Third-line Drugs Research Articles

Pharmacotherapy for Neuropathic Pain: A Review.

Neuropathic pain, comprising a range of heterogeneous conditions, is often severe and difficult to manage, and this may result in a chronic condition that negatively affects the overall functioning and quality of life in patients. The pharmacotherapy of neuropathic pain is challenging and for many patients effective treatment is lacking; therefore, evidence-based recommendations are essential. Currently, there is general agreement on which drugs are appropriate for the first-line treatment of neuropathic pain, whereas debate continues regarding second- and third-line treatments. First-line drugs for neuropathic pain include antidepressants (tricyclic antidepressants and serotonin–noradrenaline reuptake inhibitors) and anticonvulsants acting at calcium channels (pregabalin and gabapentin). Second- and third-line drugs for neuropathic pain include topical lidocaine and opioids. Although efficacious in the treatment of neuropathic pain, opioids are not considered to be a first choice because of adverse drug reactions and, more recently, because of concerns about abuse, diversion, and addiction. A clear understanding of the mechanism of action of currently available drugs is an essential step towards an effective clinical approach that aims to tailor therapies both to the specific neuropathic disease and to the needs of an individual patient. This review provides an overview of current drugs available for the treatment of neuropathic pain with an emphasis on their mechanism of action.FundingPfizer, Italy.

Availability and approval of cannabis-based medicines for chronic pain management and palliative/supportive care in Europe: A survey of the status in the chapters of the European Pain Federation.

There is considerable public and political interest in the use of cannabis products for medical purposes. The task force of the European Pain Federation (EFIC) conducted a survey with its national chapters representatives on the status of approval of all types of cannabis-based medicines, the covering of costs and the availability of a position paper of a national medical association on the use of medical cannabis for chronic pain and for symptom control in palliative/supportive care. Thirty-one out of 37 contacted councillors responded. Plant-derived tetrahydrocannabinol/cannabidiol (THC/CBD) oromucosal spray is approved for spasticity in multiple sclerosis refractory to conventional treatment in 21 EFIC chapters. Plant-derived THC (dronabinol) is approved for some palliative care conditions in four EFIC chapters. Synthetic THC analogue (nabilone) is approved for chemotherapy-associated nausea and vomiting refractory to conventional treatment in four EFIC chapters'. Eight EFIC chapters' countries have an exceptional and six chapters an expanded access programme for medical cannabis. German and Israeli pain societies recommend the use of cannabis-based medicines as third-line drug therapies for chronic pain within a multicomponent approach. Conversely, the German medical association and a team of finish experts and officials do not recommend the prescription of medical cannabis due to the lack of high-quality evidence of efficacy and the potential harms. There are marked differences between the countries represented in EFIC in the approval and availability of cannabis-based products for medical use. EFIC countries are encouraged to collaborate with the European Medicines Agency to publish a common document on cannabis-based medicines. There are striking differences between European countries in the availability of plant-derived and synthetic cannabinoids and of medical cannabis for pain management and for symptom control in palliative care and in the covering of costs by health insurance companies or state social security systems.

Emergence of untreatable, multidrug-resistant HIV-1 in patients failing second-line therapy in Kenya.

: We performed a countrywide assessment of HIV drug resistance among 123 patients with virological failure on second-line antiretroviral therapy (ART) in Kenya. The percentage of patients harbouring intermediate-to-high-level resistance was 27% for lopinavir-ritonavir, 24% for atazanavir-ritonavir and 7% for darunavir-ritonavir, and 25% had complete loss of activity to all available first and second-line drugs. Overall, one in four patients failing second-line ART have completely exhausted available antiretrovirals in Kenya, highlighting the need for increased access to third-line drugs.

Predicting the Need for Third-Line Antiretroviral Therapy by Identifying Patients at High Risk for Failing Second-Line Antiretroviral Therapy in South Africa.

