Ocorrência de múltiplas neoplasias em paciente portador de leucemia mieloide crônica: relato de caso / Occurence of multiple neoplasms in patient with chronic myeloid leukemia: case report

Introdução: A leucemia mieloide crônica é um distúrbio mieloproliferativo clonal com uma anormalidade citogenética específica, resultante da translocação entre os cromossomos 9 e 22 com consequente produção de uma proteína com atividade tirosina quinase alterada. Tratamentos históricos com drogas como bussulfan, hidroxiureia e interferon passaram a ser pouco utilizados devido ao surgimento dos inibidores de tirosina quinase, cujo principal representante é o mesilato de imatinibe. Esse fármaco é a terapia de primeira linha, sendo bem tolerado pelos pacientes e com baixo risco de eventos adversos severos. Entretanto, com cerca de dez anos de uso, ainda há preocupação com efeitos colaterais em longo prazo, tais como o desenvolvimento de segunda neoplasia. Objetivo: Descrever a ocorrência de múltiplas neoplasias em um portador de leucemia mieloide crônica. Método: Relata-se o caso de um paciente com leucemia mieloide crônica há 13 anos, tendo utilizado hidroxiureia e interferon como terapias prévias e em uso de mesilato de imatinibe há nove anos. Resultados: Há dois anos, o paciente apresentou dois nódulos em coxa esquerda que foram totalmente ressecados. Diagnosticou-se lipossarcoma mixoide e o paciente foi submetido à radioterapia. A tomografia computadorizada do abdomên de controle aos seis meses detectou nódulo espiculado na gordura mesenquimal adjacente ao jejuno/íleo. Feita laparotomia exploradora e ressecção, o anatomopatológico demonstrou fibromatose desmoide. Conclusão: O portador de tumor maligno tem risco aumentado de desenvolver uma segunda neoplasia, que pode dessa forma ocorrer nos portadores de leucemia mieloide crônica. Essa associação pode estar relacionada aos fármacos usados no tratamento da mesma.

Activity of eribulin mesylate in patients with soft-tissue sarcoma: a phase 2 study in four independent histological subtypes.

BACKGROUND: Eribulin inhibits microtubule dynamics via a mechanism distinct from that of other tubulin-targeting drugs, inducing cell-cycle arrest and tumour regression in preclinical models. We assessed the activity and safety of eribulin in four strata of patients with different types of soft-tissue sarcoma. METHODS: In this non-randomised multicentre phase 2 study, patients were included if they had progressive or high-grade soft-tissue sarcoma and had received no more than one previous combination chemotherapy or up to two single drugs for advanced disease. They were stratified by the type of soft-tissue sarcoma they had. Eribulin was given intravenously at a concentration of 1·4 mg/m(2) over 2-5 min at days 1 and 8 every 3 weeks to primarily assess progression-free survival at 12 weeks (RECIST 1.0), which we evaluated in all patients who started treatment. Safety analyses were done in all patients who started treatment. This trial is registered at ClinicalTrials.gov, number NCT00413192. FINDINGS: Of 128 patients included, 37 had adipocytic sarcoma, 40 had leiomyosarcoma, 19 had synovial sarcoma, and 32 had other sarcomas. 12 (31·6%) of 38 patients with leiomyosarcoma evaluable for the primary endpoint, 15 (46·9%) of 32 patients with adipocytic sarcoma, four (21·1%) of 19 with synovial sarcoma, and five (19·2%) of 26 in other sarcomas were progression-free at 12 weeks. The most common grade 3-4 adverse events were neutropenia (66 [52%] of 127 patients evaluable for safety), leucopenia (44 [35%]), anaemia (nine [7%]), fatigue (nine [7%]), febrile neutropenia (eight [6%]), abnormal alanine aminotransferase concentrations (six [5%]), mucositis (four [3%]), and sensory neuropathy (four [3%]). INTERPRETATION: Eribulin deserves further study in this setting, based on progression-free survival at 12 weeks in leiomyosarcoma and adipocytic sarcoma. FUNDING: Eisai Limited, Hatfield, UK.

Eribulin mesylate (Halaven) for breast cancer.

Eribulin mesylate (Halaven-Eisai) has been approved by the FDA for treatment of patients with metastatic breast cancer who have previously received at least 2 chemotherapy regimens for metastatic cancer. Prior therapy should have included an anthracycline and a taxane in either an adjuvant or metastatic setting. Other drugs used to treat anthracycline- and taxane-refractory metastatic breast cancer include capecitabine (Xeloda), gemcitabine (Gemzar, and others) and vinorelbine (Navelbine, and others).

