A Community-Based Partnership to Successfully Implement and Maintain a Breast Health Navigation Program.

Breast cancer screening combined with follow-up and treatment reduces breast cancer mortality. However, in the study clinic, only 12 % of eligible women ≥40 years received a mammogram in the previous year. The objective of this project was to implement patient navigation, in our partner health clinic to (1) identify women overdue for a mammogram; and (2) increase mammography utilization in this population over a 2-year period. Women overdue for a mammogram were identified. One patient navigator made navigation attempts over a 2-year period (2009-2011). Navigation included working around systems- and individual-level barriers to receive a mammogram as well as the appropriate follow-up post screening. Women were contacted up to three times to initiate navigation. The proportion of women navigated and who received a mammogram during the study period were compared to women who did not receive a mammogram using Chi square tests for categorical variables and t tests for continuous variables with an α = 0.05. Barriers to previous mammography were also assessed. With 94.8 % of eligible women navigated and 94 % of these women completing mammography, the implementation project reached 89 % of the target population. This project was a successful implementation of an evidence-based patient navigation program that continues to provide significant impact in a high-need area. Cost was the most commonly cite barrier to mammography. Increasing awareness of resources in the community for mammography and follow-up care remains a necessary adjunct to removing structural and financial barriers to accessing preventive services.

Blinatumomab: first global approval.

Blinatumomab (BLINCYTO™) is a novel, bispecific T-cell engaging antibody that binds cluster of differentiation (CD) 19 antigens on blast cells while also binding and activating the CD3/T cell receptor complex, causing cell lysis. The antibody is being developed by Amgen as a treatment for haematological cancers that originate from B cell lines. Blinatumomab was approved by the US FDA in December 2014 for the treatment of adults with Philadelphia chromosome (Ph)-negative relapsed/refractory B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). It is awaiting approval for this indication in the EU and is in phase III development in various countries. This article summarizes the milestones in the development of blinatumomab leading to its first approval for the treatment of Ph-negative BCP-ALL.

Dulaglutide: first global approval.

Dulaglutide (Trulicity™) is a long-acting, glucagon-like peptide-1 (GLP-1) receptor agonist that has been developed by Eli Lilly and Company for the treatment of type 2 diabetes mellitus. It consists of a dipeptidyl peptidase-IV-protected GLP-1 analogue covalently linked to a human IgG4-Fc heavy chain by a small peptide linker. The subcutaneous formulation is approved for use in type 2 diabetes in the US, has been recommended for approval in the EU in this indication, and is under regulatory review in other countries. This article summarizes the milestones in the development of subcutaneous dulaglutide leading to this first approval for type 2 diabetes.

Subcutaneous trastuzumab: a review of its use in HER2-positive breast cancer.

Trastuzumab (Herceptin®) is a humanized IgG1 monoclonal antibody that is an efficacious treatment for HER2-positive breast and gastric cancers. Subcutaneous trastuzumab is a new formulation approved in the European Union for use in patients with early or metastatic breast cancer. In the randomized, open-label, multinational HannaH (enHANced treatment with NeoAdjuvant Herceptin) study of neoadjuvant/adjuvant trastuzumab in patients with early HER2-positive breast cancer, the pharmacokinetics of neoadjuvant subcutaneous trastuzumab were similar to those after intravenous administration, meeting the noninferiority criterion for mean predose trough concentrations, as assessed prior to surgery (primary pharmacokinetic endpoint). Trastuzumab blood concentrations throughout the dosing interval remained above those considered necessary for anticancer activity. In this study, the pathologic complete response rates (primary efficacy endpoint) were 45.4 and 40.7 % in the subcutaneous and intravenous administration groups, respectively, meeting a study noninferiority criterion. In the randomized, open-label, crossover, multinational PrefHer study of neoadjuvant/adjuvant or adjuvant trastuzumab in early HER2-positive breast cancer, subcutaneous administration of trastuzumab was preferred over intravenous administration by >85 % of patients, most commonly because it was time saving and induced less pain and discomfort. In the HannaH study, the tolerability profile of subcutaneous trastuzumab was similar to that of intravenous trastuzumab, except that the rate of serious adverse events was 21 % (vs. 12 % with intravenous administration), partly because of more infections with subcutaneous administration. Whether this finding is of any clinical significance should emerge from ongoing studies. On the evidence, subcutaneous trastuzumab is an effective and generally well-tolerated treatment option that is preferred by patients over intravenous administration.

