Therapeutic response of basal cell carcinoma to the immune response modifier imiquimod 5% cream. Photodynamic therapy using topical methyl aminolevulinate vs surgery for nodular basal cell carcinoma: results of a multicenter randomized prospective trial. Basal cell carcinoma of the face: surgery or radiotherapy? Results of a randomized study. Efficacy of topical 5% imiquimod cream for the treatment of nodular basal cell carcinoma: comparison of dosing regimens. Imiquimod 5% cream for the treatment of superficial and nodular basal cell carcinoma: randomized studies comparing low-frequency dosing with and without occlusion. Comparison of the effects of intralesional interferon alfa-2a, 2b and the combination of 2a and 2b in the treatment of basal cell carcinoma. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from a randomized vehicle-controlled phase III study in Europe. Photodynamic therapy of multiple nonmelanoma skin cancers with verteporfin and red light-emitting diodes: two-year results evaluating tumor response and cosmetic outcomes. The effect of an intralesional sustained-release formulation of interferon alfa-2b on basal cell carcinomas. A pilot study to evaluate the treatment of basal cell carcinoma with 5-fluorouracil using phosphatidyl choline as a transepidermal carrier. Intralesional interferon therapy for basal cell carcinoma. Nonsurgical treatment of basal cell carcinomas with intralesional 5-fluorouracil/epinephrine injectable gel. Treatment of basal-cell carcinoma: comparison of radiotherapy and cryotherapy. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: a double-blind, randomized, vehicle-controlled study. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies. Photodynamic therapy of superficial basal cell carcinoma with 5-aminolevulinic acid with dimethylsulfoxide and ethylendiaminetetraacetic acid: a comparison of two light sources. Surgical excision vs Mohs' micrographic surgery for basal-cell carcinoma of the face: randomised controlled trial. Imiquimod 5% cream in the treatment of superficial basal cell carcinoma: results of a multicenter 6-week dose-response trial.
Basal cell carcinoma (BCC) responds to interferon therapy. Imiquimod is a cytokine and interferon inducer.
                This randomized, double-blind pilot trial evaluated the safety and efficacy of imiquimod 5% cream versus vehicle in the treatment of BCC.
                In this population of 35 patients with BCC, 24 received imiquimod 5% cream and 11 received vehicle cream in 1 of 5 dosing regimens for up to 16 weeks. Six weeks after treatment, an excisional biopsy of the target site was performed.
                BCC cleared (on the basis of histologic examination) in all 15 patients (100%) dosed twice daily, once daily, and 3 times weekly; in 3 of 5 (60%) patients dosed twice weekly; 2 of 4 (50%) dosed once weekly; and in 1 of 11 (9%) treated with vehicle. Adverse events were predominantly local reactions at the target tumor site, with the incidence and severity of local skin reactions declining in groups dosed less frequently.
                Imiquimod 5% cream shows clinical efficacy in the treatment of BCC. Photodynamic therapy (PDT) is increasingly used as a noninvasive treatment for nodular basal cell carcinoma (BCC), without a sound evidence base.
                To compare topical PDT, with the use of the sensitizer methyl aminolevulinate, and standard excision surgery in nodular BCC.
                Prospective, randomized study.
                University dermatology departments.
                A total of 101 adults with previously untreated nodular BCC.
                Patients received methyl aminolevulinate PDT (n = 52) or surgery (n = 49). The PDT was given twice, 7 days apart, with methyl aminolevulinate cream (160 mg/g) and 75 J/cm(2) red light (570-670 nm). Thirteen patients with a noncomplete response to PDT at 3 months (24% lesions) were retreated.
                Primary end point was clinically assessed lesion clearance at 3 months after treatment. Secondary end points were sustained response rate at 12 months and cosmetic outcome at 3 and 12 months. Cosmesis and lesion recurrence were further assessed at 24 months.
