Acute Toxicity of Hypofractionated and Conventionally Fractionated (Chemo)Radiotherapy Regimens for Bladder Cancer: An Exploratory Analysis from the RAIDER Trial.

AIMS: Adding concurrent (chemo)therapy to radiotherapy improves outcomes for muscle-invasive bladder cancer patients. A recent meta-analysis showed superior invasive locoregional disease control for a hypofractionated 55 Gy in 20 fractions schedule compared with 64 Gy in 32 fractions. In the RAIDER clinical trial, patients undergoing 20 or 32 fractions of radical radiotherapy were randomised (1:1:2) to standard radiotherapy or to standard-dose or escalated-dose adaptive radiotherapy. Neoadjuvant chemotherapy and concomitant therapy were permitted. We report exploratory analyses of acute toxicity by concomitant therapy-fractionation schedule combination. MATERIALS AND METHODS: Participants had unifocal bladder urothelial carcinoma staged T2-T4a N0 M0. Acute toxicity was assessed (Common Terminology Criteria for Adverse Events) weekly during radiotherapy and at 10 weeks after the start of treatment. Within each fractionation cohort, non-randomised comparisons of the proportion of patients reporting treatment emergent grade 2 or worse genitourinary, gastrointestinal or other adverse events at any point in the acute period were carried out using Fisher's exact tests. RESULTS: Between September 2015 and April 2020, 345 (163 receiving 20 fractions; 182 receiving 32 fractions) patients were recruited from 46 centres. The median age was 73 years; 49% received neoadjuvant chemotherapy; 71% received concomitant therapy, with 5-fluorouracil/mitomycin C most commonly used: 44/114 (39%) receiving 20 fractions; 94/130 (72%) receiving 32 fractions. The acute grade 2+ gastrointestinal toxicity rate was higher in those receiving concomitant therapy compared with radiotherapy alone in the 20-fraction cohort [54/111 (49%) versus 7/49 (14%), P < 0.001] but not in the 32-fraction cohort (P = 0.355). Grade 2+ gastrointestinal toxicity was highest for gemcitabine, with evidence of significant differences across therapies in the 32-fraction cohort (P = 0.006), with a similar pattern but no significant differences in the 20-fraction cohort (P = 0.099). There was no evidence of differences in grade 2+ genitourinary toxicity between concomitant therapies in either the 20- or 32-fraction cohorts. CONCLUSION: Grade 2+ acute adverse events are common. The toxicity profile varied by type of concomitant therapy; the gastrointestinal toxicity rate seemed to be higher in patients receiving gemcitabine.

Overcoming the Chasm Between Evidence and Routine Practice for Bladder Cancer; Just a Quixotic Notion?

There has been a failure to improve outcomes in bladder cancer over the last 30 years. This is despite clinical trial evidence showing a benefit of interventions such as neoadjuvant chemotherapy or concurrent radiosensitisation for non-metastatic muscle-invasive bladder cancer. The bladder cancer population is characteristically elderly, who typically suffer from multiple comorbidities. Historically, radical cystectomy has been heralded as the treatment of choice, with radiotherapy being reserved for those with inoperable tumours or those unfit for major pelvic surgery, despite a lack of robust comparative or quality of life data to support one treatment recommendation over the other. Although patients with non-metastatic muscle-invasive bladder cancer have potentially curable disease, a growing body of population-based analyses persistently highlights that most patients do not undergo curative-intent treatments - a trend that remains static. The causes for the disparity between evidence and routine practice is not clearly understood. Here, the facets of patient-centred evidence-based care, with respect to bladder conservation therapy, are examined, with proposals to reverse this unacceptable status quo.

Clinical Guidance for the Management of Patients with Urothelial Cancers During the COVID-19 Pandemic - Rapid Review.

The current COVID-19 pandemic presents a substantial obstacle to cancer patient care. Data from China as well as risk models suppose that cancer patients, particularly those on active, immunosuppressive therapies are at higher risks of severe infection from the illness. In addition, staff illness and restructuring of services to deal with the crisis will inevitably place treatment capacities under significant strain. These guidelines aim to expand on those provided by NHS England regarding cancer care during the coronavirus pandemic by examining the known literature and provide guidance in managing patients with urothelial and rarer urinary tract cancers. In particular, they address the estimated risk and benefits of standard treatments and consider the alternatives in the current situation. As a result, it is recommended that this guidance will help form a framework for shared decision making with patients. Moreover, they do not advise a one-size-fits-all approach but recommend continual assessment of the situation with discussion within and between centres.

