Requirements for dose calculation on an active scanned proton beamline for small, shallow fields.

INTRODUCTION: A growing interest in using proton pencil beam scanning in combination with collimators for the treatment of small, shallow targets, such as ocular melanoma or pre-clinical research emerged recently. This study aims at demonstrating that the dose of a synchrotron-based PBS system with a dedicated small, shallow field nozzle can be accurately predicted by a commercial treatment planning system (TPS) following appropriate tuning of both, nozzle and TPS. MATERIALS: A removable extension to the clinical nozzle was developed to modify the beam shape passively. Five circular apertures with diameters between 5 to 34mm, mounted 72cm downstream of a range shifter were used. For each collimator treatment plans with spread-out Bragg peaks (SOBP) with a modulation of 3 to 30mm were measured and calculated with GATE/Geant4 and the research TPS RayStation (RS11B-R). The dose grid, multiple coulomb scattering and block discretization resolution were varied to find the optimal balance between accuracy and performance. RESULTS: For SOBPs deeper than 10mm, the dose in the target agreed within 1% between RS11B-R, GATE/Geant4 and measurements for aperture diameters between 8 to 34mm, but deviated up to 5% for smaller apertures. A plastic taper was introduced reducing scatter contributions to the patient (from the pipe) and improving the dose calculation accuracy of the TPS to a 5% level in the entrance region for large apertures. CONCLUSION: The commercial TPS and GATE/Geant4 can accurately calculate the dose for shallow, small proton fields using a collimator and pencil beam scanning.

Stereotactical fields applied in proton spot scanning mode with range shifter and collimating aperture.

Some clinical indications require small fields with sharp lateral dose gradients, which is technically challenging in proton beam therapy. This holds especially true for low-range fields applied with the spot scanning technique, where large beam profiles entering from the beam-line or the insertion of range shifting blocks lead to large lateral gradients. We regard the latter case and solve it by shifting the range shifting block far upstream in conjunction with a collimating aperture close to the patient. The experiments of the current work are based on a commercial proton therapy treatment head designed for several delivery modes. In a research environment of the spot-scanning delivery mode a range shifter is inserted downstream of the scanning magnets in a slot which is usually employed only in a scattering delivery mode. This configuration is motivated by equations assuming a simple model of proton transport. In the experiments lateral dose planes are acquired with a scintillation screen and radiochromic films. Dose distributions are calculated with the Monte Carlo dose engine of the RayStation treatment planning system. We demonstrate that proton fields with 80%-20% lateral dose fall-off values between 1.4 mm and 4.0 mm can be achieved for water equivalent depths between 0 cm and 10 cm. The simulated lateral dose profiles agree with the experimental dose profiles. The sharpening of the field edges is set off by a broadening of the proton spots towards the center of the fields. This limits the clinical application mainly to small fields for which the distal and proximal conformality is of minor importance.

Collimated proton pencil-beam scanning for superficial targets: impact of the order of range shifter and aperture.

To assess if apertures shall be mounted upstream or downstream of a range shifting block if these field-shaping devices are combined with the pencil-beam scanning delivery technique (PBS). The lateral dose fall-off served as a benchmark parameter. Both options realizing PBS-with-apertures were compared to the uniform scanning mode. We also evaluated the difference regarding the out-of-field dose caused by interactions of protons in beam-shaping devices. The potential benefit of the downstream configuration over the upstream configuration was estimated analytically. Guided by this theoretical evaluation a mechanical adapter was developed which transforms the upstream configuration provided by the proton machine vendor to a downstream configuration. Transversal dose profiles were calculated with the Monte-Carlo based dose engine of the commercial treatment planning system RayStation 6. Two-dimensional dose planes were measured with an ionization chamber array and a scintillation detector at different depths and compared to the calculation. Additionally, a clinical example for the irradiation of the orbit was compared for both PBS options and a uniform scanning treatment plan. Assuming the same air gap the lateral dose fall-off at the field edge at a few centimeter depth is 20% smaller for the aperture-downstream configuration than for the upstream one. For both options of PBS-with-apertures the dose fall-off is larger than in uniform scanning delivery mode if the minimum accelerator energy is 100 MeV. The RayStation treatment planning system calculated the width of the lateral dose fall-off with an accuracy of typically 0.1 mm-0.3 mm. Although experiments and calculations indicate a ranking of the three delivery options regarding lateral dose fall-off, there seems to be a limited impact on a multi-field treatment plan.

