A joint physics and radiobiology DREAM team vision - Towards better response prediction models to advance radiotherapy.

Radiotherapy developed empirically through experience balancing tumour control and normal tissue toxicities. Early simple mathematical models formalized this practical knowledge and enabled effective cancer treatment to date. Remarkable advances in technology, computing, and experimental biology now create opportunities to incorporate this knowledge into enhanced computational models. The ESTRO DREAM (Dose Response, Experiment, Analysis, Modelling) workshop brought together experts across disciplines to pursue the vision of personalized radiotherapy for optimal outcomes through advanced modelling. The ultimate vision is leveraging quantitative models dynamically during therapy to ultimately achieve truly adaptive and biologically guided radiotherapy at the population as well as individual patient-based levels. This requires the generation of models that inform response-based adaptations, individually optimized delivery and enable biological monitoring to provide decision support to clinicians. The goal is expanding to models that can drive the realization of personalized therapy for optimal outcomes. This position paper provides their propositions that describe how innovations in biology, physics, mathematics, and data science including AI could inform models and improve predictions. It consolidates the DREAM team's consensus on scientific priorities and organizational requirements. Scientifically, it stresses the need for rigorous, multifaceted model development, comprehensive validation and clinical applicability and significance. Organizationally, it reinforces the prerequisites of interdisciplinary research and collaboration between physicians, medical physicists, radiobiologists, and computational scientists throughout model development. Solely by a shared understanding of clinical needs, biological mechanisms, and computational methods, more informed models can be created. Future research environment and support must facilitate this integrative method of operation across multiple disciplines.

A rare case of supraclinoid internal carotid artery (ICA) fenestration in combination with duplication of the middle cerebral artery (MCA) originating from the ICA fenestration and an associated aneurysm.

Fenestrations and duplications of the cervical and intracranial arteries are rare anatomic variants, reported to be associated with aneurysms or other vascular anomalies. We here present a patient with a supraclinoid ICA fenestration in combination with a duplication of the MCA originating from the ICA fenestration and an associated aneurysm.

Poster - Thur Eve - 46: The upcoming international code of practice for small static photon field dosimetry.

The increased use of small photon fields in stereotactic and intensity-modulated radiotherapy has raised the need for standardizing the dosimetry of such fields using procedures consistent with those for conventional radiotherapy. An international working group, established by the IAEA in collaboration with AAPM and IPEM, is finalising a Code of Practice for the dosimetry of small static photon fields. Procedures for reference dosimetry in nonstandard machine specific reference (msr) fields are provided following the formalism of Alfonso et al. (Med. Phys. 35: 5179; 2008). Reference dosimetry using ionization chambers in machines that cannot establish a conventional 10 cm × 10 cm reference field is based on either a direct calibration in the msr field traceable to primary standards, a calibration in a reference field and a generic correction factor or the product of a correction factor for a virtual reference field and a correction factor for the difference between the msr and virtual fields. For the latter method, procedures are provided for determining the beam quality in non-reference conditions. For the measurement of field output factors in small fields, procedures for connecting large field measurements using ionization chambers to small field measurements using high-resolution detectors such as diodes, diamond, liquid ion chambers, organic scintillators and radiochromic film are given. The Code of Practice also presents consensus data on correction factors for use in conjunction with measured, detector-specific output factors. Further research to determine missing data according to the proposed framework will be strongly encouraged by publication of this document.

A new formalism for reference dosimetry of small and nonstandard fields.

The use of small fields in radiotherapy techniques has increased substantially, in particular in stereotactic treatments and large uniform or nonuniform fields that are composed of small fields such as for intensity modulated radiation therapy (IMRT). This has been facilitated by the increased availability of standard and add-on multileaf collimators and a variety of new treatment units. For these fields, dosimetric errors have become considerably larger than in conventional beams mostly due to two reasons; (i) the reference conditions recommended by conventional Codes of Practice (CoPs) cannot be established in some machines and (ii) the measurement of absorbed dose to water in composite fields is not standardized. In order to develop standardized recommendations for dosimetry procedures and detectors, an international working group on reference dosimetry of small and nonstandard fields has been established by the International Atomic Energy Agency (IAEA) in cooperation with the American Association of Physicists in Medicine (AAPM) Therapy Physics Committee. This paper outlines a new formalism for the dosimetry of small and composite fields with the intention to extend recommendations given in conventional CoPs for clinical reference dosimetry based on absorbed dose to water. This formalism introduces the concept of two new intermediate calibration fields: (i) a static machine-specific reference field for those modalities that cannot establish conventional reference conditions and (ii) a plan-class specific reference field closer to the patient-specific clinical fields thereby facilitating standardization of composite field dosimetry. Prior to progressing with developing a CoP or other form of recommendation, the members of this IAEA working group welcome comments from the international medical physics community on the formalism presented here.

