Characterization of the collagen microstructural organization of human cervical tissue.

The cervix shortens and softens as its collagen microstructure remodels in preparation for birth. Altered cervical tissue collagen microstructure can contribute to a mechanically weak cervix and premature cervical dilation and delivery. To investigate the local microstructural changes associated with anatomic location and pregnancy, we used second-harmonic generation microscopy to quantify the orientation and spatial distribution of collagen throughout cervical tissue from 4 pregnant and 14 non-pregnant women. Across patients, the alignment and concentration of collagen within the cervix was more variable near the internal os and less variable near the external os. Across anatomic locations, the spatial distribution of collagen within a radial zone adjacent to the inner canal of the cervix was more homogeneous than that of a region comprising the middle and outer radial zones. Two regions with different collagen distribution characteristics were found. The anterior and posterior sections in the outer radial zone were characterized by greater spatial heterogeneity of collagen than that of the rest of the sections. Our findings suggest that the microstructural alignment and distribution of collagen varies with anatomic location within the human cervix. These observed differences in collagen microstructural alignment may reflect local anatomic differences in cervical mechanical loading and function. Our study deepens the understanding of specific microstructural cervical changes in pregnancy and informs investigations of potential mechanisms for normal and premature cervical remodeling.

A randomized phase II trial of CRLX101 in combination with bevacizumab versus standard of care in patients with advanced renal cell carcinoma.

BACKGROUND: Nanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle-drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1α and 2α. In a phase Ib/2 trial, CRLX101 + bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101 + bevacizumab versus standard of care (SOC) in refractory mRCC. PATIENTS AND METHODS: Patients with mRCC and 2-3 prior lines of therapy were randomized 1 : 1 to CRLX101 + bevacizumab versus SOC, defined as investigator's choice of any approved regimen not previously received. The primary end point was progression-free survival (PFS) by blinded independent radiological review in patients with clear cell mRCC. Secondary end points included overall survival, objective response rate and safety. RESULTS: In total, 111 patients were randomized and received ≥1 dose of drug (CRLX101 + bevacizumab, 55; SOC, 56). Within the SOC arm, patients received single-agent bevacizumab (19), axitinib (18), everolimus (7), pazopanib (4), sorafenib (4), sunitinib (2), or temsirolimus (2). In the clear cell population, the median PFS on the CRLX101 + bevacizumab and SOC arms was 3.7 months (95% confidence interval, 2.0-4.3) and 3.9 months (95% confidence interval 2.2-5.4), respectively (stratified log-rank P = 0.831). The objective response rate by IRR was 5% with CRLX101 + bevacizumab versus 14% with SOC (Mantel-Haenszel test, P = 0.836). Consistent with previous studies, the CRLX101 + bevacizumab combination was generally well tolerated, and no new safety signal was identified. CONCLUSIONS: Despite promising efficacy data on the earlier phase Ib/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101 + bevacizumab combination when compared with approved agents in patients with heavily pretreated clear cell mRCC. Further development in this disease is not planned. CLINICAL TRIAL IDENTIFICATION: NCT02187302 (NIH).

Environment-Induced Degradation of Shape Memory Alloys: Role of Alloying and Nature of Environment.

Shape memory effects coupled with superelasticity are the distinctive characteristics of shape memory alloys (SMAs), a type of metal. When these alloys are subject to thermomechanical processing, they have the inherent ability to react to stimuli, such as heat. As a result, these alloys have established their usefulness in a variety of fields and have in recent years been chosen for use in stents, sensors, actuators, and several other forms of life-saving medical equipment. When it comes to the shape memory materials, nickel-titanium (Ni-Ti) alloys are in the forefront and have been chosen for use in a spectrum of demanding applications. As shape memory alloys (SMAs) are chosen for use in critical environments, such as blood streams (arteries and veins), orthodontic applications, orthopedic implants, and high temperature surroundings, such as actuators in aircraft engines, the phenomenon of environment-induced degradation is of both interest and concern. Hence, the environment-induced degradation behavior of the shape memory alloys (SMAs) needs to be studied to find viable ways to improve their resistance to an aggressive environment. The degradation that occurs upon exposure to an aggressive environment is often referred to as corrosion. Environment-induced degradation, or corrosion, being an unavoidable factor, certain techniques can be used for the purpose of enhancing the degradation resistance of shape memory alloys (SMAs). In this paper, we present and discuss the specific role of microstructure and contribution of environment to the degradation behavior of shape memory alloys (SMAs) while concurrently providing methods to resist both the development and growth of the degradation caused by the environment.

Intratumor C-reactive protein as a biomarker of prognosis in localized renal cell carcinoma.

PURPOSE: Serum C-reactive protein has been shown to have prognostic value in localized and metastatic renal cell carcinoma. However, the prognostic value of intratumor C-reactive protein remains unknown. MATERIALS AND METHODS: A total of 95 patients with resected, clinically localized (T1-T4N0M0) clear cell renal cell carcinoma were followed postoperatively. Intratumor C-reactive protein expression was assessed in surgical specimens using immunohistochemical analysis. Patients were categorized by staining intensity into low risk (staining 0 to 1), intermediate risk (staining 2) and high risk (staining 3) groups. Kaplan-Meier and multivariate Cox regression analyses were used to examine overall survival across patient and disease characteristics. Variables examined in multivariate Cox regression analysis included T stage, Fuhrman nuclear grade, tumor size, preoperative serum C-reactive protein and intratumor C-reactive protein staining. RESULTS: Followup extended up to 46 months with a mean (SD) of 29.8 (11.0) months. Twelve patients (12.6%) died during followup. Of all tumors 49.5%, 25.3% and 25.3% were graded by intratumor C-reactive protein staining as low risk (0 to 1), intermediate risk (2) and high risk (3), respectively. After controlling for variables significant on univariate analysis, patients in the high risk (3) group experienced a 27-fold increased risk of overall mortality compared to those in the low risk (0-1) group (HR 27.767, 95% CI 1.488-518.182). After adjusting for tumor staining, preoperative serum C-reactive protein was not a significant predictor of overall survival (p = 0.741). CONCLUSIONS: Intratumor C-reactive protein may be a robust biomarker of prognosis in patients with localized renal cell carcinoma.