Screening vs. non-screening detected colorectal cancer: Differences in pre-therapeutic work up and treatment.

Objectives To compare preoperative staging, multidisciplinary team-assessment, and treatment in patients with screening detected and non-screening detected colorectal cancer. Methods Data on patient and tumour characteristics, staging, multidisciplinary team-assessment and treatment in patients with screening and non-screening detected colorectal cancer from 2008 to 2012 were collected from the Stockholm-Gotland screening register and the Swedish Colorectal Cancer Registry. Results The screening group had a higher proportion of stage I disease (41 vs. 15%; p < 0.001), a more complete staging of primary tumour and metastases and were more frequently multidisciplinary team-assessed than the non-screening group ( p < 0.001). In both groups, patients with endoscopically resected cancers were less completely staged and multidisciplinary team-assessed than patients with surgically resected cancers ( p < 0.001). No statistically significant differences were observed between the screening and non-screening groups in the use of neoadjuvant treatment in rectal cancer (68 vs.76%), surgical treatment with local excision techniques in stage I rectal cancer (6 vs. 9%) or adjuvant chemotherapy in stages II and III disease (46 vs. 52%). Emergency interventions for colorectal cancer occurred in 4% of screening participants vs. 11% of non-compliers. Conclusions Screening detected cancer patients were staged and multidisciplinary team assessed more extensively than patients with non-screening detected cancers. Staging and multidisciplinary team assessment prior to endoscopic resection was less complete compared with surgical resection. Extensive surgical and (neo)adjuvant treatment was given in stage I disease. Participation in screening reduced the risk of emergency surgery for colorectal cancer.

Relation of intraoperative temperature to postoperative mortality in open colon surgery--an analysis of two randomized controlled trials.

INTRODUCTION: The open surgical wound is exposed to cold and dry ambient air resulting in heat loss mainly through radiation and convection. This cools the wound and promotes local vasoconstriction and hypoxia. Carbon dioxide (CO2) and water vapor are greenhouse gases with a warming effect. The aim was to evaluate if warm humidified CO2 insufflated in surgical wound can affect long-term overall mortality METHODS: This is a retrospective study of two clinical trials, where patients were randomized to warm humidified CO2 (n = 80) or not (n = 78). All patients underwent elective major open colon surgery. Patients in the treatment group received insufflation of warm humidified CO2 into the open wound cavity via a gas diffuser to create a local atmosphere of 100% CO2. Temperature in the wound cavity was measured with a heat-sensitive infrared camera. Core temperature was measured at the tympanic membrane. Median follow-up was 70.9 months. RESULTS: A multivariate analysis adjusted for age (p = 0.001) and cancer (p = 0.165) showed that the larger the temperature difference between final core temperature and wound edge temperature, the lower the overall survival rate (p = 0.050). Patients receiving insufflation of warm humidified CO2 had a tendency to a better overall survival compared with control patients (p = 0.508). End-of-operation wound edge temperature was negatively associated with mortality (OR = 0.80, 95% CI = 0.68-0.95, p = 0.011), whereas mortality was positively associated with age (10-year increase, OR = 1.78, 95% CI = 1.37-2.33, p < 0.001) and cancer (OR = 8.1, 95% CI = 1.95-33.7, p = 0.004). CONCLUSIONS: A small end-of-operation temperature difference between final core and wound edge temperature was positively associated with patient survival in open colon surgery.

Local excision in early rectal cancer-outcome worse than expected: a population based study.

