Correlates of refusal of radical cystectomy in patients with muscle-invasive bladder cancer.

PURPOSE: To evaluate factors associated with radical cystectomy (RC) refusal, subsequent treatment decisions, and their influence on overall survival (OS). MATERIALS AND METHODS: We queried the National Cancer Database for patients with non-metastatic muscle-invasive bladder cancer (MIBC), cT2-T4M0. Patients who refused recommended RC were further stratified by treatment into chemotherapy, radiation therapy, chemoradiotherapy, and no treatment groups. Patients were excluded from the analysis if surgery was not planned, not recommended; or if survival data were unknown. Multivariate logistic regression modeling was utilized to identify independent predictors of refusing RC. Cox proportional hazards model with propensity score overlap weighting was utilized to identify survival predictors. Kaplan-Meier analysis was utilized to evaluate survival according to treatment. RESULTS: A total of 74,159 MIBC patients were identified. Among patients with documented reasons for no surgery, 5.4% refused RC despite physician recommendation. Predictors of refusal on multivariate analysis included female gender (P = 0.016), advancing age ≥80 (vs. <60, P < 0.001), African American race (vs. white, P < 0.001) Medicaid (vs. private insurance, P < 0.001) and advancing T stage (T4 vs. T2, P < 0.001). Patients treated at academic centers were less likely to decline RC (vs. community centers, P < 0.001). Median survival after RC was 40.44 months vs. 12.52 months in refusal group. Undergoing chemoradiation had significantly improved survival in those patients compared to monotherapy or no treatment (hazard ratio 0.25, P < 0.001). Overlap weighted model Identified RC refusal as an independent predictor of poor OS (P < 0.001). CONCLUSIONS: Several sociodemographic and clinical factors are associated with refusing radical cystectomy. Such refusal is associated with poor survival outcomes.

Rise in serum folate after androgen deprivation associated with worse prostate cancer-specific survival.

INTRODUCTION: High folate has an association with advanced prostate cancer and levels of testosterone. Herein, we perform a translational study to investigate the inverse response of serum folate in prostate cancer patients initiating androgen deprivation therapy (ADT) and a mirrored animal model. METHODS: A retrospective study was performed using the South Texas Veterans Healthcare System to identify patients with prostate cancer on ADT. We documented testosterone and folate levels before and after ADT initiation (defined by a reduction in testosterone by 50 ng/ml) as compared to those already on ADT (maintenance). Our primary outcome was overall mortality with secondary outcome of prostate cancer-specific mortality. In parallel, we tested castration of C57BL/6J mice on folate-defined diet to determine if folate levels change with response to androgen deprivation. Students' t test on continuous variables and Chi-squared test on dichotomous variables was performed along with Kaplan-Meier for time to event analysis. RESULTS: We identified 56 men with prostate cancer undergoing androgen deprivation in which folate levels had been determined. 15 out of 16 (94%) men initiating ADT had increases in their folate, which is substantially more than 67% in maintenance group (P = 0.04). We identified more rapid time to death from prostate cancer if folate levels increased to levels >200 ng/ml above their baseline (P = 0.03). Mice models demonstrated a significant rise in serum red blood cell folate after mice were castrated (P = 0.03) by an average of 1.5x over pre-castrated baseline level. By contrast, sham-castrated mice showed no increase in serum folate levels over baseline. CONCLUSION: Our study suggests that men with substantial rises in folate after initiating ADT may be associated with worse prostate cancer-specific and overall survival. Our translational experiments in mice confirmed correlation between rising in folate levels post-castration. Given this study, further investigation is warranted on the role of dietary folate consumption during initiation of ADT and progression to castrate-resistant prostate cancer.

In vivo hydroxyapatite scaffold performance in infected bone defects.

