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Diffuse large B-cell lymphoma (DLBCL) is the most common type of B-cell lymphoma. Although the multilobated subtype of DLBCL has been observed since the 1970s, little is known about the clinical significance of this unique variant in the era of rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone/prednisolone (R-CHOP) therapy. In this study, the retrospective clinicopathological analysis of 312 patients diagnosed with DLBCL showed that the multilobated DLBCL group comprised 11% of the cases and was predominantly male (p = 0.027), achieved complete remission in the first therapy (p = 0.023), and exhibited germinal center B-cell phenotypes in the Hans algorithm (p = 0.025). The multilobated DLBCL groups had a better prognosis in overall survival (OS) and progression-free survival (PFS) than the non-multilobated DLBCL group (OS, p = 0.006; PFS, p = 0.010). In the multivariate Cox regression analyses for OS, independent prognosis factors were high soluble IL-2 receptor (p = 0.025), high risk of International Prognostic Index, and multilobated morphology (p = 0.031). The most characteristic copy number gains found in more than 50% of the cases were located at 1q, 3p, 10q, 12q, and 14q. Overall, the multilobated morphology in DLBCL exhibits a good outcome in the R-CHOP era.

Cardiac light chain (AL) amyloidosis is a condition with a very poor prognosis. We report a retrospective analysis comparing the traditional melphalan and dexamethasone protocol with cyclophosphamide, bortezomib and dexamethasone in late-stage cardiac AL amyloidosis. The primary end points were overall survival and haematological response. Both regimens provided meaningful responses in this difficult to treat patient group.

Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous disease group accounting for 10% of non-Hodgkin lymphomas. PTCL patients have typically poorer outcomes compared to aggressive B-cell lymphomas. However, such outcomes are heavily dependent upon subtype. Although anthracycline-based regimens such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) remain the standard first-line treatment for most aggressive PTCLs, there are important variations including incorporation of novel agents, use of radiotherapy and judicious consideration of stem cell transplantation. Relapsed or refractory disease represents a significant area of unmet need where chemotherapy intensification has limited efficacy and novel agents such as brentuximab vedotin and pralatrexate provide additional opportunities for attainment of remission and potential stem cell transplant. In the future, pre-therapy prognostic biomarkers including genomic characterisation, may aid in risk stratification and help guide initial patient management to improve survival. There is an urgent need to better understand the pathogenesis of PTCLs to facilitate novel drug combinatorial approaches to improve survival. This position statement represents an evidence-based synthesis of the literature for application in Australian and New Zealand practice. This article is protected by copyright. All rights reserved.

Cyclophosphamide (CP) is an alkylating agent commonly included in multi-drug treatment protocols for canine cancer. As a prodrug, CP requires hepatic metabolism for activation to the intermediate compound 4-hydroxycyclophosphamide (4-OHCP) which then spontaneously forms alkylating phosphoramide mustard. CP is frequently administered in a fractionated manner, with the total dose given over multiple days. CP is reported to cause auto-induction of metabolism in humans, with faster CP clearance and relatively increased 4-OHCP formation following fractionated versus bolus dosing, however canine pharmacokinetic studies of CP dose fractionation are lacking. The study objective was to evaluate the pharmacokinetics of fractionated oral CP dosing at a dose of 200-250 mg/m(2) over three to four days in a prospectively identified population of cancer-bearing dogs. Plasma concentrations of CP and 4-OHCP were measured by ultra-high performance liquid chromatography tandem-mass spectrometry in eight dogs following the first and last doses to assess for auto-induction of CP metabolism. No significant difference in the rate of CP elimination between first and last doses were detected (0.73 ± 0.46 hr(−1) versus 1.22 ± 0.5 hr(−1); p = 0.125). Additionally, no significant difference in dose-normalized 4-OHCP exposure was identified between first and last doses (5.9 ± 2.1 hr*ng/mL versus 7.9 ± 6.4 hr*ng/mL; p = 0.936). These results suggest that fractionated dosing may not increase exposure to the active metabolite of CP in dogs as it does in humans. As such, standard bolus dosing and fractionated dosing may be equivalent in terms of bio-activation of CP in dogs administered a dose of 200-250 mg/m(2).

