Prognostic and predictive significance of nuclear HIF1α expression in locally advanced HNSCC patients treated with chemoradiation with or without nimotuzumab

Background Anti-EGFR-based therapies have limited success in HNSCC patients. Predictive biomarkers are greatly needed to identify the patients likely to be benefited from these targeted therapies. Here, we present the prognostic and predictive association of biomarkers in HPV-negative locally advanced (LA) HNSCC patients.Methods Treatment-naive tumour tissue samples of 404 patients, a subset of randomised Phase 3 trial comparing cisplatin radiation (CRT) versus nimotuzumab plus cisplatin radiation (NCRT) were analysed to evaluate the expression of HIF1α, EGFR and pEGFR by immunohistochemistry and EGFR gene copy change by FISH. Progression-free survival (PFS), locoregional control (LRC) and overall survival (OS) were estimated by Kaplan–Meier method. Hazard ratios were estimated by Cox proportional hazard models.Results Baseline characteristics of the patients were balanced between two treatment groups (CRT vs NCRT) and were representative of the trial cohort. The median follow-up was of 39.13 months. Low HIF1α was associated with better PFS [HR (95% CI) = 0.62 (0.42–0.93)], LRC [HR (95% CI) = 0.56 (0.37–0.86)] and OS [HR (95% CI) = 0.63 (0.43–0.93)] in the CRT group. Multivariable analysis revealed HIF1α as an independent negative prognostic biomarker. For patients with high HIF1α, NCRT significantly improved the outcomes [PFS:HR (95% CI) = 0.55 (0.37–0.82), LRC:HR (95% CI) = 0.55 (0.36–0.85) and OS:HR (95% CI) = 0.54 (0.36–0.81)] compared to CRT. While in patients with low HIF1α, no difference in the clinical outcomes was observed between treatments. Interaction test suggested a predictive value of HIF1α for OS (P = 0.008).Conclusions High HIF1α expression is a predictor of poor clinical response to CRT in HPV-negative LA-HNSCC patients. These patients with high HIF1α significantly benefited with the addition of nimotuzumab to CRT.Clinical trial registration Registered with the Clinical Trial Registry of India (Trial registration identifier—CTRI/2014/09/004980).Subject terms: Tumour biomarkers, Head and neck cancer, Tumour biomarkers, Head and neck cancer, Predictive markers     

Use of a dual lumen port for automated red cell exchange in adults with sickle cell disease

Red cell exchange (RCE) is a common procedure in adults with sickle cell disease (SCD). Implantable dual lumen Vortex (DLV) ports can be used for RCE in patients with poor peripheral venous access. We performed a retrospective cohort study of RCE procedures performed in adults with SCD. The main objective of the study was to compare the inlet speed, duration of procedures and rate of complications performed through DLV ports to those performed through temporary central venous and peripheral catheters. Twenty‐nine adults with SCD underwent a total of 318 RCE procedures. Twenty adults had DLV ports placed and 218 procedures were performed using DLV ports. Mean length of follow‐up after DLV port placement was 397 ± 263 days. Six DLV ports were removed due to infection and 1 for malfunction after a mean of 171 ± 120 days. Compared to temporary central venous and peripheral catheters, DLV port procedures had a greater rate of procedural complications, a longer duration, and a lower inlet speed (all P < 0.01). When accounting for the maximum allowable inlet speed to avoid citrate toxicity, 40% of DLV port procedures were greater than 10% below maximum speed, compared to 7 and 14% of procedures performed through temporary central venous and peripheral catheters (P < 0.0001). In conclusion, DLV ports can be used for RCE in adults with SCD, albeit with more procedural complications and longer duration. The smaller internal diameter and longer catheter of DLV ports compared to temporary central venous catheters likely accounts for the differences noted. J. Clin. Apheresis 30:353–358, 2015. © 2015 Wiley Periodicals, Inc.     

