A soft cable loop based gripper for robotic automation of chemistry.

Robotic automation is proving itself indispensable in the modern Chemistry laboratory, but adoption is slowed down by the technical challenges of implementing such systems. This paper reports on a novel adaptive gripper mechanism that can easily and reliably grasp cylindrical and prismatic objects of various sizes with limited clearance required. The proposed design exploits the inherent compliance of a cable that is driven to fully envelope the target object. The cable is run through a rigid finger, allowing the loop to be placed around objects with minimal clearance required and to provide support for the object once the grip is complete. Thanks to the compliant nature of the mechanism, the gripper requires minimal control effort to complete a gasping task. A prototype of the gripper has been designed and built for chemistry automation tasks, where it showed very high grasp reliability with ≤ 1 % grasp failures.

An interpretable framework for sleep posture change detection and postural inactivity segmentation using wrist kinematics.

Sleep posture and movements offer insights into neurophysiological health and correlate with overall well-being and quality of life. Clinical practices utilise polysomnography for sleep assessment, which is intrusive, performed in unfamiliar environments, and requires trained personnel. While sensor technologies such as actigraphy are less invasive alternatives, concerns about their reliability and precision in clinical practice persist. Moreover, the field lacks a universally accepted algorithm, with methods ranging from raw signal thresholding to data-intensive classification models that may be unfamiliar to medical staff. This paper proposes a comprehensive framework for objectively detecting sleep posture changes and temporally segmenting postural inactivity using clinically relevant joint kinematics, measured by a custom-made wearable sensor. The framework was evaluated on wrist kinematic data from five healthy participants during simulated sleep. Intuitive three-dimensional visualisations of kinematic time series were achieved through dimension reduction-based preprocessing, providing an out-of-the-box framework explainability that may be useful for clinical monitoring and diagnosis. The proposed framework achieved up to 99.2% F1-score and 0.96 Pearson's correlation coefficient for posture detection and inactivity segmentation respectively. This work paves the way for reliable home-based sleep movement analysis, serving patient-centred longitudinal care.

Randomized Phase III Trial of Pemetrexed Versus Docetaxel in Patients With Non-Small-Cell Lung Cancer Previously Treated With Chemotherapy.

PURPOSE: To compare the efficacy and toxicity of pemetrexed versus docetaxel in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with chemotherapy. PATIENTS AND METHODS: Eligible patients had a performance status 0 to 2, previous treatment with one prior chemotherapy regimen for advanced NSCLC, and adequate organ function. Patients received pemetrexed 500 mg/m2 intravenously (IV) day 1 with vitamin B12, folic acid, and dexamethasone or docetaxel 75 mg/m2 IV day 1 with dexamethasone every 21 days. The primary end point was overall survival. RESULTS: Five hundred seventy-one patients were randomly assigned. Overall response rates were 9.1% and 8.8% (analysis of variance P = .105) for pemetrexed and docetaxel, respectively. Median progression-free survival was 2.9 months for each arm, and median survival time was 8.3 versus 7.9 months (P = not significant) for pemetrexed and docetaxel, respectively. The 1-year survival rate for each arm was 29.7%. Patients receiving docetaxel were more likely to have grade 3 or 4 neutropenia (40.2% v 5.3%; P < .001), febrile neutropenia (12.7% v 1.9%; P < .001), neutropenia with infections (3.3% v 0.0%; P = .004), hospitalizations for neutropenic fever (13.4% v 1.5%; P < .001), hospitalizations due to other drug related adverse events (10.5% v 6.4%; P = .092), use of granulocyte colony-stimulating factor support (19.2% v 2.6%, P < .001) and all grade alopecia (37.7% v 6.4%; P < .001) compared with patients receiving pemetrexed. CONCLUSION: Treatment with pemetrexed resulted in clinically equivalent efficacy outcomes, but with significantly fewer side effects compared with docetaxel in the second-line treatment of patients with advanced NSCLC and should be considered a standard treatment option for second-line NSCLC when available.

Phase III Study of Pemetrexed in Combination With Cisplatin Versus Cisplatin Alone in Patients With Malignant Pleural Mesothelioma.

