Cost-effectiveness analysis of pembrolizumab plus chemotherapy as first-line therapy for extensive-stage small-cell lung cancer.

BACKGROUND: The phase III KEYNOTE-604 study confirmed the benefit of pembrolizumab combined with chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer (ES-SCLC). Taken into account the clinical benefits of pembrolizumab and its high cost, this study aimed to assess the cost-effectiveness of adding pembrolizumab to standard first-line etoposide-platinum (EP) for patients with ES-SCLC from the US payer perspective. METHODS: A Markov model was developed to compare the cost and quality-adjusted life-year (QALY) of pembrolizumab plus EP and placebo plus EP over a 10-year time horizon. Clinical efficacy and safety data were pooled from the KEYNOTE-604 trial. Utilities were obtained from published resources. Costs were mainly collected from Medicare in 2020. Sensitivity analyses were performed to examine the robustness of our model. RESULTS: Adding pembrolizumab to standard first-line EP resulted in the better effectiveness than EP chemotherapy alone for ES-SCLC by 0.22 QALYs. Pembrolizumab plus EP was dominated economically by placebo plus EP, leading to an incremental cost-effectiveness ratio (ICER) of $334,373/ QALY. Deterministic sensitivity analyses indicated that the uncertainty in model parameters exerted no substantial effect on our results. Probability sensitivity analysis indicated that probabilities for pembrolizumab plus EP being cost-effective within a wide range of willingness to pay were modest. CONCLUSION: From the US payer perspective, the first-line treatment for ES-SCLC with pembrolizumab plus EP was not cost-effective compared with placebo plus EP. Although pembrolizumab combination chemotherapy was beneficial to the survival of ES-SCLC, price reduction may be the necessary to improve its cost-effectiveness.

Assessment of the Anti-Cancer Efficiency of Silver Moringa oleifera Leaves Nano-extract against Colon Cancer Induced Chemically in Rats.

BACKGROUND: Colorectal cancer (CRC) categorized as the most common type of gastrointestinal cancers affected both genders equally. Chemotherapeutic drugs became limited due to their deleterious side effects. Therefore, efficiency of M. oleifera leaves extract increased by incorporating silver nanoparticles (Ag-NPs) then studied against colon cancer induced by azoxymethane (AOM) in rats. METHODS: Different hematological and biochemical measurements in addition to specific tumor and inflammatory markers were quantified. Histopathological examination for Colonic tissues was performed. Native proteins and isoenzyme patterns were electrophoretically detected in addition to assaying expression of Tumor Protein P53 (TP53) and Adenomatous Polyposis Coli (APC) genes in colonic tissues. RESULTS: M. oleifera nano-extract restored levels of the hematological and biochemical measurements in addition to levels of tumor and inflammatory markers to normalcy in both of nano-extract simult- and post-treated groups. Also, it minimized severity of the histopathological alterations in the simult-treated group and prevented it completely in the post-treated group. The lowest similarity index (SI%) values were noticed with electrophoretic protein (SI=61.54%), lipid (SI=0.00%) and calcium (SI=75.00%) moieties of protein patterns, catalase (SI=85.71%), peroxidase (SI=85.71%), α-esterase (SI=50.00%) and ß-esterase (SI=50.00%) isoenzymes in addition to altering the relative quantities of total protein and isoenzyme bands in colon of cancer induced group. Moreover, levels of TP53 and APC gene expression increased significantly (P≤0.05) in colon cancer induced group. The nano-extract prevented the qualitative and quantitative alterations in the different electrophoretic patterns in addition to restoring levels of the gene expressions to normalcy in both of simult- and post-treated groups. CONCLUSION: M. oleifera nano-extract exhibited ameliorative effect against the biochemical, physiological and molecular alterations induced by AOM in nano-extract simult- and post-treated groups.
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Longitudinal Assessment of Safety of Femoropopliteal Endovascular Treatment With Paclitaxel-Coated Devices Among Medicare Beneficiaries: The SAFE-PAD Study.

