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We describe 33 cases of myxoid pseudotumor involving the renal sinus from 31 patients. Patients included 21 men and 10 women, ages 30 to 95 years. Twenty-seven cases (82%) had an associated malignancy, including urothelial carcinoma of the renal pelvis (22 cases), clear cell renal cell carcinoma (3 cases), urothelial carcinoma of the bladder (1 case), and poorly differentiated carcinoma of uncertain lineage (1 case). The remaining 6 (18%) had no associated malignancy and included 3 nephrectomies for ureteral stricture, 2 ureteropelvic junction repairs, and 1 resection of a "periureteral mass" (subsequently shown to be myxoid pseudotumor). Myxoid pseudotumor was identified by preoperative computed tomography imaging in 2 patients (6%) and identified by the gross dissector in 9 cases (27%). The mean size was 14 mm (range: 5 to 38 mm). All cases had an admixture of adipocytes, myxoid stromal matrix, variable collagenization, and a hypocellular population of bland spindled and stellate stromal cells. No multilobated atypical stromal cells were present. Clinical follow-up was available for 28 patients (90%), ranging from 1 to 132 months (mean: 24.6 mo). No patients had adverse events related to the myxoid pseudotumor. Myxoid pseudotumor of the renal sinus is often associated with a variety of adjacent neoplastic and non-neoplastic conditions and may present as a mass lesion detectable by imaging and/or gross inspection. Awareness of this benign process is important to avoid confusion with a neoplasm, especially liposarcoma.
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Carcinoma de Células de Transição , Lipossarcoma , Neoplasias da Bexiga Urinária , Masculino , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células de Transição/patologia , Neoplasias da Bexiga Urinária/patologia , Lipossarcoma/patologia , Bexiga Urinária/patologia , Pelve Renal/patologiaRESUMO
INTRODUCTION: The Tumor-Node-Metastasis classification of renal cell carcinoma (RCC) for pT3a tumors includes sinus fat invasion (SFI), perinephric fat invasion (PFI), renal vein invasion (RVI), and/or pelvicaliceal system invasion (PSI). The purpose of this study was to determine the association between these patterns of invasion (assessed individually and cumulatively) with the development of metastases and cancer-specific mortality (CSM). MATERIALS AND METHODS: We identified 160 patients who underwent radical nephrectomy for pT3a clear cell RCC between 2011 and 2017. The association between individual patterns of invasion and metastases and cancer-specific survival were evaluated with multivariate logistic regression. Cox Hazard proportion ratios and Kaplan-Meier survival curves were generated for patterns of invasion (assessed individually and cumulatively). RESULTS: The number of individual invasive patterns was as follows: 97/160 (61%) presented with RVI, 91/160 with SFI (57%), 62/160 with PFI (39%), and 24/160 (15%) with PSI. At multivariate analysis, both PFI and RVI were associated with metastases (P < 0.001 and 0.028, respectively). PFI (hazard ratio [HR] 4.12, 95% confidence interval [CI] 2.14-7.92; P < 0.001), RVI (HR 2.44, 95% CI 1.18-5.01; Pâ¯=â¯0.015), SFI (HR 2.13, 95% CI 1.05-4.34; Pâ¯=â¯0.036) had higher CSM, while PSI (HR 1.43, 95% CI 0.65-3.16; pâ¯=â¯0.38) did not show increased CSM. Furthermore, cumulative analysis showed that multiple invasive patterns resulted in worse CSM (p < 0.001). CONCLUSIONS: In our study, PFI was associated with the most aggressive behavior while PSI was the most indolent. Furthermore, the presence of more than one pattern of invasion was associated with worse CSM. These results indicate that reporting of the individual location and cumulative amount of pT3a patterns of invasion in clear cell RCC is clinically relevant.
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Carcinoma de Células Renais/complicações , Neoplasias Renais/complicações , Nefrectomia/métodos , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/patologia , Estadiamento de Neoplasias , PrognósticoRESUMO
A 61-year-old woman with locally advanced, high-grade urothelial cell carcinoma was treated with the anti-programmed death-ligand 1 antibody atezolizumab. She initially received neoadjuvant chemotherapy and surgery that led to clinical and radiographic remission at the time of atezolizumab initiation. Within 3 months she developed new mediastinal and hilar lymphadenopathy as well as pulmonary nodules in a pattern characteristic of pulmonary sarcoidosis. Mediastinal lymph node biopsy by endobronchial ultrasound demonstrated noncaseating granulomas without evidence of malignancy or infection. Within 4 weeks of initiation of prednisone and cessation of atezolizumab there was marked reduction in intrathoracic lymphadenopathy and perilymphatic nodules. This is the first reported case of atezolizumab-induced sarcoid-like granulomatous reaction.
