SUMMARY: Brain metastases from an extracranial primary, occur in approximately 15% of cancer patients and this is estimated to be about 400,000 to 600,000 patients annually. The incidence of brain metastases has been on the rise with the availability of more effective systemic therapies and better control of systemic disease. The most frequent malignancies associated with brain metastases include Lung cancer, Breast cancer and Melanoma. Majority of the patients with brain metastases have synchronous extracerebral metastases. A significant number of patients present with solitary or fewer than 3 brain metastases and they may be amenable to focal therapeutic interventions. However, Whole Brain Radiation Therapy (WBRT) has been the standard treatment strategy since the 1950’s. It is also well recognized that WBRT can be associated with neurocognitive dysfunction. Stereotactic RadioSurgery (SRS) is a non-surgical procedure that allows delivery of significantly higher doses of precisely focused radiation to the tumor, compared to conventional radiation therapy, with less collateral damage to the surrounding normal tissue. The technologies used for SRS include GAMMA KNIFE® which uses highly focused gamma rays, Proton Beam therapy which uses ionized hydrogen or Protons, Linear Accelerator and CYBER KNIFE® which use Photons, to target the tumor tissue.
NCCTG N0574 is a federally funded, randomized phase III clinical trial, designed to determine whether cognitive deterioration occurred less frequently with SRS alone compared to SRS followed by WBRT, in patients with 1-3 brain metastases. In this study, 213 patients with 1-3 brain metastases, each measuring less than 3 cm by contrast MRI, were enrolled and randomized to SRS alone or SRS plus WBRT. All patients underwent cognitive testing before and after treatment. Sixty eight percent (68%) of the enrolled patients had a Lung primary and the median age was 60 years. Baseline characteristics were similar in both treatment groups. The median follow up was 7.2 months. The authors used several tools to assess cognitive dysfunction and the primary endpoint was the cognitive decline at 3 months following treatment. It was noted that at 3 months, with the addition of WBRT to SRS, 91.7% of patients experienced cognitive decline compared with 63.5% for those receiving SRS alone (P=0.0007) and there was statistically significant decline in immediate recall, delayed recall and verbal fluency, in the SRS plus WBRT group. Patients who received SRS plus WBRT also reported significantly worse Quality of Life. There was however better intracranial tumor control at 6 and 12 months with SRS plus WBRT compared to SRS alone (P< 0.001), but this local control had no significant impact on the median Overall Survival (OS), with similar OS outcomes noted in both treatment groups (P=0.93). The authors concluded that the addition of WBRT to SRS can result in significant decline in neurocognitive function, without any Overall Survival benefit, compared to SRS alone. It is therefore recommended that patients with newly diagnosed brain metastases amenable to SRS, be closely monitored after SRS, with consideration given to WBRT, at the time of symptomatic progression. NCCTG N0574 (Alliance): A phase III randomized trial of whole brain radiation therapy (WBRT) in addition to radiosurgery (SRS) in patients with 1 to 3 brain metastases. Brown PD, Asher AL, Ballman KV, et al. J Clin Oncol 33, 2015 (suppl; abstr LBA4)
Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system, is an evolutionary mechanism and is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4), also known as CD152, PD-1(Programmed cell Death-1), etc. By doing so, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response. The first Immune checkpoint protein to be clinically targeted was CTLA-4. YERVOY® (Ipilimumab) , an antibody that blocks Immune checkpoint protein/receptor CTLA- 4, has been shown to prolong overall survival in patients with previously treated, unresectable or metastatic melanoma. OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. The U. S. Food and Drug Administration granted approval to OPDIVO®, for the treatment of patients with metastatic Squamous Non-Small Cell Lung Cancer (NSCLC), with progression on or after platinum based chemotherapy. CheckMate 057 is a randomized, international, phase 3 study designed to evaluate the benefit of OPDIVO® for patients with Non-Squamous (NSQ) NSCLC who had progressed after platinum-based doublet chemotherapy. A total of 582 patients were randomized to receive OPDIVO® 3 mg/kg IV every 2 weeks (n=292) or TAXOTERE® 75 mg/m2 IV every 3 weeks (n=290). Eligible patients included those with advanced Non-Squamous NSCLC who had progressed after platinum-based doublet chemotherapy and a Tyrosine Kinase Inhibitor (TKI), if deemed eligible for a TKI. Treatment was continued until disease progression or unacceptable toxicity. The primary clinical endpoint was Overall Survival (OS). Secondary endpoints included Objective Response Rate (ORR), Progression Free Survival (PFS), Efficacy based on PD-L1 expression, Quality of Life, and Safety. The study was stopped earlier than expected following assessment by the independent Data Monitoring Committee (DMC) which concluded that the study met its endpoint, demonstrating superior overall survival, in patients receiving OPDIVO®, compared to the control group. Patients in the OPDIVO®, group had a significantly higher median OS compared to those in the TAXOTERE® group (12.2 months versus 9.4 months, Hazard Ratio [HR] 0.73, P=0.0015). This meant a 27% reduction in the risk of death in the OPDIVO® group and this survival benefit was seen in all predefined subgroup of patients. The Objective Response Rate (ORR) was also significantly higher for patients receiving OPDIVO® compared to TAXOTERE® (19% versus 12%, P=0.0246) and the median duration of response (DOR) was significantly higher for the OPDIVO® group (17.2 months) vs the TAXOTERE® group (5.6 months). More importantly, when tumor PD-L1 expression was correlated with Overall Survival, the median OS for OPDIVO® was 17.2 months, 18.2 months, and 19.4 months for patients with tumors having 1% or higher, 5% or higher, and 10% or higher of cells staining positive for PD-L1, respectively, compared with 9.0 months, 8.1 months, and 8.0 months with TAXOTERE® treatment. Even though this study showed significant survival outcomes for patients expressing any level of PD-L1, the magnitude of benefit was even more so, in patients with tumors expressing higher levels of PD-L1. PD-L1 expression may therefore be a predictor of response, although this should not yet be used for patient selection. Grade 3-5 adverse events occurred more often in the TAXOTERE® group compared to the OPDIVO® group (54% vs 10%). Based on this compelling data, the authors concluded that OPDIVO® significantly improves Overall Survival when compared to TAXOTERE®, in patients with advanced non-Squamous NSCLC, after failure of platinum based doublet therapy. Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC). Paz-Ares L, Horn L, Borghaei H, et al. J Clin Oncol 33, 2015 (suppl; abstr LBA109)</s
By virtue of its dual mechanism of action, it targets and destroys Myeloma cells and also enhances the activation of Natural Killer cells. Previously published phase Ib/II study, has shown encouraging activity, when Elotuzumab was combined with REVLIMID® and Dexamethasone, in patients with Relapsed/Refractory Multiple Myeloma (RRMM). ELOQUENT-2 is an open-label phase III trial in which 646 patients with Relapsed/Refractory Multiple Myeloma were randomized in a 1:1 ratio to receive Elotuzumab in combination with REVLIMID® and Dexamethasone (N=321) or REVLIMID® and Dexamethasone alone (N=325). Enrolled patients had 1–3 prior therapies