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Background and study aims: The 5-year survival rates for gastric cancer remain poor despite evolving therapies, and fiducial insertion via endoscopic ultrasound (EUS) is novel within this setting. We aimed to assess the feasibility of fiducial insertion for response assessment and anatomic localization in patients with gastric cancer. Patients and methods: A prospective phase II feasibility study was undertaken at Austin Health (Victoria, Australia) from February 2011 to November 2012. Consecutive adult patients were enrolled who had primary adenocarcinoma of the stomach with American Joint Committee on Cancer stage T1 – 3,N0 – 1,M0 – 1a and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. In addition, the patients were medically suitable for gastrectomy and chemotherapy/chemoradiotherapy. Gold fiducial markers were inserted under EUS guidance into the margins of the gastric cancer primary. The main outcome was successful insertion of the fiducial without complications for response assessment and anatomic localization. Results: A total of 15 fiducials were successfully inserted into 7 (88 %) of 8 patients. No immediate or delayed complications were noted. One patient proceeded to image-guided radiotherapy through the use of fiducials and is disease free at 12 months. Fiducials were used to assess treatment response in all patients who underwent computed tomographic imaging after insertion. Follow-up computed tomography with fiducial placement improved anatomic localization and estimation of the gastric cancer primary size in 3 (60 %) of 5 patients. Conclusions: Within the limitations of our small study cohort, fiducials were placed in gastric cancers under EUS guidance without complications, and placement was successful in the majority of our patients. Although potential benefits exist, there remain substantial limitations to the generalization of this technique across our patient population.

Introduction We sought to assess the cosmetic outcomes and the proportion of patients with late radiotherapy toxicity in a group of women with early-stage breast cancer treated with breast-conserving surgery (BCS) and adjuvant radiotherapy using a simultaneous integrated boost (SIB) technique. Methods and Materials Female patients with early-stage breast cancer (pT1-2 N0-1) treated with BCS and radiotherapy using an SIB technique were identified retrospectively from the departmental database. Radiotherapy consisted of 45 Gy in 25 fractions delivered to the whole breast with a simultaneous forward-planned conformal boost to the tumour bed of 60 Gy in 25 fractions. Demographic data, as well as prospectively collected measures of toxicity and cosmesis, were recorded and analysed. Results Fifty-five eligible patients were treated between 2009 and 2011. The median age was 61 years (range, 31 to 81 years). Median follow-up was 13.3 months. Late toxicities (including oedema, pigmentation, telangiectasia, fibrosis, osteonecrosis and pain) were graded using Common Terminology Criteria for Adverse Events v3.0 criteria. Grade 0, 1 and 2 toxicities were assigned to 52.8%, 43.4% and 3.8% of patients, respectively. There were no cases of grade 3 or greater toxicity. Ninety-eight per cent had a good or excellent cosmetic outcome based on independent assessment by both the patient and physician. One patient developed a second primary contralateral breast cancer. There were no cases of local recurrence. Conclusion The use of a conformal SIB technique is proposed as a mode of delivering adjuvant radiotherapy in early-stage breast cancer. This schedule is convenient for the patient given the shortened overall treatment time. Additionally, the SIB technique seems to be well tolerated, with minimal toxicity and acceptable cosmetic outcomes. Finally, there are dosimetric benefits with respect to target coverage and reduction of dose and dose per fraction to organs at risk.

Purpose: To demonstrate the technical feasibility of intensity modulated radiation therapy (IMRT) dose painting using C-11-choline positron emission tomography PET scans in patients with localized prostate cancer. Methods and Materials: This was an RT planning study of 8 patients with prostate cancer who had C-11-choline PET scans prior to radical prostatectomy. Two contours were semiautomatically generated on the basis of the PET scans for each patient: 60% and 70% of the maximum standardized uptake values (SUV60% and SUV70%). Three IMRT plans were generated for each patient: PLAN(78), which consisted of whole-prostate radiation therapy to 78 Gy; PLAN(78-90), which consisted of whole-prostate RT to 78 Gy, a boost to the SUV60% to 84 Gy, and a further boost to the SUV70% to 90 Gy; and PLAN(72-90), which consisted of whole-prostate RT to 72 Gy, a boost to the SUV60% to 84 Gy, and a further boost to the SUV70% to 90 Gy. The feasibility of these plans was judged by their ability to reach prescription doses while adhering to published dose constraints. Tumor control probabilities based on PET scan-defined volumes (TCPPET) and on prostatectomy-defined volumes (TCPpath), and rectal normal tissue complication probabilities (NTCP) were compared between the plans. Results: All plans for all patients reached prescription doses while adhering to dose constraints. TCPPET values for PLAN(78), PLAN(78-90), and PLAN(72-90) were 65%, 97%, and 96%, respectively. TCPpath values were 71%, 97%, and 89%, respectively. Both PLAN(78-90) and PLAN(72-90) had significantly higher TCPPET (P=.002 and .001) and TCPpath (P

Purpose: An anthropomorphic pelvic phantom was designed and constructed to meet specific criteria for multicenter radiotherapy dosimetric intercomparison. Methods: Three dimensional external and organ outlines were generated from a computed tomography image set of a male pelvis, forming the basis of design for an anatomically realistic phantom. Clinically relevant points of interest were selected throughout the dataset where point-dose values could be measured with thermoluminescence dosimeters and a small-volume ionization chamber. Following testing, three materials were selected and the phantom was manufactured using modern prototyping techniques into five separate coronal slices. Time lines and resource requirements for the phantom design and manufacture were recorded. The ability of the phantom to mimic the entire treatment chain was tested. Results: The phantom CT images indicated that organ densities and geometries were comparable to those of the original patient. The phantom proved simple to load for dosimetry and rapid to assemble. Due to heat release during manufacture, small air gaps and density heterogeneities were present throughout the phantom. The overall cost for production of the prototype phantom was comparable to other commercial anthropomorphic phantoms. The phantom was shown to be suitable for use as a ''patient'' to mimic the entire treatment chain formore » typical external beam radiotherapy for prostate and rectal cancer. Conclusions: The phantom constructed for the present study incorporates all characteristics necessary for accurate Level III intercomparison studies. Following use in an extensive Level III dosimetric comparison over a large time scale and geographic area, the phantom retained mechanical stability and did not show signs of radiation-induced degradation.« less

Purpose: To assess dose delivery accuracy to clinically significant points in a realistic patient geometry for two separate pelvic radiotherapy scenarios. Methods: An inhomogeneous pelvic phantom was transported to 36 radiotherapy centers in Australia and New Zealand. The phantom was treated according to Phase III rectal and prostate trial protocols. Point dose measurements were made with thermoluminescent dosimeters(TLDs) and an ionisation chamber. Comprehensive site-demographic, treatment planning, and physical data were collected for correlation with measurement outcomes. Results: Dose delivery to the prescription point for the rectal treatment was consistent with planned dose (mean difference between planned and measured dose − 0.1 ± 0.3% std err). Dose delivery in the region of the sacral hollow was consistently higher than planned (+1.2 ± 0.2%). For the prostate treatment,dose delivery to the prostate volume was consistent with planned doses (−0.49 ± 0.2%) and planned dose uniformity, though with a tendency to underdose the PTV at the prostate-rectal border. Measured out-of-field doses were significantly higher than planned. Conclusions: A phantom based on realistic anatomy and heterogeneity can be used to comprehensively assess the influence of multiple aspects of the radiotherapytreatment process on dose delivery. The ability to verify dose delivery for two trials with a single phantom was advantageous.

