Differences in nasal immunoglobulin A responses to influenza vaccine strains after live attenuated influenza vaccine (LAIV) immunization in children.

Different vaccine strains included in the live attenuated influenza vaccine (LAIV) have variable efficacy. The reasons for this are not clear and may include differences in immunogenicity. We report a Phase IV open-label study on the immunogenicity of a single dose of quadrivalent LAIV (Fluenz™ Tetra) in children during the 2015/16 season, to investigate the antibody responses to different strains. Eligible children were enrolled to receive LAIV; nasal samples were collected before and approximately 4 weeks after immunization. There was a significant increase in nasal immunoglobulin (Ig)A to the H3N2, B/Victoria lineage (B/Brisbane) and B/Yamagata lineage (B/Phuket) components, but not to the H1N1 component. The fold change in nasal IgA response was inversely proportional to the baseline nasal IgA titre for H1N1, H3N2 and B/Brisbane. We investigated possible associations that may explain baseline nasal IgA, including age and prior vaccination status, but found different patterns for different antigens, suggesting that the response is multi-factorial. Overall, we observed differences in immune responses to different viral strains included in the vaccine; the reasons for this require further investigation.

Natural history, reasons for, and impact of low/non-adherence to medications for osteoporosis in a cohort of community-dwelling older women already established on medication: a 2-year follow-up study.

UNLABELLED: Approximately 15 % of older women on oral medications for osteoporosis could be considered for alternatives including parenteral therapies. Collection of data on socio-demographic/clinical variables is unlikely to be helpful in predicting low/non-adherence. Alternative approaches are needed to identify individuals at risk of low/non-adherence. INTRODUCTION: This study aims to identify individual patient reasons for stopping medications for osteoporosis, and to investigate whether this can be predicted from knowledge about socio-demographic/clinical data, or whether alternative approaches need to be used. METHODS: The Cohort for Skeletal Health in Bristol and Avon (COSHIBA) recruited 3200 older women from South West UK, of whom a proportion were on medications for osteoporosis at baseline. Information on self-reported adherence and reasons for low/non-adherence were collected at 6-monthly intervals over a 2-year period. Data was also collected on potential predictors of and impact of low/non-adherence. RESULTS: Two hundred thirty-three of 3200 (7.3 %) women were on medications for osteoporosis at baseline. Mean length of time on treatment prior to enrolment was 46 months. Of those on osteoporosis medications, 94.9 % were on bisphosphonates; 8.5 % reported low adherence and 21.6 % stopped their medication completely over the 2-year follow-up period. Length of time on medication at baseline did not influence rates of low/non-adherence. Reasons for low/non-adherence to bisphosphonates included side effects (53.9 %), practical reasons such as forgetting to take them (18.0 %) and beliefs about medications (20.5 %). No convincing predictors of low/non-adherence were identified. CONCLUSIONS: Approximately 15 % of older women on oral medications for osteoporosis could be considered for alternatives including parenteral therapies. This has important implications for healthcare provision. Collection of data on socio-demographic/clinical variables is unlikely to be helpful in predicting low/non-adherence. Alternative approaches are needed to identify individuals at risk of low/non-adherence to osteoporosis medications.

Vertebral fracture assessment (VFA) by lateral DXA scanning may be cost-effective when used as part of fracture liaison services or primary care screening.

SUMMARY: We identified that use of VFA may be cost-effective in either selected women from primary care or women attending after a low trauma fracture. INTRODUCTION: Lateral DXA scanning of the spine for vertebral fracture assessment (VFA) is used for research, but its wider role is unclear. We aimed to establish whether VFA is cost-effective in women based on two different scenarios: following a low-trauma fracture, and after screening of high-risk women identified in primary care. METHODS: The fracture cohort (FC) consisted of 377 women and the primary care cohort (PCC) of 251. Vertebral fractures were identified on VFA images by quantitative morphometry (QM). Outcome was cost-effectiveness of VFA, based on predicted change in clinical management defined as the identification of a vertebral fracture in a patient who otherwise falls below the threshold for treatment. FRAX treatment thresholds assessed were (1) 20/3 % thresholds and (2) National Osteoporosis Guidelines Group (NOGG) thresholds. RESULTS: As a result, 9.8 % from FC and 13.9 % from PCC were identified with vertebral fractures. Management was changed in 21 to 22/377 (5.6-5.8 %) in FC and 12 to 26/251 (4.8-10.4 %) from PCC depending on which thresholds were used. Sensitivity analyses identified medication adherence as the assumption which most influenced the model. The best-estimate cost-per-QALY for use of VFA in FC was £3,243 for 20/3 threshold and £2,130 for NOGG; for PCC, this was £7,831 for 20/3 and was cost-saving for NOGG. Further analyses to adjust for potential false-positive vertebral fracture identification with QM showed VFA was no longer cost-effective. CONCLUSION: VFA appears to be cost-effective in routine clinical practise, particularly when relatively inaccurate methods of identification of vertebral fractures are used such as QM.