Ibrutinib: first global approval.

Ibrutinib (Imbruvica™) is a small molecule, first-in-class, once-daily, orally available, Bruton's tyrosine kinase inhibitor that is under development for the treatment of B cell malignancies, including chronic lymphocytic leukaemia (CLL), mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL), as well as multiple myeloma (MM), follicular lymphoma (FL) and Waldenstrom's macroglobulinemia (WM). It has been developed by Pharmacyclics, Inc. and Janssen Biotech, Inc. Ibrutinib acts by blocking B-cell antigen receptor signalling, thereby reducing malignant proliferation of B cells and inducing cell death. Based chiefly on findings from a phase Ib/II study, ibrutinib has been approved in the USA for the treatment of MCL in previously treated patients and is one of the first approvals through the US FDA's Breakthrough Therapy Designation Pathway. An application has been filed in the EU seeking regulatory approval in this indication. In both the USA and EU, further applications have been filed with regulatory bodies seeking approval for the use of ibrutinib in patients with previously treated CLL/small lymphocytic lymphoma (SLL). Phase III trials are underway worldwide to evaluate ibrutinib in the treatment of patients with CLL/SLL, DLBCL and MCL, and the agent is in phase II development for use in WM, FL and MM. This article summarizes the milestones in the development of ibrutinib leading to its first approval in MCL.

A method for achieving reciprocity of funding in community-based participatory research.

BACKGROUND: The St. Louis Komen Project was conceived to address disparities in breast cancer treatment and outcomes between African-American and White women in St. Louis, Missouri. Our goal was to apportion tasks and funding through a process to which all researcher partners had input and to which all could agree, thus eliminating institutionalized inequalities. METHODS: This paper describes the collaborative process and resulting division of responsibilities, determination of costs, and ultimate allocation of funds and resources, as well as the documentation employed to achieve funding reciprocity and equal accountability. RESULTS: Both communication and documentation are critical. Although the Memoranda of Understanding employed are not a panacea, they codify roles and expectations and promote trust. The process of developing financial transparency set the tone for subsequent steps in the research process. CONCLUSIONS: The exhaustive planning process and project-specific procedures developed by its partners have helped the project foster reciprocity, facilitate participation, and equitably distribute resources.

Enzalutamide: a review of its use in metastatic, castration-resistant prostate cancer.

Enzalutamide (MDV3100, XTANDI(®)) is an androgen receptor inhibitor that is indicated for the treatment of metastatic, castration-resistant, prostate cancer (mCRPC) that has progressed despite treatment with docetaxel. This article reviews the pharmacology, efficacy and tolerability of enzalutamide relevant to this indication. In a randomized, double-blind, placebo-controlled, multinational, phase III trial in patients with mCRPC progressing after docetaxel therapy, enzalutamide significantly prolonged overall survival (OS), delayed prostate specific antigen progression and prolonged radiographic progression-free survival and time to the first skeletal event. The median OS was 18.4 months in the enzalutamide group and 13.6 months in the placebo group, which represents a 37 % reduction in the mortality risk in the enzalutamide group. Enzalutamide was also associated with significant benefits in health-related quality of life and in pain palliation. Enzalutamide was generally as well tolerated as placebo during the trial, with most adverse events at a mild or moderate level of severity. Enzalutamide carries a small increased risk of seizures that appears to be dose-dependent. Enzalutamide is an efficacious and well tolerated treatment for this severe, rapidly progressive disease.

Intrathecal ziconotide: a review of its use in patients with chronic pain refractory to other systemic or intrathecal analgesics.

