Expressions of pandemic fatigue on digital platforms: a thematic analysis of sentiment and narratives for infodemic insights.

BACKGROUND: The infodemic accompanying the COVID-19 pandemic has led to an overwhelming amount of information, including questions, concerns and misinformation. Pandemic fatigue has been identified as a concern from early in the pandemic. With new and ongoing health emergencies in 2022, it is important to understand how pandemic fatigue is being discussed and expressed by users on digital channels. This study aims to explore and report on key narrative themes associated with expressions of pandemic fatigue by users on digital platforms. METHODS: This paper describes the collection of publicly available data over a 3-month period from multiple online sources using the Meltwater and CrowdTangle platforms to source data from Twitter, Facebook, Instagram, YouTube, TikTok, Pinterest, Product Reviews, Twitch, blogs & forums. A comprehensive search strategy was developed and tested. A total of 1,484,042 social media posts were identified during the time-period that included the defined search terms for pandemic fatigue. These data were initially sorted by highest levels of engagement and from this dataset, analysts reviewed the identified posts to isolate and remove irrelevant content and identify dominant narratives. A thematic analysis was carried out on these narratives to identify themes related to expression of pandemic fatigue. Two researchers reviewed the data and themes. RESULTS: The thematic analysis of narratives identified six main themes relating to expression of pandemic fatigue, and one theme of counter narratives against pandemic fatigue. Data volume increased concurrent with the time of the mpox emergency announcement. Emergent themes showed the different ways users expressed pandemic fatigue and how it was interlaced with issues of trust, preventative measure acceptance and uptake, misinformation, and being overwhelmed with multiple or sustained emergencies. CONCLUSIONS: This paper has identified the different ways users express pandemic fatigue on digital channels over a 3-month period. Better understanding the implications of the information environment on user's perceptions, questions, and concerns regarding pandemic and more broadly emergency fatigue is vital in identifying relevant interventions and, in the longer term, strengthening the global architecture for health emergency preparedness, prevention, readiness and resilience, as evidenced in this paper. There are clear pathways for further research, including incorporating additional languages and reviewing these themes over longer time periods.

Novel Strategy for the Management of Cervical Multicystic Diseases.

PURPOSE: To investigate the clinical practices of diagnosing multicystic cervical lesions as a means to develop a more appropriate diagnostic algorithm for gastric-type adenocarcinoma (GAS) and its precursors. METHODS: Clinical information for 159 surgically treated patients for multicystic disease of the uterine cervix was collected from 15 hospitals. We performed a central review of the MRI and pathological findings. The MRI findings were categorized into four types including two newly proposed imaging features based on the morphology and distribution of cysts, and the diagnosis accuracy was assessed. Among the four MRI types, types 1 and 2 were categorized as benign lesions that included LEGH; type 3 were precancerous lesions (with an assumption of atypical LEGH); and type 4 were malignant lesions. RESULTS: The central pathological review identified 56 cases of LEGH, seven with GAS, four with another form of carcinoma, and 92 with benign disease. In clinical practice, over-diagnosis of malignancy (suspicion of MDA) occurred for 12/19 cases (63.2%) and under-diagnosis of malignancy occurred for 4/11 (36%). Among the 118 patients who had a preoperative MRI and underwent a hysterectomy, type 3 or 4 MRI findings in conjunction with abnormal cytology were positively indicative of premalignancy or malignancy, with a sensitivity and specificity of 61.1% and 96.7%, respectively. CONCLUSIONS: Although the correct preoperative diagnosis of cervical cancer with a multicystic lesion is challenging, the combination of cytology and MRI findings creates a more appropriate diagnostic algorithm that significantly improves the diagnostic accuracy for differentiating benign disease from premalignancy and malignancy.

A global research agenda on public health and social measures during emergencies.

