B cell and B cell-related pathways for novel cancer treatments

B cells are recognized as the main effector cells of humoral immunity which suppress tumor progression by secreting immunoglobulins, promoting T cell response, and killing cancer cells directly. Given these properties, their anti-tumor immune response in the tumor micro-environment (TME) is of great interest. Although T cell-related immune responses have become a therapeutic target with the introduction of immune checkpoint inhibitors, not all patients benefit from these treatments. B cell and B cell-related pathways (CCL19, −21/CCR7 axis and CXCL13/CXCR5 axis) play key roles in activating immune response through humoral immunity and local immune activation via tertiary lymphoid structure (TLS) formation. However they have some protumorigenic works in the TME. Thus, a better understanding of B cell and B cell-related pathways is necessary to develop effective cancer control. In this review, we summarize recent evidences regarding the roles of B cell and B cell-related pathways in the TME and immune response and discuss their potential roles for novel cancer treatment strategies.     

An open‐label phase I/II study of cyclophosphamide,bortezomib, pegylated liposomal doxorubicin,and dexamethasone in newly diagnosed myeloma

We conducted a phase 1/2 trial evaluating the combination of cyclophosphamide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone (CVDD) for newly diagnosed multiple myeloma (MM). The primary objective of the phase 1 was to evaluate the safety and tolerability of maximum planned dose (MPD) and the phase 2 was to assess the overall response rate. Patients received 6–8 cycles of CVDD at four dose levels. There were no dose‐limiting toxicities. The MPD was cyclophosphamide 750 mg/m² IV on day 1, bortezomib 1.3 mg/m² IV on days 1, 4, 8, 11, pegylated liposomal doxorubicin 30 mg/m² IV on day 4, and dexamethasone 20 mg orally on the day of and after bortezomib (21‐d cycle). Forty‐nine patients were treated at the MPD of which 22% had high‐risk myeloma. The most common grade ≥3 toxicities included myelosuppression, infection, and fatigue. Overall response and complete response rates were 91% and 26% in standard‐risk, and 100% and 58% in high‐risk cohort, respectively. After a median follow‐up of 34 months, the median progression‐free survival was 31.3 months. The 2‐yr overall survival was 91.1% in the standard‐risk and 88.9% in the high‐risk cohort, respectively. CVDD regimen was well tolerated and was highly active in newly diagnosed MM.     

Clinical outcome of adjuvant radiotherapy for squamous cell carcinoma of the breast; a multicenter retrospective cohort study

BackgroundBecause primary squamous cell carcinoma (SCC) of the breast is a rare disease, the standard therapy has not been established. We examined the clinical outcomes of postoperative adjuvant radiotherapy for breast SCC.Material and methodsWe conducted a multicenter retrospective cohort study. Patients diagnosed with primary breast SCC who received adjuvant radiotherapy as part of their primary definitive treatment were included. Overall survival (OS), breast cancer-specific survival (BCSS), and recurrence-free interval (RFi) were evaluated.ResultsBetween January 2002 and December 2017, 25 breast SCC patients received adjuvant radiotherapy as a primary treatment were included. Median follow-up time was 43.5 months. Three (12%), fifteen (60%) and seven (28%) patients had clinical stage I, II and III disease, respectively. Fourteen patients underwent breast-conserving surgery and subsequent adjuvant radiotherapy. Eleven patients underwent mastectomy and post-mastectomy radiotherapy. Ten patients received regional lymph node irradiation. Nine (36%) patients had disease recurrence. The first site of recurrence was locoregional in five, but distant metastasis arose in one. Concurrent local and distant metastasis were seen in two. Six cases of local recurrence occurred within the irradiated site. Seven patients died, and six of the deaths were due to breast cancer. Five-year OS, BCSS, and Rfi were 69%, 70%, and 63%, respectively. In multivariate analysis, age and lymphatic invasion were associated with increased risk of recurrence.ConclusionBreast SCC has a high incidence of locoregional recurrence and poor prognosis. Age and lymphatic invasion are significant risk factors for recurrence.     

