A systematic review of geographical variation in access to chemotherapy

Abstract

Background

Rising cancer incidence, the cost of cancer pharmaceuticals and the introduction of the Cancer Drugs Fund in England, but not other United Kingdom(UK) countries means evidence of 'postcode prescribing' in cancer is important. There have been no systematic reviews considering access to cancer drugs by geographical characteristics in the UK.

Methods

Studies describing receipt of cancer drugs, according to healthcare boundaries (e.g. cancer network [UK]) were identified through a systematic search of electronic databases and grey literature. Due to study heterogeneity a meta-analysis was not possible and a narrative synthesis was performed.

Results

8,780 unique studies were identified and twenty-six included following a systematic search last updated in 2015. The majority of papers demonstrated substantial variability in the likelihood of receiving chemotherapy between hospitals, health authorities, cancer networks and UK countries (England and Wales). After case-mix adjustment, there was up to a 4–5 fold difference in chemotherapy utilisation between the highest and lowest prescribing cancer networks. There was no strong evidence that rurality or distance travelled were associated with the likelihood of receiving chemotherapy and conflicting evidence for an effect of travel time.

Conclusions

Considerable variation in chemotherapy prescribing between healthcare boundaries has been identified. The absence of associations with natural geographical characteristics (e.g. rurality) and receipt of chemotherapy suggests that local treatment habits, capacity and policy are more influential.

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Preliminary study on liver function changes after trisectionectomy with versus without prior portal vein embolization

Abstract

Purpose

Post-hepatectomy liver failure (PHLF) is the major risk factor for mortality after hepatectomy. Preoperative planning of the future liver remnant volume reduces PHLF rates; however, future liver remnant function (FLR-F) might have an even stronger predictive value. In this preliminary study, we used a new method to calculate FLR-F by the LiMAx test and computer tomography-assisted volumetric-analysis to visualize liver function changes after portal vein embolization (PVE) before extended hepatectomy.

Methods

The subjects included patients undergoing extended right hepatectomy either directly (NO-PVE group) or after PVE (PVE group). Computed tomography (CT) scan and liver function tests (LiMAx) were done before PVE and preoperatively. FLR-F was calculated and correlated with the postoperative liver function.

Results

There were 12 patients in the NO-PVE group and 19 patients in the PVE group. FLR-F and postoperative liver function correlated significantly in both groups (p = 0.036, p = 0.011), although postoperative liver function was slightly overestimated, at 32 and 45 µg/kg/min, in the NO-PVE and PVE groups, respectively. LiMAx value did not change after PVE.

Conclusions

Volume–function analysis using LiMAx and CT scan enables us to reliably predict early postoperative liver function. Global enzymatic liver function measured by the LiMAx test did not change after PVE, confirming that liver function distribution in the liver stays constant after PVE. An overestimation of FLR-F is needed to compensate for the intraoperative liver injury that occurs in patients undergoing extended hepatectomy.

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Therapeutic mammoplasty combining partial mastectomy with nipple-areola grafting for patients with early breast cancer: a case series

Abstract

Purpose

Therapeutic mammoplasty (TM) for breast cancer is a widely practiced oncoplastic technique. Intraductal spread towards the nipple or the location of the cancerous lesion on the central breast may become a contraindication for breast-conserving surgery. We herein report the results of TM in such cases.

Methods

Six patients underwent TM that combined partial mastectomy with free nipple-areola (NA) grafting. The nipple was removed together with the cancerous lesions, and the areola was preserved for NA reconstruction. The tumors were located in the lower quadrant (n = 1), the central area (n = 1), the upper-outer area (n = 2), and the upper-inner area (n = 2). The types of mammoplasty that were performed included: amputation (n = 1), inverted T mammoplasty (n = 3), and L mammoplasty (n = 2). With the exception of one patient, all patients underwent inverted T mammoplasty on the contralateral breast in order to achieve symmetry.

Results

The total surgical and plastic periods ranged from 155 to 235 min (mean 207 min) and 100 to 150 min (mean 121 min), respectively. Oncological safety and excellent cosmetic results were achieved.

Conclusions

TM combining partial mastectomy with NA grafting was successfully performed in patients with early-stage cancer in all quadrant areas.

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Expression of the apoptosis repressor with caspase recruitment domain (ARC) in liver metastasis of colorectal cancer and its correlation with DNA mismatch repair proteins and p53

Abstract

Introduction

Apoptotic signaling is one of the most important processes in the measurement of chemotherapeutic effectiveness. In apoptotic machinery, various pathways and proteins are involved (i.e., mismatch repair proteins, p53). One of the regulatory proteins is ARC, which can inhibit not only the extrinsic but also the intrinsic apoptotic signaling.

