Connecting blood and intratumoral Treg cell activity in predicting future relapse in breast cancer.

Regulatory T (Treg) cells play a major role in the development of an immunosuppressive tumor microenvironment. The origin of intratumoral Treg cells and their relationship with peripheral blood Treg cells remain unclear. Treg cells consist of at least three functionally distinct subpopulations. Here we show that peripheral blood CD45RA-FOXP3hi Treg cells (Treg II cells) are phenotypically closest to intratumoral Treg cells, including in their expression of CCR8. Analyses of T cell antigen receptor repertoires further support the hypothesis that intratumoral Treg cells may originate primarily from peripheral blood Treg II cells. Moreover, the signaling responsiveness of peripheral blood Treg II cells to immunosuppressive, T helper type 1 (TH1) and T helper type 2 (TH2) cytokines reflects intratumoral immunosuppressive potential, and predicts future relapse in two independent cohorts of patients with breast cancer. Together, our findings give important insights into the relationship between peripheral blood Treg cells and intratumoral Treg cells, and highlight cytokine signaling responsiveness as a key determinant of intratumoral immunosuppressive potential and clinical outcome.

Pembrolizumab plus vorinostat induces responses in patients with Hodgkin lymphoma refractory to prior PD-1 blockade.

This phase 1 study evaluated the addition of vorinostat to pembrolizumab in patients with relapsed/refractory (RR) classical Hodgkin lymphoma (cHL), diffuse large B-cell lymphoma, and follicular lymphoma. We report the results in cases of cHL. Adult patients with RR cHL who had received ≥1 prior lines of therapy and were ineligible for transplantation were treated in a dose-escalation cohort with 2 dose levels (DLs) and then on an expansion cohort at the recommended phase 2 dose (RP2D) in 21-day cycles. Vorinostat 100 mg twice a day (DL1) and 200 mg twice a day (DL2) was administered orally from days 1 to 5 and 8 to 12; all patients received pembrolizumab 200 mg IV every 3 weeks. The primary end point was safety and determination of RP2D. In total, 32 patients with cHL were enrolled, including 30 at DL2 (RP2D); 78% had received prior anti-programmed cell death 1 (anti-PD-1) therapy, and 56% were PD-1 refractory. Grade ≥3 adverse events (AEs) included hypertension (9%), neutropenia (9%), hypophosphatemia (9%), thrombocytopenia (6%), and lymphopenia (6%). Immune-related AEs included grade 1 or 2 thyroiditis (13%), grade 1 rash (6%), and grade 3 esophagitis/duodenitis (3%). The overall response rate (ORR) was 72% and complete response (CR) rate was 34%. Patients refractory to prior PD-1 blockade (n = 18) had ORR and CR rates of 56% and 11%, respectively. Pembrolizumab and vorinostat was well tolerated with a high ORR rate in RR cHL including in anti-PD-1-refractory disease. This trial was registered at www.clinicaltrials.gov as #NCT03150329.

Addressing challenges in low-income and middle-income countries through novel radiotherapy research opportunities.

Although radiotherapy continues to evolve as a mainstay of the oncological armamentarium, research and innovation in radiotherapy in low-income and middle-income countries (LMICs) faces challenges. This third Series paper examines the current state of LMIC radiotherapy research and provides new data from a 2022 survey undertaken by the International Atomic Energy Agency and new data on funding. In the context of LMIC-related challenges and impediments, we explore several developments and advances-such as deep phenotyping, real-time targeting, and artificial intelligence-to flag specific opportunities with applicability and relevance for resource-constrained settings. Given the pressing nature of cancer in LMICs, we also highlight some best practices and address the broader need to develop the research workforce of the future. This Series paper thereby serves as a resource for radiation professionals.

Hypoxia- and Postirradiation reoxygenation-induced HMHA1/ARHGAP45 expression contributes to cancer cell invasion in a HIF-dependent manner.

