Logic-gated tumor-microenvironment nanoamplifier enables targeted delivery of CRISPR/Cas9 for multimodal cancer therapy

Recent innovations in nanomaterials inspire abundant novel tumor-targeting CRISPR-based gene therapies. However, the therapeutic efficiency of traditional targeted nanotherapeutic strategies is limited by that the biomarkers vary in a spatiotemporal-dependent manner with tumor progression. Here, we propose a self-amplifying logic-gated gene editing strategy for gene/H2O2-mediated/starvation multimodal cancer therapy. In this approach, a hypoxia-degradable covalent-organic framework (COF) is synthesized to coat a-ZIF-8 in which glucose oxidase (GOx) and CRISPR system are packaged. To intensify intracellular redox dyshomeostasis, DNAzymes which can cleave catalase mRNA are loaded as well. When the nanosystem gets into the tumor, the weakly acidic and hypoxic microenvironment degrades the ZIF-8@COF to activate GOx, which amplifies intracellular H+ and hypoxia, accelerating the nanocarrier degradation to guarantee available CRISPR plasmid and GOx release in target cells. These tandem reactions deplete glucose and oxygen, leading to logic-gated-triggered gene editing as well as synergistic gene/H2O2-mediated/starvation therapy. Overall, this approach highlights the biocomputing-based CRISPR delivery and underscores the great potential of precise cancer therapy.

Eight children with desmoplastic small round cell tumor and literature review / 中华实用儿科临床杂志

Objective:To analyze the clinical characteristics, therapeutic modalities and prognosis of desmoplastic small round cell tumor (DSRCT) in children, and to summarize the international research progress.Methods:A total of 8 children with DSRCT admitted to Shanghai Children′s Medical Center, Shanghai Jiaotong University, School of Medicine, from January 1999 to August 2019 were retrospectively studied.The clinical characteristics, consultation process and follow-up results were summarized, and the Kaplan-Meier survival analysis method was used to calculate the survival rate.Results:Among these 8 cases, there were 6 male children and 2 female children.Seven cases originated in the abdomen and pelvis, and 1 case originated in the sacral region.All cases had infiltrate surrounding tissues or viscera, and 4 cases(50%) had extra-peritoneal metastasis, including distant lymph node metastasis, liver, lung and bone metastasis.All patients received chemotherapy, among which 3 patients received radiotherapy, and 2 patients received autologous hematopoietic stem cell transplantation.The medical follow-up was continued to February 15, 2020, with the median follow-up period being 59 months.Three cases died and 5 cases survived (2 cases in complete remission, 1 case in recurrent relapse, 2 cases in partial remission still under treatment). The median relapse time was 14.5 months, the 3-year relapse-free survival rate was (30.0±17.5)%, and 3-year overall survival was (51.4±20.4)%.Conclusions:Half of DSRCT had distant metastasis; the prognosis was poor despite the aggressive multimodality therapeutic approaches, such as chemotherapy, cytoreductive surgery, and whole abdominopelvic radiotherapy and stem cell transplantation.

Comprehensive diagnosis and treatment of long-term survival metastatic prostate cancer: a case report and literature review / 中华泌尿外科杂志

The clinical data of 1 patient with long-term survival metastatic prostate cancer were analyzed retrospectively, and the related literature was reviewed and discussed. The patient, male, 70 years old, was admitted to the hospital in 2009 due to dysuria with lower abdominal pain for one month.Blood PSA>1 000 ng/ml. The pathology of prostate biopsy was prostatic adenocarcinoma, Gleason score was 8 points (4+ 4), and was diagnosed as prostate cancer (T 4N 0M 1b) with bone metastasis. The patient underwent combined androgen-blocked treatment(castration and bicalutamide 50mg) for four years, then progressed to mCRPC. The initial treatment was continued in the fifth year due to the absence of novel therapeutic agents, and then symptoms progressed. The regimens were adjusted successively to increased anti-androgen (castration and bicalutamide 150 mg) from Jan 2015, then switch to another anti-androgen (Flutamide 250 mg) from Aug 2015, and then withdraw the anti-androgens from Feb 2016. All these treatments showed limited benefit for a relatively short time. The t-PSA increased steadily to over 1 000 ng/ml with persistent symptoms. In April 2017, he started the treatment with the original abiraterone acetate and underwent a PSA flare-up in the following month.tPSA decreased sharply since May 2017, less than 0.02ng/ml in Aug 2017. Meanwhile, the regimen relieved the ostealgia. He could take care of himself in daily life. raditional CAB therapy can maintain PSA-free progression and symptom-free progression for several years for some metastatic prostate cancer patients. After disease progression, the increased dosage of anti-androgens, the substitution of anti-androgen, and the withdrawal of anti-androgens showed limited benefit within a short time. However, the novel hormone therapy is still effective in relieving clinical symptoms and prolonging patients' survival time.