Contradictory antitumor efficacies produced by the combination of DNA attacking drugs and polyamine antimetabolites

The antitumor effects of two polyamine antimetabolites, alpha-difluoromethylornithine (DFMO) and methylglyoxal-bis-guanylhydrazone (MGBG), when combined with cis-diamminedichlroplatinum (CDDP) or mitomycin C (MMC), were studied using human gastric cancer cells xenotransplanted into nude mice. DFMO 1000 mg/kg and MGBG 50 mg/kg were given intraperitoneally for 6 successive days, while CDDP 3 mg/kg or MMC 2 mg/kg was given every second day. Although DFMO and MGBG plus MMC did suppress the tumor growth, the combination with CDDP led to no suppression, and rapid growth occurred after the cessation of therapy. The inhibition of tumoral DNA biosynthesis and a decline in polyamine levels, were also not observed. The polyamine antimetabolites when used with CDDP did not produce the desired antitumor efficacy, even though the platinum concentration in the tumor tissue was high. On the contrary, however, DFMO and MGBG when combined with MMC did suppress tumor growth, inhibited DNA biosynthesis, and tissue polyamine levels were low. These results suggest that though CDDP and MMC belong to a similar category of DNA attacking, bifunctional alkylating agents, the findings of these two drugs are contradictory. Here, the mechanism of action no doubt plays a contributory role.     

In-vitro/in-vivo correlation of pulsatile drug release from press-coated tablet formulations: a pharmacoscintigraphic study in the beagle dog.

The aim of the current study was to investigate the in-vitro and in-vivo performance of a press-coated tablet (PCT) intended for time delayed drug release, consisting of a rapidly disintegrating theophylline core tablet, press-coated with barrier granules containing glyceryl behenate (GB) and low-substituted hydroxypropylcellulose (L-HPC). The PCTs showed pulsatile release with a lag time dependent upon the GB and L-HPC composition of the barrier layer. In-vivo gamma-scintigraphic studies were carried out for PCTs containing GB:L-HPC at 65:35 w/w and 75:25 w/w in the barrier layer in four beagle dogs, in either the fed or fasted state. The in-vivo lag time in both the fed and fasted states did not differ significantly (p>0.05) from the in-vitro lag time. Additionally, no significant difference (p<0.05) between in-vivo fed and fasted disintegration times was observed, demonstrating that in-vivo performance of the PCT was not influenced by the presence or absence of food in the gastrointestinal tract. A distinct lag time was obtained prior to the appearance of drug in plasma and correlated (R2=0.98) with disintegration time observed from scintigraphic images. However, following disintegration, no difference in pharmacokinetic parameters (AUC(0-6 dis), K(el), Cmax) was observed. The current study highlighted the potential use of these formulations for chronopharmaceutical drug delivery.     

ENDOSCOPY ASSISTED REMOVAL OF FERROMAGNETIC COINS WITH NOVEL MAGNETIC INSTRUMENT

Background: Ingestion of coins is a common clinical problem in children. Many of the coins are ferromagnetic and can be retrieved with the help of a magnet. We describe the use of a novel endoscopic accessory for removing ferromagnetic coins. Material and methods: Two magnet discs of 1.5 cm diameter were joined to a 200 cm steel wire of 0.75 mm thickness with a terminal 5 cm spring. A Teflon tube (160 cm, 7 F) was used along with this instrument as a sleeve. The use of this accessory was analyzed prospectively in subjects presenting with a history of coin ingestion. The time taken for removal of coins, complications during the procedure and failure rate was noted. Effect of the magnet on cardiac rhythm was also noted during the procedure. Results: A total of 55 children (mean age 5.1 ± 2.3 years) with coin ingestion presented over a period of 1 year. Forty‐four coins were ferromagnetic. All ferromagnetic coins were removed successfully. Mean time for removal was 68 ± 22 s. No complications were encountered. Conclusion: The novel magnetic instrument is precise, safe and quick for the removal of ferromagnetic coins under direct vision.