Materials and Methods

In this study, we investigated the expression levels of ARC in colorectal liver metastasis and compared them with the expression of mismatch repair proteins and p53. Furthermore, we investigated ARC expression level depending on sex, age, tumor grade, mucin production, tumor size and number of liver metastasis.

Results

ARC expression level in colorectal cancer liver metastasis was independent from clinical data (i.e., age, gender, tumor size, tumor number or mucin production) but strongly correlated with MSH2 and MSH6 expression, which further supported the evidence for the regulatory role of MSH2 and MSH6 in apoptosis; i.e., in case of sufficient MSH2 and MSH6 expression, significantly higher ARC level is required to suppress the apoptosis. A regulatory interaction between ARC and p53 has been described, but we found no correlation between p53 expression levels and ARC levels.

Conclusion

Further studies are needed to define the exact role of ARC in apoptotic signaling and thus its role in chemoresistance and survival of tumor cells.

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Structure-based Screen Identification of a Mammalian Ste20-like Kinase 4 (MST4) Inhibitor with Therapeutic Potential for Pituitary Tumors

Pituitary tumors of the gonadotrope lineage are often large and invasive, resulting in hypopituitarism. No medical treatments are currently available. Using a combined genetic and genomic screen of individual human gonadotrope pituitary tumor samples, we recently identified the Mammalian sterile-20 like kinase 4 (MST4) as a pro-tumorigenic effector, driving increased pituitary cell proliferation and survival in response to a hypoxic microenvironment. To identify novel inhibitors of the MST4 kinase for potential future clinical use, computational-based virtual library screening was employed to dock the SelleckChem kinase inhibitor library into the ATP-binding site of the MST4 crystal structure. Several inhibitor candidates were identified with the potential to bind with high affinity. Using a TR-FRET in vitro recombinant kinase assay, hesperadin, initially described as an Aurora kinase inhibitor, exhibited potent inhibition of the MST4 kinase at nanomolar concentrations. The LβT2 gonadotrope pituitary cell hypoxic model was used to test the ability of this inhibitor to antagonize MST4 actions. Under short-term severe hypoxia (1% O2), MST4 protection from hypoxia-induced apoptosis was abrogated in the presence of hesperadin. Similarly, under chronic hypoxia (5%), hesperadin blocked the proliferative and colony forming actions of MST4 as well as the ability to activate specific downstream signaling and hypoxia inducible factor-1 (HIF-1) effectors. Together, these data identify hesperadin as the first potent, selective inhibitor of the MST4 kinase with the capacity to block pituitary tumor cell growth in a hypoxic microenvironment.

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Preclinical evaluation of a novel orally available SRC/Raf/VEGFR2 inhibitor, SKLB646, in the treatment of triple negative breast cancer

Triple-negative breast cancer (TNBC) is the most aggressive and deadly breast cancer subtype. To date, chemotherapy is the only systemic therapy and prognosis remains poor. Herein, we report the preclinical evaluation of SKLB646 in the treatment of TNBC; SKLB646 is a novel multiple kinase inhibitor developed by us recently. This compound potently inhibited SRC and VEGFR2 with IC50 values of 0.002 μM and 0.012 μM, respectively. It also considerably inhibited B-Raf and C-Raf with IC50 values of 0.022 and 0.019 μM, respectively. It exhibited significant anti-proliferation and anti-viability activities against TNBC cell lines. Studies of mechanism of action indicated that SKLB646 inhibited the activation of SRC signaling and blocked the MAPK signaling through inhibiting the Raf kinases. Interestingly, SKLB646 dose-dependently down-regulated the expression of Fra1, a transcriptional factor that plays a critical role in the epithelial-to-mesenchymal transition. Additionally, SKLB646 could inhibit HUVEC proliferation, migration and invasion. It effectively blocked the formation of intersegmental vessels in zebrafish embryos and displayed considerable antiangiogenic effects in the tumor-induced neovascularization zebrafish model. In TNBC xenograft models, SKLB646 suppressed the tumor growth in a dose-dependent manner. Moreover, SKLB646 could remarkably inhibit TNBC cell migration and invasion in vitro. Further, in an experimental lung metastasis model, the overall survival time of groups treated with SKLB646 was much lengthened compared with the control, dasatinib and paclitaxel treated groups. In a preliminary pharmacokinetic study, SKLB646 showed good pharmacokinetic properties. Taken together, the preclinical data show that SKLB646 could be a promising lead compound for the treatment of TNBC.

