , Orlandini Cinzia , Danesi Romano , Del Tacca Mario , Bruzzi Paolo , Conte Pier Franco
Published: February 2017

PURPOSE: To evaluate the incidence of clinically relevant cardiac toxicity after treatment with epirubicin/paclitaxel-containing regimens in patients with metastatic breast cancer and to identify high-risk patients in whom the benefit of chemotherapy may be negated by the occurrence of congestive heart failure (CHF).

PATIENTS AND METHODS: A total of 105 patients who were referred for epirubicin/paclitaxel treatment were included in this study. Treatment regimens were as follows: (1) epirubicin 90 mg/m2 plus paclitaxel 135 to 225 mg/m2 over 3 hours (n = 76); and (2) gemcitabine 1,000 mg/m2 on days 1 and 4 plus epirubicin/paclitaxel (n = 29). The occurrence of CHF was detected by physical examination, and left ventricular function was evaluated by bidimensional echocardiography to support the diagnosis. Cardiac risk factors examined in this study included age, prior radiotherapy to the chest, hypertension, and diabetes.

RESULTS: No patient experienced CHF while on treatment. Nine patients (9%) developed CHF after cumulative epirubicin doses of 1,080 mg/m2 (n = 4), 720 mg/m2 (n = 2), 630 mg/m2 (n = 1), and 540 mg/m2 (n = 2). One of the two patients who developed CHF after a cumulative epirubicin dose of 540 mg/m2 had received consolidation with high-dose chemotherapy. Median time to appearance of cardiologic symptoms was 3 months after the end of treatment (range, 3 to 6 months). Overall, the incidence of CHF was 13% and 4% in patients with or without cardiac risk factors, respectively. The cumulative risk of developing CHF was estimated as 7.7% at a cumulative doses of 720 mg/m2 and 48.7% at a cumulative dose of 1,080 mg/m2.

CONCLUSION: This study shows that the incidence of CHF after an epirubicin/paclitaxel regimen is low up to cumulative epirubicin doses of 990 mg/m2, thus allowing the safe administration of this regimen even in patients who received epirubicin in the adjuvant setting. However, the risk of developing CHF increases when a cumulative dose exceeding 990 mg/m2 is reached, concomitantly with the presence of an additional cardiac risk factor.
Ras Protein Farnesyltransferase: A Strategic Target for Anticancer Therapeutic Development
Authors: Rowinsky Eric K. , Windle Jolene J. , Von Hoff Daniel D.
Published: February 2017

ABSTRACT: Ras proteins are guanine nucleotide–binding proteins that play pivotal roles in the control of normal and transformed cell growth and are among the most intensively studied proteins of the past decade. After stimulation by various growth factors and cytokines, Ras activates several downstream effectors, including the Raf-1/mitogen-activated protein kinase pathway and the Rac/Rho pathway. In approximately 30% of human cancers, including a substantial proportion of pancreatic and colon adenocarcinomas, mutated ras genes produce mutated proteins that remain locked in an active state, thereby relaying uncontrolled proliferative signals. Ras undergoes several posttranslational modifications that facilitate its attachment to the inner surface of the plasma membrane. The first—and most critical—modification is the addition of a farnesyl isoprenoid moiety in a reaction catalyzed by the enzyme protein farnesyltransferase (FTase). It follows that inhibiting FTase would prevent Ras from maturing into its biologically active form, and FTase is of considerable interest as a potential therapeutic target. Different classes of FTase inhibitors have been identified that block farnesylation of Ras, reverse Ras-mediated cell transformation in human cell lines, and inhibit the growth of human tumor cells in nude mice. In transgenic mice with established tumors, FTase inhibitors cause regression in some tumors, which appears to be mediated through both apoptosis and cell cycle regulation. FTase inhibitors have been well tolerated in animal studies and do not produce the generalized cytotoxic effects in normal tissues that are a major limitation of most conventional anticancer agents. There are ongoing clinical evaluations of FTase inhibitors to determine the feasibility of administering them on dose schedules like those that portend optimal therapeutic indices in preclinical studies. Because of the unique biologic aspects of FTase, designing disease-directed phase II and III evaluations of their effectiveness presents formidable challenges.
Use of Hematopoietic Colony-Stimulating Factors: Comparison of the 1994 and 1997 American Society of Clinical Oncology Surveys Regarding ASCO Clinical Practice Guidelines
Authors: Bennett Charles L. , Weeks Jane A. , Somerfield Mark R. , Feinglass Joe , Smith Thomas J.
Published: February 2017

PURPOSE: The American Society of Clinical Oncology (ASCO) Health Services Research Committee sought to assess whether more appropriate patterns of colony-stimulating factor (CSF) use occurred after the publication of ASCO evidence-based practice guidelines in 1994 and 1996 for patients with solid tumors or lymphoma.