                Data from 97 patients (105 lesions) were included in the 3-month per-protocol analysis. Complete response rates did not differ significantly between groups (51/52 [98%] lesions with surgery vs 48/53 [91%] lesions with methyl aminolevulinate PDT; difference [95% confidence interval], 4.8% (-3.4% to 13.0%]; P =.25). At 12 months, tumor-free rates were 50 (96%) of 52 lesions with surgery vs 44 (83%) of 53 with methyl aminolevulinate PDT (P =.15). More patients treated with methyl aminolevulinate PDT than surgery had an excellent or good cosmetic outcome at all time points (significant at 12 and 24 months on patient assessment, P<.05, and at 3, 12, and 24 months on investigator evaluation, P<.001). At 24 months, 5 lesions that had initially cleared with methyl aminolevulinate PDT had recurred, compared with 1 after surgery.
                Methyl aminolevulinate PDT is an effective treatment for nodular BCC, and while there is a trend for higher recurrence with this modality, it conveys the advantage over surgery of better cosmesis. Basal cell carcinomas (BCCs) are very frequent cutaneous cancers, often located on the face. Cure rates with surgery and radiotherapy are high, but these treatments have never been compared prospectively. A randomized trial was initiated in 1982 to compare surgery and radiotherapy in the treatment of primary BCC of the face measuring less than 4 cm. The primary end point was the failure rate (persistent or recurrent disease) after 4 years of follow-up. The secondary end point was the cosmetic results assessed by the patient, the dermatologist and three persons not involved in the trial. In the course of the trial, 347 patients were treated. Of the 174 patients in the surgery group, 71% had local anaesthesia and 91% frozen section examination. Of the 173 patients in the radiotherapy group, 55% were treated with interstitial brachytherapy, 33% with contactherapy and 12% with conventional radiotherapy. The 4-year actuarial failure rate (95% CI) was 0.7% (0.1-3.9%) in the surgery group compared with 7.5% (4.2-13.1%) in the radiotherapy group (log-rank P = 0.003). The cosmetic results assessed by four of the five judges were significantly better after surgery than after radiotherapy. Eighty-seven per cent of the surgery-treated patients and 69% of the radiation-treated patients considered the cosmetic result as good (P < 0.01). Thus, in the treatment of BCC of the face of less than 4 cm in diameter, surgery should be preferred to radiotherapy. To establish a safe and efficacious dosing regimen for the treatment of primary nodular basal cell carcinoma (BCC) using 5% imiquimod cream.
                Two phase 2 studies were conducted: a 6-week, randomized, open-label, dose-response study evaluating 4 dosing regimens and a 12-week, randomized, vehicle-controlled, double-blind, dose-response study evaluating 4 dosing regimens.
                Twenty-four public and private dermatology clinics in Australia and New Zealand (6-week study) and the United States (12-week study) participated.
                The study populations comprised 99 patients enrolled in the 6-week study and 92 patients in the 12-week study. Patients were at least 18 years old and had a biopsy-confirmed diagnosis of nodular BCC.
                In the 6-week study, imiquimod was applied once daily for 3 or 7 days per week or twice daily for 3 or 7 days per week. In the 12-week study, imiquimod or placebo cream (vehicle) was applied once daily for 3, 5, or 7 days per week, or twice daily for 7 days per week. The entire tumor area was excised 6 weeks after treatment and examined histologically for evidence of remaining BCC.
                The proportion of patients having no histologic evidence of BCC in the posttreatment excision specimen.
                Dosing once daily for 7 days per week resulted in the highest clearance rate, with 25 (71%) of 35 and 16 (76%) of 21 patients showing clearance of their tumor in the 6- and 12-week studies, respectively.
                Topical 5% imiquimod cream is well tolerated and most effective in treating nodular BCC when applied once daily for 7 days per week for either 12 or 6 weeks. Imiquimod 5% cream has been investigated for non-surgical treatment of superficial and nodular basal cell carcinoma (BCC) tumours.
                Two studies were conducted to examine the effect of occlusion at low dosing frequencies on the safety and efficacy of topical imiquimod 5% cream for the treatment of superficial and nodular BCC.
                Both open-label studies were conducted in Europe. Patients diagnosed with BCC were enrolled into either the superficial (93 patients) or nodular (90 patients) study, depending on the histological confirmation of the patient's tumour subtype. Patients were randomized to one of four groups to apply imiquimod 5% cream 2 or 3 days per week either with or without occlusion. Six weeks following a 6-week treatment period, the entire target tumour area was excised and histologically examined for evidence of residual tumour.