BACKGROUND: Considering the morbidity and mortality after abdominal surgery for rectal cancer, our aim was to determine whether local excision in Stage I rectal cancer provides long-term survival equivalent to TME surgery, particularly in elderly patients. METHODS: Data on 3694 consecutive patients with Stage I rectal cancer operated 1995-2006, were collected from the Swedish Rectal Cancer Register, a population-based, prospectively sampled data-base. Risk factors for death within 5 years after surgery, local recurrence rates, cumulative relative and overall survival rates were calculated for patients ≥ and <80 years-of-age. ASA grading related to surgical technique was analysed in a separate sample. RESULTS: Local excision (LE) was associated with an increased mortality risk both ≥80 (HR 1.55) and <80 years-of-age (HR 1.45). After LE the 5-year local recurrence rate was 11.2% and the total and relative cumulative 5-year survival was 0.62 and 0.81 respectively. Hartmann's procedure (HA) showed an increased mortality risk only in younger patients (HR 2.15). The overall local recurrence rate was 7.2% with HA. Male gender (HR 1.70) and age (HR 1.06) were associated with a significantly increased mortality risk in all age groups. The ASA-grade was higher among patients operated with LE compared to Anterior Resection/Abdominoperineal resection. CONCLUSION: Local excision has a poor outcome in the elderly. A negative selection bias towards old age and high co-morbidity could explain this. Hartmann's procedure has a high risk for mortality and local recurrence in younger patients.

Association studies on 11 published colorectal cancer risk loci.

BACKGROUND: Recently, several genome-wide association studies (GWAS) have independently found numerous loci at which common single-nucleotide polymorphisms (SNPs) modestly influence the risk of developing colorectal cancer. The aim of this study was to test 11 loci, reported to be associated with an increased or decreased risk of colorectal cancer: 8q23.3 (rs16892766), 8q24.21 (rs6983267), 9p24 (rs719725), 10p14 (rs10795668), 11q23.1 (rs3802842), 14q22.2 (rs4444235), 15q13.3 (rs4779584), 16q22.1 (rs9929218), 18q21.1 (rs4939827), 19q13.1 (rs10411210) and 20p12.3 (rs961253), in a Swedish-based cohort. METHODS: The cohort was composed of 1786 cases and 1749 controls that were genotyped and analysed statistically. Genotype-phenotype analysis, for all 11 SNPs and sex, age of onset, family history of CRC and tumour location, was performed. RESULTS: Of eleven loci, 5 showed statistically significant odds ratios similar to previously published findings: 8q23.3, 8q24.21, 10p14, 15q13.3 and 18q21.1. The remaining loci 11q23.1, 16q22.1, 19q13.1 and 20p12.3 showed weak trends but somehow similar to what was previously published. The loci 9p24 and 14q22.2 could not be confirmed. We show a higher number of risk alleles in affected individuals compared to controls. Four statistically significant genotype-phenotype associations were found; the G allele of rs6983267 was associated to older age, the G allele of rs1075668 was associated with a younger age and sporadic cases, and the T allele of rs10411210 was associated with younger age. CONCLUSIONS: Our study, using a Swedish population, supports most genetic variants published in GWAS. More studies are needed to validate the genotype-phenotype correlations.

Consulting for substance abuse: mental disorders among adolescents and their parents.

Studies conducted outside of Scandinavia indicate that most adolescents with substance misuse problems suffer from co-morbid mental disorders. The present study assessed the mental health of adolescents seeking help for substance misuse problems in a large Swedish city. Parents' mental health was also examined. The sample included 97 girls with their 90 mothers and 52 fathers, and 81 boys with their 72 mothers and 37 fathers. The adolescents completed a diagnostic interview, either the Kiddie-SADs or the Structured Clinical Interview for DSM-IV (SCID) depending on their age. Their parents underwent diagnostic interviews with the SCID. Ninety per cent of the girls and 81% of the boys met criteria for at least one disorder other than substance misuse, and on average, they suffered from three other disorders, most of which had onset before substance misuse began. Almost 80% of the mothers and 67% of the fathers met criteria for at least one mental disorder other than alcohol and drug-related disorders. The findings concur with those reported from studies conducted in North America. The results suggest that in Sweden mental disorders are not being identified and effectively treated among some children and young adolescents who subsequently abuse alcohol and/or illicit drugs. Adolescents who consult for substance abuse problems require assessments and treatment by mental health professionals.

Randomized clinical trial of the costs of open and laparoscopic surgery for colonic cancer.