Importance: Paclitaxel-coated peripheral devices have been associated with increased mortality, yet this harm signal has not been replicated outside of meta-analyses of small trials. Objective: To provide a longitudinal assessment of the safety of femoropopliteal endovascular treatment with peripheral drug-coated devices (DCDs) among Medicare beneficiaries. Design, Setting, and Participants: SAFE-PAD (Safety Assessment of Femoropopliteal Endovascular Treatment With Paclitaxel-Coated Devices) was a retrospective cohort study designed with the US Food and Drug Administration to evaluate the noninferiority of mortality between DCDs and non-drug-coated devices (NDCDs) for femoropopliteal revascularization performed in 2978 inpatient and outpatient facilities in the US from April 1, 2015, through December 31, 2018. Evaluation of the primary outcome was assessed through May 31, 2020. Participants were Medicare fee-for-service beneficiaries 66 years and older with 1 or more years of enrollment prior to femoropopliteal revascularization. Prespecified subgroups included low-risk cohorts, procedure location, disease severity, and device type. Inverse probability weighting was used to account for imbalances of observed characteristics. Sensitivity analyses were used to evaluate the potential influence of unmeasured confounding. Exposures: Treatment with DCDs vs NDCDs as determined by claims codes during the index procedure. Main Outcomes and Measures: The primary outcome was all-cause mortality. Secondary outcomes included repeated hospitalization, repeated lower extremity revascularization, and lower extremity amputation. Falsification end points were acute myocardial infarction, congestive heart failure, and pneumonia. Results: Of 168 553 patients, 70 584 (41.9%) were treated with a DCD. The mean (SD) age was 77.0 (7.6) years, 75 744 (44.9%) were female, 136 916 of 167 197 (81.9%) were White individuals, 85 880 of 168 553 (51.0%) had diabetes, 82 554 of 168 553 (49.0%) used tobacco, 78 665 of 168 553 (45.7%) had critical limb ischemia (CLI), and 13 296 of 168 553 (7.9%) had a prior amputation. Median follow-up was 2.72 years (interquartile range, 0.87-3.77; longest, 5.16 years). After weighting, the cumulative incidence of all-cause mortality was 53.8% with DCDs and 55.1% with NDCDs (hazard ratio [HR], 0.95; 95% CI, 0.94-0.97; noninferiority P < .001). Cox regression and instrumental variable analyses were consistent with the primary findings. No harm associated with DCDs was observed among subgroups, including those treated with stents (HR, 0.97; 95% CI, 0.95-1.00) or balloons (HR, 0.94; 95% CI, 0.92-0.96), with or without CLI (CLI: HR, 0.95; 95% CI, 0.93-0.97; non-CLI: HR, 0.97; 95% CI, 0.95-0.99), and those within the lowest quartile of total comorbidities (HR, 0.95; 95% CI, 0.92-0.99). Conclusions and Relevance: In this initial report from the SAFE-PAD cohort study, DCDs were found to be noninferior to NCDCs in respect to mortality through a median follow-up of 2.72 years. This finding remained robust in sensitivity analyses and was consistent across prespecified subgroups.

Cost-Effectiveness of Neoadjuvant-Adjuvant Treatment Strategies for Women With ERBB2 (HER2)-Positive Breast Cancer.

Importance: The neoadjuvant treatment options for ERBB2-positive (also known as HER2-positive) breast cancer are associated with different rates of pathologic complete response (pCR). The KATHERINE trial showed that adjuvant trastuzumab emtansine (T-DM1) can reduce recurrence in patients with residual disease compared with patients treated with trastuzumab; however, T-DM1 and other ERBB2-targeted agents are costly, and understanding the costs and health consequences of various combinations of neoadjuvant followed by adjuvant treatments in the United States is needed. Objective: To examine the costs and disease outcomes associated with selection of various neoadjuvant followed by adjuvant treatment strategies for patients with ERBB2-positive breast cancer. Design, Setting, and Participants: In this economic evaluation, a decision-analytic model was developed to evaluate various neoadjuvant followed by adjuvant treatment strategies for women with ERBB2-positive breast cancer from a health care payer perspective in the United States. The model was informed by the KATHERINE trial, other clinical trials with different regimens from the KATHERINE trial, the Flatiron Health Database, McKesson Corporation data, and other evidence in the published literature. Starting trial median age for KATHERINE patients was 49 years (range, 24-79 years in T-DM1 arm and 23-80 years in trastuzumab arm). The model simulated patients receiving 5 different neoadjuvant followed by adjuvant treatment strategies. Data analyses were performed from March 2019 to August 2020. Exposure: There were 4 neoadjuvant regimens: (1) HP: trastuzumab (H) plus pertuzumab (P), (2) THP: paclitaxel (T) plus H plus P, (3) DDAC-THP: dose-dense anthracycline/cyclophosphamide (DDAC) plus THP, (4) TCHP: docetaxel (T) plus carboplatin (C) plus HP. All patients with pCR, regardless of neoadjuvant regimen, received adjuvant H. Patients with residual disease received different adjuvant therapies depending on the neoadjuvant regimen according to the 5 following strategies: (1) neoadjuvant DDAC-THP followed by adjuvant H, (2) neoadjuvant DDAC-THP followed by adjuvant T-DM1, (3) neoadjuvant THP followed by adjuvant DDAC plus T-DM1, (4) neoadjuvant HP followed by adjuvant DDAC/THP plus T-DM1, or (5) neoadjuvant TCHP followed by adjuvant T-DM1. Main Outcomes and Measures: Lifetime costs in 2020 US dollars and quality-adjusted life-years (QALYs) were estimated for each treatment strategy, and incremental cost-effectiveness ratios were estimated. A strategy was classified as dominated if it was associated with fewer QALYs at higher costs than the alternative. Results: In the base-case analysis, costs ranged from $415 833 (strategy 3) to $518 859 (strategy 4), and QALYs ranged from 9.67 (strategy 1) to 10.73 (strategy 3). Strategy 3 was associated with the highest health benefits (10.73 QALYs) and lowest costs ($415 833) and dominated all other strategies. Probabilistic analysis confirmed that this strategy had the highest probability of cost-effectiveness (>70% at willingness-to-pay thresholds of $0-200,000/QALY) and was associated with the highest net benefit. Conclusions and Relevance: These results suggest that neoadjuvant THP followed by adjuvant H for patients with pCR or followed by adjuvant DDAC plus T-DM1 for patients with residual disease was associated with the highest health benefits and lowest costs for women with ERBB2-positive breast cancer compared with other treatment strategies considered.