Little is known about the incidence, clinical characteristics and prognostic factors in HIV associated lymphoma as these are less common than HIV-negative lymphoma in China. Currently, there are no standard guidelines for treatment of these patients. Therefore, we performed a study to analyse the clinical characteristics and outcomes of newly diagnosed HIV-associated aggressive B-cell non-Hodgkin's lymphoma (NHL) patients in Chongqing University Cancer Hospital (CUCH). Totally 86 newly diagnosed HIV-associated aggressive B-cell NHL patients in CUCH, southwest China, from July 2008 to August 2021, were analysed. In the entire cohort, median age was 48 years (range, 23-87 years), and more patients were male (87.2%). Most patients had elevated lactate dehydrogenase (LDH) (82.6%), advanced ann arbor stage (80.2%) and high IPI score (IPI score, 3-5) (62.7%) at diagnosis. Median CD4+ T-cell count at diagnosis was 191/μl (range, 4-1022), 84 patients (97.7%) were on combination antiretroviral therapy (cART) at lymphoma diagnosis. In DLBCL patients, cox multivariate analysis showed that age ≥ 60 (HR = 2.251, 95%CI 1.122-4.516; p = 0.012), elevated LDH (HR = 4.452, 95%CI 1.027-19.297; p = 0.041) and received less than two cycles of chemotherapy (HR = 0.629, 95%CI 0.589-1.071; p = 0.012) were independent risk factors for adverse prognosis based on PFS. Age ≥ 60 (HR = 3.162, 95%CI 1.500-6.665; p = 0.002) and received less than two cycles of chemotherapy (HR = 0.524, 95%CI 0.347-0.791; p = 0.002) were also independent risk factor for adverse prognosis based on OS. In BL patients, cox multivariate analysis showed that elevated LDH and received less than two cycles of chemotherapy were independent risk factors for adverse prognosis. In the DLBCL group, median PFS times in the received rituximab and no received rituximab groups were not reached and 12 months, respectively (p = 0.006). Median OS times were not reached and 36 months, respectively (p = 0.021). In the BL group, median PFS times in the received rituximab and no received rituximab groups were not reached and 4.8 months, respectively (p = 0.046). Median OS times were not reached and 10.1 months, respectively (p = 0.035). Overall, these data indicated that standardized anti-lymphoma therapy and rituximab administration were significantly associated with improved outcomes in patients with HIV-associated DLBCL and BL.

Haematopoietic cell transplantation (HCT) is the only curative treatment for haematological complications in patients with Fanconi anaemia (FA). Haploidentical (haplo-) HCT is a promising alternative for FA. We aimed to analyse the outcomes of unmanipulated haplo-HCT in patients with FA with radiation-free conditioning. A total of 56 patients from 11 centres between 2013 and 2021 in China were retrospectively analysed. The mean (SD) cumulative incidence was 96.4% (0.08%) for 30-day neutrophil engraftment and 85.5% (0.24%) for 100-day platelet engraftment. With a median (range) follow-up of 2.4 (0.2-5.8) years, favourable mean (SD) overall survival of 80.9% (5.5%) and event-free survival of 79.3% (5.6%) were achieved. The mean (SD) incidences of acute graft-versus-host disease (aGvHD) Grade II-IV and Grade III-IV were 55.4% (0.45%) and 42.9 (0.45%) respectively. The mean (SD) cumulative incidence of 3-year chronic graft-versus-host disease (cGvHD) was 34.7% (0.86%) and that of moderate-to-severe cGvHD was 9.0% (0.19%). Our data demonstrate that in unmanipulated haplo-HCT for patients with FA, radiation-free regimens based on fludarabine and low-dose cyclophosphamide ± busulfan achieved favourable engraftment and survival with relatively high incidences of aGvHD and cGvHD. These results prompt the use of low-intensity conditioning without radiation and intensive GvHD prophylaxis when considering unmanipulated haplo-HCT in patients with FA.

Urotensin II (U-II) and its receptor (UT) are involved in the pathogenesis of various diseases; however, their association with the development of cystitis has not been elucidated. The present study was designed to investigate the functional role of U-II/UT signaling in cyclophosphamide (CYP)-induced cystitis. A total of 60 female rats were randomly divided into the control and CYP-treated groups. Intraperitoneal injection of CYP successfully induced cystitis in rats of the CYP-treated group. The protein and mRNA expression levels of U-II and UT were significantly enhanced in rat bladder tissues of the CYP-treated group. Furthermore, the results of the immunofluorescence staining analysis demonstrated that CYP treatment apparently increased the expression levels of UT in the urothelium layer, detrusor smooth muscle, and bladder interstitial Cajal-like cells. The selective antagonist of UT, SB657510 (10 μm), significantly suppressed the CYP-induced increase in the spontaneous contractions of muscle strips and ameliorated the bladder hyperactivity of CYP-treated rats. Moreover, CYP treatment significantly increased the protein expression levels of Ras homolog family member (Rho) A and Rho-associated protein kinase 2 in rat bladder tissues. Following pretreatment with the Rho-kinase inhibitor Y-27632 (10 μm), the inhibitory effects of SB657510 (10 μm) on the spontaneous contractions of muscle strips were eliminated. In conclusion, the results of the present study suggested that activation of U-II/UT signaling promoted the development of cystitis-associated-bladder hyperactivity by targeting the RhoA/Rho-kinase pathway, indicating that the U-II/UT signaling could serve as a novel target for the treatment of interstitial cystitis/bladder pain syndrome.

BACKGROUND The existing guidelines for lupus nephritis (LN) recommend initial prednisone doses of 0.3-1mg/kg/day. However, recent studies reported non-inferior outcomes with lower doses. The aim of this study was to compare the complete renal response rates in LN patients treated with prednisone ≤30mg/day or ≥40mg/day. PATIENTS-METHODS Patients with new-onset LN and standard immunosuppressive treatment were followed for at least 12 months, divided into medium (≤30mg/day) and high prednisone groups (≥40mg/day) and matched (propensity score) based on the baseline differences. Complete renal response was defined as proteinuria