METHODS: In 1994 and 1997, questionnaires describing clinical scenarios were mailed to ASCO members who practiced medical oncology. Physicians were asked the extent to which they preferred to use a CSF for primary prophylaxis, secondary prophylaxis, or treatment of neutropenic complications. Multiple regression analyses were used to determine predictors of overall propensity to use CSFs and, when using a CSF, propensity to support longer schedules of CSF use.

RESULTS: Decreased use of CSFs was shown in the following situations: (1) treatment for febrile neutropenia without localizing signs (39% in 1994 v 29% in 1997) or with a right lower lobe infiltrate (54% v 46%); (2) primary prophylaxis with paclitaxel for ovarian cancer (20% v 11%) or cyclophosphamide, doxorubicin, and vincristine chemotherapy for small-cell lung cancer (8.4% v 4.6%); and (3) secondary prophylaxis after afebrile neutropenia following chemotherapy for germ cell tumors (44.5% v 36.0%). One third fewer physicians supported the extended use of CSFs until an absolute neutrophil count ≥ 10,000/mm3 or a WBC count ≥ 10,000/mm3 was reached, both counts serving as criteria for stopping CSF therapy. However, we observed high rates of CSF use despite ASCO guideline recommendations against use in the following clinical situations: (1) primary prophylaxis in patients at low risk of febrile neutropenia (6% v 16%); (2) secondary prophylaxis late in the course of curative and palliative therapy (80% v 53%); and (3) treatment of afebrile and uncomplicated febrile neutropenia (30% v 60%). In 1994 and 1997, fee-for-service physicians were more likely than other physicians to prefer use of CSF support while maintaining treatment dose and schedule instead of using dose-reduction strategies, and, when using a CSF, they were more likely to support longer CSF treatment schedules (P < .05 for both scenarios).

CONCLUSION: Decreased use and more appropriate use of CSFs in accordance with ASCO guideline recommendations occurred from 1994 to 1997, but there remain many opportunities to reduce CSF use with no clinical harm. Many oncologists continue to support the use of CSFs in scenarios and with scheduling criteria that the guidelines and evidence do not support. ASCO's evidence-based guidelines should be linked with formal continuous quality improvement initiatives to substantially improve the quality of supportive oncology care.
Phase II Study of Oral Platinum Drug JM216 as First-Line Treatment in Patients With Small-Cell Lung Cancer
Authors: Fokkema E. , Groen H. J.M. , Bauer J. , Uges D. R.A. , Weil C. , Smith I. E.
Published: February 2017

PURPOSE: This multicenter phase II trial was performed to determine tumor efficacy and tolerance of the oral platinum drug JM216 in patients with small-cell lung cancer (SCLC).

PATIENTS AND METHODS: Patients with SCLC limited disease unfit for intensive chemotherapy or those with extensive disease received JM216 120 mg/m2/d for 5 consecutive days every 3 weeks. Individual dose escalation to 140 mg/m2/d was allowed if toxicity was ≤ grade 2 according to the National Cancer Institute Common Toxicity Criteria. Tumor response was evaluated according to World Health Organization criteria.

RESULTS: Twenty-seven patients were assessable for toxicity and 26 for tumor response. Eighty-eight cycles were administered. Common Toxicity Criteria grade 3 and 4 hematologic toxicities were neutropenia in 15.9% and 3.7%, lymphocytopenia in 47.6% and 17.1%, and thrombocytopenia in 19.5% and 10.3% of cycles, respectively. One patient suffered from neutropenic fever. Nausea, vomiting, and diarrhea were the most common nonhematologic toxicities. Except for grade 4 diarrhea in one patient, no grade 4 nonhematologic toxicity was observed. No severe neurotoxicity or nephrotoxicity was observed. Tumor response rate was 10 of 26 (38%; 95% confidence interval, 19% to 58%), excluding five unconfirmed partial responses. No complete responses were observed. Median overall time to progression was 110 days (range, 5 to 624 days). Median overall survival time was 210 days (range, 5 to 624 days).