Critically sized bone defects are often compounded by infectious complications. The standard of care consists of bone autografts with systemic antibiotics. These injuries and treatments lead to donor site morbidity, antibiotic resistant strains of bacteria, and often end stage amputation. This study proposes an alternative to the autograft using a porous, hydroxyapatite (HA) scaffold evaluated with and without infection and antibiotics. Twenty-four New Zealand white rabbits received either our HA scaffold or a pulverized autograft (PBA) within a surgically created critical-sized defect in the femur. The two grafts were evaluated in either septic or aseptic defects and with or without antibiotic treatment. The HA scaffolds were characterized with micro computed tomography. Post-euthanasia, micro computed tomography, histology, and white blood cells component analysis were completed. The HA had significantly greater (p < .001) mineralization to total volume than the PBA groups with 27.56% and 14.88%, respectively, and the septic HA groups were significantly greater than the aseptic groups both with and without antibiotics (p = .016). The bone quality denoted by bone mineral density was also significantly greater (p < .001) in the HA groups (67.01 ± 0.38 mgHA/cm3 ) than the PBA groups (64.66 ± 0.85 mgHA/cm3 ). The HA scaffold is a viable alternative to the bone autograft in defects with and without infection as shown by the quality and quantity of bone.

Contemporary surgical outcomes of venous tumour thrombectomy managed with intraoperative Doppler ultrasound for kidney cancer.

INTRODUCTION: Radical nephrectomy (RN) with venous tumour thrombectomy (VTT) carries a significant morbidity and mortality risk. Examination of a contemporary single-institution series permits the development of a management algorithm and an audit its results. We report outcomes following the use of intraoperative colour Doppler ultrasound and our surgical pathway. METHODS: We retrospectively reviewed the records of all patients who underwent RN with VTT for kidney cancer between January 1, 2013 and October 1, 2016. Surgical complications, postoperative complications (Clavien-Dindo classification ≥3), 90-day readmission rates, and outcomes are reported. Multivariate linear regression, logistic regression, and Cox proportional hazard modelling were used to identify associations. RESULTS: Fifty-eight patients underwent RN with VTT. Of these, 26 (45%) patients had Mayo Clinic level III or IV thrombus and nineteen required venovenous/cardiopulmonary bypass. Three patients required patch grafting. The median length of hospital stay was eight days and there were 20 major complications. The 30-day readmission rate was 21% and the 90-day mortality rate was 8.9%. In multivariate analysis, low serum albumin and age-adjusted Charlson comorbidity score predicted length of stay. Increased intraoperative blood loss was significantly associated with increasing body mass index, serum creatinine, tumour thrombus level, and a history of significant weight loss >9.1kg. Low serum hematocrit predicted 90-day mortality. CONCLUSIONS: Intraoperative colour Doppler ultrasound is a useful tool and can facilitate caval preservation. Caval grafting can be avoided in most cases. Venovenous bypass can be avoided in many level III cases. Early therapeutic anticoagulation should be instituted with caution.

Synthesis of a novel, sequentially active-targeted drug delivery nanoplatform for breast cancer therapy.

Breast cancer is the leading cause of cancer deaths among women. Paclitaxel (PTX), an important breast cancer medicine, exhibits reduced bioavailability and therapeutic index due to high hydrophobicity and indiscriminate cytotoxicity. PTX encapsulation in one-level active targeting overcomes such barriers, but enhances toxicity to normal tissues with cancer-similar expression profiles. This research attempted to overcome this challenge by increasing selectivity of cancer cell targeting while maintaining an ability to overcome traditional pharmacological barriers. Thus, a multi-core, multi-targeting construct for tumor specific delivery of PTX was fabricated with (i) an inner-core prodrug targeting the cancer-overexpressed cathepsin B through a cathepsin B-cleavable tetrapeptide that conjugates PTX to a poly(amidoamine) dendrimer, and (ii) the encapsulation of this prodrug (PGD) in an outer core of a RES-evading, folate receptor (FR)-targeting liposome. Compared to traditional FR-targeting PTX liposomes, this sequentially active-targeted dendrosome demonstrated better prodrug retention, an increased cytotoxicity to cancer cells (latter being true when FR and cathepsin B activities were both at moderate-to-high levels) and higher tumor reduction. This research may eventually evolve a product platform with reduced systemic toxicity inherent with traditional chemotherapy and localized toxicity inherent to single-target nanoplatforms, thereby allowing for better tolerance of higher therapeutic load in advanced disease states.