The importance of strong coordination for research on public health and social measures was highlighted at the Seventy-fourth World Health Assembly in 2021. This article describes efforts undertaken by the World Health Organization (WHO) to develop a global research agenda on the use of public health and social measures during health emergencies. This work includes a multistep process that started with a global technical consultation convened by WHO in September 2021. The consultation included experts from around the world and from a wide range of disciplines, such as public health, education, tourism, finance and social sciences, and aimed to identify research and implementation approaches based on lessons learnt during the coronavirus disease 2019 pandemic. To prepare for future epidemics and pandemics, it is essential to adopt a more robust, comparable and systematic research approach to public health and social measures. Such comprehensive approach will better inform agile, balanced and context-specific implementation decisions during future emergencies. This article describes the methods used to develop global research priorities for public health and social measures and the next steps needed.

La soixante-quatorzième Assemblée mondiale de la Santé en 2021 a souligné l'importance d'une coordination solide pour la recherche sur la santé publique et les mesures sociales. Le présent article décrit les efforts entrepris par l'Organisation mondiale de la santé (OMS) pour élaborer un programme de recherche mondial sur l'utilisation des mesures de santé publique et des mesures sociales lors de situations d'urgence sanitaire. Ce travail comprend un processus en plusieurs étapes qui a commencé par une consultation technique mondiale organisée par l'OMS en septembre 2021. La consultation a réuni des experts du monde entier issus d'un large éventail de disciplines telles que la santé publique, l'éducation, le tourisme, la finance et les sciences sociales. Elle visait à identifier des approches de recherche et de mise en œuvre fondées sur les enseignements tirés de la pandémie de maladie à coronavirus de 2019. Pour se préparer aux futures épidémies et pandémies, il est essentiel d'adopter une approche de recherche plus solide, comparable et systématique en matière de santé publique et de mesures sociales. Cette approche globale permettra de mieux éclairer les décisions de mise en œuvre agiles, équilibrées et adaptées au contexte lors des futures situations d'urgence. Le présent article décrit les méthodes appliquées pour définir les priorités mondiales de recherche en matière de santé publique et de mesures sociales, ainsi que les prochaines étapes à franchir.

En la 74.ª Asamblea Mundial de la Salud, celebrada en 2021, se destacó la importancia de una sólida coordinación en la investigación sobre salud pública y medidas sociales. Este artículo describe los esfuerzos que ha emprendido la Organización Mundial de la Salud (OMS) para desarrollar un programa mundial de investigación sobre el uso de medidas sociales y de salud pública durante las emergencias sanitarias. Este trabajo incluye un proceso de varios pasos que comenzó con una consulta técnica mundial que convocó la OMS en septiembre de 2021. La consulta incluyó a expertos de todo el mundo y de una gran variedad de disciplinas, como la salud pública, la educación, el turismo, las finanzas y las ciencias sociales, y tuvo como objetivo identificar enfoques de investigación y aplicación basados en las lecciones aprendidas durante la pandemia de la enfermedad por coronavirus de 2019. Para prepararse ante futuras epidemias y pandemias, es esencial adoptar un enfoque de investigación más sólido, comparable y sistemático en materia de salud pública y medidas sociales. Este enfoque integral informará mejor las decisiones de aplicación ágiles, equilibradas y adaptadas al contexto durante futuras emergencias. En este artículo se describen los métodos utilizados para elaborar las prioridades mundiales de investigación sobre salud pública y medidas sociales, así como los próximos pasos necesarios.

The role of myeloid-derived suppressor cells in increasing cancer stem-like cells and promoting PD-L1 expression in epithelial ovarian cancer.