Assessment of the role of Ga-68 PSMA I&T PET/CT in response evaluation to docetaxel therapy in castration resistant prostate cancer patients. / Evaluación del papel de la PET/TC con [68Ga]Ga-PSMA I&T en la evaluación de la respuesta a la terapia con docetaxel en pacientes con cáncer de próstata resistente a la castración.

OBJECTIVE: There have been only few studies investigating the role of PSMA ligands in the therapy response assessment of metastasized castration resistant prostate cancer (mCRPC) cases. In this study we aimed at evaluating the capability of 68Ga- prostate-specific membrane antigen (PSMA) I&T positron emission tomography/computerized tomography (PET/CT) in the assessment of therapeutic response in patients under docetaxel therapy for prostate cancer (PCa). MATERIAL AND METHODS: The clinical records of all mCRPC patients treated with docetaxel and referred to our department for 68Ga-PSMA I&T PET/CT imaging were retrospectively analysed. Sixteen patients (mean age 69 years, range 52-82 years) with castration-resistant prostate cancer patients receiving palliative docetaxel therapy and had undergone 68Ga-PSMA I&T PET/CT scan were included in the study. 68Ga-PSMA I&T PET/CT imaging was done and prostate specific antigen (PSA) levels were measured at baseline before administration of docetaxel (PET1) and after at least 3 cycles (range 4-12) of chemotherapy (PET2). Patient-based as well as lesion-based comparison of PET2 findings with PET1 findings were done. RESULTS: The change (decrease) observed in lymph node and prostate gland/prostatic bed SUVmax values after treatment compared to pretreatment was found to be statistically significant (P=.033). 3/16 patients (19%) were classified as progressive disease (PD), 4/16 (25%) as stable disease (SD), 9/16 (56%) as partial remission (PR) radiologically. An increasing PSA trend (IT) was observed in 4 patients (25%) and a decreasing PSA trend (DT) in 3 patients (18%). Nine patients showed a PSA response of ≥ 50% (56%). Of the 4 patients showing SD, 3 had IT, 3 had BR. Of the 9 patients who showed PR on PET studies, 8 patients showed BR and 1 patient showed DT. CONCLUSION: Imaging with 68Ga-PSMA PET/CT showed great concordance with biochemical response evaluation in terms of PSA levels, especially in patients showing good response to therapy. 68Ga-PSMA PET/CT was also successful in identifying progressive disease in patients showing paradoxical decline in PSA levels.

MicroRNA-Mediated Health-Promoting Effects of Phytochemicals.

Phytochemicals are known to benefit human health by modulating various cellular processes, including cell proliferation, apoptosis, and inflammation. Due to the potential use of phytochemicals as therapeutic agents against human diseases such as cancer, studies are ongoing to elucidate the molecular mechanisms by which phytochemicals affect cellular functions. It has recently been shown that phytochemicals may regulate the expression of microRNAs (miRNAs). MiRNAs are responsible for the fine-tuning of gene expression by controlling the expression of their target mRNAs in both normal and pathological cells. This review summarizes the recent findings regarding phytochemicals that modulate miRNA expression and promote human health by exerting anticancer, photoprotective, and anti-hepatosteatosis effects. Identifying miRNAs modulated by phytochemicals and understanding the regulatory mechanisms mediated by their target mRNAs will facilitate the efforts to maximize the therapeutic benefits of phytochemicals.

Assessment of the administration of maropitant and loperamide to dogs with cancer for the prevention and reduction of adverse effects associated with the administration of paclitaxel.

OBJECTIVE: To evaluate the efficacy of maropitant and loperamide for the prevention and reduction of adverse gastrointestinal effects associated with administration of paclitaxel to dogs with cancer. ANIMALS: 168 dogs with cancer. PROCEDURES: The study comprised 2 phases. For phase 1, dogs in the intervention group were administered maropitant and loperamide followed by paclitaxel. Outcomes were compared with those for a control group that received only maropitant and paclitaxel. For phase 2, all dogs of phase 1 that did not receive maropitant and loperamide and that had adverse gastrointestinal effects were enrolled; they received maropitant and loperamide and another dose of paclitaxel. RESULTS: In phase 1, significantly fewer dogs in the intervention group had adverse effects. For dogs that had adverse effects, the intervention group had a lower severity of lack of appetite and lethargy. Also, adverse effects for dogs in the intervention group were of significantly shorter duration than for the control group. In phase 2, significant reductions in adverse effects were observed after administration of maropitant and loperamide. In those dogs that still had adverse effects after administration of maropitant and loperamide, there was a significant reduction in severity of signs of nausea and lethargy. CONCLUSIONS AND CLINICAL RELEVANCE: A combination of maropitant and loperamide was found to be safe for use and effective for reducing or preventing signs of paclitaxel-induced gastrointestinal effects in dogs.

A Comprehensive Assessment of Apigenin as an Antiproliferative, Proapoptotic, Antiangiogenic and Immunomodulatory Phytocompound.