CONCLUSION: Oral JM216 is active in previously untreated patients with SCLC and shows mild toxicities.
World Health Organization Classification of Neoplastic Diseases of the Hematopoietic and Lymphoid Tissues: Report of the Clinical Advisory Committee Meeting—Airlie House, Virginia, November 1997
Authors: Harris Nancy Lee , Jaffe Elaine S. , Diebold Jacques , Flandrin Georges , Muller-Hermelink H. Konrad , Vardiman James , Lister T. Andrew , Bloomfield Clara D.
Published: February 2017

PURPOSE: The European Association of Hematopathologists and the Society for Hematopathology have developed a new World Health Organization (WHO) classification of hematologic malignancies, including lymphoid, myeloid, histiocytic, and mast cell neoplasms.

DESIGN: Ten committees of pathologists developed lists and definitions of disease entities. A clinical advisory committee (CAC) of international hematologists and oncologists was formed to ensure that the classification would be useful to clinicians. The CAC met in November 1997 to discuss clinical issues related to the classification.

RESULTS: The WHO uses the Revised European-American Lymphoma (REAL) classification, published in 1994 by the International Lymphoma Study Group, to categorize lymphoid neoplasms. The REAL classification is based on the principle that a classification is a list of “real” disease entities, which are defined by a combination of morphology, immunophenotype, genetic features, and clinical features. The relative importance of each of these features varies among diseases, and there is no one gold standard. The WHO classification applies the principles of the REAL classification to myeloid and histiocytic neoplasms. The classification of myeloid neoplasms recognizes distinct entities defined by a combination of morphology and cytogenetic abnormalities. At the CAC meeting, which was organized around a series of clinical questions, participants reached a consensus on most of the questions posed. They concluded that clinical groupings of lymphoid neoplasms were neither necessary nor desirable. Patient treatment is determined by the specific type of lymphoma, with the addition of grade within the tumor type, if applicable, and clinical prognostic factors, such as the International Prognostic Index.

CONCLUSION: The WHO classification has produced a new and exciting degree of cooperation and communication between oncologists and pathologists from around the world, which should facilitate progress in the understanding and treatment of hematologic malignancies.
Treatment of Localized Primary Non-Hodgkin's Lymphoma of Bone in Children: A Pediatric Oncology Group Study
Authors: Suryanarayan Kaveri , Shuster Jonathan J. , Donaldson Sarah S. , Hutchison Robert E. , Murphy Sharon B. , Link Michael P.
Published: February 2017

PURPOSE: The treatment of primary lymphoma of bone (PLB) in children has traditionally included radiotherapy to the primary site; more recently, it has included systemic chemotherapy. Because of concern about the untoward effects of treatment in a disease that is curable, we attempted to determine whether radiotherapy can be safely excluded from treatment.

PATIENTS AND METHODS: The results of three consecutive Pediatric Oncology Group (POG) studies were examined to determine the impact on outcome of radiotherapy as adjunctive treatment in children and adolescents receiving chemotherapy for early-stage primary lymphoma of bone.

RESULTS: From 1983 to 1997, 31 patients with localized PLB were entered onto POG studies of early-stage non-Hodgkin's lymphoma (NHL). Between 1983 and 1986, seven patients were treated with 8 months of chemotherapy with irradiation (XRT) of the primary site. After 1986, patients were treated without XRT; four received 8 months of chemotherapy, and 20 received 9 weeks of chemotherapy. Primary sites were the femur (nine), tibia (eight), mandible (five), mastoid (one), maxilla (one), zygomatic arch (one), rib (one), clavicle (one), scapula (one), ulna (one), talus (one), and calcaneous (one). Histologic classification revealed 21 cases of large-cell lymphoma, five cases of lymphoblastic lymphoma, two cases of small, noncleaved-cell lymphoma, and three cases of NHL that could not be classified further. One patient relapsed at a distant site 22 months after completion of therapy. There have been no deaths.

CONCLUSION: Localized PLB is curable in most children and adolescents with a 9-week chemotherapy regimen of modest intensity, and radiotherapy is an unnecessary adjunct.
Autoimmunity Resulting From Cytokine Treatment Predicts Long-Term Survival in Patients With Metastatic Renal Cell Cancer
Authors: Franzke Anke , Peest Dietrich , Probst-Kepper Michael , Buer Jan , Kirchner Gabriele I. , Brabant Georg , Kirchner Hartmut , Ganser Arnold , Atzpodien Jens
Published: February 2017

PURPOSE: In patients undergoing cytokine therapy, systemically applied interleukin-2 (IL-2) and/or interferon-alpha (IFN-α) have been reported to induce thyroid dysfunction as well as thyroid autoantibodies. We analyzed the correlation of thyroid autoimmunity with HLA phenotype, various other autoimmune parameters, and patient survival.