Eribulin mesylate: a promising new antineoplastic agent for locally advanced or metastatic breast cancer.

More than one million women worldwide are diagnosed with breast cancer every year. For those diagnosed with metastatic breast cancer, the 5-year survival rates are low as, ultimately, patients develop tumors that become refractory to treatment. In clinical trials, eribulin mesylate (E7389) - a novel nontaxane microtubule dynamics inhibitor - demonstrated efficacy in patients with various solid tumors, in particular, those with heavily pretreated metastatic breast cancer. The Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus E7389 (EMBRACE) study observed a significant increase in overall survival with eribulin compared with treatment of physician's choice (median: 13.1 vs 10.6 months, respectively). Based on these results, eribulin recently received approval by the US FDA for the treatment of patients with metastatic breast cancer who have received at least two prior chemotherapeutic regimens including an anthracyline and a taxane. In addition, eribulin has a manageable tolerability profile, requires no premedication and has shorter infusion times than most other microtubule-targeted agents.

Reacciones adversas del imatinib como droga de segunda línea en pacientes con leucemia mieloide crónica / Adverse reactions to imatinib as second-line drug in patients with chronic myeloid leukemia

El imatinib es un inhibidor sintético de la tirosina cinasa usado en el tratamiento de la leucemia mieloide crónica (LMC) y considerado como la droga de primera línea para el tratamiento de la enfermedad. Los efectos adversos más comunes son: náuseas, dolores musculoesqueléticos, diarrea, erupción cutánea, fatiga y mielosupresión, a expensas, fundamentalmente, de la línea granulopoyética. Se realizó un estudio en 43 pacientes adultos (23 femeninos y 20 masculinos) con LMC Ph+ en fase crónica, atendidos en el Instituto de Hematología e Inmunología y en otros servicios de hematología del país. Todos los casos presentaron resistencia o intolerancia al tratamiento con interferón alfa recombinante (INFα) y recibieron terapia con imatinib (400mg/día) en el período comprendido entre abril del 2003 hasta julio del 2008. El 48,8 por ciento de los pacientes no tuvieron reacciones adversas. Dentro de los efectos adversos no hematológicos, los más frecuentes fueron: 23,3 por ciento dolores óseos, musculares o ambos; 23,3 por ciento edemas; 20,9 por ciento hipopigmentación de la piel; y 11,6 por ciento nódulos subcutáneos. Dentro de las reacciones hematológicas, en el 14 por ciento se diagnosticó la anemia hemolítica inmune por droga; en el 11,6 por ciento la trombocitopenia inmune por droga; y en el 9,3 por ciento bicitopenia

Imatinib is a synthetic inhibitor of kinase-tyrosine used in the treatment of chronic myeloid leukemia (CML) and also is considered as the first-line drug for the treatment of this entity. The commonest side effects include: nausea, musculoskeletal pains, diarrhea, cutaneous eruption, fatigue and myelosuppression mainly at the expense of granulopoiesis line. A study was conducted in 43 adult patients (23 females and 20 males) presenting with CML pH+ in chronic phase, seen in the Hematology and Immunology Institute and in other Hematology services in our country. All cases showed resistance and intolerance to treatment with recombinant Alfa-Interferon (INFα) and Imatinib therapy (400 mg/day) from April, 2003 to July, 2008. The 48,8 percent of patients have not adverse reactions. The more frequent non-hematologic side effects include bone, muscular or both pain (23 percent), edema (23,3 percent); skin hypopigmentation (20,9 percent), and subcutaneous nodules (11,6 percent). In hematological reactions are included the drug-hemolytic anemia (14 percent) drug-immune anemia, drug immune thrombocytopenia (11,6 percent) and bicitopenia ( 9,3 percent)

Sustained antihypertensive actions of a dual angiotensin-converting enzyme neutral endopeptidase inhibitor, sampatrilat, in black hypertensive subjects.