Polymorphisms in the NMDA subunit 2B are not associated with alcohol dependence and alcohol withdrawal-induced seizures and delirium tremens.

OBJECTIVE: Ethanol-inhibited glutamatergic neurotransmission has been shown to mediate pathophysiological mechanisms in the development of alcoholism, including withdrawal symptoms. NMDA-receptor 2B (NR2B) is a subunit that confers a high sensitivity to ethanol-induced inhibition. Previously we had reported a lack of association between the single nucleotide polymorphism (SNP) rs1806201 in the NR2B gene (GRIN2B) and alcoholism. Shortly thereafter, an association between the polymorphism and early-onset alcoholism has been reported. One aim of the present study was to test whether the association between the GRIN2B polymorphism rs1806201 and early-onset alcoholism can be replicated in a larger sample. Moreover, we hypothesized that another genetic variation within GRIN2B (rs1806191) may have an effect in the etiology of alcoholism or withdrawal-related traits. METHODS: We extended our original study sample to a size of 377 patients and 464 healthy volunteers and performed a replication study, including the second GRIN2B SNP. Associations between allele, genotype and haplotype frequencies of the two polymorphisms and alcoholism as well as with patients' phenotypes were investigated. RESULTS: No associations were found between any of the two polymorphisms, tested individually or as haplotypes, and alcoholism, respectively withdrawal-related traits. CONCLUSION: Neither the analyzed SNPs nor any of their haplotypes likely modify susceptibility to alcohol dependence or withdrawal-related phenotypes.

Transportable frontal chromatographic unit for decontamination purposes based on the twin column concept.

The design and operation of a separation unit based on frontal chromatography is described. The important feature of the design is the array column --> detector --> column which allows process monitoring below the detection limits of the monitor. By using "fraternal twin columns" an in-process calibration of the detector is achieved reducing the waste production. The design contains provisions for on-line destructive and non-destructive monitoring. Tests of the unit prove its versatility with respect to decontamination processes. Due to its compactness, the unit is transportable, if not portable, and the module construction allows easy posting and set-up in areas with restricted access. The unit is capable of processing up to 5 m3 solution per year depending on the chemical system used.

Twin column chromatography for industrial-scale decontamination processes.

A frontal chromatographic unit was devised consisting of a column-detector-column array. The unit is either equipped with identical columns (identical twins) or with columns of varying length (fraternal twins). Due to the finite nature of the columns, a prerun is formed at the column walls following the same regularities as the main stream. These regularities are used for the identification of the process termination below the detection limits of the monitor. For the implementation, a clear preference is given to the employment of fraternal twins, as the feed assay can be integrated into the separation process.

Analysis of genetic variations of protein tyrosine kinase fyn and their association with alcohol dependence in two independent cohorts.

BACKGROUND: Decreased sensitivity to and increased tolerance for the effects of alcohol is a phenotype, which was shown to be associated with an increased risk for alcoholism in humans and was observed in protein tyrosine kinase (PTK) fyn knockout mice. METHODS: We performed an association study of genetic variations of PTK fyn in 430 alcohol-dependent patients and 365 unrelated control subjects from two independent samples. RESULTS: In a combined analysis, we found an association of alcohol dependence with the single nucleotide polymorphism (SNP) T137346C in the 5' untranslated region (UTR) of the gene. A relevant association could be excluded for the remaining two informative SNPs. Selection by phenotype showed that a high number of withdrawal symptoms, high amount of alcohol intake, and high maximum number of drinks compared with unrelated control subjects was associated with the SNP in the 5'-UTR region but not with the remaining SNPs. CONCLUSIONS: Our results indicate a possible association of alcohol dependence with a genotype of the SNP T137346C of the PTK fyn, with C being the risk allele.