PURPOSE: Patients with malignant pleural mesothelioma, a rapidly progressing malignancy with a median survival time of 6 to 9 months, have previously responded poorly to chemotherapy. We conducted a phase III trial to determine whether treatment with pemetrexed and cisplatin results in survival time superior to that achieved with cisplatin alone. PATIENTS AND METHODS: Chemotherapy-naive patients who were not eligible for curative surgery were randomly assigned to receive pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1, or cisplatin 75 mg/m2 on day 1. Both regimens were given intravenously every 21 days. RESULTS: A total of 456 patients were assigned: 226 received pemetrexed and cisplatin, 222 received cisplatin alone, and eight never received therapy. Median survival time in the pemetrexed/cisplatin arm was 12.1 months versus 9.3 months in the control arm (P = .020, two-sided log-rank test). The hazard ratio for death of patients in the pemetrexed/cisplatin arm versus those in the control arm was 0.77. Median time to progression was significantly longer in the pemetrexed/cisplatin arm: 5.7 months versus 3.9 months (P = .001). Response rates were 41.3% in the pemetrexed/cisplatin arm versus 16.7% in the control arm (P < .0001). After 117 patients had enrolled, folic acid and vitamin B12 were added to reduce toxicity, resulting in a significant reduction in toxicities in the pemetrexed/cisplatin arm. CONCLUSION: Treatment with pemetrexed plus cisplatin and vitamin supplementation resulted in superior survival time, time to progression, and response rates compared with treatment with cisplatin alone in patients with malignant pleural mesothelioma. Addition of folic acid and vitamin B12 significantly reduced toxicity without adversely affecting survival time.

Dynamical response and noise limit of a parametrically pumped microcantilever sensor in a Phase-Locked Loop.

We investigate the response of a digitally controlled and parametrically pumped microcantilever used for sensing in a Phase-Locked Loop (PLL). We develop an analytical model for its dynamical response and obtain an explicit dependence on the rheological parameters of the surrounding viscous medium. Linearization of this model allows to find improved responsivity to density variations in the case of parametric suppression. Experiments with a commercial microcantilever validate the model, but also reveal an increase of frequency noise in the PLL associated with the parametric gain and phase, which, in most cases, restricts the attainable limit of detection. The noise in open-loop is studied by measuring the random fluctuations of the noise-driven deflection of the microcantilever, and a model for the power spectral density of amplitude, phase and frequency noises is discussed and used to explain the frequency fluctuations in the closed-loop PLL. This work concludes that parametric pumping in a PLL does not improve the sensing performance in applications requiring detecting frequency shifts.

Photothermal Self-Excitation of a Phase-Controlled Microcantilever for Viscosity or Viscoelasticity Sensing.

This work presents a feedback closed-loop platform to be used for viscosity or viscoelasticity sensing of Newtonian or non-Newtonian fluids. The system consists of a photothermally excited microcantilever working in a digital Phase-Locked Loop, in which the phase between the excitation signal to the cantilever and the reference demodulating signals is chosen and imposed in the loop. General analytical models to describe the frequency and amplitude of oscillation of the cantilever immersed in viscous and viscoelastic fluids are derived and validated against experiments. In particular, the sensitivity of the sensor to variations of viscosity of Newtonian fluids, or to variations of elastic/viscous modulus of non-Newtonian fluids, are studied. Interestingly, it is demonstrated the possibility of controlling the sensitivity of the system to variations of these parameters by choosing the appropriate imposed phase in the loop. A working point with maximum sensitivity can be used for real-time detection of small changes of rheological parameters with low-noise and fast-transient response. Conversely, a working point with zero sensitivity to variations of rheological parameters can be potentially used to decouple the effect of simultaneous external factors acting on the resonator.

Prestrain-induced contraction in one-dimensional random elastic chains.

Prestrained elastic networks arise in a number of biological and technological systems ranging from the cytoskeleton of cells to tensegrity structures. Motivated by this observation, we here consider a minimal model in one dimension to set the stage for understanding the response of such networks as a function of the prestrain. To this end we consider a chain [one-dimensional (1D) network] of elastic springs upon which a random, zero mean, finite variance prestrain is imposed. Numerical simulations and analytical predictions quantify the magnitude of the contraction as a function of the variance of the prestrain, and show that the chain always shrinks. To test these predictions, we vary the topology of the chain, consider more complex connectivity and show that our results are relatively robust to these changes.