Design of a paclitaxel prodrug conjugate for active targeting of an enzyme upregulated in breast cancer cells.

Breast cancer is the second most common cause of cancer-related deaths in women. Chemotherapy is an important treatment modality, and paclitaxel (PTX) is often the first-line therapy for its metastatic form. The two most notable limitations related to PTX-based treatment are the poor hydrophilicity of the drug and the systemic toxicity due to the drug's nonspecific and indiscriminate distribution among the tissues. The present work describes an approach to counter both challenges by designing a conjugate of PTX with a hydrophilic macromolecule that is coupled through a biocleavable linker, thereby allowing for active targeting to an enzyme significantly upregulated in cancer cells. The resultant strategy would allow for the release of the active ingredient preferentially at the site of action in related cancer cells and spare normal tissue. Thus, PTX was conjugated to the hydrophilic poly(amdioamine) [PAMAM] dendrimer through the cathepsin B-cleavable tetrapeptide Gly-Phe-Leu-Gly. The PTX prodrug conjugate (PGD) was compared to unbound PTX through in vitro evaluations against breast cancer cells and normal kidney cells as well as through in vivo evaluations using xenograft mice models. As compared to PTX, PGD demonstrated a higher cytotoxicity specific to cell lines with moderate-to-high cathepsin B activity; cells with comparatively lower cathepsin B activity demonstrated an inverse of this relationship. Regression analysis between the magnitude of PGD-induced cytotoxic increase over PTX and cathepsin B expression showed a strong, statistically significant correlation (r(2) = 0.652, p < 0.05). The PGD conjugate also demonstrated a markedly higher tumor reduction as compared to PTX treatment alone in MDA-MB-231 tumor xenograft models, with PGD-treated tumor volumes being 48% and 34% smaller than PTX-treated volumes at weeks 2 and 3 after treatment initiation.

Osteoblast response and calcium deposition on phospholipid modified surfaces.

In this study, the effect of calcium phosphate complexed phospholipid (Ca-PL-PO4) coatings on solid surfaces on the in vitro calcium (Ca) deposition and on the osteoblast responses was evaluated. Commercially available phospholipids were converted to their Ca-PL-PO4, and were coated on glass Petri dishes. The coated dishes were immersed in the simulated body fluid for up to 14 days under sterilized conditions at 37 degrees C, and the amount of calcium (Ca) deposited was quantified. Similarly, by measuring the alkaline phosphatase specific activity, the differentiation of osteoblast precursor cells were evaluated after seeding the cells on Ca-PL-PO4 coated cell culture plastics. It was observed that all Ca-PL-PO4 enhanced Ca deposition on coated surfaces. The, polar head group of phospholipids in coated surfaces was observed to have an influence on the Ca deposition as well as the osteoblast differentiation. Among the phospholipids evaluated, phosphatidylserine (Ca-PS-PO4) exhibited the strongest calcium deposition and more enhanced alkaline phosphatase specific activity. It was therefore concluded from this study that Ca-PS-PO4 surface modification may be an alternative method for enhancing bone-implant interactions.

Osteoblast response to phospholipid modified titanium surface.

The objective of this study was to evaluate the effect of different phospholipid coatings on osteoblast responses in vitro. Commercially available phospholipids [phosphatidylcholine (PC), phosphatidyl-serine (PS) and phosphatidylinositol (PI)] were converted to their Ca-PL-PO(4) and were coated on commercially pure titanium (Ti) grade 2 disks. Using uncoated Ti surfaces as controls, cell responses to phospholipid-coated surfaces were evaluated using the American Type Culture Collection (Manassas, VA, USA) CRL-1486 human embryonic palatal mesenchyme cells (HEPM), an osteoblast precursor cell line, over a 14-day period. Total protein synthesis and alkaline phosphatase specific activity at 0, 7, and 14 days were measured. It was observed that Ti surfaces coated with PS exhibited enhanced protein synthesis and alkaline phosphatase specific activity compared to other phospholipids and uncoated surfaces. These results indicate the possible usefulness of PS-coated Ti surfaces for inducing enhanced bone formation and are very encouraging for bone and dental implantology.