On-line monitoring of a frontal chromatographic separation using inductively coupled plasma atomic emission spectroscopy.

A test array is described employing a destructive analytical technique for the long-term monitoring of an industrial-scale separation process. As an example, we chose frontal chromatography as the separation and ICP/AES as the analytical method. The feed solution of the process was conveyed by a process pump via the separation unit to a sample station, where a small portion was diverted and transported by a roller pump into the spectrometer. We equipped our array with different loops for operating the process, calibrating the instrument and verifying the calibration. We obtained identical results for the different loops by absorbing the pulsation of the process pump and arranging for identical suction lines of the spectrometer pump. Based on the results, we redesigned the sample station for a technical application using only commercially available parts.

Mixed chimerism of bone marrow vessels (endothelial cells, myofibroblasts) following allogeneic transplantation for chronic myelogenous leukemia.

Experimental findings support the hypothesis that within the functional network of the bone marrow (BM) microenvironment the endothelial cells (ECs) exert a pivotal role as gatekeepers by controlling the trafficking and homing of progenitor cells. However, little information is available concerning the origin of ECs after allogeneic bone marrow transplantation (BMT) in CML. To determine the extent of mixed chimerism (MCh) a simultaneous immunohistochemical and fluorescence in-situ hybridization (FISH) study was performed on BM biopsies derived from patients following sex-mismatched BMT with full unmanipulated BM. ECs were identified by their staining with CD34 and the myofibroblasts (MFs) of large vessels were labeled by an antibody against alpha-smooth muscle actin. For sex-typing and demonstration of the bcr/abl fusion product appropriate commercially available probes and detection systems were applied. Contrasting a total congruence of labeling in control samples five patients showed donor type ECs in the early posttransplant period in about 20%. In the remaining four patients the amount of donor type ECs increased slightly after the third month up to 30%. A total of 26 MFs could be identified lining large capillaries and arterioles that exclusively revealed a host origin. Following successful engraftment only very few of the persistent host-derived ECs also displayed the bcr/abl gene. In five patients, a conversion of MCh from donor to host type ECs was recognizable during the evolution of leukemic relapse. This finding was accompanied by a bcr/abl rearrangement of about 10% of these cells. In conclusion, following myelo-ablative therapy, a survival of a considerable number of ECs and MFs of the vessel walls has been found implying persistence of host-derived vascular structures of the BM stroma. However, in only a small proportion bcr/abl+ ECs and thus minimal residual disease was detectable. Evolution of leukemic relapse was characterized by conversion of MCh with almost total loss of donor type ECs and increase in number of bcr/abl+ ECs.

Different diurnal cycles of expression of two nitrate reductase transcripts in tobacco roots.

In roots and leaves of tobacco (Nicotiana tabacum cv. Samsun) three functional transcripts (3.6 kb, 3.1 kb, and 1.8 kb) were found to at least partly represent nitrate reductase mRNA. With specific probes for the transcripts of the different domains of nitrate reductase it was shown that the smallest transcript was shortened in the region coding for the flavin adenine dinucleotide domain and might be the transcript coding for plasma-membrane-bound nitrate reductase. The expression of the 3.1 kb and 1.8 kb transcripts in roots was differently regulated during the day-night cycle with the maximum amount of the 3.1 kb transcript in the middle and of the 1.8 kb transcript at the end of the light period.

Long-term stabilization in patients with malignant glioma after treatment with liposomal doxorubicin.

