"Trying to write a story together": general practitioners' perspectives on culturally sensitive care.

BACKGROUND: Culturally sensitive care is integral to effective and equitable healthcare delivery, necessitating an understanding and acknowledgment of patients' cultural needs, preferences, and expectations. This study investigates the perceptions of cultural sensitivity among general practitioners (GPs), focusing on their intentions, willingness and perceived responsibilities in providing care tailored to cultural needs. METHODS: In-depth interviews were conducted with 21 Flemish GPs to explore their perspectives on culturally sensitive care. Data analysis followed a conventional qualitative content analysis approach within a constructivist framework. A coding scheme was developed to identify recurring themes and patterns in the GPs' responses. RESULTS: Findings reveal that culturally sensitive care provision is perceived as a multifaceted process, initiated by an exploration phase where GPs inquire about patients' cultural needs and preferences. Two pivotal factors shaping culturally sensitive care emerged: patients' specific cultural expectations and GPs' perceived responsibilities. These factors guided the process of culturally sensitive care towards three distinct outcomes, ranging from complete adaptation to patients' cultural requirements driven by a high sense of responsibility, through negotiation and compromise, to a paternalistic approach where GPs expect patients to conform to GPs' values and expectations. Three typologies of GPs in providing culturally sensitive care were identified: genuinely culturally sensitive, surface-level culturally sensitive, and those perceiving diversity as a threat. Stereotyping and othering persist in healthcare, underscoring the importance of critical consciousness and cultural reflexivity in providing patient-centered and equitable care. CONCLUSIONS: This study emphasizes the significance of empathy and underscores the necessity for GPs to embrace the exploration and acknowledgement of patients' preferences and cultural needs as integral aspects of their professional role. It highlights the importance of shared decision-making, critical consciousness, cultural desire and empathy. Understanding these nuances is essential for enhancing culturally sensitive care and mitigating healthcare disparities.

Hemiepiphysiodesis for Lower Extremity Coronal Plane Angular Correction in the Distal Femur and Proximal Tibia in Children With Achondroplasia.

BACKGROUND: Achondroplasia is the most prevalent form of skeletal dysplasia, affecting more than 250,000 individuals. Lower extremity angular deformities, particularly genu varum, are common in children with achondroplasia, often resulting in pain and limitation of function. The authors aim to determine the utility of lower extremity growth modulation with hemiepiphysiodesis in children with achondroplasia for correction of coronal plane deformities about the knee. METHODS: The authors performed a retrospective chart review of a single center from 1/1/2000 to 12/31/2020 to identify pediatric patients with achondroplasia treated with hemiepiphysiodesis as their initial procedure at the distal femur and/or proximal tibia. Patients with adequate records and who had completed their treatment were included. Data collected included duration of treatment, complications, need for osteotomy, and radiographic measurements including initial and final mechanical axis deviation, knee mechanical axis zone, mechanical lateral distal femoral angle and medial proximal tibia angle. RESULTS: Ten patients with 17 limbs met our criteria. Nine patients (15 limbs) were treated for genu varum and 1 patient (2 limbs) was treated for genu valgum. Prior to treatment, the mechanical axis fell in zone 3 in 59% of limbs and zone 2 in 41%. Average correction in mechanical axis deviation was 26.1 mm. Average change in mechanical lateral distal femoral angle was 10.3 degrees per limb, and average change in medial proximal tibia angle was 7.1 degrees per limb. Average treatment duration was 909 days. At final follow up, 81% (14/17) of limbs had the mechanical axis in zone 1, with the remaining 18% (3/17) in zone 2. No patient/limb underwent subsequent distal femur or proximal tibia osteotomy for coronal plane alignment. CONCLUSIONS: Children with achondroplasia can successfully be treated with hemiepiphysiodesis to correct coronal plane deformities at the distal femur and proximal tibia. Using this technique, no patient in our series required an osteotomy for genu varum/valgum. LEVEL OF EVIDENCE: Therapeutic level IV, Case series.

