A Phase I/II Clinical Trial of Pembrolizumab and Cabozantinib in Metastatic Renal Cell Carcinoma.

Purpose: Immune checkpoint inhibitor and VEGFR inhibitor combinations are effective treatments for patients with metastatic renal cell carcinoma (mRCC). This phase I/II clinical trial evaluated the safety and efficacy of pembrolizumab and cabozantinib in patients with mRCC. Experimental Design: Eligible patients had mRCC with clear-cell or non-clear cell histology, adequate organ function, Eastern Cooperative Oncology Group 0-1 performance status, and no prior exposure to pembrolizumab or cabozantinib. The primary endpoint was objective response rate (ORR) at the recommended phase II dose (RP2D). Secondary endpoints included safety, disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Results: Forty-five patients were enrolled. A total of 40 patients were treated at the RP2D of pembrolizumab 200 mg i.v. every 3 weeks and cabozantinib 60 mg orally once daily, 38 of which were evaluable for response. The ORR was 65.8% [95% confidence interval (CI), 49.9-78.8] for all evaluable patients [78.6% as first-line therapy, 58.3% as second-line therapy]. The DCR was 97.4% (95% CI, 86.5-99.9). Median DoR was 8.3 months (interquartile range, 4.6-15.1). At a median follow-up of 23.54 months, the median PFS was 10.45 months (95% CI, 6.25-14.63) and median OS was 30.81 months (95% CI, 24.2-not reached). The most common grade 1 and/or 2 treatment-related adverse events (TRAE) were diarrhea, anorexia, dysgeusia, weight loss, and nausea. The most common grade 3 and/or 4 TRAEs were hypertension, hypophosphatemia, alanine transaminase elevation, diarrhea, and fatigue. There was one grade 5 TRAE of reversible posterior encephalopathy syndrome related to cabozantinib. Conclusions: Pembrolizumab and cabozantinib treatment in patients with mRCC demonstrated encouraging preliminary efficacy and a manageable toxicity profile comparable with other available checkpoint inhibitor-tyrosine kinase inhibitor combinations. Trial Registration: ClinicalTrials.gov Identifier: NCT03149822 https://clinicaltrials.gov/ct2/show/NCT03149822. Significance: This study evaluated the safety and effectiveness of the combination of pembrolizumab and cabozantinib in patients with mRCC. The safety profile was manageable. The combination showed promising activity with an objective response rate of 65.8%, median PFS of 10.45 months, and median OS of 30.81 months.

Takotsubo syndrome is a coronary microvascular disease: experimental evidence.

BACKGROUND AND AIMS: Takotsubo syndrome (TTS) is a conundrum without consensus about the cause. In a murine model of coronary microvascular dysfunction (CMD), abnormalities in myocardial perfusion played a key role in the development of TTS. METHODS AND RESULTS: Vascular Kv1.5 channels connect coronary blood flow to myocardial metabolism and their deletion mimics the phenotype of CMD. To determine if TTS is related to CMD, wild-type (WT), Kv1.5-/-, and TgKv1.5-/- (Kv1.5-/- with smooth muscle-specific expression Kv1.5 channels) mice were studied following transaortic constriction (TAC). Measurements of left ventricular (LV) fractional shortening (FS) in base and apex, and myocardial blood flow (MBF) were completed with standard and contrast echocardiography. Ribonucleic Acid deep sequencing was performed on LV apex and base from WT and Kv1.5-/- (control and TAC). Changes in gene expression were confirmed by real-time-polymerase chain reaction. MBF was increased with chromonar or by smooth muscle expression of Kv1.5 channels in the TgKv1.5-/-. TAC-induced systolic apical ballooning in Kv1.5-/-, shown as negative FS (P < 0.05 vs. base), which was not observed in WT, Kv1.5-/- with chromonar, or TgKv1.5-/-. Following TAC in Kv1.5-/-, MBF was lower in LV apex than in base. Increasing MBF with either chromonar or in TgKv1.5-/- normalized perfusion and function between LV apex and base (P = NS). Some genetic changes during TTS were reversed by chromonar, suggesting these were independent of TAC and more related to TTS. CONCLUSION: Abnormalities in flow regulation between the LV apex and base cause TTS. When perfusion is normalized between the two regions, normal ventricular function is restored.