Introduction: The management of malignant pleural mesothelioma represents one of the most challenging issues in oncology, as there is no proven long-term benefit from surgery, radiotherapy or chemotherapy alone or in combination. Locoregional progression remains the major cause of death, but radical surgical resection may produce major postoperative morbidity. While radical or postoperative radiotherapy using conventional techniques has resulted in severe toxicity with no impact on survival, recent advances in radiotherapy delivery may be more effective. Methods: We treated patients with locally advanced mesothelioma whose tumours had been sub optimally resected with high-dose three-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT) to large volumes of one hemithorax, using CT and positron emission tomography (PET) scan-based treatment planning. Clinical outcomes were assessed by determining patterns of failure and metabolic changes in total glycolytic volume (TGV) between pre- and post-irradiation 18F-FDG PET/CT scans and by recording acute and late toxicity grades. Results: Fourteen patients were analysed with 40 PET scans performed before and up to 4.5 years after radiotherapy. Eleven patients had pleurectomy/decortications, one had an extrapleural pneumonectomy and two had no surgery. Four patients who received chemotherapy had all progressed prior to radiotherapy. After radiotherapy, the in-field local control rate was 71%. No progression occurred in two patients, one was salvaged with further radiotherapy to a new site, four recurred inside the irradiated volume all with concurrent distant metastases and the other seven had distant metastases only. The TGVs were reduced by an average of 67% (range 12–100%) after doses of 45 to 60 Gy to part or all of one hemithorax. There were no serious treatment-related toxicities. Median survival was 25 months from diagnosis and 17 months after starting radiotherapy. Conclusions: We have established that mesothelioma can be locally controlled with high radiation doses using 3DCRT or IMRT, and that strict normal tissue dose constraints have limited radiation toxicities. Radiotherapy should be considered to prevent or delay the local manifestations of progressive disease in suitable patients after surgery including extrapleural pneumonectomy and pleurectomy/decortication. Higher radiation doses may allow more effective palliation.

Summary RluA is a dual-specificity enzyme responsible for pseudouridylating 23S rRNA and several tRNAs. The 2.05 A resolution structure of RluA bound to a substrate RNA comprising the anticodon stem loop of tRNA Phe reveals that enzyme binding induces a dramatic reorganization of the RNA. Instead of adopting its canonical U turn conformation, the anticodon loop folds into a new structure with a reverse-Hoogsteen base pair and three flipped-out nucleotides. Sequence conservation, the cocrystal structure, and the results of structure-guided mutagenesis suggest that RluA recognizes its substrates indirectly by probing RNA loops for their ability to adopt the reorganized fold. The planar, cationic side chain of an arginine intercalates between the reverse-Hoogsteen base pair and the bottom pair of the anticodon stem, flipping the nucleotide to be modified into the active site of RluA. Sequence and structural comparisons suggest that pseudouridine synthases of the RluA, RsuA, and TruA families employ an equivalent arginine for base flipping.

Background and Purpose Improved radiotherapy techniques in pediatric craniospinal therapy (CSRT) strive to reduce risks of late morbidity. Using a pediatric anthropomorphic phantom, this research correlated measured target and normal tissue dose to that predicted from a 3D planning system (3D-RTP). Patients and Methods A pediatric anthropomorphic phantom was planned following French Society of Pediatric Oncology (SFOP) protocols. Thermoluminescent detectors (TLDs) were used to perform dosimetric measurements during treatment. 4 and 6 MV photon fields with multi leaf collimation (MLC) or custom blocks were compared to 3D-RTP computer (ADAC Pinnacle) predictions for cranial fields. Spinal dosimetry was studied using photons (4 and 6 MV) and electrons (9 and 12 MeV). Results 3D-RTP predictions generally concurred with dose received in cranial and spinal sites. The measured dose was over-predicted significantly by the 3D-RTP in the anterior cranial fossa. Normal tissue doses were reduced when treating the spine using megavoltage electron beams instead of photons. Conclusions Treating the spinal field with electrons minimises the risk of pulmonary sequelae, however electron energy selection is critical to achieve adequate spinal field coverage. Despite adhering to a major trial protocol guideline, dose at the floor of the anterior cranial fossa remains a potential clinical problem and 3D-RTP do not predict this well.

All known pseudouridine synthases have a conserved aspartic acid residue that is essential for catalysis, Asp-48 in Escherichia coli TruB. To probe the role of this residue, inactive D48C TruB was oxidized to generate the sulfinic acid cognate of aspartic acid. The oxidation restored significant but reduced catalytic activity, consistent with the proposed roles of Asp-48 as a nucleophile and general base. The family of pseudouridine synthases including TruB also has a nearly invariant histidine residue, His-43 in the E. coli enzyme. To examine the role of this conserved residue, site-directed mutagenesis was used to generate H43Q, H43N, H43A, H43G, and H43F TruB. Except for phenylalanine, the substitutions seriously impaired the enzyme, but all of the altered TruB retained significant activity. To examine the roles of Asp-48 and His-43 more fully, the pH dependences of wild-type, oxidized D48C, and H43A TruB were determined. The wild-type enzyme displays a typical bell-shaped profile. With oxidized D48C TruB, logk(cat) varies linearly with pH, suggesting the participation of specific rather than general base catalysis. Substitution of His-43 perturbs the pH profile, but it remains bell-shaped. The ascending limb of the pH profile is assigned to Asp-48, and the descending limb is tentatively ascribed to an active site tyrosine residue, the bound substrate uridine, or the bound product pseudouridine.

Summary The use of fiducial markers (FM) in image-guided radiotherapy (IGRT) to increase treatment precision is emerging for upper gastrointestinal malignancies. To our knowledge there is no data beyond technical reports for the use of FMs in IGRT for gastric cancers in the current literature. We report a case of an 89-year old gentleman with localised gastric cancer who was deemed unfit for surgery and chemotherapy. He had FMs inserted endoscopically around the tumour via ultrasound guidance and received radiotherapy with a high-dose palliative intent via a two-phase technique to 54 Gy in 30 fractions with IGRT. The use of FMs allowed confidence in tumour delineation and together with IGRT enabled precise and safe delivery of a higher dose. The patient tolerated the treatment without significant toxicity and had no evidence of residual or recurrent tumour 12 months following radiotherapy. The use of FMs with IGRT in upper gastrointestinal malignancies warrants further collaborative studies.

Summary Prolonged waiting times for radiotherapy have resulted in many centres assigning priorities to various patient or diagnostic groups. A high risk of progression on a waiting list is one factor that would reasonably influence the priority. The present descriptive study of 27 patients with Merkel cell carcinoma (MCC) found that a median wait of 24 days for radiotherapy is associated with a high risk of progression. Eleven (41%) of 27 patients developed progressive disease, including five (45%) of 11 patients waiting for adjuvant radiotherapy. Patients treated adjuvantly also had longer waiting times prior to their initial radiotherapy consultation (median 41 days), which may have contributed to the rate of progression. Merkel cell carcinoma is an aggressive but curable malignancy and appropriate management should include efforts to minimize all potential delays prior to the commencement of radiotherapy.

