AllergoOncology - the impact of allergy in oncology: EAACI position paper.

Th2 immunity and allergic immune surveillance play critical roles in host responses to pathogens, parasites and allergens. Numerous studies have reported significant links between Th2 responses and cancer, including insights into the functions of IgE antibodies and associated effector cells in both antitumour immune surveillance and therapy. The interdisciplinary field of AllergoOncology was given Task Force status by the European Academy of Allergy and Clinical Immunology in 2014. Affiliated expert groups focus on the interface between allergic responses and cancer, applied to immune surveillance, immunomodulation and the functions of IgE-mediated immune responses against cancer, to derive novel insights into more effective treatments. Coincident with rapid expansion in clinical application of cancer immunotherapies, here we review the current state-of-the-art and future translational opportunities, as well as challenges in this relatively new field. Recent developments include improved understanding of Th2 antibodies, intratumoral innate allergy effector cells and mediators, IgE-mediated tumour antigen cross-presentation by dendritic cells, as well as immunotherapeutic strategies such as vaccines and recombinant antibodies, and finally, the management of allergy in daily clinical oncology. Shedding light on the crosstalk between allergic response and cancer is paving the way for new avenues of treatment.

Ebola virus disease: awareness among junior doctors in England.

The current Ebola virus epidemic continues to pose a threat to the UK. Junior clinicians are often at the frontline of medical care in hospitals and their awareness of the clinical features and management of the Ebola virus disease (EVD) may significantly influence the timely implementation of infection control measures. In view of this, we carried out a cross-sectional survey of 119 junior doctors across four different hospitals in England in order to assess their level of knowledge of EVD. We demonstrate that there is currently a deficiency of knowledge about critical aspects of EVD in this population.

Telomere associations in interphase nuclei: possible role in maintenance of interphase chromosome topology.

The relative sizes of individual telomeres in cultured human cells under conditions of cell cycling, replicative quiescence, cell transformation and immortalization were determined using quantitative fluorescence in situ hybridization (Q-FISH) with a telomere-specific peptide nucleic acid (PNA) probe. Results obtained from analysis of telomere length profiles (TLPs), which display the distribution of relative telomere lengths for individual cells, confirmed telomere length heterogeneity at the single cell level and proportional shortening of telomere length during replicative aging of virus-transformed cells. TLPs also revealed that some telomeric ends of chromosomes are so closely juxtaposed within interphase nuclei that their fluorescent signals appear as a single spot. These telomeric associations (TAs) were far more prevalent in interphase nuclei of noncycling normal and virus-transformed cells than in their cycling counterparts. The number of interphase TAs per nucleus observed in late-passage E6/E7-transformed cells did not increase during progression to crisis, suggesting that telomere shortening does not increase the frequency of interphase TAs. Furthermore, interphase TAs were rarely observed in rapidly cycling, telomerase-positive, immortalized cells that exhibit somewhat shortened, but stabilized, telomere length through the activity of telomerase. Our overall results suggest that the number of interphase TAs is dependent more on whether or not cells are cycling than on telomere length, with TAs being most prominent in the nuclei of replicatively quiescent cells in which nonrandom (even preferred) chromosome spatial arrangements have been observed. We propose that interphase TAs may play a role in the generation and/or maintenance of nuclear architecture and chromosome positional stability in interphase nuclei, especially in cells with a prolonged G(1)/G(0) phase and possibly in terminally differentiated cells.

[Viral screening of organ donors and human cytomegalovirus seroprevalence in the Hungarian population]. / Szervdonorok virológiai szúrése és a hazai lakosság átfertózöttsége human cytomegalovirussal.

The authors investigated 998 organ-donors for Human cytomegalovirus seroprevalence. The donors were divided into three age-groups. In organ-donors the seroprevalence was found to be 84%. A study was also conducted on a fourth group consisting of 200 residents from an old-age home. The youngest donor was 2 years of age, the eldest old-age home resident was of 92 years. The examined persons represent the hungarian population. It was found that as the result of the investigation of all 1198 subjects, the Human cytomegalovirus overall seroprevalence in Hungary is 86%. The age specific prevalence increases starting from 73% in the first group (2 to 20 years old) to 99% in the fourth group (71 to 92 years old). This has indicated that most of the population acquired the primary infection in the childhood or during early adulthood. According to these results the authors resumed that in Hungary the Human cytomegalovirus seroprevalence is high. This would cause problems when a seronegative organ-recipient needs an organ transplantation. Between males and females a significant difference of Human cytomegalovirus seroprevalence was found: 89% of females were seropositive in contrast to 81% of males (p < 0.05). The organ-donors were also examined for the presence of HBsAg, anti-HCV and anti-HIV. 1.8% of donors were HbsAg positive, 0.9% were anti-HCV positive and 1 person was anti-HIV positive, but these results weren't verificated.