and were not REVLIMID® refractory. Prior therapies included VELCADE® (Bortezomib), THALOMID® (Thalidomide) and REVLIMID®. Approximately 35% of the enrollees were refractory to the last therapy, 32% had del(17p) and 9% had t(4;14). The median age was 66 years. Elotuzumab was administered at 10 mg/kg IV weekly for the first two cycles and then once every 2 weeks thereafter. REVLIMID® was given at 25 mg orally on days 1 thru 21 of each cycle along with Dexamethasone 40 mg weekly. In the Elotuzumab group, Dexamethasone was dosed at 28 mg orally plus 8 mg IV on the weeks when Elotuzumab was administered. The cycle duration was 28 days. Treatment was administered until disease progression or unacceptable toxicity. Primary endpoints were Progression Free Survival (PFS) and Overall Response Rate (ORR). At a median follow up of 24 months, PFS in the Elotuzumab group was 19.4 months compared to 14.9 months in the REVLIMID®/Dexamethasone alone group (HR=0.70; P=0.0004). The 1-year PFS for the Elotuzumab versus control group was 68% vs 57% respectively and the 2-year PFS was 41% vs 27%. This benefit was seen across all subgroups including those with unfavorable cytogenetics. The ORR was 79% in the Elotuzumab group and 66% in the control group. (P = 0.0002). At the time of this interim analysis, more patients in the Elotuzumab group remained on therapy (35%) compared to the control group (21%) and treatment discontinuation was mainly for disease progression. Grade 3–4 toxicities occurred in 15% or more patients in the Elotuzumab group and included neutropenia and anemia. The authors concluded that Elotuzumab with its novel immunotherapeutic mechanism of action, when added to REVLIMID® and Dexamethasone, reduced the risk of disease progression by 30% in patients with Relapsed/Refractory MultipleMyeloma, and this was accomplished with manageable toxicities. Patients in this study are being followed up for long term outcomes including Overall Survival. Lonial S, Dimopoulos MA, Palumbo A, et al. ELOQUENT-2: A phase III, randomized, open-label study of lenalidomide (Len)/dexamethasone (dex) with/without elotuzumab (Elo) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2015;(suppl; abstr 8508).</s
Morbidity and mortality as well as quality of life related to bone loss among long term survivors after HSCT, has been previously published. Factors contributing to bone loss in this patient population include intensive chemotherapy, total body irradiation, post-transplantation glucocorticoid use, reduced intake and metabolism of Calcium and Vitamin D, graft versus host disease, use of Cyclosporine-A and sedentary lifestyle after transplantation. Loss of Bone Mineral Density (BMD) occurs within 6 to 12 months after transplantation at all skeletal sites, followed by initial recovery of BMD in the lumbar spine and a slower recovery of BMD in the femur neck. This bone loss may persist for 48 to 120 months or even longer. The authors in this single institution, retrospective study, calculated the cumulative incidence rates of fractures among survivors of Autologous and Allogeneic Hematopoietic Stem Cell Transplantations (HSCT) and compared the rate of fractures to that of the general US population. Data was collected from 7,620 patients over 18 years of age who underwent HSCT at The University of Texas MD Anderson Cancer Center, from January 1997 to December 2011 and these patients were observed through December 2013. The authors then calculated the cumulative incidence of fractures, with death as a competing risk and the age and sex-specific fracture incidence rates were compared with those in the US general population, using estimated rates from the 1994 National Health Interview Survey and the 2004 National Hospital Discharge Survey. Of the 7,620 patients who underwent HSCT, 56% were male and 51% underwent Autologous and 49% underwent Allogeneic stem cell transplantation. 