Molecular disorders in transitional vs. peripheral zone prostate adenocarcinoma.

Loss of heterozygosity (LOH) and microsatellite instability (MSI) have been shown to be mechanisms for tumor-suppressor gene inactivation in human oncogenesis. In our study, we examined LOH and MSI using 16 polymorphic markers of DNA for chromosomes 1, 3, 7, 8, 10 and 11. Microdissected tumor samples were isolated from 32 patients, representing 11 foci of incidentally discovered prostate cancer of the transitional zone (TZ), 12 prostate cancer of the peripheral zone (PZ) and 10 of high-grade PIN. We found loss of heterozygosity in the TZ group in 91% of informative cases (10/11) with al least 1 marker compared to 58% of cases (7/12) in PZ group and 70% of cases (7/10) in the HGPIN group. Chromosome 7 showed the highest rate of allelic loss in all 3 categories, with loss of 43% of loci in PIN, 37% in TZ tumors and 31% in PZ tumors. At chromosome 11, LOH was detected in 26% of loci in the TZ group, in 7% of loci in the PZ group and in 13% of loci in the PIN group. On chromosome 8, the PZ and HGPIN group showed allelic loss in 22% and 21% of loci, respectively, compared to 10% detected in the TZ group. The TZ group showed a significant higher rate of allelic instability compared to that observed in tumor samples from the peripheral zone: 73% of cases (8/11) showed genetic alterations (RER+ phenotype) in at least 4 loci analyzed compared to 8% and 10% in the PZ and HGPIN groups, respectively (p = 0.0006). These data suggest that transitional zone carcinoma and peripheral zone carcinoma display distinct and specific genetic alterations in different chromosomes. This diversity may help explain biologic and clinical differences between carcinomas arising in these distinct zones of the prostate. Also our results strongly suggest that the RER+ mutator phenotype could be linked to early development of transitional zone prostate carcinoma.

Vitronectin in the cirrhotic liver: an immunomarker of mature fibrosis.

Vitronectin (Vn) is a multifunctional plasma glycoprotein produced by hepatocytes. Vn has been studied extensively as a cell adhesion molecule. However, its localization in the hepatic extracellular matrix has received relatively little attention. Cryosections of 5 normal liver samples and of 20 specimens showing posthepatitic cirrhosis were stained by the avidin-biotin complex method with a well-characterized monoclonal antibody to Vn. The extent and intensity of immunostaining were assessed semiquantitatively (0, no staining; 1+, weak focal staining; 2+, strong focal staining; 3+, strong diffuse staining). Paraffin sections from the same samples were stained with Masson trichrome (MT) and Shikata orcein (Or) methods. Frozen samples from selected cases were analyzed by Western blotting. In the normal liver, 3+ staining was limited to portal vessels. The portal tract connective tissue showed minimal staining (0 to 1+). Cirrhotic septa showed strong staining (2+). Septa lacking significant inflammation and composed of dense connective tissue, as indicated by MT and Or stains, showed the strongest Vn reactions (3+). Immunoblotting data strongly correlated with Vn increase in cirrhotic livers. Vn immunoreactivity is markedly increased in the cirrhotic liver matrix, regardless of the documented decrease in plasma Vn. Binding to collagen, elastin, and proteoglycans is the current favored mechanism of Vn deposition in tissues. Previous studies in cirrhotic patients showed increased affinity of plasma Vn to collagen. Vn is also increased in aged skin, associated with dermal elastic fibers. In other tissues, Vn deposition reflects chronicity of injury. Therefore, Vn immunoreactivity in liver can be considered a marker of fibrosis, especially of chronic/mature fibrosis, paralleling previous observations on enhanced orcein staining of cirrhotic septa. Immunolabeling of biopsy specimens with Vn and tenascin, a marker of ongoing remodeling or recently formed fibrous tissue, could be diagnostically helpful.