PATIENTS AND METHODS: For this purpose, antithyroglobulin autoantibodies, antimicrosomal thyroid autoantibodies, thyroglobulin receptor autoantibodies, thyroid dysfunction, and multiple clinical parameters were determined in 329 unselected patients with metastatic renal cell cancer before and after systemic IL-2 and IFN-α2 therapy. For statistical analysis, we used both univariate and multivariate Cox proportional hazards models and the two-tailed Fisher's exact test.

RESULTS: Antithyroglobulin autoantibodies and antimicrosomal thyroid autoantibodies were detected in 60 patients (18%); positive autoantibody titers of various other autoimmune parameters were statistically unrelated. The presence of thyroid autoantibodies was correlated with prolonged survival (P < .0001). There was a statistically significant difference in frequencies of HLA-Cw7 expression between thyroid autoantibody-positive and -negative patients (P ≤ .05), and the Cw7 expression was associated with prolonged overall survival (P = .009).

CONCLUSION: The evaluation of thyroid autoantibodies during cytokine therapy could be a useful prognostic marker for patients with renal cell carcinoma who benefit from cytokine treatment. IL-2– and IFN-α2-induced tumor control and prolonged survival may require breaking of immunologic tolerance against self-antigens.
Comparative Outcomes of T-Cell–Depleted and Non–T-Cell–Depleted Allogeneic Bone Marrow Transplantation for Chronic Myelogenous Leukemia: Impact of Donor Lymphocyte Infusion
Authors: Sehn Laurie H. , Alyea Edwin P. , Weller Edie , Canning Christine , Lee Stephanie , Ritz Jerome , Antin Joseph H. , Soiffer Robert J.
Published: February 2017

PURPOSE: Donor lymphocyte infusion (DLI) can restore complete remission in patients with chronic myelogenous leukemia (CML) who have relapsed after T-cell–depleted (TCD) allogeneic bone marrow transplantation (BMT). The existence of salvage treatment for patients with DLI after TCD allogeneic BMT prompted an evaluation of overall outcome after CD6+-TCD allogeneic BMT for patients treated during the time when DLI has been available.

PATIENTS AND METHODS: We performed a retrospective analysis of outcomes of 46 patients who underwent TCD allogeneic BMT for stable-phase CML and compared these outcomes with those of 40 patients who underwent non-TCD allogeneic BMT. All subjects were patients at one of two neighboring institutions during a period when DLI was available. All patients received marrow from HLA-identical sibling donors, underwent similar myeloablative regimens, and had similar pretreatment characteristics.

RESULTS: After BMT, the TCD group had a lower incidence of grade 2 to 4 acute (15% v 37%, P = .026) and chronic graft-versus-host disease (GVHD) (18% v 42%, P = .024) than did the non-TCD group. The 1-year treatment-related mortality rates for the TCD group and the non-TCD group were 13% and 29%, respectively (P = .07). The estimated 3-year probability of relapse (cytogenetic or hematologic) was higher for patients in the TCD group than for patients in the non-TCD group (62% v 24%, P = .0003). Twenty-three patients (20 in the TCD group and three in the non-TCD group) received and were assessable for response to DLI. After DLI, 17 of 20 patients in the TCD group and two of three patients in the non-TCD group achieved complete remission. Donor lymphocyte infusion induced GVHD in nine of 23 patients. Thirty (65%) of 46 patients in the TCD group and 27 (69%) of 39 assessable patients in the non-TCD group remained alive without evidence of disease. The estimated 3-year overall survival rates were similar for the TCD group and the non-TCD group (72% v 68%, respectively; P = .38). At last follow-up, there was no difference in the overall prevalence of GVHD or the proportion of patients requiring immunosuppressive agents between groups.

CONCLUSION: These results suggest that the combination of T-cell depletion and post-BMT DLI is a viable treatment option for patients undergoing allogeneic BMT for CML and should be prospectively compared with traditional forms of GVHD prophylaxis.
Prognostic Value of p53 Genetic Changes in Colorectal Cancer
Authors: Kressner Ulf , Inganäs Mats , Byding Sara , Blikstad Ingrid , Påhlman Lars , Glimelius Bengt , Lindmark Gudrun
Published: February 2017

PURPOSE: To explore whether there is a linkage between different mutations in the p53 gene in primary colorectal cancer and the risk of death from colorectal cancer in a large group of patients with long follow-up. We also compared a complementary DNA-based sequencing method and an immunohistochemical (IHC) method for detecting p53 protein overexpression in colorectal cancer.

MATERIALS AND METHODS: The entire coding region of the p53 gene was sequenced in 191 frozen tumor samples collected from January 1988 to November 1992. RNA was extracted and synthesized to cDNA. p53 was amplified by the polymerase chain reaction, and the DO-7 monoclonal antibody was used in the IHC assessments.

