Trajectories of Quality of Life After Pelvic Exenteration: A Latent Class Growth Analysis.

BACKGROUND: Information on the course of quality of life after surgery for advanced cancers within the pelvis is important to guide patient decision-making; however, the current evidence is limited. OBJECTIVE: To identify quality-of-life trajectory classes and their predictors after pelvic exenteration. DESIGN: Prospective cohort study. SETTINGS: Highly specialized quaternary pelvic exenteration referral center. PATIENTS: Patients undergoing pelvic exenteration due to advanced/recurrent cancers within the pelvis between July 2008 and July 2022. MAIN OUTCOME MEASURES: Quality-of-life data included the 36-item Short-Form Survey (physical and mental component scores) and the Functional Assessment of Cancer Therapy-Colorectal instruments, which were collected at 11 distinct points from baseline to 5 years postoperatively. Predictors included patient characteristics and surgical outcomes. Latent class analysis was used to identify the likelihood of a better quality-of-life class, and logistic regression models were used to identify predictors of the identified classes. RESULTS: The study included 565 participants. Two distinct quality-of-life trajectory classes were identified for the Physical Component Score (class 1: high stable and class 2: high decreasing). Three distinct classes were identified for the Mental Component Score (class 1: high increasing, class 2: moderate stable, and class 3: moderate decreasing) and for Functional Assessment of Cancer Therapy-Colorectal total score (class 1: high increasing, class 2: high decreasing, and class 3: low decreasing). Across the 3 quality-of-life domains, overall survival probabilities were also higher in class 1 ( p < 0.0001). Age, repeat exenteration, neoadjuvant therapy, surgical margin, length of operation, and hospital stay were significant predictors of quality-of-life classes. LIMITATIONS: This study was conducted at a single highly specialized quaternary pelvic exenteration referral center, and findings may not apply to other centers. CONCLUSIONS: This study demonstrates that quality of life after pelvic exenteration diverges into distinct trajectories, with most patients reporting an optimal course. See Video Abstract . TRAYECTORIAS EN LA CALIDAD DE VIDA DESPUS DE EXENTERACIN PLVICA ANLISIS DE CRECIMIENTO DE CLASES LATENTES: ANTECEDENTES:La información sobre la evolución en la calidad de vida después de cirugía en cánceres avanzados situados en la pelvis es importante para guiar la toma de decisiones sobre el paciente; sin embargo, la evidencia actual es muy limitada.OBJETIVO:Identificar las clases de trayectorias en la calidad de vida y sus factores pronóstico después de la exenteración pélvica.DISEÑO:Estudio de cohortes prospectivo.AJUSTES:Centro de referencia altamente especializado en la exenteración pélvica cuaternaria.PACIENTES:Todos aquellos sometidos a exenteración pélvica por cáncer avanzados/recurrentes situados en la pelvis entre Julio de 2008 y Julio de 2022.PRINCIPALES MEDIDAS DE RESULTADO:Los datos sobre la calidad de vida incluyeron el Cuestionario de Salud SF-36 (puntuaciones de componentes físicos y mentales) y la evaluación funcional entre la terapia del cáncer/-herramientas colorrectales, recopilados en 11 puntos distintos desde el diagnóstico hasta los 5 años después de la operación.Los predictores incluyeron las características de los pacientes y los resultados quirúrgicos. Se utilizó el análisis de clases latentes para identificar la probabilidad de una mejor calidad de vida y se utilizaron modelos de regresión logística para identificar predictores de las clases identificadas.RESULTADOS:El estudio incluyó a 565 participantes. Se identificaron dos clases distintas de trayectorias de calidad de vida para la puntuación del componente físico (clase 1: alta estable y clase 2: alta decreciente), se identificaron tres clases distintas para la puntuación del componente mental (clase 1: alta creciente; clase 2: moderadamente estable; y clase 3: moderada disminución) y para la evaluación funcional de la terapia contra el cáncer-puntuación total colorrectal (clase 1: aumento alto; clase 2: disminución alta; y clase 3: disminución baja). En los tres dominios de calidad de vida, las probabilidades de supervivencia general también fueron mayores en las clases 1 (p <0,0001). La edad, las exenteraciones pélvicas repetidas, la terapia neoadyuvante, el margen quirúrgico, la duración de la operación y la estadía hospitalaria fueron predictores significativos en las clases de calidad de vida.LIMITACIONES:El presente estudio fué realizado en un único centro de referencia altamente especializado en exenteración pélvica cuaternaria y es posible que los hallazgos no se apliquen a otros centros.CONCLUSIONES:Demostramos con nuestro estudio que la calidad de vida después de la exenteración pélvica diverge en trayectorias distintas, y que la mayoría de los pacientes nos reportaron de una évolución óptima. (Traducción-Dr. Xavier Delgadillo ).

Outcomes following repeat exenteration for locally advanced pelvic malignancy.