                In both studies, the highest histologically complete response rate was seen in the 3 days per week with occlusion groups, with complete response rates of 87% and 65% for the superficial and nodular studies, respectively. Occlusion did not have a statistically significant effect on response rate at either dosing frequency. Response rates for superficial and nodular BCC tumours treated 3 days per week without occlusion were 76% and 50%, respectively.
                In the superficial study, the complete response rate of 87% in the 3 days per week with occlusion group was similar to that of daily and 5 days per week dosing without occlusion in a previous 12-week study and one study of daily dosing without occlusion for 6 weeks. All treatment groups had acceptable safety profiles in both studies. Occlusion did not have a statistically significant effect on efficacy for either superficial or nodular BCC tumours. Interferons (IFN), especially alfa-2a and 2b, are potent inhibitors of normal and malignant cell growth and effective choices in the treatment of basal cell carcinoma (BCC). The aim of the study was to evaluate the effectiveness of the IFN alfa-2a and 2b, and whether this effect may be increased by their combination. A total of 45 patients with histopathologically confirmed BCC were divided into three groups, equally. Groups 1,2 and 3 were treated with intralesional IFN alfa-2a, 2b, and the combination of 2a and 2b, respectively. Lesions were injected three times weekly in Groups 1 and 2 (total ten injections). IFN alfa-2a and 2b were injected alternately in Group 3 (5 IFN alfa-2a and 5 IFN alfa-2b). Eight weeks after completion of therapy, cytologic specimens were taken, and all cases were evaluated clinically and cytologically. Ten (66.6%) patients had a complete response (CR) and 5 (33.3%) had a partial response (PR) in Group 1. Patients in Group 2 showed 10 (66.6%) CR, 4 (26.6%) PR, and 1 (6.6%) non response. In Group 3, 11 (73.3%) patients had CR and 4 (26.6%) had PR. Follow-up periods ranged from 6-24 months, and no recurrences have been observed. These results suggest that IFN alfa-2a, 2b, and the combination of 2a and 2b appear to be effective choices for the treatment of BCC; the effectiveness is not increased by their combination. Imiquimod is an immune response modifier that acts through toll-like receptor 7 to induce cytokine production and a subsequent innate and adaptive cell-mediated immune response. Clinical studies have demonstrated clinical and histological clearance of superficial basal cell carcinoma (sBCC) after treatment with imiquimod 5% cream.
                To evaluate the safety and clinical efficacy of imiquimod (Aldaratrade mark; 3M Pharmaceuticals, St Paul, MN, U.S.A.) 5% cream for the treatment of sBCC in a multicentre, randomized, parallel, vehicle-controlled, double-blind, phase III clinical study conducted at 26 centres in Europe.
                Subjects who had at least one histologically confirmed sBCC tumour were randomized to apply imiquimod or vehicle cream to the target tumour once daily, seven times per week (7 x/week) for 6 weeks. The target tumour location was identified with an indelible ink mark before treatment initiation. The treated tumour site was clinically assessed for treatment response at 12 weeks post-treatment and was then excised for histological evaluation. Efficacy assessments included the composite response rates (proportion of subjects with clinical and histological clearance) and response rates solely based on histology (proportion of subjects with histological clearance). Safety assessments, which included adverse events and scoring of local skin reactions (LSRs), were carried out throughout the study.
                In total, 166 subjects were enrolled in this study. For the intent-to-treat dataset, there was a statistically significant difference between imiquimod and vehicle groups for both composite clearance rates (clinical and histological assessments) and histological clearance rates. Composite clearance was demonstrated in 77% and 6% of subjects treated with imiquimod and vehicle cream, respectively. Histological clearance was demonstrated in 80% and 6% of subjects treated with imiquimod and vehicle cream, respectively. The most frequently reported safety findings were investigator-assessed LSRs and spontaneous reports by subjects of application site reactions, which occurred more frequently in the imiquimod group than in the vehicle group.
                Imiquimod 5% cream administered 7 x/week for 6 weeks is a safe and effective treatment for sBCC when compared with vehicle cream. Efficient treatment of patients with multiple synchronous nonmelanoma skin cancers represents a therapeutic challenge.
                To study the safety and efficacy of photodynamic therapy (PDT) with verteporfin and red light in the treatment of multiple nonmelanoma skin cancers.
                Open-label, randomized, multicenter, dose-ranging phase 2 study conducted at 4 North American university-based dermatology clinics.