Although third-line antiretroviral therapy (ART) is available in South Africa's public sector, its cost is substantially higher than first and second line. Identifying risk factors for failure on second-line treatment remains crucial to reduce the need for third-line drugs. We conducted a case–control study including 194 adult patients (≥18 years; 70 cases and 124 controls) who initiated second-line ART in Johannesburg, South Africa. Unconditional logistic regression was used to assess predictors of virologic failure (defined as 2 consecutive viral load measures ≥1000 copies/mL, ≥3 months after switching to second line). Variables included a social instability index, ART adherence, self-reported as well as diagnosed adverse drug reactions (ADRs), HIV disclosure, depression, and factors affecting access to HIV clinics. Overall 60.0% of cases and 54.0% of controls were female. Mean ages of cases and controls were 41.8 ± 9.6 and 43.3 ± 8.0, respectively. Virologic failure was predicted by ART adherence <90% [odds ratio (OR) 4.7; 95% confidence interval (95% CI): 2.1–10.5], younger age (<40 years of age; OR 0.6; 95% CI: 0.3–1.1), high social instability (OR 3.8; 95% CI: 1.30–11.5), self-reported ADR (OR 1.9; 95% CI: 1.0–3.5), disclosure to friends/colleagues rather than partner/relatives (OR 3.4; 95% CI: 1.3–9.1), and medium/high depression compared to low/no depression (OR 4.4; 95% CI: 1.5–13.4). Our results suggest complex socioeconomic factors contributing to risk of virologic failure, possibly by impacting ART adherence, among patients on second-line therapy in South Africa. Identifying patients with possible indicators of nonadherence could facilitate targeted interventions to reduce the risk of second-line treatment failure and mitigate the demand for third-line regimens.

Влияние тофацитиниба на показатели функции и качества жизни у больных ревматоидным артритом, резистентных к синтетическим и биологическим базисным противовоспалительным препаратам, в реальной клинической практике (результаты многоцентрового наблюдательного исследования)

Tofacitinib (TOFA), a representative of a new class of targeted synthetic disease-modifying antirheumatic drugs (s-DMARD), is a promising drug for treating rheumatoid arthritis (RA) and other immune inflammatory diseases. Objective: to evaluate the efficiency and safety of therapy with TOFA in combination with methotrexate (MTX) and other s-DMARDs in real clinical practice in patients with active RA and previous ineffective therapy. Patients and methods. A 6-month Russian multicenter study of function and quality of life enrolled 101 patients with resistant RA: 18 men and 83 women; mean age, 51.03±11.28 years; mean disease duration, 105.4±81.43 months; rheumatoid factor-positive individuals (89.1%); and anticyclic citrullinated peptide antibody-positive ones (74.7%). 93 (92,1%) of these patients completed a 24-week study. TOFA was used as both second-line drug (after failure of therapy with s-DMARD) (n=74) and as a third-line drug (after failure of therapy with s-DMARDs and biological agents (BAs) (n=74). The tools RAPID3, HAQ, and EQ-5D were used to determine disease outcomes from a patient's assessment. Results. All the three tools demonstrated significant positive changes at 3–6 months following therapy initiation. RAPID3 scores for the status of a patient achieving a low disease activity or remission coincided with the mean DAS28-ESR and SDAI scores in 60% and 68% of cases, respectively. The achievement rates of the minimally clinically significant improvement (ΔHAQ≥0.22) and functional remission (HAQ≤0.5) at 6 months of TOFA therapy were 79.6 and 30.1%, respectively. The mean change value in EQ-5D scores over 6 months was -0.162±0.21. There were no significant between the groups of patients who used TOFA as a second- or third-line agent in the majority of indicators, except EQ-5D scores at 6 months. Conclusions. The results of our multicenter study using considerable Russian material confirmed the pronounced positive effect of TOFA used as a second-line agent (after s-DMARD failure) and a third-line agent (after s-DMARD and BA failure) on patients' assessment of disease activity, functional ability in daily life, and quality of life.

Update on disease-modifying therapies for multiple sclerosis

Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system (CNS). It predominantly affects young women and is one of the most common causes of disability in...

