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The title crystals, C7H2I3N, are isomorphous. Both mol-ecules lie across two crystallographic mirror planes and a twofold axis. The principal supra-molecular inter-action is centric R22(10) CN/NCâ¯I short contacts involving both ortho I atoms, with two contacts bis-ecting each cyano and iso-cyano group. These form ribbons along [010] and give rise to a planar sheet structure parallel to (100). All pairs of adjacent sheets have centric stacking, a mode not previously reported for sheets of this type. This study completes the series of homo-2,4,6-trihalobenzo-nitriles, in which I atoms give the strongest CNâ¯X and NCâ¯X inter-actions (X = F, Cl, Br, I).
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PURPOSE: The vascular disrupting agent fosbretabulin tromethamine selectively targets pre-existing tumor vasculature, which causes vascular shutdown and leads to cancer cell death and necrosis. Antiangiogenesis agents such as bevacizumab, a humanized antivascular endothelial growth factor monoclonal antibody, might prevent revascularization during and after treatment with a vascular disrupting agent. PATIENTS AND METHODS: Patients with recurrent or persistent epithelial ovarian, tubal, or peritoneal carcinoma, measurable or detectable disease, and three or fewer prior regimens were randomly assigned to bevacizumab (15 mg/kg intravenously once every 3 weeks) or the combination of bevacizumab (15 mg/kg) plus fosbretabulin (60 mg/m(2)) intravenously once every 3 weeks until disease progression or toxicity. Randomization was stratified by disease status (measurable v nonmeasurable), prior bevacizumab, and platinum-free interval. The primary end point was progression-free survival (PFS). The study was designed with 80% power for a one-sided alternative at a 10% level of significance to detect a reduction in the hazard by 37.5%. RESULTS: The study enrolled 107 patients. Median PFS was 4.8 months for bevacizumab and 7.3 months for bevacizumab plus fosbretabulin (hazard ratio, 0.69; 90% two-sided CI, 0.47 to 1.00; one-sided P = .05). The proportion responding (overall response rate) to bevacizumab was 28.2% among 39 patients with measurable disease and 35.7% among 42 patients treated with the combination. The relative probability of responding was 1.27 (90% CI, 0.74 to 2.17; one-sided P = .24). Adverse events greater than grade 3 were more common in the combination regimen than in bevacizumab only for hypertension (35% v 20%). There was one grade 3 thromboembolic event in the combination arm and one intestinal fistula in the bevacizumab only arm. CONCLUSION: On the basis of the PFS, overall response rate, and tolerability of these two antivascular therapies, further evaluation is warranted for this chemotherapy-free regimen. Fosbretabulin in combination with bevacizumab increases the risk of hypertension.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Neoplasias das Tubas Uterinas/mortalidade , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Neoplasias Peritoneais/mortalidade , Estilbenos/administração & dosagem , Estilbenos/efeitos adversosRESUMO
OBJECTIVE: This study aimed to determine surgical outcomes related to hand-assisted robotic surgery (HARS) for staging of ovarian cancer and uterine cancers with high risk of peritoneal spread and compare them to laparotomy and standard robotic-assisted surgery. METHODS: A retrospective cohort study of women undergoing staging for uterine and ovarian cancer between January 2011 and July 2013 at a major metropolitan teaching hospital was reviewed. Patients undergoing HARS were matched with patients undergoing staging laparotomy [exploratory laparotomy (XLAP)] for the same indications and with patients undergoing traditional robotic surgery (RS) for staging of endometrioid endometrial cancer. In HARS, a longer incision is used to allow palpation of the peritoneal surfaces, to exteriorize the small bowel, to examine the mesentery, and to perform omentectomy. RESULTS: One hundred five patients were analyzed (15 HARS, 45 RS, 45 XLAP). Compared with XLAP, HARS was associated with decreased blood loss (200 vs 400 mL, P = 0.011) and shorter hospital stay (1 vs 4 days, P < 0.001). Patients who had undergone HARS had fewer major complications, but those results did not reach statistical significance (0% vs 27%, P = 0.063). Hand-assisted robotic surgery was associated with higher blood loss and length of stay as compared to robotic staging of endometrioid endometrial cancer (RS). Minor wound complications were also more common (27% vs 2%, P = 0.012). CONCLUSIONS: Hand-assisted robotic surgery allows for thorough visual and tactile assessment of peritoneal surfaces. It represents a safe alternative to laparotomy for staging of ovarian and uterine cancers with high risk of peritoneal spread. Long-term follow-up study is needed to determine oncologic adequacy of HARS.