Assessment of the cytotoxicity and genotoxicity properties of Uvaria chamae P. Beauv (Annonaceae) and Morinda lucida Benth (Rubiaceae) in mice

The toxicity profile of medicinal plants is an important preclinical requirement in the development of phytomedicines. The cytotoxic and genotoxic effects of the leaf of Uvaria chamae P. Beauv (Annonaceae) and stem bark of Morinda lucida Benth (Rubiaceae) were investigated in order to provide information on their safety as antimalarial plants. The methanol extract of U. chamae and ethanol (70%) extract of M. lucida were separately orally administered (125, 250, and 750?mg/kg/day) to mice for 10 consecutive days. Cyclophosphamide (50?mg/kg, single dose) and distilled water were used as positive and negative controls, respectively. The mice were injected with colchicine (0.04%) intra-peritoneally 24?h after the last administration of the extracts and the bone marrows harvested. Giemsa-stained slides of bone marrow cells were microscopically assessed for dividing cells to determine the mitotic index (MI) and scored for chromosomal aberrations (CA) according to standard methods. chamae exhibited dose-dependent cytotoxicity. At 750?mg/kg, the MI was significantly (p?cyclophosphamide (5.83?±?0.04). The lower the MI, the higher the cytotoxicity. The activity of M. lucida was not significantly different (p?>?0.05) from that of the negative control. The total CA observed from treatment with both plants at all doses were significantly (p?U. chamae showed both cytotoxicity and genotoxicity while M. lucida exerted only genotoxic effect. Nevertheless, the two plants should be used with caution in antimalarial therapy.     

Establishment and assessment of a novel in vitro bio-PK/PD system in predicting the in vivo pharmacokinetics and pharmacodynamics of cyclophosphamide

1.?A novel bio-pharmacokinetic/pharmacodynamic (PK/PD) system was established and assessed in predicting the PK parameters and PD effects of the model drug cyclophosphamide (CP) considering the interrelationships between drug metabolism, pharmacological effects and dynamic blood circulation processes in vitro.

2.?The system contains a peristaltic pump, a reaction chamber with rat liver microsomes (RLMs) encapsulated in pluronic F127–acrylamide–bisacrylamide (FAB) hydrogels, an effector cell chamber and a recirculating pipeline. The metabolism and pharmacological effects of CP (5, 10 and 20?mM) were measured by HPLC and MTT assay. A mathematical model based on mass balance was used to predict the in vitro clearance of CP. In vivo clearance of CP was estimated by in vitro to in vivo extrapolations (IVIVE) and simulations using Simcyp® software.

3.?The predicted in vivo clearance of CP at concentrations of 5, 10 and 20?mM was 11.36, 10.12 and 10.68?mL/min/kg, respectively, within two-fold differences compared with the reported 11.1?mL/min/kg. The survival ratio of effector cells during the metabolism and circulation of CP was significantly enhanced.

4.?This system may serve as an alternative approach to predict in vivo metabolism, pharmacological effects and toxicity of drugs, ensuring an efficient drug screening process.     

环磷酰胺导致的系统性红斑狼疮女性患者卵巢功能受损及闭经情况的分析

目的 分析环磷酰胺(CTX)导致系统性红斑狼疮(SLE)女性患者卵巢功能受损及闭经情况.方法 取2013年10月-2015年10月在该院治疗的SLE女性患者98例,均接受CTX治疗,观察患者卵巢功能受损及闭经发生的情况.结果 98例患者中有51.02%出现卵巢功能受损,出现闭经者18.37%;患者治疗后雌二醇(E2)为(19.33 ±1.54)ng· L-1,明显较治疗前降低(P<0.05);患者治疗后血清促卵泡刺激素(FSH)、补体C3和补体C4分别为(21.50 ±2.41)IU· L-1、(0.60 ±0.15)g· L-1和(0.16 ±0.10)g· L-1,明显高于治疗前(P<0.05);>30~40岁组和>20~30岁组卵巢功能受损发生率分别为72.22%和52.38%,明显高于15~20岁组(P<0.05);>30~40岁组闭经发生率为38.89%,明显高于>20~30岁组和15~20岁组(P<0.05);>30~40岁组出现卵巢功能受损和闭经时CTX累积剂量分别为(14.30 ±0.83)g和(20.34 ±1.43)g,明显低于>20~30组(P<0.05).结论 CTX治疗SLE对卵巢功能有一定的损害作用,卵巢功能受损发生与患者年龄有一定关系,年龄大的患者出现卵巢功能受损时CTX累积剂量较低.     