BACKGROUND: Cancer cells in severely hypoxic regions have been reported to invade towards tumour blood vessels after surviving radiotherapy in a postirradiation reoxygenation- and hypoxia-inducible factor (HIF)-dependent manner and cause recurrence. However, how HIF induces invasiveness of irradiated and reoxygenated cancer cells remains unclear. METHODS: Here, we identified human minor histocompatibility antigen 1 (HMHA1), which has been suggested to function in cytoskeleton dynamics and cellular motility, as a responsible factor and elucidated its mechanism of action using molecular and cellular biology techniques. RESULTS: HMHA1 expression was found to be induced at the transcription initiation level in a HIF-dependent manner under hypoxia. Boyden chamber invasion assay revealed that the induction of HMHA1 expression is required for the increase in invasion of hypoxic cancer cells. Reoxygenation treatment after ionising radiation in vitro that mimics dynamic changes of a microenvironment in hypoxic regions of tumour tissues after radiation therapy further enhanced HMHA1 expression and invasive potential of HMHA1 wildtype cancer cells in ROS- and HIF-dependent manners, but not of HMHA1 knockout cells. CONCLUSION: These results together provide insights into a potential molecular mechanism of the acquisition of invasiveness by hypoxic cancer cells after radiotherapy via the activation of the ROS/HIF/HMHA1 axis.

Micro-Acoustic Holograms for Detachable Microfluidic Devices.

Acoustic microfluidic devices have advantages for diagnostic applications, therapeutic solutions, and fundamental research due to their contactless operation, simple design, and biocompatibility. However, most acoustofluidic approaches are limited to forming simple and fixed acoustic patterns, or have limited resolution. In this study,a detachable microfluidic device is demonstrated employing miniature acoustic holograms to create reconfigurable, flexible, and high-resolution acoustic fields in microfluidic channels, where the introduction of a solid coupling layer makes these holograms easy to fabricate and integrate. The application of this method to generate flexible acoustic fields, including shapes, characters, and arbitrarily rotated patterns, within microfluidic channels, is demonstrated.

A closer look at high-energy X-ray-induced bubble formation during soft tissue imaging.

Improving the scalability of tissue imaging throughput with bright, coherent X-rays requires identifying and mitigating artifacts resulting from the interactions between X-rays and matter. At synchrotron sources, long-term imaging of soft tissues in solution can result in gas bubble formation or cavitation, which dramatically compromises image quality and integrity of the samples. By combining in-line phase-contrast imaging with gas chromatography in real time, we were able to track the onset and evolution of high-energy X-ray-induced gas bubbles in ethanol-embedded soft tissue samples for tens of minutes (two to three times the typical scan times). We demonstrate quantitatively that vacuum degassing of the sample during preparation can significantly delay bubble formation, offering up to a twofold improvement in dose tolerance, depending on the tissue type. However, once nucleated, bubble growth is faster in degassed than undegassed samples, indicating their distinct metastable states at bubble onset. Gas chromatography analysis shows increased solvent vaporization concurrent with bubble formation, yet the quantities of dissolved gasses remain unchanged. By coupling features extracted from the radiographs with computational analysis of bubble characteristics, we uncover dose-controlled kinetics and nucleation site-specific growth. These hallmark signatures provide quantitative constraints on the driving mechanisms of bubble formation and growth. Overall, the observations highlight bubble formation as a critical yet often overlooked hurdle in upscaling X-ray imaging for biological tissues and soft materials and we offer an empirical foundation for their understanding and imaging protocol optimization. More importantly, our approaches establish a top-down scheme to decipher the complex, multiscale radiation-matter interactions in these applications.

Response-adapted anti-PD-1-based salvage therapy for Hodgkin lymphoma with nivolumab alone or in combination with ICE.

This phase 2 trial evaluated PET-adapted nivolumab alone or in combination with ifosfamide, carboplatin, and etoposide (NICE) as first salvage therapy and bridge to autologous hematopoietic cell transplantation (AHCT) in relapsed/refractory (RR) classical Hodgkin lymphoma (cHL). Patients with RR cHL received 240 mg nivolumab every 2 weeks for up to 6 cycles (C). Patients in complete response (CR) after C6 proceeded to AHCT, whereas patients with progressive disease at any point or not in CR after C6 received NICE for 2 cycles. The primary endpoint was CR rate per the 2014 Lugano classification at completion of protocol therapy. Forty-three patients were evaluable for toxicity; 42 were evaluable for response. Thirty-four patients received nivolumab alone, and 9 patients received nivolumab+NICE. No unexpected toxicities were observed after nivolumab or NICE. After nivolumab, the overall response rate (ORR) was 81%, and the CR rate was 71%. Among 9 patients who received NICE, all responded, with 8 (89%) achieving CR. At the end of protocol therapy, the ORR and CR rates were 93% and 91%. Thirty-three patients were bridged directly to AHCT, including 26 after Nivo alone. The 2-year progression-free survival (PFS) and overall survival in all treated patients (n = 43) were 72% and 95%, respectively. Among 33 patients who bridged directly to AHCT, the 2-year PFS was 94% (95% CI: 78-98). PET-adapted sequential salvage therapy with nivolumab/nivolumab+NICE was well tolerated and effective, resulting in a high CR rate and bridging most patients to AHCT without chemotherapy. This trial was registered at www.clinicaltrials.gov #NCT03016871.