Evolution and development of inflorescences and floral symmetry in Solanaceae.

PREMISE: The inflorescences of Solanaceae are unique and complex, which has led to long-standing disputes over floral symmetry mainly due to different interpretations of the cyme-like inflorescence structure. The main disagreements have been over how the phyllomes associated with the flower were arranged relative to the inflorescence axis especially during early flower initiation. METHODS: Here we investigated the evolution of inflorescences in Solanaceae by analyzing inflorescence structure in the context of phylogeny using ancestral state reconstruction (ASR) to determine the evolutionary transitions between loosely arranged and tightly clustered inflorescences and between monochasial-like and dichasial-like cymes. We also reconstructed two- and three-dimensional models for 12 solanaceous species that represent both inflorescence and phylogenetic diversity in the family. RESULTS: Our results indicate that the most recent common ancestor of Solanaceae had a loosely arranged and monochasial-like cyme, while tightly clustered inflorescences and dichasial-like cymes were derived. Compared to the known process of scorpioid cyme evolution, Solanaceae achieved their scorpioid cyme-like inflorescences through a previously undescribed way. Along the pedicel, the two flower-preceding prophylls are not in the typical transverse position of dicotyledonous plants; they frequently have axillary buds, and the main inflorescence axis continues in a sympodial fashion. As a result, the plane of symmetry of the flower is 36° from the median, and the inflorescence axis and the two flower-preceding prophylls are symmetrically located along that plane. CONCLUSIONS: A better understanding of the morphological evolution of solanaceous inflorescence structure helped clarify the floral symmetry of Solanaceae.

Perceived Teacher Discrimination and Depressive Feelings in Adolescents: The Role of National, Regional, and Heritage Identities in Flemish Schools.

Adolescents' identities are multiple, yet there is very little research that investigates the importance of intersecting identities, especially in relationship to teacher ethnic/racial discrimination and mental health. Multiplicity is often approached bi-dimensional (heritage and national identities) yet this study highlights the importance of regional identity. Regions are distinct socio-political contexts in relation to migration and integration dynamics. Hence, this study investigates for different combinations of national, heritage and regional identities (i.e. Flemish, Belgian and Turkish or Moroccan) the relationship between students' experiences with teacher ethnic/racial discrimination and students' depressive feelings. Latent Class Analysis of survey data involving a sample of 439 adolescents (Mage = 18, SD = 0.93; Girls = 49%) with Turkish (41%) or Moroccan origin in Flanders, shows three identification classes: full integration (35%), national integration (40%) and (weak) separation (24%). All these identity profiles had in common that heritage identification was high, yet they were highly distinct due to variation in national and regional identification. Additional, multilevel modelling showed that nationally integrated adolescents were less depressed than fully integrated adolescents. This finding illustrates the importance of adolescents' identity multiplicity for understanding their resilience in relation to teacher discrimination.

Phylogeny, divergence times, and diversification in Calophyllaceae: Linking key characters and habitat changes to the evolution of Neotropical Calophylleae.

The clusioid clade comprises five monophyletic families: Bonnetiaceae, Calophyllaceae, Clusiaceae s.s., Hypericaceae, and Podostemaceae. Even though the circumscription of these families is well established, phylogenetic relationships within some families remain unresolved. This study aims to infer phylogenetic relationships within the Neotropical Calophylleae based on a broad sampling of taxa and a multilocus approach. We then use our phylogenetic framework as basis to investigate the evolution and biogeography of Calophylleae and diversification shifts in Calophyllaceae. To reconstruct the phylogeny of the Neotropical Calophylleae, we used five plastid (matK, ndhF, rbcL, psbA-trnH, and trnK), two mitochondrial (matR and rps3), and two nuclear (EMB2765 and ITS) markers, including previously published and newly generated sequences. We sampled 74 species, increasing sampling of Neotropical taxa by 500%. Our phylogenetic hypothesis for Calophyllaceae provides additional support for the monophyly of all genera and allowed us to identify four main clades: Calophyllum, Kayea, Mammea, and the Neotropical clade. The Neotropical clade includes three main lineages, a small clade composed of Clusiella and Marila, and a large HaCaKi clade (i.e., Haplocarpa, Caraipa, and Kilmeyera) that is sister to Mahurea exstipulata. The evolution of three morphological traits (i.e., fleshy fruits, anther glands, and winged seeds) were shown to be associated with changes in evolutionary dynamics in Calophyllaceae, while a biome shift was detected in Kielmeyera, affecting net diversification within this genus. Major geological and climatic events such as the Andean uplift and a gradual decrease in temperatures seem to have influenced diversification rates within the Neotropical Calophylleae.