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Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Granuloma/diagnóstico , Imunoterapia/métodos , Neoplasias Renais/tratamento farmacológico , Linfonodos/patologia , Sarcoidose Pulmonar/diagnóstico , Urotélio/patologia , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antineoplásicos/efeitos adversos , Feminino , Granuloma/etiologia , Humanos , Neoplasias Renais/complicações , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prednisona/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Indução de Remissão , Sarcoidose Pulmonar/etiologia , Suspensão de TratamentoRESUMO
BACKGROUND: Differentiated squamous intraepithelial neoplasia (dSIN) is a pathway in the development of invasive squamous cell carcinoma (SCC) distinct from the usual-type squamous intraepithelial neoplasia (uSIN) and has not been described in the larynx. MATERIALS AND METHODS: Sixty-nine consecutive cases of SCC were identified which included 25 dSIN, 13 uSIN, and 31 mixed dSIN+usual-like SIN (u-like SIN) cases. RESULTS: dSIN was characterized by atypical squamous cells limited to the basal/parabasal layers and u-like SIN was characterized by cytologic atypia limited to less than full thickness. Despite the lack of neoplastic involvement of the full thickness of the epithelium, these types of SIN were commonly connected with invasive carcinoma. Prior biopsies demonstrating only dSIN, without the underlying invasive SCC, were underdiagnosed in 2 cases. Because of the frequent keratinization, u-like SIN likely represents the "keratinized dysplasia" and shows changes suggestive of dSIN with upward spread of neoplastic cells into the upper layer of the epithelium. CONCLUSIONS: Laryngeal dSIN represents an important but under recognized pathway of invasive SCC development. As moderate dysplasia of uSIN type are not associated with invasive SCC, labeling u-like SIN as dysplasia of grade 2 or 3 likely leads to the controversies in the current grading systems in the upper aerodigestive system and causes confusion for clinicians.
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Carcinoma in Situ/diagnóstico , Carcinoma de Células Escamosas/diagnóstico , Epitélio/patologia , Neoplasias Laríngeas/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Carcinoma in Situ/patologia , Carcinoma de Células Escamosas/patologia , Diferenciação Celular , Diagnóstico Diferencial , Feminino , Humanos , Hiperplasia , Queratinas/metabolismo , Neoplasias Laríngeas/patologia , Masculino , Pessoa de Meia-Idade , Invasividade NeoplásicaRESUMO
AIM: Comorbid cannabis abuse is common in patients with early psychosis. Little is known about the effect of stopping cannabis use on positive, negative and depressive symptoms. Few studies have controlled for multiple substance use that may mask the specific role that cannabis plays in symptom outcomes. The aim of this study was to investigate whether course and level of cannabis use negatively impacted early psychosis patient symptom profiles (positive, negative and depressive symptoms) over 24 months. METHODS: One hundred and ninety-two patients admitted to an early psychosis intervention programme in a naturalistic setting were followed across three time periods: initial presentation, 12 and 24 months. Patients' clinical characteristics (substance use, positive/negative symptoms and depressive symptoms) were assessed at each time period. RESULTS: There were no significant associations found between cannabis abuse and positive and negative symptoms. Continuation and discontinuation of cannabis use were not significant for cannabis or any other substance when compared to positive and negative symptoms. There was a significant interaction between cannabis and alcohol for depressive symptoms, where depressive symptoms were significantly higher in patients who abused cannabis without co-occurring alcohol abuse when compared to non-cannabis using patients. CONCLUSION: The current study findings indicate a complex interaction between cannabis and alcohol use in a sample of early psychosis patients across 24 months. More research is needed into the association between ceasing cannabis use and long-term outcome for early psychosis patients. Of particular importance is the interaction between level of cannabis and alcohol use as it is related to symptom outcome in early psychosis patients.