BACKGROUND: There has been no randomized clinical trial of the costs of laparoscopic colonic resection (LCR) compared with those of open colonic resection (OCR) in the treatment of colonic cancer. METHODS: A subset of Swedish patients included in the Colon Cancer Open Or Laparoscopic Resection (COLOR) trial was included in a prospective cost analysis; costs were calculated up to 12 weeks after surgery. All relevant costs to society were included. No effects of the procedures, such as quality of life or survival, were taken into account. RESULTS: Two hundred and ten patients were included in the primary analysis, 98 of whom had LCR and 112 OCR. Total costs to society did not differ significantly between groups (difference in means for LCR versus OCR euro1846; P = 0.104). The cost of operation was significantly higher for LCR than for OCR (difference in means euro1171; P < 0.001), as was the cost of the first admission (difference in means euro1556; P = 0.015) and the total cost to the healthcare system (difference in means euro2244; P = 0.018). CONCLUSION: Within 12 weeks of surgery for colonic cancer, there was no difference in total costs to society incurred by LCR and OCR. The LCR procedure, however, was more costly to the healthcare system.

The tissue-specific regulation of the carboxyl ester lipase gene in exocrine pancreas differs significantly between mouse and human.

The carboxyl ester lipase (CEL) gene is highly expressed in exocrine pancreas and expression of the human CEL gene is mediated by a strong tissue-specific enhancer, which is absolutely necessary for high-level expression. The mouse promoter, on the other hand, does not contain a corresponding enhancer element, but instead is totally dependent on another pancreas-specific element. This element is identified as a pancreatic transcription factor 1 (PTF 1)-binding site. The human CEL promoter also contains a putative PTF 1 element located at a position corresponding to the essential PTF 1 site in the mouse promoter. However, nucleotide changes in the human promoter 5' flanking this PTF 1 site have created an overlapping CCAAT/enhancer-binding protein (C/EBP)-like binding motif, interfering with the binding of PTF 1. Hence, our findings provide an example of genetic divergence between species not accompanied by difference in function.

Comparison of 0.5% intrathecal bupivacaine with 0.5% intrathecal ropivacaine in the treatment of refractory cancer and noncancer pain conditions: results from a prospective, crossover, double-blind, randomized study.

BACKGROUND AND OBJECTIVES: Intrathecal (IT) administration of bupivacaine (BUP) for treatment of "refractory" pain has sometimes been associated with unacceptable side effects. This study was undertaken to determine if IT-ropivacaine (ROP) can reduce the rate and intensity of these side effects e.g., urinary retention, paresthesia, and particularly, paresis with gait impairment. A prospective, crossover, double-blind, randomized study. METHODS: Twenty-one patients were enrolled, 9 dropped out of the study, and data were analyzed from 12 patients. Patients were treated by insertion of IT tunneled nylon catheters, continuous infusion of 0.5% ROP followed by 0.5% BUP or 0.5% BUP followed by 0.5% ROP solutions from an external electronic pump. Each local anesthetic was infused for 7 days, and their order of infusion randomized. The comparative efficacy of the ROP and BUP IT infusions was assessed from the daily doses of IT ROP and IT BUP, oral and parenteral opioids, and daily scores of nonopioid analgetic and sedative drug consumption. Self-reported pain intensity (visual analogue scale [VAS] mean scores) and scores of Bromage relaxation, ambulation, nocturnal sleep pattern, rates of side-effects attributable to the IT drugs, the patients' assessment of the IT ROP v the IT BUP periods of the trial, and the comparative daily cost of IT ROP v IT BUP were recorded. RESULTS: The daily doses of the local anesthetics used were 23% higher for ROP than for BUP. Further, the daily cost was approximately equals 3 times higher for ROP than for BUP. No other significant differences between IT ROP and IT BUP were found. CONCLUSION: The results of this study do not support the hypothesis that IT infusion of 0.5% ROP has advantages over IT infusion of 0.5% BUP when administered for relief of "refractory" pain.

A novel frequency domain fluorescence technique for determination of triplet decay times.

Frequency domain fluorescence measurement using two diode lasers with amplitude modulation in the kHz range yields a signal component at the sum frequency. This intermodulation phenomenon was observed in an aqueous solution of haematoporphyrin (HP) and could be related to triplet state population kinetics. This indirect measurement technique may allow triplet decay time measurement during photodynamic therapy (PDT) enabling monitoring of the type II phototoxic damage rate.