                Fifty-four patients with 421 multiple nonmelanoma skin cancers including superficial and nodular basal cell carcinoma and squamous cell carcinoma in situ (Bowen disease).
                A single intravenous infusion of 14 mg/m(2) of verteporfin followed 1 to 3 hours later by exposure of tumors to 60, 120, or 180 J/cm(2) of red light (688 +/- 10 nm) from a light-emitting diode panel.
                Pathologic response of treated sites was assessed at 6 months. Clinical and cosmetic responses were assessed and graded at 6 weeks, 3 months, and 6 months after verteporfin PDT, with optional follow-up visits at 12, 18, and 24 months.
                The histopathologic response, defined as absence of tumor on biopsy specimens 6 months after verteporfin PDT, ranged from 69% at 60 J/cm(2) to 93% at 180 J/cm(2). At 24 months of follow-up (276 tumors in 31 patients), the clinical complete response rate ranged from 51% at 60 J/cm(2) to 95% at 180 J/cm(2). No significant systemic adverse events were observed; most events occurred at the treated tumor sites and included events such as pain. Overall, 65% (95% confidence interval, 58%-71%) of tumors were judged to have good to excellent cosmesis at 24 months.
                A single course of verteporfin PDT showed treatment benefit for patients with multiple nonmelanoma skin cancers. Intralesional interferon alfa-2b has been proven effective in the treatment of basal cell carcinomas. Because nine injections over a 3-week period have been necessary to produce clinically significant cure rates, a sustained-release protamine zinc chelate interferon formulation has been developed. In this study, 65 basal cell carcinomas were treated in one of two dosing schedules with intralesional sustained release interferon alfa-2b (10 million IU per injection). Thirty-three patients received a single injection and 32 patients received one injection per week for 3 weeks. At study week 16, 80% of evaluable tumors treated with three injections and 52% treated with one injection were cured histologically. Two patients discontinued injections because of side effects. A sustained-release protamine zinc preparation of interferon alfa-2b shows promise as a practical, effective, and cosmetically elegant treatment for basal cell carcinoma. In certain situations, successful topical therapy of basal cell carcinoma (BCC) without the inconvenience, risk, and expense of surgery would be of great value to patients. Placing 5-fluorouracil (FU) in an appropriate carrier may solve these problems. Phosphatidyl choline (PC) penetrates effectively throughout the epidermis of shaved rabbits and may be able to carry small water-soluble molecules such as nucleotides across lipid barriers when applied topically.
                We propose that employing PC as a vehicle will facilitate the penetration of 5-FU and increase efficacy as compared to petrolatum-based 5-FU cream.
                This pilot study is a double-blinded and randomized therapeutic trial. Thirteen patients with 17 biopsy-proven, moderate thickness BCCs were randomized to receive either cream A (5% 5-FU in a PC vehicle) or cream B (Efudex(R): 5% 5-FU in a petrolatum base). Patients applied cream A or cream B twice a day for 4 weeks. The patients underwent an excisional biopsy of the treated BCC site at week 16.
                There was a 90% cure rate (9/10) in those lesions treated with 5% 5-FU in PC cream and a 57% cure rate (4/7) in those treated with 5% 5-FU in a petrolatum-based cream.
                Although the study was unable to detect any statistically significant differences in outcome between the study groups, this small pilot study shows preliminary findings which may indicate an increase in the short-term eradication of BCC using a PC-based vehicle as compared to conventional petrolatum-based formulations. In a clinical trial of 172 patients at four medical centers, interferon alfa-2b (1.5 x 10(6) IU) or a placebo was injected directly into biopsy-proved noduloulcerative or superficial basal cell carcinomas three times weekly for 3 weeks, for a cumulative dose of 13.5 million IU. Efficacy of treatment was determined at 16 to 20 weeks by examination of biopsy specimens that demonstrated cure of lesions in 86% of interferon-treated patients and in only 29% of placebo-treated patients. During the treatment course and follow-up, an initial inflammatory response was observed at the treatment sites, followed by diminished erythema, improvement in overall appearance, and a decrease in size of lesions. Side effects of treatment, mainly flu-like symptoms, were usually mild and transient and occurred more commonly in the interferon-treated group. Only three patients, all in the interferon-treated group, discontinued therapy because of side effects. One year after initiation of therapy, 81% of interferon recipients and 20% of those given the placebo remained tumor free. Noduloulcerative and superficial lesions were equally responsive to treatment with interferon. For some patients with noduloulcerative or superficial basal cell carcinomas, intralesional interferon alfa-2b may be an alternative, effective treatment. To develop a nonsurgical treatment alternative for basal cell carcinomas (BCCs), we evaluated intralesional sustained-release chemotherapy with 5-fluorouracil/epinephrine injectable gel (5-FU/epi gel).