Background and Aims Radiotherapy is an accepted modality in the treatment of esophageal cancers and is currently being evaluated in conjunction with chemotherapy for the neoadjuvant treatment of gastric cancers. Our aim was to assess whether a novel endoscopically inserted marker can be used to improve radiological assessment of the primary cancer and allow for image-guided radiotherapy. Methods A phase II feasibility study was conducted at a tertiary-care center. Twenty-six consecutive adult patients with esophagogastric cancers underwent endoscopic marking of the tumor margins with a novel radiopaque marker (mixture of lipiodol and n-butyl 2-cyanoacrylate). The main outcome measure was the successful insertion of the marker based on a combination of radiological, endoscopic, and histological assessment. Results A total of 92 markers were inserted in 26 patients. Twenty-two (88%) had follow-up imaging to assess the 81 markers inserted, 79 of which (97.5%) were visible. There were no postprocedural adverse events noted in our cohort. Radiological assessment of tumor size improved such that it was in line with the endoscopic evaluation after marker placement in 18 of 21 patients (85.7%) who had appropriate follow-up radiology imaging. Ten patients (38.5%) from our cohort underwent image-guided radiotherapy (IGRT) by using the endoscopically inserted markers. Conclusion Within the limitations of our small pilot study, endoscopic placement of our novel marker was successful in the majority of our cohort without significant adverse events. Marker placement resulted in improved radiological localization in the majority of our cohort and allowed for IGRT. (Australian New Zealand Clinical Trials Registry: ACTRN12613000239763.)

The acute and late toxicities of synchronous carboplatin, etoposide, and radiation therapy were prospectively assessed in a group of patients with high-risk Merkel cell carcinoma of the skin.Forty patients from six different centers throughout Australia were entered into a Phase II study under the auspices of the Trans-Tasman Radiation Oncology Group. The trial was activated in 1996 and continues to accrue. Patients are eligible if they have disease localized to the primary site and nodes and are required to have at least one of the following high-risk features: recurrence after initial therapy, involved nodes, primary size greater than 1 cm, gross residual disease after surgery, or occult primary with nodes. Radiation was delivered to the primary site and nodes to a dose of 50 Gy in 25 fractions over 5 weeks, and synchronous carboplatin (area under curve [AUC] 4.5) and etoposide (80 mg/M(2) i.v.) were given on days 1-3 during weeks 1, 4, 7, and 10. The median age of the group was 67 years (43-78).The median duration of follow-up was 22 months (2-45). There were no treatment-related deaths. Grade 3 or 4 skin toxicity occurred in 63% of patients (95% CI 48, 78). The most serious acute effect was on neutrophils with Grade 3 or 4 (neutrophils1 x 10(9)/L), occurring in 60% (95% CI 45, 75) of cases. Complications from neutropenia (fever and sepsis) occurred in 16 patients (40% of cases). The median time for neutropenic complications was 27 days (9-35), and 10/16 (62%) cases of neutropenic fever occurred after the second cycle of chemotherapy. The probability of Grade 3 or 4 late effects on platelets (50 x 10(9)/L) and hemoglobin (8 g/dl) was 10% (95% CI 1, 20) and 6% (95% CI 2, 15), respectively. Of the 40 patients, 35 were able to complete 4 cycles of chemotherapy. There were no factors predictive for neutropenic toxicity at a p value0.05.The protocol has acceptable toxicity, and the treatment has been deliverable in a multi-institutional trial setting. Neutropenia is likely to occur with synchronous carboplatin/etoposide and radiation in this population of patients. The risk of a febrile neutropenia was greatest at the time of the second cycle of chemotherapy, when there was moist desquamation of skin or mucosal membranes that provided a portal for infection. This should be considered in the design of subsequent protocols with chemoradiotherapy.

6-alpha-methylpenicillin N was synthesised via known routes from 6-aminopenicillanic acid, and tested as a substrate for recombinant DAOCS and DAOC/DACS. Incubation with DAOCS resulted in conversion of 2-oxoglutarate without oxidation of the penicillin substrate ('uncoupled turnover'). Incubation with DAOC/DACS resulted in oxidation to the cephem aldehyde. This is the first example of substrate-induced 'uncoupled turnover', which has been proposed to be an editing mechanism for these enzymes.

Cutaneous oedema is a relatively frequent complication in patients treated conservatively for breast cancer. The factors that contribute to this complication have not been precisely determined. We performed a pilot study to assess the usefulness of high-frequency ultrasound as a quantitative measure of cutaneous oedema. Eleven patients undergoing breast-conserving therapy for breast cancer were studied. Both the treated and untreated breasts were examined. Total cutaneous thickness provided a useful measure of cutaneous oedema. The treated breast was significantly thicker than the untreated breast (P < 0.001). The medial aspect of the breast was thicker than the lateral aspect in both the treated and untreated breast (P < 0.001). The increase in cutaneous thickness predated radiotherapy in those patients who had undergone an axillary dissection. Intrapatient variation in skin thickness was much less than interpatient variation in skin thickness (coefficient of variation 6.4% vs. 18.2% for the untreated breast; coefficient of variation 13.9% vs. 30.9% for the treated breast). Increasing cutaneous thickness was associated with decreasing cutaneous echodensity. We were unable to derive quantitative estimates of echodensity. Cutaneous oedema is an important outcome variable following conservative treatment of breast cancer. High-frequency ultrasound is able to quantify this accurately. It can readily detect changes invisible to the naked eye. High-frequency ultrasound should enable the effects of different treatment options (e.g., extent of surgery, radiotherapy, and chemotherapy) on cutaneous oedema to be differentiated and for the time course of oedema to be accurately characterised.

The purpose of the present paper was to evaluate treatment outcome after conservative breast surgery or mastectomy followed by simultaneous adjuvant radiotherapy and cyclophosphamide, methotrexate and fluorouracil (CMF) therapy. Two hundred and sixty eight (268) patients were treated at two Australian and two New Zealand centres between 1981 and July 1995. One hundred and sixty-nine patients underwent conservation surgery and 99 had mastectomies. Median follow-up was 53 months. Conventionally fractionated radiation was delivered simultaneously during the first two cycles of CMF, avoiding radiation on the Fridays that the intravenous components of CMF were delivered. In conservatively treated patients, 5-year actuarial rates of any recurrence, distant recurrence and overall survival were 34.5 +/- 5.2%, 25.4 +/- 4.5% and 75.5 +/- 4.8%, respectively. Crude incidence of local relapse at 4 years was 6.3% and at regional/distant sites was 26.3%. Highest grades of granulocyte toxicity (< 0.5 x 10(9)/L), moist desquamation, radiation pneumonitis and persistent breast oedema were recorded in 10.7, 8.5, 8.9 and 17.2%, respectively. In patients treated by mastectomy, 5-year actuarial rates of any recurrence, distant recurrence and overall survival were 59.7 +/- 7.3%, 56.7 +/- 7.4% and 50.1 +/- 7%. The crude incidence of local relapse at 4 years was 5.6% and at regional/distant sites it was 45.7%. The issue of appropriate timing of adjuvant therapies has become particularly important with the increasing acknowledgement of the value of anthracycline-based regimens. For women in lower risk categories (e.g. 1-3 nodes positive or node negative), CMF may offer a potentially better therapy, particularly where breast-conserving surgical techniques have been used. In such cases CMF allows the simultaneous delivery of radiotherapy with the result of optimum local control, without compromise or regional or systemic relapse rates. Further randomized trials that directly address the optimal integration of the two modalities, such as the one carried out in Boston, are clearly necessary.