The aim of this study was to investigate the role of myeloid-derived suppressor cells (MDSC) in the induction of cancer stem-like cells (CSC) and programmed death ligand 1 (PD-L1) expression in ovarian cancer. CSC were defined as tumor cells expressing high levels of aldehyde dehydrogenase 1 (ALDH 1). We inoculated G-CSF-expressing or Mock-expressing ovarian cancer cells into mice, and the frequencies of MDSC and CSC in tumors of these models were compared by flow cytometry. To directly demonstrate the role of MDSC in the induction of CSC and the increase in PD-L1 expression, we performed in vitro co-culture. MDSC and CSC (ALDH-high cells) were more frequently observed in G-CSF-expressing cell-derived tumors than in Mock-expressing cell-derived tumors. Co-culture experiments revealed that MDSC increased the number of CSC via the production of PGE2. Moreover, PGE2 produced by MDSC increased tumor PD-L1 expression via the mammalian target of rapamycin (mTOR) pathway in ovarian cancer cells. In an in vitro experiment in which ovarian cancer cells were co-cultured with MDSC, higher expression of PD-L1 was observed in CSC than in non-CSC (ALDH-low cells). Furthermore, by immunofluorescence staining, we found that PD-L1 was co-expressed with ALDH1 in in vivo mouse models. In conclusion, PGE2 produced by MDSC increases the stem cell-like properties and tumor PD-L1 expression in epithelial ovarian cancer. Depleting MDSC may be therapeutically effective against ovarian cancer by reducing the number of CSC and tumor PD-L1 expression.

Lymphangioleiomyoma of the Uterus and Pelvic Lymph Nodes: A Report of 3 Cases, Including the Potentially Earliest Manifestation of Extrapulmonary Lymphangioleiomyomatosis.

We present 3 cases of extrapulmonary lymphangioleiomyomatosis (LAM) identified incidentally in the uterine corpus and pelvic nodes resected for other reasons. One patient, a 47-yr-old female with corpus cancer, underwent a total hysterectomy and nodal dissection; the other 2 patients, aged 44 and 49 yr, underwent simple hysterectomy for corpus leiomyomas. None of the patients had evidence of tuberous sclerosis complex or any significant lesions in other organs. An area of spindle cell proliferation, intimately associated with dilated and tortuous lymphatic vessels, was found in the myometrium of all 3 patients, and nodal involvement with spindle cell proliferation was observed in the patient with corpus cancer. The spindle cells had faintly eosinophilic cytoplasm and a bland appearance. They were immunoreactive for α-SMA, gp100 (HMB45), and Melan-A. Tumor cell clusters lined with a single layer of lymphatic endothelium were floating in the lymphatic vessel lumen. These lesions were diagnosed as lymphangioleiomyoma in the uterine corpus and associated lymph nodes. Two of the cases seemed to be the earliest manifestations of extrapulmonary LAM, and the other case represents early-phase metastasis of LAM from the uterus. The present cases support the speculation that the uterus is the primary source of LAM cells.

Lurbinectedin (PM01183), a selective inhibitor of active transcription, effectively eliminates both cancer cells and cancer stem cells in preclinical models of uterine cervical cancer.

Objective The objective of this study was to evaluate the antitumor effects of lurbinectedin on cervical cancer with a special focus on its effects on cancer stem cells (CSCs). Methods Using two cervical cell lines (ME180 and CaSki cells), the antitumor effects of lurbinectedin were assessed in vitro using the MTS assay and colony formation assay. The growth inhibitory effects of paclitaxel and cisplatin were also evaluated as controls. By employing ALDH1 activity as a marker of CSCs, the antitumor effects of lurbinectedin on cervical CSCs and non-CSCs were individually evaluated. Finally, we investigated the mechanisms by which lurbinectedin eliminated cervical CSCs. Results Lurbinectedin had significant antitumor activity toward cervical cancer cells at low nanomolar concentrations in vitro. Mouse xenografts of cervical cancer revealed that lurbinectedin significantly inhibits tumor growth. The growth-inhibitory effect of lurbinectedin was greater than that of cisplatin and paclitaxel. ALDH-high CSCs were observed in both cervical cancer cell lines (4.4% and 2.4% in ME180 and CaSki cells, respectively). Lurbinectedin downregulated stem cell-related gene expression (Oct4, Nanog, and SOX2), inhibited HDAC1 activity, and effectively eliminated ALDH-high CSCs. Conclusions Lurbinectedin is highly effective on uterine cervical cancer because it eliminates CSCs, and lurbinectedin is a promising agent to overcome platinum resistance in cervical cancer.

