Nephrotic syndrome associated with solid malignancies: a systematic review.

BACKGROUND: Nephrotic syndrome (NS) can occur as a paraneoplastic disorder in association with various types of carcinoma. However, paraneoplastic nephrotic syndrome (PNS) is often misdiagnosed as idiopathic nephrotic syndrome or as an adverse effect of oncology treatment, leading to delayed diagnosis and suboptimal treatment. The characteristics of NS associated with solid malignancies are not yet elucidated. We systematically summarized the clinical data for 128 cases of NS combined with solid malignancies with the aim of informing the clinical management of PNS. METHODS: We searched the PubMed database for articles published from the date of inception through to October 2023 using the following keywords: "cancer" or "malignant neoplasms" or "neoplasia" or "tumors" and "nephrotic syndrome", "nephrotic" or "syndrome, nephrotic". All data were extracted from case reports and case series, and the extraction included a method for identifying individual-level patient data. RESULTS: A literature search yielded 105 cases of PNS and 23 of NS induced by cancer therapy. The median age at diagnosis was 60 years, with a male to female ratio of 1.8:1. In patients with PNS, manifestations of NS occurred before, concomitantly with, or after diagnosis of the tumor (in 36%, 30%, and 34% of cases, respectively). Membranous nephropathy (49%) was the most prevalent renal pathology and found particularly in patients with lung, colorectal, or breast carcinoma. Regardless of whether treatment was for cancer alone or in combination with NS, the likelihood of remission was high. CONCLUSION: The pathological type of NS may be associated with specific malignancies in patients with PNS. Prompt identification of PNS coupled with suitable therapeutic intervention has a significant impact on the outcome for patients.

Myeloid-derived suppressor cells in peripheral blood as predictive biomarkers in patients with solid tumors undergoing immune checkpoint therapy: systematic review and meta-analysis.

Background: Immunotherapeutic approaches, including immune checkpoint inhibitor (ICI) therapy, are increasingly recognized for their potential. Despite notable successes, patient responses to these treatments vary significantly. The absence of reliable predictive and prognostic biomarkers hampers the ability to foresee outcomes. This meta-analysis aims to evaluate the predictive significance of circulating myeloid-derived suppressor cells (MDSC) in patients with solid tumors undergoing ICI therapy, focusing on progression-free survival (PFS) and overall survival (OS). Methods: A comprehensive literature search was performed across PubMed and EMBASE from January 2007 to November 2023, utilizing keywords related to MDSC and ICI. We extracted hazard ratios (HRs) and 95% confidence intervals (CIs) directly from the publications or calculated them based on the reported data. A hazard ratio greater than 1 indicated a beneficial effect of low MDSC levels. We assessed heterogeneity and effect size through subgroup analyses. Results: Our search yielded 4,023 articles, of which 17 studies involving 1,035 patients were included. The analysis revealed that patients with lower levels of circulating MDSC experienced significantly improved OS (HR=2.13 [95% CI 1.51-2.99]) and PFS (HR=1.87 [95% CI 1.29-2.72]) in response to ICI therapy. Notably, heterogeneity across these outcomes was primarily attributed to differences in polymorphonuclear MDSC (PMN-MDSC) subpopulations and varying cutoff methodologies used in the studies. The monocytic MDSC (M-MDSC) subpopulation emerged as a consistent and significant prognostic marker across various subgroup analyses, including ethnicity, tumor type, ICI target, sample size, and cutoff methodology. Conclusions: Our findings suggest that standardized assessment of MDSC, particularly M-MDSC, should be integral to ICI therapy strategies. These cells hold the promise of identifying patients at risk of poor response to ICI therapy, enabling tailored treatment approaches. Further research focusing on the standardization of markers and validation of cutoff methods is crucial for integrating MDSC into clinical practice. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023420095, identifier CRD42023420095.

Monoclonal Antibodies for Targeted Fluorescence-Guided Surgery: A Review of Applicability across Multiple Solid Tumors.