Publication requirement for faculty promotion in medical institutions in India: 'Mind the gap'.

Background . We assessed the balance between the number of publications required by medical teachers and the publication space available in the Indian medical journals. Methods . The Medical Council of India (MCI) website, its guidelines and documents were searched and we extracted data on the number of medical colleges, undergraduate and postgraduate seats and faculty requirement. The required number of assistant professors and associate professors was calculated. The publication requirements were estimated according to MCI's February 2020 guidelines. A publication which satisfied the above guidelines for promotion was counted as 'eligible publication'. Indian medical journals indexed in any of the MCI-permitted databases were identified, and the number of eligible articles in them in 2019 was counted. Results . India has a total of 79 798 MBBS seats, 33 025 postgraduate seats and 4231 superspecialty seats in MCI-certified medical institutions and to teach them 35 285 assistant professors and 23 116 associate professors are required. Assuming that each publication could serve a maximum of 3 teachers, we will need approximately 50 696 eligible publications in the next 7 years. A search of applicable databases, identified 162 unique Indian medical journals of which 79 were indexed in PubMed/PubMed Central. Among the remaining 63 were indexed in DOAJ, 14 in EMBASE, 3 in Scopus and 3 were indexed only in WOSSCIE. These journals cumulatively published a total of 8508 eligible publications in 2019. Conclusion . The publication space in Indian medical journals is limited, thus there is a need to have a national medical repository such as MedRxiv to prevent publication in predatory journals.

Effect of kangaroo mother care on pain during orogastric tube insertion in low-birthweight newborns: An open label, randomised trial.

AIM: Non-pharmacological methods are commonly used to reduce the procedural pain in newborns. In this open label, randomised control trial, we studied the pain-reducing effect of kangaroo mother care (KMC) during orogastric tube insertion. METHODS: Newborns, with birthweight 1500-2499 g and admitted to nursery, were randomised into control (no-KMC) or intervention (KMC) arms. In intervention arm, KMC was given for 60 min before and after the procedure. Premature Infant Pain Profile-Revised (PIPP-R) score was used to assess the pain response and the pain severity was graded as minimal or no pain (≤6), mild-to-moderate (7-12) and severe (>12). The PIPP-R scoring was done before, during and at 3- and 15-min after procedure. Change in PIPP-R scores from baseline was calculated. RESULTS: Newborns included in no-KMC (n = 40) or KMC (n = 40) arms were comparable for major confounders (P > 0.05). Pre-procedural pain scores were comparable (P = 0.72). Pain scores measured during and after procedure were significantly higher in no-KMC group than KMC arm. The KMC reduced the pain score by 39%, 32% and 30% during and at 3- and 15-min after procedure respectively as compared to control (P < 0.01). The increase in PIPP-R score from pre-procedural level was 40%, 35% and 31% lower in KMC than no-KMC arm (P < 0.01). A greater proportion of newborns had significantly less severe grades of pain in the intervention arm compared to the no-KMC arm (P < 0.01). CONCLUSION: Orogastric tube placement is a painful procedure. KMC significantly reduces periprocedural pain and its effect continues for at least 15 min after the procedure.

Iron status of exclusively breastfed low-birth-weight infants born to anemic mothers and effect of maternal iron supplementation for 3 versus 6 months: A randomized double-blind placebo control trial.

Background: The effect of maternal iron supplementation during lactation on the iron status of exclusively breastfed low-birth-weight (LBW) infants is not known. Objective: (1) To find out the number of LBW exclusively breastfed infants having hemoglobin < 10.5 g/dL at 6 months when mothers received iron. (2) To find out the proportion of anemic infants when mothers received iron for 3 and 6 months. Design: The Clinical Trials Registry, India (CTRI) registered trial (CTRI/2018/08/015516) double-blind randomized control trial participants: A total of 80 anemic mothers and exclusively breastfed LBW infants. Intervention: A total of 80 anemic mothers and exclusively breastfed infants, birth weight 1,500-2,499 g, randomized into two groups of 40 each. Mothers received daily iron for 3 months and placebo for the next 3 months in group A and iron for 6 months in group B. Iron profile of mothers and infants measured at recruitment and 6 months. Results: In total, 26.6% infants developed anemia till 6 months of age, and number of anemic infants were similar whether mothers received iron for 3 (n = 9) or 6 months (n = 11). Hemoglobin (12.89 + 0.46 vs. 12.44 + 0.48 g/dL; p < 0.001) and serum ferritin (27.45 + 7.60 vs. 18.94 + 5.36 ng/mL; p < 0.001) were significantly higher in infants at 6 months of age whose mothers received iron for 6 months in comparison to 3 months. Conclusion: totally, 26.6% exclusively breastfed infants developed anemia till 6 months of age when mothers took iron; number of anemic infants were not different if mothers received iron for 3 or 6 months. A significant increase was noted in serum ferritin with slightly higher hemoglobin of infants when mothers received iron for longer duration. Clinical trial registration: [http://ctri.nic.in/Clinicaltrials/pubview.php], identifier [CTRI/2018/08/015516].