A unique respiratory adaptation in Drosophila independent of supercomplex formation.

Large assemblies of respiratory chain complexes, known as supercomplexes, are present in the mitochondrial membrane in mammals and yeast, as well as in some bacterial membranes. The formation of supercomplexes is thought to contribute to efficient electron transfer, stabilization of each enzyme complex, and inhibition of reactive oxygen species (ROS) generation. In this study, mitochondria from various organisms were solubilized with digitonin, and then the solubilized complexes were separated by blue native PAGE (BN-PAGE). The results revealed a supercomplex consisting of complexes I, III, and IV in mitochondria from bovine and porcine heart, and a supercomplex consisting primarily of complexes I and III in mitochondria from mouse heart and liver. However, supercomplexes were barely detectable in Drosophila flight-muscle mitochondria, and only dimeric complex V was present. Drosophila mitochondria exhibited the highest rates of oxygen consumption and NADH oxidation, and the concentrations of the electron carriers, cytochrome c and quinone were higher than in other species. Respiratory chain complexes were tightly packed in the mitochondrial membrane containing abundant phosphatidylethanolamine with the fatty acid palmitoleic acid (C16:1), which is relatively high oxidation-resistant as compared to poly-unsaturated fatty acid. These properties presumably allow efficient electron transfer in Drosophila. These findings reveal the existence of a new mechanism of biological adaptation independent of supercomplex formation.

Purification of Active Respiratory Supercomplex from Bovine Heart Mitochondria Enables Functional Studies.

To understand the roles of mitochondrial respiratory chain supercomplexes, methods for consistently separating and preparing supercomplexes must be established. To this end, we solubilized supercomplexes from bovine heart mitochondria with digitonin and then replaced digitonin with amphipol (A8-35), an amphiphilic polymer. Afterward, supercomplexes were separated from other complexes by sucrose density gradient centrifugation. Twenty-six grams of bovine myocardium yielded 3.2 mg of amphipol-stabilized supercomplex. The purified supercomplexes were analyzed based on their absorption spectra as well as Q10 (ubiquinone with ten isoprene units) and lipid assays. The supercomplex sample did not contain cytochrome c but did contain complexes I, III, and IV at a ratio of 1:2:1, 6 molecules of Q10, and 623 atoms of phosphorus. When cytochrome c was added, the supercomplex exhibited KCN-sensitive NADH oxidation; thus, the purified supercomplex was active. Reduced complex IV absorbs at 444 nm, so we measured the resonance Raman spectrum of the reduced amphipol-solubilized supercomplex and the mixture of amphipol-solubilized complexes I1, III2, and IV1 using an excitation wavelength of 441.6 nm, allowing measurement precision comparable with that obtained for complex IV alone. Use of the purified active sample provides insights into the effects of supercomplex formation.

The Significance of Pretreatment Thrombocytosis and Its Association With Neutrophilia in Patients With Surgically Treated Endometrial Cancer.

