bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum S-100B Protein as a Prognostic Marker in Malignant Cutaneous Melanoma
Authors: Mårtenson E. Djureen , Hansson L.O. , Nilsson B. , von Schoultz E. , Brahme E. Månsson , Ringborg U. , Hansson J.
Published: February 2017

PURPOSE: To evaluate whether S-100B protein in serum is an independent prognostic marker in malignant melanoma.

MATERIALS AND METHODS: S-100B protein in serum was analyzed in 1,007 consecutive patients with histologically verified cutaneous malignant melanoma. At the time of blood sampling, 876 patients were in clinical stage I, 35 were in stage II, and 96 were in stage III. The serum concentrations of S-100B protein were measured by a luminescence immunoassay (LIA).

RESULTS: The mean serum concentration of S-100B protein was significantly related to clinical stage, with the lowest level in stage I and the highest in stage III. In a multivariate analysis, S-100B protein levels in serum showed the strongest prognostic impact of the factors analyzed with respect to disease-specific survival in clinical stages II to III, followed by clinical stage. Serum S-100B protein was not a significant independent prognostic factor in clinical stage I, where tumor thickness showed the strongest relation to melanoma-specific survival, followed by ulceration and satellites.

CONCLUSION: This investigation contains the largest material of patients so far analyzed with the new LIA assay of S-100B protein in serum and confirms that S-100B protein in serum is correlated with clinical stage and is an independent prognostic marker in clinical stages II and III.
Effect of Pregnancy on Overall Survival After the Diagnosis of Early-Stage Breast Cancer
Authors: Gelber Shari , Coates Alan S. , Goldhirsch Aron , Castiglione-Gertsch Monica , Marini Gianluigi , Lindtner Jurij , Edelmann David Z. , Gudgeon Anne , Harvey Vernon , Gelber Richard D.
Published: February 2017

PURPOSE: To evaluate the impact of subsequent pregnancy on the prognosis of patients with early breast cancer.

PATIENTS AND METHODS: One hundred eight patients who became pregnant after diagnosis of early-stage breast cancer were identified in institutions participating in International Breast Cancer Study Group (IBCSG) studies. Fourteen had relapse of breast cancer before their first subsequent pregnancy. The remaining 94 patients (including eight who relapsed during pregnancy) formed the study group reported here. A comparison group of 188 was obtained by randomly selecting two patients, matched for nodal status, tumor size, age, and year of diagnosis from the IBCSG database, who were free of relapse for at least as long as the time between breast cancer diagnosis and completion of pregnancy for each pregnant patient. Survival comparison used Cox proportional hazards regression models.

RESULTS: Overall 5- and 10-year survival percentages (± SE) measured from the diagnosis of early-stage breast cancer among the 94 study group patients were 92% ± 3% and 86% ± 4%, respectively. For the matched comparison group survival was 85% ± 3% at 5 years and 74% ± 4% at 10 years (risk ratio, 0.44; 95% confidence interval, 0.21 to 0.96; P = .04).

CONCLUSION: Subsequent pregnancy does not adversely affect the prognosis of early-stage breast cancer. The superior survival seen in this and other controlled series may merely reflect a healthy patient selection bias, but is also consistent with an antitumor effect of the pregnancy.
Differences in Risk Factors for Local and Distant Recurrence After Breast-Conserving Therapy or Mastectomy for Stage I and II Breast Cancer: Pooled Results of Two Large European Randomized Trials
Authors: Voogd Adri C. , Nielsen Maja , Peterse Johannes L. , Blichert-Toft Mogens , Bartelink Harry , Overgaard Marie , van Tienhoven Geertjan , Andersen Knud West , Sylvester Richard J. , van Dongen Joop A. ,   for the Danish Breast Cancer Cooperative Group and the Breast Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer
Published: February 2017

PURPOSE: Risk factors for local and distant recurrence after breast-conserving therapy and mastectomy were compared to define guidelines for the decision making between both treatments.

PATIENTS AND METHODS: The data of two randomized clinical trials for stage I and II breast cancer patients were pooled. The total number of patients in the study was 1,772, of whom 879 underwent breast conservation, and 893, modified radical mastectomy. Representative slides of the primary tumor were available for histopathologic review in 1,610 cases (91%).

RESULTS: There were 79 patients with local recurrence after breast-conservation and 80 after mastectomy, the 10-year rates being 10% (95% confidence interval [CI], 8% to 13%) and 9% (95% CI, 7% to 12%), respectively. Age no more than 35 years (compared with age >60: hazard ratio [HR], 9.24; 95% CI, 3.74 to 22.81) and an extensive intraductal component (HR, 2.52; 95% CI, 1.26 to 5.00) were significantly associated with an increased risk of local recurrence after breast-conserving therapy. Vascular invasion was predictive of the risk of local recurrence, irrespective of the type of primary treatment (P < .01). Tumor size, nodal status, high histologic grade, and vascular invasion were all highly significant predictors of distant disease after breast-conserving therapy and mastectomy (P < .01). Age no more than 35 years and microscopic involvement of the excision margin were additional independent predictors of distant disease after breast-conserving therapy (P < .01).

CONCLUSION: Age no more than 35 years and the presence of an extensive intraductal component are associated with an increased risk of local recurrence after breast-conserving therapy. Vascular invasion causes a higher risk of local recurrence after mastectomy as well as after breast-conserving therapy and should therefore not be used for deciding between the two treatments.
Multimodal Treatment of Malignant Sacrococcygeal Germ Cell Tumors: A Prospective Analysis of 66 Patients of the German Cooperative Protocols MAKEI 83/86 and 89
Authors: Göbel U. , Schneider D. T. , Calaminus G. , Jürgens H. , Spaar H. J. , Sternschulte W. , Waag K. , Harms D.
Published: February 2017

PURPOSE: To evaluate a multimodal approach including surgery and cisplatinum chemotherapy for treatment of children with malignant sacrococcygeal germ cell tumors (GCT) and to compare adjuvant and neoadjuvant strategies in advanced tumors.

