A Phase I Study of the CDK4/6 Inhibitor Palbociclib in Combination with Cetuximab and Radiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma.

PURPOSE: Palbociclib, a cyclin D kinase 4 (CDK4)/6 inhibitor, has shown radiosensitizing effects in preclinical studies. There is a strong rationale for adding palbociclib to cetuximab and radiotherapy in locally advanced head and neck squamous cell carcinoma (LA-HNSCC), especially in p16-negative HNSCC. PATIENTS AND METHODS: We conducted a phase I dose-escalation study (NCT03024489) using a classical 3+3 design to determine safety, tolerability, and MTD of palbociclib, cetuximab, and intensity-modulated radiotherapy (IMRT) combination. At the recommended phase II dose (RP2D), additional p16-negative patients were enrolled. RESULTS: Twenty-seven patients with LA-HNSCC (13 in dose escalation, 14 in expansion) with oropharyngeal (41%) and hypopharyngeal (30%) cancers were enrolled. The MTD was not reached, and the RP2D of palbociclib was established at the full standard palbociclib dose of 125 mg/day for 21 days per cycle, administered for two cycles during IMRT. The most common grade 3-4 toxicities were mucositis (59%), radiation dermatitis (22%), and neutropenia (22%), with a febrile neutropenia rate of 7%. Common genomic alterations included mutations in TP53 (57%), GNAQ (35%), and PIK3CA (17%), and copy-number gains in CCND1 (22%), CCND2 (9%), and EGFR (9%). Overall, p16 expression was positive in 15% of patients. No correlation was observed between p16 status, genomic alterations, and preliminary efficacy. The objective response rate was 84%. The rates for 2-year locoregional control, event-free survival, and overall survival were 73%, 48%, and 71%, respectively. CONCLUSIONS: The palbociclib, cetuximab, and IMRT combination was well tolerated. The RP2D was established, while no MTD was determined. The regimen demonstrated promising preliminary efficacy, suggesting further investigation is warranted in patients with cisplatin-ineligible p16/human papilloma virus-unrelated LA-HNSCC.

Changes of Circulating Irisin and High-Sensitivity C-Reactive Protein Levels in Morbidly Obese Individuals with Type 2 Diabetes After Roux-en-Y Gastric Bypass.

Background: Irisin has been recently reported to provide beneficial effects in obesity and diabetes. Elevation of high-sensitivity C-reactive protein (hs-CRP) reflects the inflammatory state that has been shown to play a key role in obesity and its comorbidities. Objective: Our study aimed to compare the changes of circulating irisin levels in an obese diabetic population who underwent laparoscopic Roux-en-Y gastric bypass (LRYGB) versus a control-matched population who underwent usual medical care plus diabetes support education (DSE) program. In addition, we aimed to explore the association between circulating irisin and hs-CRP levels after the interventions. Methods: In a prospective controlled trial, we studied 58 obese individuals with type 2 diabetes before and 12 months after intervention. Twenty-nine subjects underwent LRYGB and 29 subjects received DSE. Results: At 12-month follow-up, compared with the DSE group, patients who underwent LRYGB lost more weight (LRYGB; -33.4 ± 11.2, and DSE; 0.2 ± 4.9 kg; P < .001), fat mass (P < .001), and fat-free mass (P < .05). Circulating irisin (P < .05) and hs-CRP level (P < .05) were also significantly lower. Within the LRYGB group, the reduction of irisin level was positively associated with the changes of hs-CRP levels (r = 0.39, P < .05). Conclusions: To the best of our knowledge, this is the first study showing that LRYGB significantly reduces circulating irisin levels compared with usual medical care and DSE, in an obese diabetic population. After LRYGB, the irisin reduction significantly correlates with the reduction of hs-CRP. The elevation of circulating irisin levels suggests irisin resistance in the obese state and its decrease after LRYGB might reflect the resolution of irisin resistance. Future investigations are needed to confirm and explore the mechanisms of irisin resistance in obesity, its resolution after LRYGB, and the pathophysiological significance.

Endocrine hypertension: An overview on the current etiopathogenesis and management options.

Endocrine causes of secondary hypertension include primary aldosteronism, pheochromocytoma, cushing's syndrome, hyperparathyroidism and hypo- and hyperthyroidism. They comprise of the 5%-10% of the causes of secondary hypertension. Primary hyperaldosteronism, the most common of the endocrine cause of hypertension often presents with resistant or difficult to control hypertension associated with either normo-or hypokalemia. Pheochromocytoma, the great mimicker of many conditions, is associated with high morbidity and mortality if left untreated. A complete history including pertinent family history, physical examination along with a high index of suspicion with focused biochemical and radiological evaluation is important to diagnose and effectively treat these conditions. The cost effective targeted genetic screening for current known mutations associated with pheochromocytoma are important for early diagnosis and management in family members. The current review focuses on the most recent evidence regarding causes, clinical features, methods of diagnosis, and management of these conditions. A multidisciplinary approach involving internists, endocrinologists and surgeons is recommended in optimal management of these conditions.