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Consumo de Bebidas Alcoólicas/epidemiologia , Depressão/epidemiologia , Fumar Maconha/epidemiologia , Transtornos Psicóticos/epidemiologia , Adolescente , Adulto , Canadá/epidemiologia , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Transtornos Psicóticos/diagnóstico , Fatores de Tempo , Adulto JovemRESUMO
A phase 1 study was conducted to determine the dose-limiting toxicities and maximum-tolerated dose (MTD) for bortezomib followed by romidepsin on days 1, 8, and 15 in patients with relapsed/refractory CLL/SLL or B- or T-cell lymphoma. Eighteen treated patients were evaluable for response. The MTD was 1.3 mg/m2 bortezomib and 10 mg/m2 romidepsin; median treatment duration was 3 cycles at this dose. The dose-limiting toxicities were grade 3 fatigue, vomiting, and chills. Two patients had partial responses, one lasting >2 years, 8 had stable disease, and 8 had progressive disease. The median duration of stable disease was 3.5 cycles. Correlative studies examining expression of NF-кB, XIAP, Bcl-xL, and Bim yielded variable results. The safety profile was consistent with that reported for single-agent bortezomib and romidepsin. This regimen has modest activity in heavily pretreated patients with relapsed/refractory CLL or B- or T-cell lymphoma. NCT00963274.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma Cutâneo de Células T/tratamento farmacológico , Linfoma de Células T Periférico/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Terapia Combinada , Depsipeptídeos/administração & dosagem , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Linfoma Cutâneo de Células T/diagnóstico , Linfoma de Células T Periférico/diagnóstico , Masculino , Dose Máxima Tolerável , Resultado do TratamentoRESUMO
BACKGROUND: The stroma in fine-needle aspiration biopsy (FNAB) of thyroid lesions has not been well investigated. DESIGN: We studied 256 consecutive cases of thyroid FNAB prepared with traditional smear technique. The stroma was categorized: Type 1a consisted of long (more than 3 mm), broad bands composed of mesh containing collagen fibrils thickened by entrapped blood components and follicular cells. Type 1b consisted of dense strands/bands. Type 2 was similar to Type 1a but with shorter (<2 mm) and looser stromal strands. RESULTS: Types 1a and b showed straight/curved/circular branching patterns suggestive of incomplete frameworks of nodular/papillary architectures or fragments of capsule. Type 1b stroma likely represented thick/collagenized fibrous septae. Incomplete or complete rings of small encapsulated tumor were occasionally identified. These frameworks of stroma were frequently associated with multinodular goiters (MNGs) which are often hypocellular and follicular neoplasms/papillary thyroid carcinoma with increased cellularity. Type 2 was associated with microfollicles in encapsulated neoplasms or with macrofollicles in MNG. Follicular lesions of unknown significance (n = 41) either negative (n = 26) or positive (n = 15) for carcinoma in subsequent follow-up were frequently associated with stroma characteristic of MNG and carcinoma, respectively. CONCLUSION: The preservation of the in vivo architecture of Type 1 is likely due to its elasticity. Recognition of the stromal architecture will likely facilitate the diagnosis.
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Selected patients with Gleason score (GS) 3 + 4 = 7 prostate cancer (PCa) detected on transrectal ultrasound (TRUS)-guided biopsies may be considered for active surveillance (AS); however, a proportion of these will harbor more aggressive disease. The purpose of this study was to determine if morphologies of Gleason pattern 4 PCa may predict upgrading and/or upstaging after radical prostatectomy (RP). A database search for men with GS 3 + 4 = 7 PCa diagnosed on TRUS-guided biopsy that underwent RP between January 2010 and October 2015 identified 152 patients. Two blinded genitourinary pathologists independently reviewed the biopsies and assessed ill-defined glands (IDG), fused glands, small or large cribriform patterns, and glomerulations. Patient age, serum prostate-specific antigen (PSA), percentage (%) of biopsy sites involved by 3 + 4 = 7 PCa, and overall extent of pattern 4 were also recorded. GS and stage (presence or absence of extraprostatic extension [EPE]) were retrieved from RP reports. Data were compared using independent t tests and chi-square. Inter-observer agreement was calculated using Cohen's Kappa statistic. Percent of biopsy sites and extent of pattern 4 were compared to statistically significant morphologies using the Spearman correlation. 28.3 % (43/152) of patients were upgraded to GS >3 + 4 = 7 at RP (GS 4 + 3 = 7 [N = 17], GS 4 + 3 = 7 with tertiary pattern 5 [N = 25], and GS 4 + 5 = 9 [N = 1]) and 44.1 % (67/152) showed EPE after RP. PSA was associated with both upgrading (8.5 ± 5.4 vs. 6.9 ± 3.2 ng/mL, [p = 0.04]) and EPE (8.2 ± 4.6 vs. 6.7 ± 3.2 ng/mL, [p = 0.03]). IDG, fused glands, and glomerulations were not associated with upgrading or EPE (p > 0.05) with moderate to strong inter-observer agreement (K = 0.76-0.88). There was strong inter-observer agreement for small and large cribriform formations (K = 0.93 and 0.94, respectively) and both patterns were strongly associated with upgrading (p < 0.001) and EPE (p = 0.02) on RP. Strong associations were observed between increasing number of morphologies and both upgrading (p = 0.0.25) and EPE (p < 0.001). Overall extent of pattern 4 was associated with upgrading (p = 0.009) and EPE (p = 0.019) while percent of sites involved by GS 3 + 4 = 7 was only associated with EPE (p = 0.023). Cribriform morphology correlated to percentage of sites with 3 + 4 and overall extent of pattern 4 (rho = 0.25, p = 0.002, rho = 0.20, p = 0.015, respectively). Presence of cribriform morphology on TRUS-guided biopsy is strongly associated with upgrading and upstaging at RP and shows near-perfect inter-observer agreement whereas IDG, fused glands, and glomerulations were not useful. Cribriform morphology may be of importance when considering treatment plans for patients with intermediate risk PCa.