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Histerectomia , Laparoscopia , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/secundário , Procedimentos Cirúrgicos Robóticos , Neoplasias Uterinas/patologia , Feminino , Seguimentos , Humanos , Tempo de Internação , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/cirurgia , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/cirurgia , Complicações Pós-Operatórias , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Neoplasias Uterinas/mortalidade , Neoplasias Uterinas/cirurgiaRESUMO
OBJECTIVE: This two-stage phase II study assessed activity of single agent dalantercept in patients with recurrent/persistent endometrial carcinoma (EMC). METHODS: Eligible patients had persistent/recurrent EMC after 1-2 prior cytotoxic regimens, measurable disease (RECIST 1.1), and GOG performance≤2. Dalantercept 1.2mg/kg subcutaneous was administered once every 3weeks until disease progression (PD)/development of prohibitory toxicity. Primary objectives were to estimate the proportion of patients with persistent/recurrent EMC, who survive progression-free without receiving non-protocol therapy (TPFS) for at least 6months and to estimate the proportion having objective tumor response. RESULTS: All 28 enrolled patients were eligible and evaluable. Median age: 62years. Most common histologies: 32% Grade 1/2 endometrioid and 54% serous tumors. Prior treatment: 1 or 2 regimens in 82% and 18% of patients, respectively. Eighteen patients received prior radiation therapy. Patients received 1-12 cycles of dalantercept, and 46% of patients received ≤2cycles. The most common adverse events (AE) were fatigue, anemia, constipation and peripheral edema. Grade 3/4 AEs occurred in 39% and 4% of patients. One grade 5 gastric hemorrhage in a patient with a history of radiation fibrosis/small bowel obstruction was deemed possibly dalantercept-related. All patients are off study: 86% for PD. No ORs were observed; 57% had stable disease and 11% had TPFS>6 mos. Median progression-free and overall survival: 2.1months (90% CI: 1.4-3.2) and 14.5months (90% CI: 7.0-17.5), respectively. CONCLUSIONS: Dalantercept has insufficient single agent activity in recurrent EMC to warrant further investigation at this dose level and schedule.
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Receptores de Activinas Tipo II/uso terapêutico , Neoplasias do Endométrio/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Receptores de Activinas Tipo II/efeitos adversos , Adulto , Idoso , Intervalo Livre de Doença , Neoplasias do Endométrio/irrigação sanguínea , Neoplasias do Endométrio/patologia , Feminino , Humanos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/irrigação sanguínea , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Neovascularização Patológica/tratamento farmacológico , Proteínas Recombinantes de Fusão/efeitos adversosRESUMO
INTRODUCTION: Myelodysplastic syndromes (MDSs) are associated with significant morbidity due to ineffective hematopoiesis. Given the limited number of drugs approved by the FDA, there is a need for new therapeutic options. Ezatiostat is a novel agent targeting oxidative stress via inhibition of glutathione S-transferase 1. AREAS COVERED: Herein, the authors summarize the standard of care in order to build the framework for therapeutic advancements. The purpose of this paper is to review the body of preclinical and clinical research literature on the investigational agent ezatiostat hydrochloride (TLK199) for the treatment of MDSs. The article includes details of the pathophysiology, pharmacology, toxicity and efficacy of ezatiostat hydrochloride from controlled studies in patients with myelodysplasia. EXPERT OPINION: MDS clonal heterogeneity and clonal architecture complexity has presented a significant technical challenge in developing effective therapies. Ezatiostat offers a unique and specific mechanism to improve the transfusion burden associated with myelodysplasia. Since it is tolerable as a monotherapy, combining ezatiostat with agents such as lenalidomide may have the most potential benefit.