The Trans-Tasman Radiation Oncology Group (TROG) initiated a randomized trial, testing accelerated (twice daily) radiotherapy against conventional radiotherapy for stage III and stage IV squamous cell carcinoma of the head and neck in 1991. In 1996, the Trial Management Committee arranged for a technical audit of 76 cases from 11 institutions, conducted by investigators from interstate institutions. A 10% unacceptable protocol violation rate was detected, which compares favourably with initial Radiation Therapy Oncology Group (RTOG) experience in the late 1970s. Infrastructural deficits with poor quality of documentation, incomplete retrieval of films and document return have been demonstrated in some cases. The Trans-Tasman Radiation Oncology Group is actively pursuing procedural and resourcing issues in order to redress this and is actively expanding its Quality Assurance (QA) Programme with an intercentre dosimetry study. Ultimately, comprehensive clinical and technical QA site visits are planned.

Background and purpose : Regeneration of the aerodigestive mucosa is known to occur during conventionally fractionated radiotherapy. The circumstances surrounding its time of onset and magnitude are not well understood, however. Material and methods : Mucosal reactions were observed in 100 patients undergoing conventionally fractionated treatment at 2 Gy/day over 7 weeks and 88 receiving accelerated treatment at 1.8 Gy twice daily over 312 weeks on the Trans Tasman Radiation Oncology Group head and neck cancer trials. Similar observations in 61 patients treated palliatively at dose rates between 0.8 and 240 Gy/h using ten 3.0–4.2 Gy fractions over 2 weeks are compared. Results : Several findings emerged from these studies: 1. Reactions evolved more quickly at oropharyngeal sites than in the hypopharynx. 2. Reactions at both sites evolved more rapidly at greater rates of dose accumulation. 3. The timing of reactions suggested the presence of a strong regenerative mucosal response that started before the manifestation of ‘patchy' (grade II) mucosal reactions. 4. The regenerative response was strong enough to ‘make good' damage accumulated at a rate of 2 Gy/day in over a third of cases. 5. The linear quadratic model without time correction failed to provide an adequate prediction of the frequency or intensity of mucosal reactions produced by any of the regimes. A simple model of the regenerative response is presented. Conclusions : This study suggests that the timing and magnitude of the regenerative response vary between sites and individuals but are linked to the amount of epithelial cellular depletion occurring during treatment.

The aim of this study was to compare live and photographic methods of assessing variables which can influence cosmetic outcome following breast conserving treatment. This study was undertaken in 47 patients who had previously received breast conserving surgery, radiotherapy and simultaneous chemotherapy for stage I and II breast cancer and a matched group of patients who had received surgery and radiotherapy alone. The assessment consisted of patient and spouse self-assessment, a live assessment by two trained observers and a photographic assessment by five observers, two trained and three untrained. Patients rated their outcome more favourably than their spouses, and both rated the outcomes above those of the other observers. Quantitative variables such as measurement of nipple retraction were assessed by different observers more consistently than qualitative variables such as overall perception of assessed cosmetic outcome. Upward retraction of the nipple emerged as the most powerful determinant of cosmetic outcome in the eyes of both the patient and the trained observers and was reproducibly measured by both live and photographic techniques. The distinction between post-surgical effects and post-radiation effects was more readily made by live assessment. Photographic assessment is as effective as live assessment in post-surgical cosmetic assessment. It provides reliable information about all of the factors which were important to both the patient and observers in formulating an overall cosmetic outcome score. The effects of surgery, which include nipple retraction, need to be taken into account in future trials of adjuvant therapy in which cosmesis is an important outcome measure. Stratification using upward retraction of the nipple is a possibility.

Purpose: Mucosal undersdosing as a result of electron disequilibrium at the air cavity may effect local recurrence rates for T1 and T2 larynx cancers. Secondary build-up properties of high-energy beams have been demonstrated in a slab phantom. It was the aim of this investigation to determine whether significant surface underdosing exists for the mucosa under clinical conditions. Methods and Materials: Measurements were made using a thermoluminescent dosimetry (TLD) extrapolation technique in an anatomic larynx phantom. The larynx phantom was constructed using tissue and cartilage equivalent material, based on patient cross-sectional anatomy. Three different thicknesses of LiF ribbons, 0.14, 0.39, and 0.89 mm, were placed reproducibly at 12 different positions at the anterior, posterior, and lateral walls on the endolarynx surface. Measured doses were plotted and an extrapolation was made back to the mucosal depth to obtain the dose received at each of the positions. Results were obtained for two different field configurations, opposed laterals and oblique fields, for 6-MV X rays and opposed fields from a telecesium unit. In addition, the larynx surface doses of field sizes from 4 × 6 cm2 to 7 × 6 cm2 were investigated. Results: Surface underdosing was observed owing to the secondary build-up and build-down effect of the air cavity, and the dose measured for the three extrapolation TLDs at any position varied by up to 18%. An average variation of 6% was observed. The surface underdosing was most apparent for the 6-MV opposed lateral beam technique, where mucosa doses down the 76% of the prescribed dose were observed. Mucosal underdosing at the measurement position was less marked with oblique techniques, telecesium treatment, and increasing field size. Conclusion:Because of undersdosing, some surface positions receive < 80% of the prescribed dose. This may contribute to the potential for higher recurrence rates observed with high-energy photons.

Background and purposes . To define new directions, the Trans Tasman Radiation Oncology Group (TROG) has conducted a detailed analysis of its unrandomised experience with radio-chemotherapy in oesophageal cancer. Methods and patients . Since 1984, 373 patients with oesophageal cancer have been treated on three prospective, but unrandomised, protocols involving radiation with concurrent cisplatin and infusional fluorouracil. Centres in Australia and New Zealand have contributed patients. Reasons for case selection have been examined in detail and prognostic models have been examined in the light of biases exposed. Results . Cause specific survival in 92 patients treated pre-operatively with 35 Gy, infusional fluorouracil and cisplatin was 25.5 ± 6.0% at 5 years and similar to the 5 year expectations of 169 patients treated with 60 Gy and two courses of the same chemotherapy (23.8 ± 4.7%). Analysis of failure in these groups suggests that local relapse precedes the development of metastases and competes as a cause for ultimate failure. Although patients treated surgically were less likely to relapse locally, survival was no better because more developed metastases. Some of the 112 patients treated ‘palliatively' with 30–35 Gy concurrent with chemotherapy without surgery have become long-term survivors with 5 year survival figure in this group 7.7 ± 3.4%. Apart from variables related to disease stage and performance status at presentation, tumour site emerged as a strong predictor of outcome. Prognosis worsens the nearer the tumour is to the stomach. In addition, indications of a radiation dose response relationship emerged. Conclusions . Concurrent radio-chemotherapy protocols can improve outcome in patients fit enough to tolerate these approaches. New strategies remain necessary, however.