Prospective Study on Tension Band Plating: Most Patients are Not Returning to Normal Activities 1 Month Following Surgery.

BACKGROUND: Tension band plating for temporary hemiepiphysiodesis has been reported by several authors as simple and effective for treating angular deformities of the lower limb. Anecdotally, patients have reported higher pain levels than expected given the small size of incision and relatively minimal amount of dissection, and we sought to investigate this further. METHODS: Patients 16 years old or less with lower extremity angular deformities or limb length inequality were prospectively enrolled before tension band plating from 2 pediatric institutions from July 2016 to December 2018. Participants completed postoperative questionnaires regarding their pain and activity level. Pain was assessed using the FACES Pain Scale. Patients were included if they completed the 1 month survey. RESULTS: Of the 48 patients that met inclusion criteria (mean age at surgery: 13.1 y; range: 7 to 16 y), 39 patients completed the survey at 3 months postoperatively. There was a significant change in pain level between 1 week and 1 month postoperatively (P<0.001). Eighty-three percent (34/41) of patients were still taking pain medication at 1 week, which decreased to 38% (18/48) at 1 month. At 3 months, 21% (8/39) patients reported they were still using pain medication. At 1 month, 65% of patients (31/48) had not returned to their prior activity level. Of the 39 patients who played sports, 59% (23/39) still had not fully returned to sports at 1 month. CONCLUSION: At 1 month following tension band plating, 65% of patients had not returned to their preoperative activity level, and 38% were taking pain medications. Although the tension band plate and surgical incision is small in size, patients and parents should be counseled that there are significant activity limitations and pain levels for a month or longer in many patients. LEVEL OF EVIDENCE: Level II.

Three keys to the radiation of angiosperms into freezing environments.

Early flowering plants are thought to have been woody species restricted to warm habitats. This lineage has since radiated into almost every climate, with manifold growth forms. As angiosperms spread and climate changed, they evolved mechanisms to cope with episodic freezing. To explore the evolution of traits underpinning the ability to persist in freezing conditions, we assembled a large species-level database of growth habit (woody or herbaceous; 49,064 species), as well as leaf phenology (evergreen or deciduous), diameter of hydraulic conduits (that is, xylem vessels and tracheids) and climate occupancies (exposure to freezing). To model the evolution of species' traits and climate occupancies, we combined these data with an unparalleled dated molecular phylogeny (32,223 species) for land plants. Here we show that woody clades successfully moved into freezing-prone environments by either possessing transport networks of small safe conduits and/or shutting down hydraulic function by dropping leaves during freezing. Herbaceous species largely avoided freezing periods by senescing cheaply constructed aboveground tissue. Growth habit has long been considered labile, but we find that growth habit was less labile than climate occupancy. Additionally, freezing environments were largely filled by lineages that had already become herbs or, when remaining woody, already had small conduits (that is, the trait evolved before the climate occupancy). By contrast, most deciduous woody lineages had an evolutionary shift to seasonally shedding their leaves only after exposure to freezing (that is, the climate occupancy evolved before the trait). For angiosperms to inhabit novel cold environments they had to gain new structural and functional trait solutions; our results suggest that many of these solutions were probably acquired before their foray into the cold.