To investigate the effects of pretreatment with 5-aminolevulinic acid hydrochloride combined with sodium ferrous citrate on bladder dysfunction in cyclophosphamide-induced hemorrhagic cystitis in rats.Male Wistar rats (340-460 g) were pretreated with vehicle or with 5-aminolevulinic acid hydrochloride combined with sodium ferrous citrate (100/157 or 300/471 mg/kg/day, po) once daily for 7 days before cystometry. Saline or cyclophosphamide (150 mg/kg, ip) was administered 2 days before cystometry. Cystometry was performed under urethane anesthesia (0.8 g/kg, ip) via a catheter inserted into the bladder. After cystometry, bladder tissues were collected to perform hematoxylin and eosin staining for pathological evaluation (neutrophil infiltration, edema, and bleeding scores), and for enzyme-linked immunosorbent assay and real-time polymerase chain reaction for investigating tissue levels of myeloperoxidase, and mRNA levels of haem oxygenase-1 as a cytoprotective molecule.Compared to controls, cyclophosphamide induced a shorter intercontraction interval, lower bladder compliance, increased number of non-voiding contractions, and increased pathological scores and myeloperoxidase expression in the bladder. Pretreatment with 5-aminolevulinic acid hydrochloride combined with sodium ferrous citrate (300/471 mg/kg/day) significantly improved cyclophosphamide-induced intercontraction interval shortening and increases in number of non-voiding contractions and neutrophil infiltration/bleeding scores and enhanced haem oxygenase-1 expression in the bladder. In addition, cyclophosphamide-induced decreases in bladder compliance and increases in myeloperoxidase were not detected with 5-aminolevulinic acid hydrochloride combined with sodium ferrous citrate pretreatment.Pretreatment with 5-aminolevulinic acid expects protective effects on bladder dysfunction in cyclophosphamide-induced hemorrhagic cystitis by improving inflammatory changes in bladder tissues perhaps via up-regulation of haem oxygenase-1.

In the phase 3 ANDROMEDA trial, patients treated with daratumumab, bortezomib, cyclophosphamide, and dexamethasone (D-VCd) had significantly higher rates of organ and hematologic response compared with patients who received VCd alone. Here, we present patient-reported outcomes (PROs) from the ANDROMEDA trial. PROs were assessed through cycle 6 using three standardized questionnaires. Treatment effect through cycle 6 was measured by a repeated-measures, mixed-effects model. The magnitude of changes in PROs versus baseline was generally low, but between-group differences favored the D-VCd group. Results were generally consistent irrespective of hematologic, cardiac, or renal responses. More patients in the D-VCd group experienced meaningful improvements in PROs; median time to improvement was more rapid in the D-VCd group versus the VCd group. After cycle 6, patients in the D-VCd group received daratumumab monotherapy and their PRO assessments continued, with improvements in health-related quality of life (HRQoL) reported through cycle 19. PROs of subgroups with renal and cardiac involvement were consistent with those of the intent-to-treat population. These results demonstrate that the previously reported clinical benefits of D-VCd were achieved without decrement to patients' HRQoL and provide support of D-VCd in patients with AL amyloidosis.

Pegfilgrastim, a pegylated form of granulocyte colony-stimulating factor, has reduced the risk of developing febrile neutropenia, which is associated with an increase in severe infection and prolonged hospitalization. However, pegfilgrastim administration requires that patients visit hospital following cancer chemotherapy, thus imposing a burden on patients and those around them. An on-body injector (OBI), which automatically administers pegfilgrastim about 27 hours after chemotherapy, was used in this study. The OBI, which consists of a main pump unit and infusion set, is a drug delivery device designed to be attached to the patient's body, with a timer-controlled dosing function. This study was conducted in breast cancer patients to evaluate the safety of pegfilgrastim administered subcutaneously via the OBI. The study period consisted of screening and treatment observation periods involving four cycles of neoadjuvant or adjuvant chemotherapy with docetaxel plus cyclophosphamide. One 3.6-mg pegfilgrastim dose was administered subcutaneously via OBI during each cycle of chemotherapy. The study enrolled 35 patients, and no serious adverse events or febrile neutropenia occurred. Administration of pegfilgrastim was successfully completed at all times when the OBI was attached to the patient, and no safety concerns associated with OBI function arose. For outpatients requiring pegfilgrastim following cancer chemotherapy, the use of an OBI was considered to be a safe option to reduce the need for outpatient visits that restrict their activities of daily living.

Bladder pain syndrome/interstitial cystitis (BPS/IC) is a refractory disease accompanied by bladder-related pain and hyperactivity. Studies have shown that the translocator protein (TSPO) modulates neuroinflammation and central sensitisation associated with pain. Moreover, we previously demonstrated that brain-derived neurotrophic factor (BDNF) regulates neuroinflammation and mechanical allodynia in cyclophosphamide (CYP)-induced cystitis through activation of glial cells. Here, we aimed to explore whether activation of TSPO attenuates mechanical allodynia and bladder dysfunction by regulating BDNF induced neuroinflammation in a CYP-induced cystitis model.Injection of CYP was performed to form a rat model of BPS/IC. The expression of TSPO was regulated by intrathecal injection of the TSPO agonist Ro5-4864. The von Frey filament test was applied to evaluate suprapubic allodynia. Bladder function was assessed using filling cystometry. Western blotting was used to detect the expression of TSPO, BDNF, GFAP, Iba-1, p-p38, p-JNK, TNF-α, and IL-1β, and double immunofluorescence was performed to localise TSPO in the L6-S1 spinal dorsal horn (SDH).TSPO was activated in the SDH after CYP injection and was primarily colocalised with astrocytes. Ro5-4864 reversed mechanical allodynia and bladder dysfunction induced by CYP. Moreover, the upregulation of BDNF and activation of astrocytes and microglia was suppressed by Ro5-4864, resulting in downregulation of p-p38, p-JNK, TNF-α, and IL-1β.Ro5-4864 alleviated mechanical allodynia and bladder dysfunction in the CYP model, possibly by inhibiting the elevation of BDNF and consequent activation of astrocytes and microglia induced neuroinflammation. TSPO may be a potential target for the treatment of BPS/IC.This study examined the mechanism underlying the ability of the translocator protein to modulate bladder pain syndrome/interstitial cystitis.