Alterations in exocrine pancreatic function after acute pancreatitis.

Exocrine pancreatic dysfunction (EPD) is a malabsorptive complication of pancreatic disorders that can lead to a host of symptoms ranging from flatulence to diarrhea and contribute to weight loss and metabolic bone disease. It is increasingly recognized to occur after acute pancreatitis (AP), including episodes with mild severity. The risk of developing EPD after AP is influenced by a range of factors, including the degree of acinar cell destruction and inflammation during AP, and persistent structural derangements following AP. In this article, we discuss the epidemiology, pathophysiology, and clinical management of EPD after AP while highlighting key knowledge gaps.

Development of a novel CT-based index for predicting the number of extracorporeal shockwave lithotripsy (ESWL) sessions required for successful fragmentation of obstructing pancreatic duct stones.

BACKGROUND & AIM: Extracorporeal shock wave lithotripsy (ESWL) is used for the treatment of pancreatic duct stones (PDS) in patients with chronic pancreatitis (CP). We aimed to develop a CT based index to predict the required number of ESWL sessions for technical success. METHODS: We retrospectively evaluated patients with PDS secondary to CP who underwent ESWL. Technical success was defined as the complete fragmentation of stones to <3 mm. CT features including PDS size, number, location, and density in Hounsfield units (HU) were noted. We analyzed the relationship between PDS characteristics and the number of ESWL sessions required for technical success. A multiple linear regression model was used to combine size and density into the pancreatic duct stone (PDS) index that was translated into a web-based calculator. RESULTS: There were 206 subjects (mean age 38.6 ± 13.7 years, 59.2% male) who underwent ESWL. PDS size showed a moderate correlation with the number of ESWL sessions (r = 0.42, p < 0.01). PDS in the head required a fewer number of sessions in comparison to those in the body (1.4 ± 0.6 vs. 1.6 ± 0.7, p = 0.01). There was a strong correlation between PDS density and the number of ESWL sessions (r = 0.617, p-value <0.01). The PDS index {0.3793 + [0.0009755 x PDS density (HU)] + [0.02549 x PDS size (mm)]} could accurately predict the required number of ESWL sessions with an AUC of 0.872 (p < 0.01). CONCLUSION: The PDS index is a useful predictor of the number of ESWL sessions needed for technical success that can help in planning and patient counseling.

Intracystic injection of large surface area microparticle paclitaxel for chemoablation of intraductal papillary mucinous neoplasms: Insights from an expanded access protocol.

AIMS: A novel large surface area microparticle paclitaxel (LSAM-PTX) has unique properties of long retention in cystic spaces while maintaining high drug concentration. We prospectively evaluated the safety and response of EUS-guided fine needle injection (EUS-FNI) of LSAM-PTX to chemoablate branch duct (BD)-IPMNs. METHODS: Subjects diagnosed with BD-IPMNs exhibiting at least one worrisome criteria and considered non-surgical were enrolled in a multicenter clinical trial (NCT03188991) and subsequently included in an Expanded Access Protocol (EAP) where they received EUS-FNI of LSAM-PTX (15 mg/mL). RESULTS: Six BD-IPMNs measuring (mean ± SD) 3.18 ± 0.76 cm in diameter among 5 subjects (mean age: 66 years) were treated by EUS-FNI of LSAM-PTX. A mean of 4 doses of LSAM-PTX (mean dose/cyst: 73 ± 31 mg) were administered, and subjects were followed for up to 32 months. The mean volume reduction/cyst ranged from 42 to 89% (9.58 ± 5.1 ml to 2.2 ± 1.1 ml (p = 0.016)). The mean surface area reduction ranged from 31 to 83% (21.9 ± 8.7 cm2 to 5.7 ± 2.5 cm2 (p = 0.009)). Higher dosing-frequency of EUS-FNI of LSAM-PTX significantly correlated with a reduction in cyst volume (R2 = 0.87, p = 0.03) and surface area (R2 = 0.83, p = 0.04). Comparing pre- and post-ablation samples, molecular analysis of the cyst fluid revealed a loss of IPMN-associated mutations in 5 cases (83.3%), while reemergence was observed in 1 case and persistence in 1 case. Intracystic changes (fibrosis/calcification) were observed in 83.3% (n = 5). One subject developed mild acute pancreatitis (1 of 22 EUS-FNIs of LSAM-PTX). CONCLUSION: In this EAP, EUS-FNI of LSAM-PTX into BD-IPMNs was safe and resulted in volume and surface area reduction, morphological changes, and loss of pathogenic mutations.

