Vulnerable newborn types: analysis of subnational, population-based birth cohorts for 541 285 live births in 23 countries, 2000-2021.

OBJECTIVE: To examine prevalence of novel newborn types among 541 285 live births in 23 countries from 2000 to 2021. DESIGN: Descriptive multi-country secondary data analysis. SETTING: Subnational, population-based birth cohort studies (n = 45) in 23 low- and middle-income countries (LMICs) spanning 2000-2021. POPULATION: Liveborn infants. METHODS: Subnational, population-based studies with high-quality birth outcome data from LMICs were invited to join the Vulnerable Newborn Measurement Collaboration. We defined distinct newborn types using gestational age (preterm [PT], term [T]), birthweight for gestational age using INTERGROWTH-21st standards (small for gestational age [SGA], appropriate for gestational age [AGA] or large for gestational age [LGA]), and birthweight (low birthweight, LBW [<2500 g], nonLBW) as ten types (using all three outcomes), six types (by excluding the birthweight categorisation), and four types (by collapsing the AGA and LGA categories). We defined small types as those with at least one classification of LBW, PT or SGA. We presented study characteristics, participant characteristics, data missingness, and prevalence of newborn types by region and study. RESULTS: Among 541 285 live births, 476 939 (88.1%) had non-missing and plausible values for gestational age, birthweight and sex required to construct the newborn types. The median prevalences of ten types across studies were T+AGA+nonLBW (58.0%), T+LGA+nonLBW (3.3%), T+AGA+LBW (0.5%), T+SGA+nonLBW (14.2%), T+SGA+LBW (7.1%), PT+LGA+nonLBW (1.6%), PT+LGA+LBW (0.2%), PT+AGA+nonLBW (3.7%), PT+AGA+LBW (3.6%) and PT+SGA+LBW (1.0%). The median prevalence of small types (six types, 37.6%) varied across studies and within regions and was higher in Southern Asia (52.4%) than in Sub-Saharan Africa (34.9%). CONCLUSIONS: Further investigation is needed to describe the mortality risks associated with newborn types and understand the implications of this framework for local targeting of interventions to prevent adverse pregnancy outcomes in LMICs.

Cooling and Autonomous Feedback in a Bose-Hubbard Chain with Attractive Interactions.

We engineer a quantum bath that enables entropy and energy exchange with a one-dimensional Bose-Hubbard lattice with attractive on-site interactions. We implement this in an array of three superconducting transmon qubits coupled to a single cavity mode; the transmons represent lattice sites and their excitation quanta embody bosonic particles. Our cooling protocol preserves the particle number-realizing a canonical ensemble-and also affords the efficient preparation of dark states which, due to symmetry, cannot be prepared via coherent drives on the cavity. Furthermore, by applying continuous microwave radiation, we also realize autonomous feedback to indefinitely stabilize particular eigenstates of the array.

Non-malignant occupational respiratory diseases and climate change.

BACKGROUND: Respiratory diseases of infectious, allergic, neoplastic or degenerative origin are due to the interaction of environmental and occupational risk factors, individual susceptibility and other co-factors and comorbidities. Asthma and other respiratory pathologies can be worsened by climate change and exposure to other agents in occupational environments.METHODS: PubMed and Scopus, and several websites on public and occupational health were queried to find publications and documents on work-related respiratory diseases, asthma, rhinitis, chronic obstructive pulmonary disease (COPD), pneumoconiosis and allergic alveolitis in association with climate change.RESULTS: Most of the retrieved articles concerned asthma (75 in Scopus), while the other topics were less frequently covered in the scientific literature, with a maximum of 29 papers for rhinitis and 23 for COPD. The most important terms highlighted by the word clouds were 'health', 'air', 'pollution', and, only for asthma and rhinitis, 'pollen' and 'allergic/allergy'. Website data on public and occupational health, and climate change were reported.CONCLUSIONS: Assessment and management of respiratory diseases that recognise occupational exposures should be improved, and more research into integrated approaches should be favoured. Health surveillance practices for workers exposed to agents that cause respiratory diseases should be implemented. The development of biomarkers of exposure, effect and susceptibility needs further study.

[Fitness of workers with particular sensitivity to non-ionizing radiation]. / L'idoneità dei lavoratori con particolore sensibilità alle radiazioni non ionizzanti.