Phase I pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies.

BACKGROUND: SF1126 is a peptidic pro-drug inhibitor of pan-PI3K/mTORC. A first-in-human study evaluated safety, dose limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of SF1126, in patients with advanced solid and B-cell malignancies. PATIENTS AND METHODS: SF1126 was administered IV days 1 and 4, weekly in 28day-cycles. Dose escalation utilised modified Fibonacci 3+3. Samples to monitor PK and PD were obtained. RESULTS: Forty four patients were treated at 9 dose levels (90-1110 mg/m(2)/day). Most toxicity was grade 1 and 2 with a single DLT at180 mg/m(2) (diarrhoea). Exposure measured by peak concentration (C(max)) and area under the time-concentration curve (AUC(0-)(t)) was dose proportional. Stable disease (SD) was the best response in 19 of 33 (58%) evaluable patients. MTD was not reached but the maximum administered dose (MAD) was 1110 mg/m(2). The protocol was amended to enrol patients with CD20+ B-cell malignancies at 1110 mg/m(2). A CLL patient who progressed on rituximab [R] achieved SD after 2 months on SF1126 alone but in combination with R achieved a 55% decrease in absolute lymphocyte count and a lymph node response. PD studies of CLL cells demonstrated SF1126 reduced p-AKT and increased apoptosis indicating inhibition of activated PI3K signalling. CONCLUSION: SF1126 is well tolerated with SD as the best response in patients with advanced malignancies.

Postoperative better than preoperative C-reactive protein at predicting outcome after potentially curative nephrectomy for renal cell carcinoma.

OBJECTIVES: Preoperative C-reactive protein (CRP) predicts metastasis and mortality in localized renal cell carcinoma (RCC). However, the predictive potential of after resection of localized RCC remains unclear. Therefore, we assessed the absolute ability of postoperative CRP to predict metastases and mortality as a continuous variable. METHODS: Patients with clinically localized (T1-T3N0M0) clear-cell RCC were followed for 1 year postoperatively. Metastases were identified radiologically and mortality by death certificate. Univariate and multivariate binary logistic regression analyses examined 1 year relapse-free survival (RFS) and overall survival (OS) across patient and disease characteristics. RESULTS: Of the 110 patients in this study, 16.4% developed metastases and 6.4% died. Mean (SD) postoperative CRP for patients who did and did not develop metastases were 69.06 (73.55) mg/L and 5.27 (7.80), respectively. Mean (SD) postoperative CRP for patients who did and did not die were 89.31 (69.51) mg/L and 10.88 (30.32), respectively. In multivariate analysis, T-stage (OR: 12.452, 95% CI: 2.889-53.660) and postoperative CRP ((B: .080, SE: .025; P < .001) were significant predictors of RFS. T-Stage (OR: 11.715; 95% CI: 1.102-124.519) and postoperative CRP (B: .017; SE: .007; P < .001) were also significant predictors of OS. After adjusting for postoperative CRP, preoperative CRP was not predictive of these outcomes. CONCLUSIONS: Postoperative, not preoperative, CRP is the better predictor of metastasis and mortality following nephrectomy for localized RCC. Clinicians should consider absolute postoperative CRP to identify high-risk patients for closer surveillance or additional therapy. Predictive algorithms should consider incorporating postoperative CRP as a continuous variable to maximize predictive ability.

Effect of difluoromethylornithine on host and tumor polyamine metabolism during total parenteral nutrition.

Clinical and experimental data suggest that erythrocyte (RBC) polyamine (PA) levels are markers of tumor proliferation during total parenteral nutrition (TPN). The purpose of this experiment was to determine whether the inhibition of PA synthesis during TPN was greater in tumors than in normal host tissue. Rats bearing a subcutaneous fibrosarcoma were randomized to receive a chow diet (n = 5), TPN (n = 5), or TPN + difluoromethylornithine (DFMO) (an irreversible inhibitor of ornithine decarboxylase (ODC), at 1000 mg/kg body wt/day n = 4) for 6 days by continuous central venous infusion. TPN + DFMO resulted in a higher plasma albumin level and lower tumor ODC activity compared with chow feeding or TPN. Liver ODC activity was similar for the chow fed, TPN, and TPN + DFMO groups. RBC putrescine, tumor putrescine, and tumor spermidine levels were significantly lower in the TPN + DFMO group compared with the chow fed and TPN groups. RBC spermidine, RBC spermine, and tumor spermine levels were significantly increased with TPN + DFMO compared with TPN alone. DFMO did not produce diarrhea or weight loss. Increased RBC spermidine may indicate a toxic effect of DFMO on the tumor, resulting in leakage of tumor spermidine into the extracellular space. The data suggest that DFMO during TPN can selectively inhibit tumor PA synthesis and may improve host utilization of nutrients.