RESULTS: Mutations were detected in 99 samples (52%) from 189 patients. There was a significant relationship between the p53 mutational status and the cancer-specific survival time, with shorter survival time for patients who had p53 mutations than for those who did not (P = .01, log-rank test). Mutations outside the evolutionarily conserved regions were associated with the worst prognosis. Multivariate analysis showed that the presence of p53 mutations was an independent prognostic factor (relative hazard, 1.7, P = .03). There was no significant relationship between overexpression of p53 protein, as determined by IHC analysis, and cancer-specific survival.

CONCLUSION: Mutational analyses of the p53 gene, using cDNA sequencing in colorectal cancer, provide useful prognostic information. In addition, cDNA sequencing gives better prognostic information than IHC assessment of p53 protein overexpression.
Octreotide Acetate Long-Acting Formulation Versus Open-Label Subcutaneous Octreotide Acetate in Malignant Carcinoid Syndrome
Authors: Rubin Joseph , Ajani Jaffer , Schirmer William , Venook Alan P. , Bukowski Ronald , Pommier Rodney , Saltz Leonard , Dandona Paresh , Anthony Lowell
Published: February 2017

PURPOSE: Subcutaneous (SC) octreotide acetate effectively relieves the diarrhea and flushing associated with carcinoid syndrome but requires long-term multiple injections daily. A microencapsulated long-acting formulation (LAR) of octreotide acetate has been developed for once-monthly intramuscular dosing.

PATIENTS AND METHODS: A randomized trial compared double-blinded octreotide LAR at 10, 20, and 30 mg every 4 weeks with open-label SC octreotide every 8 hours for the treatment of carcinoid syndrome. Seventy-nine patients controlled with treatment of SC octreotide 0.3 to 0.9 mg/d whose symptoms returned during a washout period and who returned for at least the week 20 evaluation constituted the efficacy-assessable population.

RESULTS: Complete or partial treatment success was comparable in each of the four arms of the study (SC, 58.3%; 10 mg, 66.7%; 20 mg, 71.4%; 30 mg, 61.9%; P ≥ .72 for all pairwise comparisons). Control of stool frequency was similar in all treatment groups. Flushing episodes were best controlled in the 20-mg LAR and SC groups; the 10-mg LAR treatment was least effective in the control of flushing. Treatment was well tolerated by patients in all four groups.

CONCLUSION: Once octreotide steady-state concentrations are achieved, octreotide LAR controls the symptoms of carcinoid syndrome at least as well as SC octreotide. A starting dose of 20 mg of octreotide LAR is recommended. Supplemental SC octreotide is needed for approximately 2 weeks after initiation of octreotide LAR treatment. Occasional rescue SC injections may be required for possibly 2 to 3 months until steady-state octreotide levels from the LAR formulation are achieved.
Cancer Control in Susceptible Groups: Opportunities and Challenges
Authors: Li Frederick P.
Published: February 2017

Cancer mortality rates in the United States have risen throughout most of this century, and a downward trend has just emerged in recent years. Nevertheless, it is predicted that cancer will soon be the leading cause of death among Americans. To gain new knowledge of etiology, we have studied persons at highest risk as human models of cancer susceptibility. Clinical observations at the bedside are used to generate etiologic hypotheses that are tested in epidemiologic studies. Companion laboratory studies can identify biologic mechanisms of predisposition. Data show that inborn mutations in cancer-predisposing genes, such as BRCA1 and BRCA2, markedly increase the risk of cancers at unusually early ages. Increasing numbers of these highly penetrant genes are being identified. These discoveries have created new opportunities for genetic testing to identify cancer-prone individuals. Individuals found to be carriers can be offered counseling to avoid environmental exposures that further elevate risk, intensive medical surveillance for early detection, participation in chemoprevention trials, and prophylactic surgery to remove at-risk tissues. However, genetic knowledge can have adverse effects, including psychologic distress, social stigmatization, and loss of health insurance. Research is needed to maximize benefits and minimize risks to the susceptible populations. Professional and public education can promote appropriate use of genetic data, and legislation may be required to prevent discrimination. Knowledge of these highly penetrant genes can be extended to common polymorphisms that modify cancer risk associated with exposures to environmental carcinogens.