Daily activity in minimal footwear increases foot strength.

The human foot is uniquely adapted to bipedal locomotion and has a deformable arch of variable stiffness. Intrinsic foot muscles regulate arch deformation, making them important for foot function. In this study we explore the hypothesis that normal daily activity in minimal footwear, which provides little or no support, increases foot muscle strength. Western adults wore minimal footwear for a six-month period (the "intervention" group). Foot strength, i.e., maximum isometric plantarflexion strength at the metatarsophalangeal joints, and foot biometrics were measured before and after the intervention. An additional group was investigated to add further insight on the long-term effects of footwear, consisting of Western adults with an average 2.5 years of experience in minimal footwear (the "experienced" group). This study shows that foot strength increases by, on average, 57.4% (p < 0.001) after six months of daily activity in minimal footwear. The experienced group had similar foot strength as the post intervention group, suggesting that six months of regular minimal footwear use is sufficient to gain full strength, which may aid healthy balance and gait.

Measuring Viscosity Using the Hysteresis of the Non-Linear Response of a Self-Excited Cantilever.

A self-oscillating microcantilever in a feedback loop comprised of a gain, a saturator, and an adjustable phase-shifter is used to measure the viscosity of Newtonian fluids. Shifting the signal of the loop with the adjustable phase-shifter causes sudden jumps in the oscillation frequency of the cantilever. The exact position of these jumps depends on whether the shift imposed by the phase-shifter is increasing or decreasing and, therefore, the self-excited cantilever exhibits a hysteretic non-linear response. This response was studied and the system modeled by a delay differential equation of motion where frequency-dependent added mass and damping terms accounted for the density and the viscosity of the medium. Experimental data were obtained for solutions with different concentrations of glycerol in water and used to validate the model. Two distinct sensing modalities were proposed for this system: the sweeping mode, where the width of the observed hysteresis depends on the viscosity of the medium, and the threshold mode, where a sudden jump of the oscillation frequency is triggered by an arbitrarily small change in the viscosity of the medium.

Microcantilever: Dynamical Response for Mass Sensing and Fluid Characterization.

A microcantilever is a suspended micro-scale beam structure supported at one end which can bend and/or vibrate when subjected to a load. Microcantilevers are one of the most fundamental miniaturized devices used in microelectromechanical systems and are ubiquitous in sensing, imaging, time reference, and biological/ biomedical applications. They are typically built using micro and nanofabrication techniques derived from the microelectronics industry and can involve microelectronics-related materials, polymeric materials, and biological materials. This work presents a comprehensive review of the rich dynamical response of a microcantilever and how it has been used for measuring the mass and rheological properties of Newtonian/non-Newtonian fluids in real time, in ever-decreasing space and time scales, and with unprecedented resolution.

AFM Characterization of the Internal Mammary Artery as a Novel Target for Arterial Stiffening.

Using the atomic force microscopy- (AFM-) PeakForce quantitative nanomechanical mapping (QNM) technique, we have previously shown that the adventitia of the human internal mammary artery (IMA), tested under dehydrated conditions, is altered in patients with a high degree of arterial stiffening. In this study, we explored the nanoscale elastic modulus of the tunica media of the IMA in hydrated and dehydrated conditions from the patients with low and high arterial stiffening, as assessed in vivo by carotid-femoral pulse wave velocity (PWV). In both hydrated and dehydrated conditions, the medial layer was significantly stiffer in the high PWV group. The elastic modulus of the hydrated and dehydrated tunica media was significantly correlated with PWV. In the hydrated condition, the expression activity of certain small leucine-rich repeat proteoglycans (SLRPs), which are associated with arterial stiffening, were found to be negatively correlated to the medial elastic modulus. We also compared the data with our previous work on the IMA adventitia. We found that the hydrated media and dehydrated adventitia are both suitable for reflecting the development of arterial stiffening and SLRP expression. This comprehensive study of the nanomechanical properties integrated with the proteomic analysis in the IMAs demonstrates the possibility of linking structural properties and function in small biological samples with novel AFM methods. The IMA is a suitable target for predicting arterial stiffening.