Ziconotide (Prialt(®)) is a synthetic conopeptide analgesic that acts by selectively antagonizing N-type voltage-gated calcium channels. Intrathecal ziconotide is the only non-opioid intrathecal analgesic that is FDA-approved for use in patients with treatment-refractory, chronic pain. The efficacy of intrathecal ziconotide was demonstrated in randomized, double-blind, placebo-controlled trials in patients with treatment-refractory noncancer-related pain or cancer- or AIDS-related pain. Across trials, ziconotide recipients had significantly greater reductions in pain intensity during ziconotide treatment than those receiving placebo (primary endpoint). At the end of the titration period, approximately one-sixth to one-third of patients with noncancer chronic pain and one-half with cancer- or AIDS-related pain who received ziconotide reached a pain response threshold (≥30 % reduction in the pain intensity score). In ziconotide responders, analgesic effects were enduring, with some patients continuing treatment over extended periods. Across trials, the chief tolerability concerns in ziconotide recipients during the titration phase and during extended treatment were related to CNS adverse events. These were mostly of mild to moderate intensity, although serious adverse events were commonly attributed to ziconotide treatment, especially in trials with rapid ziconotide titration and that permitted higher dosages. In general, clinically important non-CNS adverse events were infrequent, and during the ziconotide titration phase, relatively few patients discontinued treatment because of adverse events. Ongoing research will assess various strategies for selecting patients for ziconotide treatment and for enhancing its efficacy and tolerability. At the present time, intrathecal ziconotide provides a treatment option for patients with severe, unremitting pain who have failed to respond to other intensive analgesic regimens.

Trastuzumab: a review of its use in HER2-positive advanced gastric cancer.

Trastuzumab (Herceptin(®)) is a humanized monoclonal antibody that binds selectively to human epidermal growth factor 2 (HER2), interfering with its downstream cancer-promoting effects. This article focuses on the efficacy and tolerability of trastuzumab in HER2-positive advanced gastric cancer. The potential of trastuzumab as a cytotoxic for use in gastric cancer was confirmed by in vitro studies in HER2-positive gastric cancer cell lines and gastric cancer xenograft models. In a randomized, controlled, open-label, multinational trial in patients with HER2-positive advanced gastric cancer, trastuzumab plus chemotherapy (cisplatin plus capecitabine or 5-fluorouracil) was significantly more efficacious than chemotherapy alone, in terms of a longer median overall survival (13.8 vs. 11.1 months in the chemotherapy alone group) [primary endpoint], a longer median progression-free survival, and a higher response rate. Trastuzumab was efficacious across patient subgroups, although stronger effects were observed in a subgroup with high HER2 overexpression (immunohistochemistry 2+/fluorescence in-situ hybridization positive or immunohistochemistry 3+). There was a slightly higher tolerability burden in the trastuzumab plus chemotherapy group than with chemotherapy alone, based on small between-group numerical differences in rates of common gastrointestinal and general adverse events. Most individual adverse events reported in this trial were at a grade 1 or 2 level of severity. However, in both treatment groups approximately half of the haematological adverse were at a grade 3 or 4 level of severity, with no marked between-group differences. Trastuzumab in combination with cisplatin and a fluoropyrimidine is an effective regimen for patients with HER2-positive advanced gastric cancer, has acceptable tolerability and represents an important advance in the treatment of gastric cancer.

Fluocinolone acetonide intravitreal implant (Iluvien®): in diabetic macular oedema.

Fluocinolone acetonide intravitreal implant (Iluvien®) is an injectable, non-erodible, corticosteroid implant that is approved in several European countries for the treatment of chronic diabetic macular oedema (DMO). In analyses of two multinational trials in patients with DMO previously treated with macular laser photocoagulation, fluocinolone acetonide intravitreal implant 0.2 µg/day was significantly more efficacious than sham injection in improving visual acuity. At 24 months post injection, 29 % of fluocinolone acetonide intravitreal implant 0.2 µg/day recipients had an improvement in the best-corrected visual acuity (BCVA) letter score of ≥15 compared with 16 % in the sham injection group (p = 0.002) [primary endpoint]. Treatment benefit was most evident in the subgroup of patients whose duration of DMO was ≥3 years. In this subgroup at 36 months, 34 % of fluocinolone acetonide intravitreal implant 0.2 µg/day recipients had an increase in the BCVA score of ≥15, compared with 13 % of sham injection recipients (p < 0.001). Fluocinolone acetonide intravitreal implant recipients also had generally greater benefits than sham injection recipients on secondary endpoints. In patients who were phakic in the study eye at baseline, cataracts occurred in 82 % of fluocinolone acetonide intravitreal implant 0.2 µg/day recipients and 51 % of sham injection recipients. Overall, 37 % and 12 % of patients in the fluocinolone acetonide intravitreal implant and sham injection groups developed raised intraocular pressure (IOP), which was generally controlled with IOP-lowering drugs.