PATIENTS AND METHODS: Between 1983 and 1995, 71 patients with malignant sacrococcygeal GCT were prospectively enrolled onto the German protocols for nontesticular GCT Maligne Keimzelltumoren 83/86 and 89. Five patients who received no chemotherapy (n = 2) or nonplatinum chemotherapy (n = 2) or who did not undergo tumor resection (n = 1) were excluded from this analysis. Among the 66 patients analyzed were 14 boys and 52 girls. The median age was 17.4 months (range, 7 months to 119 months). Median follow-up was 79 months (range, 4 months to 145 months).

RESULTS: Fifty-two patients presented with locally advanced stage T2 tumors, and 30 patients had distant metastases at diagnosis. Patients received a median of eight cycles (range, four to nine cycles) of cisplatinum-based chemotherapy. Thirty-five patients underwent tumor resection at diagnosis and received adjuvant cisplatinum-based chemotherapy (group A). Thirty-one patients received up-front chemotherapy followed by delayed tumor resection (group B). Group B included more metastatic tumors than group A (group B, 19 of 31 patients; group A, 11 of 35 patients, P = .01). Preoperative chemotherapy facilitated complete tumor resections (group B, 20 of 31 patients; group A, five of 35 patients, P < .001) and avoided second-look surgery. Metastases at diagnosis and completeness of the first attempt of tumor resection were significant prognostic predictors; however, metastases were not predictive for patients treated with up-front chemotherapy. At 5 years follow-up, event-free survival was 0.76 ± 0.05 (50 of 66 patients), and overall survival was 0.81 ± 0.05 (54 of 66 patients). Four patients died as a result of therapy-related complications, and eight patients died of their tumors. Patients with locally advanced and metastatic tumors (T2b M1) fared better with neoadjuvant treatment [overall survival: 0.83 ± 0.09 (16 of 19 patients) versus 0.45 ± 0.15 (five of 11 patients), P = .01].

CONCLUSION: Even locally advanced and metastatic sacrococcygeal GCT can be successfully treated with up-front cisplatinum-based chemotherapy followed by delayed but complete tumor resection.
Treatment of Recurrent Malignant Sacrococcygeal Germ Cell Tumors: Analysis of 22 Patients Registered in the German Protocols MAKEI 83/86, 89, and 96
Authors: Schneider D. T. , Wessalowski R. , Calaminus G. , Pape H. , Bamberg M. , Engert J. , Waag K. , Gadner H. , Göbel U.
Published: February 2017

PURPOSE: To evaluate therapeutic options for recurrent malignant sacrococcygeal germ cell tumors (GCT) following three-agent, cisplatinum-based, first-line chemotherapy and tumor resection.

PATIENTS AND METHODS: Twenty-two patients were evaluated in 22 first-, 14 second-, five third-, and two fourth-relapse situations. One patient, who relapsed with pure teratoma, was excluded from the analysis of adjuvant treatment.

RESULTS: Seventeen patients presented with an isolated local recurrence, two patients showed a distant relapse, and three patients suffered from a combined local and distant recurrence. Twelve patients achieved complete remission (CR) after surgery (n = 12) and adjuvant platinum chemotherapy (n = 10). Seven of these patients remain in continuous CR, and five patients relapsed. All patients who achieved only a partial remission developed a second relapse. Three of 14 patients could be cured after a second (or further) relapse. Altogether, 10 patients survived disease free, and 12 patients died as a result of tumor progression (n = 11) or therapy-related complications (n = 1). The completeness of salvage surgery and clinical remission status after first salvage treatment were the most important prognostic parameters. In addition, patients in first or second relapse with locally advanced or poorly responding tumors benefited from preoperative chemotherapy in combination with regional hyperthermia (RHT). In some patients after microscopically incomplete resection, irradiation at doses > 45 Gy contributed to a favorable outcome.

CONCLUSION: The complete resection of the local recurrence represents the cornerstone of salvage treatment. Preoperative platinum-based chemotherapy, combined with RHT in some patients, facilitates complete tumor resection. Radiotherapy should be reserved for those patients with microscopically incomplete tumor resection. As the chance of cure decreases with further relapses, it is important to establish a stringent therapeutic strategy to avoid significant treatment delays and, most importantly, insufficient local therapy.
Complete Remission of Primary High-Grade B-Cell Gastric Lymphoma After Cure of Helicobacter pylori Infection
Authors: Morgner Andrea , Miehlke Stephan , Fischbach Wolfgang , Schmitt Wolfgang , Müller-Hermelink Hans , Greiner Axel , Thiede Christian , Schetelig Johannes , Neubauer Andreas , Stolte Manfred , Ehninger Gerhard , Bayerdörffer Ekkehard
Published: February 2017

PURPOSE: Treatment of low-grade gastric mucosa-associated lymphoid tissue lymphoma by eradication of Helicobacter pylori is reported to result in complete lymphoma remission in approximately 75% of cases. The effect that cure of the infection has on the course of a primary high-grade gastric lymphoma is largely uncertain. The aim of this study was to report the effect of cure of H pylori infection exerted in patients with high-grade B-cell gastric lymphoma.

PATIENTS AND METHODS: Eight patients (4 males and 4 females; age range, 26 to 85 years) with H pylori infection and high-grade lymphoma received eradication therapy before planned treatment. The effect of H pylori eradication on the course of high-grade lymphoma was assessed by analysis of surgical specimens (n = 2) or endoscopic biopsies (n = 6).