Our objective was to evaluate the safety and antihypertensive efficacy of sampatrilat, a novel dual inhibitor of both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), in subjects poorly responsive to ACE inhibitor monotherapy. The ability of sampatrilat (50 to 100 mg daily) (n = 28) to lower blood pressure was compared with that of the ACE inhibitor lisinopril (10 to 20 mg daily) (n = 30) using a double-blind, randomized, parallel group study design over a 56-day treatment period in black hypertensives. Changes in systolic (SBP) and diastolic (DBP) blood pressure were determined using repeated ambulatory blood pressure (ABP) monitoring. Both sampatrilat and lisinopril decreased plasma ACE concentrations after 28 and 56 days. The decrease in plasma ACE concentrations (U/L) was greater after lisinopril (-9.33 +/- 0.52) as compared with sampatrilat (-6.31 +/- 0.70) (P = .0001) therapy. Lisinopril, but not sampatrilat, increased plasma renin activity. Lisinopril produced a transient decrease in mean 24-h ABP (mm Hg) at 28 days (SBP = -9.0 +/- 2.3, DBP = -5.7 +/- 1.3; P < .01), which returned to pretreatment values by 56 days of therapy. Alternatively, sampatrilat produced a sustained decrease in mean ABP over the 56-day treatment period (day 28: SBP = -7.3 +/- 1.8, DBP = -5.2 +/- 1.2; P < .01: day 56: SBP = -7.8 +/- 1.5; DBP = -5.2 +/- 0.95; P < 0.01) with a greater treatment effect on DBP than that of lisinopril at day 56 (P = .05). Treatment-emergent adverse events were noted to be similar between both treatment groups. We conclude that the antihypertensive actions of ACE/NEP inhibitor monotherapy in black subjects offers a novel therapeutic approach to patients otherwise resistant to the sustained antihypertensive actions of ACE inhibitor monotherapy.

Phase I study of DMP 840 in pediatric patients with refractory solid tumors.

The bis-naphthalimide DMP 840 has demonstrated high level antitumor activity in a number of preclinical models and has been evaluated in several Phase I studies in adults. We enrolled 10 patients with refractory pediatric solid tumors to this Phase I study of DMP 840 given intravenously by short infusion daily for 5 days. The most frequent and dose-limiting toxicity was myelosuppression. The maximum tolerated dose on this schedule was 8.6 mg/m2 daily for 5 days. One patient had a complete response; there were no measurable tumor responses among the remaining 9 patients.

A phase I and pharmacologic study of DMP 840 administered by 24-hour infusion.

PURPOSE: DMP 840, a novel bisnaphthalimide, has demonstrated promising schedule dependent anti-tumor activity in vitro and in vivo against several tumor cell lines. A phase I study was conducted to evaluate the effect of a 24-hour infusion schedule repeated every three weeks, on the therapeutic efficacy of DMP 840. PATIENTS AND METHODS: Fourteen patients with refractory solid tumor malignancies were treated with DMP 840 at doses of 20, 40, 50 and 60 mg/m2. RESULTS: A combination of neutropenia, thrombocytopenia and stomatitis were dose-limiting at doses of 50 and 60 mg/m2 in both minimally- and extensively-pretreated patients. In contrast, all courses at lower dose levels were well tolerated. Pharmacokinetic analysis demonstrated that DMP 840 had a prolonged terminal half life (median 39 hours; range 25-86) and that dose-limiting events were significantly related to several indices of systemic DMP 840 exposure (P < 0.01, Wilcoxon Rank Sum test). CONCLUSION: The recommended dose of DMP 840 for further disease oriented evaluations is 40 mg/m2 administered over 24 hours every three weeks. The infusion duration evaluated in this study did not result in a substantial increase in the tolerable dose compared to shorter, less cumbersome schedules.

Sensitivity of fibroblasts derived from ataxia-telangiectasia patients to calicheamicin gamma 1I.

We report the hypersensitivity of SV40-transformed fibroblasts derived from ataxia telangiectasia (AT) patients to calicheamicin gamma 1I. In common with other free-radical generating agents such as bleomycin and ionizing radiation, treatment with calicheamicin gamma 1I reveals AT derived lines to be 6-fold more sensitive to this drug when compared to controls. Furthermore, in common with ionizing radiation, AT cells did not show dose-dependent inhibition of DNA synthesis after treatment with calicheamicin gamma 1I.

Potentiation of therapeutic effect of methanesulphonate and protection against its organ cytotoxicity by vitamin C in Ehrlich ascites carcinoma bearing mice.

The effect of vitamin C upon the therapeutic index and side effects produced by methanesulfonate of aminoglycols (drug 864T, NSC 140117) had been evaluated in a laboratory system. The antitumor action of 864T, vitamin C and their combination were evaluated in Ehrlich ascites carcinoma (EAC) cells in vivo. Tissue toxicity was assessed using liver and intestinal DNA, RNA, protein contents and their synthesis as parameters. In addition, G-6-pase, 5-Nase and Alk, pase activity levels in both tissues were also measured. Drug 864T (200 mg/kg) produced 50 percent long-term survivors in tumor bearing mice in addition to 10 percent early mortality while in combination with vitamin C (250 mg/kg x 6), there was 80 percent long term survivors with no mortality related to drug toxicity. No toxicity, in all the parameters used, was observed when 864T was given in combination with vitamin C. Drug 864T alone produced a significant decrease in protein content of both liver and intestinal tissue while in combination with vitamin C normal levels were maintained. In addition, all the parameters used were either elevated or decreased by 864T treatment and returned to normal levels in combination with vitamin C. This study proved that vitamin C may be useful not only to potentiate the effect of anticancer drug 864T on the Ehrlich ascites carcinoma but also to antagonize the side effects of the drug.

