Therapeutic drug monitoring for cytotoxic anticancer drugs: Principles and evidence-based practices.

Cytotoxic drugs are highly efficacious and also have low therapeutic index. A great degree of caution needs to be exercised in their usage. To optimize the efficacy these drugs need to be given at maximum tolerated dose which leads to significant amount of toxicity to the patient. The fine balance between efficacy and safety is the key to the success of cytotoxic chemotherapeutics. However, it is possibly more rewarding to obtain that balance for this class drugs as the frequency of drug related toxicities are higher compared to the other therapeutic class and are potentially life threatening and may cause prolonged morbidity. Significant efforts have been invested in last three to four decades in therapeutic drug monitoring (TDM) research to understand the relationship between the drug concentration and the response achieved for therapeutic efficacy as well as drug toxicity for cytotoxic drugs. TDM evolved over this period and the evidence gathered favored its routine use for certain drugs. Since, TDM is an expensive endeavor both from economic and logistic point of view, to justify its use it is necessary to demonstrate that the implementation leads to perceivable improvement in the patient outcomes. It is indeed challenging to prove the utility of TDM in randomized controlled trials and at times may be nearly impossible to generate such data in view of the obvious findings and concern of compromising patient safety. Therefore, good quality data from well-designed observational study do add immense value to the scientific knowledge base, when they are examined in totality, despite the heterogeneity amongst them. This article compiles the summary of the evidence and the best practices for TDM for the three cytotoxic drug, busulfan, 5-FU and methotrexate. Traditional use of TDM or drug concentration data for dose modification has been witnessing a sea change and model informed precision dosing is the future of cytotoxic drug therapeutic management.

Elasticity in crystals with a high density of local defects: Insights from ultra-soft colloids.

In complex crystals close to melting or at finite temperatures, different types of defects are ubiquitous and their role becomes relevant in the mechanical response of these solids. Conventional elasticity theory fails to provide a microscopic basis to include and account for the motion of point defects in an otherwise ordered crystalline structure. We study the elastic properties of a point-defect rich crystal within a first principles theoretical framework derived from the microscopic equations of motion. This framework allows us to make specific predictions pertaining to the mechanical properties that we can validate through deformation experiments performed in molecular dynamics simulations.

Comparison of the penetration depth of five root canal sealers: A confocal laser scanning microscopic study.

BACKGROUND: Sealer penetration into dentinal tubules eliminates the pathways for bacterial leakage and entombs intratubular bacteria. AIM: The aim of this study was to evaluate and compare the depth of radicular dentinal tubule penetration of five root canal sealers using confocal laser scanning microscopy. METHODS: Fifty freshly extracted single-rooted maxillary anterior teeth were used. After decoronation at the cementoenamel junction, they were prepared to ProTaper size F3. After irrigation with 5 mL smear clear, 5 mL 5% sodium hypochlorite and 5 mL distilled water alternatively, the samples were randomly divided into five groups (n = 10) and obturated by lateral compaction technique using the test sealers labeled by fluorescent rhodamine B dye (Mayor Diagnostics, Mumbai, India). Zinc oxide eugenol (ZOE) (Prime Dental Products), EndoREZ (Ultradent), Sealapex (SybronEndo), AH Plus (Dentsply Maillefer), and MTA-Fillapex (Angelus) formed the test groups. Teeth were then positioned in blocks of orthodontic resin. Three horizontal sections of 1-mm representing coronal middle and apical thirds were made and examined with Zeiss (laser scanning microscope [LSM] 780) confocal LSM. Images were analyzed using ZEN 2.1 software. STATISTICAL ANALYSIS: Data were recorded and subjected to statistical analysis using one-way ANOVA test. RESULTS: Maximum penetration depth was demonstrated by AH Plus in the coronal and apical thirds, MTA-Fillapex in the middle thirds, while minimum penetration depth was seen in ZOE in the coronal and middle thirds and Sealapex in the apical thirds. None of the root canal sealers were able to penetrate the complete depth of radicular dentinal tubules. CONCLUSION: While AH Plus and MTA-Fillapex showed the highest penetration into radicular dentinal tubules, ZOE and Sealapex demonstrated the least penetration.

Diabetic myonecrosis in end-stage renal disease.