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Gradação de Tumores , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Adulto , Idoso , Biópsia por Agulha , Humanos , Masculino , Pessoa de Meia-Idade , Prostatectomia/métodos , Fatores de RiscoRESUMO
A phase 1 study with carfilzomib and vorinostat was conducted in 20 B-cell lymphoma patients. Vorinostat was given orally twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 followed by carfilzomib (given as a 30-min infusion) on days 1, 2, 8, 9, 15, and 16. A treatment cycle was 28 days. Dose escalation initially followed a standard 3 + 3 design, but adapted a more conservative accrual rule following dose de-escalation. The maximum tolerated dose was 20 mg/m2 carfilzomib and 100 mg vorinostat (twice daily). The dose-limiting toxicities were grade 3 pneumonitis, hyponatremia, and febrile neutropenia. One patient had a partial response and two patients had stable disease. Correlative studies showed a decrease in NF-κB activation and an increase in Bim levels in some patients, but these changes did not correlate with clinical response.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células B/diagnóstico , Linfoma de Células B/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Terapia Combinada , Citocinas/sangue , Monitoramento de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Linfoma de Células B/sangue , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Oligopeptídeos/administração & dosagem , Retratamento , Resultado do Tratamento , VorinostatRESUMO
PURPOSE: AZD6244 is a MEK1/2 inhibitor with significant preclinical activity in multiple myeloma cells. This phase II study used a two-stage Simon design to determine the AZD6244 response rate in patients with relapsed or refractory multiple myeloma. EXPERIMENTAL DESIGN: AZD6244 (75 mg) was administered orally, twice a day, continuously for 28-day cycles. Response was evaluated after three cycles. RESULTS: Thirty-six patients received therapy. The median age was 65 years (range: 43-81) and the median number of prior therapies was 5 (range: 2-11). The most common grade 3 and 4 toxicities included anemia, neutropenia, thrombocytopenia, diarrhea, and fatigue. Three deaths occurred possibly related to AZD6244 (2 due to sepsis, 1 due to acute kidney injury). After AZD6244 discontinuation, three additional deaths occurred due to disease progression. The response rate (CR + PR) was 5.6% with a mean duration of response of 4.95 months and median progression-free survival time of 3.52 months. One patient had a very good partial response (VGPR), 1 patient had a partial response, 17 patients had stable disease, 13 patients had progressive disease, and 4 patients could not be assessed for response. Pharmacodynamic studies revealed variable effects on bone marrow CD138(+) cell MEK1/2 and ERK1/2 phosphorylation. The best clinical response, a prolonged VGPR, occurred in a patient with an MMSET translocation. CONCLUSIONS: Single-agent AZD6244 was tolerable and had minimal activity in this heavily pretreated population.
