Preoperative external beam radiotherapy and reduced dose brachytherapy for carcinoma of the cervix: survival and pathological response

PURPOSE: To evaluate the pathologic response of cervical carcinoma to external beam radiotherapy (EBRT) and high dose rate brachytherapy (HDRB) and outcome. MATERIALS AND METHODS: Between 1992 and 2001, 67 patients with cervical carcinoma were submitted to preoperative radiotherapy. Sixty-five patients were stage IIb. Preoperative treatment included 45 Gy EBRT and 12 Gy HDRB. Patients were submitted to surgery after a mean time of 82 days. Lymphadenectomy was performed in 81% of patients. Eleven patients with residual cervix residual disease on pathological specimen were submitted to 2 additional insertions of HDRB. RESULTS: median follow up was 72 months. Five-year cause specific survival was 75%, overall survival 65%, local control 95%. Complete pelvic pathological response was seen in 40%. Surgery performed later than 80 days was associated with pathological response. Pelvic nodal involvement was found in 12%. Complete pelvic pathological response and negative lymphnodes were associated with better outcome (p = .03 and p = .005). Late grade 3 and 4 urinary and intestinal adverse effects were seen in 12 and 2% of patients. CONCLUSION: Time allowed between RT and surgery correlated with pathological response. Pelvic pathological response was associated with improved outcome. Postoperative additional HDRB did not improve therapeutic results. Treatment was well tolerated

Benralizumab improves symptoms of patients with severe, eosinophilic asthma with a diagnosis of nasal polyposis

BackgroundClinically meaningful improvement in the Sino‐Nasal Outcome Test‐22 (SNOT‐22) was observed in patients with severe, eosinophilic asthma, and nasal polyposis (NP) treated with benralizumab in the ANDHI trial. A post hoc assessment of the effects of benralizumab on SNOT‐22 response and asthma efficacy measures in these patients was conducted for further characterization of the efficacy and safety of benralizumab for patients with severe asthma and NP.MethodsAdults with severe, eosinophilic asthma who had experienced ≥2 prior‐year exacerbations despite high‐dosage inhaled corticosteroid plus additional controller[s] were randomized to 24 weeks of benralizumab or placebo. Patients with physician‐diagnosed chronic rhinosinusitis with NP of any severity ongoing at baseline who consented to participate were included in the current ANDHI NP substudy population. Effect on NP symptoms was assessed by the SNOT‐22, with an improvement of at least 8.9 defined as clinically significant (responder). Effects on chronic asthma outcomes were assessed by means of annualized asthma exacerbation rate (AER), St. George’s Respiratory Questionnaire (SGRQ) total score, forced expiratory volume in one second (FEV1), and Asthma Control Questionnaire‐6 (ACQ‐6). All p‐values were nominal.ResultsOf the ANDHI population (n = 656), 23% (n = 153) participated in the NP substudy (n = 96 benralizumab; n = 57 placebo). Patients were 50% female, with mean age of 53 years, had prior‐year AER = 3.3; mean pre‐bronchodilator FEV1 = 55% predicted; and median blood eosinophil count ​= 510 cells/µl. For patients with high baseline SNOT‐22 scores (>30), benralizumab treatment improved symptoms of NP as measured by SNOT‐22 from baseline to Week 24 compared with placebo (Week 24: −10.44 [p = .0176]). Percentage of responders to SNOT‐22 was greater for benralizumab vs. placebo (71.3% vs. 45.5%; p = .0036), and effect was enhanced for patients with high baseline SNOT‐22 scores (>30). A 69% reduction vs. placebo in annualized AER (0.77 vs. 2.47; p < .0001) and greater clinically meaningful improvements from baseline in SGRQ total score (−16.7), FEV1 (+0.32 L), and ACQ‐6 (–0.88) were observed (p < .0001). Benralizumab was well‐tolerated. Frequency of adverse events (AEs) was similar for benralizumab (76.0%) and placebo (73.7%) groups. Most common AEs (frequency ≥5%) reported at a greater frequency in benralizumab vs. placebo included headache, sinusitis, pyrexia, and influenza.ConclusionsThese substudy data from ANDHI demonstrated the efficacy profile of benralizumab for patients with severe, eosinophilic asthma and NP, with improvement in SNOT‐22 and asthma outcomes.The combination of asthma and nasal polyposis provides significant treatment challenges and substantial disease burden, including a greater number of asthma exacerbations annually, which negatively impacts quality of life. Clinically meaningful improvement in the SNOT‐22 was observed early and maintained over time for patients with severe, eosinophilic asthma and nasal polyposis treated with benralizumab in the ANDHI trial. This ANDHI substudy demonstrated that benralizumab is safe and efficacious for patients with severe, eosinophilic asthma and nasal polyposis, with improvement in SNOT‐22 total scores and asthma outcomes. Abbreviation: ACQ‐6, Asthma Control Questionnaire‐6; AER, asthma exacerbation rate; CRSwNP, chronic rhinosinusitis with nasal polyposis; FEV1, forced expiratory volume in 1 second; SGRQ, St. George’s Respiratory Questionnaire; SNOT‐22, Sino‐Nasal Outcome TestPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/171162/1/all14902_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/171162/2/all14902.pd

Therapeutic strategies targeting connexins

The connexin family of channel-forming proteins is present in every tissue type in the human anatomy. Connexins are best known for forming clustered intercellular channels, structurally known as gap junctions, where they serve to exchange members of the metabolome between adjacent cells. In their single-membrane hemichannel form, connexins can act as conduits for the passage of small molecules in autocrine and paracrine signalling. Here, we review the roles of connexins in health and disease, focusing on the potential of connexins as therapeutic targets in acquired and inherited diseases as well as wound repair, while highlighting the associated clinical challenges