RESULTS: H pylori eradication was successful in all patients and led to complete remission of the lymphoma in seven patients. One patient has experienced partial remission. Two patients were referred to surgery, one of whom (stage II1E) had lymph node involvement, and the histologic work-up of the resected stomach revealed residual infiltrates of a low-grade lymphoma, which prompted consolidation chemotherapy. In one patient (initially stage I1E), abdominal lymphoma developed 6 months after eradication therapy, which regressed completely after chemotherapy. In four patients, no further treatment was given. Six patients continue in complete remission (range, 6 to 66 months).

CONCLUSION: Primary high-grade B-cell gastric lymphoma in stages IE through IIE1 associated with H pylori may regress completely after successful cure of the infection. Prospective trials are needed to investigate this treatment in larger numbers of patients.
Comparison of Cytogenetic and Molecular Genetic Detection of t(8;21) and inv(16) in a Prospective Series of Adults With De Novo Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study
Authors: Mrózek Krzysztof , Prior Thomas W. , Edwards Colin , Marcucci Guido , Carroll Andrew J. , Snyder Pamela J. , Koduru Prasad R.K. , Theil Karl S. , Pettenati Mark J. , Archer Kellie J. , Caligiuri Michael A. , Vardiman James W. , Kolitz Jonathan E. , Larson Richard A. , Bloomfield Clara D.
Published: February 2017

PURPOSE: To prospectively compare cytogenetics and reverse transcriptase–polymerase chain reaction (RT-PCR) for detection of t(8;21)(q22;q22) and inv(16)(p13q22)/t(16;16)(p13;q22), aberrations characteristic of core-binding factor (CBF) acute myeloid leukemia (AML), in 284 adults newly diagnosed with primary AML.

PATIENTS AND METHODS: Cytogenetic analyses were performed at local laboratories, with results reviewed centrally. RT-PCR for AML1/ETO and CBFβ/MYH11 was performed centrally.

RESULTS: CBF AML was ultimately identified in 48 patients: 21 had t(8;21) or its variant and AML1/ETO, and 27 had inv(16)/t(16;16), CBFβ/MYH11, or both. Initial cytogenetic and RT-PCR analyses correctly classified 95.7% and 96.1% of patients, respectively (P = .83). Initial cytogenetic results were considered to be false-negative in three AML1/ETO-positive patients with unique variants of t(8;21), and in three CBFβ/MYH11-positive patients with, respectively, an isolated +22; del(16)(q22),+22; and a normal karyotype. The latter three patients were later confirmed to have inv(16)/t(16;16) cytogenetically. Only one of 124 patients reported initially as cytogenetically normal was ultimately RT-PCR–positive. There was no false-positive cytogenetic result. Initial RT-PCR was falsely negative in two patients with inv(16) and falsely positive for AML1/ETO in two and for CBFβ/MYH11 in another two patients. Two patients with del(16)(q22) were found to be CBFβ/MYH11-negative. M4Eo marrow morphology was a good predictor of the presence of inv(16)/t(16;16).

CONCLUSION: Patients with t(8;21) or inv(16) can be successfully identified in prospective multi-institutional clinical trials. Both cytogenetics and RT-PCR detect most such patients, although each method has limitations. RT-PCR is required when the cytogenetic study fails; it is also required to determine whether patients with suspected variants of t(8;21), del(16)(q22), or +22 represent CBF AML. RT-PCR should not replace cytogenetics and should not be used as the only diagnostic test for detection of CBF AML because of the possibility of obtaining false-positive or false-negative results.
Results From a Randomized Phase III Study Comparing Combined Treatment With Histamine Dihydrochloride Plus Interleukin-2 Versus Interleukin-2 Alone in Patients With Metastatic Melanoma
Authors: Agarwala Sanjiv S. , Glaspy John , O’Day Steven J. , Mitchell Malcolm , Gutheil John , Whitman Eric , Gonzalez Rene , Hersh Evan , Feun Lynn , Belt Robert , Meyskens Frank , Hellstrand Kristoffer , Wood Diana , Kirkwood John M. , Gehlsen Kurt R. , Naredi Peter
Published: February 2017

PURPOSE: Reactive oxidative species (ROS) produced by phagocytic cells have been ascribed a role in the localized suppression of lymphocyte function within malignant tumors. Histamine has been shown to inhibit ROS formation and possibly synergize with cytokines to permit activation of natural killer cells and T cells. This study was designed to determine whether the addition of histamine to a subcutaneous (SC) regimen of interleukin-2 (IL-2) would improve the survival of metastatic melanoma patients.

PATIENTS AND METHODS: A phase III, multicenter, randomized, parallel group study comparing IL-2 plus histamine with IL-2 alone was conducted in 305 patients with advanced metastatic melanoma. Patients were randomized to IL-2 (9 MIU/m2bid SC on days 1 to 2 of weeks 1 and 3, and 2 MIU/m2bid SC on days 1 to 5 of weeks 2 and 4) with or without histamine (1.0 mg bid SC days 1 to 5, weeks 1 to 4). The primary end point, survival, was prospectively applied to all randomized patients (intent-to-treat–overall population, ITT-OA) and all patients having liver metastases at randomization (ITT-LM population). Secondary end points included safety of the combined treatment, time to disease progression, and response rate.

RESULTS: Combined treatment with histamine plus IL-2 significantly improved overall survival in the ITT-LM population (P = .004) and showed a trend for improved survival in the ITT population (P = .125). Grade 3 and 4 adverse events were comparable in the two arms.