BACKGROUND: Resistance to chemotherapeutic agents and poor blood-brain barrier penetration are major limitations in the treatment of malignant glioma. To improve drug delivery across the blood-brain barrier, the authors used doxorubicin as liposomal encapsulated formulation (Caelyx, Scheringh-Plough, Munich, Germany) in therapy of recurrent malignant glioma. METHODS: Fifteen patients with recurrent high-grade gliomas were included in the study. Of these, 13 patients could be evaluated, including 6 patients with glioblastoma, 1 patient with gliosarcoma and 6 patients with anaplastic astrocytoma. The treatment consisted of liposomal doxorubicin (20 mg/m(2)), applied intravenously every 2 weeks. RESULTS: Stabilization of the disease was observed in 54% (7 of 13) of patients. Partial response and complete response (CR) were not observed. Median time-to-progression was 11 weeks. Progression free survival at 12 months was 15%. Median overall survival (OS) after doxorubicin therapy was 40.0 weeks, whereas the median OS after diagnosis reached 20.0 months (87.0 weeks). Doxorubicin was well tolerated, with main side effects being palmoplantar erythrodysesthesia occurring in 38% and myelotoxicity (World Health Organization Grade 3-4) in 31% of the patients. CONCLUSIONS: Doxorubicin has been shown to be a safe treatment with moderate activity that may lead to long-term stabilization in recurrent high-grade glioma patients. Of note, median OS after all and after initiation of recurrence therapy was prolonged in comparison with the OS in other Phase II studies, as recently described by Wong et al. (Wong ET, Hess KR, Gleason MJ, Jaeckle KA, Kyritsis AP, Prados MD, et al. Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 1999;17:2572.).

A plasma membrane-bound enzyme of tobacco roots catalyses the formation of nitric oxide from nitrite.

Purified plasma membranes (PMs) of tobacco (Nicotiana tabacum L. cv. Samsun) roots exhibited a nitrite-reducing enzyme activity that resulted in nitric oxide (NO) formation. This enzyme activity was not detected in soluble protein fractions or in PM vesicles of leaves. At the pH optimum of pH 6.0, nitrite was reduced to NO with reduced cytochrome c as electron donor at a rate comparable to the nitrate-reducing activity of root-specific succinate-dependent PM-bound nitrate reductase (PM-NR). The hitherto unknown PM-bound nitrite: NO-reductase (NI-NOR) was insensitive to cyanide and anti-NR IgG and thereby proven to be different from PM-NR. Furthermore, PM-NR and NI-NOR were separated by gel-filtration chromatography and apparent molecular masses of 310 kDa for NI-NOR and 200 kDa for PM-NR were estimated. The PM-associated NI-NOR may reduce the apoplastic nitrite produced by PM-NR in vivo and may play a role in nitrate signalling via NO formation.

[Osteochondroplastic tracheobronchopathy]. / Tracheobronchopathia osteochondroplastica.

The words tracheobronchopathia osteochondroplastica (TO) were coined by Aschoff in 1910, defining a rare disease of the tracheobronchial system which most often is only "accidentally" discovered in the course of examinations, a bronchoscopy or computerized tomography, which are undertaken for other reasons. A characteristic sign for this disease are multiple cobblestone-like protrusions in the trachea and bronchus which are caused by calcifications, chondrifications and ossifications of the upper layer of the mucous membrane. We report on a 81-year old patient who was diagnosed with the disease while undergoing a fiberoptic bronchoscopy during a prolonged weaning phase. In the beginning we discussed the possibility of a neoplasia or a chronic inflammatory process as differential diagnosis and based on that we considered a dilatative tracheotomy for the weaning period. After histological confirmation of a TO we refrained from the measure, the reason being that in our opinion the patient would not profit from it. To reach a correct diagnosis a good interdisciplinarian cooperation is essential. The patient was successfully extubated on the 11th post-operative day after a patient conventional weaning which was supported by accompanying symptomatic measures. Apart from the case report we present a summary of the literature on TO concerning epidemiology, pathology, diagnosis and therapeutical measures.

[Positioning trauma in anesthesia and surgical intensive care medicine (2)]. / Lagerungsschäden in Anästhesie und operativer Intensivmedizin (Teil 2).

Specific modes of positioning are essential for successful surgery. These are again critically assessed in this final part of our review. Technically correct execution can minimize the risk of damage caused by positioning, although the possibility of damage still exists. First of all, the position on the fracture table is discussed. Great care must be taken concerning the perineal post and leg holder. In the lateral decubitus position, the correct positioning of head and spine as well as that of the lower arm are of great importance. When using the Trendelenburg and reverse Trendelenburg position, the effect on the cardiopulmonary system and the intracranial pressure must to be taken into consideration. Prone position and its modifications (i.e. tuck position) demand diligent care concerning the positioning of the head. There must be absolutely no bulbus compression and the abdominal wall should not be under pressure. While employing the sitting position, the patient should be adequately monitored so that venous air embolism can be recognized and treated as soon as possible. Because of the increased occurrence of grave complications, the sitting position should be used only if this is absolutely necessary.

