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1.
HPB (Oxford) ; 17(2): 131-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25123702

RESUMO

OBJECTIVES: Laparoscopy is recommended to detect radiographically occult metastases in patients with pancreatic cancer before curative resection. This study was conducted to test the hypothesis that diagnostic laparoscopy (DL) is cost-effective in patients undergoing curative resection with or without neoadjuvant therapy (NAT). METHODS: Decision tree modelling compared routine DL with exploratory laparotomy (ExLap) at the time of curative resection in resectable cancer treated with surgery first, (SF) and borderline resectable cancer treated with NAT. Costs (US$) from the payer's perspective, quality-adjusted life months (QALMs) and incremental cost-effectiveness ratios (ICERs) were calculated. Base case estimates and multi-way sensitivity analyses were performed. Willingness to pay (WtP) was US$4166/QALM (or US$50,000/quality-adjusted life year). RESULTS: Base case costs were US$34,921 for ExLap and US$33,442 for DL in SF patients, and US$39,633 for ExLap and US$39,713 for DL in NAT patients. Routine DL is the dominant (preferred) strategy in both treatment types: it allows for cost reductions of US$10,695/QALM in SF and US$4158/QALM in NAT patients. CONCLUSIONS: The present analysis supports the cost-effectiveness of routine DL before curative resection in pancreatic cancer patients treated with either SF or NAT.


Assuntos
Laparoscopia/economia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/cirurgia , Efeitos Psicossociais da Doença , Análise Custo-Benefício , Árvores de Decisões , Humanos , Terapia Neoadjuvante , Neoplasias Pancreáticas/economia , Anos de Vida Ajustados por Qualidade de Vida , Estados Unidos
2.
Oncologist ; 19(3): 266-74, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24569947

RESUMO

BACKGROUND: Borderline resectable pancreatic cancer is best treated by multimodality therapy. FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin) tripled the response rate and significantly increased median survival for patients with advanced pancreatic cancer and shows promise for neoadjuvant use. Toxicity concerns prompted a careful analysis of our initial FOLFIRINOX experience. METHODS: All patients diagnosed with borderline resectable, biopsy-proven pancreatic adenocarcinoma treated with neoadjuvant FOLFIRINOX between July 2010 and December 2012 were reviewed. Primary outcome was surgical resectability. Secondary outcomes were treatment-related toxicities and survival. RESULTS: FOLFIRINOX followed by gemcitabine- or capecitabine-based chemoradiation was initiated in 18 patients. The most common grade 3 or 4 toxicities during chemotherapy were gastrointestinal, including nausea/emesis (n = 5), weight loss (n = 3) and diarrhea (n = 2), and hematologic (n = 2; neutropenia); five patients (36%) required a total of six admissions. Neoadjuvant therapy was completed in 15 of 18 patients (83%), and 12 (67%) underwent pancreatectomy (10 Whipple, 2 total pancreatectomy) including portal vein resection/reconstruction in 10 (83%). Disease progression precluded surgery in 6 of the 18 patients (33%). All 12 resected patients had negative (R0) margins. Only 2 of 12 (17%) were node positive (median node count: 26.5 [range: 15-39]). There were no in-hospital or 30-day mortalities and no clinical pancreatic leaks or reoperations. Of the 12 patients who completed all intended therapy, 7 (58.3%) are alive, including 5 who have no evidence of disease (median months from diagnosis: 22 months [range: 18-35 months). The six patients who did not complete all planned therapy are deceased (months from diagnosis: 6.9-17.5 months). CONCLUSION: FOLFIRINOX followed by chemoradiation as neoadjuvant therapy for borderline resectable pancreatic adenocarcinoma is safe, and our initial experience suggests favorable resection rates compared with previous reports in this high-risk patient population.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Capecitabina , Quimioterapia Adjuvante , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Humanos , Irinotecano , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Resultado do Tratamento , Gencitabina
3.
Ann Surg Oncol ; 21(1): 240-7, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24114054