If LiF TLD chips of three different thicknesses (0.230, 0.099 and 0.038 g.cm -2 ) are exposed in the same radiation field it is possible to extrapolate their dose reading to an infinitesimal thin detector size. This TLD extrapolation technique was used to determine the entrance and exit surface dose on a solid water phantom in various photon beams of radiotherapy treatment units. Both build-up and build-down effect could be assessed in dose measurements for telecaesium and megavoltage X ray beams from a medical linear accelerator while a rapid dose fall-off was observed at the phantom surface in a 120 kV P beam due to electron contamination from the lead glass treatment cone. One of the major advantages of the TLD extrapolation technique is that the dose can be interpolated and extrapolated for all vital structures within the first millimetre of the skin.

An important factor in the design of primary protective barriers is the use factor. The present study was aimed at obtaining historical data on the use factor of two dual modality linear accelerators in a radiotherapy department. Gantry angle, field size, and beam modifiers were recorded for all radiation qualities in use at two medical linear accelerators with 6 MV and 18 MV x-rays and multiple electron energies ranging from 4 MeV to 20 MeV. The data for one year of clinical use was extracted from a record and verifying system and an estimate of the physics workload on the machines was obtained by going through the quality assurance records and machine log books. Of the total dose of approximately 37,000 Gy delivered in one year at isocenter on each unit 80% was given as 6 MV x-rays. As can be expected, most x-ray beams were directed at the four cardinal gantry angles with the angular distribution for 6 MV and 18 MV x-rays being very similar. Electron fields were broadly distributed around the gantry pointing down position. Less than 25% of all clinical x-ray treatment fields extended beyond a field size of 200 cm2.

Carbon-loaded thermoluminescent dosimeters (TLDs) are designed for surface/skin dose measurements. Following 4 years in clinical use at the Mater Hospital, the accuracy and clinical usefulness of the carbon-loaded TLDs was assessed.Teflon-based carbon-loaded lithium fluoride (LiF) disks with a diameter of 13 mm were used in the present study. The TLDs were compared with ion chamber readings and TLD extrapolation to determine the effective depth of the TLD measurement. In vivo measurements were made on patients receiving open-field treatments to the chest, abdomen, and groin. Skin entry dose or entry and exit dose were assessed in comparison with doses estimated from phantom measurements.The effective depth of measurement in a 6 MV therapeutic x-ray beam was found to be about 0.10 mm using TLD extrapolation as a comparison. Entrance surface dose measurements made on a solid water phantom agreed well with ion chamber and TLD extrapolation measurements, and black TLDs provide a more accurate exit dose than the other methods. Under clinical conditions, the black TLDs have an accuracy of +/- 5% (+/- 2 SD). The dose predicted from black TLD readings correlate with observed skin reactions as assessed with reflectance spectroscopy.In vivo dosimetry with carbon-loaded TLDs proved to be a useful tool in assessing the dose delivered to the basal cell layer in the skin of patients undergoing radiotherapy.

Purpose: Thii report updates local control and survival experience and focuses on treatment toxicity in 294 patients with esophageal cancer who have been treated at six Australasian centers using three prospective unrandomized protocols that used concurrent radiation, cisplatin, and modest dose infusional fluorouracii. Methods and Materials: Protocol l--“ definitive” chemoradiation. One hundred and thirty-seven patients have been treated with “definitive” radiation to 60 Gy in 6 weeks plus two courses of cisplatin (80 mg/m’) and infusional fluorouracil (800 mg/m’/day over 4 days) during the first and fourth weeks of radiation. Protocol 2--” preoperative” chemoradiation and surgery. Seventy-eight patients received chemoradiation using the same chemotherapy, but 30-35 Gy in 3-4 weeks prior to surgery. Protocol 3-“palliative” chemoradiation. Seventy-nine patients deemed incurable were treated “palliatively” with the same chemoradiation protocol without surgery. Follow-up ranges from 6 months to 7 years (mean 22 months) in live patients. Results: Durable palliation of dysphagia in all three treatment groups has been reflected by encouraging 3-year survival expectations of 43.2 + 5 % in dethtitively treated patients, 40.3 2 7.65% in surgically treated patients, and 8.5% ? 3.9% in the palliatively treated patients. There are early indications that female patients have fared better than males. Toxicity levels were modest in all three groups. Following definitive treatment, severe myelotoxicity (World Health Organization grades 3 and 4) occurred in 19%, severe esophagitis (World Health Organization grade 3) in ll%, and moderate or severe benign stricture in 17%, depending upon age and sex of the patient (being worse in female patients). Conclusions: These studies demonstrate that the concurrent addition of modest dose cisplatin and infusional dose fluorouracil to radiation in the definitive, preoperative, and palliative settings contribute to high rates of durable dysphagia-free survival, with overall survival comparable to (and possibly better than) the chemoradiation arm of the recently reported Intergroup Study, but at the cost of less morbidity. Esophageal cancer, Combined modality therapy, Chemoradiation.

Purpose : We report results of a comparison of three electron planning algorithms, an Age-Diffusion Pencil beam algorithm and two (2-D) and three dimensional (3-D) Hogstrom pencil beam algorithms, using simple 2 X 2 cm air and hard bone inhomogeneities and a complex anthropomorphic head and neck phantom. Methods and Materials : The simple inhomogeneities have variable dimensions outside the plane of calculation to test the effects of out of plane scattering on 2-D algorithms, compared with dose measured by film below the inhomogeneity in the dose fall-off range. Comparisons are also made of a parotid treatment field for 16 MeV electrons, and the dose measured by high sensitivity thermoluminescent dosimeters in the head and neck phantom. Results : Behind the simple inhomogeneities, the electron algorithms are found to underestimate the dose behind the air cavity by up to 40% and overestimate the dose behind bone by up to 30%. In the head phantom, the presence of inhomogeneities also presents problems for the algorithms, with overestimations of dose of up to 20% found behind bone-tissue interfaces, apparently due to shielding by high density bone. Overestimations of up to 17 are also found beside interfaces parallel to the beam. Underestimations of dose of up to 10% are found on the beamside of interfaces, due to under-prediction of backscattered electrons. All three investigated algorithms underestimate the dose by up to 20% behind extreme surface curvature. One algorithm is found to underestimate the dose in the falloff region while another overestimates the dose around the 90% isodose. Conclusion : Clinicians should be aware of the limitations of their planning systems.

To demonstrate the technical feasibility of intensity modulated radiation therapy (IMRT) dose painting using (11)C-choline positron emission tomography PET scans in patients with localized prostate cancer.This was an RT planning study of 8 patients with prostate cancer who had (11)C-choline PET scans prior to radical prostatectomy. Two contours were semiautomatically generated on the basis of the PET scans for each patient: 60% and 70% of the maximum standardized uptake values (SUV(60%) and SUV(70%)). Three IMRT plans were generated for each patient: PLAN(78), which consisted of whole-prostate radiation therapy to 78 Gy; PLAN(78-90), which consisted of whole-prostate RT to 78 Gy, a boost to the SUV(60%) to 84 Gy, and a further boost to the SUV(70%) to 90 Gy; and PLAN(72-90), which consisted of whole-prostate RT to 72 Gy, a boost to the SUV(60%) to 84 Gy, and a further boost to the SUV(70%) to 90 Gy. The feasibility of these plans was judged by their ability to reach prescription doses while adhering to published dose constraints. Tumor control probabilities based on PET scan-defined volumes (TCP(PET)) and on prostatectomy-defined volumes (TCP(path)), and rectal normal tissue complication probabilities (NTCP) were compared between the plans.All plans for all patients reached prescription doses while adhering to dose constraints. TCP(PET) values for PLAN(78), PLAN(78-90), and PLAN(72-90) were 65%, 97%, and 96%, respectively. TCP(path) values were 71%, 97%, and 89%, respectively. Both PLAN(78-90) and PLAN(72-90) had significantly higher TCP(PET) (P=.002 and .001) and TCP(path) (P.001 and .014) values than PLAN(78). PLAN(78-90) and PLAN(72-90) were not significantly different in terms of TCP(PET) or TCP(path). There were no significant differences in rectal NTCPs between the 3 plans.IMRT dose painting for localized prostate cancer using (11)C-choline PET scans is technically feasible. Dose painting results in higher TCPs without higher NTCPs.