[Damage due to patient positioning in anesthesia and surgical medicine (1)]. / Lagerungsschäden in Anästhesie und operativer Medizin (Teil 1).

Positioning a patient for surgery requires great care and caution. Correct positioning provides the surgeon with good access to the site, minimizes blood loss and reduces the risk of damage to nerves, soft tissue, compartments and the cardio-pulmonary system. Each position has its specific risks. These have to be evalued against the benefits. Extreme positions of the joints should be avoided whenever possible. The ulnar nerve or the plexus brachialis are at highest risk in the positioning of extremities. Good anatomical comprehension makes it possible to take effective counter-measures. In the case of damage to the ulnar nerve in spite of optimal positioning, some authors found pre-existent non-symptomatic dysfunction in up to 30% of the cases. Patients suffering from peripheral vascular disease are usually at higher risk to suffer acute ischaemia, or, in the extreme, rhabdomyolysis with compartment syndrome, when positioned with elevated extremities (as in lithotomy position) or when a tourniquet is applied. Next to other factors, the duration of surgery seems to be of some importance. Operation sites above the heart carry a higher risk of venous air embolism unrelated to the positioning. In these cases adequate monitoring should be generously applied. Loss of visus is a rare but very severe complication most often seen in connection with the prone position. Still, postoperative blindness has occurred in all positions. It is absolutely imperative to avoid all pressure to the bulbus. The same law applies to surgery and positioning: indicated and correctly executed positioning, to which the patient has effectively consented, is legal, even if damage should occur. If the plaintiff demands compensation for damage, the distribution of onus of proof depends essentially on the accuracy of documentation. If documentation is faulty, the plaintiff may be granted relief or even shift of the onus of proof. This does not apply to a criminal lawsuit; in that case, culpable medical fallibility must be proven, since otherwise, the principle of "in dubio pro reo" applies. The interdisciplinary responsibilities concerning the positioning must be clearly defined and it is essential that the documentation of positioning as well as the documentation of positioning control is carried out as accurately as possible. Correct positioning can effectively aid surgery. Slovenly positioning should not be accepted, as there is a high probability of ill effects, possibly of permanent damage.

Persistence of complexed acidic phospholipids in rapidly mineralizing tissues is due to affinity for mineral and resistance to hydrolytic attack: in vitro data.

Acidic phospholipids, complexed with calcium and inorganic phosphate, are components of extracellular matrix vesicles. Both the complexed acidic phospholipids and matrix vesicles have previously been shown to serve as hydroxyapatite (HA) nucleators in solution and when implanted in a muscle pouch. The present study supplies evidence that complexed acidic phospholipids can persist in mineralizing tissues both because of their affinity for HA and because of their resistance to hydrolysis by phospholipase A2. Calcium-phosphatidylserine-phosphate complex (CPLX-PS) synthesized with 14C-labeled phosphatidylserine (PS) was used to measure CPLX-PS affinity for HA using a Langmuir adsorption isotherm model. The affinity was shown to be higher and more specific than that of PS itself (K = 8.66 ml/mumol; N, the number of binding sites = 20.4 mumol/m2 as compared with previously reported values for PS of K = 3.33 ml/mumol, and N = 4.87 mumol/m2). Incorporated into synthetic liposomes and incubated in a calcium phosphate solution in which mineralization is induced by an ionophore, CPLX-PS showed behavior distinct from free PS. As previously reported, PS in these liposomes totally blocked HA formation. On the other hand, CPLX-PS in similar concentrations had a varied response, having no effect, slightly inhibiting, or actually promoting HA formation. CPLX-PS was also shown to be a poorer substrate for phospholipase A2 than PS, with Km = 4.63 mM for CPLX-PS and Km = 0.27 mM for PS; and Vmax = 0.029 ml/minute for CPLX-PS and Vmax = 0.066 ml/minute for PS. These data explain how complexed acidic phospholipids may persist in the growth plate and facilitate initial mineral deposition.