RESUMO

BACKGROUND: Development of cholecystitis in patients with malignancies can potentially disrupt their treatment and alter prognosis. This review aims to identify antineoplastic interventions associated with increased risk of cholecystitis in cancer patients. METHODS: A comprehensive search strategy was developed to identify articles pertaining to risk factors and complications of cholecystitis in cancer patients. FDA-issued labels of novel antineoplastic drugs released after 2010 were hand-searched to identify more therapies associated with cholecystitis in nonpublished studies. RESULTS: Of an initial 2,932 articles, 124 were reviewed in the study. Postgastrectomy patients have a high (5-30 %) incidence of gallstone disease, and 1-7 % develop symptomatic disease. One randomized trial addressing the role of cholecystectomy concurrent with gastrectomy is currently underway. Among other risk groups, patients with neuroendocrine tumors treated with somatostatin analogs have a 15 % risk of cholelithiasis, and most are symptomatic. Hepatic artery based therapies carry a risk of cholecystitis (0.02-24 %), although the risk is reduced with selective catheterization. Myelosuppression related to chemotherapeutic agents (0.4 %), bone marrow transplantation, and treatment with novel multikinase inhibitors are associated with high risk of cholecystitis. CONCLUSIONS: There are several risk factors for gallbladder-related surgical emergencies in patients with advanced malignancies. Incidental cholecystectomy at index operation should be considered in patients planned for gastrectomy, and candidates for regional therapies to the liver or somatostatin analogs. While prophylactic cholecystectomy is currently recommended for patients with cholelithiasis receiving myeloablative therapy, this strategy may have value in patients treated with multikinase inhibitors, immunotherapy, and oncolytic viral therapy based on evolving evidence.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças Biliares/induzido quimicamente , Colecistite/induzido quimicamente , Colelitíase/induzido quimicamente , Empiema/induzido quimicamente , Neoplasias Gástricas/tratamento farmacológico , Doença Aguda , Humanos , Prognóstico
4.
Surg Endosc ; 28(5): 1505-14, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24687416

RESUMO

BACKGROUND: Host factors and therapy characteristics predispose cancer patients to a high risk of acute cholecystitis. Management of cholecystitis is often difficult given complex decision making involving the underlying cancer, possible interruption of treatment, and surgical fitness of the patient. METHODS: A management pathway was developed for cholecystitis in cancer patients which incorporated patient-specific survival and risks of recurrence. Estimates were obtained from a multistage systematic review. A decision tree with a lifetime horizon was constructed to compare conventional strategies [conservative treatment (CT), percutaneous cholecystostomy (PC) and definitive cholecystectomy (DC)] with the new pathway (NP). The decision tree was optimized for highest estimated survival. Sensitivity analyses were performed. RESULTS: In low surgical risk patients with cancer-specific survival of 12 months, the NP yielded estimated survivals of 11.9 versus 11.8 (CT) versus 11.8 (PC) versus 11.9 months for the DC arm. For high-risk patients, the estimated survival was 11.6 (NP), 9.9 (DC), 11.4 (PC), and 11 (CT) months, respectively. The decision to perform a DC at 6 weeks after a PC was optimum in patients expected to survive 24 months (23.2 months from the NP) or with a shorter expected survival but a high recurrence risk (>20 %). Model estimates were robust in sensitivity analyses. CONCLUSIONS: Incorporation of the surgical risk and the risk of recurrent cholecystitis, while balancing the patient-specific survival and the impact of antineoplastic therapy in the management of cholecystitis yields improved survival. This work provides measures to evaluate surgical judgment, and can augment the physician-patient decision making.


Assuntos
Colecistectomia/métodos , Colecistite Aguda/cirurgia , Colecistostomia/métodos , Gerenciamento Clínico , Neoplasias/complicações , Colecistite Aguda/complicações , Humanos
5.
Ther Adv Med Oncol ; 16: 17588359241253113, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38770091

RESUMO

Background: KRAS wild-type (WT) pancreatic ductal adenocarcinoma (PDAC) represents a distinct entity with unique biology. The therapeutic impact of matched targeted therapy in these patients in a real-world setting, to date, is less established. Objectives: The aim of our study was to review our institutional database to identify the prevalence of actionable genomic alterations in patients with KRAS-WT tumors and to evaluate the therapeutic impact of matched targeted therapy in these patients. Design: We reviewed electronic medical records of patients with KRAS-WT PDAC and advanced disease (n = 14) who underwent clinical-grade tissue ± liquid next-generation sequencing (315-648 genes for tissue) between years 2015 and 2021. Methods: Demographic and disease characteristics were summarized using descriptive parameters. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results: Of 236 PDAC patients, 14 had advanced/metastatic disease with KRAS-WT tumors. Median age at diagnosis was 66 years. There was a high frequency of potentially actionable genomic alterations, including three (21%) with BRAF alterations, two (14%) with fusions [RET-PCM1 and FGFR2-POC1B (N = 1 each)]; and one with a druggable EGFR (EGFR E746_A755delISERD) variant; two other patients had an STK11 and a MUTYH alteration. Five patients were treated with matched targeted therapy, with three having durable benefit: (i) erlotinib for EGFR-altered tumor, followed by osimertinib/capmatinib when MET amplification emerged (first-line therapy); (ii) pralsetinib for RET fusion (fifth line); and (iii) dabrafenib/trametinib for BRAF N486_P490del (third line). Duration of time on chemotherapy-free matched targeted therapy for these patients was 17+, 11, and 18+ months, respectively. Conclusion: Sustained therapeutic benefit can be achieved in a real-world setting in a subset of patients with advanced/metastatic KRAS-WT PDAC treated with chemotherapy-free matched targeted agents. Prospective studies are warranted.