Psychologically informed practice (PIP) within the offender personality disorder pathway: Towards establishing an evidence base for approved premises.

The United Kingdom (UK) government has commissioned numerous interventions across all stages of the criminal justice pathway for managing offenders likely to have a personality disorder, with the intention to reduce reoffending, improve psychological wellbeing, and develop workforce capabilities. Psychologically Informed Practice (PIP) models underpin these. To evaluate a modified PIP model within the post-imprisonment community stage of the Offender Personality Disorder (OPD) pathway, specifically workforce development, within all London (UK) probation supervised hostels (approved premises), we used both non-equivalent control group and pre-post repeated measure designs to compare changes in staff and offender outcomes before and after introduction of a PIP model across all 12 London approved premises. Findings revealed statistically significant improvements in a number of workforce outcomes (measured using the Personality Disorder - Knowledge, Attitudes and Skills Questionnaire and Maslach Burnout Inventory) which were moderated by age and gender. Data did not support associated improvements in resident offender outcomes (progressive moves, rearrests/reoffences, or breaches leading to recalls). The modified PIP is an effective intervention model for improving some workforce outcomes among probation supervised hostel staff, particularly for women, but our findings suggest that intervention development may be required for significant improvements to be observed in resident offending outcomes. In addition, further research is necessary to determine the longer term effects of PIP on absenteeism, employee turnover, quality of resident-staff interactions, and overall culture change among staff working within the post-imprisonment community stage of the OPD pathway.

Evolution of the process underlying floral zygomorphy development in pentapetalous angiosperms.

PREMISE OF THE STUDY: Observations of floral ontogeny indicated that floral organ initiation in pentapetalous flowers most commonly results in a median-abaxial (MAB) petal during early development, a median-adaxial (MAD) petal being less common. Such different patterns of floral organ initiation might be linked with different morphologies of floral zygomorphy that have evolved in Asteridae. Here, we provide the first study of zygomorphy in pentapetalous angiosperms placed in a phylogenetic framework, the goal being to find if the different patterns of floral organ initiation are connected with particular patterns of zygomorphy. METHODS: We analyzed patterns of floral organ initiation and displays of zygomorphy, extracted from floral diagrams representing 405 taxa in 330 genera, covering 83% of orders (30 out of 36) and 37% of families (116 out of 313) in core eudicots in the context of a phylogeny using ancestral state reconstructions. KEY RESULTS: The MAB petal initiation is the ancestral state of the pattern of floral organ initiation in pentapetalous angiosperms. Taxa with MAD petal initiation represent ∼30 independent origins from the ancestral MAB initiation. There are distinct developmental processes that give rise to zygomorphy in different lineages of pentapetalous angiosperms, closely related lineages being likely to share similar developmental processes. CONCLUSIONS: We have demonstrated that development indeed constrains the processes that give rise to floral zygomorphy, while phylogenetic distance allows relaxation of these constraints, which provides novel insights on the role that development plays in the evolution of floral zygomorphy.

Correction of Angular Deformities Due to Focal Fibrocartilaginous Dysplasia Using Guided Growth: A Preliminary Report.

BACKGROUND: Focal fibrocartilaginous dysplasia (FFCD) is a rare benign disorder that may result in tethering of the physis. These most commonly occur around the knee and may result in angular deformities of the involved extremity. To date treatment has ranged from observation, to curettage, to osteotomy. Our goal with this study is to evaluate the efficacy of guided growth in treating patients with angular deformity due to FFCD. METHODS: This is a retrospective review, we included 3 patients with angular deformities due to FFCD who had undergone 8 plate placement. We reviewed their preoperative and postoperative radiographs, assessed their sagittal and coronal balance and number of procedures. RESULTS: Three patients with FFCD of the femur with an average of 14 months underwent guided growth to correct their angular deformity. Once appropriate correction was achieved the hardware was removed. At final follow-up none of the patients required further surgical intervention for their angular deformity nor had they shown any evidence of recurrence. CONCLUSIONS: FFCD is a rare benign disorder, they most commonly affects the proximal tibia and distal femur and can result in significant angular deformities. Our review of the literature found all of the cases involving the femur progressed to the point where they needed surgical intervention. This ranged from curettage to osteotomy. In this case series we present 3 cases of FFCD of the distal femur that were treated minimally invasively with guided growth. LEVEL OF EVIDENCE: Level 4.