We investigated the prognostic value of pretreatment patient-reported outcomes (PROs) in patients with diffuse large B-cell lymphoma (DLBCL) receiving obinutuzumab/rituximab plus chemotherapy in the GOYA phase III study.Patients completed the European Organization for Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) and the Functional assessment of chronic illness therapy-Lymphoma (FACT-Lym) lymphoma subscale (LYMS) during the study. PRO scales with high prognostic value were identified through Cox regression analyses of overall survival (OS) and progression-free survival (PFS). These scales were evaluated in terms of their additional prognostic value beyond the International Prognostic Index (IPI). A preliminary assessment was performed to evaluate whether the scales provided improved patient-risk stratification beyond IPI.One thousand two hundred and fifty-nine patients with valid pretreatment PRO scales were included in the analyses, and complete pretreatment data were available for 1239/1414 patients (87.6%). Four PRO scales with high prognostic value were identified: FACT-Lym LYMS and EORTC QLQ-C30 physical functioning, global health status/quality of life (QoL), and fatigue. All four scales retained significant prognostic value for OS and PFS after IPI adjustment (all p 0.05). After adjusting for multiple clinical variables (IPI, cell of origin, BCL2 status, and total metabolic tumor volume), all four scales retained significant prognostic value (all p 0.05) for OS. Only the EORTC QLQ-C30 physical functioning scale was significant (p 0.05) for PFS after adjustment for multiple clinical variables.In this large population of patients with DLBCL, pretreatment PROs provided prognostic information for OS and PFS beyond the well-established IPI.

Reactive oxygen species (ROS) exposure triggers granulosa cells' (GCs) senescence, which is an important causal factor for premature ovarian failure (POF). However, underlying mechanism in this process remains unknown. In our study, we observed increased ROS levels in POF ovarian tissues, POF patient follicular GCs and cyclophosphamide (CTX) pretreated GCs. Correspondingly, increased SIAH1, reduced TRF2 and GC senescence were also found in these cases. Silencing of SIAH1 rescued ROS-induced TRF2 reduction and cell senescence in GCs. Moreover, SIAH1 co-localized with TRF2 in the cytoplasm, facilitating its ubiquitination degradation, further leading to telomere abnormalities in GCs. In conclusion, our findings indicate that ROS induces telomere abnormalities by augmenting SIAH1-mediated TRF2 degradation, leading to cell senescence in GCs in POF processing.

The widely used alkylating agent cyclophosphamide (CY) has substantive interpatient variability in the area under the curve (AUC) of it and its metabolites. Numerous factors may influence the drug-metabolizing enzymes that metabolize CY to 4-hydroxycyclophosphamide (4HCY), the principal precursor to CY's cytotoxic metabolite. We sought to identify endogenous metabolomics compounds (EMCs) associated with 4HCY formation clearance (ratio of 4HCY/CY AUC) using global metabolomics. Patients who undergo hematopoietic cell transplantation receiving post-transplant CY (PT-CY) were enrolled, cohort 1 (n = 26) and cohort 2 (n = 25) donating longitudinal blood samples before they started HCT (pre-HCT), before infusion of the donor allograft (pre-graft), before the first dose of PT-CY (pre-CY), and 24 h after the first dose of PT-CY (24-h post-CY), which is also immediately before the second dose of CY. A total of 512 and 498 EMCs were quantitated in two cohorts, respectively. Both univariate linear regression with false discovery rate (FDR), and pathway enrichment analyses using a global association test were performed. At the pre-CY time point, no EMCs were associated at FDR less than 0.1. At pre-HCT, cohort 1 had one EMC (levoglucosan) survive the FDR threshold. At pre-graft, cohort 1 and cohort 2 had 20 and 13 EMCs, respectively, exhibiting unadjusted p values less than 0.05, with the only EMCs having an FDR less than 0.1 being two unknown EMCs. At 24-h post-CY, there were three EMCs, two ketones, and threitol, at FDR less than 0.1 in cohort 2. These results demonstrate the potential of pharmacometabonomics, but future studies in larger samples are needed to optimize CY.

