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     

Mechanism of multidrug resistance in relation to passive membrane permeation.

Passive uptake of drugs into cells is described in terms of the following steps: (1) massive immediate binding of the drugs to the outer leaflet of the plasma membrane resulting in practical equilibrium between extremely high drug concentrations at the cell surface compared to the drug concentration in the medium. (2) Due to their amphipathic nature, anticancer drugs are practically excluded from the lipid core of the membrane. They cross the lipid core by distinct flip-flop events that occur in the case of doxorubicin and daunorubicin after an average period of 0.7 and 0.15 min, respectively. (3) The drug reaching the inner leaflet of the plasma membrane is in practical equilibrium with the drug present in the cytoplasm. (4) Almost all the amounts of anticancer drugs present in the cells are bound by molecular sinks, such as DNA or cytoskeleton elements. The resistance afforded to multidrug resistant (MDR) cells by extrusion pumps, such as P-glycoprotein, is negatively correlated with the affinity of the drugs to the membranes and with their flip-flop rates across membranes. Binding rates of the drugs to membranes and intracellular sinks have no effect on drug concentration in the cytoplasm once equilibrium is reached between the passive uptake of drugs and their active extrusion.     

Antiviral activity of natural and recombinant human leukocyte interferons in tobacco protoplasts

Several purified species of human leukocyte interferon, including recombinant interferons, inhibit the multiplication of tobacco mosaic virus (TMV) in tobacco protoplasts derived from various cultivars. Viral RNA accumulation was determined by dot-blot hybridization to specific cDNA probes, and virus antigen was determined serologically. Interferon apparently inhibited both TMV-RNA replication and its expression into coat protein. However, these effects were of limited duration. Maximum effect was obtained when interferon was applied to the cells either prior to inoculation or within the first hour after inoculation. Antibodies to interferon abolished its antiviral activity in protoplasts. Tobacco protoplasts were about 1000 times more responsive to interferon than the reference animal viral-cell system and showed an "antiviral state" at a ratio of 1 molecule of interferon per cell.     

Primary carcinoma of the frontal sinus

A case of Primary Carcinoma of the Frontal Sinus.     

Hepatic capillariasis

The clinico-pathologic features of Capillaria hepatica infection in a 27-year-old Nigerian woman are discussed. This animal parasite has been encountered only rarely in humans. Less than 30 cases of human infection, mostly in children, having been recorded as far as the present authors are aware. This is the first case of hepatic capillariasis reported in West Africa. The pathologic features of this patient is marked by severe hepatic fibrosis, and this is correlated with disordered liver function. The possibility of histopathologic confusion with schistosomiasis mansoni is discussed.     

GTR with three different types of membranes in the treatment of intrabony periodontal defects: three-year results in sixty consecutive cases

The aim of the present study was to evaluate the clinical results at 3 years following treating intrabony periodontal defects with different nonresorbable and bioabsorbable membrane barriers. Sixty intrabony periodontal defects were treated according to the principles of guided tissue regeneration (GTR). Twenty pockets were treated with Gore Resolut, a bioabsorbable membrane; 20 were treated with Gore-Tex, a titanium-reinforced membrane; and 20 with nonresorbable Gore-Tex membrane (all manufactured by Gore Regenerative Technologies, Flagstaff, AZ). The therapeutic results were evaluated by assessing probing pocket depth (PPD), recession of the gingival margin (GR), and clinical attachment level (CAL) at baseline, at 1 and at 3 years after therapy. The postoperative phase was uneventful in all cases. At 1 year after surgery, the results showed a mean PPD reduction from 9.42 mm to 3.35 mm (p < 0.0001) with Resolut; from 10.30 mm to 4.00 with titanium-reinforced Gore-Tex (p < 0.0001); and from 8.40 mm to 3.73 mm (p < 0.0001) with Gore-Tex membranes. The mean GR increased from 1.92 mm to 3.70 mm (p < 0.001) with Resolut; from 0.47 mm to 2.85 mm (p < 0.0001) with titanium-reinforced Gore-Tex; and from 0.73 mm to 2.15 mm (p < 0.0001) with Gore-Tex membranes. The mean CAL changed from 11.35 mm to 6.92 mm (p < 0.001) with Resolut; from 10.78 mm to 6.85 mm (p < 0.0001) with titanium-reinforced Gore-Tex; and from 9.13 mm to 5.87 mm (p < 0.0001) with Gore-Tex membranes. The clinical results at 3 years were not significantly different when compared with the 1-year results (p > 0.05). No significant differences existed between the mean changes in PPD, GR, and CAL in the three different test groups. Furthermore, one tooth scheduled for extraction for periodontal and prosthodontic reasons was treated with Resolut. Histological analysis 6 months after treatment demonstrated the neoformation of a connective tissue attachment and of new alveolar bone. This additional evidence thus proved that treatment with bioabsorbable membranes according to GTR principles delivers not only clinical improvement, but also histological periodontal regeneration.     

An unusual case of Plasmodium vivax malaria monoinfection associated with crescentic glomerulonephritis: a need for vigilance

Plasmodium vivax infection is increasingly a major public health burden and the second most frequent human malaria. Higher levels of clinical severity and chloroquine resistance are major factors responsible for such increases. Malarial glomerular injury is uncommon and mainly observed in Plasmodium malariae-infected patients. Occasionally, transient immune complex-mediated glomerulonephritis is associated with Plasmodium falciparum infection. Coexistent crescentic glomerulonephritis and vivax malaria have not previously been reported. We report a fatal case of P. vivax malaria, who presented with acute renal failure. P. vivax monoinfection status was diagnosed with peripheral blood smear and rapid antigen test. Further evaluation for renal failure related to systemic illness and immunological markers were inconclusive. He was treated with antimalarial drugs, hemodialysis, and supportive therapy. Renal biopsy performed for nonrecovering renal failure reveled crescentic glomerulonephritis. This case highlights the need to thoroughly search for malaria-associated crescentic glomerulonephritis using renal biopsy after nonrecovering renal failure.     

T-cell Responses in Oiled Guillemots and Swans in a Rehabilitation Setting

Aquatic birds are commonly affected by oil spills. Despite rehabilitation efforts, the majority of rehabilitated common guillemots (Uria aalge) do not survive, whereas mute swans (Cygnus olor) tend to have higher postrelease survival. Polyaromatic hydrocarbons (PAHs) present in crude oil and diesel are immunotoxic in birds affecting cell-mediated responses to immunogens. Because it is a target of PAH toxicity, T-lymphocyte response to controlled mitogen administration (phytohemagglutinnin test) was investigated in a scoping study as a potentially useful minimally invasive in vivo test of cell-mediated immunity. The test was performed on 69 mute swans and 31 common guillemots stranded on the Norfolk and Lincolnshire coastline and inland waterways in England (UK) either due to injury or to contamination with crude or diesel oil. T-lymphocyte response was significantly decreased in swans with greater oil scores. T-lymphocyte responses were also decreased in guillemots, but this finding was not statistically significant.