AIM: This study aims to assess surgical outcomes and survival following first, second and third pelvic exenterations for pelvic malignancy. METHOD: Consecutive patients undergoing pelvic exenteration for pelvic malignancy at a quaternary referral centre from January 1994 and December 2017 were included. Demographics and surgical outcomes were compared between patients who underwent first, second and third pelvic exenterations by generalized mixed modelling with repeated measures. Survival was assessed using Cox proportional hazards models and Kaplan-Meier plots. RESULTS: Of the 642 exenterations reviewed, 29 (4.5%) were second and 6 (0.9%) were third exenterations. Patients selected for repeat exenteration were more likely to have asymptomatic local recurrences detected on routine surveillance (P < 0.001). Postoperative wound complications increased with repeat exenteration (6%, 17%, 33%; P = 0.003, respectively). Additionally, postoperative length of stay increased from 27 to 38 and 48 days, respectively (P = 0.004). Median survival from first exenteration was 4.75, 5.30 and 8.14 years respectively amongst first, second and third exenteration cohorts (P = 0.849). Median survival from the most recent exenteration was 4.75 years after a first exenteration, 2.02 years after a second exenteration and 1.45 years after a third exenteration (P = 0.0546). CONCLUSION: This study demonstrates that repeat exenteration for recurrent pelvic malignancy is feasible but is associated with increased complication rates and length of admission and reduced likelihood of attaining R0 margin. Moreover, these data indicate that repeat exenteration does not afford a survival advantage compared with patients having a single exenteration. These data suggest that repeat exenteration for recurrent pelvic malignancy may be of questionable therapeutic value.

Hedgehog-GLI signaling in Foxd1-positive stromal cells promotes murine nephrogenesis via TGFß signaling.

Normal kidney function depends on the proper development of the nephron: the functional unit of the kidney. Reciprocal signaling interactions between the stroma and nephron progenitor compartment have been proposed to control nephron development. Here, we show that removal of hedgehog intracellular effector smoothened (Smo-deficient mutants) in the cortical stroma results in an abnormal renal capsule, and an expanded nephron progenitor domain with an accompanying decrease in nephron number via a block in epithelialization. We show that stromal-hedgehog-Smo signaling acts through a GLI3 repressor. Whole-kidney RNA sequencing and analysis of FACS-isolated stromal cells identified impaired TGFß2 signaling in Smo-deficient mutants. We show that neutralization and knockdown of TGFß2 in explants inhibited nephrogenesis. In addition, we demonstrate that concurrent deletion of Tgfbr2 in stromal and nephrogenic cells in vivo results in decreased nephron formation and an expanded nephrogenic precursor domain similar to that observed in Smo-deficient mutant mice. Together, our data suggest a mechanism whereby a stromal hedgehog-TGFß2 signaling axis acts to control nephrogenesis.

Urogenital development in Pallister-Hall syndrome is disrupted in a cell-lineage-specific manner by constitutive expression of GLI3 repressor.

Pallister-Hall syndrome (PHS) is a rare disorder caused by mutations in GLI3 that produce a transcriptional repressor (GLI3R). Individuals with PHS present with a variably penetrant variety of urogenital system malformations, including renal aplasia or hypoplasia, hydroureter, hydronephrosis or a common urogenital sinus. The embryologic mechanisms controlled by GLI3R that result in these pathologic phenotypes are undefined. We demonstrate that germline expression of GLI3R causes renal hypoplasia, associated with decreased nephron number, and hydroureter and hydronephrosis, caused by blind-ending ureters. Mice with obligate GLI3R expression also displayed duplication of the ureters that was caused by aberrant common nephric duct patterning and ureteric stalk outgrowth. These developmental abnormalities are associated with suppressed Hedgehog signaling activity in the cloaca and adjacent vesicular mesenchyme. Mice with conditional expression of GLI3R were utilized to identify lineage-specific effects of GLI3R. In the ureteric bud, GLI3R expression decreased branching morphogenesis. In Six2-positive nephrogenic progenitors, GLI3R decreased progenitor cell proliferation reducing the number of nephrogenic precursor structures. Using mutant mice with Gli3R and Gli3 null alleles, we demonstrate that urogenital system patterning and development is controlled by the levels of GLI3R and not by an absence of full-length GLI3. We conclude that the urogenital system phenotypes observed in PHS are caused by GLI3R-dependent perturbations in nephric duct patterning, renal branching morphogenesis and nephrogenic progenitor self-renewal.

GLI3 repressor controls functional development of the mouse ureter.

Obstructive and nonobstructive forms of hydronephrosis (increased diameter of the renal pelvis and calyces) and hydroureter (dilatation of the ureter) are the most frequently detected antenatal abnormalities, yet the underlying molecular mechanisms are largely undefined. Hedgehog (Hh) proteins control tissue patterning and cell differentiation by promoting GLI-dependent transcriptional activation and by inhibiting the processing of GLI3 to a transcriptional repressor. Genetic mutations that generate a truncated GLI3 protein similar in size to the repressor in humans with Pallister-Hall syndrome (PHS; a disorder whose characteristics include renal abnormalities) and hydroureter implicate Hh-dependent signaling in ureter morphogenesis and function. Here, we determined that Hh signaling controls 2 cell populations required for the initiation and transmission of coordinated ureter contractions. Tissue-specific inactivation of the Hh cell surface effector Smoothened (Smo) in the renal pelvic and upper ureteric mesenchyme resulted in nonobstructive hydronephrosis and hydroureter characterized by ureter dyskinesia. Mutant mice had reduced expression of markers of cell populations implicated in the coordination of unidirectional ureter peristalsis (specifically, Kit and hyperpolarization-activation cation-3 channel [Hcn3]), but exhibited normal epithelial and smooth muscle cell differentiation. Kit deficiency in a mouse model of PHS suggested a pathogenic role for GLI3 repressor in Smo-deficient embryos; indeed, genetic inactivation of Gli3 in Smo-deficient mice rescued their hydronephrosis, hydroureter, Kit and Hcn3 expression, and ureter peristalsis. Together, these data demonstrate that Hh signaling controls Kit and Hcn3 expression and ureter peristalsis.