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Benzimidazóis/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , MAP Quinase Quinase Quinases/antagonistas & inibidores , MAP Quinase Quinase Quinases/genética , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia/patologia , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
PURPOSE: This phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, Waldenstrom macroglobulinemia, and mantle cell lymphoma). EXPERIMENTAL DESIGN: Patients received bortezomib (intravenous push), followed by alvocidib (1-hour infusion), on days 1, 4, 8, and 11 of a 21-day treatment cycle. Patients experiencing responses or stable disease continued on treatment at the investigator's discretion. A standard 3+3 dose-escalation design was used to identify the MTD based on DLTs, and pharmacokinetic and pharmacodynamic studies were conducted. RESULTS: A total of 44 patients were enrolled, with 39 patients assessed for response. The MTD was established as 1.3 mg/m(2) for bortezomib and 40 mg/m(2) for alvocidib. The most common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. The most common nonhematologic toxicities included diarrhea, fatigue, and sensory neuropathy. Three complete remissions (8%) and 10 partial remissions (26%) were observed for a total response rate of 33%. Pharmacokinetic findings with the current dosing regimen were consistent with the comparable literature and the hybrid dosing regimen. Pharmacodynamic study results did not correlate with clinical responses. CONCLUSIONS: The combination of bortezomib and alvocidib is tolerable, and an MTD has been established for this schedule. The regimen appears to be efficacious in patients with relapsed/refractory multiple myeloma or indolent non-Hodgkin lymphoma. As the nonhybrid regimen is less cumbersome than the previous hybrid dosing schedule regimen, the current schedule is recommended for successor studies.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos B/patologia , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/farmacocinética , Bortezomib , Terapia Combinada , Esquema de Medicação , Monitoramento de Medicamentos , Feminino , Flavonoides/administração & dosagem , Flavonoides/farmacocinética , Humanos , Transtornos Linfoproliferativos/diagnóstico , Masculino , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Pirazinas/administração & dosagem , Pirazinas/farmacocinética , Recidiva , Retratamento , Resultado do TratamentoRESUMO
T cell repertoire diversity is generated in part by recombination of variable (V), diversity (D), and joining (J) segments in the T cell receptor ß (TCR) locus. T cell clonal frequency distribution determined by high-throughput sequencing of TCR ß in 10 stem cell transplantation (SCT) donors revealed a fractal, self-similar frequency distribution of unique TCR bearing clones with respect to V, D, and J segment usage in the T cell repertoire of these individuals. Further, ranking of T cell clones by frequency of gene segment usage in the observed sequences revealed an ordered distribution of dominant clones conforming to a power law, with a fractal dimension of 1.6 and 1.8 in TCR ß DJ and VDJ containing clones in healthy stem cell donors. This self-similar distribution was perturbed in the recipients after SCT, with patients demonstrating a lower level of complexity in their TCR repertoire at day 100 followed by a modest improvement by 1 year post-SCT. A large shift was observed in the frequency distribution of the dominant T cell clones compared to the donor, with fewer than one third of the VDJ-containing clones shared in the top 4 ranks. In conclusion, the normal T cell repertoire is highly ordered with a TCR gene segment usage that results in a fractal self-similar motif of pattern repetition across levels of organization. Fractal analysis of high-throughput TCR ß sequencing data provides a comprehensive measure of immune reconstitution after SCT.
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Receptores de Antígenos de Linfócitos T alfa-beta/genética , Transplante de Células-Tronco , Linfócitos T/imunologia , Condicionamento Pré-Transplante , Soro Antilinfocitário/farmacologia , Soro Antilinfocitário/uso terapêutico , Células Clonais , Fractais , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/terapia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Agonistas Mieloablativos/farmacologia , Agonistas Mieloablativos/uso terapêutico , Receptores de Antígenos de Linfócitos T alfa-beta/química , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Linfócitos T/classificação , Linfócitos T/patologia , Quimeras de Transplante/imunologia , Transplante HomólogoRESUMO
PURPOSE: A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, and mantle cell lymphoma). EXPERIMENTAL DESIGN: Patients received bortezomib by intravenous push on days 1, 4, 8, and 11. Patients also received alvocidib on days 1 and 8 by 30-minute bolus infusion followed by a 4-hour continuous infusion. Treatment was on a 21-day cycle, with indefinite continuation for patients experiencing responses or stable disease. Dose escalation employed a standard 3 + 3 design until the MTD was identified on the basis of DLTs. Pharmacokinetic studies and pharmacodynamic studies were conducted. RESULTS: Sixteen patients were treated. The MTD was established as 1.3 mg/m(2) for bortezomib and 30 mg/m(2) for alvocidib (both the 30-minute bolus and 4-hour infusions). Common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. Common nonhematologic toxicities included fatigue and febrile neutropenia. DLTs included fatigue, febrile neutropenia, and elevated aspartate aminotransferase (AST) levels. Two complete responses (CR; 12%) and five partial responses (PR; 31%) were observed at the MTD (overall response rate = 44%). Pharmacokinetic results were typical for alvocidib and pharmacodynamic studies yielded variable results. CONCLUSIONS: The combination of bortezomib and alvocidib is tolerable and an MTD has been established for the tested schedule. The regimen appears active in patients with relapsed and/or refractory multiple myeloma or non-Hodgkin's lymphoma, justifying phase II studies to determine the activity of this regimen more definitively.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ácidos Borônicos/administração & dosagem , Flavonoides/administração & dosagem , Leucemia de Células B/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Piperidinas/administração & dosagem , Pirazinas/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ácidos Borônicos/efeitos adversos , Bortezomib , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Flavonoides/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Pirazinas/efeitos adversos , Recidiva , Falha de TratamentoRESUMO
The epithelial to mesenchymal transition is a developmental process allowing epithelial cells to dedifferentiate into cells displaying mesenchymal phenotypes. The pathological role of epithelial to mesenchymal transition has been implicated in invasion and metastasis for numerous carcinomas, yet limited data exist addressing whether mesenchymal transition (MT) occurs in malignant melanoma cells. Our group developed an in-vitro three-dimensional culture system to address MT in melanoma cells upon transforming growth factor-ß/ tumor necrosis factor-α treatment. Loss of E-cadherin is one of the best indicators of MT in epithelial cells. Not surprisingly, E-cadherin was expressed in only three of 12 (25%) melanoma cell lines and all three mesenchymal proteins, N-cadherin, vimentin, and fibronectin, were expressed by seven (58%) melanoma cell lines. However, after cytokine treatment, two or more mesenchymal proteins were elevated in nine (75%) melanoma cell lines. Data support the transforming growth factor-ß production by melanoma cells which may induce/support MT. Evaluation of E-cadherin, N-cadherin, and Snail expression in melanoma tissue samples are consistent with an inverse coupling of E-cadherin and N-cadherin expression, however, there are also examples suggesting a more complex control of their expression. These results indicate that malignant melanoma cell lines are susceptible to MT after cytokine treatment and highlight the importance of understanding the effects of cytokines on melanoma to undergo MT.