Fosnetupitant (FosNTP), an intravenous neurokinin 1 receptor antagonist, demonstrated a favorable safety profile with a potentially low risk of injection site reactions (ISRs) and promising antiemetic efficacy in patients receiving cisplatin-based highly emetogenic chemotherapy in a previous phase 2 study. We conducted a randomized, double-blind safety study to evaluate the safety profile of FosNTP, including ISRs, in patients receiving doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide (AC/EC) chemotherapy.Patients scheduled to receive AC/EC were randomized 1:1 to receive 235 mg of FosNTP or 150 mg of fosaprepitant (FosAPR), both in combination with 0.75 mg of intravenous palonosetron and 9.9 mg of dexamethasone on day 1. The stratification factors were age category (55 vs ≥55 years) and study site. The primary end point was the incidence of treatment-related adverse events (TRAEs) with FosNTP.Overall, 102 patients were randomized to FosNTP (n = 52) or FosAPR (n = 50), and all were treated with the study drug and evaluated for safety. The primary end point, the incidence of TRAEs, was similar with FosNTP (21.2%; 95% confidence interval [CI], 11.1%-34.7%) and FosAPR (22.0%; 95% CI, 11.5%-36.0%), with any-cause ISRs observed in 5.8% and 26.0% of patients, respectively, and treatment-related ISRs observed in 0% and 10.0%, respectively. The overall (0-120 hour) complete response (defined as no emetic event and no rescue medication) rate, standardized by age category in the full analysis set, was 45.9% (23 of 51 patients) with FosNTP and 51.3% (25 of 49 patients) with FosAPR.FosNTP demonstrated a favorable safety profile with a very low risk of ISRs in the AC/EC setting.

Purpose Primary mediastinal B‐cell lymphoma (PMBCL) is a rare subtype of diffuse large B‐cell lymphoma (DLBCL). Despite its aggressive course, PMBCL is considered curable. While in recent years dose‐adjusted (DA) EPOCH‐R (rituximab, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) has become widely endorsed as first‐line therapy for newly‐diagnosed PMBCL, the optimal treatment for this disease and the role of radiotherapy (RT) remains unclear. DA‐EPOCH‐R provides good clinical outcomes, albeit is associated with short‐ and long‐term toxicity. To address this issue, the current retrospective bi‐icenter analysis compared efficacy and toxicity of DA‐EPOCH‐R and a less toxic R‐CHOP/R‐ICE regimen used for the treatment of newly‐diagnosed PMBCL. Patients and Methods The study included all patients with a histologically confirmed PMBCL diagnosis treated with DA‐EPOCH‐R or R‐CHOP/R‐ICE between 01/2013‐12/2020 at two tertiary medical centers. Patient demographic and clinical data were derived from institutional electronic medical records. The analysis included 56 patients: 31 received DA‐EPOCH‐R and 25 – R‐CHOP/R‐ICE. Results At a median follow‐up of 1.9 years (IQR 3.1 years), similar progression‐free survival (2.1 versus 2.4 years; p = 0.7667), overall survival (2.5 versus 2.7 years; p = 0.8047) and complete response (80%) were observed in both groups. However, DA‐EPOCH‐R was associated with significantly longer hospitalization required for its administration (p, Primary mediastinal B‐cell lymphoma (PMBCL) is a rare subtype of diffuse large B‐cell lymphoma that is considered curable despite its aggressive course. DA‐EPOCH‐R, widely employed as a first‐line therapy for newly diagnosed PMBCL, offers good clinical results, but its utility is hampered by high rates of short‐ and long‐term toxicity. Our findings suggest that the use of R‐CHOP/R‐ICE could be consider as an alternative to DA‐EPOCH‐R in PMBCL patients, since the former regimen, while providing similarly encouraging outcomes, is associated with lower toxicity and significantly reduced hospitalization.

AIMS This study aimed to prepare swim bladder hydrolysate (SBH) with Mn

STUDY OBJECTIVE: Alemtuzumab is a monoclonal antibody that targets the cell surface antigen CD52 on lymphocytes. Although it is used for the treatment of hematologic malignancies, such as chronic lymphocytic leukemia, and incorporated into many hematopoietic stem cell transplant (HSCT) conditioning regimens, few studies have evaluated the pharmacology of alemtuzumab in adult patients with sickle cell disease (SCD). We therefore examined the pharmacokinetics (PK) and pharmacodynamics (PD) of alemtuzumab in adults with SCD who received a matched related donor HSCT to determine if the clearance of alemtuzumab affects transplant outcomes. DESIGN: PK and PD analysis of patient data from a single-center clinical trial. SETTING: Clinical research center. PATIENTS: Twenty-two adult patients with SCD who received one of two nonmyeloablative allogeneic HSCT regimens: alemtuzumab and total body irradiation (Alem-TBI) or pentostatin, cyclophosphamide, alemtuzumab, and total body irradiation (Pento-Cy-Alem-TBI). MEASUREMENTS AND MAIN RESULTS: Alemtuzumab serum concentrations, absolute lymphocyte counts, T-cell (CD3), and myeloid (CD14/15) chimerism were collected at distinct time points and analyzed. A semi-mechanistic PK population model was built to understand inter-individual differences in pharmacology. Alemtuzumab was detectable up to 28 days post-HSCT. The mean alemtuzumab level 7 days after transplant for patients on Alem-TBI was 818 ng/ml, significantly lower than the mean level of 1502 ng/ml for patients on Pento-Cy-Alem-TBI (p < 0.001), but this difference decreased as time progressed. The clearance of alemtuzumab was linear, and the half-life was longer in the Pento-Cy-Alem-TBI group (average half-life = 61.1 h) compared to the Alem-TBI group (average half-life = 44.1 h) (p < 0.001). The CD3 chimerism at 2 and 4 months after transplant positively correlated with alemtuzumab levels collected on day 14 after transplant (R(2) = 0.40 and p = 0.004 at 2 months, R(2) = 0.36 and p = 0.005 at 4 months), but this significance was lost by 6 months after HSCT. No correlation was seen between alemtuzumab levels and CD14/15 chimerism. CONCLUSION: Between 2 and 4 months after transplant, higher alemtuzumab levels measured 14 days after transplant correlated with patients having better engraftment, suggesting more lymphodepletion may be needed to reduce graft failure in these two non-myeloablative matched related donor HSCT regimens.