Chromosome spatial order in human cells: evidence for early origin and faithful propagation.

We have investigated the origin and nature of chromosome spatial order in human cells by analyzing and comparing chromosome distribution patterns of normal cells with cells showing specific chromosome numerical anomalies known to arise early in development. Results show that all chromosomes in normal diploid cells, triploid cells and in cells exhibiting nondisjunction trisomy 21 are incorporated into a single, radial array (rosette) throughout mitosis. Analysis of cells using fluorescence in situ hybridization, digital imaging and computer-assisted image analysis suggests that chromosomes within rosettes are segregated into tandemly linked "haploid sets" containing 23 chromosomes each. In cells exhibiting nondisjunction trisomy 21, the distribution of chromosome 21 homologs in rosettes was such that two of the three homologs were closely juxtaposed, a pattern consistent with our current understanding of the mechanism of chromosomal nondisjunction. Rosettes of cells derived from triploid individuals contained chromosomes segregated into three, tandemly linked haploid sets in which chromosome spatial order was preserved, but with chromosome positional order in one haploid set inverted with respect to the other two sets. The spatial separation of homologs in triploid cells was chromosome specific, providing evidence that chromosomes occupy preferred positions within the haploid sets. Since both triploidy and nondisjunction trisomy 21 are chromosome numerical anomalies that arise extremely early in development (e.g., during meiosis or during the first few mitoses), our results support the idea that normal and abnormal chromosome distribution patterns in mitotic human cells are established early in development, and are propagated faithfully by mitosis throughout development and into adult life. Furthermore, our observations suggest that segregation of chromosome homologs into two haploid sets in normal diploid cells is a remnant of fertilization and, in normal diploid cells, reflects segregation of maternal and paternal chromosomes.

The relationship of nasopharyngeal carcinomas and second independent malignancies based on the Radiation Therapy Oncology Group experience.

The authors sought to learn if the incidence of second independent malignancies after the irradiation of carcinomas of the nasopharynx is similar to that observed after treatment of tumors arising in other head and neck sites. One hundred twenty-one patients who had primary carcinomas of the nasopharynx who were treated solely by ionizing radiation (according to the specifications of a Radiation Therapy Oncology Group protocol) were identified and their subsequent well-being was reviewed. Overall there was a 4.1% incidence of second malignancies (2% after 3 years, 5% after 5 years, and 8% after 8 years) with most arising in the upper aerodigestive tract. This rate is significantly less than the rate associated with other head and neck sites. It is not significantly different from the rate of first malignancies observed in an age-matched and sex-matched population. When only those patients who were free of all evidence of neoplastic disease 6 months after the completion of radiotherapy are considered, similar analysis leads to similar outcomes. The authors conclude that the risk of second malignancies after the successful irradiation of carcinomas of the nasopharynx is substantially less than after treatment of tumors at other head and neck sites.

Elapsed treatment days--a critical item for radiotherapy quality control review in head and neck trials: RTOG report.

For all randomized trials since 1978, the Radiation Therapy Oncology Group has required the study chairman for radiation therapy to review the treatment given to each patient. The chairman scores the compliance of the treatment borders, total dose, fraction, and total elapsed time relative to the protocol prescription at the primary site, regional nodes, and any critical structure. The individual parameters are then considered together to derive an "overall" treatment score. For two RTOG head and neck studies in patients with moderately and very advanced carcinomas, the "overall" treatment was classified as unacceptable if the treatment at primary was scored unacceptable with respect to dose, fractionation, and field borders. However, prolonged elapsed treatment was not included. Analysis of these studies with 426 evaluable patients was performed to assess the relationship of unacceptable "overall" treatment compliance with outcome. Patients with prolonged treatment elapsed days (14 days beyond the protocol prescription) exhibited significantly poorer loco-regional control (13% vs. 27% at 3 years with p = .007) and absolute survival (13% vs. 26% at 3 years with p = .01). As a result, the criteria for unacceptable "overall" treatment were revised to include prolonged elapsed treatment days. Further multivariate analyses showed the revised criteria identified patients with significantly poorer loco-regional control and absolute survival even after adjusting for other prognostic factors.

The role of hemoglobin concentration in the outcome of misonidazole-sensitized radiotherapy of head and neck cancers: based on RTOG trial #79-15.