Long-term outcomes of second-line antiretroviral treatment in an adult and adolescent cohort in Myanmar

ABSTRACT Background: Myanmar has a high burden of Human Immunodeficiency Virus (HIV) and second-line antiretroviral treatment (ART) has been available since 2008 in the public health sector. However, there have been no published data about the outcomes of such patients until now. Objective: To assess the treatment and programmatic outcomes and factors associated with unfavorable outcomes (treatment failure, death and loss to follow-up from care) among people living with HIV (aged ≥ 10 years) receiving protease inhibitor-based second-line ART under the Integrated HIV Care Program in Myanmar between October 2008 and June 2015. Design: Retrospective cohort study using routinely collected program data. Results: Of 824 adults and adolescents on second-line ART, 52 patients received viral load testing and 19 patients were diagnosed with virological failure. However, their treatment was not modified. At the end of a total follow-up duration of 7 years, 88 (11%) patients died, 35 (4%) were lost to follow-up, 21 (2%) were transferred out to other health facilities and 680 (83%) were still under care. The incidence rate of unfavorable outcomes was 7.9 patients per 100 person years follow-up. Patients with a history of injecting drug use, with a history of lost to follow-up, with a higher baseline viral load and who had received didanosine and abacavir had a higher risk of unfavorable outcomes. Patients with higher baseline C4 counts, those having taken first-line ART at a private clinic, receiving ART at decentralized sites and taking zidovudine and lamivudine had a lower risk of unfavorable outcomes. Conclusions: Long-term outcomes of patients on second-line ART were relatively good in this cohort. Virological failure was relatively low, possibly because of lack of viral load testing. No patient who failed on second-line ART was switched to third-line treatment. The National HIV/AIDS Program should consider making routine viral load monitoring and third-line ART drugs available after a careful cost–benefit analysis.

Conceptualising the Factors Affecting Retention in Care of Patients on Antiretroviral Treatment in Kabwe District, Zambia, Using the Ecological Framework.

Background HIV remains a major public health challenge in Zambia. The roll-out of antiretroviral treatment (ART) has engendered new challenges in retention in care. Objective To conceptualise the factors affecting retention in care of ART patients at three primary healthcare facilities using the ecological framework. Method Qualitative data were collected through in-depth interviews with 45 ART patients and three focus group discussions with 20 healthcare providers from three primary healthcare facilities in Kabwe district, Zambia, and subjected to thematic content analysis. Results Individual level barriers to retention in care included side effects, gaining weight, belief in faith healing, and use of herbal remedies and alcohol. Interpersonal barriers such as stigma and nondisclosure of HIV status were reported. At the institutional level, inadequate space in the clinic, long waiting times, long travel distances, and shortage of third-line drugs presented barriers to retention in care. Food shortages and patient mobility were reported as community barriers to retention in care. Conclusion The ecological framework conceptualises the complex and dynamic factors affecting retention in ART care and highlights the need for multifaceted interventions that combine health education, disease management, and opportunities for income generation in a socially responsive and accountable environment.

The Importance of Mutational Analysis in Chronic Myeloid Leukaemia for Treatment Choice

Since their introduction in 2001, tyrosine kinase inhibitors (TKIs) targeting BCR-ABL have become the standard therapy for chronic myeloid leukaemia (CML). While allogeneic hematopoietic stem cell transplant is a recognised curative treatment for CML, TKIs prevent progression to advanced phase in most patients, and spectacularly improve the disease burden (in deep molecular responders) and the overall survival of CML patients. However, mutations in the BCR-ABL kinase domain affect a significant proportion of CML patients and have been associated with primary or secondary (refractory disease following an initial response) resistance to imatinib. Such resistance may emerge at any time during TKI therapy and are a major mechanism of treatment failure, in addition to BCR-ABL1-independent treatment resistance and treatment intolerance mechanisms. In the context of the above-described clinical settings, the management of CML patients remains challenging. The detection of mutations following imatinib resistance is therefore crucial to ensure appropriate second or third-line drug selection.

Madagascan isolates of Plasmodium falciparum showing low sensitivity to artemether in vitro.