Comparison of urological outcomes and quality of life after pelvic exenteration: partial vs radical cystectomy.

OBJECTIVE: To compare perioperative morbidity, functional and quality-of-life (QoL) outcomes in patients with partial cystectomy vs radical cystectomy as part of pelvic exenteration. PATIENTS AND METHODS: Retrospective analysis of a prospectively maintained database of pelvic exenteration patients (1998-2021) was conducted in a single centre. Study outcomes included postoperative complications, quality-of-life, functional and stoma-related outcomes. The 36-item Short-Form Health Survey Physical and Mental Health Components, Functional Assessment of Cancer Therapy-Colorectal questionnaires and Distress Thermometer were available pre- and postoperatively. QoL outcomes were compared at the various time points. Stoma embarrassment and care scores were compared between patients with a colostomy, urostomy, and both. RESULTS: Urological complications were similar between both groups, but patients with partial cystectomy experienced less wound-related complications. Overall, 34/81 (42%) partial cystectomy patients reported one or more long-term voiding complication (i.e., incontinence [17 patients], frequency [six], retention [three], high post-voiding residuals [10], permanent suprapubic catheter/indwelling catheter [14], recurrent urinary tract infection [nine], percutaneous nephrostomy [three], progression to urostomy [three]). The QoL improved following surgery in both the partial and radical cystectomy groups, differences between cohorts were not significant. Patients with two stomas reported higher embarrassment scores than patients with one stoma, although this did not result in more difficulties in stoma care. CONCLUSIONS: Partial cystectomy patients have fewer postoperative wound-related complications than radical cystectomy patients, but often experience long-term voiding issues. The QoL outcomes are similar for both cohorts, with significant improvement following surgery.

Impact of Intraoperative Decision-Making on Pathological Margin Status in Patients Undergoing Pelvic Exenteration for Locally Recurrent Rectal Cancer.

BACKGROUND: A key component of preoperative preparation for pelvic exenteration surgery is development of an operative plan in a multidisciplinary setting, based on the extent of local tumor invasion on preoperative imaging. Changes to the extent of resection or operative plan may occur intraoperatively based on intraoperative findings. OBJECTIVE: To report the frequency and extent of intraoperative deviation from the planned extent of resection during pelvic exenteration for locally recurrent rectal cancer, and whether this resulted in a more or less radical resection. DESIGN: Retrospective observational study. SETTINGS: A high-volume pelvic exenteration center. PATIENTS: Patients who underwent pelvic exenteration for locally recurrent rectal cancer between January 2015 and December 2020. MAIN OUTCOME MEASURES: Frequency and extent of intraoperative deviation from the planned extent of resection, R0 resection rate. RESULTS: 136 patients underwent pelvic exenteration for locally recurrent rectal cancer, of which 110 (81%) had R0 resection margins. 12 patients were excluded due to missing information and 49 patients (40%) had a change to the operative plan. Operative changes were major in 30 patients (61%), more radical in 40 patients (82%), and margin relevant in 24 patients (49%). In patients where there was a change to the operative plan and R0 resection was achieved, the median distance to a relevant margin was 2.5 mm (range, 0.1-10mm). Of eight patients with a change in operative plan and R1 resection, three were margin relevant of which all were considered major, and two were more radical and one was less radical. LIMITATIONS: Generalizability outside of specialist units may be limited. CONCLUSIONS: Intraoperative changes to the planned extent of resection occur commonly and most often results in an unanticipated major, more radical resection. Such changes may contribute to high rates of R0 resection margins in specialist PE units that employ an ultra-radical approach in these patients. See Video Abstract.

