Response to sunitinib (Sutent) in chemotherapy refractory clear cell ovarian cancer

• Case describes a response to sunitinib in clear cell ovarian cancer. • Discussion of unique molecular characteristics of clear cell ovarian cancers; • Practical points regarding dosing and toxicity when using sunitinib discussed

The management of patients with learning difficulties and testicular cancer: overcoming barriers to improve care

Cancer-specific survival rates in patients with learning difficulties (LD) are poorer than the general population. Issues such as delayed diagnosis, compliance, consent and needs for individualised care and support requirements can make it more demanding to manage these patients in a busy clinical environment. Our case highlights a patient with learning disabilities who presented with advanced testicular cancer due to delayed detection, and the challenges needing consideration to ensure such patients receive good care. This report also highlights an example of adapting curative intent treatment to an individual with complex needs, and the importance of patient and family involvement in decision-making to ensure these vulnerable patients receive safe and effective healthcare. The practicalities of multidisciplinary team working in the context of key legislation and existing frameworks to guide practice in the management of LD patients are also discussed

Dose intense chemotherapy in the management of poor prognosis and relapsed testicular cancer: experiences and controversies

INTRODUCTION: The treatment of poor prognosis chemotherapy naïve or relapsed testicular cancer is challenging. In poor prognosis treatment naïve disease, the outlook for patients with standard approaches utilising three weekly cisplatin based regimens, most commonly bleomycin, etoposide and cisplatin (BEP) is suboptimal, and one can expect more than half of patients to relapse or progress and need salvage treatment. Recent randomised studies have lent weight to the use of dose intensified treatments in these selected patient groups. In relapsed testicular cancer, post platinum based chemotherapy controversy exists as to the optimum relapse regimen as significant cure rates can be expected by re-treating with both conventional dose and high dose or dose intense regimens. AREAS COVERED: This review seeks to outline the evidence for alternative approaches beyond standard three weekly cisplatin based regimens in poor risk metastatic disease. It also explores the evidence available for selection between conventional dose and high dose strategies on relapse. EXPERT COMMENTARY: An overview of the data is presented to support personalising therapy selection in both poor risk and relapsed metastatic germ cell tumors

Investigating the benefits of molecular profiling of advanced non-small cell lung cancer tumors to guide treatments.

In this study we utilized data on patient responses to guided treatments, and we evaluated their benefit for a non-small cell lung cancer cohort. The recommended therapies used were predicted using tumor molecular profiles that involved a range of biomarkers but primarily used immunohistochemistry markers. A dataset describing 91 lung non-small cell lung cancer patients was retrospectively split into two. The first group's drugs were consistent with a treatment plan whereby all drugs received agreed with their tumor's molecular profile. The second group each received one or more drug that was expected to lack benefit. We found that there was no significant difference in overall survival or mortality between the two groups. Patients whose treatments were predicted to be of benefit survived for an average of 402 days, compared to 382 days for those that did not (P = 0.7934). In the matched treatment group, 48% of patients were deceased by the time monitoring had finished compared to 53% in the unmatched group (P = 0.6094). The immunohistochemistry biomarker for the ERCC1 receptor was found to be a marker that could be used to predict future survival; ERCC1 loss was found to be predictive of poor survival

Extracellular vesicles swarm the cancer microenvironment: from tumor–stroma communication to drug intervention

Intercellular communication sets the pace for transformed cells to survive and to thrive. Extracellular vesicles (EVs), such as exosomes, microvesicles and large oncosomes, are involved in this process shuttling reciprocal signals and other molecules between transformed and stromal cells, including fibroblasts, endothelial and immune cells. As a result, these cells are adapted or recruited to a constantly evolving cancer microenvironment. Moreover, EVs take part in the response to anticancer therapeutics not least by promoting drug resistance throughout the targeted tumor. Finally, circulating EVs can also transport important molecules to remote destinations in order to prime metastatic niches in an otherwise healthy tissue. Although the understanding of EV biology remains a major challenge in the field, their characteristics create new opportunities for advances in cancer diagnostics and therapeutics

Saleability of Anti-malarials in Private Drug Shops in Muheza, Tanzania: A Baseline study in an era of assumed Artemisinin Ccombination Therapy (ACT).