6.
Eur Arch Otorhinolaryngol ; 270(10): 2695-700, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23632870

RESUMO

The aim of this study is to analyze change in pitch following feminization laryngoplasty, a technique to alter the vocal tract of male to female transgender patients. This is a retrospective review of 94 patients undergoing feminization laryngoplasty between June 2002 and April 2012 of which 76 individuals completed follow-up audio recordings. Feminization laryngoplasty is a procedure removing the anterior thyroid cartilage, collapsing the diameter of the larynx as well as shortening and tensioning the vocal folds to raise the pitch. Changes in comfortable speaking pitch, lowest vocal pitch and highest vocal pitch are assessed before and after surgery. Acoustic parameters of speaking pitch and vocal range were compared between pre- and postoperative results. The average comfortable speaking pitch preoperatively, C3# (139 Hz), was raised an average of six semitones to G3 (196 Hz), after surgical intervention. The lowest attainable pitch was raised an average of seven semitones and the highest attainable pitch decreased by an average of two semitones. One aspect of the procedure, thyrohyoid approximation (introduced in 2006 to alter resonance), did not affect pitch. Feminization laryngoplasty successfully increased the comfortable fundamental frequency of speech and removed the lowest notes from the patient's vocal range. It does not typically raise the upper limits of the vocal range.


Assuntos
Laringoplastia/métodos , Cirurgia de Readequação Sexual/métodos , Cartilagem Tireóidea/cirurgia , Pessoas Transgênero , Prega Vocal/cirurgia , Voz , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Qualidade da Voz , Adulto Jovem
7.
Eur Arch Otorhinolaryngol ; 270(3): 995-9, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23143641

RESUMO

The objectives of this study were: (1) to determine the percentage of patients seen in a private laryngology clinic with voice-related disorders previously diagnosed with and treated for laryngopharyngeal reflux (LPR); (2) to determine how many of those patients are found to have disorders other than LPR as a cause for their voice disorder. A retrospective, chart-review analysis of new patients was conducted from January 2005 through December 2007 in a private laryngology clinic setting. Patients with a previous diagnosis of LPR as the cause of hoarseness, with or without anti-reflux treatment were included. Incomplete charts and patients with additional diagnoses besides LPR where excluded. Patient charts were analyzed in search of different variables including chief complaint, previous medications and final diagnosis among others. 784 consecutive charts were reviewed. Inclusion criteria were met in 105 charts. 82 % had no improvement or felt worse after previous anti-reflux treatment while 18 % had significant or mild improvement. However, all patients remained with some degree of hoarseness. Final diagnosis by the author was diverse though none of the patients had laryngopharyngeal reflux as a final diagnosis and none of them noted worsening of their voice after respective treatment. Only 6 % felt the same after treatment and 9 % could not be found for follow-up. LPR has become an over-diagnosed entity. With a thorough history, vocal capability testing and physical exam, an accurate diagnosis for hoarseness can be made in the vast majority of cases. LPR may not be the cause of voice disorders and should not be assigned as a de facto diagnosis just because the cause of hoarseness is not readily identifiable.


Assuntos
Erros de Diagnóstico/estatística & dados numéricos , Rouquidão/diagnóstico , Doenças da Laringe/diagnóstico , Refluxo Laringofaríngeo/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Disfonia/diagnóstico , Feminino , Rouquidão/etiologia , Humanos , Refluxo Laringofaríngeo/complicações , Masculino , Pessoa de Meia-Idade , Pólipos/diagnóstico , Estudos Retrospectivos , Paralisia das Pregas Vocais/diagnóstico , Adulto Jovem
8.
Laryngoscope ; 133(9): 2301-2307, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-36576093