Chapter IV and V of Title VIII of D.Lgs 81/2008, implementing the Directives 2004/40/EC respectively (protection of workers exposed to electromagnetic fields) and 2006/25/EC (protection of workers exposed to artificial optical radiation), make frequent reference to the workers as "at particular risk" namely those workers who, by their biological or pathological characteristics, lifestyles, multiple exposure to other risk factors, may be more susceptible to the effects of electromagnetic fields or optical radiation. The identification of workers with particular sensitivity is essential for health surveillance, in particular regarding the determination of fitness. The operational guidance on Title VIII of D.Lgs 81/2008 drafted by the Italian Technical Coordination for Safety in the workplace of Regions and Autonomous Provinces (Document No. 1-2009), in collaboration with ISPESL and ISS, includes a preliminary identification of the categories of workers considered most susceptible to the risk from exposure to electromagnetic fields and optical radiation. On the basis of this information the authors identified more focused and structured classes of workers to be considered as "particularly sensitive to risk", it is not only related to a specific wavelength, but based on a comprehensive risk assessment in individual exposure situation, with regard to the exposure levels, any multiple exposures, the possibility of adequate personal protection.

[EU directive on electromagnetic fields and its implementation]. / Direttiva sui campi elettromagnetici e suo recepimento.

Critical features in applying the EU directive 2004/40/CE on the minimum health and safety requirements regarding the exposure of workers to risks arising from electromagnetic fields, jointly with the need to update the scientific rationale on the basis of the new international recommendations (ICNIRP), lead the EU Commission to stop the implementation of the directive by the member states and to start a pathway of consultation and study involving experts and representatives of Institutions and social partners. The process is ongoing, but the analysis of critical features of the EU directive 2004/40/CE allowed to identify the reference points in order to arrange a new directive.

Metabolic profile during pregnancy in BRISA birth cohorts of Ribeirão Preto and São Luís, Brazil.

During pregnancy, metabolic changes that develop in women may increase the risk of diseases and conditions that may also harm the life of the growing fetus. The aim of the present study was to identify and compare the metabolic profile (MP) during pregnancy in two birth cohorts in 2010 in the cities of Ribeirão Preto (RP) and São Luís (SL), Brazil. Pregnant women (1393 in RP and 1413 in SL) were studied; information was obtained through questionnaires in addition to anthropometric, biochemical, and blood pressure measurements. Data are presented as means and proportions. To compare the characteristics of pregnant women in both cities, chi-squared and Student's t-tests were applied, with 5% significance level. Ribeirão Preto presented higher mean values than SL for pre-gestational body mass index (24.5 vs 23 kg/m2, P<0.001), systolic (108.4 vs 102.8 mmHg, P<0.001) and diastolic (65.9 vs 61.8 mmHg, P<0.001) blood pressure, total cholesterol (226.3 vs 213.7 mg/dL, P<0.001) and fractions, and glycemia (84.5 vs 80.2 mg/dL, P<0.001), except for triglycerides (P=0.135). Women from RP also showed higher rates of pre-gestational overweight and obesity compared with SL (40.1 vs 25.8%). In the present study, pregnant women in RP had a worse gestational metabolic profile than those in SL, with higher pre-gestational excess weight, indicating that nutritional transition was more advanced in the more developed city.

Is birth weight associated with pregestational maternal BMI? BRISA Cohort, Ribeirão Preto, Brazil.

Given the increase of women with excess weight or obesity and its possible effects on birth weight, the present study aimed to investigate the association between pregestational maternal body mass index (BMI) and birth weight in a birth cohort from Ribeirão Preto, SP, Brazil. This was a prospective study conducted on 1362 mother-child pairs involving singleton births. The women were evaluated using standardized questionnaires during the second trimester of pregnancy and at the time of childbirth. Information about the newborns was obtained from their medical records. The dependent variable was birth weight, categorized as low, adequate, or high. The independent variable was pregestational maternal BMI, categorized as malnutrition, adequate weight, overweight, and obesity. A multinomial regression model was used to estimate the crude and adjusted relative risk (RR) of low and high birth weight. A high frequency of pregestational excess weight (39.6%) was detected and found to be independently associated with high birth weight (RR=2.13, 95%CI: 1.19-3.80 for overweight and RR=3.34, 95%CI: 1.80-6.19 for obese pregnant women). There was no association between pregestational malnutrition and low birth weight (RR=1.70; 95%CI: 0.81-3.55). The present data showed a high rate of women with excess pregestational weight, supporting the hypothesis that pregestational BMI may contribute to high birth weight babies and indicating the need for actions aiming to prevent excessive weight in women at reproductive age.