Stereotactically guided laser therapy of occult breast tumors: work-in-progress report.

HYPOTHESIS: Mammographically detected breast tumors can be completely ablated with laser energy. DESIGN: Nonrandomized control trial. SETTING: A university hospital ambulatory care center. PATIENTS: Thirty-six patients with mammographically detected well-defined breast tumors were selected. INTERVENTIONS: The diagnosis of malignant neoplasms and determination of prognostic factors were established by image-guided needle-core biopsy. Patients were treated on a stereotactic table, using a 16- to 18-gauge laser probe, with an optic fiber transmitting a predetermined amount of laser energy. A multisensor thermal probe was inserted into the breast adjacent to the laser probe to monitor treatment. In the last 10 patients, the tumor blood flow was evaluated before and after laser therapy with contrast-enhanced color Doppler ultrasound. One to 8 weeks after laser therapy, the tumors were surgically removed and serially sectioned. MAIN OUTCOME MEASURE: Complete necrosis in 66% of tumors. RESULTS: Total tumor ablation with negative margins was observed whenever 2500 J/mL of tumor was given or the thermal sensors recorded 60 degrees C. Microscopic examination at 1 week showed disintegration of malignant cells, with peripheral acute inflammatory response and at 4 to 8 weeks extensive fibrosis. Contrast-enhanced color Doppler ultrasound revealed loss of tumor circulation after therapy, and positron emission tomography scan correlated well with histologic findings. There were no systemic adverse effects. Two patients sustained 3 x 4-mm skin burns around the laser needle. CONCLUSION: A stereotactically guided minimally invasive technique may be effective for the treatment of mammographically detected breast cancer.

A novel, nuclear pore-associated, widely distributed molecule overexpressed in oncogenesis and development.

Nuclear pore complexes are large, elaborate macromolecular structures that mediate the bidirectional nucleocytoplasmic traffic. In vertebrates, nuclear pore complexes comprise 50 to 100 proteins termed nucleoporins (Nup). An 88-kd nucleoporin (Nup88) has been recently cloned and characterized, and found to be associated in a dynamic subcomplex with the oncogenic nucleoporin CAN/Nup 214. We have produced a polyclonal antiserum to Nup88, and found that it immunoreacts convincingly in conventional tissue sections of 214 samples of malignant tumors of many types. All carcinomas were stained irrespective of site or line of differentiation; the majority of cases reacted strongly and extensively. In situ carcinomas and highly dysplastic epithelia were similarly reactive. Samples of malignant mesotheliomas, gliomas, sarcomas, and lymphoreticular tumors were also stained. Substantial reactions were also found in certain fetal tissues. Focal reactions were noted in some reactive-proliferative processes. Most benign epithelial and mesenchymal tumors and hyperplasias, and normal adult tissues reacted weakly and sporadically or not at all. Immunoblot analysis of selected samples strongly corroborated those findings. If further substantiated, our findings indicate that Nup88 could be regarded as a selective yet broadly based proliferation marker of potential significance in the histological evaluation and diagnosis of malignant transformation. Its ready applicability on conventional paraffin sections and on cytological preparations may broaden its clinical and investigative significance.

Epithelial tumors of the lung.

Our knowledge and understanding of bronchopulmonary tract tumors have grown considerably; modern pathology enables the phenotyping of many tumors with increasingly improving techniques and tools and, arguably, improving criteria. By the same token, at least some of the new data may not be readily grafted onto traditional classification schemes. Some traditional designations will be dropped and replaced. And, although it has been overenthusiastically argued that molecular classifications may be attained, that ideal might not be truly an improvement. For classifications to be useful, they should be relatively simple, easily reproducible, and clinically significant. Still, modern marker pathology has revealed new vistas for the evaluation, diagnosis, and therapy of at least some tumors. These developments merit optimism but also caution from clinicians and pathologists.

Lack of CD 29 (beta1 integrin) and CD 54 (ICAM-1) adhesion molecules in intravascular lymphomatosis.