RESUMO

OBJECTIVE: Transfeminine patients (transwomen/feminine nonbinary folks assigned male at birth) can undergo chondrolaryngoplasty ("tracheal shave") to feminize their neck appearance. While isolated cases of vocal complications have been reported following the procedure, aggregated outcomes have not been quantitatively studied. We present acoustic and stroboscopic data to describe a patient cohort with vocal complications after chondrolaryngoplasty and discuss reparative surgical technique. METHODS: Subjective and objective data, including videostroboscopy, were collected from patients with voice complaints after chondrolaryngoplasty. Dislocated anterior commissures were reconstructed with feminization laryngoplasty. Postoperative voice data were recorded and statistically compared to preoperative data using paired t-tests. RESULTS: On consecutive chart review, of the 94 transfeminine women with prior outside history of chondrolaryngoplasty, 27 (29%) reported chronic postoperative hoarseness, deepened pitch, or loss of upper register. On endoscopy, short, lax vocal folds with persistent anterior glottic gap and phase asymmetry were commonly noted; anterior commissure dislocation was confirmed in-office by using needle localization through absent thyroid cartilage. After open resuspension of the anterior commissure with feminization laryngoplasty, post-repair modal-speaking, minimum, and maximum fundamental frequencies (F0) increased on average by 7, 8, and 5 semitones, respectively (p < 0.01), when compared to pre-repair values. On average, perioperative maximum phonation time did not change significantly (p = 0.15). Average self-assessment of vocal femininity increased by 48% (p < 0.01). CONCLUSION: Anterior commissure dislocation should be suspected with signs of vocal impairment after chondrolaryngoplasty. Following proper diagnosis, resuspension of the anterior commissure via feminization laryngoplasty approach can be an effective reparative technique. LEVEL OF EVIDENCE: This work represents a 2011 OCEBM Level 4 evidence as a case series Laryngoscope, 133:2301-2307, 2023.


Assuntos
Laringoplastia , Pessoas Transgênero , Voz , Recém-Nascido , Humanos , Masculino , Feminino , Qualidade da Voz , Feminização/cirurgia , Prega Vocal/cirurgia , Laringoplastia/efeitos adversos , Laringoplastia/métodos , Resultado do Tratamento
9.
Otolaryngol Clin North Am ; 55(4): 767-774, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35934513

RESUMO

The national otolaryngology-head and neck surgery (OHNS) landscape of transgender and nonbinary/gender-nonconforming (TNG) care education and gender-affirming surgical training is variable with limited availability. However, specialized and innovative training with breadth and depth is available at select training sites focusing on facial and/or vocal gender affirmation throughout the United States. With growing trainee interest, program and fellowship director-related efforts to expand training, and progressive arcs of social change focusing on protections and promotion of TNG health, the future of OHNS training opportunities to serve TNG patients is promising.


Assuntos
Internato e Residência , Otolaringologia , Pessoas Transgênero , Bolsas de Estudo , Identidade de Gênero , Humanos , Otolaringologia/educação , Estados Unidos
10.
Invest New Drugs ; 29(2): 316-22, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19997959

RESUMO

PURPOSE: To assess the safety, maximum-tolerated dose (MTD), and dose-limiting toxicities (DLT), of motexafin gadolinium (MGd), given in combination with doxorubicin, in patients with advanced solid tumors. STUDY DESIGN: The combination of MGd and doxorubicin was administered every 28 days (cycle 1) and then every 21 days (subsequent cycles). The dose of MGd, given daily for 3 days, was escalated from 1.0 mg/kg/d to 3.3 mg/kg/d, while the dose of doxorubicin was held at 30 mg/m². RESULTS: Fifteen patients received 37 cycles of treatment, for a median of 2 cycles per patient (range 0-6 cycles). Three patients (20%) completed 6 cycles of therapy. The MTD was identified as MGd, 2 mg/kg/day and doxorubicin, 30 mg/m². Dose limiting toxicities included grade 3 hypertension, pneumonia, bacteremia, and elevated GGT. Serious adverse events also included pulmonary embolism and urinary tract infection requiring hospitalization. There was no exacerbation of cardiac toxicity. No patients attained a response to treatment. Six patients (54%) had stable disease. The median time to disease progression, or to last assessment, was 49 days (range 8-195 days). CONCLUSIONS: The combination of MGd and doxorubicin was fairly well tolerated. However, due to emerging preclinical data suggesting that MGd inhibits ribonucleotide reductase, further development of the combination of MGd plus doxorubicin is not recommended.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doxorrubicina/uso terapêutico , Metaloporfirinas/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Demografia , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Masculino , Metaloporfirinas/administração & dosagem , Metaloporfirinas/efeitos adversos , Pessoa de Meia-Idade , Neoplasias/patologia , Resultado do Tratamento
11.
J Endod ; 46(2): 244-251.e1, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32040423

