***TASK*** the task is to summarize an input biomedical literature in six sentences 
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    Input: BACKGROUND Cushing 's disease is a rare debilitating endocrine disorder for which few prospect i ve interventional studies have been done . We report results of the first phase 3 trial assessing long-acting intramuscular pasireotide in patients with Cushing 's disease . METHODS In this phase 3 clinical trial we recruited patients aged 18 years or older with persistent , recurrent , or de-novo ( non-surgical c and i date s ) Cushing 's disease who had a mean urinary free cortisol ( mUFC ) concentration ( from three 24 h sample s ) of 1·5 - 5·0 times the upper limit of normal ( ULN ) , a normal or greater than normal morning plasma adrenocorticotropic hormone concentration , and a pituitary source of Cushing 's syndrome , from 57 sites across 19 countries . Exclusion criteria included previous pasireotide treatment , mitotane therapy within 6 months , and pituitary irradiation within 10 years . We r and omly allocated patients 1:1 ( block size of four ) using an interactive-response-technology system to intramuscular pasireotide 10 mg or 30 mg every 4 weeks for 12 months ( in the core phase ) . We stratified r and omisation by screening mUFC concentration ( 1·5 to < 2·0 × ULN and 2·0 - 5·0 × ULN ) . The dose could be uptitrated ( from 10 mg to 30 mg or from 30 mg to 40 mg ) at month 4 if the mUFC concentration was greater than 1·5 × ULN , and at month 7 , month 9 , or month 12 if the mUFC concentration was greater than 1·0 × ULN . Investigators , patients , site personnel , and those assessing outcomes were masked to dose group allocation . The primary endpoint was the proportion of patients in each group with an mUFC concentration of less than or equal to the ULN at month 7 . Efficacy analyses were based on intention to treat . This trial is registered with Clinical Trials.gov , number NCT01374906 . FINDINGS Between Dec 28 , 2011 , and Dec 9 , 2014 , we r and omly allocated 150 patients to  receive pasireotide 10 mg ( 74 [ 49 % ] patients ) or 30 mg ( 76 [ 51 % ] patients ) . The primary efficacy endpoint was met by 31 ( 41·9 % [ 95 % CI 30·5 - 53·9 ] ) of 74 patients in the 10 mg group and 31 ( 40·8 % [ 29·7 - 52·7 ] ) of 76 in the 30 mg group . The most common adverse events were hyperglycaemia ( 36 [ 49 % ] in the 10 mg group and 36 [ 47 % ] in the 30 mg group ) , diarrhoea ( 26 [ 35 % ] and 33 [ 43 % ] ) , cholelithiasis ( 15 [ 20 % ] and 34 [ 45 % ] ) , diabetes mellitus ( 14 [ 19 % ] and 18 [ 24 % ] ) , and nausea ( 15 [ 20 % ] and 16 [ 21 % ] ) . Serious adverse events suspected to be study drug related were reported in eight ( 11 % ) patients in the 10 mg group and four ( 5 % ) in the 30 mg group . Two ( 3 % ) patients in the 30 mg group died during the study ( pulmonary artery thrombosis and cardiorespiratory failure ) ; neither death was judged to be related to the study drug . INTERPRETATION Long-acting pasireotide normalised mUFC concentration in about 40 % of patients with Cushing 's disease at month 7 and had a similar safety profile to that of twice-daily subcutaneous pasireotide . Long-acting pasireotide is an efficacious treatment option for some patients with Cushing 's disease who have persistent or recurrent disease after initial surgery or are not surgical c and i date s , and provides a convenient monthly administration schedule . FUNDING Novartis Pharma AG BACKGROUND Cabergoline is a long-acting dopamine receptor agonist used to treat prolactinomas . Identification of D(2 ) receptors in corticotroph tumors led to clinical trials of cabergoline therapy in limited cases of Nelson 's syndrome , ectopic ACTH-secreting tumors , and recently Cushing 's disease ( CD ) . OBJECTIVE To evaluate the long-term efficacy of cabergoline monotherapy in patients with CD . METHODS Retrospective analysis of non-r and omized clinical therapy with cabergoline in 30 patients with CD treated in academic centers of Buenos Aires and Montreal .  