Diffuse large B‐cell lymphoma (DLBCL) is a clinically heterogeneous entity, in which the first‐line treatment currently consists of an immuno‐chemotherapy regimen (R‐CHOP). However, around 30% of patients will not respond or will relapse. Overexpression of c‐MYC or p53 is frequently found in DLBCL, but an association with prognosis remains controversial, as for other biomarkers previously linked with DLBCL aggressivity (CD5, CD23, or BCL2). The aim of this study was to explore the expression of these biomarkers and their correlation with outcome, clinical, or pathological features in a DLBCL cohort. Immunohistochemical (c‐MYC, p53, BCL2, CD5, and CD23), morphological (‘starry‐sky’ pattern [SSP]), targeted gene panel sequencing by next‐generation sequencing (NGS), and fluorescence in situ hybridisation analyses were performed on tissue microarray blocks for a retrospective cohort of 94 R‐CHOP‐treated de novo DLBCL. In univariate analyses, p53 overexpression (p53high) was associated with unfavourable outcome (p = 0.04) and with c‐MYC overexpression (p = 0.01), whereas c‐MYC overexpression was linked with an SSP (p = 0.004), but only tended towards an inferior prognosis (p = 0.06). Presence of a starry‐sky morphology was found to be correlated with better survival in p53high DLBCL (p = 0.03) and/or c‐MYC‐positive DLBCL (p = 0.002). Furthermore, NGS data revealed that these three variables were associated with somatic mutations (PIM1, TNFRSF14, FOXO1, and B2M) involved in B‐cell proliferation, survival, metabolism, and immune signalling. Taken together, these results show that the SSP pattern seems to be a protective factor in high‐risk DLBCL subgroups and highlight cell death as a built‐in failsafe mechanism to control tumour growth.

Background In an era of targeted therapies, patients with cancer in resource-constraint countries continue to struggle to find affordable care. Methods The present study is a multicenter prospective single-arm study. Patients with expected delay in surgery, unresectable or metastatic cancers, and patients not suitable for surgery or conventional chemotherapy were included. Oral methotrexate 15 mg/m2 once a week and oral celecoxib 200 mg twice daily was used for metronomic therapy. Results At 8 weeks, a clinically complete response was seen in 2.5%, partial response in 46.6%, stable disease in 39.8%, and disease progression in 11%. Size less than 4 cm, alveolobuccal subsite, and well-differentiated histology were significantly associated with no disease progression. Conclusion Constraint-adapted approach of using methotrexate and celecoxib is economical with good compliance, minimal toxicity, and good efficacy. It is feasible for use in diverse settings. Individualized selection of patients based on response predictors may maximize metronomic therapy's benefit.

During 2020, the concurrent novel COVID-19 pandemic lead to widespread cryopreservation of allogeneic hematopoietic cell transplant grafts based on National Marrow Donor Program and European Society of Blood and Marrow Transplantation recommendations, in order to secure grafts before the start of conditioning chemotherapy. We sought to examine the impact of this change in practice on patient outcomes. We analyzed the outcomes of 483 patients who received hematopoietic stem cell transplantation (HSCT) between August 2017 and August 2020, at Princess Margaret Cancer Centre, Canada, in the retrospective study, comparing the outcomes between those who received cryopreserved or fresh peripheral blood stem cell grafts. Overall compared with those who received fresh grafts (n = 348), patients who received cryopreserved grafts (n = 135) had reduced survival and GRFS, reduced incidence of chronic graft-versus-host disease (GvHD), delay in neutrophil engraftment, and higher graft failure (GF), with no significant difference in relapse incidence or acute GvHD. However, recipients of cryopreserved matched-related donor HSCT showed significantly worse OS, NRM, GRFS compared with fresh grafts. Multivariable analysis of the entire cohort showed significant impact of cryopreservation on OS, relapse, cGvHD, GF, and GRFS. We conclude that cryopreservation was associated with inferior outcomes post-HSCT, possibly due to the combination of ATG and post-transplant cyclophosphamide impacting differential tolerance to cryopreservation on components of the stem cell graft; further studies are warranted to elucidate mechanisms for this observation.

Aim To review the clinical features of systemic lupus erythematosus (SLE) complicated by central nervous system (CNS) infection due to Listeria monocytogenes. Method A patient with SLE receiving high-dose glucocorticoids combined with cyclophosphamide who developed multiple brain abscesses due to Listeria infection is described. The case is compared with known cases in a literature review. Results A review of the literature showed that CNS infections are rare bacterial complications of SLE, but they can be a significant cause of mortality, especially those due to L. monocytogenes. The most significant risk factor for listerial meningitis is a prior history of receiving immunosuppressive therapy. At-risk patients should avoid unpasteurized milk and soft cheeses along with deli-style, ready-to-eat prepared meats, particularly poultry products. The case we report is the fifth SLE patient with multiple brain abscesses due to L. monocytogenes, and the first to be discharged with no sequelae. Timely and accurate identification and treatment of CNS infections and neuropsychiatric lupus are very important for favorable disease prognosis. Conclusion Repeated blood culture is helpful for early diagnosis, and empirical anti-infective treatment that covers L. monocytogenes is recommended for SLE patients with risk factors when CNS infection occurs. A comprehensive assessment might be helpful to distinguish CNS infections from neuropsychiatric SLE. For severe infection, the dosage of steroids does not need to be reduced immediately but can be gradually adjusted based on the results of a comprehensive evaluation of the disease.