Artemether-lumefantrine (ALu) replaced sulphadoxine-pymimethamine (SP) as the official first-line anti-malarial in Tanzania in November 2006. So far, artemisinin combination therapy (ACT) is contra-indicated during pregnancy by the national malaria treatment guidelines, and pregnant women depend on SP for Intermittent Preventive Treatment (IPTp) during pregnancy. SP is still being dispensed by private drug stores, but it is unknown to which extent. If significant, it may undermine its official use for IPTp through induction of resistance. The main study objective was to perform a baseline study of the private market for anti-malarials in Muheza town, an area with widespread anti-malarial drug resistance, prior to the implementation of a provider training and accreditation programme that will allow accredited drug shops to sell subsidized ALu. All drug shops selling prescription-only anti-malarials, in Muheza town, Tanga Region voluntarily participated from July to December 2009. Qualitative in-depth interviews were conducted with owners or shopkeepers on saleability of anti-malarials, and structured questionnaires provided quantitative data on drugs sales volume. All surveyed drug shops illicitly sold SP and quinine (QN), and legally amodiaquine (AQ). Calculated monthly sale was 4,041 doses, in a town with a population of 15,000 people. Local brands of SP accounted for 74% of sales volume, compared to AQ (13%), QN (11%) and ACT (2%). In community practice, the saleability of ACT was negligible. SP was best-selling, and use was not reserved for IPTp, as stipulated in the national anti-malarial policy. It is a major reason for concern that such drug-pressure in the community equals de facto intermittent presumptive treatment. In an area where SP drug resistance remains high, unregulated SP dispensing to people other than pregnant women runs the risk of eventually jeopardizing the effectiveness of the IPTp strategy. Further studies are recommended to find out barriers for ACT utilization and preference for self-medication and to train private drug dispensers

Rapid increase of Plasmodium falciparum dhfr/dhps resistant haplotypes, after the adoption of sulphadoxine-pyrimethamine as first line treatment in 2002, in southern Mozambique

<p>Abstract</p> <p>Background</p> <p>In late 2002, the health authorities of Mozambique implemented sulphadoxine-pyrimethamine (SP)/amodiaquine (AQ) as first-line treatment against uncomplicated falciparum malaria. In 2004, this has been altered to SP/artesunate in line with WHO recommendations of using Artemisinin Combination Therapies (ACTs), despite the fact that all the neighbouring countries have abandoned SP-drug combinations due to high levels of SP drug resistance. In the study area, one year prior to the change to SP/AQ, SP alone was used to treat uncomplicated malaria cases. The study described here investigated the immediate impact of the change to SP on the frequency of SP and CQ resistance-related haplotypes in the <it>Plasmodium falciparum </it>genes <it>Pfdhfr, Pfdhps </it>and <it>Pfcrt </it>before and a year after the introduction of SP.</p> <p>Methods</p> <p>Samples were collected during two cross sectional surveys in early 2002 and 2003 involving 796 and 692 children one year or older and adults randomly selected living in Maciana, an area located in Manhiça district, Southern Mozambique. Out of these, 171 and 173 <it>P. falciparum </it>positive samples were randomly selected to measure the frequency of resistance- related haplotypes in <it>Pfdhfr, Pfdhps </it>and <it>Pfcrt </it>based on results obtained by nested PCR followed by sequence-specific oligonucleotide probe (SSOP)-ELISA.</p> <p>Results</p> <p>The frequency of the SP-resistance associated <it>Pfdhps </it>double mutant (SGEAA) haplotype increased significantly from 14% to 35% (P < 0.001), while the triple mutant <it>Pfdhfr </it>haplotype (CIRNI) remained high and only changed marginally from 46% to 53% (P = 0.405) after one year with SP as first-line treatment in the study area. Conversely, the combined <it>Pfdhfr/Pfdhps </it>quintuple mutant haplotype increased from 8% to 26% (P = 0.005). The frequency of the chloroquine resistance associated <it>Pfcrt</it>-CVIET haplotype was above 90% in both years.</p> <p>Conclusion</p> <p>These retrospective findings add to the general concern on the lifespan of the combination of SP/artesunate in Mozambique. The high frequency of quintuple <it>Pfdhfr</it>/<it>Pfdhps </it>haplotypes found here as early as 2002 most likely cause ideal conditions for the development of artesunate tolerance in the <it>P. falciparum </it>populations and may even endanger the sensitivity to the second-line drug, Coartem^®.</p

The Use of Transdermal Estrogen in Castrate-resistant, Steroid-refractory Prostate Cancer

BACKGROUND: Androgen-deprivation therapy is the mainstay of treatment for metastatic prostate cancer. Corticosteroids and estrogens are also useful agents in castration-resistant prostate cancer (CRPC). However, oral estrogens are associated with thromboembolic events, which limits their use, and transdermal estrogens may offer a safer alternative. This study was carried out to determine the safety and effectiveness of transdermal estrogens in CRPC. PATIENTS AND METHODS: Forty-one patients with CRPC and steroid-resistant prostate cancer were eligible for this dose-escalation study of transdermal estradiol. A starting dose of 50 mcg/24 hours was applied and increased if prostate-specific antigen (PSA) rose > 5 ng/mL in steps to 300 mcg/24 hours. The primary endpoint was PSA response, and secondary outcomes included incidence of thromboembolic events and progression-free survival. Patients who progressed were offered diethylstilbestrol. RESULTS: Five (13%) of 40 patients had > 50% PSA reduction for at least 1 month at any transdermal estradiol dose. No venous-thromboembolic events were observed, and responses plateaued at 200 mcg/24 hours. A correlation between PSA response and rising sex hormone binding globulin was seen. Fifty percent of patients subsequently responded to low-dose diethylstilbestrol. CONCLUSION: Transdermal estradiol appears to be a low toxicity treatment option to control CRPC after failure of steroid therapy. Modulation of sex hormone binding globulin by transdermal estradiol may be one mechanism of action of estrogens on CRPC. Oral estrogens remain effective after the use of transdermal estradiol