Performance Analysis of Conventional Machine Learning Algorithms for Diabetic Sensorimotor Polyneuropathy Severity Classification Using Nerve Conduction Studies.

Background: Diabetic sensorimotor polyneuropathy (DSPN) is a major form of complication that arises in long-term diabetic patients. Even though the application of machine learning (ML) in disease diagnosis is very common and well-established in the field of research, its application in DSPN diagnosis using nerve conduction studies (NCS), is very limited in the existing literature. Method: In this study, the NCS data were collected from the Diabetes Control and Complications Trial (DCCT) and its follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) clinical trials. The NCS variables are median motor velocity (m/sec), median motor amplitude (mV), median motor F-wave (msec), median sensory velocity (m/sec), median sensory amplitude (µV), Peroneal Motor Velocity (m/sec), peroneal motor amplitude (mv), peroneal motor F-wave (msec), sural sensory velocity (m/sec), and sural sensory amplitude (µV). Three different feature ranking techniques were used to analyze the performance of eight different conventional classifiers. Results: The ensemble classifier outperformed other classifiers for the NCS data ranked when all the NCS features were used and provided an accuracy of 93.40%, sensitivity of 91.77%, and specificity of 98.44%. The random forest model exhibited the second-best performance using all the ten features with an accuracy of 93.26%, sensitivity of 91.95%, and specificity of 98.95%. Both ensemble and random forest showed the kappa value 0.82, which indicates that the models are in good agreement with the data and the variables used and are accurate to identify DSPN using these ML models. Conclusion: This study suggests that the ensemble classifier using all the ten NCS variables can predict the DSPN severity which can enhance the management of DSPN patients.

Machine Learning-Based Diabetic Neuropathy and Previous Foot Ulceration Patients Detection Using Electromyography and Ground Reaction Forces during Gait.

Diabetic neuropathy (DN) is one of the prevalent forms of neuropathy that involves alterations in biomechanical changes in the human gait. Diabetic foot ulceration (DFU) is one of the pervasive types of complications that arise due to DN. In the literature, for the last 50 years, researchers have been trying to observe the biomechanical changes due to DN and DFU by studying muscle electromyography (EMG) and ground reaction forces (GRF). However, the literature is contradictory. In such a scenario, we propose using Machine learning techniques to identify DN and DFU patients by using EMG and GRF data. We collected a dataset from the literature which involves three patient groups: Control (n = 6), DN (n = 6), and previous history of DFU (n = 9) and collected three lower limb muscles EMG (tibialis anterior (TA), vastus lateralis (VL), gastrocnemius lateralis (GL)), and three GRF components (GRFx, GRFy, and GRFz). Raw EMG and GRF signals were preprocessed, and different feature extraction techniques were applied to extract the best features from the signals. The extracted feature list was ranked using four different feature ranking techniques, and highly correlated features were removed. In this study, we considered different combinations of muscles and GRF components to find the best performing feature list for the identification of DN and DFU. We trained eight different conventional ML models: Discriminant analysis classifier (DAC), Ensemble classification model (ECM), Kernel classification model (KCM), k-nearest neighbor model (KNN), Linear classification model (LCM), Naive Bayes classifier (NBC), Support vector machine classifier (SVM), and Binary decision classification tree (BDC), to find the best-performing algorithm and optimized that model. We trained the optimized the ML algorithm for different combinations of muscles and GRF component features, and the performance matrix was evaluated. Our study found the KNN algorithm performed well in identifying DN and DFU, and we optimized it before training. We found the best accuracy of 96.18% for EMG analysis using the top 22 features from the chi-square feature ranking technique for features from GL and VL muscles combined. In the GRF analysis, the model showed 98.68% accuracy using the top 7 features from the Feature selection using neighborhood component analysis for the feature combinations from the GRFx-GRFz signal. In conclusion, our study has shown a potential solution for ML application in DN and DFU patient identification using EMG and GRF parameters. With careful signal preprocessing with strategic feature extraction from the biomechanical parameters, optimization of the ML model can provide a potential solution in the diagnosis and stratification of DN and DFU patients from the EMG and GRF signals.