This study aims to review the status of the clinical use of monoclonal antibodies (mAbs) that have completed or are in ongoing clinical trials for targeted fluorescence-guided surgery (T-FGS) for the intraoperative identification of the tumor margins of extra-hematological solid tumors. For each of them, the targeted antigen, the mAb generic/commercial name and format, and clinical indications are presented, together with utility, doses, and the timing of administration. Based on the current scientific evidence in humans, the top three mAbs that could be prepared in a GMP-compliant bank ready to be delivered for surgical purposes are proposed to speed up the translation to the operating room and produce a few readily available "off-the-shelf" injectable fluorescent probes for safer and more effective solid tumor resection.

Secondary solid malignancies and precancerous lesions after allogeneic hematopoietic stem cell transplantation using non-total body irradiation-based conditioning in acute myeloid leukemia.

INTRODUCTION: Long-term survivors have an increased risk of developing secondary solid malignancies (SSMs) after allogeneic-hematopoietic stem cell transplantation (allo-HSCT) with graft-versus-host disease (GVHD) potentially modulating these risks. METHODS: This retrospective study analyzed the cumulative incidences of SSMs after chemotherapy-based conditioning for allo-HSCT patients with acute myeloid leukemia (n = 266) transplanted at the University Hospital Regensburg between 1999 and 2016. RESULTS: The median follow-up was 11.4 years (Interquartile range, 9.0-14.9). The 100-day cumulative incidence of grade II-IV acute GVHD (aGVHD) was 44.4% [95% CI (38.3, 50.2)], while the 5-year cumulative incidence of chronic GVHD (cGVHD, requiring systemic immunosuppression) was 36.9% [95% CI (31.1, 42.6)]. The cumulative incidences of secondary squamous cell carcinomas (SCCs) at 10 and 15 years were 4.2% [95% CI (2.2, 7.2)] and 8.1% [95% CI (4.6, 12.8)], while the cumulative incidences of non-SCCs at 10 and 15 years were 5.4% [95% CI (3.1, 8.7)] and 6.9% [95% CI (4.0, 10.8)]. Antithymocyte globulin (ATG) was associated with reduced incidences of SCCs but not of non-SCCs. Patients with grade II-IV aGVHD had increased rates of SCCs after adjusting with patient age and ATG, while patients with cGVHD showed only a trend for increased rates of SCCs. CONCLUSION: The data indicate that aGVHD and cGVHD affect the rates of secondary SCCs. While the use of ATG is associated with lower incidences of SCCs via reduction of GVHD, there was no association of ATG with non-SCCs.

New Emerging Targets in Cancer Immunotherapy: The Role of B7-H3.

Immune checkpoints (ICs) are molecules implicated in the fine-tuning of immune response via co-inhibitory or co-stimulatory signals, and serve to secure minimized host damage. Targeting ICs with various therapeutic modalities, including checkpoint inhibitors/monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), and CAR-T cells has produced remarkable results, especially in immunogenic tumors, setting a paradigm shift in cancer therapeutics through the incorporation of these IC-targeted treatments. However, the large proportion of subjects who experience primary or secondary resistance to available IC-targeted options necessitates further advancements that render immunotherapy beneficial for a larger patient pool with longer duration of response. B7-H3 (B7 Homolog 3 Protein, CD276) is a member of the B7 family of IC proteins that exerts pleiotropic immunomodulatory effects both in physiologic and pathologic contexts. Mounting evidence has demonstrated an aberrant expression of B7-H3 in various solid malignancies, including tumors less sensitive to current immunotherapeutic options, and has associated its expression with advanced disease, worse patient survival and impaired response to IC-based regimens. Anti-B7-H3 agents, including novel mAbs, bispecific antibodies, ADCs, CAR-T cells, and radioimmunotherapy agents, have exhibited encouraging antitumor activity in preclinical models and have recently entered clinical testing for several cancer types. In the present review, we concisely present the functional implications of B7-H3 and discuss the latest evidence regarding its prognostic significance and therapeutic potential in solid malignancies, with emphasis on anti-B7-H3 modalities that are currently evaluated in clinical trial settings. Better understanding of B7-H3 intricate interactions in the tumor microenvironment will expand the oncological utility of anti-B7-H3 agents and further shape their role in cancer therapeutics.

Tumor abnormal protein as a promising biomarker for screening solid malignancies and monitoring recurrence and metastasis.