RESUMO

INTRODUCTION: This study evaluated and compared the shaping ability of the WaveOne Gold (Dentsply/Tulsa Dental Specialties, Tulsa, OK), TRUShape 3D Conforming File (Dentsply/Tulsa Dental Specialties), EdgeCoil (EdgeEndo, Albuquerque, NM), and XP-3D Shaper (Brasseler USA, Savannah, GA) endodontic file systems on oval-shaped canals using micro-computed tomographic (micro-CT) technology. METHODS: Thirty-two oval-shaped, single-canal extracted human teeth were decoronated 1 mm coronal to the cementoenamel junction and scanned via a micro-CT scanner (µCT100; Scanco Medical, Bassersdorf, Switzerland). Teeth were divided into 4 groups (n = 8) and instrumented according to the manufacturer's instructions. Coregistered images, before and after root canal preparation, were evaluated for morphometric measurements of the surface area, volume, structure model index (SMI), conicity, and percent of walls untouched using the manufacturer's evaluation software (IPL Register, Scanco Medical). Data were statistically compared between groups using 1-way analysis of variance and within groups using a paired sample t test. RESULTS: Instrumentation with all file types increased the surface area, volume, and conicity between and within groups. There was no statistically significant difference between the groups for any of the rotary instruments used (P < .05). CONCLUSIONS: Instrumentation of oval-shaped canals with WaveOne Gold, TRUShape, EdgeCoil, and XP-3D Shaper rotary endodontic instruments similarly increase the volume, surface area, and conicity. None of the file systems were capable of contacting all of the surface area in any canal.


Assuntos
Cavidade Pulpar , Ouro , Preparo de Canal Radicular , Desenho de Equipamento , Humanos , Microtomografia por Raio-X
12.
Oncology ; 76(5): 333-7, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19307739

RESUMO

OBJECTIVES: There is a paucity of data exploring treatment options for refractory pancreatic cancer. Oxaliplatin has interesting activity in second-line therapy. Fixed-dose-rate gemcitabine (GFDR, 10 mg/m(2)/min) has shown promising results in patients with advanced pancreatic cancer over standard-dose-rate (30 min) gemcitabine (GSDR). METHODS: We conducted a retrospective analysis of the experience of our cancer center with GFDR and oxaliplatin (GEMOX) in patients who failed GSDR. GEMOX consisted of gemcitabine 1,000 mg/m(2) over 100 min on day 1 and oxaliplatin 100 mg/m(2) over 2 h on day 2 every 2 weeks. Eligible patients were required to have measurable metastatic adenocarcinoma of the pancreas and to have failed prior GSDR. RESULTS: Seventeen patients (median age 62 years) who were treated at the Ohio State University with GEMOX following GSDR failure between November 2003 and January 2008 were included in this study. Twenty-four percent of all patients had a partial response, 29% had stable disease and 47% had progressive disease. The median progression-free survival was 2.6 months and the median overall survival was 6.4 months. There were no unexpected toxicities. CONCLUSION: GEMOX shows interesting activity and acceptable tolerability in patients with metastatic pancreatic cancer who failed prior GSDR. Our results are consistent with previously published results.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Relação Dose-Resposta a Droga , Feminino , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/tratamento farmacológico , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos Retrospectivos , Terapia de Salvação , Taxa de Sobrevida , Resultado do Tratamento , Gencitabina
13.
Cancer Chemother Pharmacol ; 62(4): 727-33, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18172649

RESUMO

INTRODUCTION: Chemotherapy regimens including gemcitabine in combination with microtubule inhibitors such as docetaxel and paclitaxel have wide clinical application. Patupilone is a novel tubulin-polymerizing agent with activity against paclitaxel-resistant cell lines. We conducted a phase I trial to assess the maximum tolerated dose, dose limiting toxicity (DLT) and antitumor activity of gemcitabine and patupilone. METHODS: Patients with refractory solid tumors enrolled in cohorts of three. Cohorts received fixed doses of gemcitabine (1,000 or 750 mg/m(2)) along with escalating doses of patupilone (1.5-3 mg/m(2)) on days 1 and 8 of a 21-day cycle. RESULTS: Twenty-seven patients received a total of 99 courses of treatment on study. Hematologic toxicity in the first cohort required a modification of the protocol to decrease the gemcitabine dose. Subsequent patients received gemcitabine 750 mg/m(2) and escalating doses of patupilone from 1.5 to 3 mg/m(2). DLTs were grade 3 asthenia and grade 3 dehydration. There was also one treatment-related death due to neutropenic infection. Other clinically significant toxicities were persistent asthenia and persistent nausea. Four patients, one each with pancreatic cancer, esophageal carcinoma, cholangiocarcinoma and gallbladder carcinoma, experienced a partial response. CONCLUSIONS: The dose-limiting toxicities of gemcitabine and patupilone were asthenia and dehydration. Dose reductions also occurred due to persistent fatigue that was not dose-limiting. However, patients with advanced malignancies were able to tolerate gemcitabine and patupilone at doses that resulted in clinical benefit. The recommended phase II dose for this schedule is gemcitabine 750 mg/m(2) and patupilone 1.5 mg/m(2) on days 1 and 8 of a 21-day cycle.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Relação Dose-Resposta a Droga , Epotilonas/administração & dosagem , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Resultado do Tratamento , Gencitabina
14.
J Inorg Biochem ; 102(4): 693-8, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18061679