Ipilimumab: a guide to its use in advanced melanoma.

Ipilimumab (Yervoy™), a recombinant monoclonal antibody targeted at cytotoxic T-lymphocyte-associated antigen 4, is approved for the treatment of advanced melanoma. In a placebo-controlled trial in previously treated patients with advanced melanoma, ipilimumab, without or with an investigational glycoprotein (gp) 100 peptide vaccine, was associated with significantly longer median overall survival than gp100 peptide vaccine monotherapy. The risk of death relative to the gp100 peptide vaccine was reduced by 34% with ipilimumab monotherapy and by 32% with ipilimumab plus gp100 peptide vaccine. Overall survival did not differ significantly between treatment with ipilimumab monotherapy and ipilimumab plus gp100 peptide vaccine. Novel immune-related events that are not typical of other anticancer agents, most commonly dermatologic and gastrointestinal disorders, can occur with ipilimumab, necessitating specific monitoring and management protocols.

Ipilimumab: in previously treated patients with advanced melanoma.

Ipilimumab is a recombinant, fully human, monoclonal antibody targeted at cytotoxic T-lymphocyte-associated antigen 4 that is available for the treatment of advanced melanoma. This review focuses on the efficacy and tolerability of ipilimumab in advanced melanoma and provides an overview of its pharmacology. In a randomized, double-blind, multinational, phase III trial in previously treated patients with advanced melanoma, median overall survival (OS) was significantly longer with ipilimumab 3 mg/kg plus glycoprotein (gp) 100 peptide vaccine or ipilimumab plus placebo than with gp100 peptide vaccine plus placebo (10.0 and 10.1 vs 6.4 months). Hazard ratios for death were 0.68 (p < 0.001) with ipilimumab plus gp100 peptide vaccine versus gp100 peptide vaccine plus placebo and 0.66 (p = 0.003) for ipilimumab plus placebo versus gp100 peptide vaccine plus placebo, with corresponding 32% and 34% relative reductions in the risk of death. There was no significant difference in OS between patients receiving ipilimumab plus gp100 peptide vaccine and those receiving ipilimumab plus placebo. Novel immune-related events that are not typical of other anticancer agents, most commonly dermatologic and gastrointestinal disorders, can occur with ipilimumab, necessitating specific monitoring and management protocols. In the phase III trial, grade 3/4 immune-related adverse events occurred in 10-15% of ipilimumab 3 mg/kg recipients versus 3% of gp100 peptide vaccine plus placebo recipients. In all, 2.1% of patients died as a result of treatment-related adverse events, with half of the deaths attributed to immune-related adverse events.

Imatinib: as adjuvant therapy for gastrointestinal stromal tumour.

Imatinib is a protein-tyrosine kinase inhibitor with antitumour effects in patients with gastrointestinal stromal tumour (GIST) that is indicated for the treatment of unresectable and/or metastatic GIST and as adjuvant therapy in patients with KIT-positive GIST. Imatinib binds to and inhibits KIT and platelet-derived growth factor receptor (PDGFR)-α tyrosine kinases, interfering with their downstream tumourogenic processes. Cell lines with KIT mutations that are common in patients with GIST were sensitive to imatinib at low in vitro concentrations. Patients with exon 11 KIT mutations were significantly more likely to have partial tumour responses and longer overall survival (OS) and were significantly less likely to have progression of disease than patients with exon 9 KIT mutations or no detectable KIT or PDGFR mutations. In a large (n > 700) randomized, double-blind, placebo-controlled, multinational trial (ACOSOG [American College of Surgeons Oncology Group] Z9001), patients who received 1 year of adjuvant treatment with oral imatinib 400 mg/day after surgical resection of GIST had significantly longer recurrence-free survival than placebo recipients, with an overall hazard ratio of 0.35 (95% CI 0.22, 0.53) [primary endpoint]. At the time of reporting, there was no significant between-group difference in OS. In patients with GIST who received adjuvant imatinib in this trial, adverse events were mostly of mild or moderate severity; the imatinib treatment group had an almost 2-fold higher rate of US National Cancer Institute Common Toxicity Criteria grade 3 or 4 adverse events than the placebo group.