Background: Tumor abnormal protein (TAP), the sugar chain protein released by tumor cells during metabolism, allows the development of a technique that exploits aggregated tumor-associated abnormal sugar chain signals in diagnosing malignancies. Clinically, we have found that TAP detection can well predict some malignancies, but several physicians have not paid attention, and related studies have been minimal. Methods: We evaluated TAP's ability to distinguish between malignancies and benign diseases by receiver operating characteristic (ROC) curve analysis and studied the possibility of monitoring malignancy progression by evaluating TAP levels in follow-up. We used Kaplan-Meier survival curves and Cox proportional hazard regression models to investigate the relationship between TAP and prognosis. Results: TAP levels were higher in whole solid malignancies and every type of solid malignancy than in benign patients. ROC curve analysis showed that TAP levels aid in distinguishing between malignancies and benign diseases. TAP levels decreased in patients with complete remission (CR) after treatment and increased in patients with relapse from CR. Patients with metastases had higher TAP levels than non-CR patients without metastases. There was no difference in overall survival among patients with different TAP levels, and multivariate analysis suggested that TAP was not an independent risk factor for solid malignancies. Conclusion: TAP is an effective screening biomarker for many solid malignancies that can be used to monitor the progression of malignancies but not to prognosticate.

Características de los pacientes con neoplasias hematológicas y con tumores sólidos atendidos por un equipo de soporte paliativo hospitalario / Characteristics of patients with hematological and solid tumors malignancies attended by a hospital palliative care service

Antecedentes y objetivo: El interés por la atención paliativa en pacientes con neoplasias hematológicas está aumentando. Nuestro objetivo es describir las características de pacientes oncológicos valorados por un equipo de soporte paliativo en un hospital terciario y analizar las diferencias entre pacientes hematológicos y con tumores sólidos. Método: Estudio observacional descriptivo longitudinal retrospectivo con una cohorte de pacientes hospitalizados con enfermedad oncológica (hematológica o tumor sólido) valorados por equipo de soporte paliativo hospitalario. Comparamos variables clínicas, asistenciales y de supervivencia. El análisis de datos se realizó con la versión 15 del programa SPSS. Resultados: De enero de 2015 a diciembre de 2018 se valoraron 1025 pacientes oncológicos (10,8 % hematológicos, 89,2 % sólidos). No se encontraron diferencias en situación funcional medida por la Palliative Performance Scale, presentación de síntoma principal, porcentaje de pacientes con dolor, tiempo de seguimiento ni en porcentaje de fallecidos en el ingreso en que fueron valorados. El paciente hematológico, comparado con el oncológico, tiene menos tratamiento opioide pautado (43 vs. 53 %; p = 0,035), es seguido con más frecuencia por recurso paliativo hospitalario que domiciliario (46,55 vs. 29,44 % el primero; 15,5 vs. 33,06 % el segundo; p = 0,001 en distribución) y fallece más en hospital (82,9 vs. 65,5 %; p = 0,024). Conclusiones: Los pacientes con neoplasia hematológica presentan una carga sintomática similar a los pacientes con tumor sólido. Es importante identificar mejor sus necesidades para que puedan beneficiarse, como se ha demostrado con los pacientes oncológicos, de la atención integrada junto a los servicios de hematología con modelos de intervención acordes a sus necesidades y las trayectorias específicas de las enfermedades hematológicas. (AU)

Background and objective: Interest in palliative care for patients with hematologic malignancies is increasing. Our goal is to describe the features of cancer patients evaluated by a supportive and palliative care service in a tertiary referral hospital, and to analyze the differences between patients with hematological malignancies and solid tumors. Method: A retrospective longitudinal descriptive observational study was carried out in a cohort of hospitalized patients with oncological diseases (hematological or solid tumor) evaluated by a palliative care service. We compared clinical, healthcare and survival variables between both groups. The analysis was performed using the SPSS v.15 package. Results: From January 2015 to December 2018, 1025 cancer patients were evaluated (10.8 % hematological tumor, 89.2 % solid tumors). No differences were found in functional status as measured by the Palliative Performance Scale, presentation of main symptom, percentage of patients with pain, time of follow-up, or percentage of deaths on admission to the evaluation. The hematological patient, compared to the oncological one, has less prescribed opioid treatment (43 % vs 53 %, p = 0.035), received greater hospital palliative care rather than home-based care (46.55 % vs 29.44 % the former and 15.5 % vs 33.06 % the latter, p = 0.001), and dies more frequently in a hospital (82.9 % vs. 65.5 %, p = 0.024). Conclusions: Patients with hematological malignancies present a symptomatic burden similar to that of those with solid tumors. It is important to better identify their needs so that they can benefit, as has been demonstrated with cancer patients, from integrated care together with hematology services using intervention models according to their needs and specific disease trajectories. (AU)

Safety, tolerability, pharmacokinetics, and antitumour activity of oleclumab in Japanese patients with advanced solid malignancies: a phase I, open-label study.

