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Key defining attributes of an antibody-drug conjugate (ADC) include the choice of the targeting antibody, linker, payload, and the drug-to-antibody ratio (DAR). Historically, most ADC platforms have used the same DAR for all targets, regardless of target characteristics. However, recent studies and modeling suggest that the optimal DAR can depend on target expression level and intratumoral heterogeneity, target internalization and trafficking, and characteristics of the linker and payload. An ADC platform that enables DAR optimization could improve the success rate of clinical candidates. Here we report a systematic exploration of DAR across a wide range, by combining THIOMAB protein engineering technology with Dolasynthen, an auristatin-based platform with monomeric and trimeric variants. This approach enabled the generation of homogeneous, site-specific ADCs spanning a discrete range of DARs 2, 4, 6, 12, and 18 by conjugation of trastuzumab IgG1 THIOMAB constructs with 1, 2, or 3 engineered cysteines to monomeric or trimeric Dolasynthen. All ADCs had physicochemical properties that translated to excellent in vivo pharmacology. Following a single dose of ADCs in a HER2 xenograft model with moderate antigen expression, our data demonstrated comparable pharmacokinetics for the conjugates across all DARs and dose-dependent efficacy of all test articles. These results demonstrate that the Dolasynthen platform enables the generation of ADCs with a broad range of DAR values and with comparable physiochemical, pharmacologic, and pharmacokinetics profiles; thus, the Dolasynthen platform enables the empirical determination of the optimal DAR for a clinical candidate for a given target.
Assuntos
Imunoconjugados , Humanos , Imunoconjugados/química , Ensaios Antitumorais Modelo de Xenoenxerto , Trastuzumab/farmacologia , Trastuzumab/química , Receptor ErbB-2/metabolismo , CisteínaRESUMO
Morphological alterations of the nuclear texture are a hallmark of carcinogenesis. At later stages of disease, these changes are well characterized and detectable by light microscopy. Evidence suggests that similar albeit nanoscopic alterations develop at the predysplastic stages of carcinogenesis. Using the novel optical technique partial wave spectroscopic microscopy, we identified profound changes in the nanoscale chromatin topology in microscopically normal tissue as a common event in the field carcinogenesis of many cancers. In particular, higher-order chromatin structure at supranucleosomal length scales (20-200 nm) becomes exceedingly heterogeneous, a measure we quantify using the disorder strength (Ld ) of the spatial arrangement of chromatin density. Here, we review partial wave spectroscopic nanocytology clinical studies and the technology's promise as an early cancer screening technology.
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BACKGROUND: The locoregional recurrence (LRR) rate after mastectomy is reported to be similar with immediate reconstruction. We aimed to identify characteristics of LRR after transverse rectus abdominis myocutaneous (TRAM) reconstruction. METHODS: We retrospectively reviewed patients undergoing immediate TRAM reconstruction for breast cancer who were diagnosed with LRR. RESULTS: We identified 18 LRR (4.6 %) in 18 of 390 patients who underwent immediate TRAM reconstructions for breast cancer from 1998 to 2008. The median follow-up was 69.2 months. The mean age at time of mastectomy was 49.5 years. All LRR were detected by physical examination. The LRR occurred in the TRAM subcutaneous tissue (n = 9), five in the ipsilateral axillary lymph node and four in the supraclavicular lymph node. Of the 18 patients who developed LRR, 14 (77.7 %) presented with stage 0-1-2 and 4 (22.2 %) with stage 3 disease at the time of the original mastectomy. The average time for a LRR to present was 35.8 months after initial mastectomy and reconstruction. For patients who initially presented with stage 3 disease, the average time to LRR was shorter (22.9 months). Nine patients (50.0 %) were found to have metastatic disease at the time of the LRR, and 6 (33.3 %) died of disease. CONCLUSIONS: All TRAM LRR were detected by routine physical examination by the patient or the surgeon. Our findings suggest that routine history and clinical breast examination of the breast reconstructed with a TRAM flap along with patient self-awareness are reliable in the diagnosis of LRR.