Mutualism Persistence and Abandonment during the Evolution of the Mycorrhizal Symbiosis.

Mutualistic symbioses with mycorrhizal fungi are widespread in plants. The majority of plant species associate with arbuscular mycorrhizal (AM) fungi. By contrast, the minority associate with ectomycorrhizal (EM) fungi, have abandoned the symbiosis and are nonmycorrhizal (NM), or engage in an intermediate, weakly AM symbiosis (AMNM). To understand the processes that maintain the mycorrhizal symbiosis or cause its loss, we reconstructed its evolution using a ∼3,000-species seed plant phylogeny integrated with mycorrhizal state information. Reconstruction indicated that the common ancestor of seed plants most likely associated with AM fungi and that the EM, NM, and AMNM states descended from the AM state. Direct transitions from the AM state to the EM and NM states were infrequent and generally irreversible, implying that natural selection or genetic constraint could promote stasis once a particular state evolved. However, the evolution of the NM state was more frequent via an indirect pathway through the AMNM state, suggesting that weakening of the AM symbiosis is a necessary precursor to mutualism abandonment. Nevertheless, reversions from the AMNM state back to the AM state were an order of magnitude more likely than transitions to the NM state, suggesting that natural selection favors the AM symbiosis over mutualism abandonment.

Non-equilibrium dynamics and floral trait interactions shape extant angiosperm diversity.

Why are some traits and trait combinations exceptionally common across the tree of life, whereas others are vanishingly rare? The distribution of trait diversity across a clade at any time depends on the ancestral state of the clade, the rate at which new phenotypes evolve, the differences in speciation and extinction rates across lineages, and whether an equilibrium has been reached. Here we examine the role of transition rates, differential diversification (speciation minus extinction) and non-equilibrium dynamics on the evolutionary history of angiosperms, a clade well known for the abundance of some trait combinations and the rarity of others. Our analysis reveals that three character states (corolla present, bilateral symmetry, reduced stamen number) act synergistically as a key innovation, doubling diversification rates for lineages in which this combination occurs. However, this combination is currently less common than predicted at equilibrium because the individual characters evolve infrequently. Simulations suggest that angiosperms will remain far from the equilibrium frequencies of character states well into the future. Such non-equilibrium dynamics may be common when major innovations evolve rarely, allowing lineages with ancestral forms to persist, and even outnumber those with diversification-enhancing states, for tens of millions of years.

The ethnic prejudice of Flemish teachers: The role of ethnic school composition and of teachability.

OBJECTIVES: The aim of this study is to investigate the association between ethnic composition in school and the ethnic prejudice of teachers, controlling for the individual characteristics of teachers and their perceptions of pupils' teachability. METHOD: Multilevel analyses were carried out on data for 499 Flemish teachers in 44 Flemish (Belgian) secondary schools, collected through an online questionnaire. In this study, ethnic prejudice means a negative attitude to Moroccans, Turks, and Eastern Europeans. A scale was created by taking the mean scores for 18 items, with higher scores indicating greater ethnic prejudice (Quillian, 1995; Witte, 1999). RESULTS: Teachers with long-term higher education or a university diploma are shown to be less ethnically prejudiced than teachers with a lower level of education. Moreover, teachers who work at a school with a greater number of ethnic minority pupils, and at the same time evaluate their pupils as more teachable, are less ethnically prejudiced. CONCLUSIONS: These findings highlight the need for more research into the underlying processes, such as pupils' teachability, that influence the relationship between school characteristics and the ethnic prejudice of teachers. More knowledge about the context-specific factors and processes that mediate and/or moderate this relationship can increase the theoretical understanding of the development of ethnic prejudice. It can also highlight particular social characteristics, which can be the focus of social and organizational policy aimed at reducing ethnic prejudices. (PsycINFO Database Record

Perceived Ethnic Discrimination by Teachers and Ethnic Minority Students' Academic Futility: Can Parents Prepare Their Youth for Better or for Worse?