[Use of the comet test in occupational medicine and industrial toxicology: considerations and prospects]. / Impiego del comet test in medicina del lavoro e tossicologia industriale: considerazioni e prospettive.

The comet test (Single Cell Gel Electrophoresis or SCGE) is an easy to perform, rapid and highly sensitive genotoxicity assay; it requires small amounts of biological substrate and is applicable in vivo and in vitro to a wide variety of cells and tissues. Modified versions of the comet test able to detect oxidative damage or the effects of agents inducing DNA-DNA or DNA-protein crosslinks are available. Similarly to other genotoxicity assays, the comet test is not predictive far individual cancer risk. Limitations and critical features presently linked to comet test applications, with particular regard to the biomonitoring of individuals exposed to genotoxic agents, include: lack of sensitivity with respect to aneugens (agents inducing numerical chromosomal aberrations), possible underestimation of genotoxic potency of agents with mixed action mechanisms, sensitivity depending on the genotoxic agent itself, dependence an biological substrate with regard to the influence of cytotoxicity on the assay results, influence of age, tobacco smoke, alcohol and drug consumption, diet, kinetics of DNA adducts and DNA repair mechanisms. Consequently, a routine use of the comet test in biological monitoring of individuals that are occupationally and environmentally exposed to genotoxic agents is submitted to its validation by multicentric studies on large population samples with different exposure patterns, with a suitable characterisation of the role played by the above mentioned factors. Human studies should also be increasingly focused on the direct cellular targets of exposure to genotoxicants (e.g. epithelial cells of oral cavity and airways).

Is birth weight associated with pregestational maternal BMI? BRISA Cohort, Ribeirão Preto, Brazil

Given the increase of women with excess weight or obesity and its possible effects on birth weight, the present study aimed to investigate the association between pregestational maternal body mass index (BMI) and birth weight in a birth cohort from Ribeirão Preto, SP, Brazil. This was a prospective study conducted on 1362 mother-child pairs involving singleton births. The women were evaluated using standardized questionnaires during the second trimester of pregnancy and at the time of childbirth. Information about the newborns was obtained from their medical records. The dependent variable was birth weight, categorized as low, adequate, or high. The independent variable was pregestational maternal BMI, categorized as malnutrition, adequate weight, overweight, and obesity. A multinomial regression model was used to estimate the crude and adjusted relative risk (RR) of low and high birth weight. A high frequency of pregestational excess weight (39.6%) was detected and found to be independently associated with high birth weight (RR=2.13, 95%CI: 1.19-3.80 for overweight and RR=3.34, 95%CI: 1.80-6.19 for obese pregnant women). There was no association between pregestational malnutrition and low birth weight (RR=1.70; 95%CI: 0.81-3.55). The present data showed a high rate of women with excess pregestational weight, supporting the hypothesis that pregestational BMI may contribute to high birth weight babies and indicating the need for actions aiming to prevent excessive weight in women at reproductive age.

Metabolic profile during pregnancy in BRISA birth cohorts of Ribeirão Preto and São Luís, Brazil

During pregnancy, metabolic changes that develop in women may increase the risk of diseases and conditions that may also harm the life of the growing fetus. The aim of the present study was to identify and compare the metabolic profile (MP) during pregnancy in two birth cohorts in 2010 in the cities of Ribeirão Preto (RP) and São Luís (SL), Brazil. Pregnant women (1393 in RP and 1413 in SL) were studied; information was obtained through questionnaires in addition to anthropometric, biochemical, and blood pressure measurements. Data are presented as means and proportions. To compare the characteristics of pregnant women in both cities, chi-squared and Student's t-tests were applied, with 5% significance level. Ribeirão Preto presented higher mean values than SL for pre-gestational body mass index (24.5 vs 23 kg/m2, P<0.001), systolic (108.4 vs 102.8 mmHg, P<0.001) and diastolic (65.9 vs 61.8 mmHg, P<0.001) blood pressure, total cholesterol (226.3 vs 213.7 mg/dL, P<0.001) and fractions, and glycemia (84.5 vs 80.2 mg/dL, P<0.001), except for triglycerides (P=0.135). Women from RP also showed higher rates of pre-gestational overweight and obesity compared with SL (40.1 vs 25.8%). In the present study, pregnant women in RP had a worse gestational metabolic profile than those in SL, with higher pre-gestational excess weight, indicating that nutritional transition was more advanced in the more developed city.

