Inorganic Nanozyme with Combined Self-Oxygenation/Degradable Capabilities for Sensitized Cancer Immunochemotherapy

Recently emerged cancer immunochemotherapy has provided enormous new possibilities to replace traditional chemotherapy in fighting tumor.However,the treatment efficacy is hampered by tumor hypoxiainduced immunosuppression in tumor microenvironment(TME).Herein,we fabricated a self-oxygenation/degradable inorganic nanozyme with a core-shell structure to relieve tumor hypoxia in cancer immunochemotherapy.By integrating the biocompatible CaO2 as the oxygen-storing component,this strategy is more effective than the earlier designed nanocarriers for delivering oxygen or H2O2,and thus provides remarkable oxygenation and long-term capability in relieving hypoxia throughout the tumor tissue.Consequently,in vivo tests validate that the delivery system can successfully relieve hypoxia and reverse the immunosuppressive TME to favor antitumor immune responses,leading to enhanced chemoimmunotherapy with cytotoxic T lymphocyte-associated antigen 4 blockade.Overall,a facile,robust and effective strategy is proposed to improve tumor oxygenation by using self-decomposable and biocompatible inorganic nanozyme reactor,which will not only provide an innovative pathway to relieve intratumoral hypoxia,but also present potential applications in other oxygen-favored cancer therapies or oxygen deficiency-originated diseases.

HCV infection, B-cell non-Hodgkin's lymphoma and immunochemotherapy: Evidence and open questions

There is plenty of data confirming that hepatitis C virus (HCV) infection is a predisposing factor for a B-cell non-Hodgkin's lymphoma (B-NHL) outbreak, while relatively few reports have addressed the role of HCV in affecting B-NHL patients' outcome. HCV infection may influence the short-term outcome of B-NHL because of the emergence of severe hepatic toxicity (HT) during immunochemotherapy. Furthermore, the long term outcome of HCV-related liver disease and patients' quality of life will possibly be affected by Rituximab maintenance, multiple-lines of toxicity during chemotherapy and hematopoietic stem cell transplantation. In this review, data dealing with aggressive and low-grade B-NHL were separately analyzed. The few retrospective papers reporting on aggressive B-NHL patients showed that HCV infection is a risk factor for the outbreak of severe HT during treatment. This adverse event not infrequently leads to the reduction of treatment density and intensity. Existing papers report that low-grade B-NHL patients with HCV infection may have a more widespread disease, more frequent relapses or a lower ORR compared to HCV-negative patients. Notwithstanding, there is no statistical evidence that the prognosis of HCV-positive patients is inferior to that of HCV-negative subjects. HCV-positive prospective studies and longer follow-up are necessary to ascertain if HCV-positive B-NHL patients have inferior outcomes and if there are long term sequels of immunochemotherapies on the progression of liver disease.

Primary gastric non-Hodgkin lymphomas:Recent advances regarding disease pathogenesis and treatment

Primary gastric lymphomas(PGLs)are distinct lymphoproliferative neoplasms described as heterogeneous entities clinically and molecularly.Their main histological types are diffuse large B-cell lymphoma(DLBCL)or mucosaassociated lymphoma tissue.PGL has been one of the main fields of clinical research of our group in recent years.Although gastric DLBCLs are frequent,sufficient data to guide optimal care are scarce.Until today,a multidisciplinary approach has been applied,including chemotherapy,surgery,radiotherapy or a combination of these treatments.In this minireview article,we provide an overview of the clinical manifestations,diagnosis and staging of these diseases,along with their molecular pathogenesis and the most important related clinical published series.We then discuss the scientific gaps,perils and pitfalls that exist regarding the aforementioned studies,in parallel with the unmet need for future research and comment on the proper methodology for such retrospective studies.Aiming to fill this gap,we retrospectively evaluated the trends in clinical presentation,management and outcome among 165 patients with DLBCL PGL who were seen in our institutions in 1980-2014.The study cohort was divided into two subgroups,comparing the main 2 therapeutic options[cyclophosphamide doxorubicin vincristine prednisone(CHOP)vs rituximab-CHOP(R-CHOP)].A better outcome with immunochemotherapy(R-CHOP)was observed.In the next 2 mo,we will present the update of our study with the same basic conclusion.