The most common reasons for HSCT were hematologic malignancies other than Multiple Myeloma (67%), Multiple Myeloma (22%) and other solid tumors (11%). The median follow up was 85 months. Fractures occurred in 8% of patients (N = 602) of whom 419 patients had an Autologous stem cell transplantation and 183 patients had Allogeneic stem cell transplantation. The incidence of fracture was higher in patients older than age 50 years, 5 times higher among patients with Multiple Myeloma compared to other hematologic malignancies and patients who underwent Autologous transplantation were 45% more likely to develop a fracture than those who underwent an Allogeneic transplantation. When age- and sex-specific fracture incidence rates after HSCT were compared with National Health Interview Survey data, females were at approximately 8 times greater risk and men 45-64 years old were at approximately 7-9 times greater risk of sustaining a fracture. The authors concluded that the incidence of fractures after HSCT is significantly higher and all patients undergoing HSCT should be considered to be at risk for post-transplantation bone loss. Measures to prevent bone loss and fractures include physical exercise, Vitamin D and Calcium supplementation, avoiding tobacco products, abstaining from excess alcohol intake and fall prevention. The authors recommend that patients undergoing HSCT should have a Dual Energy X-ray Absorptiometry scan performed at baseline and at 6 months following transplantation. Increased Incidence of Fractures in Recipients of Hematopoietic Stem-Cell Transplantation. Pundole XN, Barbo AG, Lin H, et al. J Clin Oncol 2015; 33:1364-1370
The two vaccines studied were GVAX and CRS-207. GVAX is an allogeneic whole cell vaccine developed from Pancreatic Cancer cell lines. These cancer cells are irradiated, to prevent them from dividing and are genetically modified to secrete GM-CSF (Granulocyte Macrophage Colony Stimulating Factor). GM-CSF is important for the growth and activation of dendritic cells also known as Antigen Presenting Cells. This vaccine when injected attracts the dendritic cells to the vaccine injection site and the dendritic cells in turn, pick up the antigens from the vaccine and present them to the patient’s immune system. The immune system then mounts a response by activating tumor specific T-cells. This vaccine therefore theoretically boosts the body’s immune system to fight the patient’s tumor, without causing collateral damage. The second vaccine CRS-207 is live-attenuated (weakened) Listeria monocytogenes bacterium which expresses mesothelin and stimulates innate and adaptive immunity. It is genetically engineered to elicit an immune response against the tumor-associated antigen mesothelin, which has been shown to be expressed at higher levels on Pancreatic Cancer cells than on normal cells. Previous studies have demonstrated that survival can be improved by induction of mesothelin specific T-cell responses. In this study, 90 patients with metastatic Pancreatic Adenocarcinoma were randomly assigned in a 2:1 ratio to receive two doses of GVAX followed by four doses of CRS-207 in Group A and six doses of GVAX alone in the Group B. Treatment was given every 3 weeks and low-dose CYTOXAN® (Cyclophosphamide) was given IV, the day before GVAX in both groups, to inhibit regulatory (suppressive) T-cells. More than 80% of the patients had at least one prior treatment for metastatic disease and 50% had two or more prior treatments. The Primary endpoint was overall survival. Secondary endpoints included safety, clinical and immune responses. At a planned interim analysis, the median Overall Survival (OS) was 6.1 months in Group A patients who had received the combination of two vaccines compared to 3.9 months in Group B patients who received GVAX alone (HR=0.59, P=0.02), resulting in a 41% reduction in risk of death with the combination immunotherapy. The one year survival probability doubled with the dual vaccine with an estimated one year survival of 24% for the combination immunotherapy group (Group A) compared with 12% for the GVAX alone group (Group B). The median OS in an updated analysis of patients who received three total doses which included at least two doses of GVAX and at least one dose of CRS-207 was 9.7 months compared to 4.6 months for those who received three doses of GVAX alone (HR=0.53, P=0.02), a 47% reduction in the risk of death. In the subgroup of patients who had two or more prior chemotherapy regimens, combination immunotherapy given as third line therapy or greater resulted in a median OS of 5.7 months compared to 3.7 months with GVAX alone (HR=0.30, P<0.001), a 70% reduction in risk of death. Stabilization or reduction of tumor marker CA 