Apigenin (4',5,7-trihydroxyflavone) (Api) is an important component of the human diet, being distributed in a wide number of fruits, vegetables and herbs with the most important sources being represented by chamomile, celery, celeriac and parsley. This study was designed for a comprehensive evaluation of Api as an antiproliferative, proapoptotic, antiangiogenic and immunomodulatory phytocompound. In the set experimental conditions, Api presents antiproliferative activity against the A375 human melanoma cell line, a G2/M arrest of the cell cycle and cytotoxic events as revealed by the lactate dehydrogenase release. Caspase 3 activity was inversely proportional to the Api tested doses, namely 30 µM and 60 µM. Phenomena of early apoptosis, late apoptosis and necrosis following incubation with Api were detected by Annexin V-PI double staining. The flavone interfered with the mitochondrial respiration by modulating both glycolytic and mitochondrial pathways for ATP production. The metabolic activity of human dendritic cells (DCs) under LPS-activation was clearly attenuated by stimulation with high concentrations of Api. Il-6 and IL-10 secretion was almost completely blocked while TNF alpha secretion was reduced by about 60%. Api elicited antiangiogenic properties in a dose-dependent manner. Both concentrations of Api influenced tumour cell growth and migration, inducing a limited tumour area inside the application ring, associated with a low number of capillaries.

Cucurbitacins as Anticancer Agents: A Patent Review.

BACKGROUND: Cucurbitacins belong to a group of tetracyclic triterpenoids that display a wide range of biological effects. In the past, numerous cucurbitacins have been isolated from natural sources and many active compounds have been synthesized using the privileged scaffold in order to enhance its cytotoxic effects. OBJECTIVE: This review covers patents on the therapeutic effects of natural cucurbitacins and their synthetic analogs published during the past decade. By far, the majority of patents published are related to cancer and Structure-Activity Relationships (SAR) of these compounds are included to lend gravitas to this important class of natural products. METHODS: The date about the published patents was downloaded via online open access patent databases. RESULTS: Cucurbitacins display significant cytotoxic properties, in particular cucurbitacins B and D which possess very potent effects towards a number of cancer cells. Numerous cucurbitacins isolated from natural sources have been derivatized through chemical modification at the C(2)-OH and C(25)- OH groups. Most importantly, an acyl ester of the C(25)-OH and, iso-propyl, n-propyl and ethyl ether groups of the C(2)-OH demonstrated the most increased cytotoxic activity. CONCLUSION: The significant cytotoxic effects of natural and semi-synthetic cucurbitacins make them attractive as new drug candidates. Moreover, cucurbitacins have the capability to form conjugates with other anticancer drugs which will synergistically enhance their anticancer effects. The authors believe that in order to get lead compounds, there should be a greater focus on the synthesis of homodimers, heterodimers, and halo derivatives of cucurbitacins. In the opinion of the authors the analysis of the published patents on the cucurbitacins indicates that these compounds can be developed into a regimen to treat a wide spectrum of cancers.

The inhibitory effect of Manuka honey on human colon cancer HCT-116 and LoVo cell growth. Part 1: the suppression of cell proliferation, promotion of apoptosis and arrest of the cell cycle.

Numerous investigations have been made on plant phenolic compounds and cancer prevention in recent decades. Manuka honey (MH) represents a good source of phenolic compounds such as luteolin, kaempferol, quercetin, gallic acid and syringic acid. The aim of this work was to evaluate the chemopreventive effects of MH on human colon cancer HCT-116 and LoVo cells. Both cells were exposed to different concentrations of MH (0-20 mg mL-1 for HCT-116 cells and 0-50 mg mL-1 for LoVo cells) for 48 h to measure apoptosis and cell cycle arrest as well as apoptosis and cell cycle regulatory gene and protein expression. MH exhibited profound inhibitory effects on cellular growth by reducing the proliferation ability, inducing apoptosis and arresting the cell cycle in a dose-dependent manner. Interestingly, MH treatment in non-malignant cells did not exert any significant toxicity at similar concentrations. The apoptosis event was associated with the increasing expression of p53, cleaved-PARP and caspase-3 and with the activation of both intrinsic (caspase-9) and extrinsic (caspase-8) apoptotic pathways. MH induced cell cycle arrest in the S phase in HCT-116 cells, and simultaneously, in LoVo cells, it occurred in the G2/M phase through the modulation of cell cycle regulator genes (cyclin D1, cyclin E, CDK2, CDK4, p21, p27 and Rb). The expression of p-Akt was suppressed while the expression of p-p38MAPK, p-Erk1/2 and endoplasmic stress markers (ATF6 and XBP1) was increased for apoptosis induction. Overall, these findings indicate that MH could be a promising preventive or curative food therapy for colon cancer.

Citrus medica: nutritional, phytochemical composition and health benefits - a review.

Citrus medica (Citron) is an underutilized fruit plant having various bioactive components in all parts of the plant. The major bioactive compounds present are iso-limonene, citral, limonene, phenolics, flavonones, vitamin C, pectin, linalool, decanal, and nonanal, accounting for several health benefits. Pectin and heteropolysachharides also play a major role as dietary fibers. The potential impact of citron and its bioactive components to prevent or reverse destructive deregulated processes responsible for certain diseases has attracted different researchers' attention. The fruit has numerous nutraceutical benefits, proven by pharmacological studies; for example, anti-catarrhal, capillary protector, anti-hypertensive, diuretic, antibacterial, antifungal, anthelmintic, antimicrobial, analgesic, strong antioxidant, anticancerous, antidiabetic, estrogenic, antiulcer, cardioprotective, and antihyperglycemic. The present review explores new insights into the benefits of citron in various body parts. Throughout the world, citron has been used in making carbonated drinks, alcoholic beverages, syrup, candied peels, jams, marmalade, cordials, and many other value added products, which suggests it is an appropriate raw material to develop healthy processed food. In the present review, the fruit taxonomical classification, beneficial phytochemicals, antioxidant activities, and health benefits are discussed.