J Clin Oncol 17:719–725. © 1999 by American Society of Clinical Oncology.
Quality of Life in Head and Neck Cancer Patients: Validation of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-H&N35
Authors: Bjordal Kristin , Hammerlid Eva , Ahlner-Elmqvist Marianne , de Graeff Alexander , Boysen Morten , Evensen Jan F. , Biörklund Anders , de Leeuw J. Rob J. , Fayers Peter M. , Jannert Magnus , Westin Thomas , Kaasa Stein
Published: February 2017

PURPOSE: The aim of this study was to define the scales and test the validity, reliability, and sensitivity of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-H&N35, a questionnaire designed to assess the quality of life of head and neck (H&N) cancer patients in conjunction with the general cancer-specific EORTC QLQ-C30.

PATIENTS AND METHODS: Questionnaires were given to 500 H&N cancer patients from Norway, Sweden, and the Netherlands as part of two prospective studies. The patients completed the questionnaires before, during (Norway and Sweden only), and after treatment, yielding a total of 2070 completed questionnaires.

RESULTS: The compliance rate was high, and the questionnaires were well accepted by the patients. Seven scales were constructed (pain, swallowing, senses, speech, social eating, social contact, sexuality). Scales and single items were sensitive to differences between patient subgroups with relation to site, stage, or performance status. Most scales and single items were sensitive to changes, with differences of various magnitudes according to the site in question. The internal consistency, as assessed by Cronbach's alpha coefficient, varied according to assessment point and within subsamples of patients. A low overall alpha value was found for the speech and the senses scales, but values were higher in assessments of patients with laryngeal cancer and in patients with nose, sinus, and salivary gland tumors. Scales and single items in the QLQ-H&N35 seem to be more sensitive to differences between groups and changes over time than do the scales and single items in the core questionnaire.

CONCLUSION: The QLQ-H&N35, in conjunction with the QLQ-C30, provides a valuable tool for the assessment of health-related quality of life in clinical studies of H&N cancer patients before, during, and after treatment with radiotherapy, surgery, or chemotherapy.
Quality of Life and Performance in Advanced Head and Neck Cancer Patients on Concomitant Chemoradiotherapy: A Prospective Examination
Authors: List Marcy A. , Siston Amy , Haraf Daniel , Schumm Phil , Kies Merrill , Stenson Kerstin , Vokes Everett E.
Published: February 2017

PURPOSE: To prospectively evaluate performance and quality of life (QOL) in advanced-stage head and neck cancer (HNC) patients on a curative-intent, concomitant-chemoradiotherapy (CT/XRT) (twice-daily radiation, fluorouracil, hydroxyurea, and cisplatin) regimen aimed at improving locoregional control, survival, and QOL.

PATIENTS AND METHODS: Sixty-four patients were assessed before, during, and at 3-month intervals after treatment. Standardized measures of QOL (Functional Assessment of Cancer Therapy–Head and Neck), performance (Performance Status Scale for Head and Neck Cancer Patients and Karnofsky Performance Status Rating Scale), and patient-reported symptoms (McMaster University Head and Neck Radiotherapy Questionnaire) were administered.

RESULTS: Acute treatment toxicities were severe, with declines in virtually all QOL and functional domains. Marked improvement was seen by 12 months; general functional and physical measures returned to baseline levels of good to excellent. Although up to a third of the patients continued to report problems with swallowing, hoarseness, and mouth pain, these difficulties were present in similar magnitudes before treatment. The following symptoms were more frequent at 12 months: dry mouth (58% v 17%), difficulties tasting (32% v 8%), and soft food diet (82% v 42%). Twelve-month diet was not related to pretreatment functioning, disease, treatment, or patient characteristics. Twelve-month QOL was best predicted by pretreatment QOL, with very little relationship to residual side effects or functional impairments. Small numbers of patients in four of the five disease sites precluded examination of outcome by site.

CONCLUSION: These data support the feasibility of intense CT/XRT as primary treatment for advanced HNC. Results confirm acute toxicity but indicate that many of the treatment-related performance and QOL declines resolve by 12 months. The persistent inability to eat a full range of foods warrants further attention and monitoring.
RASand Leukemia: From Basic Mechanisms to Gene-Directed Therapy
Authors: Beaupre Darrin M. , Kurzrock Razelle
Published: February 2017

PURPOSE AND DESIGN: The purpose of this review is to provide an overview of the literature linking Ras signaling pathways and leukemia and to discuss the biologic and potential therapeutic implications of these observations. A search of MEDLINE from 1966 to October 1998 was performed.

RESULTS: A wealth of data has been published on the role of Ras pathways in cancer. To be biologically active, Ras must move from the cytoplasm to the plasma membrane. Importantly, a posttranslational modification—addition of a farnesyl group to the Ras C-terminal cysteine—is a requisite for membrane localization of Ras. Farnesylation of Ras is catalyzed by an enzyme that is designated farnesyltranferase. Recently, several compounds have been developed that can inhibit farnesylation. Preclinical studies indicate that these molecules can suppress transformation and tumor growth in vitro and in animal models, with little toxicity to normal cells.