CONCLUSION: Use of histamine as an adjunct to IL-2 is safe, well tolerated, and associated with a statistically significant prolongation of survival compared with IL-2 alone in metastatic melanoma patients with liver involvement. Further trials to confirm and understand the role of histamine in this combination treatment are underway.
Phase I Study of the Intravenous Administration of AttenuatedSalmonella typhimuriumto Patients With Metastatic Melanoma
Authors: Toso John F. , Gill Vee J. , Hwu Patrick , Marincola Francesco M. , Restifo Nicholas P. , Schwartzentruber Douglas J. , Sherry Richard M. , Topalian Suzanne L. , Yang James C. , Stock Frida , Freezer Linda J. , Morton Kathleen E. , Seipp Claudia , Haworth Leah , Mavroukakis Sharon , White Donald , MacDonald Susan , Mao John , Sznol Mario , Rosenberg Steven A.
Published: February 2017

PURPOSE: A strain of Salmonella typhimurium (VNP20009), attenuated by chromosomal deletion of the purI and msbB genes, was found to target to tumor and inhibit tumor growth in mice. These findings led to the present phase I study of the intravenous infusion of VNP20009 to patients with metastatic cancer.

PATIENTS AND METHODS: In cohorts consisting of three to six patients, 24 patients with metastatic melanoma and one patient with metastatic renal cell carcinoma received 30-minute intravenous bolus infusions containing 106to 109cfu/m2of VNP20009. Patients were evaluated for dose-related toxicities, selective replication within tumors, and antitumor effects.

RESULTS: The maximum-tolerated dose was 3 × 108cfu/m2. Dose-limiting toxicity was observed in patients receiving 1 × 109cfu/m2, which included thrombocytopenia, anemia, persistent bacteremia, hyperbilirubinemia, diarrhea, vomiting, nausea, elevated alkaline phosphatase, and hypophosphatemia. VNP20009 induced a dose-related increase in the circulation of proinflammatory cytokines, such as interleukin (IL)-1β, tumor necrosis factor alpha, IL-6, and IL-12. Focal tumor colonization was observed in two patients receiving 1 × 109cfu/m2and in one patient receiving 3 × 108cfu/m2. None of the patients experienced objective tumor regression, including those patients with colonized tumors.

CONCLUSION: The VNP20009 strain of Salmonella typhimurium can be safely administered to patients, and at the highest tolerated dose, some tumor colonization was observed. No antitumor effects were seen, and additional studies are required to reduce dose-related toxicity and improve tumor localization.
Brief Chemotherapy and Involved-Region Irradiation for Limited-Stage Diffuse Large-Cell Lymphoma: An 18-Year Experience From the British Columbia Cancer Agency
Authors: Shenkier Tamara N. , Voss Nicholas , Fairey Randall , Gascoyne Randy D. , Hoskins Paul , Klasa Richard , Klimo Paul , O’Reilly Susan E. , Sutcliffe Simon , Connors Joseph M.
Published: February 2017

PURPOSE: To evaluate clinical outcome of patients with limited-stage diffuse large-cell lymphoma (DLCL) treated with three cycles of chemotherapy followed by involved-region irradiation (IRRT).

PATIENTS AND METHODS: Adults with limited-stage DLCL were treated with brief doxorubicin-containing chemotherapy regimens between 1980 and 1998. IRRT was administered 3 to 4 weeks after the third chemotherapy treatment in a dose equivalent to 30 Gy in 10 fractions.

RESULTS: Three hundred and eight patients (median age, 64 years) were included, and 299 experienced complete remission. After a median follow-up of 86 months, 64 patients developed progressive disease, and 104 patients died (43 from lymphoma, three from toxicity, and 58 from other causes). Actuarial overall and progression-free survival (PFS) rates were, respectively, 80% and 81% at 5 years and 63% and 74% at 10 years. For subgroups identified using the Miller modification of the International Prognostic Index (IPI), the overall survival rates at 5 and 10 years were, respectively, 97% and 89% (no factors), 77% and 56% (one or two factors), and 58% and 48% (three or four factors), and the 5-year and 10-year PFS rates were, respectively, 94% and 89% (no factors), 79% and 73% (one or two factors), and 60% and 50% (three or four factors). Men with testicular presentation, had a definitely inferior outcome.

CONCLUSION: Long-term outcome with three cycles of doxorubicin-based chemotherapy and IRRT confirms that this is a successful approach for the majority of patients with limited-stage DLCL. Subgroups with worse prognoses can be identified, and these patients should be offered alternative treatment approaches.
Campath-1H Treatment of T-Cell Prolymphocytic Leukemia in Patients for Whom at Least One Prior Chemotherapy Regimen Has Failed
Authors: Keating M. J. , Cazin B. , Coutré S. , Birhiray R. , Kovacsovics T. , Langer W. , Leber B. , Maughan T. , Rai K. , Tjønnfjord G. , Bekradda M. , Itzhaki M. , Hérait P.
Published: February 2017

PURPOSE: We conducted a retrospective analysis to evaluate the safety and efficacy of Campath-1H, an anti-CD52 humanized monoclonal antibody, in previously treated T-prolymphocytic leukemia (T-PLL) patients in a compassionate-use program.

PATIENTS AND METHODS: Seventy-six patients with T-PLL (including four chemotherapy-naive patients) received 3, 10, and 30 mg of Campath-1H on sequential days, followed by 30 mg three times weekly, as 2-hour intravenous infusions, for 4 to 12 weeks.