In vitro effects of radiographic contrast media on the complement system.

The effect of several radiographic contrast media on the complement system in vitro was examined using quantitative crossed immunoelectrophoresis. Diatrizoate, iothalamate, metrizoate, and methiodal did not cause electrophoretic conversion of C3 or properdin factor B. In fact, the small degree of spontaneous conversion occurring when serum is incubated in polypropylene tubes was inhibited by these contrast media or by hypertonic sodium chloride. Metrizamide caused enhanced conversion of C3 and factor B that was only partially inhibited by ethylene glycol tetracetic acid (EGTA) but completely inhibited by ethylenediaminetetraacetic acid (EDTA). Iodipamide caused a unique electrophoretic alteration of C3 that was not affected by EDTA or several other inhibitors and that was not identical with the usual products of C3 activation. Iodipamide in very low concentrations inhibited complement activation through the classical pathway.

Adhesive arachnoiditis following lumbar myelography.

Late sequelae (adhesive arachnoiditis) have been reported following myelography with the oily contrast medium (Pantopaque) and with the ionic water-soluble contrast media methiodal sodium (Abrodil, Conturex, Kontrast U) meglumine iothalamate (Conray Meglumine) and meglumine iocarmate (Bis-Conray, Dimer-X). Adhesive arachnoiditis has not yet been reported after the use of the nonionic water-soluble contrast medium metrizamide (Amipaque). Thus, this is considered the contrast medium of choice for lumbar myelography. Using the recommended dose of 10 ml with an iodine concentration of 170 mg/ml for this examination, adhesive arachnoiditis is unlikely to occur. Increased osmolality of spinal fluid after injection of contrast medium is related to increased frequency of arachnoiditis.

Yoshi 864 (1-propanol, 3,3'-iminodi-, dimethanesulfonate [ester], hydrochloride): a phase II study in solid tumors.

Two hundred and eight acceptable patients were treated with Yoshi 864 (2 mg/kg/day by iv push X 5 days repeated once every 6 weeks). Toxicity was minimal. There was an overall response rate of 11%. Cross resistance with other alkylating agents may not be present. Because of its lack of toxicity, Yoshi 864 should be further evaluated in chronic myelocytic leukemia, lymphomas, and carcinomas of the ovary and bladder where significant responses were seen. It should also be evaluated in combinations as a replacement for other alkylating agents which cause more nausea and vomiting.

The postoperative myelogram. Radiographic evaluation of arachnoiditis and dural/arachnoidal tears.

Either arachnoriditis or dural/arachnoidal tears may cause symptoms in the postoperative spinal patient. Surgery and myelography as causes of arachnoiditis are discussed. Intradural arachnoid cyst formation and intramedullary cavitation may present as unusual sequelae of arachnoiditis. Extra-dural cysts and cerebrospinal fluid fistulas resulting from dural/arachnoidal tears are unusual postoperative complications presenting striking myelographic features. Their mechanisms of formation, clinical significance, and radiographic features are discussed.

Yoshi 864 (NSC 102627) 1-propanol, 3, 3'-iminodi-dimethanesulfonate (ester) hydrochloride: a phase 1 study.

Yoshi 864 was given i.v. push daily times 5 with 6 weeks' followup. Dose escalation was from 0.25 mg/kg to 2.7 mg/kg. Toxicity and effectiveness were first seen at 1.5 mg/kg. Twenty-five courses were given to 16 patients at or above this level. In 16 of 22 courses, exclusive of CML, thrombopenia and/or leukopenia occurred. Mean platelet and WBC nadirs occurred on day 24 and 29 with recovery taking 1-2 weeks and 2-3 weeks respectively. Hb fell in 11 courses. At 2.7 mg/kg, nausea and vomiting lasting 6-12 days occurred in 3 of 7 courses; during 5 coures patients slept 20 hours a day, and 1 was comatose for 2 days. Two patients with squamous cell carcinoma and 1 with an unknown primary responded. Both patients with CML had clinical remissions. It is recommended that a cooperative Phase II Study in a broad spectrum of human solid tumors including lymphomas and chronic myelocytic leukemia be undertaken at a dose level of 2 mg/kg.