Pazopanib: in advanced renal cell carcinoma.

Pazopanib is an orally administered, multi-tyrosine kinase inhibitor that interrupts tumor growth in renal cell carcinoma. In a randomized, double-blind, placebo-controlled, multinational trial in patients with locally advanced or metastatic renal cell carcinoma, the median progression-free survival (PFS) of patients who were treated with pazopanib 800 mg once daily was significantly longer than that of placebo recipients (9.2 vs 4.2 months; hazard ratio 0.46 [95% CI 0.34, 0.62]). In prespecified analyses in treatment-naive and cytokine-pretreated patients, grouped according to prior treatment history, age, sex, Memorial Sloan-Kettering Cancer Center risk category, and Eastern Cooperative Oncology Group performance status, median PFS was significantly longer in pazopanib than placebo recipients in all subgroups. Pazopanib recipients also had a significantly higher overall response rate than placebo recipients; in pazopanib recipients, the median time to response was 11.9 weeks and the median duration of response was 58.7 weeks. Oral pazopanib had an acceptable tolerability profile in patients with advanced renal cell carcinoma. Adverse events were common in pazopanib and placebo recipients and were mostly of mild to moderate severity.

Ofatumumab.

Ofatumumab is a fully human anti-CD20 monoclonal antibody that induces antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity in CD20-expressing B lymphocytes. Ofatumumab is highly potent in lysing B cells, and this appears to stem from its binding site on the short extracellular loop of the target CD20 protein and its slow release from the target molecule. In a pivotal, noncomparative study in patients with fludarabine- and alemtuzumab-refractory chronic lymphocytic leukaemia (CLL), ofatumumab induced objective responses in 58% (99% CI 40, 74) of patients, which met a prespecified superiority criterion. The median duration of response was 7.1 months. The median progression-free survival was 5.7 months and the median overall survival was 13.7 months. In patients with fludarabine- and alemtuzumab-refractory CLL, infections and neutropenia were the most frequent treatment-related adverse events (all grades) that occurred during ofatumumab treatment; infections that commenced during treatment led to death in five patients (8%).

Gefitinib: a review of its use in the treatment of locally advanced/metastatic non-small cell lung cancer.

Gefitinib (Iressa) is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that offers treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), in particular in those who are harbouring EGFR mutations. In a large phase III trial (IPASS) in chemotherapy-naive Asian patients with adenocarcinoma who were never smokers or former light smokers, oral gefitinib was more effective than carboplatin plus paclitaxel in prolonging progression-free survival (PFS). In a prespecified subgroup analysis, EGFR-mutation-positive status was associated with a positive response to gefitinib treatment. Furthermore, a trial in chemotherapy-naive patients with NSCLC that was restricted to those with EGFR mutations found that gefitinib recipients had significantly longer PFS than carboplatin plus paclitaxel recipients. In large phase III trials (INTEREST, V-15-32) in unselected, previously treated patients, the overall survival (OS) in gefitinib recipients was noninferior to, or not significantly different from, that of docetaxel recipients. In a placebo-controlled trial in previously treated patients (ISEL), pre-planned subgroup analyses in Asian patients and non-smokers showed that in these subgroups gefitinib prolonged OS, and that EGFR biomarkers predicted a positive response to gefitinib. Gefitinib was also associated with greater improvements in quality of life (QOL) in both chemotherapy-naive and previously treated patients. A head-to-head trial of gefitinib versus erlotinib in EGFR-mutation-positive patients would help position gefitinib relative to erlotinib in this population. Further research is also required to identify factors associated with non-response to EGFR-tyrosine-kinase inhibitors in EGFR-mutation-positive patients. Gefitinib was a generally well tolerated treatment, with rash and diarrhoea being the most common treatment-emergent adverse events. Interstitial lung disease (ILD) is a serious co-morbidity of NSCLC associated with gefitinib and other cancer treatments; ILD-type events occurred with an overall incidence of approximately 1% in gefitinib recipients participating in clinical trials, and were more common in Asian patients. Notably, gefitinib was associated with significantly fewer haematological and neurological adverse effects than comparator chemotherapy regimens. Gefitinib as monotherapy is an effective treatment for patients with locally advanced or metastatic NSCLC with EGFR mutations.