RESULTS: Median patient age was 60 years (range, 35 to 84). Spleen liver, lymph node, and skin involvement were present in 64%, 40%, 54%, and 18% of patients, respectively. All tested patients had CD2, CD7, CD4, and/or CD8 positivity, whereas CD5 and CD3 were positive in 98% and 96% of tested patients, respectively. The objective response rate was 51% (95% confidence interval [CI], 40% to 63%), with a 39.5% complete response (CR) rate (95% CI, 28% to 51%). The median duration of CR was 8.7 months (range, 0.13+ to 44.4), and median time to progression was 4.5 months (range, 0.1 to 45.4) compared with 2.3 months (range, 0.2 to 28.1) after first-line chemotherapy. The median overall survival was 7.5 months (14.8 months for CR patients). The most common Campath-1H–related adverse events were acute reactions during or immediately after infusions. Fifteen infectious episodes occurred during treatment in 10 patients (13%), leading to treatment discontinuation in three. Eight patients experienced possibly related, late-onset infections. Severe thrombocytopenia and/or neutropenia occurred in six patients (8%), leading to treatment discontinuation in four. Two treatment-related deaths occurred.

CONCLUSION: Campath-1H is an active drug in T-PLL patients for whom first-line therapy has failed. It has a favorable risk/benefit ratio and should be prospectively investigated in chemotherapy-naive patients.
Phase II Trial of a Single Weekly Intravenous Dose of Ranpirnase in Patients With Unresectable Malignant Mesothelioma
Authors: Mikulski Stanislaw M. , Costanzi John J. , Vogelzang Nicholas J. , McCachren Spence , Taub Robert N. , Chun Hoo , Mittelman Abraham , Panella Timothy , Puccio Carmelo , Fine Robert , Shogen Kuslima
Published: February 2017

PURPOSE: A multicenter phase II trial of ranpirnase (Onconase; Alfacell Corp, Bloomfield, NJ) as a single agent was conducted to further assess the safety and clinical efficacy of this novel antitumor ribonuclease. Patients with unresectable and histologically confirmed malignant mesothelioma (MM) were eligible.

PATIENTS AND METHODS: One hundred five patients with Eastern Cooperative Oncology Group performance status 0 to 2 were enrolled onto the study. Thirty-seven percent of patients had not responded to prior chemotherapy. The primary end point of the study was survival. Tumor responses and time to progression were also assessed. The Cancer and Leukemia Group B (CALGB) prognostic group criteria were used to define a treatment target group (TTG). Both the intent-to-treat (ITT) and the TTG populations were analyzed for survival.

RESULTS: Median survival times of 6 months for the ITT and 8.3 months for the TTG populations were observed. The 1- and 2-year survival rates were 34.3% and 21.6% for ITT, respectively, and 42% and 26.8% for TTG, respectively. Among the 81 patients assessable for tumor response, four had partial responses, two had minor regressions, and thirty-five experienced stabilization of previously progressive disease. Patients with responses and stable disease demonstrated markedly prolonged survival. Ranpirnase was well tolerated in the majority of patients, and there were no drug-related deaths.

CONCLUSION: Ranpirnase demonstrated activity and a tolerable toxicity profile in patients with unresectable MM. The prognostic value of the CALGB groups was confirmed.
Increased Risk of Ischemic Stroke After Radiotherapy on the Neck in Patients Younger Than 60 Years
Authors: Dorresteijn Lucille D.A. , Kappelle Arnoud C. , Boogerd Willem , Klokman Willem J. , Balm Alfons J.M. , Keus Ronald B. , van Leeuwen Flora E. , Bartelink Harry
Published: February 2017

PURPOSE: To estimate the risk of ischemic stroke in patients irradiated for head and neck tumors.

PATIENTS AND METHODS: The incidence of ischemic stroke was determined in 367 patients with head and neck tumors (162 larynx carcinomas, 114 pleomorphic adenomas, and 91 parotid carcinomas) who had been treated with local radiotherapy (RT) at an age younger than 60 years. Relative risk (RR) of ischemic stroke was determined by comparison with population rates from a stroke-incidence register, adjusted for sex and age. Other risk factors for stroke (hypertension, smoking, hypercholesterolemia, diabetes mellitus [DM]) were registered. The median follow-up time after RT was 7.7 years (3,011 person-years of follow-up).

RESULTS: Fourteen cases of stroke occurred (expected, 2.5; RR, 5.6; 95% confidence interval [CI], 3.1 to 9.4): eight in patients with laryngeal carcinoma (expected ,1.56; RR, 5.1; 95% CI, 2.2 to 10.1), four in pleomorphic adenoma patients (expected, 0.71; RR, 5.7; 95% CI, 1.5 to 14.5), and two in parotid carcinoma patients (expected, 0.24; RR, 8.5, 95% CI, 1.0 to 30.6). Five of six strokes in patients irradiated for a parotid tumor occurred at the ipsilateral side. Analysis of other risk factors for cerebrovascular disease showed hypertension and DM to cause an increase of the RR after RT. After more than 10 years’ follow-up, the RR was 10.1 (95% CI, 4.4 to 20.0). The 15-year cumulative risk of stroke after RT on the neck was 12.0% (95% CI, 6.5% to 21.4%).

CONCLUSION: This is the first study to demonstrate an increased risk of stroke after RT on the neck. During medical follow-up, preventive measures should be taken to reduce the impact of the risk factors for cerebrovascular disease, to decrease stroke in these patients.
Safety and Efficacy of Alteplase for Restoring Function in Occluded Central Venous Catheters: Results of the Cardiovascular Thrombolytic to Open Occluded Lines Trial
Authors: Deitcher Steven R. , Fesen Mark R. , Kiproff Paul M. , Hill Patricia A. , Li Xin , McCluskey Edward R. , Semba Charles P.
Published: February 2017

PURPOSE: To evaluate the safety and efficacy of alteplase (TPA) for restoring function to occluded central venous catheters (CVCs).

PATIENTS AND METHODS: The study design was a phase III, open-label, single-arm multicenter trial. Subjects with occluded, nondialysis CVCs were enrolled. All subjects received a 2-mg dose of TPA within the dysfunctional catheter lumen that was allowed to dwell for 30 to 120 minutes. Functionality was tested at 30 and 120 minutes. If the CVC remained obstructed at 120 minutes, a second 2-mg TPA dose was allowed to dwell for 30 to 120 minutes. The primary safety end point was the rate of intracranial hemorrhage (ICH) within 5 days of treatment, and serious adverse events were recorded up to 30 days.