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Impact of spot size and beam-shaping devices on the treatment plan quality for pencil beam scanning proton therapy

Publication date: Available online 29 December 2015
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Maryam Moteabbed, Torunn I. Yock, Nicolas Depauw, Thomas M. Madden, Hanne M. Kooy, Harald Paganetti
PurposeThis study aims to assess the clinical impact of spot size and the addition of apertures and range compensators on the treatment quality of pencil beam scanning (PBS) proton therapy and to define when PBS could improve upon passive scattering proton therapy (PSPT).Methods and materialsThe patient cohort included fourteen pediatric patients treated with PSPT. Six PBS plans were created and optimized for each patient using three spot sizes (∼12, 5.4, and 2.5 mm median sigma at isocenter for 90-230 MeV range), and adding apertures and compensators to plans with the two larger spots. Conformity and homogeneity indices, dose-volume histogram parameters, equivalent uniform dose (EUD), normal tissue complication probability (NTCP) and integral dose were quantified and compared with the respective PSPT plans.ResultsThe results clearly indicated that PBS with the largest spots does not necessarily offer a dosimetric or clinical advantage over PSPT. With comparable target coverage, the mean dose (Dmean) to healthy organs was on average 6.3% larger than PSPT when using this spot size. However, adding apertures to plans with large spots improved the treatment quality by decreasing the average Dmean and EUD by up to 8.6 and 3.2% of the prescribed dose, respectively. Decreasing the spot size further improved all plans, lowering the average Dmean and EUD by up to 11.6% and 10.9% compared to PSPT, respectively, and eliminated the need for beam-shaping devices. The NTCP decreased with spot size and addition of apertures, with maximum reduction of 5.4% relative to PSPT.ConclusionsThe added benefit of using PBS strongly depends on the delivery configurations. Facilities limited to large spot sizes (>∼8 mm median sigma at isocenter) are recommended to use apertures in order to reduce the treatment-related toxicities, at least for complex and/or small tumors.

Teaser

The clinical impact of spot size and additional application of beam-shaping devices (apertures and range compensators) for pencil beam scanning proton therapy was investigated. No clinical advantage over passive scattering was realized when spot size was relatively large (∼12 mm median sigma at the isocenter). Plans superior to passive scattering were achieved when decreasing the spot size and/or adding beam-shaping devices to larger spots.


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Metastatic breast cancer patients treated with low-dose metronomic chemotherapy with cyclophosphamide and celecoxib: clinical outcomes and biomarkers of response

Abstract

Background

Preclinical results showing therapeutic effect and low toxicity of metronomic chemotherapy with cyclophosphamide (Cy) + celecoxib (Cel) for mammary tumors encouraged its translation to the clinic for treating advanced breast cancer patients (ABCP).

Patients and methods

A single-arm, mono-institutional, non-randomized, phase II, two-step clinical trial (approved by Bioethics Committee and Argentine Regulatory Authority) was designed. Patients received Cy (50 mg po.d) + Cel (200 mg p.o.bid). Patient eligibility criteria included: ABCP who progressed to anthracyclines, taxanes and capecitabine, ≤4 chemotherapy schemes, with good performance status. Several pro- and anti-angiogenic molecules and cells were determined as biomarkers. Informed consent was signed by all patients. Primary endpoint was clinical benefit (CB).

Results

Twenty patients were enrolled. Main clinical outcomes were prolonged disease stabilization and partial remission in 10/20 and 1/20 patients, respectively. CB was 55 %, and time to progression (TTP) was 21.1 weeks. Median TTP in patients who achieved CB was 35.6 weeks, and mean overall survival was 44.20 weeks. There were no grade 3/4 toxicities associated with treatment. Circulating endothelial cells (CECs) increased at the time of progression in patients who showed CB (P = 0.014). Baseline CECs and circulating endothelial progenitor cells showed marginal associations with TTP. Serum VEGF decreased (P = 0.050), sVEGFR-2 increased (P = 0.005) and VEGF/sVEGFR-2 ratio decreased during treatment (P = 0.041); baseline VEGF and VEGF/sVEGFR-2 were associated with TTP (P = 0.035 and P = 0.030, respectively), while sVEGFR-2 did not.

Conclusions

Treatment was effective, showing low toxicity profile and excellent tolerability. The combination had anti-angiogenic effect. Increased levels of CEC could be useful for detecting progression. Baseline VEGF and VEGF/sVEGFR-2 values could be useful as early predictors of response.

Trial registration

ANMAT#4596/09.

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