OBJECTIVE: The aim of this study was to investigate the prognostic significance of a pretreatment thrombocytosis and its association with neutrophilia in patients with surgically treated endometrial cancer. METHODS: The baseline characteristics and outcome data of 508 patients with surgically treated endometrial cancer between January 2000 and December 2010 were collected and retrospectively reviewed. The patients were separated into 4 groups according to their platelet counts and the neutrophil counts, and the progression-free and overall survival rates of the 4 groups were compared. A Cox proportional hazards regression model was used to explore the independent prognostic factors. RESULTS: Pretreatment thrombocytosis was found to be associated with advanced stage (P = 0.0186), nonendometrioid histology (P = 0.0139), a deeper myometrial invasion (P = 0.0103), lymphovascular space involvement (P = 0.0404), cervical involvement (P = 0.004), positive peritoneal cytology (P = 0.0198), lymph node metastasis (P = 0.0301), and more frequent treatment failure (P = 0.0006). Multivariate analysis demonstrated that an older age (hazard ratio [HR], 2.54; 95% confidence interval [CI], 1.46-4.51; P = 0.0009), advanced clinical stage (HR, 5.27; 95% CI, 2.94-9.86; P < 0.0001), lymphovascular space involvement (HR, 3.37; 95% CI, 1.74-7.07; P = 0.0002), and pretreatment thrombocytosis (HR, 4.99; 95% CI, 2.47-9.39; P < 0.0001) were significant predictors of survival. When examined according to clinical stage, pretreatment thrombocytosis was prognostically significant only in patients with stage III-IV disease. The neutrophil count in patients who display thrombocytosis was significantly greater than that observed in patients without thrombocytosis (median, 6702 vs 4406/µL; P < 0.0001). Moreover, patients who displayed both thrombocytosis and neutrophilia had significantly shorter survival than that in those with either thrombocytosis or neutrophilia alone. CONCLUSIONS: Presence of thrombocytosis at the time of the initial diagnosis is an independent predictor of shorter survival in patients with advanced-stage (stages III-IV) endometrial cancer. Moreover, pretreatment thrombocytosis and concurrent neutrophilia are an independent predictor of shorter survival regardless of clinical stage.

Predictors of Survival in Patients With FIGO Stage IVB Cervical Cancer.

OBJECTIVE: The aim of this study was to identify prognostic factors and establish a model for predicting life expectancy in International Federation of Gynecology and Obstetrics stage IVB cervical cancer patients. METHODS: The baseline characteristics and outcome data of patients with stage IVB cervical cancer between May 1994 and October 2014 were collected and retrospectively reviewed. A Cox proportional hazards regression model was used to identify independent predictors of survival in stage IVB cervical cancer patients. RESULTS: A total of 107 patients were included in our database. The median overall survival (OS) period was 16 months. Multivariate analysis revealed that the metastatic site (hazards ratio, 3.09; 95% confidence interval, 1.94-4.88; P < 0.0001) and a white blood cell (WBC) count exceeding 10,000/µL (hazards ratio, 2.02; 95% confidence interval, 1.19-3.30; P = 0.0102) were significant prognostic factors in terms of OS. Patient survival was inversely correlated with the number of these prognostic factors possessed. When the patients were divided into 3 prognostic groups, the median OS of the patients with 0, 1, or 2 poor prognostic factors was 26, 12, and 7 months, respectively. Among the patients with WBC counts of less than 10,000/µL, treatment with radiotherapy resulted in improved survival compared with chemotherapy or palliative care alone. In contrast, radiotherapy had minimal effects on survival in patients with WBC counts of greater than 10,000/µL. CONCLUSIONS: The metastatic site and an elevated WBC count are significant prognostic factors in patients with stage IVB cervical cancer. Our prognostic model composed of these 2 clinical variables might enable physicians to predict survival more accurately.

The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer.

The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway plays a critical role in the malignant transformation of human tumors and their subsequent growth, proliferation, and metastasis. Preclinical investigations have suggested that the PI3K/AKT/mTOR pathway is frequently activated in ovarian cancer, especially in clear cell carcinoma and endometrioid adenocarcinoma. Thus, this pathway is regarded as an attractive candidate for therapeutic interventions, and inhibitors targeting different components of this pathway are in various stages of clinical development. Here, we highlight the recent progress that has been made in our understanding of the PI3K/AKT/mTOR pathway and discuss the potential of therapeutic agents that target this pathway as treatments for ovarian cancer and the obstacles to their development.

Prognostic significance of systemic neutrophil and leukocyte alterations in surgically treated endometrial cancer patients: a monoinstitutional study.

