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We present a new methodology for simultaneously assessing competitive market structure and deriving market segments. A hierarchical or ultrametric tree representation is estimated in a maximum likelihood framework from collected paired-comparison choice data. The derived tree portrays both brands and consumers/households/segments as terminal nodes, where the `closer' a brand is to a particular consumer/household/segment in the tree, the higher the predicted probability of that consumer/household/segment choosing that particular brand. This paper initially presents an introduction to the problem of market structure assessment. We review the extensive marketing literature on market structure and survey several competing methodologies. The proposed stochastic ultrametric tree unfolding methodology is technically described and several program options are indicated. An illustration of the proposed methodology is presented with respect to paired comparison choice data collected from a convenience sample involving the over-the-counter analgesics market. Finally, several areas for future research are identified. [ABSTRACT FROM AUTHOR]

Background: Fast medical progress poses a significant challenge to doctors, who are asked to find the right balance between life-prolonging and palliative care. Literature indicates room for enhancing openness to discuss ethical sensitive issues within and between teams, and improving decision-making for benefit of the patient at end-of-life., Methods: Stepped wedge cluster randomized trial design, run across 10 different departments of the Ghent University Hospital between January 2022 and January 2023. Dutch speaking adult patients and one of their relatives will be included for data collection. All 10 departments were randomly assigned to start a 4-month coaching period. Junior and senior doctors will be coached through observation and debrief by a first coach of the interdisciplinary meetings and individual coaching by the second coach to enhance self-reflection and empowering leadership and managing group dynamics with regard to ethical decision-making. Nurses, junior doctors and senior doctors anonymously report perceptions of excessive treatment via the electronic patient file. Once a patient is identified by two or more different clinicians, an email is sent to the second coach and the doctor in charge of the patient. All nurses, junior and senior doctors will be invited to fill out the ethical decision making climate questionnaire at the start and end of the 12-months study period. Primary endpoints are (1) incidence of written do-not-intubate and resuscitate orders in patients potentially receiving excessive treatment and (2) quality of ethical decision-making climate. Secondary endpoints are patient and family well-being and reports on quality of care and communication; and clinician well-being. Tertiairy endpoints are quantitative and qualitative data of doctor leadership quality., Discussion: This is the first randomized control trial exploring the effects of coaching doctors in self-reflection and empowering leadership, and in the management of team dynamics, with regard to ethical decision-making about patients potentially receiving excessive treatment., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Benoit et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Invertebrate and vertebrate nervous systems generate different types of dopaminergic neurons in distinct parts of the brain. We have taken a genetic approach to understand how the four functionally related, but lineally unrelated, classes of dopaminergic neurons of the nematode Caenorhabditis elegans , located in distinct parts of its nervous system, are specified. We have identified several genes involved in the generation of a specific dopaminergic neuron type that is generated from the so-called postdeirid lineage, called PDE. Apart from classic proneural genes and components of the mediator complex, we identified a novel, previously uncharacterized zinc finger transcription factor, ztf-6 Loss of ztf-6 has distinct effects in different dopamine neuron-producing neuronal lineages. In the postdeirid lineage, ztf-6 is required for proper cell division patterns and the proper distribution of a critical cell fate determinant, the POP-1/TCF-like transcription factor., (Copyright © 2018 Doitsidou et al.)