Outcomes Following Pelvic Exenteration for Locally Recurrent Rectal Cancer With and Without En Bloc Sacrectomy.

BACKGROUND: Extended radical resection is often the only chance of cure for locally recurrent rectal cancer. Recurrence in the posterior compartment often necessitates en bloc sacrectomy as part of pelvic exenteration to obtain clear resection margins and provide survival benefit. OBJECTIVE: To compare oncological outcomes, morbidity, and quality-of-life outcomes following pelvic exenteration with and without en bloc sacrectomy for recurrent rectal cancer. DESIGN: Comparative cohort study with retrospective analysis of prospectively collected data. SETTING: This study was conducted at a high-volume pelvic exenteration center. PATIENTS: Patients who underwent pelvic exenteration for locally recurrent rectal cancer between 1994 and 2022. MAIN OUTCOME MEASURES: Overall survival, postoperative morbidity, R0 resection margin, and quality-of-life outcomes. RESULTS: Of 965 patients, 305 (31.6%) underwent pelvic exenteration for locally recurrent rectal cancer. Among these patients, 64.3% were men and the median age was 62 years (range, 29-86). One hundred eighty-five patients (60.7%) underwent en bloc sacrectomy, 65 (35.1%) underwent high transection, and 119 (64.3%) had sacrectomy below S2. R0 resection was achieved in 80% of patients with sacrectomy and 72.5% of patients without sacrectomy. Sacrectomy patients experienced more postoperative complications without increased mortality. The median overall survival was 52 months; median survival was 47 months with sacrectomy and 73 months without ( p = 0.059). Quality-of-life scores were not significantly different across physical component ( p = 0.346), mental component ( p = 0.787), or Functional Assessment of Cancer Therapy-Colorectal ( p = 0.679) scores at 24-month follow-up. LIMITATIONS: The generalizability of these findings may be limited outside of subspecialist exenteration units. Selection bias exists in a retrospective analysis. CONCLUSIONS: Patients undergoing pelvic exenteration with and without en bloc sacrectomy for locally recurrent rectal cancer experience similar rates of R0 resection, survival, and quality-of-life outcomes. As R0 remains the most important predictor of survival, the requirement of sacral resection should prompt referral to a subspecialist center that performs sacrectomy routinely. See Video Abstract . RESULTADOS DESPUS DE LA EXENTERACIN PLVICA PARA EL CNCER DE RECTO CON RECURRENCIA LOCAL, CON Y SIN SACRECTOMA EN BLOQUE: ANTECEDENTES:La resección radical ampliada es generalmente la única posibilidad de curación para el cáncer de recto con recurrencia local. La recurrencia en el compartimento posterior generalmente requiere sacrectomía en bloque como parte de la exenteración pélvica para obtener márgenes de resección claros y proporcionar un beneficio de supervivencia.OBJETIVO:Comparar los resultados oncológicos, de morbilidad y de calidad de vida después de la exenteración pélvica con y sin sacrectomía en bloque para el cáncer de recto recurrente.DISEÑO:Estudio de cohorte comparativo con análisis retrospectivo de datos recopilados prospectivamente.AMBIENTE AJUSTE:Estudio realizado en un centro de exenteración pélvica de alto volumen.PACIENTES:Aquellos sometidos a exenteración pélvica por cáncer de recto con recurrencia local entre 1994 y 2022.PRINCIPALES MEDIDAS DE RESULTADO:Supervivencia general, morbilidad posoperatoria, margen de resección R0 y resultados de calidad de vida.RESULTADOS:305 (31,6%) de 965 pacientes se sometieron a exenteración pélvica por cáncer de recto con recurrencia local. El 64,3% de los pacientes eran hombres con una mediana de edad de 62 años (rango 29-86). 185 pacientes (60,7%) fueron sometidos a sacrectomía en bloque, 65 (35,1%) fueron sometidos a transección alta, 119 (64,3%) tuvieron sacrectomía por debajo de S2. La resección R0 se logró en el 80% de los pacientes con sacrectomía y en el 72,5% sin ella. Los pacientes de sacrectomía experimentaron más complicaciones postoperatorias sin aumento de la mortalidad. La mediana de supervivencia global fue de 52 meses, 47 meses con sacrectomía y 73 meses sin sacrectomía ( p = 0,059). Las puntuaciones de calidad de vida no fueron significativamente diferentes entre las puntuaciones del componente físico ( p = 0,346), componente mental ( p = 0,787) o la evaluación funcional de la terapia contra el cáncer - colorrectal ( p = 0,679) a los 24 meses de seguimiento.LIMITACIONES:La generalización de estos hallazgos puede estar limitada fuera de las unidades de exenteración de subespecialistas. Existe un sesgo de selección en un análisis retrospectivo.CONCLUSIONES:Los pacientes sometidos a exenteración pélvica con y sin sacrectomía en bloque por cáncer de recto con recurrencia local experimentan tasas similares de resección R0, supervivencia y resultados de calidad de vida. Como R0 sigue siendo el predictor más importante de supervivencia, la necesidad de resección sacra debe provocar la derivación a un centro subespecialista que realice sacrectomía de forma rutinaria. (Traducción-Dr. Fidel Ruiz Healy ).