                To optimize the dose and treatment schedule, we compared the safety, tolerance, and efficacy of six treatment regimens of 5-FU/epi gel in patients with BCCs.
                Two doses and four treatment schedules of 5-FU/epi gel were compared in an open-label, randomized study of 122 patients with biopsy-proven BCCs. One BCC per patient was treated for up to 4 to 6 weeks, then observed for 3 months at which time the tumor site was completely excised for histologic examination.
                Overall, 91% of evaluable treated tumors (106 of 116) in all regimens had histologically confirmed complete tumor resolution. No clinically significant treatment-related systemic adverse events occurred. The best response rate, tolerance, and patient compliance with assigned dose were in patients receiving 0.5 ml of 5-FU/epi gel three times a week for 2 weeks. The complete response rate based on histologic assessment in this group was 100%.
                Results demonstrate that treatment of BCC with 5-FU/epi gel is both safe and effective, may result in histologically confirmed complete response rates comparable to surgery, and provides a nonsurgical treatment alternative in selected patients. A prospective randomised trial to compare radiotherapy and cryotherapy in the treatment of basal-cell carcinomas was carried out in 93 patients. Two years after treatment, 4% of tumours treated with radiotherapy and 39% of those treated with cryotherapy had recurred. It is concluded that cryotherapy does not offer a satisfactory alternative to radiotherapy in the treatment of basal-cell carcinomas. Imiquimod 5% cream may provide an effective nonsurgical treatment for superficial basal cell carcinoma (sBCC) based on results of previous studies.
                The objective of this phase II dose-response study was to explore various dosing regimens using imiquimod 5% cream for sBCC to find the most effective frequency of dosing with tolerable side effects.
                Patients (n = 128) were dosed twice daily, once daily, 5 times a week, or 3 times a week in this 12-week, randomized, double-blind, vehicle-controlled study. At 6 weeks after treatment, the entire tumor area was clinically evaluated, excised, and examined exhaustively for histologic evidence of residual sBCC.
                Complete response rates were 100% (10/10), 87.1% (27/31), 80.8% (21/26), and 51.7% (15/29) for patients in the twice daily, once daily, 5 times a week, and 3 times a week imiquimod groups, respectively, and 18.8% (6/32) in the vehicle group.
                Imiquimod 5% cream was effective in the treatment of sBCC. Daily or 5 times a week dosing for 12 weeks demonstrated high efficacy results with acceptable safety profiles. Imiquimod is an immune response modifier that is a Toll-like receptor 7 agonist that induces interferon and other cytokines through the innate immune system and stimulates cell-mediated immunity through T cells. Imiquimod has been shown to be efficacious as a topical treatment for basal cell carcinoma (BCC).
                We sought to evaluate the efficacy and safety of imiquimod 5% cream compared with vehicle for treating superficial BCC (sBCC).
                Two identical studies were conducted. Subjects with one sBCC were dosed with imiquimod or vehicle cream once daily 5 or 7x/week for 6 weeks in these 2 randomized, double-blind, vehicle-controlled Phase III studies. The lesion site was clinically examined 12 weeks posttreatment and then excised for histological evaluation.
                Data from both studies were pooled. Composite clearance rates (combined clinical and histological assessments) for the 5 and 7x/week imiquimod groups were 75% and 73%, respectively. Histological clearance rates for the 5 and 7x/week imiquimod groups were 82% and 79%, respectively. Increasing severity of erythema, erosion, and scabbing/crusting was associated with higher clearance rates.