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Inibidores Enzimáticos/uso terapêutico , Glutationa/análogos & derivados , Síndromes Mielodisplásicas/tratamento farmacológico , Animais , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacologia , Glutationa/efeitos adversos , Glutationa/farmacologia , Glutationa/uso terapêutico , Glutationa Transferase/antagonistas & inibidores , Humanos , Síndromes Mielodisplásicas/fisiopatologia , Estresse Oxidativo/efeitos dos fármacosRESUMO
BACKGROUND: Primary angiosarcoma of the breast (PAOB) is rare and institutional series have provided conflicting data on the effect of grade on prognosis. PATIENTS AND METHODS: Using a case listing session of Surveillance, Epidemiology, and End Results (SEER) 18 (1973-2010) we examined outcomes for patients with PAOB. Analyses were conducted with SEER*Stat 8.1.2, Microsoft Excel 2007, and GraphPad Prism 6. Comparisons were made using the Fisher exact test and log rank test (Mantel-Cox); P values were 2-sided. RESULTS: Two hundred twenty-six women with PAOB were identified; median age was 49 (range, 15-107) years and 82% (185) were white. Seventy-two percent (162) had localized disease, 15% (34) regional disease, 7% (16) distant disease, and 6% (14) had unknown staging. Fourteen percent (32) had Grade 1, 24% (55) Grade 2, 30% (68) Grade 3 disease, and grade was unknown in 32% (72) of patients. Median overall survival (OS) for patients with localized, regional, and distant disease was 172, 24, and 16 months, respectively (P < .001). Median OS for patients with localized Grade 1 and 2 disease was not reached versus 36 months for Grade 3 disease (P < .001); 3-year OS was 89% (78) versus 47% (32). There was a strong trend for patients with Grade 3 disease to undergo mastectomy (44%, n = 30 vs. 23%, n = 20; P = .070) and 24% (55) of all patients received radiation. Radiation did not improve survival for localized Grade 1 and 2 disease (P = .676), or Grade 3 disease (P = .589); surgery and grade subgroups were too small for meaningful comparisons regarding radiation. CONCLUSION: Histologic grade is a significant predictor of survival for patients with localized PAOB. Regardless of grade, adjuvant radiation did not confer a survival benefit for patients with localized disease.
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Neoplasias da Mama/patologia , Hemangiossarcoma/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/mortalidade , Feminino , Hemangiossarcoma/mortalidade , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Programa de SEER , Adulto JovemRESUMO
PURPOSE: The doublet gemcitabine and carboplatin is effective for the treatment of recurrent ovarian cancer, while multi-agent chemotherapy with bevacizumab may add additional benefit. This phase II study tested the efficacy and safety of a biweekly gemcitabine, carboplatin, and bevacizumab combination in patients with platinum-sensitive recurrent ovarian, peritoneal, or tubal cancer (ROC). PATIENTS AND METHODS: Eligible patients received concurrent gemcitabine 1000 mg/m(2), carboplatin area under the curve 3, and bevacizumab 10 mg/kg administered intravenously on days 1 and 15 every 28 days for six cycles or up to 24 cycles if clinical benefit occurred. The primary end points were progression-free survival (PFS) by RECIST, and safety; the secondary end points were objective response rates and overall survival. RESULTS: Overall, 45 patients were enrolled. The median PFS was 13.3 months (95% CI, 11.3 to 15.3). The objective response rate was 69%. Grade 4 hematologic toxicities included neutropenia (27%) and thrombocytopenia (2%). Grades 3 and 4 non-hematologic toxicities included fatigue (18%), pain (9%), and nausea/vomiting (4%). There were 2 episodes of cerebrovascular accidents, 2 noted DVTs, and no episodes of bowel perforation. Median OS was 36.1 months (95% CI, 26.7 to 45.5). CONCLUSION: Biweekly gemcitabine, carboplatin, and bevacizumab were an effective regimen in recurrent ovarian cancer, with comparable toxicity to recently reported day 1 gemcitabine, carboplatin, bevacizumab, and day 8 gemcitabine. Response rate and PFS are improved from reported outcomes of the gemcitabine carboplatin doublet. The degree to which biweekly dosing may present a more rationale schedule for this triplet should be evaluated further.