Assuntos
Neoplasias da Mama/cirurgia , Mamoplastia/efeitos adversos , Mastectomia/efeitos adversos , Recidiva Local de Neoplasia/etiologia , Reto do Abdome/cirurgia , Retalhos Cirúrgicos/cirurgia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/cirurgia , Carcinoma Intraductal não Infiltrante/mortalidade , Carcinoma Intraductal não Infiltrante/patologia , Carcinoma Intraductal não Infiltrante/cirurgia , Carcinoma Lobular/mortalidade , Carcinoma Lobular/patologia , Carcinoma Lobular/cirurgia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
In April 2007, the National Quality Forum (NQF) endorsed the first nationally recognized hospital-based performance measures for quality of care for breast cancer. The aim of this study was to measure quality of care at our AVON Center for Breast Care (AVONCBC) using these indicators. We retrospectively reviewed tumor registry and medical records of females under age 70 diagnosed with breast cancer in years 2005-2006. For patients diagnosed with hormone receptor negative breast cancer, 22 of 29 (75.9%) and 28 of 32 (87.5%) were considered for or received chemotherapy in 2005 and 2006, respectively. Of those patients, 21 of 29 (72.4%) and 24 of 32 (75.0%) were considered for or received chemotherapy within the NQF 4-month period. For patients undergoing breast conserving surgery (BCS), 20 of 23 (86.9%) in 2005 and 37 of 39 (94.9%) in 2006 were referred for adjuvant radiation therapy. The proportion of patients who received radiation therapy within 1 year of diagnosis was 18 of 23 (78.2%) and 29 of 39 (74.4%) for diagnosis years 2005 and 2006, respectively. The vast majority of patients in our AVONCBC are referred to medical and/or radiation oncology for adjunctive therapy and about three-fourths receive treatment compliant with the NQF QI. To increase our compliance rate, we are developing methods to improve access to the multiple disciplines in our AVONCBC. Using the NQF indicators serves to assess hospital performance at a systems-level and as a useful method for tracking cancer quality of care.
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Neoplasias da Mama/terapia , Indicadores de Qualidade em Assistência à Saúde , Qualidade da Assistência à Saúde , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
INTRODUCTION: Margin status is an important prognostic factor for local recurrence after breast-conserving surgery (BCS) in patients with breast malignancy. It is unclear whether the removal of additional tumor cavity margins reduces the reoperation rate and is cosmetically acceptable. This study compares the reoperation rates, volume of breast excised in cm(3), and number of pathology slides examined in two groups of patients who underwent BCS with or without four or five additional margins (BCS + M). METHODS: We retrospectively analyzed 320 patients who underwent BCS or BCS + M for stage 0-I-II breast cancer from 2004 to 2007. We classified the margins as negative (>or=1 mm), close (<1 mm), or positive based on the distance from the tumor to the margin of resection. RESULTS: Of 320 cases analyzed, 199 (62.2%) underwent BCS and 121 (37.8%) had BCS + M. Overall, patients with BCS + M had a higher negative margins rate (85.1% vs. 57.2%, P < 0.05) and a lower reoperation rate. However, when ductal carcinoma in situ (DCIS) and infiltrating ductal carcinoma (IDC) were analyzed separately, only patients with IDC showed a higher negative margin rate (91% vs. 62.1%, P < 0.001) and a lower volume of breast tissue excised (205.63 vs. 392.27, P = 0.03). There was no significant increase in pathology workload in both groups. CONCLUSIONS: Resection of four to five additional margins during BCS for early-stage invasive breast cancer results in a higher rate of negative microscopic margins, lower volume of breast excised, and subsequently, a lower reoperation rate. The advantages of this approach include improved patient satisfaction and decreased cost.