Analgesia en el paciente con abuso de sustancias nocivas / Analgesia in the patient with noxious substance abuse

Resumen: En los últimos años se ha incrementado de manera considerable el uso y abuso de diversas sustancias nocivas, incluida entre ellas los opioides, ya sea por prescripción médica o de manera recreativa. Este aumento genera una población de pacientes que van a requerir una atención especializada al momento de ser hospitalizados o al realizarse alguna intervención quirúrgica. Anestesiólogos, cirujanos y enfermeras deben estar familiarizados con los fenómenos farmacológicos típicos de los usuarios. El uso y abuso de sustancias puede disminuir la eficacia de los opioides para el control del dolor agudo de causa quirúrgica, por lo que se recomiendan estrategias con analgesia multimodal con técnicas neuroaxiales y regionales, lo cual ha demostrado un mejor control del dolor agudo postoperatorio.

Abstract: In recent years, the use and abuse of various harmful substances has increased considerably, including opioids, either by medical prescription or recreationally. This increase generates a population of patients that will require specialized attention at the moment of being hospitalized or when performing some surgical intervention. Anesthesiologists, surgeons and nurses should be familiar with the typical pharmacological phenomena of users. The use and abuse of substances can decrease the efficacy of opioids for the control of acute pain due to surgery, which is why strategies with multimodal analgesia including neuroaxial and regional techniques are recommended, which has shown better control of acute postoperative pain.

Dolor postoperatorio: factores de riesgo y abordaje / Postoperative pain: risk factors and approach

ResumenEl dolor es una experiencia universal pero única para cada individuo. El proceso patológico que culmina en una intervención quirúrgica es una de las principales fuentes de dolor, muchas veces abordado y manejado de manera subóptima o en entornos que carecen de la organización adecuada. La utilización de la historia clínica y examen físico para la identificación de factores de riesgo conocidos para dolor postoperatorio agudo y crónico son fundamentales al elaborar un plan de manejo del dolor efectivo. Según las recomendaciones, se obtiene una mejor respuesta con el uso de terapia multimodal farmacológica y no farmacológica que involucra celecoxib preoperatorio, anestesia regional periférica o neuraxial, manejo de dolor postoperatorio con antiinflamatorios no esteroideos (AINES), acetaminofén, gabapentina o pregabalina; implementación de terapia cognitiva y de comportamiento. Monitoreo y valoración periódica del paciente para evaluar su respuesta a analgésicos y efectos adversos asociado a coordinación y planeamiento eficaz de protocolos y guías en cada centro de salud, se han visto de utilidad al valorar a un grupo tan heterogéneo e impredecible.

Abstract:Pain is a universal experience but unique for every individual. The pathological processes that end in a surgical intervention are some of the main pain sources, often approached and managed suboptimally or without proper organization. The use of clinical history and physical examination to identify known risk factors to postoperative acute and chronic pain are fundamental to elaborate an effective pain management plan. According to recommendations, the outcome improves with pharmacological and non-pharmacological multimodal analgesia, including celecoxib before surgery, peripheral regional anesthesia or neuraxial techniques, management of postoperative pain with nonsteroidal anti-inflammatory drugs, acetaminophen, gabapentin or pregabalin; implementation of cognitive - behavioral therapy. Monitoring and periodic assessments associated with coordination and planning of protocols and guidelines in every clinical center, have been useful to evaluate a heterogeneous and unpredictable group, in order to establish the patients' response to analgesics and their adverse effects.