RESUMO

The metal chelator Triapine, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, is a potent inhibitor of ribonucleotide reductase. EPR spectra consistent with signals from Fe-transferrin, heme, and low-spin iron or cupric ion were observed in peripheral blood mononuclear cells (PBMCs) obtained from patients treated with Triapine. One signal that is unequivocally identified is the signal for Fe-transferrin. It is hypothesized that Fe uptake is blocked by reactive oxygen species generated by FeT(2) or CuT that damage transferrin or transferrin receptor. A potential source for the increase in the heme signal is cytochrome c released from the mitochondria. These results provide valuable insight into the in vivo mechanism of action of Triapine.


Assuntos
Monócitos/química , Neoplasias/tratamento farmacológico , Piridinas/uso terapêutico , Tiossemicarbazonas/uso terapêutico , Citocromos c/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica , Humanos
15.
Clin Cancer Res ; 13(12): 3623-9, 2007 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-17510207

RESUMO

PURPOSE: To assess the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacodynamics, and antitumor activity of continuous weekly-administered paclitaxel and BMS-214662, a novel farnesyl transferase inhibitor. EXPERIMENTAL DESIGN: Patients were treated every week as tolerated with i.v. paclitaxel (fixed dose, 80 mg/m(2)/wk) administered over 1 h followed by i.v. BMS-214662 (escalating doses, 80-245 mg/m(2)/wk) over 1 h starting 30 min after completion of paclitaxel. RESULTS: Twenty-six patients received 94 courses (one course, 21 days) of study treatment. Two patients received five courses of BMS-214662 as a weekly 24-h infusion (209 mg/m(2)/wk). The most common toxicities were grade 1 to 2 nausea/vomiting and/or diarrhea. DLTs observed at or near the MTD (200 mg/m(2)/wk) were grade 4 febrile neutropenia with sepsis occurring on day 2 of course 1 (245 mg/m(2)/wk), reversible grade 3 to 4 serum transaminase increases on day 2, and grade 3 diarrhea (200 and 245 mg/m(2)/wk). Objective partial responses were observed in patients with pretreated head and neck, ovarian, and hormone-refractory prostate carcinomas, and leiomyosarcoma. The observed pharmacokinetics of paclitaxel and BMS-214662 imply no interaction between the two. Significant inhibition (>80%) of farnesyl transferase activity in peripheral mononuclear cells was observed at the end of BMS-214662 infusion. CONCLUSIONS: Pretreated patients with advanced malignancies can tolerate weekly paclitaxel and BMS-214662 at doses that achieve objective clinical benefit. Due to multiple DLTs occurring at the expanded MTD, the recommended phase 2 dose and schedule is paclitaxel (80 mg/m(2) over 1 h) and BMS-214662 (160 mg/m(2) over 1 h) administered weekly.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzodiazepinas/administração & dosagem , Imidazóis/administração & dosagem , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagem , Adulto , Idoso , Benzodiazepinas/efeitos adversos , Benzodiazepinas/farmacocinética , Feminino , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Paclitaxel/farmacocinética
16.
Clin Adv Hematol Oncol ; 6(1): 44-54, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18322441

RESUMO

BACKGROUND: Animal models suggest that growth hormone participates in hepatocarcinogenesis. OBJECTIVE: To correlate the effect of octreotide long-acting release (LAR) on insulin-like growth factor-I (IGF-I) and -II (IGF-II) with response and survival in patients with unresectable and metastatic hepatocellular carcinoma. METHODS: We conducted a phase II, single-institution trial of octreotide-LAR (30 mg intramuscularly every 4 weeks) in 15 patients while monitoring serum IGF-I and -II levels. RESULTS: Patients (median CLIP score 2, Okuda stage II, and ECOG performance status 1) were treated for a median of 2.0 cycles. No responses occurred. Median overall survival was 116 days (range, 27-937 days) and median progression-free survival was 60 days (range, 27-444 days). One patient had prolonged stable disease (16 months). There were no grade 4 and four grade 3 toxicities: abdominal cramping, elevated creatinine, diarrhea, and dyspnea. Median serum IGF-I decreased from baseline (42.2 ng/mL; range, 14.2-109 ng/mL) to day 29 (27.9 ng/mL; range, 5.7-71.1 ng/mL), and median serum IGF-II decreased from baseline (25,000 ng/mL; range, 12,400-93,600 ng/mL) to day 29 (18,400 ng/mL; range, 4,061-79,400 ng/mL; 2-sided P<.006 and P<.04, respectively; Wilcoxon signed rank test). This suppression did not correlate with clinical activity. Baseline serum IGF-I >30 ng/mL was associated with greater progression-free survival and overall survival (P=.0005 and P=.0173, respectively; 2-sided log-rank test). CONCLUSIONS: Octreotide-LAR lowered serum IGF-I and -II levels; however, this lowering did not correlate with clinical activity. There were no responses, and progression-free survival and overall survival were similar to historical patients not on treatment. Baseline serum IGF-I predicted prognosis.