                Imiquimod appears to be safe and effective for the treatment of sBCC when compared with vehicle cream. The difference in clearance rates between the two imiquimod dosing groups was not significant. The 5x/week regimen is recommended. The aim of this prospective randomized study was to compare the clinical and cosmetic outcome of superficial basal cell carcinomas (BCC), using either laser or broadband halogen light, in photodynamic therapy with topical 5-aminolevulinic acid (ALA). A total of 83 patients with 245 superficial BCC were included in the study. Standard treatment involved 15 min of local pretreatment with 99% dimethylsulfoxide (DMSO) before topical application of 20% ALA with DMSO (2%) and ethylendiaminetetraacetic acid (2%) as cofactors for 3 h before light exposure with either laser or a broadband lamp (BL). A complete response was achieved in 95 lesions (86%) in the laser group and 110 lesions (82%) in the BL group 6 months after treatment. Of these, 80 lesions (84%) in the laser group and 101 lesions (92%) in the lamp group were independently evaluated to have an excellent or good cosmetic post-treatment score. No serious adverse events were reported. This study shows that there is no statistical significant difference in cure the rate (P = 0.49) and the cosmetic outcome (P = 0.075) with topical application of a modified ALA-cream between light exposure from a simple BL with continuous spectrum (570-740 nm) or from a red-light laser (monochromatic 630 nm). Cost and safety are further elements in favor of the BL in this setting. Rates of recurrence of facial basal-cell carcinoma are consistently lower after Mohs' micrographic surgery (MMS) than after other treatments, such as surgical excision (SE). However, MMS is more time-consuming and therefore more expensive than SE. We investigated the types of facial basal-cell carcinomas in which MMS was more effective than SE.
                408 primary and 204 recurrent facial carcinomas (374 and 191 patients, respectively) were analysed separately in this prospective randomised study. Patients were assigned SE or MMS (each 204 primary, 102 recurrent), and received treatment at two hospitals in the Netherlands. The primary outcome was recurrence of carcinoma. Analysis was by intention to treat.
                Of the basal-cell carcinomas included in the trial, 397 primary (198 MMS, 199 SE) and 201 recurrent (99, 102) tumours were actually treated. Of patients with primary carcinomas, 21 had both MMS and SE on different tumours. Nine with recurrent carcinomas had both treatments on different skin tumours. 66 primary and 13 recurrent carcinomas were lost to follow-up. Of the primary carcinomas, five (3%) recurred after SE compared with three (2%) after MMS during 30 months of follow-up. Of the recurrent carcinomas, three (3%) recurred after SE and none after MMS during 18 months of follow-up. Four recurrent carcinomas randomly assigned to the SE group were treated with MMS. Although both differences favoured MMS, they were not significant (primary, difference 1% [95% CI -2.5% to 3.7%], p=0.724; recurrent, 3.2% [-2.0% to 5.0%], p=0.119). Total operative costs of MMS were higher than those of SE (primary 405.79 Euros vs 216.86 Euros, recurrent 489.06 Euros vs 323.49 Euros; both p<0.001).
                No definitive conclusion on recurrence rates of primary or recurrent basal-cell carcinomas is yet possible. Although recurrence rates were lower after MMS than after SE, the differences were not significant. Superficial basal cell carcinoma (sBCC) is an increasingly common tumor in fair-skinned populations throughout the world. Imiquimod, an immune response modifier that induces cytokines including interferons, has been shown in preliminary studies to have an effect when applied topically to BCC.
                We conducted a multicenter, randomized, open-label dose-response trial of imiquimod 5% cream in the treatment of primary sBCC assessing efficacy and safety of different dose regimens.
                Ninety-nine patients were randomized to 6 weeks' application of imiquimod in 1 of 4 treatment regimens: twice every day, once every day, twice daily 3 times/week, once daily 3 times/week. The treatment site was excised and examined histologically 6 weeks after cessation of imiquimod.
                Intention-to-treat analysis revealed 100% (3/3) histologic clearance in the twice-daily regimen, 87.9% (29/33) clearance in the once every day regimen, 73.3% (22/30) clearance in the twice-daily 3 times/week regimen, and 69.7% (23/33) clearance in the once-daily 3 times/week regimen. Dose-related inflammatory skin reactions at the site of application were common. The majority were well tolerated and only 1 patient withdrew from the trial as a result of a medication-related skin reaction.
                Imiquimod 5% cream appears to have potential as a patient-administered treatment option in sBCC.