Site-Specific Dolasynthen Antibody-Drug Conjugates Exhibit Consistent Pharmacokinetic Profiles across a Wide Range of Drug-to-Antibody Ratios.

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.

Economic Policies and Intimate Partner Violence Prevention: Emerging Complexities in the Literature.

Although the question of whether economic policies serve to reduce rates of intimate partner violence (IPV) has long been raised, rigorous tests of this question have only begun to take place recently. Given the mixed evidence to date, much remains unknown about the circumstances in which a positive or negative relationship holds between changes in financial well-being and IPV. We describe an empirically based theoretical model that may link economic empowerment to IPV and that highlights research questions for further testing. This model reflects two theoretical pathways through which economic policies may reduce IPV: A program may activate social and psychological empowerment as protective factors and a program may deactivate cognitive and behavioral risk factors such as stress and substance abuse. We then consider the relevance of each of a range of economic policies and review existing experimental evidence regarding the effect of such programs on IPV. We discuss unconditional and conditional cash transfers, savings programs, microfinance and income generation programs, and economic programs combined with relationship-related training. Gaps in research on this topic and emerging complexities in the literature suggest the following three key areas that would benefit from greater research and evaluation: comparison across programs based on size and design, assessment of the returns to economic empowerment of young adults, and more evaluations in high-income countries.

The transformation of the nuclear nanoarchitecture in human field carcinogenesis.

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.

Locoregional recurrence after mastectomy with immediate transverse rectus abdominis myocutaneous (TRAM) flap reconstruction.

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.

Using National Quality Forum breast cancer indicators to measure quality of care for patients in an AVON comprehensive breast center.

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.

The effects of additional tumor cavity sampling at the time of breast-conserving surgery on final margin status, volume of resection, and pathologist workload.

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.

The dangerous shortage of domestic violence services.

Domestic violence is a serious, preventable health problem affecting more than thirty million Americans annually, yet little is known about federally funded service provision. We used the National Census of Domestic Violence Services, an innovative victim-safety focused survey, to count services provided by more than 2,000 programs. During the twenty-four-hour survey period, 48,350 people used these services. The results show substantial unmet demand for services (10 percent of requests) because of resource constraints, particularly in rural, economically disadvantaged, and minority communities. Greater funding of domestic violence programs, particularly housing support, is likely to be a cost-effective public health investment.

Herbal/hormonal dietary supplement possibly associated with prostate cancer progression.

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.

Differential expression of Bcl-2 and Bax may enhance neuroblastoma survival.

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.