CONCLUSION: An increasing body of data suggests that disruption of Ras signaling pathways, either directly through mutations or indirectly through other genetic aberrations, is important in the pathogenesis of a wide variety of cancers. Molecules such as farnesyl transferase inhibitors that interfere with the function of Ras may be exploitable in leukemia (as well as in solid tumors) as novel antitumor agents.
American Society of Clinical Oncology 1998 Update of Recommended Breast Cancer Surveillance Guidelines
Authors: Smith Thomas J. , Davidson Nancy E. , Schapira David V. , Grunfeld Eva , Muss Hyman B. , Vogel Victor G. , Somerfield Mark R.
Published: February 2017

OBJECTIVE: To determine an effective, evidence-based, postoperative surveillance strategy for the detection and treatment of recurrent breast cancer. Tests are recommended only if they have an impact on the outcomes specified by American Society of Clinical Oncology (ASCO) for clinical practice guidelines.

POTENTIAL INTERVENTION: All tests described in the literature for postoperative monitoring were considered. In addition, the data were critically evaluated to determine the optimal frequency of monitoring.

OUTCOME: Outcomes of interest include overall and disease-free survival, quality of life, toxicity reduction, and secondarily cost-effectiveness.

EVIDENCE: A search was performed to determine all relevant articles published over the past 20 years on the efficacy of surveillance testing for breast cancer recurrence. These publications comprised both retrospective and prospective studies.

VALUES: Levels of evidence and guideline grades were rated by a standard process. More weight was given to studies that tested a hypothesis directly relating testing to one of the primary outcomes in a randomized design.

BENEFITS, HARMS, AND COSTS: The possible consequences of false-positive and -negative tests were considered in evaluating a preference for one of two tests providing similar information. Cost alone was not a determining factor.

RECOMMENDATIONS: The attached guidelines and text summarize the updated recommendations of the ASCO breast cancer expert panel. Data are sufficient to recommend monthly breast self-examination, annual mammography of the preserved and contralateral breast, and a careful history and physical examination every 3 to 6 months for 3 years, then every 6 to 12 months for 2 years, then annually. Data are not sufficient to recommend routine bone scans, chest radiographs, hematologic blood counts, tumor markers (carcinoembryonic antigen, cancer antigen [CA] 15-5, and CA 27.29), liver ultrasonograms, or computed tomography scans.

VALIDATION: The recommendations of the breast cancer expert panel were evaluated and supported by the ASCO Health Services Research Committee reviewers and the ASCO Board of Directors.

SPONSOR: American Society of Clinical Oncology.
Front-Line Treatment of Advanced Non–Small-Cell Lung Cancer With Docetaxel and Gemcitabine: A Multicenter Phase II Trial
Authors: Georgoulias Vassilis , Kouroussis Charalambos , Androulakis Nikos , Kakolyris Stelios , Dimopoulos Meletios-Athanasios , Papadakis Emmanuel , Bouros Dimosthenis , Apostolopoulou Fotini , Papadimitriou Christos , Agelidou Athina , Hatzakis Kostas , Kalbakis Kostas , Kotsakis Athanasios , Vardakis Nikos , Vlachonicolis John
Published: February 2017

PURPOSE: To evaluate the tolerance and efficacy of the combination of docetaxel and gemcitabine in patients with advanced non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Fifty-one chemotherapy-naive patients with NSCLC were treated with gemcitabine 900 mg/m2 intravenously on days 1 and 8 and docetaxel 100 mg/m2 intravenously on day 8 with granulocyte colony-stimulating factor (150 μg/m2, subcutaneously) support from day 9 to day 15. Treatment was repeated every 3 weeks.

RESULTS: The patients' median age was 64 years. The World Health Organization performance status was 0 to 1 in 39 patients and 2 in 12 patients. Fifteen patients (29%) had stage IIIB disease, and 36 (71%) had stage IV; histology was mainly squamous cell carcinoma (59%). A partial response was achieved in 19 patients (37.5%; 95% confidence interval, 24% to 50%); stable disease and progressive disease were each observed in 16 patients (31.4%). The median duration of response and the time to tumor progression were 5 and 6 months, respectively. The median survival was 13 months, and the actuarial 1-year survival was 50.7%. Grade 4 anemia and thrombocytopenia were rare (2%). Four patients (8%) developed grade 3 or 4 neutropenia, and all were complicated with fever; there was no treatment-related death. Grade 3 or 4 diarrhea occurred in three patients (6%), grade 2 or 3 neurotoxicity in four patients (8%), grade 2 or 3 asthenia in 10 patients (20%), and grade 2 or 3 edema in 10 patients (20%).