Dabigatran etexilate.

Dabigatran etexilate is an orally administered prodrug of dabigatran, which is a potent, concentration-dependent inhibitor of thrombus formation and thrombin-induced platelet aggregation. Dabigatran etexilate pharmacokinetics were linear across a wide dosage range. There were no clinically important pharmacokinetic interactions with digoxin (a P-glycoprotein substrate), pantoprazole (a proton-pump inhibitor) or drugs that are substrates and/or inhibitors of hepatic cytochrome P450 enzymes. In two large, randomized, double-blind trials of the prevention of venous thromboembolism (VTE) in patients undergoing total hip or total knee replacement surgery, orally administered dabigatran etexilate 220 mg/day was noninferior to subcutaneous enoxaparin sodium 40 mg/day for the primary composite endpoint of total VTE events or all-cause mortality during the treatment period. There were no significant differences between dabigatran etexilate and enoxaparin sodium in major VTE events and VTE-related mortality. Across trials, < or =0.5% of patients experienced a symptomatic pulmonary embolus or died. Dabigatran etexilate was generally well tolerated. In patients undergoing total hip or total knee replacement surgery, there was no significant difference between dabigatran etexilate and enoxaparin sodium recipients in the incidence of major or minor bleeding.

Anastrozole: a review of its use in postmenopausal women with early-stage breast cancer.

Anastrozole (Arimidex) is an aromatase inhibitor approved in the EU, the US and in other countries worldwide for use as an adjuvant treatment in postmenopausal women with early-stage, hormone receptor-positive breast cancer. It is also approved in the EU and other countries worldwide for continuing adjuvant treatment in women who have already had 2-3 years of adjuvant tamoxifen treatment for breast cancer. Anastrozole is an effective primary adjuvant treatment for postmenopausal women with early-stage breast cancer. In patients with hormone receptor-positive tumours, 5 years of anastrozole treatment was more efficacious in reducing breast cancer recurrence than 5 years of tamoxifen, both in a head-to-head comparison and in switching trials when given after 2-3 years of tamoxifen treatment. The treatment benefits have now been shown to extend to 100 months following breast surgery. To date, overall survival was better in anastrozole than tamoxifen recipients in one switching trial and in a meta-analysis of three switching trials. There was no increased benefit in health-related quality of life with anastrozole over tamoxifen. In women who had received 5 years of tamoxifen treatment, continuation of treatment with anastrozole further reduced the risk of breast cancer recurrence. Ongoing head-to-head trials against other third-generation aromatase inhibitors will provide data as to its relative efficacy against these agents. Anastrozole is a generally well tolerated treatment for early-stage breast cancer. Like other aromatase inhibitors, its most important adverse effect was an increased risk of bone fractures, which for anastrozole was restricted to the treatment period. It is still unclear whether primary adjuvant treatment extended beyond 5 years is of benefit and whether primary adjuvant treatment with anastrozole for 5 years is preferable to switching to anastrozole after 2-3 years of tamoxifen treatment. However, the evidence to date establishes anastrozole as a valuable adjuvant and extended adjuvant treatment for postmenopausal women with hormone receptor-positive, early-stage breast cancer.

Nelarabine.

Nelarabine is an anticancer prodrug of arabinofuranosylguanine (ara-G), which is metabolized in cells to the cytotoxic metabolite ara-G triphosphate (ara-GTP). Ara-GTP competes with deoxyguanosine triphosphate for incorporation into DNA. Once incorporated, it inhibits DNA synthesis and leads to high molecular weight DNA fragmentation and cell death. In paediatric and adult patients with T-cell acute lymphoblastic leukaemia or T-cell lymphoblastic lymphoma, nelarabine induced a complete response, with or without complete haematological recovery, in approximately one-fifth of patients who had not responded to, or had relapsed following treatment with, two or more prior chemotherapy regimens. The median overall survival time was 13.1 and 20.6 weeks in paediatric and adult patients, with corresponding 1-year survival rates of 14% and 29%. Treatment-emergent adverse events were common, but non-haematological events were mostly of mild or moderate severity. Neurological events, which may be severe and irreversible, were the most likely adverse events to limit treatment.