Paclitaxel as Albumin-Bound Nanoparticles with Gemcitabine for Untreated Metastatic Pancreatic Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited Celgene Ltd to submit clinical and cost-effectiveness evidence for paclitaxel as albumin-bound nanoparticles (Nab-Pac) in combination with gemcitabine (Nab-Pac + Gem) for patients with untreated metastatic pancreatic cancer. The STA was a review of NICE's 2015 guidance (TA360) in which Nab-Pac + Gem was not recommended for patients with untreated metastatic pancreatic cancer. The review was prompted by a proposed Patient Access Scheme (PAS) discount on the price of Nab-Pac and new evidence that might lead to a change in the guidance. The Liverpool Reviews and Implementation Group at the University of Liverpool was the Evidence Review Group (ERG). This article summarises the ERG's review of the company's evidence submission for Nab-Pac + Gem, and the Appraisal Committee (AC) decision. The final scope issued by NICE listed three comparators: gemcitabine monotherapy (Gem), gemcitabine in combination with capecitabine (Gem + Cap), and a combination of oxaliplatin, irinotecan, leucovorin and fluorouracil (FOLFIRINOX). Clinical evidence for the comparison of Nab-Pac + Gem versus Gem was from the phase III CA046 randomized controlled trial. Analysis of progression-free survival (PFS) and overall survival (OS) showed statistically significant improvement for patients treated with Nab-Pac + Gem versus Gem. Clinical evidence for the comparison of Nab-Pac + Gem versus FOLFIRINOX and versus Gem + Cap was derived from a network meta-analysis (NMA). Results of the NMA did not indicate a statistically significant difference in OS or PFS for the comparison of Nab-Pac + Gem versus either Gem + Cap or FOLFIRINOX. The ERG's main concerns with the clinical effectiveness evidence were difficulties in identifying the patient population for whom treatment with Nab-Pac + Gem is most appropriate, and violation of the proportional hazards (PH) assumption in the CA046 trial. The ERG highlighted methodological issues in the cost-effectiveness analysis pertaining to the modelling of survival outcomes, estimation of drug costs and double counting of adverse-event disutilities. The AC accepted all the ERG's amendments to the company's cost-effectiveness model; however, these did not make important differences to the incremental cost-effectiveness ratios (ICERs). The company's base-case ICER was £46,932 per quality-adjusted life-year (QALY) gained for the comparison of Nab-Pac + Gem versus Gem. Treatment with Nab-Pac + Gem was dominated both by treatment with Gem + Cap and with FOLFIRINOX in the company's base case. The AC concluded that the most plausible ICER for treatment with Nab-Pac + Gem versus Gem was in the range of £41,000-£46,000 per QALY gained. The AC concluded that Nab-Pac + Gem was not cost effective compared with Gem + Cap or FOLFIRINOX, and accepted that treatment with Nab-Pac + Gem met the end-of-life criteria versus Gem but did not consider Nab-Pac + Gem to meet the end-of-life criteria compared with Gem + Cap or FOLFIRINOX. The AC also concluded that although patients who would receive Nab-Pac + Gem rather than FOLFIRINOX or Gem + Cap were difficult to distinguish, they were identifiable in clinical practice. The AC recommended treatment with Nab-Pac + Gem for patients with untreated metastatic pancreatic cancer for whom other combination chemotherapies were unsuitable and who would otherwise receive Gem.

Assessment Tools for Peripheral Neuropathy in Pediatric Oncology: A Systematic Review From the Children's Oncology Group.

Peripheral neuropathy is a known side effect of several chemotherapy agents, including vinca alkaloids and platinum-based chemotherapy. Early recognition and monitoring of this side effect is an important role of the pediatric oncology nurse. There are a variety of peripheral neuropathy assessment tools currently in use, but the usefulness of these tools in identifying and grading neuropathy in children varies, and there is currently no standardized tool in place to evaluate peripheral neuropathy in pediatric oncology. A systematic review was performed to identify the peripheral neuropathy assessment tools that best evaluate the early onset and progression of peripheral neuropathy in pediatric patients receiving vincristine. Because of the limited information available in pediatric oncology, this review was extended to any pediatric patient with neuropathy. A total of 8 studies were included in the evidence synthesis. Based on available evidence, the pediatric-modified Total Neuropathy Scale (ped-m TNS) and the Total Neuropathy Score-pediatric version (TNS-PV) are recommended for the assessment of vincristine-induced peripheral neuropathy in children 6 years of age and older. In addition, several studies demonstrated that subjective symptoms alone are not adequate to assess for vincristine-induced peripheral neuropathy. Nursing assessment of peripheral neuropathy should be an integral and regular part of patient care throughout the course of chemotherapy treatment.