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Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Bevacizumab , Carboplatina/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Quimioterapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , GencitabinaRESUMO
BACKGROUND: R1507 is a human IgG1 Mab that binds to the insulin-like growth factor-1 receptor (IGF-1R) and inhibits IGF-1- or IGF-2-mediated anchorage-independent growth of malignant cells. A phase 1b study evaluated the safety, tolerability and efficacy of R1507 in combination with multiple standard oncology regimens. METHODS: R1507 (3, 5, 9, 10 and 16 mg/kg IV, Q2 W or Q3 W) was added to six treatment regimens: gemcitabine + erlotinib (GE); paclitaxel + bevacizumab (PB); carboplatin + etoposide (CE); mFOLFOX6 + bevacizumab (FB); capecitabine + trastuzumab (CT); and sorafenib (S). If tolerable, R1507 dose was escalated utilizing a 3 + 3 + 6 and a 3 + 9 design. RESULTS: A total of 104 patients enrolled into regimens 1-6: 93 % were non-recent diagnoses. Eighteen withdrew for safety [one death, 17 adverse events (AEs)]. A total of 1,337 AEs any grade, across regimens and doses were nausea, vomiting and diarrhea. A total of 123 had grade ≥3 AEs (n = 28 dose level 1; n = 95 dose level 1) and in 60 patients were myelosuppression, fatigue and mucosal inflammation. ORR (PR plus SD) of evaluable patients across six regimens was 36 % with five PRs: regimens PB (non-small cell lung cancer, nasopharyngeal cancer), CE (melanoma), FB (colon cancer) and S (GIST). The GIST pt (>4 prior therapies) had a PR for 3 years. Three patients (breast cancer, melanoma and adenoid cystic carcinoma) were on study for >1 year; 76 % of patients had SD or better for 4 months. CONCLUSIONS: R1507 added to six standard oncology regimens was well tolerated with an ORR of 36 %.
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Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias/tratamento farmacológico , Administração Intravenosa , Anticorpos Monoclonais Humanizados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Receptor IGF Tipo 1/imunologiaAssuntos
Sarcoma/patologia , Sarcoma/terapia , Neoplasias Uterinas/patologia , Neoplasias Uterinas/terapia , Adenossarcoma/patologia , Adenossarcoma/terapia , Carcinossarcoma/patologia , Carcinossarcoma/terapia , Feminino , Humanos , Leiomiossarcoma/patologia , Leiomiossarcoma/terapia , Sarcoma do Estroma Endometrial/patologia , Sarcoma do Estroma Endometrial/terapiaRESUMO
BACKGROUND: Between 30% and 50% of women who have high-grade uterine leiomyosarcoma (uLMS) limited to the uterus at diagnosis remain progression-free at 2 years. Adjuvant pelvic radiation does not improve outcome. The objective of the current study was to determine the 2-year and 3-year progression-free survival (PFS) among a prospective cohort of women who received adjuvant gemcitabine plus docetaxel followed by doxorubicin. METHODS: Women with uterus-limited, high-grade uLMS and adequate organ function were eligible. Within 12 weeks of complete resection and after confirmation that they had no evidence of disease on computed tomography (CT) images, the patients received 4 cycles of fixed-dose-rate gemcitabine plus docetaxel. Those who were confirmed disease-free on CT scans after cycle 4 received 4 cycles of doxorubicin. CT imaging for recurrence was performed every 3 months for 2 years, then every 6 months for 3 years. RESULTS: In total, 47 women were enrolled (46 evaluable) in 3 years. Characteristics included a median age of 53 years; 1988 International Federation of Gynecology and Obstetrics stage I disease in 81% of patients, stage II disease in 15%, and serosa-only stage IIIA disease in 4%; American Joint Committee on Cancer stage II disease in 13% of patients and stage III disease in 87%; a median tumor size of 8 cm (range, 2.5-30 cm); and a median mitotic rate of 18 mitoses per 10 high-power fields (range, 5-83 mitoses per 10 high-power fields). At a median follow-up of 39.8 months, 21 of 46 patients developed recurrent disease (45.7%). The median time to recurrence was 27.4 months (range, 3-40 months). Seventy-eight percent of patients (95% confidence interval, 67%-91%) were progression-free at 2 years, and 57% (95% confidence interval, 44%-74%) were progression-free at 3 years. The median PFS was not reached and exceeded 36 months. CONCLUSIONS: Among women with high-grade, uterus-limited uLMS who received treatment with adjuvant gemcitabine plus docetaxel followed by doxorubicin, 78% remained progression-free at 2 years, and 57% remained progression-free at 3 years. A randomized trial of adjuvant chemotherapy versus observation to determine whether adjuvant chemotherapy can improve survival in women with uterus-limited uLMS is underway.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leiomiossarcoma/tratamento farmacológico , Neoplasias Uterinas/tratamento farmacológico , Adulto , Idoso , Quimioterapia Adjuvante , Estudos de Coortes , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Docetaxel , Doxorrubicina/administração & dosagem , Feminino , Humanos , Leiomiossarcoma/patologia , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/patologia , Estudos Prospectivos , Taxoides/administração & dosagem , Resultado do Tratamento , Neoplasias Uterinas/patologia , GencitabinaRESUMO
Primary squamous cell carcinoma of the endometrium (PSCCE) is a rare entity, with fewer than 100 cases reported in the literature. We report two cases of PSCCE and review the literature regarding associated markers and treatment outcomes. Many different markers have been tested for association with PSCCE, with mixed results. Thus, it is likely that several etiologic factors are responsible for the development of PSCCE. Further, due to the rarity of the condition, the optimal postoperative management of patients with PSCCE remains to be defined.