OBJECTIVE: The aim of this study was to investigate the prognostic significance of an elevated neutrophil count at the time of the initial diagnosis in patients with surgically treated endometrial cancer. METHODS: The baseline characteristics and outcome data of patients who were diagnosed with endometrial cancer between January 2000 and December 2010 were collected and retrospectively reviewed. The patients were separated into two groups according to their neutrophil counts. The clinicopathological characteristics and overall survival rates of the two groups were compared. A Cox proportional hazard regression model was used to investigate the prognostic significance of an elevated neutrophil count among patients with surgically treated endometrial cancer. RESULTS: An elevated neutrophil count was found to be associated with an advanced clinical stage (P<0.0001), lymphovascular space involvement (P=0.0003), cervical involvement (P=0.0049), the proportion of patients that received adjuvant therapy (P=0.0020), elevated NLR (P<0.0001), and treatment failure (P<0.0001). Multivariate analyses demonstrated that age (hazard ratio (HR)=2.23, 95% confidence interval (95% CI)=1.30 to 3.91; P=0.0035), clinical stage (HR=4.72, 95% CI=2.61 to 8.90; P<0.0001), lymphovascular space involvement (HR=3.15, 95% CI=1.60 to 6.68; P=0.0007), an elevated neutrophil count (HR=2.76, 95% CI=1.43 to 5.03; P=0.0033), and an elevated white blood cell count (HR=2.79, 95% CI=1.50 to 4.96; P=0.0017) were significant predictors of survival. CONCLUSION: The elevated neutrophil or leukocyte counts at the time of the initial diagnosis are independent prognostic factors in patients with surgically treated endometrial cancer.

Prognostic Significance of Pretreatment Thrombocytosis in Cervical Cancer Patients Treated With Definitive Radiotherapy.

OBJECTIVE: The aim of this study was to investigate the prevalence and prognostic significance of an elevated platelet count at the time of the initial diagnosis in patients with cervical cancer who are treated with definitive radiotherapy. METHODS: The baseline characteristics and outcome data of cervical cancer patients who were treated with definitive radiotherapy between November 1993 and December 2011 were collected and retrospectively reviewed. The patients were separated into 2 groups according to their platelet counts. The clinicopathological characteristics and overall survival rates of the 2 groups were compared. A Cox proportional hazards regression model was used to investigate the prognostic significance of an elevated platelet count. RESULTS: An elevated platelet count was found to be associated with younger age (P = 0.0003), an advanced clinical stage (P < 0.0001), larger tumors (P = 0.0025), lower hemoglobin levels (P < 0.0001), and more frequent treatment failure (P = 0.0015). Multivariate analysis demonstrated that an advanced clinical stage (hazards ratio [HR], 2.93; 95% confidence interval [CI], 1.47-6.70; P = 0.0015), nonsquamous cell carcinoma histology (HR, 2.67; 95% CI, 1.52-4.42; P = 0.0011), larger tumors (HR, 3.86; 95% CI, 2.18-7.03; P < 0.0001), lower hemoglobin levels (HR, 1.99; 95% CI, 1.34-2.93; P = 0.0008), and an elevated platelet count (HR, 1.65; 95% CI, 1.03-2.56; P = 0.0395) were significant predictors of survival. CONCLUSIONS: An elevated platelet count at the time of the initial diagnosis is an independent prognostic factor in cervical cancer patients who are treated with definitive radiotherapy.

Reirradiation using high-dose-rate interstitial brachytherapy for locally recurrent cervical cancer: a single institutional experience.