Clinical features and treatment outcomes of primary ocular adnexal mucosa-associated lymphoid tissue lymphoma: a single center retrospective analysis of 64 patients in China

AIM: To investigate the clinical features, treatment and prognosis of primary ocular adnexal mucosa-associated lymphoid tissue lymphoma(POAML).METHODS: A retrospective analysis was performed on 64 patients with POAML who were admitted to the First Affiliated Hospital of Zhengzhou University from January 2006 to December 2018.RESULTS: With a median follow-up of 61 mo(range, 2-156 mo), estimated overall survival(OS) rate and progressionfree survival(PFS) rate at 10 y reached 94.5% and 61.5%, respectively. Median OS time and PFS time were not reached. During this period, only 3 patients died, but none of them died directly due to disease progression. One patient(1.6%) developed transformation to diffuse large B-cell lymphoma(DLBCL). Of the 56 patients achieved complete remission after first-line treatment, 5(8.9%) developed local and/or systemic relapse eventually. Patients ≥60 y had significantly shorter PFS than younger patients(P=0.01). For patients with early stages(Ann Arbor stage I and stage II), univariate analysis confirmed that radiotherapydose lower than 32 Gy were independently associated with shorter PFS(P=0.04). Other factors including gender, bone marrow involvement, the initial location of the disease, and the laterality were not associated with PFS.CONCLUSION: The data from our center indicate that POAML has a slow clinical progression and has an excellent clinical outcome. Patients with POAML harbor a continual risk of relaps and transformation to aggressive subtype of lymphoma.

Hemophagocytic lymphohistiocytosis: Recent progress in the pathogenesis, diagnosis and treatment

Hemophagocytic lymphohistiocytosis(HLH) is a hyperinflammatory syndrome that develops as a primary(familial/hereditary) or secondary(non-familial/hereditary) disease characterized in the majority of the cases by hereditary or acquired impaired cytotoxic T-cell(CTL) and natural killer responses. The molecular mechanisms underlying impaired immune homeostasis have been clarified, particularly for primary diseases. Familial HLH(familial hemophagocytic lymphohistiocytosis type 2-5, Chediak-Higashi syndrome, Griscelli syndrome type 2, Hermansky-Pudlak syndrome type 2) develops due to a defect in lytic granule exocytosis, impairment of(signaling lymphocytic activation molecule)-associated protein, which plays a key role in CTL activity [e.g., X-linked lymphoproliferative syndrome(XLP) 1], or impairment of X-linked inhibitor of apoptosis, a potent regulator of lymphocyte homeostasis(e.g., XLP2). The development of primary HLH is often triggered by infections, but not in all. Secondary HLH develops in association with infection, autoimmune diseases/rheumatological conditions and malignancy. The molecular mechanisms involved in secondary HLH cases remain unknown and the pathophysiology is not the same as primary HLH. For either primary or secondary HLH cases, immunosuppressive therapy should be given to control the hypercytokinemia with steroids, cyclosporine A, or intravenous immune globulin, and if primary HLH is diagnosed, immunochemotherapy with a regimen containing etoposide or anti-thymocyte globulin should be started. Thereafter, allogeneic hematopoietic stem-cell transplantation is recommended for primary HLH or secondary refractory disease(especially EBVHLH).

Use of entecavir in hepatitis B virus reactivation of a patient with non-Hodgkin's lymphoma

We read with interest the case report by Liu et al and the correspondence by Tuna et al regarding this case. Liu et al described hepatitis B virus(HBV) reactivation in a patient with non-Hodgkin's lymphomaafter withdrawal of lamivudine prophylaxis. When HBV reactivation was observed three months after lamivudine withdrawal, entecavir 0.5 mg daily was started. HBV DNA level was moderately elevated(104 copies/m L) at that time. So, we could not understand why a potent antiviral like entecavir was required for this case. In addition to this, entecavir must be used at a dose of 1 mg in patients with prior prophylactic treatment with lamivudine. As stated by Tuna et al duration of lamivudine prophylaxis in this case might be insufficient and HBV reactivation might have occured for this reason. So, we suppose that resolution of HBV reactivation might also be achieved with lamivudine instead of entecavir in this case.

Rituximab maintenance in follicular lymphoma patients

Rituximab maintenance(RM)therapy following successful induction has recently emerged as a highly effective treatment for follicular lymphoma(FL).Randomized trials analyzing the impact of RM compared to observation alone have demonstrated a significantly better outcome in terms of progression-free survival(but not overall survival)in patients(pts)who received as first-line treatment single-agent rituximab,standard chemotherapy(CVP)and recently also immunochemotherapy(R-CHOP,R-CVP or R-FND),as shown by preliminary results of the PRIMA trial.Also in the setting of relapsed disease,RM has shown significant benefit either after chemotherapy or immunochemotherapy.RM has been generally well tolerated,and treated pts developed only mild toxicity,mainly a small increased rate of neutropenia,hypogammaglobulinaemia and self-limiting upper-respiratory tract infections.Moreover,no cumulative or unexpected toxicities were observed and quality of life was not affected.These data have established RM therapy as an important part of multi-modal therapeutic strategies in patients affected by FL.