Adjuvant chemotherapy with vincristine, cyclophosphamide, and doxorubicin after radiotherapy in local-regional nasopharyngeal cancer: results of a 4-year multicenter randomized study.

To evaluate the effect of adjuvant chemotherapy in patients with local-regional nasopharyngeal carcinoma (NPC) (squamous or undifferentiated) in complete remission at the end of curative radiotherapy (RT) 229 patients were randomized from 1979 to 1983 in a multicenter study to no further therapy (116 patients) or a combination of vincristine, cyclophosphamide, and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) (VCA) for six monthly cycles (113 patients). The RT and RT + VCA groups were well balanced for median age (50 v 49 years), histology (undifferentiated carcinoma, 73% v 70%), tumor extent (tumor limited to nasopharynx, 57% v 57%), and nodal extent (negative nodes 26% v 24%, nodes in the lower cervical levels, 17% v 16%). RT was delivered to the nasopharynx, the base of the skull, and bilateral cervical nodes using a split course technique over 10 weeks up to the dose of 60 to 70 Gy in involved sites and 50 Gy to negative nodes. Response to RT was evaluated within 65 days post-RT treatment. Analysis at 48 months did not show significant difference between the two treatment groups in terms of relapse-free survival (RT, 55.8%, RT + VCA, 57.7%, P = .45) and overall survival (RT, 67.3%, RT + VCA, 58.5%, P = .13). The pattern of relapse was similar in the two treatment arms. Distant metastases were the cause of treatment failure in about 50% of relapsing patients. Although the results of the present study did not show any benefit from VCA administered after curative RT, combined systemic chemotherapy should be further explored due to the high incidence of local and distant failure after intensive RT.

All-trans retinoic acid (ATRA) in patients with chronic myeloid leukemia in the chronic phase.

Since in vitro observations indicated that all-trans retinoic acid (ATRA), especially in combination with IFNalpha, can exert significant suppressive effects on Ph+ cells, we investigated the effects and the pharmacokinetic profile of ATRA in a selected cohort of patients with Ph+ chronic myeloid leukemia (CML) in chronic phase. Eighteen patients were treated with ATRA at a dose of 80 mg/m2/day (p.o.), divided into two equal doses after meals, for 7 consecutive days every other week for a maximum of 12 courses (1 course = 1 week on and 1 week off). Pharmacokinetic profiles of ATRA were evaluated during intermittent therapy on days 1 and 7 of course 1; on day 1 of course 2; on day 1 of course 6. Out of the 18 patients treated with ATRA, 11 (61%) went off study before the sixth course of treatment because of progressive hyperleukocytosis (seven cases), or thrombocytosis (one case), or refusal (three cases). Seven (39%) patients completed the first six courses (12 weeks) of treatment with ATRA and two of them (11%) maintained a white blood cell (WBC) <10 x 10[9]/l which was induced by the pretreatment with hydroxyurea. One patient completed the 12th course of ATRA maintaining WBC <10 x 10(9)/l, platelets <500 x 10(9)/l and spleen not palpable. The treatment with ATRA was well tolerated and only one patient discontinued the therapy because of non-hematological side-effects. The area under the concentration-time curve (AUC) decreased significantly (P< 0.001) during the first week of therapy. By adopting an intermittent dosing regimen, 1 week on/ 1 week off (1 course), at the start of courses 2 and 6, we obtained the ATRA AUCs equivalent to the ones achieved on day 1 of course 1. In conclusion, our results showed that ATRA alone appeared to be unable to control the WBC expansion in the CML patients in chronic phase. Moreover, it did not induce any remarkable cytoreductive effects on the platelet count and on the hemoglobin level. The major interest of ATRA would be in combination with other therapies. If ATRA was given in combination with IFNalpha or other agents, dose reduction of these would not be planned. On the basis of the pharmacokinetic profile, ATRA should be administered intermittently rather than continuously.