Radiotherapy Management of Muscle Invasive Bladder Cancer: Evaluation of a National Cohort.

AIMS: With the failure to improve outcomes of patients with bladder cancer over the last 30 years, this study was developed to benchmark contemporary UK radiotherapy practice for the management of muscle invasive bladder cancer (MIBC) against published national guidance. MATERIALS AND METHODS: All UK radiotherapy centres were invited to complete a questionnaire for each patient with MIBC starting bladder radiotherapy over a 16-week period from December 2016. RESULTS: Sixty-nine per cent (41/59) of UK radiotherapy centres completed a detailed questionnaire for 508 patients. The median age was 78 years and 64% (n = 323 patients) had stage II or III disease. Treatment intent was radical in 54% (n = 275). From transurethral resection of the bladder tumour, patients waited 57 days before starting neoadjuvant chemotherapy (NAC) (interquartile range 46-72 days). Patients who had radical radiotherapy as their first definitive treatment waited a median of 82 days (interquartile range 62-105 days). NAC was considered in 66% (n = 182) of all radical cases and given in 43% (n = 119). Concurrent radiosensitisation (CRT) was considered for 53% (n = 146) and delivered in 40% (n = 109) of patients. The most common fractionation was 55 Gy/20 fractions/4 weeks in 49% (n = 134) for radical patients and 36 Gy/6 fractions/6 weeks in 25% (n = 57) for palliative patients. CONCLUSION: This is the largest multicentre prospective study to define contemporary management of MIBC in patients receiving radiotherapy within the UK. The population studied is the oldest described to date. Timelines to starting definitive treatment confirm an urgent need to streamline the pathway. An increasing use of NAC is described, although the penetrance of CRT is disappointingly low. Areas for improvement with regards to the delivery and quality of radiotherapy have been identified. The detail within this study can be used to inform practice and future trial design, ultimately with the aim of improving outcomes for patients with MIBC.

Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.

Background: Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC + AAP versus SOC + DocP. Method: Recruitment to SOC + DocP and SOC + AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for ≥2 years and RT to the primary tumour. Stratified randomisation allocated pts 2 : 1 : 2 to SOC; SOC + docetaxel 75 mg/m2 3-weekly×6 + prednisolone 10 mg daily; or SOC + abiraterone acetate 1000 mg + prednisolone 5 mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC + AAP, and HR > 1 favours SOC + DocP. Results: A total of 566 consenting patients were contemporaneously randomised: 189 SOC + DocP and 377 SOC + AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66 years and median PSA 56 ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1.16 (95% CI 0.82-1.65); failure-free survival HR = 0.51 (95% CI 0.39-0.67); progression-free survival HR = 0.65 (95% CI 0.48-0.88); metastasis-free survival HR = 0.77 (95% CI 0.57-1.03); prostate cancer-specific survival HR = 1.02 (0.70-1.49); and symptomatic skeletal events HR = 0.83 (95% CI 0.55-1.25). In the safety population, the proportion reporting ≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC + DocP, and 40%, 7% and 1% SOC + AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm. Conclusions: This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs. Trial registration: Clinicaltrials.gov: NCT00268476.

Preventing tuberculosis in the foreign-born population of Canada: a mathematical modelling study.

BACKGROUND: Foreign-born persons in Canada contribute 67% of all tuberculosis (TB) cases annually, but represent only 21% of the total population. Molecular epidemiological studies suggest that most foreign-born TB cases result from the reactivation of latent tuberculous infection (LTBI) acquired before immigration. OBJECTIVE: To estimate the effect on incidence of a prevention strategy that would screen selected immigrants at arrival for LTBI and offer preventive treatment to those who test positive. DESIGN: A deterministic model was developed to quantify the incidence of active TB in immigrants to Canada and validated with national immigration and TB case data. RESULTS: Model simulations suggested that it would be optimal to screen and treat LTBI in new immigrants from countries of birth with an estimated TB incidence rate in excess of 50 per 100 000 person-years. If this strategy had been implemented in 1986, the national TB incidence rate would have fallen by 18.5%, from 5.4 to 4.4 cases per 100 000 population by 2002. CONCLUSION: This study suggests that screening and treating LTBI in foreign-born persons from high TB incidence countries is the most effective strategy in terms of total persons screened and treated and percentage reduction in national incidence.