Primary adrenal diffuse large B-cell lymphoma with normal adrenal cortex function:A case report

BACKGROUND Diffuse large B-cell lymphoma,which accounts for about approximately 30%to 40%of non-Hodgkin's lymphomas,is the most common type and is a class of aggressive B-cell lymphomas.However,diffuse large B-cell lymphomas primary to the adrenal gland are rare.CASE SUMMARY A 73-year-old man was admitted with abdominal pain and fatigue.After admission,enhanced adrenal computed tomography indicated irregular masses on both adrenal glands,with the larger one on the left side,approximately 8.0 cm×4.3 cm in size.The boundary was irregular,and surrounding tissues were compressed.No obvious enhancement was observed in the arterial phase.Resection of the left adrenal gland was performed.Pathological diagnosis revealed diffuse large B-cell lymphoma.After surgery,the patient received RCHOP immunochemotherapy.During the fourth immunochemotherapy,patient condition deteriorated,and he eventually died of respiratory failure.CONCLUSION R-CHOP is the conventional immunochemotherapy for primary adrenal diffuse large B-cell lymphoma.Surgery is mainly used to diagnose the disease.Hence,the ideal treatment plan remains to be confirmed.

‘Les liaisons dangereuses’: Hepatitis C, Rituximab and B-cell non-Hodgkin’s lymphomas

Rituximab has provided a revolutionary contribution to the treatment of B-cell non-Hodgkin’s lymphomas (NHL). A high prevalence of hepatitis C virus (HCV) infection has been described in B-cell NHL patients. Cases of liver dysfunction in HCV-positive patients have been reported with Rituximab-containing regimens. In this paper we review the recent data regarding the effects of Rituximab in NHL patients with HCV infection. We also added a section devoted to improving communication between oncohaematologists and hepatologists. Furthermore, we propose a common methodological ground to study hepatic toxicity emerging during chemotherapy.

Outcomes in refractory diffuse large B-cell lymphoma:results fromamulticenter real-world study in China

Background:Diffuse large B-cell lymphoma(DLBCL)patients refractory to rituximab-based immunochemotherapy have a dismal prognosis.However,the definition of refractory DLBCL remains inconsistent and no large cohort study data is available from Asian countries.To validate the definition and outcomes of refractory DLBCL in China,we conducted a multicenter,retrospective cohort study.Methods:The REtrospective AnaLysis of Treatment REspoNse of refractory DLBCL(REAL-TREND)study was performed using real-world data from 8 centers in China.DLBCL patients with curative intent were included in the REAL-TREND dataset.Overall survival(OS)was estimated using the Kaplan-Meier method and compared by the log-rank test.Due to heterogeneity in response rates among different centers,the response rates of refractory patients were pooled using random-effect models.Multivariate survival analysis was performed using the Cox regression model.Results:A total of 2778 DLBCL patients diagnosed between January,2010 and December,2015 were enrolled to this study.After validating previous definitions,the SCHOLAR-1 study was most suitable to define refractory DLBCL.The estimated 5-year cumulative incidence of refractory patients was 20%(95% confidence Interval[CI]=18%-22%).After the determination of refractory disease,overall response rate and complete remission rate were 30%(95%CI=22%-38%)and 9%(95%CI=4%-15%),respectively.Patients with either no response to immunochemotherapy or relapse within 12 months after stem-cell transplantation had inferior survival with a median OS of 5.9 months(95%CI=5.5-7.1 months)and 2-year OS rate of 16%(95%CI=12%-20%).International prognostic index score 4-5(hazard ratio[HR]=2.22;95%CI=1.47-3.35),central nervous systemrelapse(HR=1.43;95%CI=1.04-1.97),and best response status(HR=2.68;95%CI=1.42-5.03 for partial remission.HR=5.97,95%CI=3.21-11.11 for stable disease/progressive disease)were independent unfavorable prognostic factors.Conclusions:This is the first large-scale Asian cohort study focusing on outcomes of refractory DLBCL.The definition of the SCHOLAR-1 study identifies patients with homogenously inferior survival,thus is appropriate to select refractory DLBCL.Due to poor clinical outcomes in the rituximab era,patients with refractory DLBCL may be potential candidates for novel treatment modalities.