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Carcinoma de Células Escamosas/patologia , Neoplasias do Endométrio/patologia , Endométrio/patologia , Idoso , Carcinoma de Células Escamosas/cirurgia , Neoplasias do Endométrio/cirurgia , Endométrio/cirurgia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Cuidados Pós-OperatóriosRESUMO
OBJECTIVES: Aflibercept targets vascular endothelial growth factor and placental growth factor. We evaluated activity and toxicity of aflibercept in recurrent/persistent endometrial cancer patients. Biomarkers and association with clinical characteristics and outcome were explored. METHODS: Eligible patients had measurable disease; 1-2 prior cytotoxic regimens; performance status 0-2. Aflibercept 4 mg/kg IV q14 days (28-day cycles) was administered until disease progression or prohibitive toxicity. Primary endpoints were the proportion of patients with progression-free survival at 6 months (PFS6) and tumor response rate. A flexible two-stage group sequential design to detect 20% increases in the proportion of patients responding or enduring PFS6 with 90% power (α=10%) was employed. RESULTS: Forty-nine patients were enrolled; five were excluded: wrong primary (2), second primary (1), wrong cell type (1); and never treated (1). Median age was 64 (range 48-83). Eighteen patients (41%) had two prior regimens; 27 (61%) had prior radiation. The PFS6 rate was 41%; three patients (7%, 90% CI: 2-17) had partial response. Of note, 10 patients (23%) met the PFS6 endpoint without starting a subsequent therapy; the remaining eight patients discontinued therapy for toxicity and started another therapy before 6 months elapsed. Median PFS and overall survival were 2.9 months and 14.6 months, respectively. Significant grade 3/4 toxicities were: cardiovascular (23%/5%), constitutional (7%/0), hemorrhage (2%/5%), metabolic (7%/2%), and pain (18%/0). Two treatment-related deaths were recorded: GI perforation (1), and arterial rupture (1). FGF1 expression was associated with response. CONCLUSIONS: Aflibercept met pretrial activity parameters, but was associated with significant toxicity at this dose and schedule in this population.
