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Standardized local staging and neoadjuvant therapy are Commission on Cancer and National Accreditation Program for Rectal Cancer quality measures for the management of rectal cancer. Previous studies suggested that up to 25% of stage II/III rectal cancer patients do not receive neoadjuvant therapy. We hypothesized that failure to receive neoadjuvant therapy may be caused by failure to properly stage patients prior to surgery.The purpose of this study is to determine if lack of local rectal cancer staging is associated with underutilization of neoadjuvant therapy and determine risk factors for omission of neoadjuvant therapy.Retrospective cohort study. Bivariate and multivariable analysis were performed on patient, tumor, and 30-day outcome factors associated with neoadjuvant therapy and staging.A total of 31 hospitals participating in the Michigan Surgical Quality Collaborative Colorectal Cancer Project from January 2014 to December 2019.Elective, clinical stage II/III, mid-to-low rectal cancer resections. Patients with upper rectal cancer were excluded.Percentage of patients receiving neoadjuvant therapy.The final cohort was 350 cases with clinical stage II/III mid or low rectal cancer. 80.9% had neoadjuvant therapy, and 83.2% had magnetic resonance imaging and/or endoscopic ultrasound. There was a significant association between receiving neoadjuvant therapy and MRI/ERUS staging (p0.0001). 87% of patients who had imaging with MRI/ERUS received NT, while 49% of patients who did not have MRI/ERUS staging had NT. Multivariate analysis revealed that risk factors for omission of neoadjuvant therapy were older age and incomplete staging.Observational study with possibility of unmeasured confounding variables.Neoadjuvant therapy is underutilized in patients with stage II/III rectal cancer. Omission of pretreatment staging with MRI/ERUS is associated with omission of neoadjuvant therapy. These data suggest the need for regional and national quality improvement strategies to standardize the multidisciplinary management of rectal cancer. See Video Abstract at http://links.lww.com/DCR/B923.

Context: Treatment of 21-hydroxylase deficiency (21OHD) is difficult to optimize. Normalization of excessive ACTH and adrenal steroid production commonly requires supraphysiologic doses of glucocorticoids. Objectives: We evaluated the safety and tolerability of the selective corticotropin releasing factor type 1 (CRF1) receptor antagonist NBI-77860 in women with classic 21OHD and tested the hypothesis that CRF1 receptor blockade decreases early-morning ACTH and 17α-hydroxyprogesterone (17OHP) in these patients. Participants: The study enrolled eight classic 21OHD females, ages 18–58 years, seen at a single tertiary referral university setting. Design: This was a phase Ib, single-blind, placebo-controlled, fixed-sequence, single-dose trial. During three treatment periods separated by 3-week washout intervals, patients sequentially received placebo, NBI-77860 300 mg, and NBI-77860 600 mg at 10 pm; glucocorticoid therapy was withheld for 20 hours. We evaluated ACTH, 17OHP, androstenedione, and testosterone as well as NBI-77860 pharmacokinetics over 24 hours. Results: Dose-dependent reductions of ACTH and/or 17OHP were observed in six of eight subjects. Relative to placebo, NBI-77860 led to an ACTH and 17OHP reduction by a mean of 43% and 0.7% for the 300 mg dose, respectively, and by 41% and 27% for the 600 mg dose, respectively. Both NBI-77860 doses were well tolerated. Conclusion: The meaningful reductions in ACTH and 17OHP following NBI-77860 dosing in 21OHD patients demonstrate target engagement and proof of principle in this disorder. These promising data provide a rationale for additional investigations of CRF1 receptor antagonists added to physiologic doses of hydrocortisone and fludrocortisone acetate for the treatment of classic 21OHD.

Chronic supraphysiological glucocorticoid therapy controls the androgen excess of 21-hydroxylase deficiency (21OHD) but contributes to the high prevalence of obesity, glucose intolerance, and reduced bone mass in these patients. Abiraterone acetate (AA) is a prodrug for abiraterone, a potent CYP17A1 inhibitor used to suppress androgens in the treatment of prostate cancer.The objective of the study was to test the hypothesis that AA added to physiological hydrocortisone and 9α-fludrocortisone acetate corrects androgen excess in women with 21OHD without causing hypertension or hypokalemia.This was a phase 1 dose-escalation study.The study was conducted at university clinical research centers.We screened 14 women with classic 21OHD taking hydrocortisone 12.5-20 mg/d to enroll six participants with serum androstenedione greater than 345 ng/dL (12 nmol/L).AA was administered for 6 days at 100 or 250 mg every morning with 20 mg/d hydrocortisone and 9α-fludrocortisone acetate.The primary endpoint was normalization of mean predose androstenedione on days 6 and 7 (230 ng/dL [8 nmol/L)] in greater than 80% of participants. Secondary end points included serum 17-hydroxyprogesterone and testosterone (T), electrolytes, plasma renin activity, and urine androsterone and etiocholanolone glucuronides.With 100 mg/d AA, mean predose androstenedione fell from 764 to 254 ng/dL (26.7-8.9 nmol/L). At 250 mg/d AA, mean androstenedione normalized in five participants (83%) and decreased from 664 to 126 ng/dL (23.2-4.4 nmol/L), meeting the primary end point. Mean androstenedione declined further during day 6 to 66 and 38 ng/dL (2.3 and 1.3 nmol/L) at 100 and 250 mg/d, respectively. Serum T and urinary metabolites declined similarly. Abiraterone exposure was strongly negatively correlated with mean androstenedione. Hypertension and hypokalemia were not observed.AA 100-250 mg/d added to replacement hydrocortisone normalized several measures of androgen excess in women with classic 21OHD and elevated serum androstenedione.

Adrenocortical carcinoma (ACC) is an aggressive malignancy, which lacks an effective systemic treatment. Abnormal activation of insulin-like growth factor receptor 1 (IGF1R) has been frequently observed. Preclinical studies demonstrated that pharmacological inhibition of IGF1R signaling in ACC has antiproliferative effects. A previous phase I trial with an IGF1R inhibitor has demonstrated biological activity against ACC. The objective of this study is to assess the efficacy of the combination of the IGF1R inhibitor cixutumumab (IMC-A12) in association with mitotane as a first-line treatment for advanced/metastatic ACC. We conducted a multicenter, randomized double-arm phase II trial in patients with irresectable recurrent/metastatic ACC. The original protocol included two treatment groups: IMC-A12 + mitotane and mitotane as a single agent, after an initial single-arm phase for safety evaluation with IMC-A12 + mitotane. IMC-A12 was dosed at 10 mg/kg intravenously every 2 weeks. The starting dose for mitotane was 2 g daily, subsequently adjusted according to serum levels/symptoms. The primary endpoint was progression-free survival (PFS) according to RECIST (Response Evaluation Criteria in Solid Tumors). This study was terminated before the randomization phase due to slow accrual and limited efficacy. Twenty patients (13 males, 7 females) with a median age of 50.2 years (range 21.9-79.6) were enrolled for the single-arm phase. Therapeutic effects were observed in 8/20 patients, including one partial response and seven stable diseases. The median PFS was 6 weeks (range 2.66-48). Toxic events included two grade 4 (hyperglycemia and hyponatremia) and one grade 5 (multiorgan failure). Although the regimen demonstrated activity in some patients, the relatively low therapeutic efficacy precluded further studies with this combination of drugs.