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 ).

Exploring the Comparability Between EQ-5D and the EQ Health and Wellbeing in the General Australian Population.

OBJECTIVES: The EQ Health and Wellbeing (EQ-HWB) is a novel measure that conceptually overlaps with the 5-level EQ-5D (EQ-5D-5L) while capturing broader dimensions of health and well-being. This study aimed to explore the extent to which the EQ-HWB and EQ-5D-5L capture overlapping or complementary constructs and to explore the discriminative ability of the EQ-HWB Short version (EQ-HWB-S) as a multiattribute utility instrument in the Australian setting. METHODS: A secondary analysis of data from a nationally representative cross-sectional survey of 2002 Australian adults was performed. The survey included socioeconomic questions and health characteristics and the EQ-HWB and EQ-5D-5L instruments. Convergent and known-group validity were evaluated through Spearman rank correlation and multivariable regression analyses, respectively. An exploratory factor analysis was also performed to explore the underlying constructs of the 2 measures. RESULTS: Correlation coefficients varied from moderate to strong (rs ≥ 0.40) between the EQ-5D-5L and the corresponding EQ-HWB dimensions (all P < .001). Based on the exploratory factor analysis, both instruments measure similar underlying constructs, with the EQ-HWB capturing broader aspects of well-being. The known-group analysis demonstrated the relative discriminative ability of the EQ-HWB-S in capturing broader aspects of health and well-being. CONCLUSIONS: The EQ-HWB was at least moderately correlated with the EQ-5D-5L in overlapping domains/dimensions and demonstrated greater sensitivity in participants with mental health problems versus the EQ-5D-5L. Our findings support future research exploring the value of the EQ-HWB-S as a multiattribute utility instrument for the general Australian population.

Recommendations for 46,XX Congenital Adrenal Hyperplasia Across Two Decades: Insights from the North American Differences of Sex Development Clinician Survey.

Several aspects of clinical management of 46,XX congenital adrenal hyperplasia (CAH) remain unsettled and controversial. The North American Disorders/Differences of Sex Development (DSD) Clinician Survey investigated changes, over the last two decades, in clinical recommendations by specialists involved in the management of newborns with DSD. Members of the (Lawson Wilkins) Pediatric Endocrine Society and the Societies for Pediatric Urology participated in a web-based survey at three timepoints: 2003-2004 (T1, n = 432), 2010-2011 (T2, n = 441), and 2020 (T3, n = 272). Participants were presented with two clinical case scenarios-newborns with 46,XX CAH and either mild-to-moderate or severe genital masculinization-and asked for clinical recommendations. Across timepoints, most participants recommended rearing the newborn as a girl, that parents (in consultation with physicians) should make surgical decisions, performing early genitoplasty, and disclosing surgical history at younger ages. Several trends were identified: a small, but significant shift toward recommending a gender other than girl; recommending that adolescent patients serve as the genital surgery decision maker; performing genital surgery at later ages; and disclosing surgical details at younger ages. This is the first study assessing physician recommendations across two decades. Despite variability in the recommendations, most experts followed CAH clinical practice guidelines. The observation that some of the emerging trends do not align with expert opinion or empirical evidence should serve as both a cautionary note and a call for prospective studies examining patient outcomes associated with these changes.