Peroxide-enhanced endoanal ultrasound in preoperative assessment of complex fistula-in-ano.

BACKGROUND: In complex fistula-in-ano, preoperative imaging can help identify secondary tracts and abscesses that can be missed, leading to recurrence. We evaluated hydrogen peroxide-enhanced endoanal ultrasound (PEEUS) in the characterization of fistula compared with standard clinical and operative assessment. METHODS: Patients with complex fistula-in-ano treated between February 2008 and May 2009 at our institution were prospectively evaluated by PEEUS with recording of the preoperative clinical examination and intraoperative details of the fistula. Of the 135 patients with fistula-in-ano, 68 met the inclusion criteria for complex fistula-in-ano. Correlation of clinical findings and PEEUS to the gold standard intraoperative findings was assessed in characterizing the fistula. The percent agreement between the clinical and PEEUS findings against the gold standard was derived, and the kappa statistic for agreement was determined. RESULTS: The mean age of the cohort was 42.54 ± 10.86 years. The fistula tracts were curvilinear, high, and transsphincteric in 16 (23.53%), 8 (11.76%), and 42 (61.76%) patients, respectively. Secondary tracts and associated abscess cavities were seen in 28 (33.82%) and 35 (51.47%) patients, respectively. PEEUS correlated better than clinical examination with regard to site (92.65 vs 79.41%; p < 0.001) and course (91.18 vs 77.94%; p < 0.001) of secondary tract and associated abscesses (89.71 vs 80.88%; p = 0.02). There was a trend of better correlation of PEEUS compared to clinical examination in classifying the primary tract as per Park's system (88.24 vs 79.41%; p = 0.06), but it did not reach statistical significance. PEEUS and clinical examination were comparable in correlation of the level of the primary tract (kappa: 0.86 vs 0.78; p = 0.22) and the site of internal opening (kappa: 0.97 vs 0.89; p = 0.22). The operative decision was changed in 13 (19.12%) subjects based on PEEUS findings. CONCLUSIONS: PEEUS is a feasible and efficient tool in the routine preoperative assessment of complex fistula-in-ano.

Incorporating environmental stochasticity within a biological population model.

The birth and death transition rates for a population are modelled as functions of both the population size and the environmental condition. An assortment of important theoretical results and techniques that can be utilized to analyze such a population's behaviour is covered. Consequently, these results and techniques are used to study two examples. Firstly, we study a population with a stable equilibrium state, whose per capita birth and death rates are linearly related to the environmental condition. (The environmental condition in turn is modelled as an Ornstein-Uhlenbeck process.) Secondly, we study a population affected by two interdependent environmental factors.

Permissive hypercapnia in neonates: the case of the good, the bad, and the ugly.

Advances in neonatology have resulted in an increase in the absolute number of survivors with chronic lung disease (CLD), though its overall incidence has not changed. Though the single most important high-risk factor for CLD is prematurity, the focus of attention has recently changed over to minimizing the impact of other two risk factors: baro/volutrauma related to mechanical ventilation, and oxygen toxicity. Permissive hypercapnia (PHC) or controlled ventilation is a strategy that minimizes baro/volutrauma by allowing relatively high levels of arterial CO(2), provided the arterial pH does not fall below a preset minimal value. The benefits of PHC are primarily mediated by the reduction of lung stretch that occurs when tidal volumes are minimized. PHC can be a deliberate choice to restrict ventilation in order to avoid overdistention, while application of high airway pressures and large tidal volumes would permit normocapnia, or relative hypocapnia (PaCO(2), < or = 25-30 mmHg), but may result in CLD and be harmful to the developing lung. The current concept that PaCO(2) levels of 45-55 mmHg in high-risk neonates are "safe" and "well tolerated" is based on limited data. Further prospective trials are needed to study the definition, safety and efficacy of PHC in ventilated preterm and term neonates. However, designing disease/gestational-postnatal age-specific clinical trials of PHC will be difficult in neonates, given the diverse pathophysiology of their diseases and the various ventilatory modes/variables currently available. The potential benefits and adverse effects of PHC are reviewed, and its relationship to current ventilatory strategies like synchronized mechanical ventilation and high-frequency ventilation in high-risk neonates is briefly discussed.