In a patterns of practice study 14 Australasian radiation oncologists were invited to define tumour and target volumes in 12 sample cases of non-small cell carcinoma of the lung (NSCCL) firstly using orthogonal simulator AP and lateral radiographic views, then using computed tomography (CT) slices obtained in the treatment position. In addition, they were asked to complete questionnaires addressing their criteria for determining treatment policy and their reasons for choosing specific tumour and target volume boundaries in individual cases. Significant variations in choice of size and position of both tumour and target volume were apparent between clinicians. These variations, however were no greater for simulator planned volumes than for CT planned volumes, except in cases selected for palliative treatment, were CT planned volumes were significantly larger. Failure to include tumour extensions, the mistaken inclusion of normal structures as tumour, and major differences in allowance for microscopic tumour spread were identified as the most significant cause for variation in the size and positioning of target volumes between clinicians. Differences over margins to allow for factors such as variation in day-to-day set-up, patient movement, equipment-related factors, etc, were also apparent. CT and simulator planned target volumes were equally successful in adequate tumour coverage; 79162 (49%), and 80162 (49%) respectively. Gross miss of tumour was more common in simulator planned target volumes than CT planned target volumes; 70162 (43%) and 55162 (34%), respectively. This study supports the integration of diagnostic expertise into the planning process for simulator and CT planning, but suggests that substantial practice variation would still exist in planning for radiotherapy in NSCCL.

Thirty-two patients with locally advanced head and neck cancer have been treated with concurrent weekly carboplatin and conventional radiation therapy (RT) (2 Gy fractions 4-5 days/week to a total dose of 64-70 Gy over 7-8 weeks) in a Phase I/II study. Carboplatin was administered weekly during RT at doses of 75-150 mg/m2/wk as a 1-hour infusion. The maximum tolerated dose of carboplatin was 130 mg/m2/wk, with myelosuppression, predominantly neutropenia, being dose limiting. Other systemic toxicities were insignificant and no overlapping toxicity was evident. Ultimate locoregional control and survival probabilities were disappointing. It is suggested that either further studies using radiation and carboplatin at the dose 130 mg/m2/wk, or variations on dose and scheduling be performed prior to the instigation of Phase III studies.

A unifying approach to cumulative dose-volume histogram (CDVH) reduction analysis is presented, utilising two weighted linear interpolation models (VWD, DWV), two weighted probability models (VWP, DWP) and a novel integral probability model (IPM). As a test of their predictive value these algorithms were applied to CDVH data generated from lung doses, measured by TLD arrays in a female anthropomorphic phantom. Three arbitrary configurations of breast size and location of “target volume” within the breast were “treated”, using an appropriate electron field (Varian Clinac 1800) or double-plane iridium-192 implant. Calculated effective doses from each of the reduction algorithms showed the iridium implant to be dosimetrically the most favourable in two the three configurations. Likewise, complication probabilities, based on a logistic dose-volume response function showed lung complication probabilities to be lower for the interstitial technique in the same situations. All algorithms tested showed reasonable consistency, with the exception of the VWD. The rationale and value of comparative rather than absolute dose-volume histogram analyses are discussed.

This paper describes the process and results of a survey of linear accelerator outputs as part of an Australasian Level III Dosimetry Intercomparison. This study involved the measurement of accelerator output under reference conditions ('Level I') with a small-volume ionisation chamber in water for 47 beams at 36 radiotherapy centres using the IAEA TRS 398 dose-to-water protocol. The mean ratio of measured to locally-determined accelerator output was 1.003 +/- 0.009 (1 standard deviation) with a range from 0.981 to 1.024. No correlation could be found between output ratio and accelerator type or local output calibration protocol. The small-volume chamber used satisfied most requirements for the study though showed some variation in sensitivity via repeated cross-calibration with a chamber calibrated at a primary standards laboratory.

Telomerase activity is primarily determined by transcriptional regulation of the catalytic subunit, human telomerase reverse transcriptase (hTERT). Several mRNA splice variants for hTERT have been identified, but it is not clear if telomerase activity is determined by the absolute or relative levels of full-length (functional) and variant hTERT transcripts. We have developed an SYBR green-based reverse transcription-quantitative polymerase chain reaction assay for the enumeration of the four common hTERT mRNA variants and correlated these with telomerase activity and telomere length in 24 human melanoma cell lines. All except five of the lines expressed four hTERT transcripts, with an overall significant level of co-occurrence between absolute mRNA levels of full-length alpha+/beta+ hTERT and the three splice variants alpha-/beta+, alpha+/beta-, and alpha-/beta-. On average, alpha+/beta+ made up the majority (48.1%) of transcripts, followed by alpha+/beta- (44.6%), alpha-/beta- (4.4%), and alpha-/beta+ (2.9%). Telomerase activity ranged from 1 to 247 relative telomerase activity and correlated most strongly with the absolute amount of alpha+/beta+ (R = 0.791, P = .000004) and the relative amount of alpha+/beta- (R = -0.465, P = .022). This study shows that telomerase activity in melanoma cells is best determined by the absolute expression of full-length hTERT mRNA and indicates a role for the hTERT beta deletion variant in the negative regulation of enzyme activity.

To identify factors that can influence breast edema in women undergoing breast-conserving therapy. Breast edema was assessed clinically and via high frequency ultrasound (HFUS) prior to, during and following radiotherapy. Fifty-four women were assessed. Breast edema was present prior to radiotherapy in patients who had undergone level 2 node dissection or had wound infection after sentinel node dissection. Edema increased during and after radiotherapy and peaked at 4–6 months. The time course of breast edema was related to the extent of nodal dissection, postoperative wound infection and regional radiotherapy. HFUS prior to irradiation was found to be no better than clinical assessment in predicting prolonged parenchymal breast edema but was significantly better at the end of irradiation. Breast edema levels are minimal in patients who do not undergo axillary node dissection or have an uncomplicated sentinel node dissection. Most edema is due to compromise of the draining lymphatics, which relates largely to the extent of axillary node dissection. HFUS appears to be a useful in the research setting in quantifying the effect of techniques that aim to reduce complications such as edema.