Nanomechanics and ultrastructure of the internal mammary artery adventitia in patients with low and high pulse wave velocity.

The collagen-rich adventitia is the outermost arterial layer and plays an important biomechanical and physiological role in normal vessel function. While there has been a lot of effort to understand the role of the medial layer on arterial biomechanics, the adventitia has received less attention. In this study, we hypothesized that different ultrastructural and nanomechanical properties would be exhibited in the adventitia of the internal mammary artery (IMA) in patients with a low degree of arterial stiffening as compared to those with a high degree of arterial stiffening. Human IMA biopsies were obtained from a cohort of patients with arterial stiffening assessed via carotid-femoral PWV. Patients were grouped as low PWV (8.5 ±â€¯0.7 ms-1, n = 8) and high PWV (13.4 ±â€¯3.0 ms-1, n = 9). Peakforce QNM atomic force microscopy (AFM) was used to determine the nanomechanical and morphological properties of the IMA. The nano-scale elastic modulus was found to correlate with PWV. We show for the first time that nano-scale alterations in adventitial collagen fibrils in the IMA are evident in patients with high PWV, even though the IMA is not involved in the carotid-femoral pathway. Our approach provides new insight into systemic structure-property changes in the vasculature, and also provides a method of characterizing small biopsy samples to predict the development of arterial stiffening. STATEMENT OF SIGNIFICANCE: Arterial stiffening occurs as part of the natural aging process and is strongly linked to cardiovascular risk. Although arterial stiffening is routinely measured in vivo, little is known about how localised changes in artery structure and biomechanics contributes to in vivo arterial stiffening. This study focusses on the role of the outermost layer of arteries, the adventitia, in arterial stiffening. The study provides data on nano-scale changes in collagen fibril structure and mechanical properties in the adventitia and shows how it relates to in vivo stiffness measurements in the vascular system. This is the first study to link in vivo arterial stiffening with nanomechanical changes in artery biopsy samples. Hence, this approach could be used to develop new diagnostic methods for vascular disease.

Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer.

PURPOSE: Brain metastases develop in one third of patients with advanced HER2+ breast cancer. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Lapatinib, an epidermal growth factor receptor/HER2 inhibitor, was associated with regressions of CNS lesions in a small phase 2 trial. The current study was done to further evaluate the CNS activity of lapatinib. The study was later amended to allow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine. EXPERIMENTAL DESIGN: Eligible patients had HER2+ breast cancer, progressive brain metastases, prior trastuzumab, and cranial radiotherapy. The primary end point was CNS objective response, defined as >or=50% volumetric reduction of CNS lesion(s) in the absence of increasing steroid use, progressive neurologic signs and symptoms, or progressive extra-CNS disease. RESULTS: Two-hundred and forty-two patients entered the study. CNS objective responses to lapatinib were observed in 6% of patients. In an exploratory analysis, 21% of patients experienced a >or=20% volumetric reduction in their CNS lesions. An association was observed between volumetric reduction and improvement in progression-free survival and neurologic signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a >or=20% volumetric reduction in their CNS lesions. CONCLUSIONS: This study confirms the modest CNS antitumor activity of lapatinib. Additional responses were observed with the combination of lapatinib and capecitabine. Further studies of lapatinib-based regimens for CNS metastases from HER2+ breast cancer are warranted.

Nicotine dependence, psychological distress and personality traits as possible predictors of smoking cessation. Results of a double-blind study with nicotine patch.

AIM: Nicotine replacement therapy (NRT) is an effective treatment for smokers who want to quit, however, the rates of successful quitting can be improved even more. In this context, nicotine dependence (assessed via the Fagerström Tolerance Questionnaire, FTQ), psychological distress (measured via the Symptom Rating Test, SRT), and personality traits (evaluated via the Adult Eysenck Personality Inventory, AEPI) were evaluated as possible predictors of smoking cessation. RESULTS: A total of 297 cigarette smokers were followed for one year as part of a NRT double-blind, parallel group, randomized trial. Baseline nicotine dependence (weeks 12 and 26: p<0.05), AEPI neuroticism (weeks 12 and 52: p<0.05), and AEPI psychoticism (weeks 12 and 52: p<0.05) scores significantly influenced the outcome of smoking cessation during one-year of follow-up. An increase in psychological distress during follow-up was associated with a lower probability of quitting smoking (p=0.000). CONCLUSIONS: Nicotine dependence, neuroticism, psychoticism and, over time, psychological distress were the main factors influencing the long-term outcome (i.e., up to 12 months) of smoking cessation under NRT.