Henna causes life threatening haemolysis in glucose-6-phosphate dehydrogenase deficiency.

Haemolytic crisis in glucose-6-phosphate dehydrogenase deficient individuals following topical application of henna occurred in four children: a female neonate (haemoglobin 50 g/l, serum bilirubin 700 micromol/l), who recovered after exchange transfusion; a male infant (haemoglobin 28 g/l) who died despite transfusion; and two preschool children (haemoglobin 40 and 41 g/l respectively).

Pharmacokinetics of CAMPATH-1H in BMT patients.

BACKGROUND: CAMPATH-1 (CD52)Abs are used in stem-cell transplantation for prevention of GvHD and rejection. The humanized Ab CAMPATH1H has recently replaced the rat Ab CAMPATH-1G. There was a concern whether it might have a longer half-life in vivo and, possibly, cause prolonged immunosuppression post-transplant. METHODS: Serum samples were collected pre- and post-transplant from patients receiving CAMPATH-1H at 10 mg/day according to two protocols: (A) from Day -5 to Day +4 (total dose, 100 mg), (B) from Day -10 to Day -6 (total dose, 50 mg). The Ab concentrations were measured using an immunofluorescence assay. RESULTS: Lymphocytes were substantially depleted by the second day of treatment and were below 0.1 x 10(9)/L by the day of transplant and for at least 1 month post-transplant. By Day 90 there was a greater recovery in Group B, to a median of 0.32 x 10(9)/L compared with 0.25 x 10(9)/L in Group A. By Day 180, both groups had recovered to approx 0.52 x 10(9)/L. Serum concentrations of CAMPATH-1H on the day of transplant were well above the level necessary for opsonization of lymphocytes. The peak Ab concentration was 6.1 micro g/mL in Group A and 2.5 micro g/mL in Group B. CAMPATH-1H could be detected in Group A for 23 days post-transplant, significantly longer than in Group B (11 days). The terminal half-life in the two groups was similar (range 15-21 days) and contrasts with the half-life of < 1 day previously estimated for CAMPATH-1G. There were no cases of graft failure and the incidence of GvHD was similar in the two groups. DISCUSSION: The humanized Ab CAMPATH-1H appears to persist in the circulation for longer than the original rat Ab CAMPATH-1G. This might contribute to delayed lymphocyte recovery and prohibit the use of early donor-lymphocyte infusions. A short course of treatment given early pre-transplant is likely to be preferable to the extended course given both pre- and post-transplant.

Successful use of topical nitroglycerine in ischaemia associated with umbilical arterial line in a neonate.

Ischaemic changes associated with umbilical arterial cannulation is an important cause of neonatal morbidity in the NICU. We report successful use of topical nitroglycerine in an infant with ischaemic changes over the right buttock following insertion of an umbilical arterial catheter.

Anthrax toxin fusion proteins for intracellular delivery of macromolecules

The dominant role played by the anthrax toxin in Bacillus anthracis pathogenesis shows that the toxin has evolved to be an efficient system for delivering its two catalytic protein components, oedema factor and lethal factor (LF), into the cytosol of host cells. This system involves binding of the protective antigen (PA) toxin component to a ubiquitous (and still unidentified) receptor, proteolytic activation at the cell surface, internalization by endocytosis and translocation through an early endosome membrane to the cytosol (Leppla 1995). We and colleagues showed that the system can be exploited to deliver heterologous polypeptides to the cytosol (Arora et al. 1992; Milne et al. 1995). This work used the catalytic domains of other toxins which are normally translocated across membranes (Arora & Leppla 1994). Immunity to intracellular pathogens depends on the cytosolic processing of antigens to produce peptides that are presented on the cell surface bound to MHC Class I molecules. The anthrax toxin delivery system provides a way to mimic this process. We made a fusion protein containing the (non-catalytic) amino terminal domain of LF and the gp120 envelope glycoprotein of HIV-1. Administration of this recombinant protein along with PA to antigen-presenting cells sensitized them to cytolysis by cytotoxic T-cells specific to gp120 peptides (Goletz et al. 1997). Further exploitation of the anthrax toxin system as a cell-targeting reagent would be facilitated by achieving cell type specificity. The recent determination of the PA structure (Petosa et al. 1997) allows rational engineering to modify or replace the receptor-binding domain with specific ligand structures. A model system was produced by fusing a c-Myc peptide to the carboxyl terminus of PA so as to target hybridoma cells expressing cell surface antibodies to this peptide. Killing of the hybridoma cells was shown to be specific by competition with the peptide and with non-toxic mutants of PA (Varughese et al. 1998).