Diabetic myonecrosis or muscle infarction (DMI), a clinicoradiological entity is an underdiagnosed complication of diabetes mellitus. It refers to spontaneous aseptic necrosis of skeletal muscles commonly of the lower limb without evidence of any large vessel disease. It presents as painful swollen limb without any external insult in patients with long-standing diabetes mellitus with other microvascular complications especially nephropathy. We present four instances of DMI in our patients who had end-stage renal disease with a varied course.

Bendamustine in combination with ifosfamide, etoposide, and vinorelbine (VIBE) is an effective salvage regimen for heavily pre-treated patients with relapsed or refractory Hodgkin lymphoma:a single-center experience

Background@#This study evaluated the outcomes of patients with refractory/relapsed Hodgkin lymphoma (RRHL) treated with a bendamustine-based regimen in combination with ifosfamide, etoposide, and vinorelbine (VIBE). @*Methods@#Consecutive RRHL patients who were treated with the VIBE regimen were identified and studied for clinicopathologic characteristics, response to VIBE regimen, event-free survival (EFS), and feasibility of an autologous stem-cell transplant (autoSCT). @*Results@#In total, 24 patients received the VIBE regimen, and a median of 3 cycles were administered. In this cohort, 80% of the patients had received ≥2 prior lines of therapy. The overall and complete response rates with VIBE were 79% and 42%, respectively. After a median follow-up (following VIBE regimen) of 14 months (range, 3‒76), the 3-year EFS and OS were 46% and 74%, respectively. Of the eligible patients, 92% underwent successful AutoSCT. The mean CD34+ cell count in the autograft was 5.5×106/kg (SD 2.07). Neutropenia was the commonest hematologic toxicity and it was observed in 42% of the patients. However, only 9% of the patients developed grade III/IV febrile neutropenia. Chemotherapy-induced nausea and vomiting were the second most common grade III/IV toxicities in our cohort of patients. @*Conclusion@#In this retrospective analysis, the combination regimen, VIBE, has shown good efficacy in heavily pre-treated patients with RRHL without compromising stem cell collection. These encouraging results provide a rationale for further development of this regimen.

Bendamustine in combination with ifosfamide, etoposide, and vinorelbine (VIBE) is an effective salvage regimen for heavily pre-treated patients with relapsed or refractory Hodgkin lymphoma:a single-center experience

Background@#This study evaluated the outcomes of patients with refractory/relapsed Hodgkin lymphoma (RRHL) treated with a bendamustine-based regimen in combination with ifosfamide, etoposide, and vinorelbine (VIBE). @*Methods@#Consecutive RRHL patients who were treated with the VIBE regimen were identified and studied for clinicopathologic characteristics, response to VIBE regimen, event-free survival (EFS), and feasibility of an autologous stem-cell transplant (autoSCT). @*Results@#In total, 24 patients received the VIBE regimen, and a median of 3 cycles were administered. In this cohort, 80% of the patients had received ≥2 prior lines of therapy. The overall and complete response rates with VIBE were 79% and 42%, respectively. After a median follow-up (following VIBE regimen) of 14 months (range, 3‒76), the 3-year EFS and OS were 46% and 74%, respectively. Of the eligible patients, 92% underwent successful AutoSCT. The mean CD34+ cell count in the autograft was 5.5×106/kg (SD 2.07). Neutropenia was the commonest hematologic toxicity and it was observed in 42% of the patients. However, only 9% of the patients developed grade III/IV febrile neutropenia. Chemotherapy-induced nausea and vomiting were the second most common grade III/IV toxicities in our cohort of patients. @*Conclusion@#In this retrospective analysis, the combination regimen, VIBE, has shown good efficacy in heavily pre-treated patients with RRHL without compromising stem cell collection. These encouraging results provide a rationale for further development of this regimen.

Genomic Landscape and Targeted Treatment of Gallbladder Cancer: Results of a First Ongoing Prospective Study.