Hybrid Soft-Rigid Active Prosthetics Laboratory Exercise for Hands-On Biomechanical and Biomedical Engineering Education.

This paper introduces a hands-on laboratory exercise focused on assembling and testing a hybrid soft-rigid active finger prosthetic for biomechanical and biomedical engineering (BME) education. This hands-on laboratory activity focuses on the design of a myoelectric finger prosthesis, integrating mechanical, electrical, sensor (i.e., inertial measurement units (IMUs), electromyography (EMG)), pneumatics, and embedded software concepts. We expose students to a hybrid soft-rigid robotic system, offering a flexible, modifiable lab activity that can be tailored to instructors' needs and curriculum requirements. All necessary files are made available in an open-access format for implementation. Off-the-shelf components are all purchasable through global vendors (e.g., DigiKey Electronics, McMaster-Carr, Amazon), costing approximately USD 100 per kit, largely with reusable elements. We piloted this lab with 40 undergraduate engineering students in a neural and rehabilitation engineering upper year elective course, receiving excellent positive feedback. Rooted in real-world applications, the lab is an engaging pedagogical platform, as students are eager to learn about systems with tangible impacts. Extensions to the lab, such as follow-up clinical (e.g., prosthetist) and/or technical (e.g., user-device interface design) discussion, are a natural means to deepen and promote interdisciplinary hands-on learning experiences. In conclusion, the lab session provides an engaging journey through the lifecycle of the prosthetic finger research and design process, spanning conceptualization and creation to the final assembly and testing phases.

UBA6 Inhibition Accelerates Lysosomal TRPML1 Depletion and Exosomal Secretion in Lung Cancer Cells.

Ubiquitin-like modifier-activating enzyme 6 (UBA6) is a member of the E1 enzyme family, which initiates the ubiquitin-proteasome system (UPS). The UPS plays critical roles not only in protein degradation but also in various cellular functions, including neuronal signaling, myocardial remodeling, immune cell differentiation, and cancer development. However, the specific role of UBA6 in cellular functions is not fully elucidated in comparison with the roles of the UPS. It has been known that the E1 enzyme is associated with the motility of cancer cells. In this study, we verified the physiological roles of UBA6 in lung cancer cells through gene-silencing siRNA targeting UBA6 (siUBA6). The siUBA6 treatment attenuated the migration of H1975 cells, along with a decrease in lysosomal Ca2+ release. While autophagosomal proteins remained unchanged, lysosomal proteins, including TRPML1 and TPC2, were decreased in siUBA6-transfected cells. Moreover, siUBA6 induced the production of multivesicular bodies (MVBs), accompanied by an increase in MVB markers in siUBA6-transfected H1975 cells. Additionally, the expression of the exosomal marker CD63 and extracellular vesicles was increased by siUBA6 treatment. Our findings suggest that knock-down of UBA6 induces lysosomal TRPML1 depletion and inhibits endosomal trafficking to lysosome, and subsequently, leads to the accumulation of MVBs and enhanced exosomal secretion in lung cancer cells.

A Review on Endoscopic Management of Acute Cholecystitis: Endoscopic Ultrasound-Guided Gallbladder Drainage and Endoscopic Transpapillary Gallbladder Drainage.

A percutaneous cholecystostomy tube (PCT) is the conventionally favored nonoperative intervention for treating acute cholecystitis. However, PCT is beset by high adverse event rates, need for scheduled reintervention, and inadvertent dislodgement, as well as patient dissatisfaction with a percutaneous drain. Recent advances in endoscopic therapy involve the implementation of endoscopic transpapillary drainage (ETP-GBD) and endoscopic ultrasound-guided gallbladder drainage (EUS-GBD), which are increasingly preferred over PCT due to their favorable technical and clinical success combined with lower complication rates. In this article, we provide a comprehensive review of the literature on EUS-GBD and ETP-GBD, delineating instances when clinicians should opt for endoscopic management and highlighting potential risks associated with each approach.

Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer (UK TACT2; CRUK/05/19): quality of life results from a multicentre, phase 3, open-label, randomised, controlled trial.