Identification of a receptor-binding region within domain 4 of the protective antigen component of anthrax toxin.

Anthrax toxin from Bacillus anthracis is a three-component toxin consisting of lethal factor (LF), edema factor (EF), and protective antigen (PA). LF and EF are the catalytic components of the toxin, whereas PA is the receptor-binding component. To identify residues of PA that are involved in interaction with the cellular receptor, two solvent-exposed loops of domain 4 of PA (amino acids [aa] 679 to 693 and 704 to 723) were mutagenized, and the altered proteins purified and tested for toxicity in the presence of LF. In addition to the intended substitutions, novel mutations were introduced by errors that occurred during PCR. Substitutions within the large loop (aa 704 to 723) had no effect on PA activity. A mutated protein, LST-35, with three substitutions in the small loop (aa 679 to 693), bound weakly to the receptor and was nontoxic. A mutated protein, LST-8, with changes in three separate regions did not bind to receptor and was nontoxic. Toxicity was greatly decreased by truncation of the C-terminal 3 to 5 aa, but not by their substitution with nonnative residues or the extension of the terminus with nonnative sequences. Comparison of the 28 mutant proteins described here showed that the large loop (aa 704 to 722) is not involved in receptor binding, whereas residues in and near the small loop (aa 679 to 693) play an important role in receptor interaction. Other regions of domain 4, in particular residues at the extreme C terminus, appear to play a role in stabilizing a conformation needed for receptor-binding activity.

Microlissencephaly.

An inbred Arab family with three neonates affected by microlissencephaly syndrome is reported. Brain magnetic resonance imaging in the index case revealed very thin brain mantle with agyria-pachygyria, agenesis of the corpus callosum, and hypoplasia of the brainstem and cerebellum. All three neonates had microcephaly, arthrogryposis multiplex congenita, and micropenis. The presence of three affected newborn infants in a consanguineous family suggests an autosomal-recessive mode of inheritance of this syndrome. The spectrum of microlissencephaly syndrome is reviewed.

Internalization of a Bacillus anthracis protective antigen-c-Myc fusion protein mediated by cell surface anti-c-Myc antibodies.

BACKGROUND: Anthrax toxin, secreted by Bacillus anthracis, consists of protective antigen (PA) and either lethal factor (LF) or edema factor (EF). PA, the receptor-binding component of the toxin, translocates LF or EF into the cytosol, where the latter proteins exert their toxic effects. We hypothesized that anthrax toxin fusion proteins could be used to kill virus-infected cells and tumor cells, if PA could be redirected to unique receptors found only on these cells. MATERIALS AND METHODS: To test this hypothesis in a model system, amino acids 410-419 of the human p62(c-myc) epitope were fused to the C-terminus of PA to redirect PA to the c-Myc-specific hybridoma cell line 9E10. RESULTS: The PA-c-Myc fusion protein killed both mouse macrophages and 9E10 hybridoma cells when administered with LF or an LF fusion protein (FP59), respectively. Similar results were obtained with PA, which suggests that PA-c-Myc used the endogenous PA receptor to enter the cells. By blocking the endogenous PA receptors on 9E10 cells with the competitive inhibitor PA SNKEDeltaFF, the PA-c-Myc was directed to an alternate receptor, i.e., the anti-c-Myc antibodies presented on the cell surface. The c-Myc IgG were proven to act as receptors because the addition of a synthetic peptide containing the c-Myc epitope along with PA SNKEDeltaFF further reduced the toxicity of PA-c-Myc + FP59. CONCLUSION: This study shows that PA can be redirected to alternate receptors by adding novel epitopes to the C-terminus of PA, enabling the creation of cell-directed toxins for therapeutic purposes.

Infant feeding practices in Papua New Guinea.