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Biomarcadores Tumorais/biossíntese , Transição Epitelial-Mesenquimal/fisiologia , Melanoma/metabolismo , Melanoma/patologia , Antígenos CD/biossíntese , Caderinas/biossíntese , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Fenótipo , Fatores de Transcrição da Família Snail , Fatores de Transcrição/biossíntese , Fator de Crescimento Transformador beta/biossíntese , Fator de Crescimento Transformador beta/farmacologia , Fator de Crescimento Transformador beta1/biossíntese , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
BACKGROUND: Lumpectomy re-excision to obtain negative margins is common. We compare the effect of two specimen orientation approaches on lumpectomy re-excision rates. METHODS: All women undergoing lumpectomy for breast cancer by a single surgeon between 03/2007 - 02/2009 were included. Lumpectomies underwent standard inking (SI) after surgery by a pathologist from 03/2007-02/2008 while intraoperative inking (II) with direct surgeon input was done from 03/2008-02/2009. Rates of margin positivity and re-excision were compared between these methods. RESULTS: 65 patients were evaluated, reflecting SI in 39 and II in 26 cases. Margin positivity rates of 46% [SI] vs. 23% [II] (p = 0.06) and re-excision rates of 38% [SI] vs. 19% [II] were observed. Residual disease at re-excision was found in 27% [SI] vs. 67% [II] of cases. CONCLUSIONS: Intraoperative inking in this practice offered a simple way to reduce re-excision rates after lumpectomy and affect an improvement in quality of patient care.
Assuntos
Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/cirurgia , Carcinoma Intraductal não Infiltrante/cirurgia , Carcinoma Lobular/cirurgia , Mastectomia Segmentar , Neoplasia Residual/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Carcinoma Lobular/patologia , Estudos de Coortes , Feminino , Humanos , Tinta , Período Intraoperatório , Pessoa de Meia-Idade , Neoplasia Residual/patologia , Reoperação , Estudos Retrospectivos , Resultado do TratamentoRESUMO
PURPOSE: To test the hypothesis that decrease in DNA methylation will increase the expression of cancer-testis antigens (CTA) and class I major histocompatibility complex (MHC)-encoded molecules by ovarian cancer cells, and thus increase the ability of these cells to be recognized by antigen-reactive CD8(+) T cells. METHODS: Human ovarian cancer cell lines were cultured in the presence or absence of varying concentrations of the DNA demethylating agent 5-aza-2'-deoxycytidine (DAC) for 3-7 days. The expression levels of 12 CTA genes were measured using the polymerase chain reaction. The protein expression levels of class I MHC molecules and MAGE-A1 were measured by flow cytometry. T cell reactivity was determined using interferon-gamma ELISpot analysis. RESULTS: DAC treatment of ovarian cancer cell lines increased the expression of 11 of 12 CTA genes tested including MAGE-A1, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A10, MAGE-A12, NY-ESO-1, TAG-1, TAG-2a, TAG-2b, and TAG-2c. In contrast, DAC treatment decreased the already low expression of the MAGE-A2 gene by ovarian cancer cells, a finding not previously observed in cancers of any histological type. DAC treatment increases the expression of class I MHC molecules by the cells. These effects were time-dependent over a 7-day interval, and were dose-dependent up to 1-3 microM for CTA and up to 10 microM for class I MHC molecules. Each cell line tested had a unique pattern of gene upregulation after exposure to DAC. The enhanced expression levels increased the recognition of 2 of 3 antigens recognized by antigen-reactive CD8(+) T cells. CONCLUSIONS: These results demonstrate the potential utility of combining DAC therapy with vaccine therapy in an attempt to induce the expression of antigens targeted by the vaccine, but they also demonstrate that care must be taken to target inducible antigens.