BACKGROUND: Cluster of differentiation (CD) 73-targeted immunotherapy and CD73 inhibition may reduce adenosine production, which can augment the host and/or immunotherapy response to tumours. We aimed to assess the safety and tolerability, pharmacokinetics, and antitumour activity of oleclumab, an anti-CD73 monoclonal antibody, in adult Japanese patients with advanced solid malignancies resistant to standard therapy. METHODS: In this phase I, single-centre, open-label study, patients received oleclumab 1500 mg (Cohort 1) or 3000 mg (Cohort 2) intravenously every 2 weeks. RESULTS: In total, six patients were enrolled in the study (three in each cohort), and all six patients received the study treatment. The median patient age was 56.0 years and 4/6 were males. All patients (100%) reported adverse events (AEs) during the study; five (83.3%) patients reported AEs related to the study treatment. One (16.7%) patient reported a Grade 3 AE (neutrophil count decreased) that was not related to the study treatment. No AEs with an outcome of death were reported, and no patients reported AEs or serious AEs leading to oleclumab discontinuation/dose interruption. No dose-limiting toxicities were reported, and no patient discontinued due to an AE related to the study treatment. Oleclumab exposure increased dose proportionally. No patient achieved disease control at 8 weeks, and all six patients developed progressive disease. CONCLUSIONS: Oleclumab was well tolerated in adult Japanese patients with advanced solid malignancies and no unexpected safety concerns were raised; oleclumab exposure increased with dose. Future studies on combination therapy with other agents are warranted.

Bispecific Antibodies: A Novel Approach for the Treatment of Solid Tumors.

Advancement in sequencing technologies allows for the identification of molecular pathways involved in tumor progression and treatment resistance. Implementation of novel agents targeting these pathways, defined as targeted therapy, significantly improves the prognosis of cancer patients. Targeted therapy also includes the use of monoclonal antibodies (mAbs). These drugs recognize specific oncogenic proteins expressed in cancer cells. However, as with many other types of targeting agents, mAb-based therapy usually fails in the long-term control of cancer progression due to the development of resistance. In many cases, resistance is caused by the activation of alternative pathways involved in cancer progression and the development of immune evasion mechanisms. To overcome this off-target resistance, bispecific antibodies (bsAbs) were developed to simultaneously target differential oncogenic pathway components, tumor-associated antigens (TAA) and immune regulatory molecules. As a result, in the last few years, several bsAbs have been tested or are being tested in cancer patients. A few of them are currently approved for the treatment of some hematologic malignancies but no bsAbs are approved in solid tumors. In this review, we will provide an overview of the state-of-the-art of bsAbs for the treatment of solid malignancies outlining their classification, design, main technologies utilized for production, mechanisms of action, updated clinical evidence and potential limitations.

Pneumocystis jirovecii Pneumonia in Patients with Solid Malignancies: A Retrospective Study in Two Hospitals.

Pneumocystis jirovecii pneumonia (PJP) is a rare opportunistic infection in patients with solid malignancies. This study aimed to examine the characteristics of patients with solid cancers and PJP. We retrospectively reviewed the medical records of patients with solid tumors and PJP over an 11-year period, enrolling a total of 47 patients (30-day survival group: n = 20, 30-day mortality group: n = 27). Only 34% of patients received ≥20 mg of prednisolone for ≥2 weeks, and the 30-day mortality rate was 57.4%. The 30-day survival group included more women and patients with colon cancer than the mortality group. Furthermore, absolute lymphocyte counts (ALCs) were decreased at PJP symptom onset, as compared with the values observed 1-3 months earlier. Increased oxygen demand and low ALCs after 5-7 days of PJP treatment were also related to poor prognosis. Due to the limitations of this retrospective study, further studies that adhere to the PJP criteria of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium will be needed to evaluate PJP in solid malignancies more clearly.