Studies of the regulation of the mouse carboxyl ester lipase gene in mammary gland.

The lactating mammary gland and pancreas of mouse constitute the main tissues for synthesis and secretion of a bile-salt-stimulated lipase called carboxyl ester lipase (CEL). In this paper we have analysed the endogenous CEL gene expression in mammary gland. It is shown that the gene is expressed at day 14 of pregnancy, which is synchronous with that of the whey acidic protein (WAP) gene. Even though the CEL and WAP genes are induced at the same time during mammary gland differentiation, their regulation is different with respect to dependence on lactogenic hormones. The high induction of the WAP gene expression due to the activation of signal transducer and activator of transcription (STAT)5 by prolactin has not been observed for the CEL gene, even though it has been demonstrated that both STAT5 isoforms interact with one of the gamma-interferon activation sequence sites in the promoter of the CEL gene. Hence we have demonstrated that the prolactin/STAT5 signal is not involved in a general and significant activation of 'milk genes'. Instead of a direct effect of the lactogenic hormones, the up-regulation of the CEL gene is correlated with an increase in the number of differentiated epithelial cells. Furthermore, promoter studies using the mammary-gland-derived cell line, HC11, show that a major positive element in the CEL gene promoter interacts with a member(s) of the CCAAT-binding transcription factor/nuclear factor 1 family, binding to a palindromic site. Binding of this factor(s) is important for the tissue-specific activation of the CEL gene in the mammary gland, because no activation by this factor(s) was seen in cells of pancreatic origin.

Transcriptional regulation of the human carboxyl ester lipase gene in exocrine pancreas. Evidence for a unique tissue-specific enhancer.

The human carboxyl ester lipase (CEL) is an important enzyme for the intestinal absorption of dietary lipids. The gene is highly expressed in exocrine pancreas and in the mammary gland during pregnancy and lactation. In this paper, we have focused on its transcriptional regulation in exocrine pancreas. Reporter gene analysis in cell cultures reveals that a high level of tissue-specific expression is established by the proximal 839 base pairs of the 5'-flanking region. This is due to a strong enhancer, located at -672 to -637. Transfections in mammary gland-derived cells reveal that the enhancer is pancreas-specific and does not contribute to the mammary gland expression. This indicates that the expression of the CEL gene in the mammary gland and pancreas, respectively, is due to two different regulatory systems. Further characterizations of the enhancer reveal that it is composed of two closely located cis-elements. The proximal element mediates a positive effect, whereas the distal element exerts a silencing effect on the positive proximal element. The functional enhancer complex is composed of ubiquitously expressed factors, since similar interactions are achieved with nuclear extracts from cells derived from other tissues. However, no enhancer activity is achieved in such cells. Hence, the net enhancer activity is the result of a tissue-specific balance between factors interacting with the two elements. Since none of the described cis-elements show any clear homology to known cis-elements, we propose that the interacting complex is composed of yet unidentified transcription factors.

EDTA chelation therapy in the treatment of vascular disease.

Ethylenediamine tetraacetic acid (EDTA) chelation therapy has been used for decades for the treatment of vascular disease, alone or in combination with other treatments. This article includes a historic review of the research literature, current evidence of effectiveness, potential mechanisms of action of EDTA, and some brief case reports. The authors conclude that EDTA chelation therapy is a valuable therapeutic option for vascular disease, either alone or in conjunction with standard treatment protocols.

Continuous intracisternal and high cervical intrathecal bupivacaine analgesia in refractory head and neck pain.