This study focuses on the interplay of perceived ethnic discrimination by teachers, parents' ethnic socialization practices, and ethnic minority students' sense of academic futility. Since discrimination creates barriers beyond control of the individual, the first research goal is to examine the association of perceived ethnic discrimination by teachers with ethnic minority students' sense of academic futility. The second research goal is to focus on the role of perceived parental ethnic socialization (e.g., cultural socialization and preparation for bias) to get a better understanding of the interaction between family level factors and the potentially negative consequences of ethnic teacher discrimination. A multilevel analysis on 1181 ethnic minority students (50.6 % girls; mean age = 15.5), originating from migration, in 53 secondary schools in Flanders (Belgium) shows that the frequent perception of ethnic discrimination by teachers is associated with stronger feelings of academic futility, and if these students also received high levels of parents' ethnic socialization, they perceive even stronger feelings of futility. The group of ethnic minority students, who perceive frequent ethnic teacher discrimination, is a group at risk, and parents' ethnic socialization does not seem able to change this.

The role of molecular analysis in the diagnosis and surveillance of pancreatic cystic neoplasms.

CONTEXT: Molecular analysis of pancreatic cyst fluid obtained by EUS-FNA may increase diagnostic accuracy. We evaluated the utility of cyst-fluid molecular analysis, including mutational analysis of K-ras, loss of heterozygosity (LOH) at tumor suppressor loci, and DNA content in the diagnoses and surveillance of pancreatic cysts. METHODS: We retrospectively reviewed the Columbia University Pancreas Center database for all patients who underwent EUS/FNA for the evaluation of pancreatic cystic lesions followed by surgical resection or surveillance between 2006-2011. We compared accuracy of molecular analysis for mucinous etiology and malignant behavior to cyst-fluid CEA and cytology and surgical pathology in resected tumors. We recorded changes in molecular features over serial encounters in tumors under surveillance. Differences across groups were compared using Student's t or the Mann-Whitney U test for continuous variables and the Fisher's exact test for binary variables. RESULTS: Among 40 resected cysts with intermediate-risk features, molecular characteristics increased the diagnostic yield of EUS-FNA (n=11) but identified mucinous cysts less accurately than cyst fluid CEA (P=0.21 vs. 0.03). The combination of a K-ras mutation and ≥2 loss of heterozygosity was highly specific (96%) but insensitive for malignant behavior (50%). Initial data on surveillance (n=16) suggests that molecular changes occur frequently, and do not correlate with changes in cyst size, morphology, or CEA. CONCLUSIONS: In intermediate-risk pancreatic cysts, the presence of a K-ras mutation or loss of heterozygosity suggests mucinous etiology. K-ras mutation plus ≥2 loss of heterozygosity is strongly associated with malignancy, but sensitivity is low; while the presence of these mutations may be helpful, negative findings are uninformative. Molecular changes are observed in the course of cyst surveillance, which may be significant in long-term follow-up.

Phylogenomics and a posteriori data partitioning resolve the Cretaceous angiosperm radiation Malpighiales.