Intravascular Lymphomatosis (IL) is a rare and usually aggressive form of non-Hodgkin's lymphoma characterized by the growth of neoplastic cells within vascular lumina that usually presents with skin or central nervous system (CNS) involvement. The mechanism(s) for the selective intravascular growth of this neoplasm remain(s) unexplained. We now report clinical and immunohistologic data on surgical material from 6 cases of IL; in 4 of 6 cases, autopsies were performed. Our IL cases shared the following features: (1) B-cell lineage; (2) lack of skin involvement at presentation; (3) aggressive behavior; and (4) lack of extravascular lymphomatous masses; in addition, 1 case had an associated gastric low-grade MALT lymphoma. We studied by immunohistochemistry formalin-fixed, paraffin-embedded sections with monoclonal antibodies to molecules known to be involved in lymphocyte and endothelial adhesion phenomena, that is, CD29 (beta1 integrin subunit), CD43 (leukosialin), CD44 (H-CAM), CD54 (ICAM-1), embryonal N-CAM (e-NCAM), and EMA (episialin). In all cases, the surfaces of IL aggregates reacted for CD44 but were consistently negative for CD29; also absent was CD54. Conversely, the integrity of the endothelial cells was underscored by their even reactivity for CD29, CD44, and CD54. Given that CD29 is currently regarded as critical for lymphocyte trafficking in general and for transvascular migration in particular, and CD54 is also involved in transvascular lymphocyte migration, we conclude that their consistent absence in IL may contribute to its intravascular and disseminated distribution pattern. The rather frequent association of IL with various conventional lymphomas is known; yet, one of our cases appears to be the first report of IL associated with a low-grade MALT lymphoma.

Enhanced tenascin expression correlates with inflammation in primary sclerosing cholangitis.

Tenascin (Tn) is an extracellular matrix (ECM) glycoprotein upregulated during development, repair and oncogenesis. In the normal adult liver, Tn is limited to vessels and, focally, to sinusoidal walls. In this study, samples were obtained from 12 livers removed during transplantation for primary sclerosing cholangitis (PSC). Paraffin sections were immunostained with monoclonal antibodies BC-4 which recognizes all isoforms of Tn and alpha-SMA-1 to alpha smooth muscle actin (alpha-SMA). Intense Tn reactions were noted in areas of ductular proliferation and inflammation at the parenchyma-stroma interface. In the absence of ductular proliferation, no selective Tn upregulation was noted. Staining was preferentially located adjacent to ductular basement membranes, with minimal extension into the surrounding ECM. Advanced histologic stages with micronodules rimmed by proliferating ductules showed the most florid Tn reactions, whereas fibrous septa and edematous perinodular haloes did not react. Increased periductal Tn was also seen associated with active inflammation, notably around large, dilated septal ducts, while fibro-obliterative ductal lesions and "onion skin fibrosis" did not stain. Focally enhanced Tn staining was noted in sinusoids neighboring ductular proliferation, and in dilated sinusoids within cirrhotic nodules. Reactions with alpha-SMA-1 highlighted myofibroblasts and activated Ito cells in topographic association with Tn reactions. We conclude that Tn is upregulated in PSC where it is preferentially localized in the remodeling matrix encompassing proliferating ductules and in altered periductal matrix. Our results suggest that Tn determinations in tissue or serum samples might be helpful in the clinical assessment of "activity" in PSC.

Demonstrability of the glycoprotein A-80 in postradiation prostatic carcinoma.

Radiation therapy results in significant morphological changes in prostatic carcinoma, including decreased cancer size, acinar shrinkage and distortion, cytoplasmic vacuolization, and nuclear pyknosis. Benign acini usually display enlarged, atypical cells with hyperchromatic nuclei. These changes confound the evaluation of limited postradiation samples. The glycoprotein A-80 is known to be upregulated in prostatic intraepithelial neoplasia (PIN) and prostatic carcinoma. In this study, we assessed the expression of A-80 in radiation-treated prostatic carcinoma. Paraffin sections from 64 postradiation prostatic carcinomas obtained at salvage prostatectomy were immunostained with a monoclonal antibody to A-80; selected sections were doubly immunostained with antibodies to A-80 and various cytokeratin polypeptides. All cases showed readily detectable and often intense staining in the cytoplasm of cancer cells and in intraluminal material of malignant acini. The extent and intensity of the reactions were independent of cancer size and grade. Strong reactions were seen in preserved and distorted acini, clear cell areas, single cancer cells, and in colloid pools with few or no recognizable cancer cells. PIN was present in 34 cases (53%), of which 27 (79%) stained strongly for A-80; atrophic and hyperplastic acini generally did not stain, irrespective of the degree of cellular atypia. The A-80 glycoprotein appears remarkably durable and is readily demonstrable in postradiation prostatic carcinoma despite profound architectural and cytologic changes. This characteristic may prove useful in evaluating small samples for confirmation of diagnosis and determination of extent of residual or recurrent prostatic carcinoma after radiation therapy.