Concern about a possibly increasing prevalence of bottle-feeding led in 1995 to an Infant Feeding Survey of 1822 mothers attending urban health facilities. Infant feeding practices including feeding of colostrum, exclusive breastfeeding, weaning practices and bottle-feeding were assessed. This revealed that 28.8% of mothers had not given colostrum to their babies, that 43.5% of 3-month-old babies were exclusively breastfed, and that solids were introduced before 4 months of age in over half of the study population. Bottle-feeding was used by 20% of the study population. Feeding practices differed in women of Highlands and of Coastal origin. The findings emphasize the need to strengthen health education programmes which take into account the mothers' different cultural backgrounds. The issue of breast-feeding by mothers in paid employment needs to be addressed.

PIP: Recognizing the many benefits of breast-feeding, the government of Papua New Guinea (PNG) legislated to protect the practice 4 years before the introduction of the World Health Organization Code of Marketing restricting access to bottle feeding supplies. While exclusive breast-feeding for 4-6 months is recommended policy, it was noticed that many mothers introduce solids and fluids other than breast milk much earlier. In 1995, the Pediatric Society of PNG conducted a feeding survey to assess the prevalence of bottle feeding and review the effects of the imposed legislation. Infant feeding practices, including the feeding of colostrum, exclusive breast-feeding, weaning practices, and bottle feeding were assessed among 1822 mothers of children under age 2 years attending urban health facilities. 28.8% of the mothers had not given colostrum to their babies, 43.5% of 3-month old babies were exclusively breast-fed, and solids were introduced before age 4 months in more than half of the study population. 20% of the study population bottle fed. The prevalence of exclusive breast-feeding among employed Highlands women was lower than among employed Coastal women, but the difference was not statistically significant. Study findings point to the need to strengthen health education programs which take into account mothers' different cultural backgrounds. The issue of breast-feeding by mothers in paid employment also needs to be addressed.

A light-repressed transcript found in Synechococcus PCC 7002 is similar to a chloroplast-specific small subunit ribosomal protein and to a transcription modulator protein associated with sigma 54.

The gene encoding a novel light-repressed transcript (lrtA) contained within a 2.7-kbp EcoRI fragment has been cloned and sequenced from the unicellular cyanobacterium, Synechococcus PCC 7002. Northern analysis indicates that this transcript is synthesized rapidly in the dark, but upon 20 min of illumination, transcript levels fall below detectable limits. An open reading frame was located 378 bases from the start of the transcript which encodes a 21-kDa protein with significant homology to two hitherto different proteins. The protein sequence LrtA showed 37% sequence identity and 58% sequence similarity to the chloroplast-specific small subunit ribosomal protein, S30, and 37% sequence identity and 60% sequence identity and 60% sequence similarity to the reported transcription modulator protein of sigma 54 found in Klebsiella pneumonia and Azotobacter vinelandii. Expression of the lrtA gene product is not detectable within 1 h after placing the cells in the dark, however, within 2.5 min of illumination, [35S]methionine incorporated into a 21-kDa protein. To a lessor extent, [35S]methionine incorporation into a 17- and a 14-kDa protein was also seen which was followed by two other recognizable waves of translation at 5 and 10 min. This incorporation was not blocked by rifampicin added to dark-adapted cells prior to illumination. [35S]Methionine pulsed-labeling experiments suggested that the translation of lrtA occurred only during the first 10 min of reillumination of dark-adapted cells. The loss of initial [35S]methionine labeling in the light of the 21-kDa protein in a kanamycin-interrupted lrtA gene mutant suggests that the lrtA codes for the 21-kDa protein.

Osteogenic sarcoma and Rothmund Thomson syndrome.

Rothmund Thomson syndrome (RTS) is a rare autosomal recessive disorder characterised by poikiloderma, dermal atrophy, dystrophic nails, short stature and hypogonadism. An increased incidence of malignancy has been reported in patients with this syndrome secondary, it is postulated, to DNA repair defects. We report the occurrence of an osteogenic sarcoma in an 11-year-old Irish girl with RTS. Although fibroblast cultures demonstrated enhanced radiosensitivity, there was no undue toxicity associated with treatment, which included methotrexate, cisplatinum and Adriamycin. Following conservative surgery, she is currently off treatment and disease-free 2 years from diagnosis.