The angiosperm order Malpighiales includes ~16,000 species and constitutes up to 40% of the understory tree diversity in tropical rain forests. Despite remarkable progress in angiosperm systematics during the last 20 y, relationships within Malpighiales remain poorly resolved, possibly owing to its rapid rise during the mid-Cretaceous. Using phylogenomic approaches, including analyses of 82 plastid genes from 58 species, we identified 12 additional clades in Malpighiales and substantially increased resolution along the backbone. This greatly improved phylogeny revealed a dynamic history of shifts in net diversification rates across Malpighiales, with bursts of diversification noted in the Barbados cherries (Malpighiaceae), cocas (Erythroxylaceae), and passion flowers (Passifloraceae). We found that commonly used a priori approaches for partitioning concatenated data in maximum likelihood analyses, by gene or by codon position, performed poorly relative to the use of partitions identified a posteriori using a Bayesian mixture model. We also found better branch support in trees inferred from a taxon-rich, data-sparse matrix, which deeply sampled only the phylogenetically critical placeholders, than in trees inferred from a taxon-sparse matrix with little missing data. Although this matrix has more missing data, our a posteriori partitioning strategy reduced the possibility of producing multiple distinct but equally optimal topologies and increased phylogenetic decisiveness, compared with the strategy of partitioning by gene. These approaches are likely to help improve phylogenetic resolution in other poorly resolved major clades of angiosperms and to be more broadly useful in studies across the Tree of Life.

Physical properties of odorants affect behavior of trained detection dogs during close-quarters searches.

Trained detection dogs have a unique ability to find the sources of target odors in complex fluid environments. How dogs derive information about the source of an odor from an odor plume comprised of odorants with different physical properties, such as diffusivity, is currently unknown. Two volatile chemicals associated with explosive detection, ammonia (NH3, derived from ammonium nitrate-based explosives) and 2-ethyl-1-hexanol (2E1H, associated with composition C4 plastic explosives) were used to ascertain the effects of the physical properties of odorants on the search behavior and motion of trained dogs. NH3 has a diffusivity 3.6 times that of 2E1H. Fourteen civilian detection dogs were recruited to train on each target odorant using controlled odor mimic permeation systems as training aids over 6 weeks and then tested in a controlled-environment search trial where behavior, motion, and search success were analyzed. Our results indicate the target-odorant influences search motion and time spent in the stages of searching, with dogs spending more time in larger areas while localizing NH3. This aligns with the greater diffusivity of NH3 driving diffusion-dominated odor transport when dogs are close to the odor source in contrast to the advection-driven transport of 2E1H at the same distances.

Phase I study of PM00104 (Zalypsis®) administered as a 1-hour weekly infusion resting every fourth week in patients with advanced solid tumors.

PM00104 (Zalypsis®) is a new synthetic alkaloid with potent cytotoxic activity against tumor cell lines. This phase I clinical trial determined the maximal tolerated dose (MTD) and recommended dose (RD) for phase II trials of PM00104 administered as a 1-hour intravenous (i.v.) infusion weekly for three consecutive weeks resting every fourth week (d1,8,15 q4wk). Forty-nine patients with advanced solid malignancies received PM00104 following a toxicity-guided, accelerated, dose-escalation design. Doses evaluated ranged from 0.07 to 3.0 mg/m(2). Dose-limiting toxicities (DLTs) appeared at the highest doses tested and comprised grade 3 diarrhea and grade 4 lipase increase at 2.0 mg/m(2); grade 1 thrombocytopenia and grade 2 neutropenia with two infusion omissions, grade 3 fatigue and grade 4 febrile neutropenia at 2.5 mg/m(2); and grade 3/4 fatigue, grade 4 neutropenia lasting >5 days and grade 4 thrombocytopenia at 3.0 mg/m(2). RD was established at 2.0 mg/m(2). PM00104-related adverse events at the RD were mostly grade 1/2, with fatigue, nausea and vomiting as the most common. Transient and manageable myelosuppression and transaminase increases were also reported. Main pharmacokinetic parameters increased linearly with dose. Disease stabilization lasting ≥ 3 months was found in 4 patients with cervical carcinoma, colorectal adenocarcinoma, lachrymal adenoid carcinoma, and bladder carcinoma (n=1 each). In conclusion, PM00104 2.0 mg/m(2) 1-hour, d1,8,15 q4wk showed a positive risk-benefit ratio, which has supported its further evaluation in three ongoing phase II clinical trials.