[Bystander effect: critical review and implications for risk assessment in radioprotection]. / Effetto bystander: rassegna critica e implicazioni per la valutazione del rischio in radioprotezione.

A growing experimental evidence indicates that ionizing radiation is able to determine relevant biological effects, including reduction in cell survival, cytogenetic alterations, gene mutations, induction of apoptosis and gene expression modification, in cells not directly hit by radiation. Such a phenomenon, known as bystander effect, has been described for radiation of different quality (alpha, gamma, X, beta radiation, heavier ions) and for different types of cells; it is relevant at low doses (even few mGy) and in many cases it seems to be persistent over time. Bystander effect is surely mediated by soluble factors released by irradiated cells into the extracellular environment and/or by the passage of mediators through gap junctions. The search of the effect in vivo, the setting up of models of risk assessment at low doses of ionizing radiation accounting for the bystander effect and the identification and quantification of this effect in relation to chemical agents displaying genotoxic and carcinogenic potential are primary research goals.

Evaluación de fenotipos nutricionales del recién nacido con el estándar INTERGROWTH-21st para predicción de morbilidad y mortalidad neonatales / Evaluation of the INTERGROWTH-21st project newborn standard for neonatal phenotypes and neonatal morbidity and mortality / Avaliação dos fenótipos nutricionais do recém-nascido com o padrão INTERGROWTH-21st para predição de morbimortalidade neonatal

Introducción: El uso de referencias locales o estándares para estudios neonatales aún requiere su validación a través de indicadores de morbilidad y mortalidad. Objetivo: Comparar la capacidad predictiva del estándar INTERGROWTH-21st(IG-21st) y una referencia argentina (Urquia) mediante los fenotipos de crecimiento fetal y morbi-mortalidad neonatales. Métodos: Estudio de cohorte retrospectivo de recién nacidos vivos entre 33 y 42 semanas del Hospital Materno-Infantil Ramón Sarda (Buenos Aires, Argentina), entre 1996-2001 (n = 25948). Los fenotipos pequeños (PEG) y grandes para la edad gestacional, acortado y emaciado y un índice compuesto de morbilidad / mortalidad neonatal (CNMM) se contrastaron entre IG-21st y la referencia Urquia. Resultados: El 3er percentil del peso al nacer de Urquia fue menor que el de IG-21st antes de las 37 semanas; 2.3%, 5.9% y 8.9 de los RN fueron <3o, <10° y > 97° percentil, respectivamente, bajo el estándar IG-21st, mientras que 3,7%, 10,1% y 8,4% fueron <3 °, <10 ° y> 97 ° percentil, respectivamente, bajo la referencia Urquia. Acortados fueron 16.1% y emaciados 0.9%, bajo IG-21st. CNMM bajo IG-21st fueron 28.5%, 19.6% y 8.5% en peso<3o, <10º y >97º percentil, respectivamente, mientras que 21.8%, 14.2% y 8.0% ocurrieron en peso< 3°, <10° y > 97° percentil bajo Urquia. Acortados fueron 17.3% y emaciados 18.3%. Los RN <3er°, <10° y > 97° percentil bajo IG-21st mostraron mayor riesgo de CNMM en comparación con la referencia Urquia. Conclusiones: El estándar IG-21st identificó mayor riesgo de morbilidad y mortalidad que la referencia Urquia. (AU)