Urinary beta-2 microglobulin as an early predictive biomarker of acute kidney injury in neonates with perinatal asphyxia.

To evaluate the role of urinary beta-2 microglobulin (B2mG) as an early predictive biomarker of acute kidney injury (AKI) in neonates with perinatal asphyxia. In this prospective cohort study, 80 term infants with perinatal asphyxia were included. The neonates were divided into AKI and no-AKI groups. Urinary B2mG levels were measured at 24 h of life. The diagnostic efficacy of the biomarker was determined using receiver operating characteristic (ROC) curves. Compared to infants without AKI, infants with AKI had higher levels of urinary B2mG (mean 6.8 versus 2.6 mg/L, p < 0.001). Area under the receiver operating characteristic curve (ROC curve) was 0.944. The balanced sensitivity/specificity trade-off was found at a cut-off value of 3.8 mg/L (81% sensitive and 81.6% specific).Conclusion Urinary B2mG can be useful to predict AKI early in term neonates with perinatal asphyxia. What is Known: • AKI is seen in 20-40% of neonates with asphyxia. • AKI affects the treatment plan and the prognosis of such neonates. What is New: • Urinary biomarkers are the easiest way to diagnose AKI in asphyxiated neonates. • Beta 2 microglobulin is the cheapest and readily available one such urinary biomarker with good sensitivity and specificity.

Machine Learning-Based Epileptic Seizure Detection Methods Using Wavelet and EMD-Based Decomposition Techniques: A Review.

Epileptic seizures are temporary episodes of convulsions, where approximately 70 percent of the diagnosed population can successfully manage their condition with proper medication and lead a normal life. Over 50 million people worldwide are affected by some form of epileptic seizures, and their accurate detection can help millions in the proper management of this condition. Increasing research in machine learning has made a great impact on biomedical signal processing and especially in electroencephalogram (EEG) data analysis. The availability of various feature extraction techniques and classification methods makes it difficult to choose the most suitable combination for resource-efficient and correct detection. This paper intends to review the relevant studies of wavelet and empirical mode decomposition-based feature extraction techniques used for seizure detection in epileptic EEG data. The articles were chosen for review based on their Journal Citation Report, feature selection methods, and classifiers used. The high-dimensional EEG data falls under the category of '3N' biosignals-nonstationary, nonlinear, and noisy; hence, two popular classifiers, namely random forest and support vector machine, were taken for review, as they are capable of handling high-dimensional data and have a low risk of over-fitting. The main metrics used are sensitivity, specificity, and accuracy; hence, some papers reviewed were excluded due to insufficient metrics. To evaluate the overall performances of the reviewed papers, a simple mean value of all metrics was used. This review indicates that the system that used a Stockwell transform wavelet variant as a feature extractor and SVM classifiers led to a potentially better result.

Performance Analysis of Conventional Machine Learning Algorithms for Diabetic Sensorimotor Polyneuropathy Severity Classification.

BACKGROUND: Diabetic peripheral neuropathy (DSPN), a major form of diabetic neuropathy, is a complication that arises in long-term diabetic patients. Even though the application of machine learning (ML) in disease diagnosis is a very common and well-established field of research, its application in diabetic peripheral neuropathy (DSPN) diagnosis using composite scoring techniques like Michigan Neuropathy Screening Instrumentation (MNSI), is very limited in the existing literature. METHOD: In this study, the MNSI data were collected from the Epidemiology of Diabetes Interventions and Complications (EDIC) clinical trials. Two different datasets with different MNSI variable combinations based on the results from the eXtreme Gradient Boosting feature ranking technique were used to analyze the performance of eight different conventional ML algorithms. RESULTS: The random forest (RF) classifier outperformed other ML models for both datasets. However, all ML models showed almost perfect reliability based on Kappa statistics and a high correlation between the predicted output and actual class of the EDIC patients when all six MNSI variables were considered as inputs. CONCLUSIONS: This study suggests that the RF algorithm-based classifier using all MNSI variables can help to predict the DSPN severity which will help to enhance the medical facilities for diabetic patients.