A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses.

PURPOSE: Lapatinib is a small molecule, dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor type 2 (HER2). Initial results of a phase III trial demonstrated that lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that progressed following prior therapy including trastuzumab. Updated efficacy and initial biomarker results from this trial are reported. METHODS: Women with HER2-positive, locally advanced or metastatic breast cancer previously treated with anthracycline-, taxane-, and trastuzumab-containing regimens were randomized to lapatinib 1,250 mg/day continuously plus capecitabine 2,000 mg/m(2) days 1-14 of a 21-day cycle or capecitabine 2,500 mg/m(2) on the same schedule. The primary endpoint was time to progression (TTP) as determined by an independent review panel. Relationship between progression-free survival (PFS) and tumor HER2 expression and serum levels of HER2 extracellular domain (ECD) were assessed. RESULTS: 399 women were randomized. The addition of lapatinib prolonged TTP with a hazard ratio (HR) of 0.57 (95% CI, 0.43-0.77; P < 0.001) and provided a trend toward improved overall survival (HR: 0.78, 95% CI: 0.55-1.12, P = 0.177), and fewer cases with CNS involvement at first progression (4 vs. 13, P = 0.045). Baseline serum HER2 ECD did not predict for benefit from lapatinib. CONCLUSION: The addition of lapatinib to capecitabine provides superior efficacy for women with HER2-positive, advanced breast cancer progressing after treatment with anthracycline-, taxane-, and trastuzumab-based therapy. Biomarker studies could not identify a subgroup of patients who failed to benefit from the addition of lapatinib to capecitabine.

In vitro chemosensitivity of freshly explanted tumor cells to pemetrexed is correlated with target gene expression.

AIM OF THE STUDY: mRNA expression of genes involved in the mechanism of action of pemetrexed was correlated with in vitro chemosensitivity of freshly explanted human tumor specimens. EXPERIMENTAL DESIGN: Chemosensitivity to pemetrexed was studied in soft-agar. Multiplex rtPCR experiments for reduced folate carrier (RFC), folate receptor-alpha (FR-alpha), folylpolyglutamate synthetase (FPGS), thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyl transferase (GARFT), mrp4, and mrp5 were performed in parallel. Correlations, threshold optimization, sensitivity, specificity, and efficiency were analyzed using the appropriate statistical methodologies. RESULTS: In 61 samples, low levels of TS, GARFT, DHFR, and mrp4 gene expression significantly correlated with chemosensitivity to pemetrexed. Optimization analyses demonstrated threshold values of 144 copies for TS and six copies for mrp4 relative to 10(4) copies of beta-actin. CONCLUSIONS: These results form a rational basis for the design of clinical trials to evaluate the expression of these enzymes as predictors for treatment outcome.

Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy.

PURPOSE: To compare the efficacy and toxicity of pemetrexed versus docetaxel in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with chemotherapy. PATIENTS AND METHODS: Eligible patients had a performance status 0 to 2, previous treatment with one prior chemotherapy regimen for advanced NSCLC, and adequate organ function. Patients received pemetrexed 500 mg/m(2) intravenously (i.v.) day 1 with vitamin B(12), folic acid, and dexamethasone or docetaxel 75 mg/m(2) i.v. day 1 with dexamethasone every 21 days. The primary end point was overall survival. RESULTS: Five hundred seventy-one patients were randomly assigned. Overall response rates were 9.1% and 8.8% (analysis of variance P =.105) for pemetrexed and docetaxel, respectively. Median progression-free survival was 2.9 months for each arm, and median survival time was 8.3 versus 7.9 months (P = not significant) for pemetrexed and docetaxel, respectively. The 1-year survival rate for each arm was 29.7%. Patients receiving docetaxel were more likely to have grade 3 or 4 neutropenia (40.2% v 5.3%; P <.001), febrile neutropenia (12.7% v 1.9%; P <.001), neutropenia with infections (3.3% v 0.0%; P =.004), hospitalizations for neutropenic fever (13.4% v 1.5%; P <.001), hospitalizations due to other drug related adverse events (10.5% v 6.4%; P =.092), use of granulocyte colony-stimulating factor support (19.2% v 2.6%, P <.001) and all grade alopecia (37.7% v 6.4%; P <.001) compared with patients receiving pemetrexed. CONCLUSION: Treatment with pemetrexed resulted in clinically equivalent efficacy outcomes, but with significantly fewer side effects compared with docetaxel in the second-line treatment of patients with advanced NSCLC and should be considered a standard treatment option for second-line NSCLC when available.

Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.

PURPOSE: Patients with malignant pleural mesothelioma, a rapidly progressing malignancy with a median survival time of 6 to 9 months, have previously responded poorly to chemotherapy. We conducted a phase III trial to determine whether treatment with pemetrexed and cisplatin results in survival time superior to that achieved with cisplatin alone. PATIENTS AND METHODS: Chemotherapy-naive patients who were not eligible for curative surgery were randomly assigned to receive pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1, or cisplatin 75 mg/m2 on day 1. Both regimens were given intravenously every 21 days. RESULTS: A total of 456 patients were assigned: 226 received pemetrexed and cisplatin, 222 received cisplatin alone, and eight never received therapy. Median survival time in the pemetrexed/cisplatin arm was 12.1 months versus 9.3 months in the control arm (P =.020, two-sided log-rank test). The hazard ratio for death of patients in the pemetrexed/cisplatin arm versus those in the control arm was 0.77. Median time to progression was significantly longer in the pemetrexed/cisplatin arm: 5.7 months versus 3.9 months (P =.001). Response rates were 41.3% in the pemetrexed/cisplatin arm versus 16.7% in the control arm (P <.0001). After 117 patients had enrolled, folic acid and vitamin B12 were added to reduce toxicity, resulting in a significant reduction in toxicities in the pemetrexed/cisplatin arm. CONCLUSION: Treatment with pemetrexed plus cisplatin and vitamin supplementation resulted in superior survival time, time to progression, and response rates compared with treatment with cisplatin alone in patients with malignant pleural mesothelioma. Addition of folic acid and vitamin B12 significantly reduced toxicity without adversely affecting survival time.

Homocysteine and methylmalonic acid: markers to predict and avoid toxicity from pemetrexed therapy.

The purpose of this study was to identify predictive factors for severe toxicity caused by antifolate-chemotherapy using pemetrexed (ALIMTA, LY231514), as a model. Data on potential predictive factors for severe toxicity from pemetrexed were collected from 246 patients treated between 1995 and 1999. Multivariate stepwise regression methods were used to identify markers predictive of severe toxicity. Using a multiple logistic regression model allowed us to quantify the relative risk of developing toxicities and to generate a validated clinical hypothesis on ways to improve the safety profile of pemetrexed. Pretreatment total plasma homocysteine (tHcy) levels significantly predict severe thrombocytopenia and neutropenia with or without associated grade 3/4 diarrhea, mucositis, or infection. Pretreatment methylmalonic acid (MMA) levels significantly and independently predict grade 3/4 diarrhea and mucositis; however, these toxicities are still predicted by tHcy alone. Patients with elevated baseline levels of tHcy alone, or of both tHcy and MMA, were found to have a high risk of severe toxicity that led us to postulate that reducing tHcy would result in a reduction of severe toxicity with no harm to efficacy. This study points out for the first time the importance of pretreatment tHcy levels in predicting severe toxicity associated with an antifolate and sets the stage for a prospective clinical intervention to protect patients from pemetrexed-induced severe toxicity and possibly improve the drug's efficacy. Antifolates as a class have been associated with sporadic severe myelosuppression with gastrointestinal toxicity. Although infrequent, a combination of such toxicities can carry a high risk of mortality. This phenomenon had been unpredictable until now. Our work shows that by measuring tHcy, one can identify patients that are at risk of toxicity before treatment. Most importantly, decreasing homocysteine levels via vitamin supplementation leads to a better safety profile of pemetrexed and possibly to an improved efficacy.