RESULTS: Nine hundred ninety-five patients received treatment (female, 562; male, 433; mean age, 50.7 years; range, 2 to 91 years). CVCs treated were as follows: single (26%), double (39%), or triple (6%) lumen catheters or ports (29%). The primary end point was 0% ICH within 5 days. There were no cases of death, major bleeding episodes, or embolic events attributable to treatment. Flow was successfully restored in 52% and 78% of CVCs at 30 and 120 minutes after one dose, and 84% and 87% at 30 and 120 minutes after a second dose, respectively. Restoration of flow was 86%, 93%, 90%, and 79%, for single, double, and triple lumen catheters and ports, respectively. Estimated 30-day catheter patency was 74%.

CONCLUSION: A regimen of up to two 2-mg doses of TPA is safe and effective for the restoration of flow to occluded central venous catheters.
Impact of Body-Size Measures on Irinotecan Clearance: Alternative Dosing Recommendations
Authors: Mathijssen Ron H.J. , Verweij Jaap , de Jonge Maja J.A. , Nooter Kees , Stoter Gerrit , Sparreboom Alex
Published: February 2017

PURPOSE: To evaluate relationships between various body-size measures and irinotecan (CPT-11) clearance and metabolism in cancer patients, and to provide future dosing recommendations for this agent.

PATIENTS AND METHODS: Pharmacokinetic data were obtained from 82 adult patients (50 men, 32 women; median age, 54 years) receiving CPT-11 as a 90-minute intravenous infusion (dose range, 175 to 350 mg/m2). In each patient, plasma samples were collected at timed intervals in the first administration of a 3-week schedule, and CPT-11 and its metabolite, SN-38, were measured by a liquid chromatographic assay.

RESULTS: The mean (± SD) CPT-11 clearance was 33.6 ± 10.8 L/h, with an interindividual variability (IIV) of 32.1%. When clearance was adjusted for body-surface area (BSA), the IIV was similar (34.0%). In addition, in a multiple linear regression analysis, none of the studied measures (BSA, lean body mass, [adjusted] ideal body weight, and body mass index) was a significant covariate (P > .13; r2 < .014) in our population. Similarly, BSA did not significantly contribute to variability in the relative extent of conversion to SN-38 (P = .26).

CONCLUSION: BSA is not a predictor of CPT-11 clearance or SN-38 pharmacokinetics and does not contribute to reducing kinetic variability. These findings provide a rationale for the conduct of a comparative phase III study between BSA-based dosing and flat or fixed dosing of CPT-11.
Temozolomide in Combination With Docetaxel in Patients With Advanced Melanoma: A Phase II Study of the Hellenic Cooperative Oncology Group
Authors: Bafaloukos D. , Gogas H. , Georgoulias V. , Briassoulis E. , Fountzilas G. , Samantas E. , Kalofonos Ch. , Skarlos D. , Karabelis A. , Kosmidis P.
Published: February 2017

PURPOSE: Temozolomide is a novel oral alkylating agent that is effective against melanoma. Moreover, temozolomide readily crosses the blood-brain barrier and may consequently be effective in patients with brain metastases. This phase II study was performed to assess the efficacy and safety of the combination regimen of temozolomide and docetaxel in patients with advanced metastatic melanoma.

PATIENTS AND METHODS: Sixty-five patients with metastatic melanoma were enrolled. Treatment consisted of intravenous docetaxel (80 mg/m2) on day 1 and oral temozolomide (150 mg/m2) on days 1 to 5, every 4 weeks, for a maximum of six cycles.

RESULTS: Sixty-two patients were eligible for the efficacy and safety analysis. Seventeen patients (27%) achieved an objective response, including five complete (8%) and 12 partial responses (19%). Median response duration was 9.5 months. Among responders, median time to progression (TTP) was 11.2 months and median overall survival (OS) was 16 months. For all treated patients, the median TTP was 4 months and median OS was 11 months. Three (38%) of eight patients who presented with brain metastases had a partial response for 5, 6, and 12 months. Of 52 patients who did not have brain involvement at presentation, only four (8%) developed brain metastases at a median follow-up of 14 months. Myelosuppression was the primary toxicity.

CONCLUSION: The combination of temozolomide and docetaxel was effective and well tolerated as first-line treatment for patients with advanced metastatic melanoma and demonstrated encouraging antitumor activity against brain metastases.
Rapidly Alternating COPP/ABV/IMEP Is Not Superior to Conventional Alternating COPP/ABVD in Combination With Extended-Field Radiotherapy in Intermediate-Stage Hodgkin’s Lymphoma: Final Results of the German Hodgkin’s Lymphoma Study Group Trial HD5
Authors: Sieber Markus , Tesch Hans , Pfistner Beate , Rueffer Ulrich , Lathan Bernd , Brosteanu Oana , Paulus Ursula , Koch Tina , Pfreundschuh Michael , Loeffler Markus , Engert Andreas , Josting Andreas , Wolf Jürgen , Hasenclever Dirk , Franklin Jeremy , Duehmke Eckhart , Georgii Axel , Schalk Klaus-Peter , Kirchner Hartmut , Doelken Gottfried , Munker Reinhold , Koch Peter , Herrmann Richard , Greil Richard , Anselmo Anna Paola , Diehl Volker
Published: February 2017

PURPOSE: To investigate whether treatment results in intermediate-stage Hodgkin’s lymphoma can be improved by rapid application of non–cross-resistant drugs, the 10-drug regimen cyclophosphamide, vincristine, procarbazine, and prednisone (COPP), doxorubicin, bleomycin, and vinblastine (ABV), and ifosfamide, methotrexate, etoposide, and prednisone (IMEP), repeated every 6 weeks, was compared with conventional alternating COPP/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) administered every 8 weeks.