BACKGROUND: The upper cervical component of the spinomesencephalic tract and cranial nerves V, VII (nervus intermedius), IX, and X are involved in mechanisms of acute and chronic pain from head and neck structures. To date there is no reliable method for relief of refractory pain (i.e., pain that cannot be relieved by conventional pharmacologic therapies) from these structures. Therefore, we explored continuous intracisternal infusion of bupivacaine for the treatment of refractory pain of the head and neck. METHODS: Intracisternal catheters were inserted in 13 adults with refractory nonmalignant (n = 4) and malignant (n = 9) pain from the head, face, mouth, neck, and upper extremities; 0.5% plain bupivacaine was infused continuously at rates of 1-7 (median 1.5) mg/h with optional bolus doses of 0.5-2.0 mg 4-2 times/h. The efficacy was assessed from pain relief (daily VAS(max), VAS(min), and VAS(mean) scores 0-10), daily doses of intracisternal bupivacaine and total opioid (expressed as mg parenteral morphine-eq), amount of nocturnal sleep, and rates of adverse effects. RESULTS: The 13 patients were treated for 3-182 days (median 37, total 712 days), 3 patients being treated at home for 10-112 days (median 88, total 210 days). In one patient, the efficacy of the treatment could not be estimated because of advanced senility. Eleven of the remaining 12 patients obtained acceptable pain relief with daily doses of intracisternal bupivacaine ranging from 20 to 118 mg (median 37 mg): VAS(mean) scores decreased from 7 to 2, mean pain relief increased for 30% to 80%, total opioid daily dose decreased from 53 to 36 mg parenteral morphine-eq, and nocturnal sleep increased from 2 to >6h (all figures are median values). Speech, eating, walking, and natural functions were generally not affected. Side effects such as tiredness and malaise, somnolence and sleep, feeling of coldness in the neck and skull base, transient post-spinal puncture headache, paresthesias, hoarseness, dysphagia, transient paresis of the upper/lower extremities, episodic miosis and conjunctival hyperemia, and transient orthostatic arterial hypotension were each observed in one or two patients. No patient presented clinical evidence of phrenic nerve paralysis. There was no nausea or vomiting. No persistent neurologic deficit or death could be attributed to the intracisternal pain treatment. CONCLUSIONS: Continuous intracisternal infusion of bupivacaine may be a useful method in exceptional, well selected patients with refractory pain from the head and neck structures. Further studies are necessary to establish the indications and the safety of the method.

A constitutional mutation within the retinoblastoma gene detected by PFGE.

Retinoblastoma may be caused by constitutional mutations in the retinoblastoma gene which segregates as an autosomal dominant inherited predisposition for developing retinoblastoma tumours. Since 75% of these cases are new mutations, there is a need for methods to identify carriers of such germ-line mutations, so that informed genetic counselling is available to patients and close relatives. We have used pulsed-field gel electrophoresis in screening 20 unrelated cases with bilateral retinoblastoma. One constitutional mutation could be detected, and was found to be caused by a balanced chromosome (4;13) translocation with the breakpoint within intron 17 of the retinoblastoma gene.

Physical mapping of the NF2/meningioma region on human chromosome 22q12.

Loss of genetic information from chromosome 22 has been implicated in the development of neurofibromatosis type 2, meningioma, and several other neoplasia. Molecular studies indicate that genes within chromosomal band 22q12 may be involved in tumorigenesis. We have mapped 29 loci into 16 groups in this region, using pulsed-field gel electrophoresis, fluorescence in situ suppression hybridization, and somatic cell hybrid mapping. The region spans more than 5 Mb of genomic DNA and contains the genes for neurofibromatosis type 2 and meningioma. The order of loci presented here provides the framework for the fine mapping of this region using cosmids and yeast artificial chromosomes, and it facilitates the speedy cloning of novel genes from 22q12.

Intragenic reorganization of RB1 in a complex (4;13) rearrangement demonstrated by FISH.

Reciprocal chromosome translocations with no apparent loss of material are the most common de novo structural rearrangements in man. The large majority of these cases have been characterized cytogenetically but very few have been investigated at the molecular level. Using fluorescence in situ hybridization (FISH) we have studied the organization of the tumor suppressor gene RB1 in a patient with retinoblastoma and a rearrangement between chromosomes 4 and 13. In addition to the hybridization signal on the normal chromosome 13, three distinct sites of hybridization of RB1 probes on the translocated chromosomes were detected. These findings show that a complex rearrangement occurred involving at least three breaks on chromosome 13, two of them in the RB1 gene. This also demonstrates that FISH, which offers resolution between that of fine molecular methods and classical cytogenetics, is a valuable tool for investigating organization of sequences at breakpoints of chromosomal rearrangements.