The pseuoduridine synthases (psi synthases) isomerize uridine (U) to pseudouridine (psi) in RNA, and they fall into five families that share very limited sequence similarity but have the same overall fold and active-site architecture, including an essential Asp. The mechanism by which the psi synthases operate remains unknown, and mechanistic work has largely made use of RNA containing 5-fluorouridine (f5U) in place of U. The psi synthase TruA forms a covalent adduct with such RNA, and heat disruption of the adduct generates a hydrated product of f5U, which was reasonably concluded to result from the hydrolysis of an ester linkage between the essential Asp and f5U. In contrast, the psi synthase TruB, which is a member of a different family, does not form an adduct with f5U in RNA but catalyzes the rearrangement and hydration of the f5U, which labeling studies with [18O]water showed does not result from ester hydrolysis. To extend the line of mechanistic investigation to another family of psi synthases and an enzyme that makes an adduct with f5U in RNA, the behavior of RluA toward RNA containing f5U was examined. Stem-loop RNAs are shown to be good substrates for RluA. Heat denaturation of the adduct between RluA and RNA containing f5U produces a hydrated nucleoside product, and labeling studies show that hydration does not occur by ester hydrolysis. These results are interpreted in light of a consistent mechanistic scheme for the handling of f5U by psi synthases.

The pseudouridine synthase TruB is responsible for the universally conserved post-transcriptional modification of residue 55 of elongator tRNAs. In addition to the active site, the “thumb,” a peripheral domain unique to the TruB family of enzymes, makes extensive interactions with the substrate. To coordinate RNA binding and release with catalysis, the thumb may be able to sense progress of the reaction in the active site. To establish whether there is a structural correlate of communication between the active site and the RNA-sequestering thumb, we have solved the structure of a catalytically inactive point mutant of TruB in complex with a substrate RNA, and compared it to the previously determined structure of an active TruB bound to a reaction product. Superposition of the two structures shows that they are extremely similar, except in the active site and, intriguingly, in the relative position of the thumb. Because the two structures were solved using isomorphous crystals, and because the thumb is very well ordered in both structures, the displacement of the thumb we observe likely reflects preferential propagation of active site perturbations to this RNA-binding domain. One of the interactions between the active site and the thumb involves an active site residue whose hydrogen-bonding status changes during the reaction. This may allow the peripheral RNA-binding domain to monitor progress of the pseudouridylation reaction.

Purpose: The effectiveness of synchronous carboplatin, etoposide, and radiation therapy in improving survival was evaluated by comparison of a matched set of historic control subjects with patients treated in a prospective Phase II study that used synchronous chemotherapy and radiation and adjuvant chemotherapy. Patients and Methods: Patients were included in the analysis if they had disease localized to the primary site and nodes, and they were required to have at least one of the following high-risk features: recurrence after initial therapy, involved nodes, primary size greater than 1 cm, or gross residual disease after surgery. All patients who received chemotherapy were treated in a standardized fashion as part of a Phase II study (Trans-Tasman Radiation Oncology Group TROG 96:07) from 1997 to 2001. Radiation was delivered to the primary site and nodes to a dose of 50 Gy in 25 fractions over 5 weeks, and synchronous carboplatin (AUC 4.5) and etoposide, 80 mg/m(2) i.v. on Days 1 to 3, were given in Weeks 1, 4, 7, and 10. The historic group represents a single institution's experience from 1988 to 1996 and was treated with surgery and radiation alone, and patients were included if they fulfilled the eligibility criteria of TROG 96:07. Patients with occult cutaneous disease were not included for the purpose of this analysis. Because of imbalances in the prognostic variables between the two treatment groups, comparisons were made by application of Cox's proportional hazard modeling. Overall survival, disease-specific survival, locoregional control, and distant control were used as endpoints for the study. Results: Of the 102 patients who had high-risk Stage I and II disease, 40 were treated with chemotherapy (TROG 96:07) and 62 were treated without chemotherapy (historic control subjects). When Cox's proportional hazards modeling was applied, the only significant factors for overall survival were recurrent disease, age, and the presence of residual disease. For disease-specific survival, recurrent disease was the only significant factor. Primary site on the lower limb had an adverse effect on locoregional control. For distant control, the only significant factor was residual disease. Conclusions: The multivariate analysis suggests chemotherapy has no effect on survival, but because of the wide confidence limits, a chemotherapy effect cannot be excluded. A study of this size is inadequately powered to detect small improvements in survival, and a larger randomized study remains the only way to truly confirm whether chemotherapy improves the results in high-risk MCC. (c) 2006 Elsevier Inc.

This report presents an update of tumour response experience in patients with locally advanced head and neck cancer treated on the low dose rate teletherapy project at the Mater Misericordiae Hospital, Newcastle. Long-term progression-free survival figures are disappointing in all dose rate/total dose groupings and offer little encouragement that an improvement in therapeutic ratio can be achieved for head and neck cancer patients using teletherapy apparatus adjusted to treat at low and intermediate dose rates.

Purpose To describe the natural history of mucosal changes, in particular the development of telangiectases in the rectum, after radiotherapy (RT) for prostate cancer. Methods and materials Twenty patients undergoing local-field, nonconformal RT for prostate cancer underwent flexible sigmoidoscopy every 6 months for up to 3 years after RT completion. Telangiectasis was scored as absent, single, multiple, or multiple confluent. The site and circumferential extent were also documented. The patients filled in a diary to document the symptoms they were experiencing, including rectal bleeding. Results Of the 20 patients, 12 developed multiple telangiectases, and 10 of these had rectal bleeding, which in all cases was mild. Telangiectasis was most commonly seen between 4 (anorectal junction) and 8 cm from the anal verge. In 5 patients, 4 of whom had multiple telangiectases, spontaneous resolution occurred. Conclusion Late radiation effects in the rectum do not appear to be permanent in all cases. This first prospective prolonged evaluation may provide an explanation for the observation that rectal bleeding resolves in a large proportion of patients with mild symptoms after RT. The reasons for improvement in the late radiation changes in the rectum compared with the permanent changes seen in organs such as the skin are unknown.

Purpose: The effectiveness of synchronous carboplatin, etoposide, and radiation therapy was prospectively assessed in a group of patients with high-risk Merkel cell carcinoma (MCC) of the skin. Patients and Methods: Patients were eligible if they had disease localized to the primary site and nodes, and were required to have at least one of the following high risk features: recurrence after initial therapy, involved nodes, primary tumor size greater than 1 cm, gross residual disease after surgery, or occult primary with nodes. Radiation was delivered to the primary site and nodes to a dose of 50 Gy in 25 fractions over 5 weeks and synchronous carboplatin (area under the curve, 4.5) and intravenous etoposide 80 mg/m2 days 1 to 3 was given in weeks 1, 4, 7, and 10. The median age of the group was 67 (range, 43–86) years, and there were 39 males and 14 females. Involved nodes (stage II) were present in 33 cases (62%). The sites involved were head and neck (22 patients), occult primary (13 patients), upper limb (eight patients), lower limb (eight patients), and trunk (two patients). Results: Fifty-three patients were entered between 1996 and 2001. The median potential follow-up was 48 months. There were no treatment related deaths. The 3-year overall survival, locoregional control, and distant control were 76%, 75%, and 76%, respectively. Tumor site and the presence of nodes were factors that were predictive for local control and survival. Multivariate analysis indicated that the major factor influencing survival was the presence of nodes; however, this was not a significant factor in locoregional control. Conclusion: High levels of locoregional control and survival have been achieved with the addition of chemotherapy to radiation treatment for high-risk MCC of the skin. The role of chemoradiotherapy for high-risk MCC warrants further investigation.