In Madagascar, although chloroquine (CQ) remains the first-line treatment of choice for malaria, the gradual spread of resistance to this antimalarial drug is of increasing concern. As part of a larger investigation of the effectiveness of the second- and third-line drugs used to treat malaria, the in-vitro susceptibilities of Plasmodium falciparum collected in Madagascar to CQ, mefloquine (MQ) and artemether (ART) were therefore investigated. Median inhibitory concentrations (IC(50)) were determined for isolates collected from residents of two villages in the foothills of the central highlands. The IC(50) for ART ranged from 0.23-17.50 nM [N = 51; geometric mean = 4.02 nM; 95% confidence interval (CI) = 2.99-5.05 nM], four isolates exhibiting IC(50) (> 12 nM) indicative of resistance to this drug. The artemether IC(50) were found to be correlated with those of CQ (N = 46; Spearman's r = 0.51; P = 0.0002), which varied widely (0.4-254.3 nM; mean = 23.4 nM; CI = 7.1-39.7 nM; N = 46). Five (11%) of the 46 isolates exposed to CQ in vitro were considered resistant to this drug (i.e. to have IC(50) > 100 nM), with IC(50) ranging from 109-245.3 nM (mean = 171.6 nM; CI = 110.4-232.8 nM). However, all the CQ-resistant isolates were considered sensitive to ART and vice versa. All the isolates tested also appeared sensitive to MQ (IC(50) = 2.21-43.1 nM; mean = 10.5 nM; CI = 7.95-13.07 nM; N = 46), the IC(50) for MQ being correlated with those for CQ (N = 46; Spearman's r =0.46; P = 0.001). There was no significant correlation between ART and MQ activities. Although the sample was fairly small, the present results indicate that P. falciparum in Madagascar is generally becoming less sensitive to CQ and ART. The observation of a correlation between the IC(50) for these two drugs perhaps indicates that artemisinin derivatives would be better used in combination with antimalarial drugs other than 4-aminoquinolines.

Patterns of anti-diabetic medication use in patients with type 2 diabetes mellitus in England and Wales.

The purpose of this study is to characterise how Type 2 Diabetes Mellitus (T2DM) is treated in England and Wales and whether this adheres to 2009 National Institute for Health and Care Excellence (NICE) guidance on management of T2DM. Data for T2DM patients aged 18+ years prescribed at least one anti-diabetic drug between 01/01/2000-30/06/2012 were extracted from the Clinical Practice Research Datalink. We examined the sequences in which anti-diabetic drugs were prescribed and, for patients on the most common anti-diabetic drug pathways, evaluated average HbA1c values at treatment initiation and at progression to a second or third-line anti-diabetic drug class, including insulin. The cohort included 123 671 patients, 56% males, 95% aged 40+ and 79% with at least one recorded HbA1c level. Metformin was the first prescription for 98 957 (80%) patients, with mean HbA1c of 8.68% prior to initiation (95% confidence interval [CI] 8.67, 8.69). A total of 19 890 (16%) patients received sulphonylureas first-line (mean HbA1c = 9.31%, 95%CI 9.27, 9.35). 1402 (12%) insulin users were prescribed insulin first-line (mean HbA1c = 9.89%, 95%CI 9.59, 10.19). A total of 96 895 (78%) patients were managed in line with one of the treatment pathways recommended by NICE. Patients prescribed insulin second-line after metformin had a mean HbA1c of 10.11% (95%CI 9.83, 10.38) prior to first prescription of insulin and 9.98% (95%CI 9.73, 10.23) at baseline. Both values were significantly higher than other groups initiating new treatment. In over three-quarters of patients, anti-diabetic drugs are being prescribed per NICE guidance. When insulin is being used earlier than recommended, there appears to be a need for urgent and rapid glycaemic control. © 2016 Crown Copyright. Pharmacoepidemiology and Drug Safety © 2016 John Wiley & Sons, Ltd.

Multidrug-Resistant Staphylococcus aureus, India, 2013-2015.

To the Editor: Methicillin-resistant Staphylococcus aureus (MRSA) is a versatile pathogen capable of causing a wide variety of human diseases. Increased frequency of S. aureus infections imposes a high and increasing burden on healthcare resources. In many countries, MRSA infections in hospitals are common. Data from the National Nosocomial Infections Surveillance system suggest that, in the United States, incidence of nosocomial MRSA infections is steadily increasing and that these infections account for >60% of intensive care unit admissions (1,2). S. aureus has developed resistance to several antimicrobial drugs, including second- and third-line drugs. Only a few drugs, such as vancomycin (a glycopeptide), daptomycin (a lipopeptide), and linezolid (an oxazolidinone), have been approved for the treatment of serious infections caused by MRSA. Another drug, tigecycline (a glycylcycline), has shown good activity against MRSA strains in vitro (3). The epidemiology of MRSA is constantly changing, which results in variation in its drug-resistance patterns throughout regions and countries (4). Therefore, to support clinicians in preventing and treating infection, epidemiologic surveillance is essential. We report resistance patterns of S. aureus collected over 2 years (December 2013–November 2015) from blood samples of patients admitted to 1 hospital in Odisha, eastern India.