Assuntos
Antígenos de Neoplasias/biossíntese , Antimetabólitos Antineoplásicos/farmacologia , Azacitidina/análogos & derivados , Expressão Gênica/efeitos dos fármacos , Antígenos de Histocompatibilidade Classe I/biossíntese , Neoplasias Ovarianas/genética , Antígenos de Neoplasias/efeitos dos fármacos , Antígenos de Neoplasias/imunologia , Azacitidina/farmacologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Metilação de DNA/efeitos dos fármacos , Decitabina , Feminino , Citometria de Fluxo , Expressão Gênica/imunologia , Antígenos de Histocompatibilidade Classe I/efeitos dos fármacos , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Neoplasias Ovarianas/imunologia , Reação em Cadeia da Polimerase , Regulação para CimaRESUMO
BACKGROUND: Human cancer vaccines incorporating autologous tumor cells carry a risk of implantation and subsequent metastasis of viable tumor cells into the patient who is being treated. Despite the fact that the melanoma cell preparations used in a recent vaccine trial (Mel37) were gamma-irradiated (200 Gy), approximately 25% of the preparations failed quality control release criteria which required that the irradiated cells incorporate 3H-thymidine at no more than 5% the level seen in the non-irradiated cells. We have, therefore, investigated ultraviolet (UV)-irradiation as a possible adjunct to, or replacement for gamma-irradiation. METHODS: Melanoma cells were gamma- and/or UV-irradiated. 3H-thymidine uptake was used to assess proliferation of the treated and untreated cells. Caspase-3 activity and DNA fragmentation were measured as indicators of apoptosis. Immunohistochemistry and Western blot analysis was used to assess antigen expression. RESULTS: UV-irradiation, either alone or in combination with gamma-irradiation, proved to be extremely effective in controlling the proliferation of melanoma cells. In contrast to gamma-irradiation, UV-irradiation was also capable of inducing significant levels of apoptosis. UV-irradiation, but not gamma-irradiation, was associated with the loss of tyrosinase expression. Neither form of radiation affected the expression of gp100, MART-1/MelanA, or S100. CONCLUSION: These results indicate that UV-irradiation may increase the safety of autologous melanoma vaccines, although it may do so at the expense of altering the antigenic profile of the irradiated tumor cells.
Assuntos
Vacinas Anticâncer , Raios gama , Melanoma/terapia , Células Tumorais Cultivadas/efeitos da radiação , Raios Ultravioleta , Apoptose/efeitos da radiação , Western Blotting , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta à Radiação , Humanos , Imuno-HistoquímicaRESUMO
BACKGROUND: We hypothesized that lymph nodes draining sites of cutaneous vaccination could be identified by sentinel node biopsy techniques, and that measuring T-cell response with lymphocytes obtained from these lymph nodes would provide a more sensitive measure of immunogenicity than would the same measurement made with peripheral blood lymphocytes (PBL). METHODS: ELISpot analysis was used to determine the magnitude of vaccine-specific T-cell response in the sentinel immunized nodes (SIN), random lymph nodes, and peripheral blood lymphocytes (PBL) obtained from patients enrolled in clinical trials of experimental melanoma vaccines. RESULTS: The SIN biopsy was successful in 97% of cases and morbidity was very low. The T-cell response to vaccination was detected with greater sensitivity in the SIN (57%) than in PBL (39%), and evaluation of T-cell responses in the SIN and the PBL together yielded T-cell responses in 63% of patients. When the T-cell responses from a SIN and a random lymph node were compared in four patients, immune responses were detected to one of the vaccine peptides in three of these four patients. In all of those cases, responses were present in the SIN but absent from the random lymph node. CONCLUSION: Measurements of T-cell responsiveness to cutaneous immunization are more frequently positive in the SIN than they are in the PBL, however evaluation of both the SIN and PBL permit a more sensitive measure of T-cell immunogenicity than use of either single source.