Serum parameters as prognostic biomarkers in a real world cancer patient population treated with anti PD-1/PD-L1 therapy.

BACKGROUND: Immune checkpoint inhibitors (ICI) are regarded as a standard of care in multiple malignancies. We hypothesized that serum parameters are of prognostic value in ICI treated patients suffering from solid tumours. METHODS: Data from 114 patients treated with ICIs for solid malignancies from 2015 to 2019 at the Medical University of Vienna were collected retrospectively. Data included baseline characteristics, cancer type, serum parameters such as lactate dehydrogenase (LDH), C-reactive protein (CRP), albumin (Alb) and lymphocyte counts as well as overall survival (OS) and progression free survival. Additionally, the Gustave Roussy Immune Score (GRIm score) and the Glasgow prognostic score (GPS) were calculated. Cox regression models including time-dependent effects and strata for tumour type were used. Prognostic factors were pre-selected using a relaxed LASSO approach. RESULTS: The majority of patients were male (64.9%). The most common cancer types were non-small cell lung cancer (30.7%) and renal cell carcinoma (21.9%). Increased LDH and CRP were associated with poor 6-month OS (Hazard ratios (HR)=1.16 and 1.06 per 20% LDH/CRP increase; 95% CI 1.07-1.26 and 95% CI 1.03-1.09, respectively; p < .001). Both GRIm Score and GPS had a significant influence on OS (GRIm: HR = 2.84, 95% CI 1.72-4.69; p < .001 for high vs. low; GPS HR 3.57, 95% CI 1.76-7.25; p < .001 for poor vs. good). The proportion of explained variation (PEV) of our full multivariable model was significantly higher compared to the GRIm and GPS (PEV = 29.5% vs. 14.8% and 14.65%). When grouped into quartiles according to the individual 8-weeks change, both increased LDH and CRP correlated with poor OS (LDH (p=.001) and CRP (p < .001)). CONCLUSION: The results of this analysis suggest that serum parameters might have prognostic value for the outcome of cancer patients treated with ICI, regardless of the tumour type.Key messagesIn this retrospective analysis, 114 patients with solid tumours were included. The results of this analysis point out that pre-treatment LDH, CRP and albumin levels are strongly prognostic for a poor 6-month OS.In addition to that, a high GRIm-score and poor GPS were associated with a worse OS (GRIm: HR = 2.84, 95% CI 1.72-4.69; p < .001 for high vs. low; GPS HR = 3.57, 95% CI 1.76-7.25; p < .001 for poor vs. good).Pre-treatment serum parameters might have prognostic value for the outcome of cancer patients treated with ICI, regardless of the tumour type.

Treatment Outcomes and Its Associated Factors Among Adult Patients with Selected Solid Malignancies at Kenyatta National Hospital: A Hospital-Based Prospective Cohort Study.

Introduction: The treatment outcome of cancer is poor in the African setting due to inadequate treatment and diagnostic facilities. However, there is a paucity of data on solid cancers in Kenya. Hence, this study aimed to investigate the treatment outcomes and its determinant factors among adult patients diagnosed with selected solid malignancies at Kenyatta National Hospital (KNH). Materials and Methods: A prospective cohort study was employed at the Oncology Department of KNH from 1st July 2020 to 31st December 2021. All new patients with a confirmed diagnosis of lymphoma, prostate cancer and breast cancer were studied. A consecutive sample of 99 breast cancer, 50 lymphomas, and 82 prostate cancer patients was included in the study. Semi-structured questionnaires consisting of socio-demographics, clinical characteristics, and quality of life were employed to collect the data. All enrolled patients were followed prospectively for 12 months. Treatment outcomes were reported as mortality, cancer-specific survival and health-related quality of life. The data were entered and analyzed using the SPSS 20.0 statistical software. Survival outcomes and its predictors were evaluated using the Kaplan-Meier analysis and Cox regression analyses, respectively. Results: The study showed that the mortality rate among breast and prostate cancer patients was 3% and 4.9%, respectively. In contrast, the mortality rate was 10% among lymphoma patients. Most of the patients had partial remission and a good overall global health-related quality of life. Older age above 60 years, co-morbidity, distant metastasis and advanced stages of disease were significant predictors of mortality. Conclusion: Although the mortality was not high at 12 months, only a few patients had complete remission. For many patients, the disease was progressing, despite 12-month mortality was not high. Therefore, longer follow-up will be required to report cancer mortality accurately. In addition, most of the patients had a good overall global health-related quality of life.