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Neoplasias do Endométrio/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Endométrio/química , Neoplasias do Endométrio/mortalidade , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/química , Recidiva Local de Neoplasia/mortalidade , Receptores de Fatores de Crescimento do Endotélio Vascular , Proteínas Recombinantes de Fusão/efeitos adversosRESUMO
PURPOSE: Two cases of successful desensitization to docetaxel after severe hypersensitivity reactions are reported. SUMMARY: Two patients with gynecological malignancies (uterine leiomyosarcoma and ovarian adenocarcinoma) experienced severe hypersensitivity reactions with docetaxel, including flushing, numbness, sharp radiating pain, severe nausea and vomiting, apnea, and unresponsiveness. Both patients received ondansetron before docetaxel. One patient received dexamethasone, diphenhydramine, and famotidine premedication before docetaxel, as she had previously reacted to paclitaxel. Docetaxel infusions were stopped, and the reactions were treated with diphenhydramine and dexamethasone (one patient also received famotidine). After resolution of symptoms, the docetaxel was not reinitiated due to the nature of the reactions. For the next cycle, both patients received a graded drug challenge or desensitization. Both were pre-medicated with dexamethasone, diphenhydramine, and famotidine. The docetaxel was given as infusions of 0.1%, 1%, and 10% of the dose, with each infusion given over one hour. After this, the remainder of the dose was infused over one hour. Both patients tolerated this desensitization well and completed a total of three and four cycles each. The first patient to receive the desensitization did complain of chest pain during the first desensitization, and the infusion rate was decreased to administer the drug over two hours. After she tolerated two cycles of two-hour infusions, the infusion rate was increased to administer each docetaxel infusion over one hour. CONCLUSION: Two patients who had severe hypersensitivity reactions to docetaxel successfully received further docetaxel doses via a desensitization procedure that involved the sequential administration of solutions containing increasing concentrations of the drug.
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Antineoplásicos/efeitos adversos , Dessensibilização Imunológica/métodos , Hipersensibilidade a Drogas/prevenção & controle , Taxoides/efeitos adversos , Adulto , Antineoplásicos/imunologia , Antineoplásicos/uso terapêutico , Docetaxel , Hipersensibilidade a Drogas/etiologia , Hipersensibilidade a Drogas/imunologia , Feminino , Neoplasias dos Genitais Femininos/tratamento farmacológico , Humanos , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Taxoides/imunologia , Taxoides/uso terapêutico , Resultado do TratamentoRESUMO
PURPOSE: The Gynecologic Oncology Group (GOG) conducted a phase II trial to assess the efficacy and tolerability of the anti-EGFR antibody cetuximab, in persistent or recurrent carcinoma of the cervix. PATIENTS AND METHODS: Eligible patients had cervical cancer, measurable disease, and GOG performance status ≤2. Treatment consisted of cetuximab 400 mg/m(2) initial dose followed by 250 mg/m(2) weekly until disease progression or prohibitive toxicity. The primary endpoints were progression-free survival (PFS) at 6 months and response. The study used a 2-stage group sequential design. RESULTS: Thirty-eight patients were entered with 3 exclusions, leaving 35 evaluable for analysis. Thirty-one patients (88.6%) received prior radiation as well as either 1 (n=25, 71.4%) or 2 (n=10) prior cytotoxic regimens. Twenty-four patients (68.6%) had a squamous cell carcinoma. Grade 3 adverse events possibly related to cetuximab included dermatologic (n=5), GI (n=4), anemia (n=2), constitutional (n=3), infection (n=2), vascular (n=2), pain (n=2), and pulmonary, neurological, vomiting and metabolic (n=1 each). No clinical responses were detected. Five patients (14.3%; two-sided 90% CI, 5.8% to 30%) survived without progression for at least 6 months. The median PFS and overall survival (OS) times were 1.97 and 6.7 months, respectively. In this study, all patients with PFS at 6 months harbored tumors with squamous cell histology. CONCLUSION: Cetuximab is well tolerated but has limited activity in this population. Cetuximab activity may be limited to patients with squamous cell histology.
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Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antineoplásicos/efeitos adversos , Cetuximab , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
Melanocortin-3 receptors (Mc3rs) in the central nervous system are involved in expression of anticipatory rhythms and synchronizing clocks maintaining circadian rhythms during restricted feeding (RF) [mice housed under a 12-h light-dark cycle with lights on between zeitgeber time (ZT) 0 to ZT12 fed 60% of normal calories between ZT7 and ZT11]. Because the systems governing circadian rhythms are important for adaptation to RF, we investigated whether Mc3rs are required for metabolic adaption to RF. Mc3r(-/-) mice subjected to RF exhibited normal weight loss; however, they developed hyperinsulinemia, glucose intolerance, increased expression of lipogenic genes, and increased ketogenesis relative to controls. Rhythmic expression of transcription factors regulating liver clock activity and energy metabolism (Bmal1, Rev-erbalpha, Pgc1, Foxo1, Hnf4alpha, and Pck1) was severely compromised in Mc3r(-/-) mice during RF. Inhibition of neural melanocortin receptors by agouti-related peptide also attenuated rhythmicity in the hepatic expression of these genes during RF. Collectively, these data suggest that neural Mc3rs are important for adapting metabolism and maintaining rhythms of liver metabolism during periods when feeding is restricted to the light cycle.-Sutton, G. M., Begriche, K., Kumar, K. G., Gimble, J. M., Perez-Tilve, D., Nogueiras, R., McMillan, R. P., Hulver, M. W., Tschöp, M. H., Butler, A. A. Central nervous system melanocortin-3 receptors are required for synchronizing metabolism during entrainment to restricted feeding during the light cycle.