Cabergoline was initiated at 0.5 - 1.0 mg/week and adjusted up to a maximal dose of 6 mg/week based on urinary free cortisol ( UFC ) levels . Complete response to cabergoline was defined as a sustained normalization of UFC with at least two normal values measured at 1 - 3 months interval ; partial response was defined as a decrease of UFC to < 125 % of the upper limit of normal , and treatment failure as UFC ≥ 125 % of it . RESULTS Within 3 - 6 months , complete response was achieved in 11 patients ( 36.6 % ) and partial response in 4 patients ( 13.3 % ) . After long-term therapy , nine patients ( 30 % ) remain with a complete response after a mean of 37 months ( range from 12 to 60 months ) with a mean dose of 2.1 mg/week of cabergoline . Two patients escaped after 2 and 5 years of complete response , but one patient transiently renormalized UFC after an increase in cabergoline dosage . No long-term response was maintained in four initial partial responders . CONCLUSIONS Cabergoline monotherapy can provide an effective long-term medical therapy for selected patients with CD , but requires close follow-up for dose adjustments Cushing 's syndrome ( CS ) is a serious condition requiring drug management in diverse clinical setting s. Fifty four patients ( 44 females , 10 males ) with CS , aged 14 - 63 , received  ketoconazole ( KTZ ) prior to surgery ( n= 27 ) , as complementary therapy after surgery and /or radiotherapy ( n= 16 ) , or as primary treatment ( n= 11 ) . It was given at a 600 ( 500 - 600 ) mg/day ( median - Cl195 ) maintenance dose for periods ranging from 15 days to 13 years . Clinical signs , hepatic enzymes and urinary free cortisol ( UFC ) were evaluated before and during KTZ treatment . UFC normalised or decreased to subnormal values in 85 % of the patients , in 5 to 150 days after starting treatment ; although failing to normalise , UFC decreased to 12 - 48 % of pre-treatment values in the remaining patients . Clinical signs improved throughout . Side effects were adrenal insufficiency ( 18.5 % ) , reversible hepatic toxicity ( 11 % ) , allergic skin rash ( 5.5 % ) and gastric intolerance ( 3.7 % ) ; in 11 % of patients , an " escape phenomenon " was observed . Twenty-four out of the total ( 44.4 % ) were treated for prolonged periods , from one up to 13 years . In conclusion , this study confirms that KTZ is an effective and generally well tolerated treatment for CS particularly : a ) shortly before surgery , b ) because of persistent hypercortisolism after surgery or awaiting the results of radiotherapy , c ) as a reasonable option in patients with CS of unknown aetiology and , d ) as long-term therapy in any case of unsolved hypercortisolism after failure of current treatments CONTEXT AND OBJECTIVE The role of cabergoline in Cushing 's disease ( CD ) remains controversial . The experience is limited to case reports and few open studies that report the effects determined after ≥1 month of treatment . In prolactinomas and dopamine-responsive GH-secreting tumours , effects of cabergoline are seen within days or weeks . Here , we search ed for short-term effects of cabergoline in CD . DESIGN Twenty patients ( 19 naïve and one recurrent ) were included in a prospect i ve study . Cabergoline was administered in increasing doses of 0.5 - 5 mg/week over 6 weeks . METHODS Urinary free cortisol ( UFC ) 24 h , morning cortisol and ACTH , and salivary cortisol at 0800 , 1600 and 2300 h were determined once weekly throughout . Diurnal curves ( six sample s ) of serum cortisol were measured at start and end . RESULTS At study end , the median cabergoline dose was 5 mg , range 2.5 - 5 mg/week . The prolactin levels , markers of compliance , were suppressed in all patients . During the treatment , hypercortisolism varied , gradual and dose-dependent reductions were not seen . Five patients had a > 50 % decrease of UFC , three had a > 50 % rise of UFC . Salivary cortisol at 2300 h showed a congruent > 50 % change with UFC in two of the five cases with decreased UFC , and in one of the three cases with increased UFC . One patient with decreases in both UFC and 2300 h salivary cortisol also had a reduction in diurnal serum cortisol during the course of the study . CONCLUSIONS