Assuntos
Antineoplásicos Hormonais/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Fator de Crescimento Insulin-Like II/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Octreotida/farmacologia , Idoso , Preparações de Ação Retardada , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Prognóstico
17.
Int J Radiat Oncol Biol Phys ; 68(1): 13-23, 2007 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-17448867

RESUMO

PURPOSE: To standardize the indications, techniques, multimodality treatment approaches, and dosimetry to be used for yttrium-90 (Y90) microsphere hepatic brachytherapy. METHODS AND MATERIALS: Members of the Radioembolization Brachytherapy Oncology Consortium met as an independent group of experts in interventional radiology, radiation oncology, nuclear medicine, medical oncology, and surgical oncology to identify areas of consensus and controversy and to issue clinical guidelines for Y90 microsphere brachytherapy. RESULTS: A total of 14 recommendations are made with category 2A consensus. Key findings include the following. Sufficient evidence exists to support the safety and effectiveness of Y90 microsphere therapy. A meticulous angiographic technique is required to prevent complications. Resin microsphere prescribed activity is best estimated by the body surface area method. By virtue of their training, certification, and contribution to Y90 microsphere treatment programs, the disciplines of radiation oncology, nuclear medicine, and interventional radiology are all qualified to use Y90 microspheres. The panel strongly advocates the creation of a treatment registry with uniform reporting criteria. Initiation of clinical trials is essential to further define the safety and role of Y90 microspheres in the context of currently available therapies. CONCLUSIONS: Yttrium-90 microsphere therapy is a complex procedure that requires multidisciplinary management for safety and success. Practitioners and cooperative groups are encouraged to use these guidelines to formulate their treatment and dose-reporting policies.


Assuntos
Braquiterapia/métodos , Neoplasias Hepáticas/radioterapia , Microesferas , Radioisótopos de Ítrio/uso terapêutico , Braquiterapia/normas , Embolização Terapêutica/métodos , Física Médica/normas , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Seleção de Pacientes , Dosagem Radioterapêutica
18.
Otolaryngol Head Neck Surg ; 136(6): 894-9, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17547976

RESUMO

OBJECTIVE: Objective evaluation of botulinum toxin A (BTX-A) dosing by determination of the statistical relationship between injection amount and duration of side effects and normal voice in adductor spasmodic dysphonia (SD) patients. From this information, to provide a rational guide to determine the initial and follow-up BTX-A amounts for injection. STUDY DESIGN AND SETTING: Private laryngology clinic. Statistical analysis was performed on data obtained from 101 patients with SD. RESULTS: Significant and predictable positive correlations were found between duration of side effects and duration of normal voice after BTX-A injection in patients with SD. Dose of BTX-A injected also appeared to have a significant positive correlation with duration of side effects, but a negative correlation with duration of normal voice. A trend toward more severe side effects was seen with larger doses of BTX-A injections. CONCLUSIONS AND SIGNIFICANCE: Increased understanding of the response of the human voice over time after BTX-A injection at various doses suggests new ideas to further increase clinical efficacy with the use of lower BTX-A doses.


Assuntos
Toxinas Botulínicas Tipo A/efeitos adversos , Fármacos Neuromusculares/efeitos adversos , Distúrbios da Voz/tratamento farmacológico , Qualidade da Voz/efeitos dos fármacos , Toxinas Botulínicas Tipo A/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Injeções Intramusculares , Masculino , Fármacos Neuromusculares/administração & dosagem , Espectrografia do Som , Resultado do Tratamento
19.
Clin Cancer Res ; 11(21): 7851-60, 2005 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-16278408