Background and Purpose: A previous study in our department demonstrated the negative impact on freedom from biochemical failure (FFBF) of using too narrow planning target volume (PTV) margins during prostate image-guided radiotherapy (IGRT). Here, we investigated the impact of appropriate PTV margins and rectal distention on FFBF., Methods and Materials: A total of 50 T1-T3N0M0 prostate cancer patients were treated with daily IGRT by implanted markers. In the first 25 patients, PTV margins were 3mm laterolateral, 5mm anterioposterior and 4mm craniocaudal. The subsequent 25 patients were treated with isotropic margins of 6mm. The rectal cross-sectional area (CSA) was determined on the planning CT. Median follow-up was 61months., Results: The overall 5-year FFBF was 83%. A 6mm PTV margin was related to increased 5-year FFBF on univariate analysis (96% vs 74% with the tighter PTV margins, p=0.04). The 5-year FFBF of patients with a rectal distention on the planning CT was worse compared to those with limited rectal filling (75% for CSA⩾9cm(2) vs 89% for CSA<9cm(2), p=0.02), which remained significant on multivariate analysis (p=0.04)., Conclusion: This retrospective study illustrated the positive impact of PTV margin adaptation and addressed the importance of avoiding rectal distention at time of the planning CT., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To report late gastrointestinal (GI) and genitourinary (GU) toxicity, biochemical and clinical outcomes, and overall survival after hypofractionated radiation therapy for prostate cancer (PC)., Methods and Materials: Three institutions included 113 patients with T1 to T3N0M0 PC in a phase II study. Patients were treated with 56 Gy in 16 fractions over 4 weeks. Late toxicity was scored using Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria extended with additional symptoms. Biochemical outcome was reported according to the Phoenix definition for biochemical failure., Results: The incidence of late GI and GU toxicity was low. The 3-year actuarial risk of developing late GU and GI toxicity of grade≥2 was 13% and 8% respectively. Five-year biochemical non-evidence of disease (bNED) was 94%. Risk group, T stage, and deviation from planned hormone treatment were significant predictive factors for bNED. Deviation from hormone treatment remained significant in multivariate analysis. Five-year clinical non evidence of disease and overall survival was 95% and 91% respectively. No patient died from PC., Conclusions: Hypofractionated high-dose radiation therapy is a valuable treatment option for patients with PC, with excellent biochemical and clinical outcome and low toxicity., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Methylation of histone H3 lysine 4 (H3K4me), a mark associated with gene activation, is mediated by SET1 and the related mixed lineage leukemia (MLL) histone methyltransferases (HMTs) across species. Mammals contain seven H3K4 HMTs, Set1A, Set1B, and MLL1-MLL5. The activity of SET1 and MLL proteins relies on protein-protein interactions within large multisubunit complexes that include three core components: RbBP5, Ash2L, and WDR5. It remains unclear how the composition and specificity of these complexes varies between cell types and during development. Caenorhabditis elegans contains one SET1 protein, SET-2, one MLL-like protein, SET-16, and single homologs of RbBP5, Ash2L, and WDR5. Here we show that SET-2 is responsible for the majority of bulk H3K4 methylation at all developmental stages. However, SET-2 and absent, small, or homeotic discs 2 (ASH-2) are differentially required for tri- and dimethylation of H3K4 (H3K4me3 and -me2) in embryos and adult germ cells. In embryos, whereas efficient H3K4me3 requires both SET-2 and ASH-2, H3K4me2 relies mostly on ASH-2. In adult germ cells by contrast, SET-2 serves a major role whereas ASH-2 is dispensable for H3K4me3 and most H3K4me2. Loss of SET-2 results in progressive sterility over several generations, suggesting an important function in the maintenance of a functional germ line. This study demonstrates that individual subunits of SET1-related complexes can show tissue specificity and developmental regulation and establishes C. elegans as a model to study SET1-related complexes in a multicellular organism.

The use of whole pelvic radiotherapy (WPRT) for high-risk and lymph node-positive prostate cancer (PC) remains controversial. The purpose of this study was to evaluate the acute toxicity associated with helical tomotherapy in the treatment of high-risk and lymph node-positive prostate cancer. To do so, twenty-eight patients were treated to a dose of 54 Gy in daily fractions of 1.8 Gy to the pelvic lymph node area, while the prostate and the seminal vesicles received a simultaneous integrated boost (SIB) to a dose of 70.5 Gy. A SIB to a dose of 60 Gy was delivered to the involved lymph node region(s) in 8 patients with pelvic lymph node metastases. All patients received concurrent hormonal treatment. The incidence of grade 2 and 3 acute gastrointestinal (GI) toxicity was 7% and 0% respectively. Grade 2 and 3 acute genito-urinary (GU) side effects were observed in 14% and 4% of the patients respectively. No grade 4 side effects occurred. No increased toxicity was observed in the 8 lymph node-positive patients receiving a simultaneous pelvic nodal dose escalation. In conclusion, WPRT with a SIB to the prostate and seminal vesicles by helical tomotherapy resulted in a favourable toxicity profile. Pelvic nodal dose escalation in node-positive patients is feasible without increasing toxicity.