Efficacy of Core Needle Biopsy in the Diagnosis of Pediatric Extracranial Solid Malignancies: A 10-Year Study.

Introduction: Core needle biopsies of solid masses in children are a minimally invasive technique. It guides to a definitive diagnosis and facilitates management. Aims and Objectives: To determine the accuracy, sensitivity, and specificity of core needle biopsies in diagnosing pediatric solid masses. Materials and Methods: A retrospective analysis of 430 children, who underwent core needle biopsy for solid masses between January 2007 and December 2016 at CMC Vellore, was done. Results: Retroperitoneal and intra-abdominal masses constituted 66% of cases. Real-time image guidance was used in 44% of cases. An accurate diagnosis was obtained in 93.6% of cases, while results did not correlate with the final diagnosis in 3.4%. Three percent had inadequate or necrotic tissue. None of the children had postprocedure complications. Conclusion: Core needle biopsies serve as good diagnostic modality, with minimal risks, in making a conclusive diagnosis and deciding on the line of management.

COVID-19 in cancer patients.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, has currently affected >220 million individuals worldwide. The complex interplay of immune dysfunction, active malignancy, the effect of cancer treatment on the immune system and additional comorbidities associated with cancer and COVID-19 all affect the outcomes of COVID-19 in patients with cancer. We have discussed the published findings (through the end of September 2021) on the effects of cancer on the morbidity and mortality of COVID-19, common factors between cancer and COVID-19, the interaction of cancer and COVID-19 treatments, the impact of COVID-19 on cancer clinical services, immune test findings in cancer patients with COVID-19 and the long-term effects of COVID-19 on cancer survivors.

COVID-19 vaccination in cancer patients: a narrative review.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected over 220 million individuals worldwide, and has been shown to cause increased disease severity and mortality in patients with active cancer versus healthy individuals. Vaccination is important in reducing COVID-19-associated morbidity and mortality. Thus, the aim of this article was to review the existing knowledge on effectiveness, immunogenicity and safety of COVID-19 vaccines in patients with cancer. Fifty-four articles were included following a search of PubMed and Google Scholar databases for studies published between January 2020 and September 2021 that investigated humoral and cell-mediated immune responses following COVID-19 vaccination in patients with cancer. Immunogenicity of vaccines was found to be lower in patients with cancer versus healthy individuals, and humoral immune responses were inferior in those with haematological versus solid cancers. Patient-, disease-, and treatment-related factors associated with poorer vaccine responses should be identified and corrected or mitigated when possible. Consideration should be given to offering patients with cancer second doses of COVID vaccine at shorter intervals than in healthy individuals. Patients with cancer warrant a third vaccine dose and must be prioritized in vaccination schedules. Vaccine adverse effect profiles are comparable between patients with cancer and healthy individuals.

Is pyoderma gangrenosum associated with solid malignancies? Insights from a population-based cohort study.

BACKGROUND: The question of whether solid malignancies (SMs) are associated with pyoderma gangrenosum (PG) remains to be conclusively answered. OBJECTIVE: To evaluate the risk of SM among patients with PG and the odds of PG after a diagnosis of SM. METHODS: A population-based retrospective cohort study was conducted to study the risk for SM in patients with PG (n = 302) as compared with age-, sex- and ethnicity-matched control subjects (n = 1799). A case-control design was used to estimate the odds of PG in those with a preexisting history of SM. RESULTS: The prevalence of a preexisting SM was comparable in patients with PG and controls (7.5% vs. 8.8%, respectively; P = 0.490). The odds of having PG following a diagnosis of a SM was not statistically increased (OR, 0.85; 95% CI, 0.53-1.36). The incidence of SM was 6.8 (95% CI, 3.5-12.2) and 7.9 (95% CI, 6.1-10.1) per 1000 person-years among patients with PG and controls, respectively. Patients with PG were not more likely to develop SM as compared to controls (HR, 0.86; 95% CI, 0.44-1.69). Patients with a dual diagnosis of PG and SM were older and had more frequent comorbid conditions and increased mortality. CONCLUSIONS: SM is not associated with provoking PG, and patients with PG are not at an increased risk of developing SM. A thorough routine screening for SM in patients with new-onset PG is an unnecessary approach based on the study findings.