Assuntos
Vacinas Anticâncer/imunologia , Linfonodos/imunologia , Linfócitos T Citotóxicos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Ensaios Clínicos como Assunto , Estudos de Viabilidade , Humanos , Melanoma/imunologia , Pessoa de Meia-Idade , Monitorização Imunológica , Proteínas de Neoplasias/imunologia , Fragmentos de Peptídeos/imunologia , Biópsia de Linfonodo Sentinela , Neoplasias Cutâneas/imunologia , VacinaçãoRESUMO
Nine participants with epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, who were human leukocyte antigen (HLA)-A1, HLA-A2, or HLA-A3, were eligible to enroll in a phase 1 study designed to assess the safety and immunogenicity of a peptide-based vaccine. Participants received 5 class I major histocompatibility complex-restricted synthetic peptides derived from multiple ovarian cancer-associated proteins plus a class II major histocompatibility complex-restricted synthetic helper peptide derived from tetanus toxoid protein. The vaccines were administered with granulocyte macrophage-colony stimulating factor in Montanide ISA-51 adjuvant over a 7-week period. All vaccine-related toxicities were grade 1 to 2, the most common being injection site reaction (grade 2, 100%), fatigue (grade 1, 78%), and headache (grade 1, 67%). Lymphocytes from the peripheral blood and a node draining a secondary vaccine site (sentinel immunized node) were harvested during the course of vaccination and T-cell responses to the peptides were evaluated using an enzyme-linked immunosorbent spot assay. CD8 T-cell responses were detected in 1 participant ex vivo and in 8 of 9 participants (89%) after in vitro stimulation. All 4 HLA-A2 and HLA-A3-restricted peptides were immunogenic. This includes 2 peptides, folate binding protein (FBP191-199) and Her-2/neu754-762, which had not previously been evaluated in vaccines in humans. Responding T cells required over 200 nM for half-maximal reactivity. These data support continued investigation of these peptides as immunogens for patients with ovarian cancer but, owing to low potency, also suggest a need for additional immunomodulation in combination with vaccines to increase the magnitude and to improve the quality of the T-cell responses.
Assuntos
Vacinas Anticâncer , Neoplasias Epiteliais e Glandulares/terapia , Neoplasias Ovarianas/terapia , Neoplasias Peritoneais/terapia , Linfócitos T/imunologia , Vacinação , Antígenos de Neoplasias/administração & dosagem , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , DNA Helicases/administração & dosagem , Proteínas de Ligação a DNA/administração & dosagem , Relação Dose-Resposta Imunológica , Feminino , Humanos , Epitopos Imunodominantes/administração & dosagem , Epitopos Imunodominantes/imunologia , Interferon gama/imunologia , Interferon gama/metabolismo , Manitol/administração & dosagem , Manitol/efeitos adversos , Manitol/análogos & derivados , Antígenos Específicos de Melanoma , Proteínas de Neoplasias/administração & dosagem , Proteínas de Neoplasias/imunologia , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/imunologia , Neoplasias Epiteliais e Glandulares/patologia , Ácidos Oleicos/administração & dosagem , Ácidos Oleicos/efeitos adversos , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/imunologia , Neoplasias Peritoneais/imunologia , Neoplasias Peritoneais/patologia , Proteínas de Ligação a RNA , Linfócitos T/metabolismo , Resultado do Tratamento , Vacinação/efeitos adversos , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/efeitos adversosRESUMO
PURPOSE: The efficient identification of peptide antigens recognized by ovarian cancer-specific cytotoxic T lymphocytes (CTL) requires the use of well-characterized ovarian cancer cell lines. To develop such a panel of cell lines, 11 ovarian cancer cell lines were characterized for the expression of class I and class II major histocompatibility complex (MHC)-encoded molecules, 15 tumor antigens, and immunosuppressive cytokines [transforming growth factor beta (TGF-beta) and IL-10]. METHODS: Class I MHC gene expression was determined by polymerase chain reaction (PCR), and class I and class II MHC protein expression was determined by flow cytometry. Tumor antigen expression was determined by a combination of polymerase chain reaction (PCR) and flow cytometry. Cytokine expression was determined by ELISA. RESULTS: Each of the ovarian cancer cell lines expresses cytokeratins, although each cell line does not express the same cytokeratins. One of the lines expresses CD90, which is associated with a fibroblast lineage. Each of the cell lines expresses low to moderate amounts of class I MHC molecules, and several of them express low to moderate amounts of class II MHC molecules. Using a combination of PCR and flow cytometry, it was determined that each cell line expressed between six and thirteen of fifteen antigens tested. Little to no TGF-beta3 was produced by any of the cell lines, TGF-beta1 was produced by three of the cell lines, TGF-beta2 was produced by all of the cell lines, with four of the cell lines producing large amounts of the latent form of the molecule, and IL-10 was produced by one of the cell lines. CONCLUSIONS: Each of the 11 ovarian cancer lines is characterized by a unique expression pattern of epithelial/fibroblast markers, MHC molecules, tumor antigens, and immunosuppressive cytokines. Knowledge of these unique expression patterns will increase the usefulness of these cell lines in identifying the antigens recognized by ovarian cancer-specific CTL.