Assuntos
Restrição Calórica , Sistema Nervoso Central/metabolismo , Fotoperíodo , Receptor Tipo 3 de Melanocortina/fisiologia , Proteína Relacionada com Agouti/farmacologia , Animais , Sistema Nervoso Central/efeitos da radiação , Eletroforese em Gel de Poliacrilamida , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Ácidos Graxos/metabolismo , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/metabolismo , Intolerância à Glucose/genética , Teste de Tolerância a Glucose , Hiperinsulinismo/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Mutantes , Receptor Tipo 3 de Melanocortina/antagonistas & inibidores , Receptor Tipo 3 de Melanocortina/genéticaRESUMO
BACKGROUND: 2-Methoxyestradiol (Panzem, 2ME2) is an endogenous metabolite of estradiol that destabilizes microtubules and exerts anti-angiogenic properties. This study was conducted to determine the activity and safety of 2ME2 administered as a NanoCrystal dispersion (NCD) formulation in patients with recurrent, platinum-resistant epithelial ovarian cancer (EOC). METHODS: Eligible patients had relapsed, platinum-resistant or refractory EOC with measurable or detectable disease. There was no limit on the number of prior treatment regimens. 2ME2 NCD 1000 mg orally four times daily (q.i.d.) was administered continuously during 4 week cycles. The primary endpoint was objective response rate (ORR). Secondary endpoints were assessment of toxicity, rate of clinical benefit defined as the number of patients experiencing an objective response, a CA125 response or stable disease (SD) >3 months, mean change in CA-125, progression-free survival (PFS), and pharmacokinetic analyses of 2ME2. RESULTS: Eighteen patients were enrolled. Median age was 65.5 (range 40-73). Patients had received a median of five prior treatments. The most common adverse events were fatigue (78%), nausea (78%), diarrhea (39%), neuropathy (50%), edema (39%), and dyspnea (44%), the majority being grade 1-2. There were no objective responses, but seven patients had SD as best response. Of those, two patients had SD for greater than 12 months. The rate of clinical benefit was 31.3%. Fairly stable plasma levels of 2ME2 ranging within the predicted therapeutic window were observed. CONCLUSIONS: The NCD formulation of 2ME2 is well tolerated in patients with heavily pretreated EOC. Few of these heavily pretreated patients had sustained stable disease.
Assuntos
Antineoplásicos/uso terapêutico , Estradiol/análogos & derivados , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , 2-Metoxiestradiol , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Antígeno Ca-125/sangue , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Estradiol/efeitos adversos , Estradiol/sangue , Estradiol/farmacocinética , Estradiol/uso terapêutico , Feminino , Humanos , Hidroxiestronas/sangue , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Compostos Organoplatínicos/farmacologia , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/metabolismo , Neoplasias Peritoneais/sangue , Neoplasias Peritoneais/metabolismoRESUMO
Obesity and nutrient homeostasis are linked by mechanisms that are not fully elucidated. Here we describe a secreted protein, adropin, encoded by a gene, Energy Homeostasis Associated (Enho), expressed in liver and brain. Liver Enho expression is regulated by nutrition: lean C57BL/6J mice fed high-fat diet (HFD) exhibited a rapid increase, while fasting reduced expression compared to controls. However, liver Enho expression declines with diet-induced obesity (DIO) associated with 3 months of HFD or with genetically induced obesity, suggesting an association with metabolic disorders in the obese state. In DIO mice, transgenic overexpression or systemic adropin treatment attenuated hepatosteatosis and insulin resistance independently of effects on adiposity or food intake. Adropin regulated expression of hepatic lipogenic genes and adipose tissue peroxisome proliferator-activated receptor gamma, a major regulator of lipogenesis. Adropin may therefore be a factor governing glucose and lipid homeostasis, which protects against hepatosteatosis and hyperinsulinemia associated with obesity.