Cabergoline seems to be of little value in the management of CD . Only one patient had a response-like pattern . Given the known variability of disease activity in CD , this might represent a chance finding Cushing ’s disease ( CD ) is associated with increased morbidity and mortality . Until now , no medical treatment has been shown to be totally satisfactory when administrated alone . This study aim ed to assess the effectiveness of cabergoline with added ketoconazole and of the same combination in reverse , using urinary free cortisol ( UFC ) and late night salivary cortisol ( LNSC ) levels as biochemical markers of the treatments ’ efficacy in CD patients . A prospect i ve analysis conducted on 14 patients ( f/m = 12/2 ; median age 52 , range 33–70 years ) divided into two groups : 6 patients initially treated with cabergoline for 4–6 months ( rising from 0.5–1 mg/week up to 3.0 mg/week ) , after which ketoconazole was added ( group A ) ; and 8 patients first took ketoconazole alone for 4–6 months ( rising from 200 mg/day to 600 mg/day ) , then cabergoline was added ( group B ) . Patients were compared with 14 age-matched patients in prolonged remission after effective neurosurgery for CD . The combination therapy led to UFC normalization in 79 % of patients with no differences between the groups ; only one patient failed to respond at all . Neither drug succeeded in controlling the disease when taken alone . LNSC dropped when compared to baseline levels , but not to a significant degree ( p = 0.06 ) , and it remained significantly higher than in controls ( p = 0.0006 ) . Associating cabergoline with ketoconazole may represent an effective second-line treatment , achieving a satisfactory reduction in UFC levels and clinical improvement . Although the combined treatment lowered patients ’ LNSC levels , they remained higher than normal , indicating a persistent sub clinical hypercortisolism ; the implication s of this condition need to be considered . No differences emerged between the two treatment schedules BACKGROUND Cushing 's disease is associated with high morbidity and mortality . Pasireotide , a potential therapy , has a unique , broad somatostatin-receptor-binding profile , with high binding affinity for somatostatin-receptor subtype 5 . METHODS In this double-blind , phase 3 study , we r and omly assigned 162 adults with Cushing 's disease and a urinary free cortisol level of at least 1.5 times the upper limit of the normal range to receive subcutaneous pasireotide at a dose of 600 μg ( 82 patients ) or 900 μg ( 80 patients ) twice daily . Patients with urinary free cortisol not exceeding 2 times the upper limit of the normal range and not exceeding the baseline level at month 3 continued to receive their r and omly assigned dose ; all others received an additional 300 μg twice daily . The primary end point was a urinary free cortisol level at or below the upper limit of the normal range at month 6 without an increased dose . Open-label treatment continued through month 12 . RESULTS Twelve of the 82 patients in the 600-μg group and 21 of the 80 patients in the 900-μg group met the primary end point . The median urinary free cortisol level decreased by approximately 50 % by month 2 and remained stable in both groups . A normal urinary free cortisol level was achieved more frequently in patients with baseline levels not exceeding 5 times the upper limit of the normal range than in patients with higher baseline levels . Serum and salivary cortisol and plasma corticotropin levels decreased , and clinical signs and symptoms of Cushing 's disease diminished . Pasireotide was associated with hyperglycemia-related adverse events in 118 of 162 patients ; other adverse events were similar to those associated with other somatostatin analogues . Despite declines in cortisol levels , blood glucose and glycated hemoglobin levels increased soon after treatment initiation and then stabilized ; treatment with a glucose-lowering medication was 
    Output:
    
Conclusions This meta- analysis shows that medication induces cortisol normalization effectively in a large percentage of patients .