Background Prognosis of gallbladder cancer (GBC) has not changed in the past 20 years. Comprehensive genomic profiling (CGP) carries potential to determine the actionability for multiple targets, including ERBB2 , ERBB3 , MET , ROSI , FGFR , and PIK3 . This study evaluates the role of CGP and targeted therapies. Methods This is a multicenter, prospective, single-arm study. All consecutive patients of unresectable and/or metastatic GBC of age ≥18 years were enrolled. Hybrid capture-based CGP was performed by Foundation Medicine CDx. All patients received first-line chemotherapy with gemcitabine-cisplatin regimen. Patients with ERBB2/3 amplification received trastuzumab with capecitabine or nab-paclitaxel, and patients with MET amplification were treated with crizotinib. For ERBB2/3 mutations, lapatinib plus capecitabine regimen was used. Results Fifty patients were studied with a median age of 56 years (range 26-83) and a male-to-female ratio of 1:1.6. ERBB2 and ERBB3 amplification was seen in 9 (18%) and 2 (4%) patients, respectively. Four patients with ERBB2 amplification received trastuzumab and/or lapatinib, showed partial response, and maintained response beyond 12 weeks. One patient had mixed response, whereas two patients progressed on trastuzumab and lapatinib. Three patients with ERBB3 mutations showed response to lapatinib-capecitabine. One patient with MET amplification responded to crizotinib for 4 weeks. PIK3 mutations were present in 14% of cases and were independent of ERBB aberrations. Conclusion GBC is enriched in 28% of patients with ERBB2 and ERBB3 amplifications and/or mutations. Responses are seen with lapatinib in concurrent ERBB2 mutation and amplification. ERBB3 mutation showed response to lapatinib. MET and PIK3 are new findings in GBC, which may be targeted.

Assessment of subclinical atherosclerosis and endothelial dysfunction in chronic kidney disease by measurement of carotid intima media thickness and flow-mediated vasodilatation in North Indian population.

BACKGROUND: Chronic kidney disease (CKD) predisposes to accelerated atherosclerosis that is measured by carotid artery intima media thickness (CIMT) and brachial artery flow-mediated dilation (FMD). The aim of this study was to assess the noninvasive risk markers of subclinical atherosclerosis and endothelial dysfunction and their correlation with disease severity. METHODS AND RESULTS: This was a cross-sectional study conducted in 62 patients with CKD: 38 predialysis and 24 on hemodialysis and 50 age- and gender-matched controls. In both the patients and controls, high-sensitivity C-reactive protein (CRP) levels, %FMD, and CIMT were measured. Patients with CKD had increased CRP levels {[5.8 (1.0-6.0)] mg/L vs [1.0 (0.5-2.20)] mg/L; P < 0.001}; %FMD was significantly lower in patients on hemodialysis (5.51%) compared with stage IV (7.62%) and stage III (15.02%) and 17.95% in control subjects (P < 0.001); and CIMT values in hemodialysis patients (0.88 ± 0.06 mm) were significantly higher compared with stage IV (0.67 ± 0.10) and stage III (0.61 ± 0.12) (P < 0.001). Increased CIMT values were seen in patients with CKD (0.82 ± 0.21 mm) than in the healthy controls (0.55 ± 0.16 mm). In patients with CKD, a significant negative correlation was found between CRP levels and FMD responses (r = -0.315; P < 0.001), while a significant positive correlation was found between CRP and CIMT values (r = 0.327; P < 0.001). Compared with predialysis, hemodialysis subjects had significantly lower FMD and higher CRP and IMT values. CONCLUSION: CKD confers a higher inflammatory status when compared with apparently healthy general population. Abnormal FMD responses and CIMT values are more commonly found in dialysis patients. Our findings suggest that CIMT and FMD can be used as noninvasive markers for early risk assessment and stratification in various stages of CKD.

A weeping ulcer that vanished with a ‘SMILE’

No abstract available.

Yielding of glass under shear: A directed percolation transition precedes shear-band formation.

Under external mechanical loading, glassy materials, ranging from soft matter systems to metallic alloys, often respond via formation of inhomogeneous flow patterns, during yielding. These inhomogeneities can be precursors to catastrophic failure, implying that a better understanding of their underlying mechanisms could lead to the design of smarter materials. Here, extensive molecular dynamics simulations are used to reveal the emergence of heterogeneous dynamics in a binary Lennard-Jones glass, subjected to a constant strain rate. At a critical strain, this system exhibits for all considered strain rates a transition towards the formation of a percolating cluster of mobile regions. We give evidence that this transition belongs to the universality class of directed percolation. Only at low shear rates, the percolating cluster subsequently evolves into a transient (but long-lived) shear band with a diffusive growth of its width. Finally, the steady state with a homogeneous flow pattern is reached. In the steady state, percolation transitions also do occur constantly, albeit over smaller strain intervals, to maintain the stationary plastic flow in the system.