Volumetric assessment of tumor size changes in pediatric low-grade gliomas: feasibility and comparison with linear measurements.

PURPOSE: We report a retrospective comparison between bi-dimensional RANO criteria and manual volumetric segmentation (MVS) in pediatric low-grade gliomas. METHODS: MRI FLAIR or T1 post contrast images were used for assessment of tumor response. Seventy patients were included in this single center study, for each patient two scans were assessed ("time 0" and "end of therapy") and response to therapy was evaluated for both methods. Inter-reader variability and average time for volumetric assessment were also calculated. RESULTS: Fourteen (20%) of the 70 patients had discordant results in terms of response assessment between the bi-dimensional measurements and MVS. All volumetric response assessments were in keeping with the subjective analysis of tumor (radiology report). Of the 14 patients, 6 had stable disease (SD) on MVS and progressive disease (PD) on 2D assessment, 5 patients had SD on MVS and partial response (PR) on 2D assessment, 2 patients had PD on MVS and SD on 2D assessment, and 1 patient had PR on MVS and SD on 2D analysis. The number of discordant results rises to 21(30%) if minor response is integrated in the response assessment. MVS was relatively fast and showed high inter-reader concordance. CONCLUSION: Our analysis shows that therapeutic response classification may change in a significant number of children by performing a volumetric tumor assessment. Furthermore, MVS is not particularly time consuming and has very good inter-reader concordance.

Preclinical renal chemo-protective potential of Prunus amygdalus Batsch seed coat via alteration of multiple molecular pathways.

Prunus amygdalus Batsch (almond) is a classical nutritive traditional Indian medicine. Along with nutritive with anti-oxidant properties, it is, clinically, used in the treatment of various diseases with underlying anti-oxidant mechanism. This study is an effort to scrutinise the renal protective effect of P. amygdalus Batsch or green almond (GA) seed coat extract and its underlying mechanism in animal model of Ferric nitrilotriacetate (Fe-NTA) induced renal cell carcinoma (RCC). RCC was induced in Swiss Albino Wistar rats by intraperitoneal injection of Fe-NTA. The rats were then treated with ethanolic extract of GA (25, 50 and 100 mg/kg per oral) for 22 weeks. Efficacy of GA administration was evaluated by change in biochemical, renal, macroscopical and histopathological parameters and alterations. Additionally, interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and inflammatory mediator including prostaglandin E2 (PGE2), nuclear factor-kappa B (NF-κB) were also observed to explore the possible mechanisms. The oral administration of GA significantly (p < .001) altered the Fe-NTA induced RCC in rats by inhibition of renal nodules, decolourisation of tissues, tumour promoter marker including thymidine 3[H] incorporation, ornithine decarboxylase, renal parameters and anti-oxidant parameters in serum. Additionally, GA treatment significantly (p < .001) down-regulated the IL-6, IL-1ß, TNF-α, inflammatory mediators PGE2 and NF-κB in a dose-dependent manner. Histopathology observation supported the renal protective effect of GA by alteration in necrosis, size of Bowman capsules and inflammatory cells. Hence, it can be concluded that GA possesses observable chemo-protective action and effect on Fe-NTA induced RCC via dual inhibition mechanism one by inhibiting free radical generation and second by inhibiting inflammation.

A comparative assessment of antiproliferative properties of resveratrol and ethanol leaf extract of Anogeissus leiocarpus (DC) Guill and Perr against HepG2 hepatocarcinoma cells.

BACKGROUND: Epidemiological and experimental evidences have shown cancer as a leading cause of death worldwide. Although the folklore use of plants as a reliable source of health-restoring principles is well-documented, the search for more of such plants that are active against diseases, such as cancer, continues. We report here a laboratory-based evidence of the relevance of an ethanol leaf extract of Anogeissus leiocarpus (A2L) in comparison with resveratrol, a natural polyphenol, in cancer therapy. METHODS: The quantitative assessment of flavonoid and phenolic contents involved quercetin and gallic acid as standards, respectively were determined using spectrophotometry. Cytotoxicity was determined fluorometrically using propidium-iodide-staining method. Antioxidant status, adenosine triphosphate (ATP) levels, caspase activities and mitochondrial integrity were assessed using fluorometry/luminometry. RESULTS: The antioxidant assay demonstrated that A2L possesses a strong antioxidant capacity as compared with the reference compounds, ascorbic acid and butylated hydroxytoluene. This is further buttressed by the significantly high level of phenolics obtained in the quantitative assessment of the extract. A 72-h post-treatment examination indicated that both A2L and resveratrol modulate the proliferation of HepG2 liver carcinoma cells in a time- and concentration-dependent manner. Determination of the total nuclei area, propidium-iodide negative and positive nuclei areas all further buttress the modulation of cell proliferation by A2L and resveratrol with the indication that the observed cell death is due to apoptosis and necrosis at lower and higher concentrations of treatments respectively. At lower concentrations (0.39-3.13 µg/mL), resveratrol possesses higher tendencies to activate caspases 3 and 7. Bioenergetically, both resveratrol and A2L do not adversely affect the cells at lower concentrations (0.39-6.25 µg/mL for resveratrol and 12.5-100.0 µg/mL for A2L) except at higher concentrations (12.5-25.0 µg/mL for resveratrol and 200-800 µg/mL for A2L) which are more pronounced in A2L-treated cells. Furthermore, the antioxidant status of HepG2 cells is not perturbed by resveratrol as compared with A2L. Assessment of 24-h post-treatment mitochondrial function shows that resveratrol is not mitotoxic as compared with A2L which exhibits mitotoxicity at its highest concentration. CONCLUSIONS: Taken together, findings from this study showed that A2L possesses strong antiproliferative activity and its prospect in the management of hepatocellular carcinoma deserves further investigation.