The aims of this analysis were to determine the effect of anaemia on loco-regional control, relapse-free survival, cause-specific survival, overall survival, and acute and late radiation therapy toxicity in patients with Stage III and IV squamous cell carcinoma of the head and neck treated with radiotherapy.Between 1991 and 1998, 350 patients were randomly assigned to either conventional radiotherapy, (70 Gy in 35 fractions in 49 days) or to accelerated radiotherapy (59.4 Gy in 33 fractions in 24 days). Patients were divided into two groups according to their haemoglobin level: a normal haemoglobin group (/=13 g/dl in males,/=12 g/dl in females) and a low haemoglobin group (13 g/dl in males,12 g/dl in females). The influence of anaemia on cause-specific survival and the development of confluent mucositis independent of other variables was tested using Cox proportional hazards model.Of 350 patients recruited to the trial, 238 had haemoglobin measurements and were eligible for inclusion in this secondary analysis. One hundred and ninety-three were considered to have normal haemoglobin, and 45 patients were considered to be anaemic. There were significant differences between the groups in loco-regional control, relapse-free survival, cause-specific survival and overall survival, with hazards ratios of 0.56 (95% confidence interval (CI) 0.34-0.94), 0.57 (95% CI 0.35-0.92), 0.49 (95% CI 0.29-0.85) and 0.43 (95% CI 0.26-0.70) in favour of the normal haemoglobin group. Using Cox proportional hazards modelling, haemoglobin level was a significant predictor of cause-specific survival in addition to disease site, stage, and Eastern Cooperative Oncology Group status. There were no statistically significant differences between the groups in the development of acute or late reactions.Significant reductions in loco-regional control, disease-free survival, cause-specific survival and overall survival occur in the presence of anaemia. No significant differences in normal tissue toxicity have been identified in this analysis.

Introduction Fatigue is commonly reported in patients receiving radiotherapy for breast conservation, but the underlying mechanisms remain unclear. Methods Patients with early breast cancer participating in a prospective study of the impact of inflammatory processes on early and delayed breast morbidity were assessed for fatigue levels using the Functional Assessment of Cancer Therapy (FACT) fatigue subscale before and at intervals during and after radiotherapy. Blood for analysis of a variety of circulating cytokines, coagulation factors, peripheral blood indices and biochemical factors was collected at the same time points. Results Fifty-two eligible patients were assessed. Twenty-one patients (43%) developed significant fatigue during radiotherapy, whereas 28 (54%) developed minimal or no fatigue. Fatigue appeared to plateau between week 4 of treatment and 2 weeks after treatment. The fatigue was beginning to settle by 6 weeks after treatment. Significant fatigue was predicted by a higher baseline fatigue score, red cell count, neutrophil count, and D-dimer level. Baseline fatigue correlated with higher body mass index, C-reactive protein, soluble thrombomodulin, tissue plasminogen activator, von Willebrand factor antigen, interleukin-6, ICAM-1, hemoglobin and red cell, monocyte, and neutrophil counts. There were also significant correlations between body mass index and tissue plasminogen activator, C-reactive protein, interleukin-6, ICAM-1, and red cell count. After these factors were controlled for, baseline fatigue was seen to be associated with higher body mass index, soluble thrombomodulin, tissue plasminogen activator, von Willebrand factor antigen, monocyte count, and neutrophil count. Multiple logistic regression procedures indicated that the most predictive factors for fatigue during radiotherapy were higher baseline fatigue level and higher baseline neutrophil and red cell counts. Conclusion This study has shown that significant fatigue is common in patients receiving breast irradiation and is precipitated during radiotherapy in some patients but not others. The factors shown to be associated with fatigue in this study will be helpful in shaping future studies.

Purpose: To quantify the oral mucosal cell density and proliferation rate during conventional radiotherapy of head-and-neck tumors and to compare these parameters with clinical scoring of oral mucositis. Methods and Materials: Between 1996 and 1999, 22 patients were included in this study. Mucosal biopsies were taken before or during the radiotherapy course (5 × 2 Gy/wk). Biopsies were incubated in vitro with tritiated thymidine immediately after excision to label DNA-synthesizing cells. Results: Epithelial cell density followed a biphasic radiation response. A steep decrease to about 50% of the preirradiation value (1000 cells/mm epithelium) during Week 1 was followed by a more gradual loss to about 400 cells at the end of treatment. The initial phase was based on the depression of proliferation, with 5–10 labeled cells/mm at the end of Week 1 vs. 60 labeled cells/mm in controls. Subsequently, proliferation was partially restituted at 20 labeled cells/mm. A significant difference in cell numbers was seen between Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Grade 0 (∼850 cell/mm) and Grade 2 (325/mm) or Grade 3 (370/mm). No significant differences were observed between reaction grades 1, 2, and 3. Conclusion: Conventionally fractionated radiotherapy induces a rapid suppression in cell production in Week 1, which results in a prompt reduction in cell numbers. Subsequently, a partial restoration of proliferation significantly reduces the rate of cell loss. These processes clearly precede the clinical response. Regeneration, defined as restoration of cellularity, is already under way when the maximal clinical response is observed. Clinical reaction grading corresponds poorly to cellular density measures during conventional fractionation.

SUMMARY Tumour responses in 25 patients with locally advanced head and neck cancer, treated on an experimental fractionated low dose rate (FLDR) teletherapy program are reported. Treatment was given at dose rates ranging from 1.8 to 3 Gy/h to a range of total doses from 32–38 Gy, with palliative intent. The total doses delivered have been predicted by the linear quadratic formula to be equivalent to 33–41 Gy using conventionally fractionated high dose rate treatment, in terms of acute normal tissue effects. A complete response rate (no visible or palpable disease 2 months after treatment) was observed in 28% of cases. Analysis of these response rates suggests that the linear quadratic formula may underestimate the anti-tumour effect of FLDR teletherapy at the various dose rates and total dose permutations in this study.

On the basis of sequence alignments, the pseudouridine synthases were grouped into four families that share no statistically significant global sequence similarity, though some common sequence motifs were discovered [Koonin, E. V. (1996) Nucleic Acids. Res. 24, 2411-2415; Gustafsson, C., Reid, R., Greene, P. J., and Santi, D. V. (1996) Nucleic Acids Res. 24, 3756-3762]. We have investigated the functional significance of these alignments by substituting the nearly invariant lysine and proline residues in Motif I of RluA and TruB, pseudouridine synthases belonging to different families. Contrary to our expectations, the altered enzymes display only very mild kinetic impairment. Substitution of the aligned lysine and proline residues does, however, reduce structural stability, consistent with a temperature sensitive phenotype that results from substitution of the cognate proline residue in Cbf5p, a yeast homologue of TruB [Zerbarjadian, Y., King, T., Fournier, M. J., Clarke, L., and Carbon, J. (1999) Mol. Cell. Biol. 19, 7461-7472]. Together, our data support a functional role for Motif I, as predicted by sequence alignments, though the effect of substituting the highly conserved residues was milder than we anticipated. By extrapolation, our findings also support the assignment of pseudouridine synthase function to certain physiologically important eukaryotic proteins that contain Motif I, including the human protein dyskerin, alteration of which leads to the disease dyskeratosis congenita.