Recent data from the DAHANCA (Danish Head and Neck Cancer) 2 study implies a positive effect of high hemoglobin concentration in concert with misonidazole for the treatment of head and neck cancers by radiotherapy. We have therefore reviewed and updated our analysis of RTOG protocol 79-15, which included the effect of misonidazole plus radiotherapy in a presumably similar population. Despite additional follow-up and more sophisticated analysis, our analysis does not demonstrate an influence of hemoglobin concentration on any of the outcome measures we examined. Possible explanations for the difference in findings of RTOG 79-15 and DAHANCA 2 are discussed. Radiation therapy of head and neck squamous cancers, Hypoxia and hemoglobin conc. in head and neck cancers, Oral cavity cancer, Effect of radiation therapy, Oropharynx cancer, Hemoglobin and radiotherapy, Hemoglobin concentration, Effect upon radiotherapy, Irradiation of oropharynx cancer, Hgb effect.

Failure of misonidazole-sensitized radiotherapy to impact upon outcome among stage III-IV squamous cancers of the head and neck.

As part of the RTOG research effort in the treatment of advanced, inoperable squamous cancer of the head and neck region, the hypoxic cell sensitizer, misonidazole, was selected for investigation as an adjuvant to definitive irradiation. Based upon a pilot experience (78-02) showing a 67% complete response rate among 36 AJC Stage III-IV patients receiving full-dose irradiation and 6 weekly p.o. doses of misonidazole, a phase III trial was carried out from '79-'83. Three hundred and six patients were entered, 42% of whom had oropharyngeal primaries and with 78% of all cases representing T3 or T4 (inoperable) lesions. Only 16% of the entire series presented with N0 necks. Fractionation was altered among the misonidazole-receiving patients, in contrast to "standard" 5 treatments per week among "control" patients, such that 2 separate treatments were given on each day of p.o. misonidazole administration (2.0 gm/m2/wk X 6 doses, 2.5 Gy in a.m., 2.1 Gy in p.m.). Total tumor doses were identical among the two treatment arms except that a limitation of 40.0 Gy to spinal cord was specified for sensitized radiotherapy vs. 45.0 Gy for "control" patients. Primary tumor clearance was observed to be 55-60%, with minor variations according to tumor stage and site. The local regional control rate among radiotherapy-alone patients was 26% at 2 years compared to 22% (2 years) within the misonidazole-receiving group. Analysis of survival revealed no advantage to the sensitized patients, with 55 +/- 2% surviving 1 year and 22 +/- 1% living 3 years following treatment in both treatment categories. Distant metastases as first site of failure (12-13%) and the local failure among initial complete responders (46%) showed no advantage to the misonidazole group. Although a misonidazole dosage of 2.0 gm/m2/wk X 6 (12 gm/m2 total) is well tolerated, no clinical benefit was demonstrated in this randomized trial. Other nitroimidazole analogs (e.g. SR-2508) are now being investigated.

Tumor regression and other prognosticators in advanced head and neck cancers: a sequel to the RTOG methotrexate study.

The randomized Radiation Therapy Oncology Group (RTOG) Methotrexate trial in advanced squamous cancers of the head and neck has reported no control or survival benefits when the chemotherapy adjuvant was administered to patients just prior to definitive irradiation. The required data collection and outcome reporting among 146 patients bearing oral cavity primaries and 354 patients with oropharyngeal cancers has allowed a multi-variate approach seeking answers to many unresolved questions. As anticipated, the ability to control these squamous cancers is largely a function of size (T & N stage) with a superior clearance among T3-4 primaries of the oropharynx (66%) contrasted to identically staged oral cavity tumors (48%). Adjusted median survival is more than doubled to 26.6 months or 19.8 months among oral cavity and oropharynx patients respectively, when compared to the 8 month median survival when neither primary nor cervical nodes are controlled. Lymph node deposits also impact upon survival, especially among oropharynx patients where the 17.6 month adjusted median survival among N0 patients declines to 11.0 months when the primaries are associated with N3 nodes. Surprisingly, the ability to control nodel deposits of all sizes (N1, N2, or N3) is superior among oropharynx patients when compared with identical oral cavity metastases (e.g. 71.4% adjusted clearance in N3 oropharyngeal deposits versus 46.1% in N3 nodes secondary to oral cavity primaries). Adjustments for maldistribution of advanced N-stages in association with T-4 primary stage eliminated an apparent T-stage effect upon nodal clearance within both anatomic regions. Finally, the association of T and N-stage upon distant metastases was investigated, with the surprising conclusion that neither initial T nor N-stage exerts any apparent influence on the observed 10-12% occurrence. The interrelationship of these various prognostic variables is explored using the Cox and logistic models.