BACKGROUND: Adjuvant chemotherapy for patients with early breast cancer improves outcomes but its toxicity affects patients' quality of life (QOL). The UK TACT2 trial investigated whether accelerated epirubicin improves time to recurrence and if oral capecitabine is non-inferior to cyclophosphamide, methotrexate, and fluorouracil (CMF) for efficacy with less toxicity. Results showed no benefit for accelerated epirubicin and capecitabine was non-inferior. As part of the QOL substudy, we aimed to assess the effect of chemotherapies on psychological distress, physical symptoms, and functional domains. METHODS: TACT2 was a multicentre, phase 3, open-label, parallel-group, randomised, controlled trial done in 129 UK centres. Participants were aged 18 years or older with histologically confirmed node-positive or high-risk node-negative invasive primary breast cancer, who had undergone complete excision, and due to receive adjuvant chemotherapy. Patients were randomly assigned (1:1:1:1) to four cycles of 100 mg/m2 epirubicin either every 3 weeks (standard epirubicin) or every 2 weeks with 6 mg pegfilgrastim on day 2 of each cycle (accelerated epirubicin), followed by four 4-week cycles of either CMF (600 mg/m2 cyclophosphamide intravenously on days 1 and 8 or 100 mg/m2 orally on days 1-14; 40 mg/m2 methotrexate intravenously on days 1 and 8; and 600 mg/m2 fluorouracil intravenously on days 1 and 8 of each cycle) or four 3-week cycles of 2500 mg/m2 capecitabine (1250 mg/m2 given twice daily on days 1-14 of each cycle). The randomisation schedule was computer generated in random permuted blocks, stratified by centre, number of nodes involved (none vs 1-3 vs ≥4), age (≤50 years vs >50 years), and planned endocrine treatment (yes vs no). QOL was one of the secondary outcomes and is reported here. All patients from a subset of 44 centres were invited to complete QOL questionnaires (Hospital Anxiety and Depression Scale [HADS] and European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire 30-item core module [QLQ-C30] and Quality of Life Questionnaire breast module [QLQ-BR23]) at baseline, end of standard or accelerated epirubicin, end of CMF or capecitabine, and at 12 and 24 months after randomisation. The QOL substudy prespecified two coprimary QOL outcomes assessed in the intention-to-treat population: overall QOL (reported elsewhere) and HADS total score. Prespecified secondary QOL outcomes were EORTC QLQ-C30 subscales of physical function, role function, and fatigue and EORTC QLQ-BR23 subscales of sexual function and systemic therapy side-effects. This trial is registered with ISRCTN, ISRCTN68068041, and ClinicalTrials.gov, NCT00301925. FINDINGS: From Dec 16, 2005, to Dec 5, 2008, 4391 patients (20 [0·5%] of whom were male) were enrolled in TACT2; 1281 (85·8%) of 1493 eligible patients were included in the QOL substudy. Eight (0·6%) participants in the QOL substudy were male and 1273 (99·4%) were female. Median follow-up was 85·6 months (IQR 80·6-95·9). Analysis was performed on the complete QOL dataset (as of Sept 15, 2011) when all participants had passed the 24-month timepoint. Prerandomisation questionnaires were completed by 1172 (91·5%) patients and 1179 (92·0%) completed at least one postrandomisation questionnaire. End-of-treatment HADS depression score (p=0·0048) and HADS total change score (p=0·0093) were worse for CMF versus capecitabine. Accelerated epirubicin led to worse physical function (p=0·0065), role function (p<0·0001), fatigue (p=0·0002), and systemic side-effects (p=0·0001), but not sexual function (p=0·36), compared with standard epirubicin during treatment, but the effect did not persist. Worse physical function (p=0·0048), sexual function (p=0·0053), fatigue (p<0·0001), and systemic side-effects (p<0·0001), but not role functioning (p=0·013), were seen for CMF versus capecitabine at end of treatment; these differences persisted at 12 months and 24 months. INTERPRETATION: Accelerated epirubicin was associated with worse QOL than was standard epirubicin but only during treatment. These findings will help patients and clinicians make an informed choice about accelerated chemotherapy. CMF had worse QOL effects than did capecitabine, which were persistent for 24 months. The favourable capecitabine QOL compared with CMF supports its use as an adjuvant option after neoadjuvant chemotherapy in patients with triple-negative breast cancer. FUNDING: Cancer Research UK, Amgen, Pfizer, and Roche.