OBJECTIVES: This study aimed to evaluate the effectiveness and feasibility of reirradiation using high-dose-rate interstitial brachytherapy (HDR-ISBT) in patients with recurrent cervical cancer. METHODS: The records of 52 consecutive women with central pelvic recurrence who were salvaged with HDR-ISBT-based reirradiation were retrospectively reviewed. Data regarding the primary disease, follow-up findings, recurrence, the treatment outcome, and toxicities were collected. Multivariate analysis was performed using the Cox proportional hazards regression model to identify predictors of the response to HDR-ISBT. Survival rate was calculated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: A total of 52 patients who had been treated with HDR-ISBT-based reirradiation were included in our database. The local control rate was 76.9% (40/52), and the median postrecurrence survival period was 32 months. Grade 3 or 4 late toxicities were observed in 13 patients (25%). Multivariate analysis revealed that tumor size and the treatment-free interval were significant poor prognostic factors of postrecurrence survival. In a comparison between the patients who were salvaged with HDR-ISBT-based reirradiation (ISBT group) and those who were treated with palliative therapy alone (palliative group), we found that among the patients who displayed 0 or 1 poor prognostic factors, the patients in the ISBT group survived significantly longer than those in the palliative group. In contrast, similar survival rates were seen in both groups among the patients with 2 or more poor prognostic factors. CONCLUSIONS: Reirradiation using HDR-ISBT is effective and feasible in patients with recurrent cervical cancer. Our 2-clinical variable prognostic model might enable physicians to identify patients who would not derive clinical benefit from HDR-ISBT and offer them the opportunity to receive other types of treatment.

Combination treatment with trabectedin and irinotecan or topotecan has synergistic effects against ovarian clear cell carcinoma cells.

OBJECTIVES: The objective of this study was to investigate the chemotherapeutic agents that produce the strongest synergistic effects when combined with trabectedin against ovarian clear cell carcinoma (CCC), which is regarded as an aggressive chemoresistant histological subtype. METHODS: Using 4 human CCC cell lines (RMG1, RMG2, KOC7C, and HAC2), the cytotoxicities of trabectedin, SN-38, topotecan, doxorubicin, cisplatin, and paclitaxel as single agents were first assessed using the MTS assay. Then, the cytotoxicities of combination treatments involving trabectedin and 1 of the other 4 agents were evaluated by isobologram analysis to examine whether these combinations displayed synergistic, additive, or antagonistic effects. The antitumor activities of the combination treatments were also examined using cisplatin-resistant and paclitaxel-resistant CCC sublines, which were derived from the parental CCC cells by continuously exposing them to cisplatin or paclitaxel. Finally, we determined the effect of everolimus on the antitumor efficacy of trabectedin-based combination chemotherapy. RESULTS: Concurrent exposure to trabectedin and SN-38 or topotecan resulted in synergistic interactions in all 4 CCC cell lines. Among the tested combinations, trabectedin plus SN-38 was the most effective cytotoxic regimen. The combination of trabectedin plus SN-38 also had strong synergistic effects on both the cisplatin-resistant and paclitaxel-resistant CCC cell lines. Treatment with everolimus significantly enhanced the antitumor activity of trabectedin plus SN-38 or topotecan. CONCLUSIONS: Combination treatment with trabectedin and SN-38 displays the greatest cytotoxic effect against ovarian CCC. Our in vitro study provides the rationale for future clinical trials of trabectedin plus irinotecan with or without everolimus in patients with ovarian CCC in both the front-line chemotherapy setting and as a second-line treatment of recurrent CCC that had previously been treated with cisplatin or paclitaxel.

A phase I study of concurrent weekly carboplatin and paclitaxel combined with intensity-modulated pelvic radiotherapy as an adjuvant treatment for early-stage cervical cancer patients with positive pelvic lymph nodes.