CONCLUSION: The combination of docetaxel/gemcitabine is well tolerated, can be used for outpatients, and is active for the treatment of advanced NSCLC. This treatment merits further comparison with other cisplatin- or carboplatin-based combinations.
Prognostic Significance of Extent of Disease in Bone in Patients With Androgen-Independent Prostate Cancer
Authors: Sabbatini P. , Larson S. M. , Kremer A. , Zhang Z.-F. , Sun M. , Yeung H. , Imbriaco M. , Horak I. , Conolly M. , Ding C. , Ouyang P. , Kelly W. K. , Scher H. I.
Published: February 2017

PURPOSE: To evaluate the prognostic significance of a bone scan index (BSI) based on the weighted proportion of tumor involvement in individual bones, in relation to other factors and to survival in patients with androgen-independent prostate cancer.

PATIENTS AND METHODS: Baseline radionuclide bone scans were reviewed in 191 assessable patients with androgen-independent disease who were enrolled onto an open, randomized trial of liarozole versus prednisone. The extent of skeletal involvement was assessed by scoring each scan using the BSI and independently according to the number of metastatic lesions. The relationship of the scored bone involvement to other known prognostic factors was explored in single- and multiple-variable analyses.

RESULTS: In single-variable analyses, the pretreatment factors found to be associated with survival were age (P = .0446), performance status (P = .0005), baseline prostate-specific antigen (P = .0001), hemoglobin (P = .0001), alkaline phosphatase (P = .0002), AST (P = .0021), lactate dehydrogenase (P = .0001), and treatment (P = .0098). The extent of osseous disease was significant using both the BSI (P = .0001) and the number of lesions present (P = .0001). In multiple-variable proportional hazards analyses, only BSI, age, hemoglobin, lactate dehydrogenase, and treatment arm were associated with survival. When the patient population was divided into three equal groups, with BSI values of < 1.4%, 1.4% to 5.1%, and > 5.1%, median survivals of 18.3, 15.5, and 8.1 months, respectively, were observed (P = .0079).

CONCLUSION: The BSI quantifies the extent of skeletal involvement by tumor. It allows the identification of patients with distinct prognoses for stratification in clinical trials. Further study is needed to assess the utility of serial BSI determinations in monitoring treatment effects. The BSI may be particularly useful in the evaluation of agents for which prostate-specific antigen changes do not reflect clinical outcomes accurately.
Correlation Between Uracil and Dihydrouracil Plasma Ratio, Fluorouracil (5-FU) Pharmacokinetic Parameters, and Tolerance in Patients With Advanced Colorectal Cancer: A Potential Interest for Predicting 5-FU Toxicity and Determining Optimal 5-FU Dosage
Authors: Gamelin E. , Boisdron-Celle M. , Guérin-Meyer V. , Delva R. , Lortholary A. , Genevieve F. , Larra F. , Ifrah N. , Robert J.
Published: February 2017

PURPOSE: Patients with genetic fluorouracil (5-FU) catabolic deficiencies are at high risk for severe toxicity. To predict 5-FU catabolic deficiencies and toxic side effects, we conducted a prospective study of patients treated for advanced colorectal cancer by high-dose 5-FU.

PATIENTS AND METHODS: Eighty-one patients were treated with weekly infusions of 5-FU and folinic acid. The initial 5-FU dose of 1,300 mg/m2 was individually adjusted according to a dose-adjustment chart. Plasma concentrations of uracil (U) and its dihydrogenated metabolite, dihydrouracil (UH2), were measured before treatment, and the ratio of UH2 to U was calculated. Pharmacokinetic and pharmacodynamic studies were conducted to look for a relationship between the ratio of UH2 to U and 5-FU metabolic outcome and tolerance.

RESULTS: The UH2-U ratios were normally distributed (mean value, 2.82; range, 0.35 to 7.13) and were highly correlated to (1) 5-FU plasma levels after the first course of treatment (r = .58), (2) 5-FU plasma clearance (r = .639), and (3) individual optimal therapeutic 5-FU dose (r = .65). Toxic side effects were observed only in patients with initial UH2-U ratios of less than 1.8. No adverse effects were noted in patients with UH2-U ratios of greater than 2.25.

CONCLUSION: The UH2-U ratio, easily determined before treatment, could help to identify patients with metabolic deficiency and, therefore, a risk of toxicity.