Assuntos
Proteínas Sanguíneas/fisiologia , Metabolismo Energético , Metabolismo dos Lipídeos , Proteínas/fisiologia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Benzoatos/química , Benzoatos/metabolismo , Benzilaminas/química , Benzilaminas/metabolismo , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Células Cultivadas , Proteínas de Ligação a DNA/agonistas , Proteínas de Ligação a DNA/metabolismo , Jejum , Fígado Gorduroso/metabolismo , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Leptina/metabolismo , Receptores X do Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Dados de Sequência Molecular , Obesidade/genética , Obesidade/metabolismo , Receptores Nucleares Órfãos , Peptídeos , Proteínas/genética , Proteínas/metabolismo , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/metabolismoRESUMO
BACKGROUND: Ovarian tumors frequently express c-Kit and/or platelet-derived growth factor receptors (PDGFRs). Imatinib mesylate blocks the growth of ovarian cancer cells in vitro and may enhance the activity of chemotherapy. This study was conducted to determine the activity of imatinib in combination with docetaxel in patients with recurrent, platinum-resistant epithelial ovarian cancer (EOC). METHODS: Eligible patients had recurrent, platinum-resistant, or refractory EOC that expressed PDGFRalpha or c-kit, as determined by immunohistochemistry. Imatinib mesylate at a dose of 600 mg orally once daily was administered continuously with docetaxel at a dose of 30 mg/m(2) given intravenously once weekly in Weeks 1 through 4 of every 6-week cycle. The primary endpoint was objective response rate (ORR) as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: Thirty-four patients were screened for PDGFRalpha and c-kit expression to enroll 23 patients between December 2003 and October 2005. Four patients had c-kit-positive/PDGFR-negative tumors, 11 patients had PDGFR-positive/c-kit-negative tumors, and 8 patients had c-kit-positive/PDGFR-positive tumors. The median patient age was 56 years (range, 33-76 years). Patients had received a median of 3 prior treatments. The ORR was 21.7% and included 1 complete and 4 partial responses. An additional 3 patients had stable disease for more than 4 months. Expression of PDGFR, c-kit, phosphatase and tensin homolog (PTEN), and phosphorylated protein kinase B (Akt) did not predict response to therapy. The most common adverse events encountered were fatigue (83%), nausea (74%), diarrhea (61%), anorexia (52%), and edema (65%), and the majority of those events were graded as grade 1 or 2. CONCLUSIONS: The combination imatinib and docetaxel was tolerated in patients with heavily pretreated EOC that expressed c-kit or PDGFRalpha. Few patients had sustained responses or stable disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Taxoides/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas , Docetaxel , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Mesilato de Imatinib , Pessoa de Meia-Idade , Proteína Oncogênica v-akt/análise , Compostos Organoplatínicos/uso terapêutico , Neoplasias Ovarianas/metabolismo , Neoplasias Peritoneais/secundário , Proteínas Proto-Oncogênicas c-kit/análise , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/análise , Recidiva , Análise de Sobrevida , Resultado do TratamentoRESUMO
Melanocortin receptors are considered promising candidates for the treatment of behavioral and metabolic disorders ranging from obesity to anorexia and cachexia. These experiments examined the response of mice to peripheral injections of two compounds. PG932 is a derivative of SHU9119 which is non-selective antagonist of melanocortin-3 and melanocortin-4 receptors (Mc3r and Mc4r). PG946 is a derivative of a hybrid of alpha- and beta-MSH, and is a moderately selective Mc3r antagonist. SHU9119 increases food intake when administered intracerebroventricularly but is without effect when injected into the periphery. In contrast, PG932 was found to be highly effective at stimulating food intake when administered peripherally by intraperitoneal injection. The orexigenic effect of PG932 required functional Mc4r, suggesting that inhibition of this receptor is involved in the stimulation of food intake. PG946 did not significantly affect on feeding behavior. PG932 is thus a useful new compound for studies examining the regulation of appetite and energy balance, and may also prove useful for the treatment of cachectic conditions.