Successful Outcome in Patients with Fanconi Anemia Undergoing T Cell-Replete Mismatched Related Donor Hematopoietic Cell Transplantation Using Reduced-Dose Cyclophosphamide Post-Transplantation

Allogeneic hematopoietic cell transplantation (HCT) has been shown to restore normal hematopoiesis in patients with Fanconi anemia (FA), with excellent results in matched related donor HCT. Outcomes of alternative donor HCT are less favorable, however. In patients without FA, several reports have documented stable engraftment and/or a low risk of graft-versus-host disease (GVHD) using unmanipulated HLA-mismatched related donors and post-HCT cyclophosphamide (PT-CY) for GVHD prophylaxis. Data on the use of this approach in patients with FA are scarce, and thus we launched a study of HLA-mismatched related donor HCT in these patient. Here we report our findings in 19 patients. The conditioning was fludarabine 30 mg/m²/day for 5 days, antithymocyte globulin 5 mg/kg/day for 4 days, and total body irradiation (total dose, 200 cGy). GVHD prophylaxis was cyclosporine and mycophenolate and reduced doses of PT-CY, 25 mg/kg, on days +3 and +5. All patients exhibited absolute neutrophil count recovery. Grade III-IV acute GVHD occurred in 3 patients, and chronic GVHD occurred in 1 patient. At a mean follow-up of 38.3 ± 5.8 months, the 5-year probability of overall survival for our patients was 89.2% ± 7.2%. The regimen was well tolerated; hemorrhagic cystitis occurred in 7 patients, and severe mucositis occurred in 5 patients. There were 2 deaths; the primary cause of death was severe GVHD in 1 patient and leukemia recurrence in the other. We conclude that in patients with FA lacking a matched related donor, the use of mismatched related HCT with low-dose PT-CY is a viable option; it is well tolerated, with a high rate of engraftment and an acceptable incidence of GVHD.     

Fludarabine and Total-Body Irradiation Conditioning before Ablative Haploidentical Transplantation: Long-Term Safety and Efficacy

Although myeloablative conditioning (MAC) before haploidentical donor transplant (HIDT) with post-transplant cyclophosphamide is being increasingly used, the optimal preparative regimen remains unclear. In our initial trial, the feasibility of HIDT following a MAC preparative regimen using fludarabine and 12 Gy of total-body irradiation was demonstrated in 30 patients. We now present long-term outcome results, including an additional 52 patients, now with 47 months (16 to 96) median follow-up. Median patient age was 42 (19 to 61) years. The most common diagnoses were acute myelogenous leukemia (51%) and acute lymphoblastic leukemia (33%), and 39% had a high/very high disease risk index (DRI). Engraftment was universal with no cases of primary or secondary graft failure. Grade 3 to 4 acute graft-versus-host disease (GVHD) and moderate to severe chronic GVHD occurred in 17% and 23%, respectively. Nonrelapse mortality (NRM) was 7% at 1 year and 13% at 4 years. Estimated 4-year overall survival (OS), disease-free survival, and cumulative incidence of relapse (CIR) were 67%, 60%, and 27%, respectively. CIR was significantly higher in patients with high/very high- versus low/intermediate-risk DRI (38% versus 20%, P= .032), which led to inferior 4-year OS (50% versus 77%, P = .001). Median time to systemic immunosuppressive therapy (IST) discontinuation was 7.8 months, with 84% of patients off IST at 2 years post-transplant. Current GHVD-free, relapse-free survival (CGRFS) at 2, 3, and 4 years was 60%, 57%, and 60%, respectively. This approach to MAC HIDT results in universal engraftment; low rates of NRM, infection, and clinically significant GVHD; and relatively rapid IST discontinuation, resulting in high rates of CGRFS and survival.