Tubercular infection in children living with adults receiving Directly Observed Treatment Short Course (DOTS): a follow up study.

BACKGROUND: Children living with sputum smear-positive adult tuberculosis (TB) patients are vulnerable to acquire tubercular infection. Contact tracing is an important strategy to control tubercular infection in the community. This study was done to find out prevalence of tuberculosis and tubercular infection in children living with sputum smear-positive adult patients receiving DOTS at recruitment and to find out incidence of tubercular infection and disease in these children on follow up. METHOD: Children (< 15 years) living in contact with adults on DOTS were grouped as < 6 years and 6-14 years. They were further sub grouped as being - uninfected, infected, diseased and on prophylaxis and were followed at 3, 6 and 9 months. Tuberculin skin test (TST) and chest X-ray were done. RESULTS: At recruitment 152 children were enrolled and 21.1% (n = 32) had TB. On follow up, 4.3% (n = 5), 5.8% (n = 6) and 11.6% (n = 11) children developed TB after 3, 6 and 9 months respectively.9 children did not come for the last follow up so the overall prevalence of TB disease at 9 months was 37.7% (n = 54). Out of the 128 children with TST reading 23.4% (n = 30) child contacts were found to be infected already at recruitment. The incidence of TST conversion was 20.7% (n = 18), 26.9% (n = 18) and 16.3% (n = 7) respectively. The overall prevalence of tubercular infection in the children, who were in contact with TB patients for 9 months was 74.5% (n = 73). CONCLUSION: About half the children were either suffering from TB or tubercular infection on recruitment. During 9 months follow up 22 unaffected children developed disease and 43acquired infection.

Validation of Serum Aminotransferases Levels to Define Severe Dengue Fever in Children.

PURPOSE: We aimed to study the pattern of liver-injury in children with dengue fever (DF) and validate serum aminotransferase ≥1,000 IU/L as a marker of severe DF. METHODS: Children admitted with DF were included. DF was defined by presence of clinical criteria and positive serological or antigen tests in absence of other etiology. DF severity was graded as dengue without or with warning signs and severe dengue. Liver-injury was defined as alanine aminotransferase (ALT) more than twice the upper limit of normal (boys, 30 IU/L; girls, 21 IU/L). RESULTS: Of 372 children with DF, 144 (38.7%) had liver-injury. Risk of liver-injury and aminotransferase levels increased with DF severity (p<0.001). Recommended ALT and aspartate aminotransferase (AST) cut-off at ≥1,000 IU/L had sensitivity 4.8% (5/105), specificity 99.3% (265/267) for detection of severe DF. In children with ALT and AST <1,000 IU/L (n=365), the area under receiver operating curves for prediction for severe DF, were 0.651 (95% confidence interval [CI], 0.588-0.714; p<0.001) for ALT and 0.647 (95% CI, 0.582-0.712; p<0.001) for AST. Serum ALT at 376 IU/L and AST at 635 IU/L had sensitivity and specificity comparable to ≥1,000 IU/L for defining severe DF. CONCLUSION: Liver-injury is common in DF. The ALT and AST levels increase with DF severity. ALT and AST levels of ≥1,000 IU/L could be lowered to 376 IU/L and 635 IU/L respectively for defining severe DF.

Diagnosis of insomnia sleep disorder using short time frequency analysis of PSD approach applied on EEG signal using channel ROC-LOC.

Insomnia is a sleep disorder in which the subject encounters problems in sleeping. The aim of this study is to identify insomnia events from normal or effected person using time frequency analysis of PSD approach applied on EEG signals using channel ROC-LOC. In this research article, attributes and waveform of EEG signals of Human being are examined. The aim of this study is to draw the result in the form of signal spectral analysis of the changes in the domain of different stages of sleep. The analysis and calculation is performed in all stages of sleep of PSD of each EEG segment. Results indicate the possibility of recognizing insomnia events based on delta, theta, alpha and beta segments of EEG signals.