RESUMO

At present, a variety of agents targeting tumor angiogenesis are under clinical investigation as new therapies for patients with cancer. Overexpression of the alpha(v)beta(3) integrin on tumor vasculature has been associated with an aggressive phenotype of several solid tumor types. Murine models have shown that antibodies targeting the alpha(v)beta(3) integrin can affect tumor vasculature and block tumor formation and metastasis. These findings suggest that antibodies directed at alpha(v)beta(3) could be investigated in the treatment of human malignancies. The current phase I dose escalation study evaluated the safety of MEDI-522, a monoclonal antibody specific for the alpha(v)beta(3) integrin, in patients with advanced malignancies. Twenty-five patients with a variety of metastatic solid tumors were treated with MEDI-522 on a weekly basis with doses ranging from 2 to 10 mg/kg/wk. Adverse events were assessed weekly; pharmacokinetic studies were done; and radiographic staging was done every 8 weeks. In addition, dynamic computed tomography imaging was done at baseline and at 8 weeks in patients with suitable target lesions amenable to analysis, to potentially identify the effect of MEDI-522 on tumor perfusion. Treatment was well tolerated, and a maximum tolerated dose was not identified by traditional dose-limiting toxicities. The major adverse events observed were grade 1 and 2 infusion-related reactions (fever, rigors, flushing, injection site reactions, and tachycardia), low-grade constitutional and gastrointestinal symptoms (fatigue, myalgias, and nausea), and asymptomatic hypophosphatemia. Dynamic computed tomography imaging suggested a possible effect on tumor perfusion with an increase in contrast mean transit time from baseline to the 8-week evaluation with increasing doses of MEDI-522. No complete or partial responses were observed. Three patients with metastatic renal cell cancer experienced prolonged stable disease (34 weeks, >1 and >2 years) on treatment. With this weekly schedule of administration, and in the doses studied, MEDI-522 seems to be without significant toxicity, may have effects on tumor perfusion, and may have clinical activity in renal cell cancer. These findings suggest the MEDI-522 could be further investigated as an antiangiogenic agent for the treatment of cancer.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/farmacologia , Integrina alfaVbeta3/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Adulto , Idoso , Anticorpos Monoclonais/química , Área Sob a Curva , Carcinoma de Células Renais/patologia , Ensaios Clínicos como Assunto , Estudos de Coortes , Meios de Contraste , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Integrina alfaVbeta3/química , Neoplasias Renais/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias/imunologia , Neovascularização Patológica , Perfusão , Modelos de Riscos Proporcionais , Fatores de Tempo , Tomografia Computadorizada por Raios X
20.
Clin Cancer Res ; 11(9): 3410-6, 2005 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-15867242

RESUMO

PURPOSE: To define the toxicities, pharmacodynamics, and clinical activity of the proteasome inhibitor, PS-341 (bortezomib), in patients with advanced malignancies. PATIENTS AND METHODS: Twenty-eight patients (14 male and 14 female) received PS-341 twice weekly for 4 of 6 weeks (schedule I). Because toxicity necessitated dose omissions on this schedule, 16 additional patients (12 male and 4 female) received PS-341 twice weekly for 2 of every 3 weeks (schedule II). A total of 73 courses of treatment was given (median, 2; range, 1-4). Inhibition of 20S proteasome activity in peripheral blood mononuclear cells (PBMC) and accumulation of proteasome-targeted polypeptides in tumor tissue were evaluated as pharmacodynamic markers of PS-341 activity. RESULTS: The most common toxicity was thrombocytopenia, which was dose limiting at 1.7 mg/m2 (schedule I) and 1.6 mg/m2 (schedule II), respectively. Sensory neuropathy was dose-limiting in a patient in schedule I. Grade > or =3 toxicities for schedule I were constipation, fatigue, myalgia, and sensory neuropathy. Grade > or =3 toxicities for schedule II were dehydration resulting from diarrhea, nausea and vomiting, fatigue, hypoglycemia, and hypotension. The maximum tolerated dose was 1.5 mg/m2 for both schedules. Reversible dose-dependent decreases in 20S proteasome activity in PBMCs were observed, with 36% inhibition at 0.5 mg/m2, 52% at 0.9 mg/m2, and 75% at 1.25 mg/m2. Accumulation of proteasome-targeted polypeptides was detected in tumor samples after treatment with PS-341. A patient with multiple myeloma had a partial response. CONCLUSION: PS-341 given 1.5 mg/m2 twice weekly for 2 of every 3 weeks is well tolerated and should be further studied.


Assuntos
Antineoplásicos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Neoplasias/tratamento farmacológico , Pirazinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/induzido quimicamente , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Western Blotting , Ácidos Borônicos/efeitos adversos , Ácidos Borônicos/farmacologia , Bortezomib , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Ciclina E/metabolismo , Inibidor de Quinase Dependente de Ciclina p27 , Diarreia/induzido quimicamente , Relação Dose-Resposta a Droga , Esquema de Medicação , Fadiga/induzido quimicamente , Feminino , Humanos , Proteínas I-kappa B/metabolismo , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Náusea/induzido quimicamente , Neoplasias/metabolismo , Neoplasias/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pirazinas/efeitos adversos , Pirazinas/farmacologia , Trombocitopenia/induzido quimicamente , Resultado do Tratamento , Proteínas Supressoras de Tumor/metabolismo , Vômito/induzido quimicamente , Proteína X Associada a bcl-2
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