AIMS The therapeutic effect of estrogen on interstitial cystitis/bladder pain syndrome is unclear. We aim to explore the effect of estrogen on bladder overactivity in rats with cyclophosphamide-induced cystitis and its underlying mechanism. METHODS In vivo cystometry was used to determine the effect of estrogen on bladder excitability. The effect of estrogen on the expression of P2X3 receptors in bladder epithelium was detected by real-time polymerase chain reaction and western blot. Effect of P2X3 receptors in bladder urothelium on stretch-released adenosine triphosphate was performed by a Flexcell FX5000 Compression system and an Enzyme-Linked Immunosorbent Assay Kit. RESULTS Estrogen deprivation significantly increased the urinary frequency, while supplementation with diarylpropionitrile (DPN), an estrogen receptor β (ERβ) agonist, alleviated the urinary frequency. 17β-Estradiol and DPN decreased the expression of P2X3 receptors in urothelium cells which was partially inhibited by ERβ antagonist 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol. Meanwhile, inhibiting the expression of P2X3 receptors by ERβ agonist or antagonizing the function of P2X3 receptors by selective P2X3 receptor antagonist AF-353 or A-317491 significantly reduced the stretch-released ATP from urothelium cells. CONCLUSIONS Estrogen has a direct effect on the regulation of bladder overactivity in rats with cyclophosphamide-induced cystitis by downregulating the expression of bladder epithelial P2X3 receptors through ERβ and reducing the adenosine triphosphate released from urothelium during bladder filling, thereby inhibiting the generation of the micturition reflex.

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed or refractory large B-cell lymphoma (R/R LBCL). To reduce axi-cel–related toxicity, several exploratory safety management cohorts were added to ZUMA-1 (NCT02348216), the pivotal phase 1/2 study of axi-cel in refractory LBCL. Cohort 4 evaluated the rates and severity of cytokine release syndrome (CRS) and neurologic events (NEs) with earlier corticosteroid and tocilizumab use. Primary endpoints were incidence and severity of CRS and NEs. Patients received 2 × 106 anti-CD19 CAR T cells/kg after conditioning chemotherapy. Forty-one patients received axi-cel. Incidences of any-grade CRS and NEs were 93% and 61%, respectively (grade ≥ 3, 2% and 17%). There was no grade 4 or 5 CRS or NE. Despite earlier dosing, the cumulative cortisone-equivalent corticosteroid dose in patients requiring corticosteroid therapy was lower than that reported in the pivotal ZUMA-1 cohorts. With a median follow-up of 14·8 months, objective and complete response rates were 73% and 51%, respectively, and 51% of treated patients were in ongoing response. Earlier and measured use of corticosteroids and/or tocilizumab has the potential to reduce the incidence of grade ≥ 3 CRS and NEs in patients with R/R LBCL receiving axi-cel.

Purpose Some studies have indicated that using 500 mg/m2 rituximab combined with CHOP‐14 may be beneficial for elderly men but not women with diffuse large B‐cell lymphoma (DLBCL). The purpose of this study was to investigate the potential benefit of escalated doses of rituximab with CHOP‐21 as the first‐line treatment in male patients with DLBCL. Methods We performed a retrospective cohort study to analyze the survival benefit of rituximab 500 mg/m2 plus the CHOP‐21 regimen (Escalated‐R‐CHOP‐21) as the first‐line treatment compared with using rituximab 375 mg/m2 plus the CHOP‐21 regimen (Standard‐R‐CHOP‐21) in men with DLBCL. We used propensity score matching to maximize the balance of the observed covariables. The primary endpoints of this study were the progression‐free survival (PFS) rate and overall survival (OS) rate at 3 years. Results After a median follow‐up of 47 months (IQR 31–65), no significant difference in PFS and OS was found for men treated with Escalated‐R‐CHOP‐21 compared with Standard‐R‐CHOP‐21 [3‐year PFS: 69.7% versus 71.9%, p = 0.867; 3‐year OS: 83.0% versus 82.4%, p = 0.660]. After 1:1 propensity score matching, we found that the patients using Escalated‐R‐CHOP‐21 had statistically significant survival benefits relative to Standard‐R‐CHOP‐21 among the 96 matched elderly male patients for 3‐year PFS [75.5% (95% CI 62.8–88.2) versus 58.2% (95% CI 44.3–72.1); p = 0.019] and 3‐year OS [86.6% (95% CI 76.4–96.8) versus 65.8% (95% CI 52.1–79.5); p = 0.017]. However, no differences in survival were observed for younger male patients. Furthermore, the dose effect in PFS of Escalated‐R‐CHOP‐21 was more obvious for elderly male patients with no high‐risk extranodal sites (p = 0.005 and interaction p = 0.030). Conclusion Escalated‐R‐CHOP‐21 could be a safe and effective option for treating elderly male patients with DLBCL. This study provides new insight into optimizing the standard treatment regimen, which may have important therapeutic implications in elderly male patients with DLBCL., In this study, we investigated the potential benefit of rituximab 500 mg/m2 plus the CHOP‐21 regimen (Escalated‐R‐CHOP‐21) as the first‐line treatment compared with using rituximab 375 mg/m2 plus the CHOP‐21 regimen (Standard‐R‐CHOP‐21) in male patients with DLBCL. We found that only elderly men had statistically significant survival benefits from Escalated‐R‐CHOP‐21 than Standard‐R‐CHOP‐21 of 3‐year PFS [75.5% (95% CI 62.8–88.2) vs. 58.2% (95%CI 44.3–72.1); p = 0.019] and 3‐year OS [86.6% (95% CI 76.4–96.8) vs. 65.8.0% (95% CI 52.1–79.5); p = 0.017] without causing severe toxicity after propensity score matching.