OBJECTIVES: The objective of this study was to determine the maximum tolerated dose (MTD) and acute dose-limiting toxicities (DLTs) of intravenous carboplatin plus paclitaxel combined with intensity-modulated pelvic radiotherapy (pelvic IMRT) as an adjuvant treatment for early-stage cervical cancer patients with positive pelvic lymph nodes. METHODS: Women with uterine cervical cancer who were treated with radical hysterectomy and pelvic lymphadenectomy and displayed positive pelvic lymph nodes were eligible for this study. The patients were postoperatively treated with pelvic IMRT (50.4 Gy). The concurrent weekly chemotherapy consisted of carboplatin (area under the curve [AUC], 2) and paclitaxel (starting at 35 mg/m² and escalating by 5 mg/m² in 3 patient cohorts). The primary end point of the escalation study was acute DLT that occurred within 30 days of the completion of radiation therapy. RESULTS: Nine patients were enrolled and treated at 2 dose levels until DLT occurred. The median age of the patients was 47 years (range, 28-66 years). The median radiotherapy treatment time was 39.5 days (range, 38-64 days). At dose level I (35 mg/m² paclitaxel), 2 grade 3 leukopenia and a neutropenia were observed, but no DLT occurred. At dose level II (40 mg/m² paclitaxel), the first patient experienced a grade 2 hypersensitive reaction, which resulted in discontinuation of planned treatment. Thus, 2 more patients were evaluated at this dose level. Of these, 1 patient experienced febrile neutropenia, which was considered to be a DLT, and the other patient experienced long-lasting grade 3 leukopenia and grade 3 neutropenia, which resulted in the discontinuation of chemotherapy for 2 weeks (a DLT). We then evaluated 3 more patients at dose level 1, but no DLT occurred. The MTD of paclitaxel and carboplatin was thus defined as 35 mg/m² and an AUC of 2.0, respectively. CONCLUSIONS: Weekly paclitaxel/carboplatin and pelvic IMRT is a reasonable adjuvant treatment regimen for cervical cancer patients after radical hysterectomy. The MTD of paclitaxel and carboplatin for future phase II trials of this regimen is 35 mg/m² and an AUC of 2.0, respectively.

Enormous cystic tumor of peritoneal psammocarcinoma exhibiting complete response to Cisplatin and cyclophosphamide after suboptimal cytoreduction: case report and review of the literature.

Psammocarcinoma is a serous peritoneal tumor arising from the ovary or the peritoneum and characterized by low-grade nuclear features, extensive psammoma bodies, and invasiveness. Only 62 cases have ever been documented, 30 primary peritoneal and 32 primary ovarian, most of which presented as small tumors. Adjuvant therapies, including chemotherapy and radiation, were performed in 12 of the primary peritoneal cases, without any clear evidence of benefit. We present a case of an unusually large primary peritoneal psammocarcinoma with unexpected outcome. The patient was a 38-year-old woman with a tumor of the peritoneum which adhered densely to the uterus and rectum and developed into the intra-abdominal cavity and retroperitoneal space. After adhesiolysis of the tumor and rectum, suboptimal surgical reduction left a 4 cm × 2 cm tumor segment. Postoperative chemotherapy, consisting of paclitaxel and carboplatin (TC) for 1 course, and cyclophosphamide and cisplatin (CP) for 5 courses, was conducted. The residual tumor responded completely to the chemotherapy and the patient is alive today, with no evidence of disease 15 months after the surgery. Our case implies that CP therapy is a potential regimen of postoperative remission-induction therapy for suboptimally resected primary peritoneal psammocarcinoma.

A comprehensive monitoring and evaluation framework for evidence to policy networks.

OBJECTIVE: To describe the development of a framework for monitoring and evaluating knowledge translation (KT) networks. METHOD: The framework was developed using mixed methods over four phases, including i) a targeted literature review of KT networks, activities and indicators, ii) two scoping reviews to further enhance the set of indicators, iii) peer-reviews by international KT experts and an online expert consultation, and iv) piloting. RESULTS: A comprehensive theory of change (ToC) and indicators, both for the Network Secretariat and its participating member countries, were identified to develop the monitoring and evaluation framework. The framework includes (i) a ToC, including three key indicator domains across the results chain (outputs, short term outcomes, intermediate outcomes), and (ii) indicators for the three key domains, that can be selected depending on the stage of network maturity, along with suggested data collection methods. The three key indicator domains are 1) KT capacity and skill building; 2) network (structure, governance and leadership); and 3) KT/evidence-informed policy value and culture. CONCLUSION: The monitoring and evaluation framework that links KT activities with policy and health outcomes fills an important gap in optimizing KT procedures, generating lessons learned and increasing accountability of major multipartner KT networks.