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Neoplasias da Mama/cirurgia , Carcinoma Intraductal não Infiltrante/cirurgia , Mastectomia Segmentar/métodos , Reoperação , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoAssuntos
Doenças Mamárias/induzido quimicamente , Granuloma de Corpo Estranho/induzido quimicamente , Parafina/efeitos adversos , Adulto , Biópsia por Agulha , Doenças Mamárias/diagnóstico , Doenças Mamárias/cirurgia , Implantes de Mama/efeitos adversos , Feminino , Seguimentos , Granuloma de Corpo Estranho/diagnóstico , Granuloma de Corpo Estranho/cirurgia , Humanos , Imuno-Histoquímica , Mamoplastia/métodos , Mamografia , Parafina/administração & dosagem , Medição de Risco , Retalhos Cirúrgicos , Resultado do TratamentoRESUMO
BACKGROUND: Patients seek herbal/hormonal dietary supplements (HHDS) to prevent and/or solve health and aging issues. After two men developed an unusual course of clinically aggressive prostate cancer within months of starting daily consumption of the same HHDS product, we investigated the effect of this product on prostate cancer progression. METHODS: We evaluated serum levels of total testosterone, luteinizing hormone, and follicle-stimulating hormone and screened prostate biopsy and metastatic specimens for androgen receptor protein expression and mutations. We did hormone analyses and capillary electrophoresis. We tested the effect of the HHDS product on androgen receptor-negative (DU-145 and PC-3) and androgen receptor-positive (LNCaP) human prostate cancer cell lines. RESULTS: Both patients had low hormone levels. The androgen receptor was expressed in all primary and metastatic prostate cancer tissues and no mutations were identified. Hormone analysis revealed that the HHDS contained testosterone and estradiol. The HHDS product was a more potent dose-dependent stimulator of cancer cell growth than testosterone both in androgen receptor-negative and receptor-positive cell lines. Blocking experiments with increasing concentrations of bicalutamide did not prevent the HHDS product-stimulated growth. We filed an adverse event report with the Food and Drug Administration who issued a warning letter. The manufacturer responded by removing this HHDS product from the market. CONCLUSIONS: The HHDS product contained one or more endocrinologically active tumor-promoting components that had cellular androgen receptor status-independent activity. The HHDS product exhibited potent prostate cancer growth stimulatory activity that was more powerful than that of testosterone, independent of the androgen-receptor status of prostate cancer cells, and resistant to antiandrogen blockade.
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Androgênios/efeitos adversos , Suplementos Nutricionais/efeitos adversos , Neoplasias da Próstata/fisiopatologia , Idoso , Linhagem Celular Tumoral , Progressão da Doença , Humanos , Masculino , Pessoa de Meia-Idade , Próstata/efeitos dos fármacos , Neoplasias da Próstata/etiologia , Receptores Androgênicos/metabolismo , Testosterona/metabolismoRESUMO
BACKGROUND/PURPOSE: Aggressive tumors may alter their expression of Bcl-2 proteins to decrease apoptosis and increase survival. The authors reported previously that neuroblastoma cells have diminished apoptosis when placed in coculture with hepatocytes to stimulate a metastatic environment. It was hypothesized that the expression of proapoptotic (Bax) and prosurvival (Bcl-2 and Mcl-1) proteins would be altered in neuroblastoma cells grown in a cell culture model of metastatic neuroblastoma. METHODS: Human neuroblastoma cells (IMR-32) were grown alone or in coculture with human hepatocytes for 2, 3, or 4 days. Bcl-2, Mcl-1, and Bax mRNA were measured with reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Bcl-2, an antiapoptotic protein, was significantly increased in cocultured neuroblastoma cells by day 4. Bax, a proapoptotic protein, was significantly diminished by day 3. No significant change in Mcl-1 occurred in this study. CONCLUSIONS: When neuroblastoma cells placed in coculture, the prosurvival protein, Bcl-2, is upregulated whereas the proapoptotic protein, Bax, is downregulated. The combination of these changes can maximally enhance the survival rate of neuroblastoma cells in coculture. The propensity for neuroblastoma to either metastasize or regress may be associated with its ability to differentially regulate the expression of different members of the Bcl-2 protein family.