Background Scarce data exist on the impact of granulocyte-colony stimulating factor (G-CSF) type on the mobilizing capacity of CD34+ cells, graft cellular composition, and outcome in myeloma (MM) patients. Patients and methods In this prospective multicenter study, 70 patients with MM received filgrastim (FIL) and 20 patients received pegfilgrastim (PEG) as a G-CSF after low-dose cyclophosphamide. Flow cytometry was used to analyze the mobilization of CD34+ cells and cellular composition of blood grafts, hematologic recovery, and survival after auto-SCT according to the G-CSF choice. Results The CD34+ cell yield of the first apheresis was higher in the FIL group (5.3 vs. 4.2 × 106 /kg, p = .025). The better mobilizing capacity was observed in the FIL group especially after bortezomib-based induction based on the higher first apheresis yield of CD34+ cells (7.5 vs. 4.4 × 106 /kg, p = .001). The median CD19+ cell count (1.0 vs. 0.4 × 106 /kg, p = .010) and the number of CD3+ T lymphocytes (43.1 vs. 31.8 × 106 /kg, p = .122) in the infused graft were higher in the patients mobilized with FIL. Both early (day +15) (56 vs. 108 × 109 /L, p = .002) and later platelet recovery at 6 months (191 vs. 226 × 109 /L, p = .026) were faster in the PEG group. Conclusion G-CSF type seems to impact on the mobilization capacity and cellular composition of infused graft and also platelet recovery post-transplant. A randomized study might be warranted to verify the effects of G-CSF choice in the mobilization field.

Background Multiple myeloma (MM) is an incurable hematologic malignancy, and outcomes remain poor for patients with triple-class relapsed/refractory MM (RRMM). Descriptive analyses were performed on available data for patient characteristics, disease course, and outcomes of the KCd on triple-class RRMM patients at our institution. Patients and methods Twenty-three patients with triple-class RRMM treated with KCd between June 2017 and October 2020 were included in our analysis. The regimen KCd consisted of 28 days cycles of carfilzomib 20/36 mg/m2 IV on days 1, 2, 8, 9, 15, and 16, cyclophosphamide 300 mg/m2 IV weekly, and dexamethasone (20-40) mg orally weekly. Results Patients received a median of 6 (3-10) prior regimens. The median number of cycles administered was 4 (1-11) cycles. Overall response rate was 52%, 6 patients (26%) achieved very good partial response (VGPR), 6 patients (26%) achieved partial response (PR), and 5 patients (22%) achieved stable disease (SD). Progression-free survival (PFS) and Overall-survival (OS) were 4 and 11.9 months, respectively. There was no reported treatment-related mortality. The most common grade ≥3 adverse events were neutropenia (26%), thrombocytopenia (56.5%), and anemia (56.5%). Conclusions KCd showed clinically meaningful efficacy and manageable safety profile in patients with triple-class RRMM in real-world.

Background Resveratrol, a kind of polyphenolic phytoalexin, could be obtained from numerous natural foods. Although resveratrol is demonstrated to have various bioactivities, little is known about the regulation of intestinal barrier function under immunosuppression. The present study is aimed to investigate the regulating effect of resveratrol on intestinal barrier function in immunosuppressive mice induced by cyclophosphamide. Results The effects of resveratrol on intestinal biological barrier were evaluated by 16S rRNA and metagenome sequencing analysis. The results showed that resveratrol could improve diversity of the intestinal microbiota and intestinal flora structure by increasing the abundance of probiotics, and resveratrol regulated the function of gut microbiota to resist immunosuppression. Resveratrol could significantly upregulate the secretion of secretory immunoglobulin A and promote the transcriptional levels of test cytokines, including tumor necrosis factor α, interferon-γ, interleukin-4 and interleukin-6 in jejunum and ileum mucosa, suggesting improved intestinal immune barrier by resveratrol. The mRNA and protein levels of tight junction proteins involved in intestinal physical barrier function, including ZO-1, Claudin-1 and Occludin, were increased after resveratrol treatment. The protein levels of toll like receptors 4 (TLR4), phosphorylation nuclear factor kappa-B (NF-κB-p65) and inhibitor of nuclear factor kappa-B kinase α were decreased by resveratrol treatment when compared with the untreated group, indicating the inhibition of TLR4/NF-ĸB signaling pathway. Conclusion These results provide new insights into regulation of the intestinal barrier function by resveratrol under immunosuppression and potential applications of resveratrol in recovering the intestinal function. This article is protected by copyright. All rights reserved.