Multimodal therapy for locally advanced prostate cancer: the roles of radiotherapy, androgen deprivation therapy, and their combination

Locally advanced prostate cancer (LAPC) is defined as histologically proven T3–4 prostatic adenocarcinoma. In this review, we define the individual roles of radiotherapy (RT), short-term (ST-) and long-term (LT-) androgen deprivation therapy (ADT), and their combination in multimodal therapy for LAPC. Despite limitations in comparing the clinical outcomes among published papers, in the present study, a trend of 10-year clinical outcomes was roughly estimated by calculating the average rates weighted by the cohort number. With RT alone, the following rates were estimated: 87% biochemical failure, 34% local failure (LF), 48% distant metastasis (DM), 38% overall survival (OS), and 27% disease-specific mortality (DSM). Those associated with ADT alone were 74% BCF, 54% OS, and 25% DSM, which appeared to be better than those of RT alone. The addition of ADT to RT produced a notable local and systemic effect, regardless of ST- or LT-ADT. The LF rate decreased from 34% with RT alone to 21% with ST-ADT and further to 15% with LT-ADT. The DM and DSM rates also showed a similar trend among RT alone, RT+ST-ADT, and RT+LT-ADT. The combination of RT+LT-ADT resulted in the best long-term clinical outcomes, indicating that both RT and ADT are important parts of multimodal therapy.

Multimodal therapy for locally advanced prostate cancer: the roles of radiotherapy, androgen deprivation therapy, and their combination

Locally advanced prostate cancer (LAPC) is defined as histologically proven T3–4 prostatic adenocarcinoma. In this review, we define the individual roles of radiotherapy (RT), short-term (ST-) and long-term (LT-) androgen deprivation therapy (ADT), and their combination in multimodal therapy for LAPC. Despite limitations in comparing the clinical outcomes among published papers, in the present study, a trend of 10-year clinical outcomes was roughly estimated by calculating the average rates weighted by the cohort number. With RT alone, the following rates were estimated: 87% biochemical failure, 34% local failure (LF), 48% distant metastasis (DM), 38% overall survival (OS), and 27% disease-specific mortality (DSM). Those associated with ADT alone were 74% BCF, 54% OS, and 25% DSM, which appeared to be better than those of RT alone. The addition of ADT to RT produced a notable local and systemic effect, regardless of ST- or LT-ADT. The LF rate decreased from 34% with RT alone to 21% with ST-ADT and further to 15% with LT-ADT. The DM and DSM rates also showed a similar trend among RT alone, RT+ST-ADT, and RT+LT-ADT. The combination of RT+LT-ADT resulted in the best long-term clinical outcomes, indicating that both RT and ADT are important parts of multimodal therapy.

Hacia una terapia multimodal en el cansancio oncológico: estudio piloto fase 2, prospectivo, randomizado y doble ciego / Towards multimodal therapy in cancer fatigue: a pilot phase 2 study, prospective, randomized and double blind

El cansancio oncológico es uno de los síntomas más frecuentes e incapacitantes en este tipo de pacientes, tanto durante su tratamiento como en estados avanzados de su enfermedad y afecta en forma significativa la dimensión física, afectiva y cognitiva del paciente. Sin embargo, es el síntoma menos estudiado por la oncología moderna.Actualmente, no contamos con un estándar de tratamiento. La mejor evidencia disponible muestra en pequeño estudio asociado al beneficio de la dexametasona versus placebo en fatiga oncológica en casos con enfermedad avanzada; además, existe evidencia de resultados positivos mediante estrategias no farmacológicas, como los programas de ejercicios aeróbicos y técnicas de manejo del estrés. Este estudio tiene por propósito investigar la eficacia en el cansancio oncológico en enfermedad avanzada de un tratamiento multimodal (basado en estrategias no farmacológicas más uso de dexametasona) versus tratamiento farmacológico sólo usando dexametasona (terapia unimodal). Para ello, en estudio prospectivo y doble ciego, se randomizó 1:1 80 pacientes entre 20 y 80 años de edad con neoplasias avanzadas a tratamiento multimodal o brazo A (terapia farmacológica y no farmacológica) versus terapia unimodal o brazo B (terapia farmacológica sola). Al inicio del estudio se permitió el ingreso de pacientes con fatiga 4 o más sobre 10 aplicando instrumento Brief Fatigue Inventory, que es una forma de Escala Visual Análoga (EVA) aplicada al cansancio oncológico; y al menos otros 2 síntomas relacionados (depresión, ansiedad y/o insomnio), con función cognitiva normal, sin infecciones sobreagregadas, sin neoplasia encefálica, con función tiroidea normal y hemoglobina mayor de 9 gr/dl (recuérdese que una disfunción tiroidea o la anemia favorecen la sensación de fatiga y de no excluirse estos factores no permitiría sacar conclusiones válidas). Al mes de tratamiento se reevaluó mediante EVA la fatiga (end point primario)...