19-9, was seen in 27% of patients receiving combination immunotherapy compared to 9% in those who received GVAX alone (P=0.08). The median OS in patients with stable or better CA 19-9 response was 10.3 months compared with 4 months in those with CA 19-9 progression (HR=0.43, P=0.02). Toxicities included local reactions after GVAX and transient fevers, chills, and lymphopenia after CRS-207 administration. The authors concluded that immunotherapy with a combination of two vaccines improved Overall Survival with minimal toxicity, for patients with metastatic Pancreatic Carcinoma, who had failed prior therapies. Safety and Survival With GVAX Pancreas Prime and Listeria Monocytogenes–Expressing Mesothelin (CRS-207) Boost Vaccines for Metastatic Pancreatic Cancer. Le DT, Wang-Gillam A, Picozzi V, et al. J Clin Oncol 2015; 33:1325-1333
Classical Hodgkin Lymphoma is a malignancy of primarily B lymphocytes and is characterized by the presence of large mononucleated Hodgkin (H) and giant multinucleated Reed-Sternberg (RS) cells collectively known as Hodgkin and Reed-Sternberg cells (HRS). The HRS cells in turn recruit an abundance of ineffective inflammatory cells and infiltrates of immune cells. Preclinical studies suggest that HRS cells evade immune detection by exploiting the pathways associated with immune checkpoint, Programmed Death-1 (PD-1) and its ligands PD-Ls. The most common genetic abnormality in Nodular sclerosis subtype of Hodgkin lymphoma is the selective amplification of genes on the short arm of chromosome 9 (9p24.1) which includes JAK-2 with resulting increased expression of PD-1 ligands such as PDL1 and PDL2 on HRS cells as well as increased JAK-STAT activity, essential for the proliferation and survival of Hodgkin Reed-Sternberg (HRS) cells. Infection with Epstein–Barr virus (EBV) similarly can increase the expression of PDL1 and PDL2 in EBV-positive Hodgkin's lymphomas. It would therefore seem logical to block/inhibit immune check point PD-1 rather than both its ligands, PDL1 and PDL2. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be to a significant extent related to their ability to escape immune surveillance by inhibiting T lymphocyte activation. The T cells of the immune system therefore play a very important role in modulating the immune system. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system, is an evolutionary mechanism and is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By doing so, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response. 
The authors in this study enrolled 23 patients with relapsed or refractory Hodgkin's lymphoma of whom 87% had received three or more prior therapies. Seventy eight percent (78%) of the patients had previously received ADCETRIS® (Brentuximab) and 78% had undergone autologous stem-cell transplantation. All patients with the exception of one patient had the nodular-sclerosis subtype of Hodgkin's lymphoma. The median age was 35 years. Patients received OPDIVO® (Nivolumab) at a dose of 3 mg/kg every 2 weeks and treatment was continued until patients had a complete response, tumor progression, or severe toxicities. OPDIVO® is an immune checkpoint PD-1 (Programmed cell Death 1) targeted, fully human, immunoglobulin G4 monoclonal antibody. The median number of OPDIVO® doses that patients received was 16 and the median duration of treatment was 36 weeks. The authors noted an Objective Response Rate of 87% with a complete response of 17%, and a partial response of 70%, in this heavily pretreated group of patients. Stable disease was noted in 13% of the patients. The Progression Free Survival at 24 weeks was 86%.Most of the adverse events were grade 1 and grade 2. Analyses of pretreatment tumor specimens revealed increased expression of PDL1 and PDL2. Reed–Sternberg cells showed nuclear positivity of phosphorylated STAT3, suggestive of active JAK-STAT signaling. The authors concluded that OPDIVO® is highly active with favorable toxicities in heavily pretreated relapsed or refractory Hodgkin's lymphoma “highlighting the genetically defined sensitivity to PD-1 blockade”. PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin's Lymphoma. Ansell SM, Lesokhin AM, Borrello I, et al. N Engl J Med 2015; 372:311-319