Plasma cell leukemia in North India: retrospective analysis of a distinct clinicohematological entity from a tertiary care center and review of literature

BACKGROUND: Plasma cell leukemia (PCL) is a rare and aggressive plasma cell neoplasm. In PCL, clonal plasma cells comprise ≥20% of the peripheral blood (PB) leukocytes and/or the absolute clonal PB plasma cell count is ≥2×10(9)/L. Primary PCL (PPCL) originates de novo, whereas, secondary PCL (SPCL) evolves from pre-existing multiple myeloma. METHODS: Clinicohematological features, immunophenotypic profile, and survival of PCL patients were analyzed retrospectively. RESULTS: Between January 2007 and December 2014, ten PPCL and four SPCL patients were investigated (8 PPCLs and 3 SPCLs had complete clinical data). All were North Indians, sharing common geography and ethnicity. Our cohort showed less frequent renal failure, more frequent hepatomegaly, and non-secretory type disease. In contrast to western literature, flow cytometric immunophenotyping of our cohort revealed altered expression of CD138 (67%), CD56 (33%), and CD20 (0%). With novel therapeutic agents, these PPCL patients had a median overall survival of 15 months. CONCLUSION: We highlight that our PPCL patients from North India had distinct clinicohematological and immunophenotypic profiles. The significance of our findings must be tested in a larger patient cohort and must be supported by molecular and cytogenetic investigations to unmask possible significant effects on pathogenesis.

The Diagnostic Dilemma of Neurolymphomatosis

Neurolymphomatosis (NL) defined as infiltration of the central nervous system or the peripheral nervous system (PNS) by malignant lymphoma cells is a rare clinical entity. However, the increasing use of fluorodeoxyglucose positron-emission tomography (FDG-PET) and magnetic resonance imaging in evaluating PNS disorders is resulting in; this condition being recognized more frequently. Here; we report five NL patients and review the current literature. We report five patients with non-Hodgkin's lymphoma (NHL) and NL, all of whom were men aged 47-69 years. The clinical presentation varied from symmetrical peripheral neuropathy to mononeuropathy. Peripheral neuropathy was the presenting manifestation of a systemic lymphoma in two patients (40%). Neuroimaging as well as whole-body FDG-PET helped in determining the correct diagnosis in all of the patients. NL is an unusual presentation of NHL resulting from infiltration of the PNS by malignant lymphomatous cells. While evaluating peripheral neuropathy, a high degree of suspicion of NL is required since the presenting symptoms vary, conventional radiology has only modest sensitivity, and a pathological diagnosis is often difficult. FDG-PET helps in the early diagnosis and treatment of this condition.

The Diagnostic Dilemma of Neurolymphomatosis

Neurolymphomatosis (NL) defined as infiltration of the central nervous system or the peripheral nervous system (PNS) by malignant lymphoma cells is a rare clinical entity. However, the increasing use of fluorodeoxyglucose positron-emission tomography (FDG-PET) and magnetic resonance imaging in evaluating PNS disorders is resulting in; this condition being recognized more frequently. Here; we report five NL patients and review the current literature. We report five patients with non-Hodgkin's lymphoma (NHL) and NL, all of whom were men aged 47-69 years. The clinical presentation varied from symmetrical peripheral neuropathy to mononeuropathy. Peripheral neuropathy was the presenting manifestation of a systemic lymphoma in two patients (40%). Neuroimaging as well as whole-body FDG-PET helped in determining the correct diagnosis in all of the patients. NL is an unusual presentation of NHL resulting from infiltration of the PNS by malignant lymphomatous cells. While evaluating peripheral neuropathy, a high degree of suspicion of NL is required since the presenting symptoms vary, conventional radiology has only modest sensitivity, and a pathological diagnosis is often difficult. FDG-PET helps in the early diagnosis and treatment of this condition.