Background: The combination of radiotherapy plus long-term medical suppression of androgens (> or = 2 years) improves overall survival in patients with locally advanced prostate cancer. We compared the use of radiotherapy plus short-term androgen suppression with the use of radiotherapy plus long-term androgen suppression in the treatment of locally advanced prostate cancer., Methods: We randomly assigned patients with locally advanced prostate cancer who had received external-beam radiotherapy plus 6 months of androgen suppression to two groups, one to receive no further treatment (short-term suppression) and the other to receive 2.5 years of further treatment with a luteinizing hormone-releasing hormone agonist (long-term suppression). An outcome of noninferiority of short-term androgen suppression as compared with long-term suppression required a hazard ratio of more than 1.35 for overall survival, with a one-sided alpha level of 0.05. An interim analysis showed futility, and the results are presented with an adjusted one-sided alpha level of 0.0429., Results: A total of 1113 men were registered, of whom 970 were randomly assigned, 483 to short-term suppression and 487 to long-term suppression. After a median follow-up of 6.4 years, 132 patients in the short-term group and 98 in the long-term group had died; the number of deaths due to prostate cancer was 47 in the short-term group and 29 in the long-term group. The 5-year overall mortality for short-term and long-term suppression was 19.0% and 15.2%, respectively; the observed hazard ratio was 1.42 (upper 95.71% confidence limit, 1.79; P=0.65 for noninferiority). Adverse events in both groups included fatigue, diminished sexual function, and hot flushes., Conclusions: The combination of radiotherapy plus 6 months of androgen suppression provides inferior survival as compared with radiotherapy plus 3 years of androgen suppression in the treatment of locally advanced prostate cancer. (ClinicalTrials.gov number, NCT00003026.), (2009 Massachusetts Medical Society)

Purpose: To evaluate the effect of rectal distention on the planning computed tomogram on freedom from biochemical failure (FFBF) of prostate cancer patients treated with image-guided conformal arc radiotherapy., Methods and Materials: The outcomes of 238 patients with T1-T3N0M0 tumors were analyzed, with a median follow-up of 53 months (range, 24-93 months). In 213 patients, daily co-registration of X-rays and digitally reconstructed radiographs was used for positioning, whereas in 25 patients positioning was done using direct prostate visualization with implanted markers. The rectal average cross-sectional area was determined on the planning computed tomogram., Results: The 5-year freedom from Grade 3 to 4 late gastrointestinal and urinary side effect, according to the Radiation Therapy Oncology Group criteria, was 100% and 99.4% respectively. The 5-year FFBF was 88.4%. On multivariate analysis the following variables were significantly related to worse FFBF: risk group according to the National Comprehensive Cancer Network (high- to very high risk vs. intermediate- to low-risk), dose (70 vs. 78 Gy), average cross-sectional area (> or =16 vs. <16 cm(2)) and, unexpectedly, the use of implanted markers as opposed to bony structures for patient positioning. In retrospect, the margins around the clinical target volume appeared to be inadequate in the cases in which markers were used., Conclusion: Overall, the outcome of patients treated with image-guided conformal arc radiotherapy is excellent. We were able to confirm the negative prognostic impact of a distended rectum on the planning computed tomogram described by others. The study illustrates the potential danger of image guidance techniques as to margin reduction around the clinical target volume.

Purpose: Assessment of rectal distention in a group of patients who are not receiving daily rectum emptying procedures during a course of prostate cancer radiotherapy to investigate which patients could benefit from daily rectum emptying., Methods and Materials: Eighteen patients underwent daily megavoltage CT (MVCT) scanning with positioning based on bony anatomy. Emptying the rectum was only performed before planning CT and not during the actual treatment. The rectal average cross-sectional area (CSA) was determined on the MVCTs. The relative CSA (CSA(rel)) was defined as CSA on MVCT / CSA on planning CT. Additional prostate soft tissue matching was performed to verify the influence of rectal distention on prostate motion., Results: Two distinct subgroups could be defined a posteriori. One group had a limited and stable rectal distention with a CSA (mean+/-SD) of 6.6+/-2.1cm(2), in contrast with a second group with large and variable rectal filling with a CSA of 9.5+/-3.7cm(2) (p<0.01). Mean anterior-posterior prostate displacement was 0.4+/-2.4 mm in the stable group versus -2.4+/-6.1 mm in the unstable group (p<0.01). A mean CSA(rel) of 1.35 of the first 3 days as cut-off value allowed for a correct a priori classification of 90% and 85% of the patients from groups 1 and 2, respectively., Conclusion: Based on a few measurements of the CSA by daily MVCT imaging at the first days of treatment, rectum emptying may be omitted in part of the patients.