Approximately 1% – 2% of lung adenocarcinomas harbor ROS1 gene rearrangements. ROS1 gene is located on chromosome 6q22 (long arm of chromosome 6) and plays an important role in cell growth and development. ROS1 gene fusion with another gene results in a mutated DNA sequence which then produces an abnormal protein responsible for unregulated cell growth and cancer. ROS1 gene rearrangement has been identified as a driver mutation in Non Small cell Lung Cancer with adenocarcinoma histology. This is more common in nonsmokers or in light smokers (<10 pack years) who are relatively young (average age of 50 years) and thus share similar characteristics with ALK-positive patients. The ROS protein and the ALK protein have similar structure and function and are sensitive to Tyrosine Kinase Inhibitors such as XALKORI® (Crizotinib) and ZYKADIA® (Ceritinib). ROS1 mutations have been also been associated with Cholangiocarcinoma (Bile duct cancer) and Glioblastoma multiforme. ROS1 rearrangements are mutually exclusive with other oncogenic mutations found in NSCLC such as EGFR mutations, KRAS mutations and ALK rearrangement. The presence of a ROS1 rearrangement can be detected by Fluorescence In Situ Hybridization (FISH), ImmunoHistoChemistry (IHC), Reverse Transcriptase– Polymerase Chain Reaction (RT-PCR) and Next Generation-Sequencing. XALKORI® is a small molecule Tyrosine Kinase Inhibitor that targets ALK, MET and ROS1 tyrosine kinases. In a previously published expansion cohort of the phase 1 study by Shaw and colleagues ( NEJM 2014; 371:1963-1971), XALKORI® showed significant activity in patients with in patients with advanced ROS1rearranged NSCLC. The authors in this publication provided additional evidence that ROS1 gene rearrangement is an actionable target in NSCLC, by conducting a retrospective study in centers that tested for ROS1 rearrangement and evaluated the outcomes of ROS1-positive NSCLC patients, who had been treated with XALKORI®. They included 32 patients with NSCLC whose tumors showed ROS1 rearrangement and who had received off-label treatment with XALKORI®. The median age was 50.5 years. They noted an overall response rate of 80% and a disease control rate, 86.7%. The median Progression Free Survival (PFS) was 9.1 months, and the PFS rate at 12 months was 44%. This impressive efficacy data again validates that similar to EGFR mutations and ALK rearrangements, ROS1 gene rearrangements are molecular drivers and patients with NSCLC with adenocarcinoma histology should be tested for ROS1. Crizotinib Therapy for Advanced Lung Adenocarcinoma and a ROS1 Rearrangement: Results From the EUROS1 Cohort. Mazières J, Zalcman G, Crinò L, J Clin Oncol. 2015;33:992-999
CYRAMZA® (Ramucirumab) is a recombinant human IgG1 monoclonal antibody that binds to Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) and blocks binding of the VEGFR ligands VEGF-A, VEGF-C, and VEGF-D and thus inhibits ligand-induced proliferation and migration of endothelial cells. This is unlike AVASTIN®, which inhibits VEGF-A. Several studies have demonstrated that continuing VEGF inhibition along with standard second-line chemotherapy beyond disease progression has a significant advantage, in patients with mCRC. Two observational studies (BRiTE and ARIES) as well as an open label phase III study have all shown improvement in median Overall Survival (OS) when AVASTIN® was continued beyond first progression and given along with second line chemotherapy. In the VELOUR trial, FOLFIRI in combination with ZALTRAP® (Aflibercept), a VEGF-A, VEGF-B and Placental Growth Factor inhibitor, when given as second line therapy for those patients with mCRC who had progressed on AVASTIN® plus ELOXATIN® containing regimen, resulted in a significant improvement in the median PFS and OS.
When a smoker inhales through the mouth piece of an E-cigarette, the air flow triggers a sensor that switches on a small lithium battery powered heater, which in turn vaporizes liquid nicotine along with PolyEthylene Glycol (PEG) present in a small cartridge. The PEG vapor looks like smoke. The potent liquid form of nicotine extracted from tobacco is tinctured with fragrant flavors such as chocolate, cherry and bubble gum, coloring substances, as well other chemicals and these e-liquids are powerful neurotoxins. With the rapid growth of the E-cigarette industry and the evidence of potential dangers and risk to public health, particularly children, experts from the world's leading lung organizations were compelled to release a position statement on electronic cigarettes, specifically focusing on their potential adverse effects on human health and calling on government organizations to ban or restrict the use of E-cigarettes, until their impact on health is better understood. According to the National Youth Tobacco Survey, the use of e-cigarettes has tripled from 2013 to 2014 among middle school and high school students. Epidemiological data have shown that nicotine use is a gateway to the use of cocaine and marijuana and subsequent lifelong addiction. E-cigarettes and other Electronic Nicotine Delivery Systems (ENDS), unlike combustible cigarettes and many other tobacco products are not currently regulated by the U.S. Food and Drug Administration.