Integrin laminin receptor profile of pulmonary squamous cell and adenocarcinomas.

The differential expression of laminin receptors has been shown to modulate the invasive capability of malignant cells. We have investigated the reactivity of human pulmonary squamous carcinomas (SSC, n = 20) and adenocarcinomas (ADC, n = 20) with monoclonal antibodies to the cytoplasmic and extracellular domains of the integrin subunits alpha3 and alpha6. Integrins containing these subunits are laminin receptors. Monoclonal antibodies to beta1 and beta4 subunits, the beta1C splice variant of beta1, as well as to Ki-67, were also used. Reverse transcription polymerase chain reaction (PCR) single-strand conformational polymorphism analysis was done to detect possible mutations in the cytodomains. All carcinomas expressed alpha3 extensively; alpha3 expression predominated (40 of 40) over alpha6 (25 of 40). In all alpha6-positive carcinomas, alpha6A was expressed, whereas alpha6B was weakly expressed only in some of them. No mutations of the intracytoplasmic domain A of alpha3 and of the A or B intracytoplasmic domains of alpha6 were shown. Notably, in normal bronchial epithelium, alpha6 colocalized with beta4, whereas in the tumors, alpha6A frequently overlapped with beta1 in a circumferential pattern; alpha6beta1 coexpression was also shown by coprecipitation experiments. Strong and extensive beta4 reactions were invariably polarized at the cell/stroma interface in SCC and ADC. An inverse correlation was found between the expression of beta1C and Ki-67. The prevalence of alpha6A in pulmonary SCC and ADC is in contrast with previous results in colonic ADC in which alpha6B prevails, and alpha6 predominates over alpha3. The absence of mutations of the cytodomains suggests that the integrin subunits of these carcinomas are potentially active. Predominance of alpha3 over alpha6 and of alpha6A over alpha6B may contribute to explain the aggressive and metastatic behavior of lung carcinomas.

Immunolocalization of integrins in the normal lung and in pulmonary carcinomas.

Cryosections of normal adult lung (n = 7) and pulmonary epithelial tumors, including squamous (n = 8), adeno (n = 8), bronchioloalveolar (n = 5), and large cell (n = 4) carcinomas (SCC, ACC, BAC, LCC), carcinoids (Cd, n = 7), and neuroendocrine carcinomas (NEC) of variable grades (n = 14) were immunostained by the avidin-biotin peroxidase (ABC) method with monoclonal antibodies to the alpha1-6 and alpha(v) and the beta1-4 integrin subunits. Normal adult alveolar septae showed variably intense immunoreactivity for alpha1,3,6 and beta1, whereas reactions for alpha5 and alpha(v) were weaker and uneven; the remaining integrin subunits were not detected. Bronchial and bronchiolar epithelium showed variably intense staining for alpha2.3,6,v and beta1,4. Reactions were often, though not invariably, basally polarized. SCC, ADC, and LCC showed variably intense reactions for alpha2.3,6,v and beta1,4. BAC were strongly and uniformly stained for alpha1.3 and beta1. In Cd, alpha1,2,3,v and beta1 reactions were noted, whereas in NEC, weak alpha1,3 and beta1 staining was detected with only traces of alpha6 and alpha(v). We conclude that alveolar epithelial cells do not express the hemidesmosome-associated, laminin-binding integrin alpha6beta4 of the bronchial epithelium but rather the alpha1beta1 and alpha3beta1, collagen IV, and laminin receptors, respectively. SCC, ADC, and sampled LCC express an integrin repertory qualitatively similar to that of the bronchial epithelium. Distinct from the latter, the integrin repertory of BAC parallels that of the alveolar epithelium by its strong expression of the multipotential alpha1beta1 and alpha3beta1 integrins. NEC tumors do not display the laminin receptors alpha6beta4 and alpha6beta1 shown by SCC and ADC but express instead alpha1beta1, a collagen IV-laminin receptor rarely found in epithelial neoplasms except for BAC. In NEC tumors, integrins, especially alpha2, decrease with dedifferentiation. Notably distinct from epithelial mesotheliomas, the major fibronectin-binding integrin alpha5beta1 was not found in any type of lung carcinoma.