The Cancer Fatigue is one of the most common and disabling symptoms in these patients both during treatment and in advanced stages of their disease; and significantly affect the physical , emotional and cognitive dimension of the patient. And yet it is the symptom less studied by modern oncology. Currently we do not have a standard treatment. The best available evidence shows benefit in small study of dexamethasone versus placebo in cancer fatigue in patients with advanced disease; there is also evidence of positive results by non-pharmacological strategies such as aerobic exercise programs and stress management techniques. This study is aimed to investigate the efficacy in cancer fatigue in advanced disease of a multimodal treatment (based on nonpharmacological strategies more use of dexamethasone) versus using dexamethasone treatment alone (unimodal therapy). To do this in prospective, double-blind study 80 patients 1:1 between 20 and 80 years old with advanced malignancies were randomized to arm A multimodal treatment (pharmacological and nonpharmacological therapy) versus unimodal therapy or arm B (single drug therapy). At study entry patients were allowed to fatigue 4 or more out of 10 using Brief Fatigue Inventory instrument, which is a form of visual analog scale (EVA) applied to cancer fatigue; and at least 2 other related symptoms (depression, anxiety and / or insomnia), with normal cognitive function , without a superimposed infections, without brain cancer, with normal thyroid function and increased hemoglobin 9 g / dl (remember that thyroid dysfunction or anemia favors the sensation of fatigue and not excluded these factors would not draw valid conclusions)...

Two Cases of Pleuropulmonary Blastomas in Children / 대한소아혈액종양학회지

Pleuropulmonary blastoma (PPB) is a rare primary malignant neoplasm with poor prognosis in children. PPB originates from the lung, the pleura, or the mediastinum. Histologically, it is characterized by a primitive, mixed blastematous, sarcomatous appearance and the absence of epithelial cell. Initial presenting symptoms are cough, fever and dyspnea. We experienced two cases of PPB (type I and type II). Complete surgical removal is always required for the treatment and chemotherapy and radiotherapy is needed as adjuvant therapy. We report two cases of pleuropulmonary blastoma treated with surgical removal, chemotherapy (vincristine, actinomycin D, cyclophosphamide) and radiotherapy.

Current Status of Multimodal Therapy for Advanced Gastric Carcinoma / 中国普外基础与临床杂志

Objective To review the research advancement of multimodal therapy for advanced gastric carcinoma.Methods The literatures on multimodal therapy for advanced gastric carcinoma in recent years were collected and reviewed.Results The multimodal therapy,such as preoperative chemotherapy,preoperative adjuvant chemoradiotherapy,preoperative interventional chemoradiotherapy for advanced gastric carcinoma was effective because it could increase the rate of R0 resection for the patients with advanced gastric carcinoma.And it can decrease the mortality rate after operation,extend the overall survival time and improve patients' life quality.Conclusion Multimodal therapy is a promising method for the treatment of advanced gastric carcinoma and it should be further developed.

Adenocarcinoma of esophagogastric junction:concept and strategy / 中国癌症杂志

In contrast to the decreasing prevalence of gastric cancer and esophageal cancer,there has been an alarm rise in the incidence and prevalence of adenocarcinoma of esophagogastric junction during recent literatures.Many discrepancies exists in the current literature,however,regarding the etiology,classification and surgical treatment of the tumor.This confusion is due to a lack of clear current UICC recommendation for the classification and staging.Consequently,the selection of the surgical procedure for tumor is controversial.A clear definition and classification is,therefore,the prerequisite for a discussion of the optimal surgical approach.This review give a detailed description of the related concept and recent advances in treatment of adenocarcinoma of the esophagogastric junction.