Docetaxel in hormone-sensitive advanced prostate cancer; GENESIS-SEFH evaluation reporta.

Prostate cancer (PC) is the most common urogenital malignancy in older men and the second leading cause of death by cancer in men in Europe. Current therapeutic practice considers Androgen Deprivation Therapy (ADT) as first line treatment for clinically localized prostate cancer at high-risk, either locally advanced or metastatic. ADT can be achieved through orchiectomy (surgical castration), luteinizing hormone-releasing hormone (LHRH) agonists, or through complete androgen blockade (LHRH agonist combined with an anti-androgen). Docetaxel in combination with prednisone or prednisolone is indicated for the treatment of patients with hormone-refractory metastatic prostate cancer. The CHAARTED and STAMPEDE clinical trials studied the effect of bringing forward the use of docetaxel added on to ADT in the context of hormone-sensitive patients. The CHAARTED clinical trial showed a significant increase in a variable with maximum relevance such as Overall Survival (OS), with a difference of 13.6 months between medians. There was also clinical benefit in the secondary variables: median time until castration-resistant disease or until clinical progression. In the STAMPEDE clinical trial, which included 39% of non-metastatic patients, a 10-month difference between medians was demonstrated in OS, and 17 months in the primary co-variable of Progression Free Survival. The most frequent adverse events were: neutropenia, febrile neutropenia, leucopenia, and general disorders such as asthenia, lethargy or fever. According to data from the CHAARTED and STAMPEDE studies, and the incremental cost of € 3 196.98 for adding on docetaxel to standard treatment, the estimated additional cost for each year of life gained is compatible with an incremental cost-effectiveness ratio between € 2 267.36 and € 3 851.78. In view of the efficacy and safety results, the proposed positioning is: to advance the use of docetaxel added to androgen deprivation therapy to first-line metastatic hormone-sensitive prostate cancer, regardless of metastatic volume, in those patients who meet the CHAARTED study criteria.

El cáncer de próstata (CP) es el tumor maligno urogenital más frecuente en hombres de edad avanzada y la segunda causa de muerte por cáncer en hombres en Europa. La práctica terapéutica actual considera como primera línea la terapia de privación de andrógenos (ADT; androgen deprivation therapy) en el cáncer de próstata clínicamente localizado de alto riesgo, localmente avanzado o metástasico. La ADT se realiza mediante orquiectomía (castración quirúrgica), agonistas de la hormona liberadora de hormona luteinizante (LHRH), o bien mediante el bloqueo androgénico completo (agonista LHRH más antiandrógeno). El docetaxel en combinación con prednisona o prednisolona está indicado para el tratamiento de pacientes con cáncer de próstata hormono-refractariometastásico. Los ensayos clínicos CHAARTED y STAMPEDE analizaron el efecto de adelantar el uso de docetaxel añadido a la ADT en el contexto del paciente hormonosensible. En el ensayo CHAARTED se demostró un aumento significativo en la variable de máxima relevancia como es la supervivencia global (SG), con una diferencia de medianas de 13,6 meses. También se obtuvo beneficio clínico en las variables secundarias mediana de tiempo hasta enfermedad resistente a la castración o hasta progresión clínica. En el ensayo STAMPEDE, en el que se incluyeron un 39% de pacientes no metastásicos, se demostró una diferencia de medianas de 10 meses en la SG y de 17 meses en la covariable principal de supervivencia libre de progresión. Los eventos adversos más frecuentes fueron: neutropenia, neutropenia febril, leucopenia y alteraciones generales tales como astenia, letargia o fiebre. Según los datos del estudio CHAARTED y STAMPEDE y el coste incremental de 3.196,98 € de añadir docetaxel a la terapia de referencia, por cada año de vida ganado el coste adicional estimado es compatible con un coste/eficacia incremental (CEI) entre 2.267,36 € y 3.851,78 €. A la vista de los importantes resultados de eficacia y el perfil manejable de seguridad, el posicionamiento propuesto es adelantar el uso de docetaxel añadido a la ADT a la primera línea del cáncer de próstata metastásico hormonosensible, en aquellos pacientes que cumplan los criterios básicos del estudio CHAARTED.