Bowel Habits of Healthy Indian Children Less Than Two Years of Age.

Objectives: To define the normal frequency and consistency of stools of healthy Indian children between 0-24 months of age. Material and Methods: Parents of children aged up to 24 months were asked on a three-day recall basis about their child's usual bowel habits and dietary history. Bowel habit was recorded in terms of number of stools the child passes per day, stool consistency, the age at which night bowel movements stopped, and age of regular bowel movements. Feeding type was recorded as exclusive breast feed, mixed milk feeds or on solid feeds. The bowel habits were correlated with the age of the child and type of feeding. Results: Children in first six months of life had stools which were predominantly "pasty" and "runny like cream" with a frequency of one to two per day. On analyzing the combined effect of type of milk feed and age on bowel frequency and consistency children beyond one month of age either on exclusive breast feed or on mixed milk feed had similar frequency and consistency of stools. By one year of age more than 90% of children had attained regular stool pattern and no night time bowel movements. Conclusions: First of its kind study from India which describes the stool pattern of normal health children less than two years of age.

Comparative economics of a 12-gene assay for predicting risk of recurrence in stage II colon cancer.

BACKGROUND: Prior economic analysis that compared the 12-gene assay to published patterns of care predicted the assay would improve outcomes while lowering medical costs for stage II, T3, mismatch-repair-proficient (MMR-P) colon cancer patients. This study assessed the validity of those findings with real-world adjuvant chemotherapy (aCT) recommendations from the US third-party payer perspective. METHODS: Costs and quality-adjusted life-years (QALYs) were estimated for stage II, T3, MMR-P colon cancer patients using guideline-compliant, state-transition probability estimation methods in a Markov model. A study of 141 patients from 17 sites in the Mayo Clinic Cancer Research Consortium provided aCT recommendations before and after knowledge of the 12-gene assay results. Progression and adverse events data with aCT regimens were based on published literature. Drug and administration costs for aCT were obtained from 2014 Medicare Fee Schedule. Sensitivity analyses evaluated the drivers and robustness of the primary outcomes. RESULTS: After receiving the 12-gene assay results, physician recommendations in favor of aCT decreased 22 %; fluoropyrimidine monotherapy and FOLFOX recommendations each declined 11 %. Average per-patient drugs, administration, and adverse events costs decreased $US2,339, $US733, and $US3,211, respectively. Average total direct medical costs decreased $US991. Average patient well-being improved by 0.114 QALYs. Savings are expected to persist even if the cost of oxaliplatin drops by >75 % due to generic substitution. CONCLUSIONS: This study provides evidence that real-world changes in aCT recommendations due to the 12-gene assay are likely to reduce direct medical costs and improve well-being for stage II, T3, MMR-P colon cancer patients.

Prospective multicenter study of the impact of oncotype DX colon cancer assay results on treatment recommendations in stage II colon cancer patients.

The Oncotype DX colon cancer assay is a clinically validated predictor of recurrence risk in stage II colon cancer patients. This prospective study evaluated the impact of recurrence score (RS) results on physician recommendations regarding adjuvant chemotherapy in T3, mismatch repair-proficient (MMR-P) stage II colon cancer patients. Patients and Methods. Stage IIA colon cancer patients were enrolled in 17 centers. Patient tumor specimens were assessed by the RS test (quantitative reverse transcription-polymerase chain reaction) and mismatch repair (immunohistochemistry). For each patient, the physician's recommended postoperative treatment plan of observation, fluoropyrimidine monotherapy, or combination therapy with oxaliplatin was recorded before and after the RS and mismatch repair results were provided. Results. Of 221 enrolled patients, 141 patients had T3 MMR-P tumors and were eligible for the primary analysis. Treatment recommendations changed for 63 (45%; 95% confidence interval: 36%-53%) of these 141 T3 MMR-P patients, with intensity decreasing for 47 (33%) and increasing for 16 (11%). Recommendations for chemotherapy decreased from 73 patients (52%) to 42 (30%), following review of RS results by physician and patient. Increased treatment intensity was more often observed at higher RS values, and decreased intensity was observed at lower values (p = .011). Conclusion. Compared with traditional clinicopathological assessment, incorporation of the RS result into clinical decision making was associated with treatment recommendation changes for 45% of T3 MMR-P stage II colon cancer patients in this prospective multicenter study. Use of the RS assay may lead to overall reduction in adjuvant chemotherapy use in this subgroup of stage II colon cancer patients.