A study in high-risk, maximally pretreated patients to determine the potential use of PCSK9 inhibitors at various thresholds of total and LDL cholesterol levels

Purpose of the studyStatins and ezetimibe reduce low-density lipoprotein cholesterol (LDL-c) and cardiovascular disease (CVD) risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors lower LDL-c by 50%–70% and might be...

Protease Inhibitor Resistance in the First 3 Years of Second-Line Antiretroviral Therapy for HIV-1 in Sub-Saharan Africa.

As antiretroviral therapy (ART) programs in sub-Saharan Africa mature, increasing numbers of persons with human immunodeficiency virus (HIV) infection will experience treatment failure, and require second- or third-line ART. Data on second-line failure and development of protease inhibitor (PI) resistance in sub-Saharan Africa are scarce. HIV-1-infected adults were included if they received >180 days of PI-based second-line ART. We assessed risk factors for having a detectable viral load (VL, ≥400 cps/mL) using Cox models. If VL was ≥1000 cps/mL, genotyping was performed. Of 227 included participants, 14.6%, 15.2% and 11.1% had VLs ≥400 cps/mL at 12, 24, and 36 months, respectively. Risk factors for a detectable VL were as follows: exposure to nonstandard nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based (hazard ratio, 7.10; 95% confidence interval, 3.40-14.83; P < .001) or PI-based (7.59; 3.02-19.07; P = .001) first-line regimen compared with zidovudine/lamivudine/NNRTI, PI resistance at switch (6.69; 2.49-17.98; P < .001), and suboptimal adherence (3.05; 1.71-5.42; P = .025). Among participants with VLs ≥1000 cps/mL, 22 of 32 (69%) harbored drug resistance mutation(s), and 7 of 32 (22%) harbored PI resistance. Although VL suppression rates were high, PI resistance was detected in 22% of participants with VLs ≥1000 cps/mL. To ensure long-term ART success, intensified support for adherence, VL and drug resistance testing, and third-line drugs will be necessary.

Quality-of-life aspects in idiopathic epilepsy in dogs

Quality of life (QoL) plays a significant role in the treatment of dogs with idiopathic epilepsy (IE), yet is so far understudied. This study describes the outcome evaluation of an...

Output-driven feedback system control platform optimizes combinatorial therapy of tuberculosis using a macrophage cell culture model

Tuberculosis (TB) remains a major global public health problem, and improved treatments are needed to shorten duration of therapy, decrease disease burden, improve compliance, and combat emergence of drug resistance. Ideally, the most effective regimen would be identified by a systematic and comprehensive combinatorial search of large numbers of TB drugs. However, optimization of regimens by standard methods is challenging, especially as the number of drugs increases, because of the extremely large number of drug-dose combinations requiring testing. Herein, we used an optimization platform, feedback system control (FSC) methodology, to identify improved drug-dose combinations for TB treatment using a fluorescence-based human macrophage cell culture model of TB, in which macrophages are infected with isopropyl β-D-1-thiogalactopyranoside (IPTG)-inducible green fluorescent protein (GFP)-expressing Mycobacterium tuberculosis (Mtb). On the basis of only a single screening test and three iterations, we identified highly efficacious three- and four-drug combinations. To verify the efficacy of these combinations, we further evaluated them using a methodologically independent assay for intramacrophage killing of Mtb; the optimized combinations showed greater efficacy than the current standard TB drug regimen. Surprisingly, all top three- and four-drug optimized regimens included the third-line drug clofazimine, and none included the first-line drugs isoniazid and rifampin, which had insignificant or antagonistic impacts on efficacy. Because top regimens also did not include a fluoroquinolone or aminoglycoside, they are potentially of use for treating many cases of multidrug- and extensively drug-resistant TB. Our study shows the power of an FSC platform to identify promising previously unidentified drug-dose combinations for treatment of TB.

Systematic review of adherence rates by medication class in type 2 diabetes: a study protocol

IntroductionTreatment options for type 2 diabetes are becoming increasingly complex with people often prescribed multiple medications, and may include both oral and injectable therapies. There is ongoing debate about which...