The use of local references or standard for neonatal studies still requires their validation through indicators of morbidity and mortality. Objective: evaluate the performance of the INTERGROWTH-21st Project (IG-21) standard and a commonly used Argentinian reference (Urquia) by examining the differences in the frequency of growth phenotypes, and the associated neonatal morbidity and mortality. Methods: Retrospective cohort study of all singleton live-births from Sarda Maternity Hospital (Buenos Aires, Argentina) between 33 and 42 gestational age, using information obtained from a Perinatal Surveillance System (Agustina) dataset between 1996-2001 (n = 25948). Phenotypes small-and large-for-gestational age, stunting and waisting and a composite of neonatal morbidity/mortality (CNMM) werecontrasted between the IG-21 standard and Urquia reference. Results: the Urquia 3rd centile value was lower than IG-21 before 37 weeks, but then it surpassed IG-21 until term. Among Sarda, 2.3%, 5.9% and 8.9 were <3rd, <10th and >97th centile, respectively, under the IG-21 standard, while 3.7%, 10.1% and 8.4% were <3rd, <10th and >97th centile, respectively, under the Urquia reference. Stunting and waisting were 16.1% and 0.9%, respectively under IG-21. The IG-21 detection rates of CNMM showed that 28.5%, 19.6% and 8.5% occurred among weight<3rd,<10th and >97th centile, respectively, while 21.8%, 14.2% and 8.0% occurred among <3rd, <10th and >97th centile under the Urquia criteria. Newborn weight <3rd,<10th and >97th centile under IG-21 showed higher neonatal CNMM risk compared with Urquia reference. Conclusions: The IG-21 standard identified a higher risk of neonatal morbidity and mortality than the Urquia reference. (AU)

Introdução: O uso de referências locais ou padrões para estudos neonatais ainda exige validação por meio de indicadores de morbimortalidade. Objetivo: Comparar a capacidade preditiva do padrão INTERGROWTH-21st (IG-21st) e uma referência argentina (Urquia) examinando as diferenças nos fenótipos de crescimento fetal neonatal e morbimortalidade. Métodos: Estudo de coorte retrospectivo de recém-nascidos vivos (RNV) entre 33 e 42 semanas do Hospital Materno Infantil Ramón Sarda (Buenos Aires, Argentina), entre 1996-2001 (n = 25948). Fenótipos pequeno (PEG) e grande para idade gestacional, encurtado e emaciado e um índice composto de morbimortalidade neonatal (CNMM) foram contrastados entre o IG-21st e a referência de Urquia. Resultados: o 3º percentil do peso ao nascer de Urquia foi inferior ao do IG-21st antes de 37 semanas; 2,3%, 5,9% e 8,9 dos RNV apresentaram percentil <3, <10 e> 97, respectivamente, segundo o padrão IG-21st, enquanto 3,7%, 10,1% e 8,4% foram < percentil 3, <10 e> 97, respectivamente, sob a referência Urquia. Encurtados foram 17,3% e emaciados 18,3% sob IG-21st. Os RNV <3º, <10º e> 97º percentil no IG-21st apresentaram maior risco de CNMM em comparação com a referência Urquia. Conclusões: O padrão IG-21st identificou um risco maior de morbimortalidade do que a referência Urquia. (AU)

From chemoprevention and organ preservation programmes to postoperative management: major achievements and strategies of the EORTC Head and Neck Cancer Group.

The purpose of this article is to review the most significant results of the clinical studies conducted in the past two decades by the EORTC Head and Neck Cancer Group (HNCG). As for phase III trials, the HNCG investigated, besides the efficacy of chemopreventive drugs, the impact of cytostatic agents on various therapeutic targets, in combination or not with surgery and chemotherapy. These targets were: (a) chemo-prevention in curatively treated early stage disease; (b) organ preservation programmes in patients with operable tumour, comparing immediate surgery versus first-line chemotherapy; (c) postoperative management of locally advanced tumours, comparing radio-chemotherapy versus radiotherapy alone. Other phase II and phase III studies were also completed to investigate drug activity in advanced and/or recurrent head and neck squamous cell and adenoid cystic carcinomas. The present article will also analyse the strategies developed within the Group in the field of translational research.

Epstein-Barr virus genomes in undifferentiated and squamous cell nasopharyngeal carcinomas in Italian patients.

Although undifferentiated carcinoma (UC) and squamous cell carcinoma (SCC) of the nasopharynx are regarded as two distinct histopathologic and clinical entities, it is unclear whether, like UC, SCC carries Epstein-Barr virus (EBV) genomes. We used the polymerase chain reaction (PCR) on paraffin-embedded biopsy specimens to test for the presence of EBV DNA in 20 cases of UC and 9 cases of SCC. Multiple copies of the viral genome were regularly detected in all UCs; however, of the nine cases of SCC, seven had no detectable EBV DNA and two contained viral genomes in a low copy number. In parallel, a marked difference in the serum levels of anti-EBV antibodies between patients with UC and SCC was found. Our findings provide evidence for the specific association of EBV with UC in Italian patients and prove by means of a highly sensitive molecular technique that SCC is occasionally related to EBV DNA. Because of the absence of EBV DNA in most cases of SCC and the minimal viral DNA copy number in the few EBV-associated cases of SCC, a different pathway of oncogenic transformation and growth of the nasopharyngeal epithelium is suggested for SCC and UC.