Long-term disease control in patients with newly diagnosed multiple myeloma after suspension of lenalidomide therapy.

There are no systematic data regarding nonmaintained induction for those patients with multiple myeloma (MM) who do not receive consolidative autologous stem cell transplantation. Of 173 patients with newly diagnosed MM treated with lenalidomide and dexamethasone (LenDex) as primary therapy, 31 patients had their lenalidomide discontinued for reasons other than progression or alternate therapy. Median progression free survival (PFS) from the time of discontinuing lenalidomide was longer in patients who received lenalidomide ≥ 1 year (39 vs. 13 months, P < 0.05); there was no difference in PFS for those treated for 1-2 years as compared to ≥ 2 years. Among those taking lenalidomide for ≥ 1 year PFS was superior in patients who were in very good partial response (VGPR) or better as compared to those with partial response (48.4 versus 14.8 months, P < 0.05). All patients who progressed and were rechallenged with LenDex responded. These analyses illustrate that discontinuation of lenalidomide after 1 year among those patients achieving a ≥VGPR can result in long-term disease control.

Risk of intracranial hemorrhage and cerebrovascular accidents in non-small cell lung cancer brain metastasis patients.

BACKGROUND: Brain metastases confer significant morbidity and a poorer survival in non-small cell lung cancer (NSCLC). Vascular endothelial growth factor-targeted antiangiogenic therapies (AAT) have demonstrated benefit for patients with metastatic NSCLC and are expected to directly inhibit the pathophysiology and morbidity of brain metastases, yet patients with brain metastases have been excluded from most clinical trials of AAT for fear of intracranial hemorrhage (ICH). The underlying risk of ICH from NSCLC brain metastases is low, but needs to be quantitated to plan clinical trials of AAT for NSCLC brain metastases. METHODS: Data from MD Anderson Cancer Center Tumor Registry and electronic medical records from January 1998 to March 2006 was interrogated. Two thousand one hundred forty-three patients with metastatic NSCLC registering from January 1998 to September 2005 were followed till March 2006. Seven hundred seventy-six patients with and 1,367 patients without brain metastases were followed till death, date of ICH, or last date of study, whichever occurred first. RESULTS: The incidence of ICH seemed to be higher in those with brain metastasis compared with those without brain metastases, in whom they occurred as result of cerebrovascular accidents. However, the rates of symptomatic ICH were not significantly different. All ICH patients with brain metastasis had received radiation therapy for them and had been free of anticoagulation. Most of the brain metastasis-associated ICH's were asymptomatic, detected during increased radiologic surveillance. The rates of symptomatic ICH, or other cerebrovascular accidents in general were similar and not significantly different between the two groups. CONCLUSIONS: In metastatic NSCLC patients, the incidence of spontaneous ICH appeared to be higher in those with brain metastases compared with those without, but was very low in both groups without a statistically significant difference. These data suggest a minimal risk of clinically significant ICH for NSCLC brain metastasis patients and proposes having more well designed prospective trail to see the role of AAT in this patient population.

Currying the heart: curcumin and cardioprotection.

Curcumin (diferuoylmethane) is the active ingredient of turmeric (curcuma longa). There has been a surge of research in its anti-inflammatory and antioxidative properties, and its cardiovascular effects. A host of studies in in vitro and in vivo models of cardiac injury show that curcumin treatment reduces reactive oxygen species generation, monocyte adhesion to activated endothelial cells, and phosphorylation of c-Jun N-terminal kinase, p38 mitogen activated protein kinase and signal transducer and activator of transcription-3, and subsequent downstream signals. These alterations lead to preservation of myocardial function following ischemic or biochemical insult to the heart. Recent studies in models of pressure overload show that curcumin can reduce cardiac remodeling by altering reninangiotensin-system-transforming growth factor beta1 and collagen axis. Studies need to be done in humans to define the potential of curcumin in limitation of cardiac injury and preservation of cardiac function following ischemia.