Lidocaine response rate in aEEG‐confirmed neonatal seizures: Retrospective study of 413 full‐term and preterm infants

To investigate the seizure response rate to lidocaine in a large cohort of infants who received lidocaine as second- or third-line antiepileptic drug (AED) for neonatal seizures. Full-term (n = 319) and preterm (n = 94) infants, who received lidocaine for neonatal seizures confirmed on amplitude-integrated EEG (aEEG), were studied retrospectively (January 1992-December 2012). Based on aEEG findings, the response was defined as good (>4 h no seizures, no need for rescue medication); intermediate (0-2 h no seizures, but rescue medication needed after 2-4 h); or no clear response (rescue medication needed <2 h). Lidocaine had a good or intermediate effect in 71.4%. The response rate was significantly lower in preterm (55.3%) than in full-term infants (76.1%, p < 0.001). In full-term infants the response to lidocaine was significantly better than midazolam as second-line AED (21.4% vs. 12.7%, p = 0.049), and there was a trend for a higher response rate as third-line AED (67.6% vs. 57%, p = 0.086). Both lidocaine and midazolam had a higher response rate as third-line AED than as second-line AED (p < 0.001). Factors associated with a good response to lidocaine were the following: higher gestational age, longer time between start of first seizure and administration of lidocaine, lidocaine as third-line AED, use of new lidocaine regimens, diagnosis of stroke, use of digital aEEG, and hypothermia. Multivariable analysis of seizure response to lidocaine included lidocaine as second- or third-line AED and seizure etiology. Seizure response to lidocaine was seen in ~70%. The response rate was influenced by gestational age, underlying etiology, and timing of administration. Lidocaine had a significantly higher response rate than midazolam as second-line AED, and there was a trend for a higher response rate as third-line AED. Both lidocaine and midazolam had a higher response rate as third-line compared to second-line AED, which could be due to a pharmacologic synergistic mechanism between the two drugs.

Vaccinal Prevention of Pneumococcal Infection in Children

научный биометрический журнал, который знакомит читателя с клиническими рекомендациями и особенностями применения лекарственных и вакцинных средств у детей, предоставляет исчерпывающую информацию о воздействии лекарственных средств на плод, о проводимых в

Targeting Disease Persistence in Gastrointestinal Stromal Tumors.

SummaryGastrointestinal stromal tumors (GISTs) represent 20%-40% of human sarcomas. Although approximately half of GISTs are cured by surgery, prognosis of advanced disease used to be poor due to the high resistance of these tumors to conventional chemo- and radiotherapy. The introduction of molecularly targeted therapy (e.g., with imatinib mesylate) following the discovery of the role of oncogenic mutations in the receptor tyrosine kinases KIT and platelet-derived growth factor α (PDGFRA) significantly increased patient survival. However, GIST cells persist in 95%-97% of imatinib-treated patients who eventually progress and die of the disease because of the emergence of clones with drug-resistant mutations. Because these secondary mutations are highly heterogeneous, even second- and third-line drugs that are effective against certain genotypes have only moderately increased progression-free survival. Consequently, alternative strategies such as targeting molecular mechanisms underlying disease persistence should be considered. We reviewed recently discovered cell-autonomous and microenvironmental mechanisms that could promote the survival of GIST cells in the presence of tyrosine kinase inhibitor therapy. We particularly focused on the potential role of adult precursors for interstitial cells of Cajal (ICCs), the normal counterpart of GISTs. ICC precursors share phenotypic characteristics with cells that emerge in a subset of patients treated with imatinib and in young patients with GIST characterized by loss of succinate dehydrogenase complex proteins and lack of KIT or PDGFRA mutations. Eradication of residual GIST cells and cure of GIST will likely require individualized combinations of several approaches tailored to tumor genotype and phenotype. Gastrointestinal stromal tumors (GISTs) are one of the most common connective tissue cancers. Most GISTs that cannot be cured by surgery respond to molecularly targeted therapy (e.g., with imatinib); however, tumor cells persist in almost all patients and eventually acquire drug-resistant mutations. Several mechanisms contribute to the survival of GIST cells in the presence of imatinib, including the activation of "escape" mechanisms and the selection of stem-like cells that are not dependent on the expression of the drug targets for survival. Eradication of residual GIST cells and cure of GIST will likely require individualized combinations of several approaches tailored to the genetic makeup and other characteristics of the tumors.