Budgetary Impact of Cabazitaxel Use After Docetaxel Treatment for Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: With the approval of several new treatments for metastatic castration-resistant prostate cancer (mCRPC), budgetary impact is a concern for health plan decision makers. Budget impact models (BIMs) are becoming a requirement in many countries as part of formulary approval or reimbursement decisions. Cabazitaxel is a second-generation taxane developed to overcome resistance to docetaxel and is approved for the treatment of patients with mCRPC previously treated with a docetaxel-containing regimen. OBJECTIVE: To estimate a 1-year projected budget impact of varying utilization rates of cabazitaxel as a second-line treatment for mCRPC following docetaxel, using a hypothetical U.S. private managed care plan with 1 million members. METHODS: A BIM was developed to evaluate costs for currently available treatment options for patients with mCRPC previously treated with docetaxel. Treatments included in the model were cabazitaxel, abiraterone acetate, enzalutamide, and radium-223, with utilization rates derived from market research data. Medication costs were calculated according to published pricing benchmarks factored by dosing and duration of therapy as stated in the prescribing information for each agent. Published rates and costs of grade 3-4 adverse events were also factored into the model. In addition, the model reports budget impact under 2 scenarios. In the first base-case scenario, patient out-of-pocket costs were subtracted from the total cost of treatment. In the second scenario, all treatment costs were assumed to be paid by the plan. RESULTS: In a hypothetical 1 million-member health plan population, 100 patients were estimated to receive second-line treatment for mCRPC after treatment with docetaxel. Using current utilization rates for the 4 agents of interest, the base-case scenario estimated the cost of second-line treatment after docetaxel to be $6,331,704, or $0.528 per member per month (PMPM). In a scenario where cabazitaxel use increases from the base-rate case of 24% to a hypothetical rate of 33%, the PMPM cost would decrease to $0.524, reflecting a cost saving of $0.004 PMPM and equating to incremental savings of $49,546, or $497 per patient per year (PPPY). In the second scenario, when out-of-pocket costs were not considered, the cost of second-line treatment after docetaxel was estimated as $6,733,594, or $0.561 PMPM. With a hypothetical increase in cabazitaxel use (24%-33%), the PMPM cost would decrease to $0.554, reflecting savings of $0.007 PMPM and equating to incremental savings of $86,136, or $864 PPPY. The primary driver of cost savings with increased cabazitaxel use was lower acquisition cost. One-way sensitivity analyses revealed that the model results were robust over a wide range of input values (utilization, prevalence, and population parameters). CONCLUSIONS: In the presented BIM, an increase in cabazitaxel use is expected to result in modest cost savings to the health plan. Patient coinsurance savings may also be realized based on applicable Medicare Part B and Part D calculations. This BIM presents an objective, comprehensive, robust, and user-adaptable tool that health plans and medical decision makers may use to evaluate potential economic impact of formulary and reimbursement decisions. DISCLOSURES: Research and analysis were funded by Sanofi US. The sponsor had the opportunity to review the final draft; however, the authors were responsible for all content and editorial decisions. Flannery, Drea, Hudspeth, and Miao are employees of Sanofi. Miao is an owner of stock in Sanofi. Corman, Gao, and Xue are employees of Pharmerit International and served as consultants to Sanofi during this study. All authors contributed to study design and data collection and analysis. The manuscript was written by Flannery, along with the other authors, and revised by all the authors.

Ethnobotanics used in folk medicine of Tamil culture in Sri Lanka: a scientific review.

Tamil culture has recognized the potential use of plant herbs for prevention and treatment of different diseases. These folk remedies have been practiced by Sri Lankan Tamils even after modernization. This review focuses on frequently used medicinal plants among Sri Lankan Tamil communities, such as Cuminum cyminum, Azadirechta indica, Coriandrum sativum, Sesamum indicum, Zingiber officinale, Trigonella foenum-graecum, Moringa oleifera, Plectranthus amboinicus, Allium sativum and Curcuma longa, for their documented medicinal properties, which include antimicrobial, antioxidant, antitumor, anti-inflammatory, antihypertensive, hypocholesterolemic, antidiabetic and diuretic effects.

Population pharmacokinetic-pharmacodynamic modeling and model-based prediction of docetaxel-induced neutropenia in Japanese patients with non-small cell lung cancer.

PURPOSE: Docetaxel is used to treat many cancers, and neutropenia is the dose-limiting factor for its clinical use. A population pharmacokinetic-pharmacodynamic (PK-PD) model was introduced to predict the development of docetaxel-induced neutropenia in Japanese patients with non-small cell lung cancer (NSCLC). METHODS: Forty-seven advanced or recurrent Japanese patients with NSCLC were enrolled. Patients received 50 or 60 mg/m2 docetaxel as monotherapy, and blood samples for a PK analysis were collected up to 24 h after its infusion. Laboratory tests including absolute neutrophil count data and demographic information were used in population PK-PD modeling. The model was built by NONMEM 7.2 with a first-order conditional estimation using an interaction method. Based on the final model, a Monte Carlo simulation was performed to assess the impact of covariates on and the predictability of neutropenia. RESULTS: A three-compartment model was employed to describe PK data, and the PK model adequately described the docetaxel concentrations observed. Serum albumin (ALB) was detected as a covariate of clearance (CL): CL (L/h) = 32.5 × (ALB/3.6)0.965 × (WGHT/70)3/4. In population PK-PD modeling, a modified semi-mechanistic myelosuppression model was applied, and characterization of the time course of neutrophil counts was adequate. The covariate selection indicated that α1-acid glycoprotein (AAG) was a predictor of neutropenia. The model-based simulation also showed that ALB and AAG negatively correlated with the development of neutropenia and that the time course of neutrophil counts was predictable. CONCLUSION: The developed model may facilitate the prediction and care of docetaxel-induced neutropenia.