Identification, sequencing and mutagenesis of the gene for a D-carbamoylase from Agrobacterium radiobacter.

A clone positive for D-carbamoylase activity (2.7 kb HindIII-BamHI DNA fragment) was obtained by screening a genomic library of Agrobacterium radiobacter in Escherichia coli. This DNA fragment contains an open reading frame of 912 bp which is predicted to encode a peptide of 304 amino acids with a calculated molecular mass of 34247 Da. The D-carbamoylase gene, named cauA, was placed under the control of T7 RNA-dependent promoter and expressed in E. coli BL21(DE3). After induction with isopropyl-thio-beta-D-galactopyranoside, the synthesis of D-carbamoylase in E. coli reached about 40% of the total protein. The expressed protein was shown to possess a molecular mass, on SDS-PAGE, of 36 kDa and showed an enhanced stability with respect to that of the wild-type enzyme derived from A. radiobacter. Site-directed mutagenesis experiments allowed us to establish that a Pro14-->Leu14 exchange leads to an inactive enzyme species, while a Cys279-->Ser279 exchange did not impair the functional properties of the enzyme.

Surgery versus combined therapies for cancer of the anterior floor of the mouth.

We report the results of treatment in a consecutive series of 75 patients operated on at the Istituto Nazionale Tumori of Milan, from January 1965 to December 1979, for cancer of the anterior floor of the mouth. Most of the tumors were advanced: 39 were treated with simple resection, and 36 underwent combined treatment, consisting of surgery associated with either chemotherapy or surgery. Three- and five-year observed survival rates of the whole series were good (41% and 25%, respectively), considering the tumor stage of these patients, but the determined survival rates were particularly high (56% and 46%, respectively). No real advantage was found in the use of multiple planned sequential therapies over surgery alone, and deaths from intercurrent diseases seemed to be more frequent in the patients who underwent combined therapies. We conclude that for patients in poor general condition, such as those with carcinomas of the anterior floor of the mouth, aggressive and complex treatments should be considered with caution in controlled clinical trials.

Prognostic significance of lymphatic spread in head and neck carcinomas: therapeutic implications.

A series of 618 patients with neck dissections were performed in 455 consecutively admitted patients with head and neck carcinomas at the Istituto Nazionale Tumori, Milan, from 1976 to 1978. Clinical and pathologic node factors were considered in an effort to correlate lymph node involvement with prognosis. Actuarial survival decreased with the increase in the size of nodes, although no significant difference was found for all categories and the prognosis was poor when nodes were greater than 5 cm and/or hypomobile (33%, 5-year survival). The presence of histologically proven neck metastases significantly reduces the 5-year survival, and the presence of distant metastases correlates directly with the pathologic staging of neck nodes.

Mucosal malignant melanoma of head and neck: forty-eight cases treated at Istituto Nazionale Tumori of Milan.

A series of 48 cases of malignant mucosal melanomas treated at the Milan Cancer Institute from 1975 to 1990 is retrospectively reviewed. There were 34 males and 14 females, and their ages ranged from 21 to 79 years (mean, 58). The site of origin of the tumor was the nasal cavity in 26 cases, the oral cavity in 15, larynx in two, lip mucosa in two, pharynx in two and upper esophagus in one. At presentation, the neoplasm was limited to the primary site in 60.4% of the patients. Most patients (34) were treated with surgery alone. Nine were treated with surgery combined with chemo- and/or radiotherapy and five with radiotherapy combined with chemotherapy and/or immunotherapy. Only when surgery was part of the treatment (42 of 48 cases) the patients were rendered disease free, but no further relapse of disease was documented in only five of these patients. The observed 2- and 5-year survival rate of the entire group was 45% and 21%, respectively. The 4-year disease-free survival rate was 7%. The median interval between therapy and the first relapse was 8.5 months (range, 1-66). In 44% of the patients the first recurrence of the tumor was at the primary site.