Stability of the glycoprotein A-80 in prostatic carcinoma subsequent to androgen deprivation therapy.

Androgen deprivation therapy (ADT) results in profound morphologic changes in the benign and malignant prostatic epithelium, including acinar shrinkage and distortion, cytoplasmic clearing, and nuclear hyperchromatism. Data on the immunophenotype of prostatic carcinoma following ADT are limited. A-80 is an oncodevelopmental, mucinous glycoprotein that is strongly and consistently upregulated in high-grade prostatic intraepithelial neoplasia and adenocarcinoma; its expression following ADT has not been investigated. We applied a monoclonal antibody to A-80 to paraffin sections of 54 prostatic carcinomas surgically removed after ADT (Leupron with or without flutamide) and found immunoreactions in 53 of 54 samples (98%). Intense staining was seen in cancer glands, solid aggregates, single cells, and mucinous pools as well as in poorly defined acini lined by shrunken and distorted cells that were difficult to identify as malignant. Hemangiopericytoma-like areas showed A-80 staining in the lumina. Normal, metaplastic, hyperplastic, and atrophic ducts were not similarly reactive. Our findings indicate that there is remarkable stability of the upregulated A-80 glycoprotein in prostatic adenocarcinoma after ADT, despite severe architectural and cytologic alterations. The A-80-reactive colloid pools may reflect ruptured neoplastic glands and spillage of secreted material into stromal spaces. Strong A-80 staining, combined with sporadic cytokeratin reactions in the lumina of hemagiopericytomatous areas, suggests that these are souvenirs of carcinomatous glands revealed by antigenic relics of their component cells. The persistence of A-80 immunoreactivity provides a useful marker for recognizing and monitoring prostatic carcinoma after ADT.

Differential diagnosis of small cell neuroendocrine carcinoma of the lung.

The clinical significance of a tumor classification rests in its usefulness to predict the natural history and response to therapeutic intervention of given tumor types. In this context, the importance of distinguishing between SCNC and neoplasms with which it has been confused is evident. In 1990, we re-evaluated a series of 50 patients who underwent a complete resection for tumors in which the diagnosis of small cell carcinoma was thought to have been established. Adjuvant therapy was given to nearly all patients, either pre- or postoperatively. We re-evaluated the histology of these tumors in light of the differential diagnosis described previously and correlated the diagnosis with the survival curves. We found that WDNC of any subtype has a much better prognosis than SCNC. Even locally advanced WDNC has a better prognosis than stage I completely resected SCNC (Fig. 9). Others have reported similar observations based on their own retrospective studies. Preliminary observations on completely resected chest wall PNETs suggest that these tumors also have a more favorable prognosis than SCNC. Given the difficulty in distinguishing SCNC from other tumors described previously, and the fact that most SCNC are treated without resection, the clinician should be familiar with certain features that are unusual for SCNC, and, therefore, suggest reconsideration of the diagnosis. In our patient population, SCNC is rarely seen in a lifetime nonsmoker and is distinctly unusual in an ex-smoker of 15 years of longer. T with chest wall invasion is a very unusual clinical stage for true SCNC. Small cell neuroendocrine carcinoma can invade the chest wall, but this is almost always in the presence of extensive mediastinal or distant metastases. Clinicians should also be wary of accepting the diagnosis of SCNC when serial radiographs suggest that the lesion is not growing or growing very slowly. Untreated SCNC usually demonstrates some growth over a 3-month period of observation. Finally, SCNC tends to be a chemosensitive neoplasm, at least initially. The occasional tumors that do not respond tend to enlarge and disseminate rapidly. If a tumor neither decreases nor increases in diameter over a 3-month period of presumably appropriate chemo- or radiotherapy, the diagnosis of SCNC should be questioned. Over the last 15 years, several reports have suggested a role for resection in the management of SCNC, especially for tumors diagnosed at an early stage. Other reports may have unwittingly exaggerated the long-term survival of SCNC treated by currently available chemo- and radiotherapy protocols. A careful re-evaluation of the diagnostic material in such cases may lead to more consistent results and the development of more rational therapeutic protocols.