Design and synthesis of novel Flavone-based histone deacetylase inhibitors antagonizing activation of STAT3 in breast cancer.

Histone deacetylases (HDACs) inhibitors have demonstrated a great clinical achievement in hematological malignancies. However, the efficacy of HDACs inhibitors in treating solid tumors remains limited due to the complicated tumor microenvironment. In this study, we designed and synthesized a class of novel HDACs inhibitors based on the structure of flavones and isoflavones, followed by biological evaluation. To be specific, a lead compound 15a was discovered with strong anti-proliferative effects on a variety of solid tumor cells, especially for breast cancer cells with resistance to SAHA. Studies demonstrated that 15a could significantly inhibit the activity of HDAC 1, 2, 3 (class I) and 6 (class IIB), leading to a dose-dependent accumulation of acetylated histones and α-Tubulin, cell cycle arrest (G1/S phase) and apoptosis in breast cancer cells. Furthermore, the lead compound 15a could also antagonize the activation of STAT3 induced by HDACs inhibition in some breast cancer cells, which further reduced the level of pro-survive proteins in tumor cells and enhanced anti-tumor activity regulated by STAT3 signaling in vivo. Overall, our findings demonstrated that the novel compound 15a might be a HDACs inhibitor candidate, which could be used as promising chemotherapeutic agent for breast cancer.

Programming CAR T cells to enhance anti-tumor efficacy through remodeling of the immune system.

Chimeric antigen receptor (CAR) T cells have been indicated effective in treating B cell acute lymphoblastic leukemia and non-Hodgkin lymphoma and have shown encouraging results in preclinical and clinical studies. However, CAR T cells have achieved minimal success against solid malignancies because of the additional obstacles of their insufficient migration into tumors and poor amplification and persistence, in addition to antigen-negative relapse and an immunosuppressive microenvironment. Various preclinical studies are exploring strategies to overcome the above challenges. Mobilization of endogenous immune cells is also necessary for CAR T cells to obtain their optimal therapeutic effect given the importance of the innate immune responses in the elimination of malignant tumors. In this review, we focus on the recent advances in the engineering of CAR T cell therapies to restore the immune response in solid malignancies, especially with CAR T cells acting as cellular carriers to deliver immunomodulators to tumors to mobilize the endogenous immune response. We also explored the sensitizing effects of conventional treatment approaches, such as chemotherapy and radiotherapy, on CAR T cell therapy. Finally, we discuss the combination of CAR T cells with biomaterials or oncolytic viruses to enhance the anti-tumor outcomes of CAR T cell therapies in solid tumors.

Systematic review about etiologic association to the leukoerythroblastic reaction.

BACKGROUND AND PURPOSE: Leukoerythroblastic reaction (LER) is characterized by the presence of immature erythroid cells and myeloid precursors (metamyelocytes, myelocytes, promyelocytes, myeloblasts, and blasts) as well as, exclusively in myelofibrotic disorders, teardrop cells in the peripheral blood (J Pathol Bacteriol, 42, 1936, 541; Semaine Med, 22, 1902, 373). Research on how to interpret LER and its meaning in clinical practice is scarce, and there is no consensus on the diagnostic criteria. We summarize the current evidence with the aim of clarifying the knowledge on this subject. METHODS: We conducted a comprehensive search of the PubMed-MEDLINE, EMBASE and ELSEVIER databases, the Cochrane Library, Google Scholar, and medical journals to identify relevant papers. RESULTS: Our search identified 425 papers, of which, 35 (11 trials and 24 case reports) ultimately met the inclusion criteria. These showed two principal groups of diseases associated with leukoerythroblastosis (LEB), corresponding to solid and hematological malignancies. The other etiologies, in order of frequency, were hemolytic diseases, infection, and others, while hemorrhage was only reported in the trials group. CONCLUSION: The literature on LER is scarce and heterogeneous. The etiological factors of LER are diverse, and its presence in malignant disease is an indicator of disease progression and an adverse prognosis suggesting poor survival. In those cases where LER had neither hematological nor solid neoplasms, its manifestation, prognosis and its impact on our daily clinical practice are unknown.