Prevalence of molecular markers of anti-malarial drug resistance in Plasmodium vivax and Plasmodium falciparum in two districts of Nepal

<p>Abstract</p> <p>Background</p> <p>Sulphadoxine-pyrimethamine (SP) and chloroquine (CQ) have been used in treatment of falciparum and vivax malaria in Nepal. Recently, resistance to both drugs have necessitated a change towards artemisinin combination therapy (ACT) against <it>Plasmodium falciparum </it>in highly endemic areas. However, SP is still used against <it>P. falciparum </it>infections in low endemic areas while CQ is used in suspected cases in areas with lack of diagnostic facilities. This study examines the prevalence of molecular markers of CQ and SP resistance in <it>P. falciparum </it>and <it>Plasmodium vivax </it>to determine if high levels of <it>in vivo </it>resistance are reflected at molecular level as well.</p> <p>Methods</p> <p>Finger prick blood samples (n = 189) were collected from malaria positive patients from two high endemic districts and analysed for single nucleotide polymorphisms (SNPs) in the resistance related genes of <it>P. falciparum </it>and <it>P. vivax </it>for CQ (<it>Pfcrt, Pfmdr1, Pvmdr1</it>) and SP (<it>Pfdhfr, Pfdhps, Pvdhfr</it>), using various PCR-based methods.</p> <p>Results and discussion</p> <p>Positive <it>P. vivax </it>and <it>P. falciparum </it>infections were identified by PCR in 92 and 41 samples respectively. However, some of these were negative in subsequent PCRs. Based on a few <it>P. falciparum </it>samples, the molecular level of CQ resistance in <it>P. falciparum </it>was high since nearly all parasites had the <it>Pfcrt </it>mutant haplotypes CVIET (55%) or SVMNT (42%), though frequency of the <it>Pfmdr1 </it>wild type haplotype was relatively low (35%). Molecular level of SP resistance in <it>P. falciparum </it>was found to be high. The most prevalent <it>Pfdhfr </it>haplotype was double mutant CNRNI (91%), while frequency of <it>Pfdhps </it>double mutant SGEAA and AGEAA were 38% and 33% respectively. Combined, the frequency of quadruple mutations (CNRNI-SGEAA/AGEAA) was 63%. Based on <it>P. vivax </it>samples, low CQ and SP resistance were most likely due to low prevalence of <it>Pvmdr1 </it>Y976F mutation (5%) and absence of triple/quadruple mutations in <it>Pvdhfr</it>.</p> <p>Conclusions</p> <p>Based on the limited number of samples, prevalence of CQ and SP resistance at molecular levels in the population in the study area were determined as high in <it>P. falciparum </it>and low in <it>P. vivax</it>. Therefore, CQ could still be used in the treatment of <it>P. vivax </it>infections, but this remains to be tested <it>in vivo </it>while the change to ACT for <it>P. falciparum </it>seems justified.</p

Rapid screening for glucose-6-phosphate dehydrogenase deficiency and haemoglobin polymorphisms in Africa by a simple high-throughput SSOP-ELISA method

BACKGROUND: Mutations in the haemoglobin beta-globin (HbB) and glucose-6-phosphate dehydrogenase (G6PD) genes cause widespread human genetic disorders such as sickle cell diseases and G6PD deficiency. In sub-Saharan Africa, a few predominant polymorphic variants of each gene account for a majority of these deficiencies. Examining at a larger scale the clinical importance of these independent genetic disorders, their possible association with malaria pathogenesis and innate resistance, and their relevance for antimalarial drug treatment, would be easier if an accurate screening method with limited costs was available. METHODS: A simple and rapid technique was developed to detect the most prominent single nucleotide polymorphisms (SNPs) in the HbB and G6PD genes. The method is able to detect the different haemoglobin polymorphisms A, S, C and E, as well as G6PD polymorphisms B, A and A- based on PCR-amplification followed by a hybridization step using sequence-specific oligonucleotide probes (SSOPs) specific for the SNP variants and quantified by ELISA. RESULTS: The SSOP-ELISA method was found to be specific, and compared well to the commonly used PCR-RFLP technique. Identical results were obtained in 98% (haemoglobin) and 95% (G6PD) of the tested 90 field samples from a high-transmission area in Tanzania, which were used to validate the new technique. CONCLUSION: The simplicity and accuracy of the new methodology makes it suitable for application in settings where resources are limited. It would serve as a valuable tool for research purposes by monitoring genotype frequencies in relation to disease epidemiology