PATIENTS AND METHODS: From January 1988 to January 1993, 996 patients in stage I or II Hodgkin’s lymphoma with at least one risk factor (massive mediastinal tumor, massive spleen involvement, extranodal disease, elevated ESR, or more than two lymph node areas involved) and all patients in stage IIIA Hodgkin’s lymphoma were randomized to receive two cycles of COPP/ABVD or COPP/ABV/IMEP followed by extended-field radiotherapy.

RESULTS: Both regimens produced similar rates for treatment responses (complete remission, 93% v 94%), freedom from treatment failure (80% v 79%), and overall survival (88% for both regimens) at a median follow-up time of 7 years. Most serious toxicities during chemotherapy were similar in both regimens. However, World Health Organization grade 3 and 4 leukocytopenia occurred significantly more frequently in the COPP/ABV/IMEP arm (53% v 44% of patients; P = .010). There were no differences in the number of serious infections and toxic deaths during therapy. The number of second malignancies was also the same in both arms (22 each).

CONCLUSION: Alternating COPP/ABVD and rapid alternating COPP/ABV/IMEP in combination with extended-field radiotherapy are equally effective in intermediate-stage Hodgkin’s lymphoma and produce excellent long-term treatment results.
Impact of BRCA1/BRCA2 Mutation Testing on Psychologic Distress in a Clinic-Based Sample
Authors: Schwartz Marc D. , Peshkin Beth N. , Hughes Chanita , Main David , Isaacs Claudine , Lerman Caryn
Published: February 2017

PURPOSE: Despite the increasingly widespread availability of BRCA1 and BRCA2 genetic testing, little is known about the psychologic impact of such testing in the clinical setting. The objective of this study was to examine the long-term psychologic impact of receiving BRCA1/2 test results within a clinic-based testing program.

PATIENTS AND METHODS: The participants were 279 high-risk women who underwent genetic counseling and testing for alterations in the BRCA1/2 genes. At baseline (before genetic testing) and at 6 months after the disclosure of mutation status, we measured perceived risk for breast and ovarian cancer, cancer-specific distress, and general distress. We examined the impact of the test result on each of these outcomes at the 6-month follow-up. Analyses were conducted separately for probands and their relatives who were unaffected with cancer.

RESULTS: We found no effect of test result among affected probands. Among unaffected relatives, we found that participants who received definitive negative test results exhibited significant reductions in perceived risk and distress compared with participants who received positive test results. Importantly, relatives who received positive test results did not exhibit increased distress or perceived risk.

CONCLUSION: These results suggest that clinic-based BRCA1/2 testing can lead to psychologic benefits for individuals who receive negative test results. At 6 months after disclosure, those who receive positive or uninformative test results do not exhibit increased psychologic distress or perceived risk.
Comprehensive Comparison of Health-Related Quality of Life After Contemporary Therapies for Localized Prostate Cancer
Authors: Wei John T. , Dunn Rodney L. , Sandler Howard M. , McLaughlin P. William , Montie James E. , Litwin Mark S. , Nyquist Linda , Sanda Martin G.
Published: February 2017

PURPOSE: Health-related quality-of-life (HRQOL) concerns are pivotal in choosing prostate cancer therapy. However, concurrent HRQOL comparison between brachytherapy, external radiation, radical prostatectomy, and controls is hitherto lacking. HRQOL effects of hormonal adjuvants and of cancer control after therapy also lack prior characterization.

PATIENTS AND METHODS: A cross-sectional survey was administered to patients who underwent brachytherapy, external-beam radiation, or radical prostatectomy during 4 years at an academic medical center and to age-matched controls. HRQOL among controls was compared with therapy groups. Comparison between therapy groups was performed using regression models to control covariates. HRQOL effects of cancer progression were evaluated.

RESULTS: One thousand fourteen subjects participated. Compared with controls, each therapy group reported bothersome sexual dysfunction; radical prostatectomy was associated with adverse urinary HRQOL; external-beam radiation was associated with adverse bowel HRQOL; and brachytherapy was associated with adverse urinary, bowel, and sexual HRQOL (P ≤ .0002 for each). Hormonal adjuvant symptoms were associated with significant impairment (P < .002). More than 1 year after therapy, several HRQOL outcomes were less favorable among subjects after brachytherapy than after external radiation or radical prostatectomy. Progression-free subjects reported better sexual and hormonal HRQOL than subjects with increasing prostate-specific antigen (P < .0001).

CONCLUSION: Long-term HRQOL after prostate brachytherapy showed no benefit relative to radical prostatectomy or external-beam radiation and may be less favorable in some domains. Hormonal adjuvants can be associated with significant impairment. Progression-free survival is associated with HRQOL benefits. These findings facilitate patient counseling regarding HRQOL expectations and highlight the need for prospective studies sensitive to urinary irritative and hormonal concerns in addition to incontinence, sexual, and bowel HRQOL domains.
Risk of Second Cancer in Patients With Hairy Cell Leukemia: Long-Term Follow-Up
Authors: Federico Massimo , Zinzani Pier Luigi , Frassoldati Antonio , Vinceti Marco , Modè Alessia , Annino Luciana , Chisesi Teodoro , Pagnucco Guido , Invernizzi Rosangela , Spriano Mauro , Resegotti Luigi , Bendandi Maurizio , Damasio Eugenio E.
Published: February 2017

PURPOSE: The purpose of the present study was to assess the risk of second cancers in patients with hairy cell leukemia (HCL).