Purpose: To evaluate the prognostic significance of primary tumor location and to examine whether the effect of adjuvant radiotherapy on survival varies according to tumor location in women with axillary node-positive (ALN+) breast cancer (BC)., Patients and Methods: Data were abstracted from the SEER database for 24,410 women aged 25-95 years, diagnosed between 1988-1997 with nonmetastatic T1-T2, ALN+ BC. Subgroup analyses were performed using interactions within proportional hazards models. Event was defined as death from any cause. Prognostic variables were selected using Akaike Information Criteria. Joint significances of subgroups were evaluated with Wald test., Results: Median follow-up was 10 years. In joint models, statistically significant interactions were found between tumor location, nodal involvement, type of surgery, and radiotherapy. Factorial presentation of interactions showed consistent 13% proportional reduction of mortality in all subgroups, except in women with medial tumors with > or = 4 ALN+ treated with mastectomy. In this subgroup, use of radiotherapy was associated with a 16% proportional increase in mortality., Conclusion: Medial tumor location is a significant adverse prognostic factor that should be considered in treatment decision- making for women with ALN+ BC. Improved survival was observed with radiotherapy use in all subgroups, except in women with medial tumors with > or = 4 ALN+ treated with postmastectomy radiotherapy. These findings raise concern that the favorable effect of radiotherapy may be offset by excess toxicities in the latter subgroup.

Purpose: To investigate predictors for gastrointestinal (GI) and genitourinary (GU) acute toxicity after a short-course hypofractionated radiotherapy regimen for prostate cancer., Materials and Methods: Three institutions included 102 patients with T1-T3N0M0 prostate cancer in a Phase II study. Patients were treated with 56 Gy in 16 fractions over 4 weeks. Acute toxicity was scored weekly during treatment and 1 and 2 months after treatment using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria extended with additional symptoms and the International Prostate Symptom Index (IPSS). Correlation with a number of clinical and dosimetric parameters was assessed by univariate and multivariate analyses., Results: No Grade 3 or 4 GI side effects were observed. Grades 1 and 2 rectal GI toxicity occurred in 36%, and 38%, respectively. Corresponding figures for Grades 1 and 2 GU toxicity were 42% and 39%, respectively. Grade 3 or higher GU toxicity was detected in 4% of patients. In multivariate analysis, percent rectal volumes higher than 8% receiving doses >/=53 Gy (V(53)) were statistically correlated to Grade 2 acute rectal reaction (p = 0.006). For GU morbidity, only the IPSS pretreatment score was independently associated (p = 0.0036) with an increase in GU acute effects., Conclusions: Acute GU and GI toxicity were comparable with other series. Our data show that increased incidence and intensity of acute toxicity is a transient effect related to shorter overall treatment time rather than a larger effect in biological equivalent dose with respect to a conventional fractionation regime.

The purpose of external beam radiotherapy is to sterilize malignant tumours and at the same time to avoid complications by radiation injury to the surrounding healthy tissues. Modern radiation techniques in recent years have allowed to safely escalate the dose by approximately 10% for the treatment of prostate cancer, resulting in a disease control that is nowadays comparable to surgery or permanent seed implant brachytherapy. Two recent technical developments have dramatically increased the precision of radiation dose delivery: conformal radiotherapy and image guided radiotherapy (IGRT). Conformal radiotherapy aims to shape the dose distribution to the shape of the target. At least equally important as conformality is the accurate spatial delivery of the conformal dose distribution to the target. Conventional patient positioning by skin drawings and lasers is an imprecise way to target the prostate within the pelvis. The need for adequate patient/target setup led in recent years to the development of a variety of solutions. They bear in common that setup is no longer guided by skin marks but by some imaging modality. An ideal IGRT system would allow for daily prostate imaging without possible introduction of errors due to image-acquisition itself, do so within a reasonable time frame, without the necessity for implanted radio-opaque markers and preferentially without exposing the patient to radiation. A solution that combines all these features is inexistent so far.

The limited ability to control for the location of a tumour compromises the accuracy with which radiation can be delivered to tumour-bearing tissue. The resultant requirement for larger treatment volumes to accommodate target uncertainty restricts the radiation dose because more surrounding normal tissue is exposed. With image-guided radiotherapy (IGRT) these volumes can be optimized and tumoricidal doses can be delivered, achieving maximal tumour control with minimal complications. Moreover, with the ability of high-precision dose delivery and real-time knowledge of the target volume location, IGRT has initiated the exploration of new indications for radiotherapy, some of which were previously considered infeasible.

We treated 36 cases of stage I/II non-small cell lung cancer in inoperable patients. Treatments were planned to a total isocenter dose of 60Gy (8x7.5Gy) based on a dynamic field shaping arc, employing one arc to span as much area as possible and if needed additional weighted segments. The 2 year infield progression free probability is 65%. Disease-specific survival is 75% at 2 years. No patients experienced grade 3-4 toxicity.