PATIENTS AND METHODS: We investigated the incidence of additional cancers in those patients registered in the nationwide registry of the Italian Cooperative Group for the Study of HCL, asking the cooperating centers for additional information on initial and subsequent therapies and on time and type of second malignancies, if they developed. Here we report the final results of this survey, consisting of 54 cases of second malignancies (excluding nine cases of epithelial skin cancer) which developed in 54 patients of 1,022 with adequate follow-up.

RESULTS: The cumulative risk of development of a second cancer was 5%, 10%, and 14% at 5, 10, and 15 years, respectively. The incidence of second malignancies was not significantly higher than the expected rate (standardized incidence ratio [SIR], 1.01; 95% confidence interval [CI], 0.74 to 1.33; P = 1.0). However, the SIR of non-Hodgkin’s lymphoma in the entire cohort was 5.3 (95% CI, 1.9 to 11.5). Second malignancies occurred in eight (4.7%) of 386 patients who never received interferon (IFN), nine (5.9%) of 495 patients treated with IFN at the time of diagnosis, and seven (6.9%) of 102 patients who received IFN as second-line therapy. These differences were not statistically significant. Analysis of the separate calendar periods did not reveal any particular trends with respect to variations in SIR.

CONCLUSION: The present study does not support the suspicion that patients with HCL are at increased risk of additional second malignancies, although the incidence of lymphoid neoplasms was significantly higher than expected. In addition, our data indicate that IFN therapy did not exert an oncogenic effect in such patients.
Primary Cutaneous Follicular Lymphoma: An Assessment of Clinical, Histopathologic, Immunophenotypic, and Molecular Features
Authors: Mirza I. , Macpherson N. , Paproski S. , Gascoyne R. D. , Yang B. , Finn W. G. , Hsi E. D.
Published: February 2017

PURPOSE: Unlike nodal follicular lymphoma (NFL), Primary cutaneous follicular lymphomas (PCFLs) rarely express Bcl-2 protein or t(14;18)(q32;q21) (Bcl-2/IgH). The aim of this study was to further characterize PCFL in a large series from North America.

PATIENTS AND METHODS: Clinical data and archival formalin-fixed, paraffin-embedded tissue were obtained from 32 patients. PCFL was defined as follicular lymphoma limited to the skin at the time of diagnosis and within the first 6 months after diagnosis. Specimens were analyzed for the expression of CD3, CD10, CD20, Bcl-2, and Bcl-6 proteins by immunohistochemistry as well as for the presence of t(14;18)(q32;q21) by polymerase chain reaction.

RESULTS: The male-to-female ratio was 1.5:1, with a median age of 60 years. Twenty-four patients had lesions on the head and neck, five had lesions on the trunk, and three had lesions on both head and trunk. Follow-up data were available in all cases, with a mean length of 35.8 months. The majority of the patients were treated with radiation therapy. All patients were alive at last follow-up except one. Recurrence was noted in seven patients (22%), after a mean disease-free survival time of 17.7 months. CD10 and Bcl-6 expression were seen in 29 (91%) of 32 and 31 (97%) of 32 cases, respectively. Bcl-2 expression was noted in 13 (41%) of 32 cases. PCR results for t(14;18)(q32;q21) were positive in 11 (34%) of 32 patients and showed correlation with Bcl-2 protein expression. The sequencing of the t(14;18)(q32;q21) amplicons confirmed unique breakpoints in each of the seven tested cases. Comparison between the Bcl-2 and/or t(14;18)(q32;q21)-positive and t(14;18)(q32;q21)-negative cases revealed no significant difference in age, site, clinical course, or outcome.

CONCLUSION: We demonstrated Bcl-2 protein expression and t(14;18)(q32;q21) in a significant minority of cases, suggesting a relationship with NFL. It remains to be seen whether, on longer follow-up, there is any clinical difference in cases with and without t(14;18)(q32;q21).
Phase II Study of Troxacitabine, a Novel Dioxolane Nucleoside Analog, in Patients With Refractory Leukemia
Authors: Giles Francis J. , Garcia-Manero Guillermo , Cortes Jorge E. , Baker Sharyn D. , Miller Carol B. , O'Brien Susan M. , Thomas Deborah A. , Andreeff Michael , Bivins Carol , Jolivet Jacques , Kantarjian Hagop M.
Published: February 2017

PURPOSE: To investigate the activity of a novel dioxolane
l
-nucleoside analog, troxacitabine (
l
-(−)-OddC, BCH-4556), in patients with refractory leukemia.

PATIENTS AND METHODS: Study participants were patients with refractory or relapsed acute myeloid (AML) or lymphocytic (ALL) leukemia, myelodysplastic syndromes (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP). Troxacitabine was provided as an intravenous infusion for more than 30 minutes daily for 5 days at a dose of 8.0 mg/m
2
/d (40 mg/m
2
per course). Courses were given every 3 to 4 weeks according to antileukemic efficacy.

RESULTS: Forty-two patients (AML, 18 patients; MDS, one patient; ALL, six patients; CML-BP, 17 patients) were treated. Median age was 51 years (range, 23 to 80 years); 22 patients were male. Stomatitis was the most significant adverse event, with three patients (7%) and two patients (5%), respectively, experiencing grade 3 or 4 toxicity. Ten patients (24%) had grade 3 hand-foot syndrome, and two patients (5%) had grade 3 skin rash. One patient (2%) had grade 3 fatigue and anorexia. Marrow hypoplasia occurred between days 14 and 28 in 12 (75%) of 16 assessable patients with AML. Two complete remissions and one partial remission (18%) were observed in 16 assessable patients with AML. None of six patients with ALL responded. Six (37%) of 16 assessable patients with CML-BP experienced a return to chronic-phase disease.

CONCLUSION: Troxacitabine has significant antileukemic activity in patients with AML and CML-BP.