An Unusual Case of Anti-Glomerular Basement Membrane Disease and Phospholipase A2 Receptor-Associated Membranous Nephropathy After Exposure to Hydrocarbons.

We present a rare case of a patient with toluene exposure manifesting as anti-glomerular basement membrane (GBM) disease on a background of phospholipase A2 receptor (PLA2R)-associated membranous nephropathy. A 23-year-old man presented to the emergency department with hypertension, headache, hemoptysis, anemia, acute kidney injury, glomerular hematuria, and proteinuria. He endorsed repeated exposure to toluene-containing products while repairing dirt bikes. Serologies were positive for anti-GBM antibodies. Kidney biopsy showed crescentic glomerulonephritis with linear immunoglobulin G and granular PLA2R staining by immunofluorescence. He was initially treated with high-dose steroids, plasmapheresis, and hemodialysis for pulmonary-renal syndrome followed by oral cyclophosphamide and prednisone, which were discontinued after 3 months when follow-up biopsies confirmed little chance for renal recovery. He remained on dialysis 1 year later. This case exhibits a unique presentation of anti-GBM syndrome and underlying membranous nephropathy following repeated hydrocarbon exposure. Inhaled toxins promote recurrent localized inflammation, unmasking previously hidden epitopes. Early diagnosis and appropriate use of immunosuppressive and extracorporeal therapies are necessary to prevent morbidity and to improve survival in this rare condition.

Incidence, Risk Factors, Characteristics, and Outcome of Chronic Graft Versus Host Disease in Children Undergoing Haploidentical Peripheral Blood Stem Cell Transplant With Post-transplant Cyclophosphamide.

AIM: Chronic graft versus host disease (cGVHD) is a major cause of morbidity postallogeneic peripheral blood stem cell transplant (PBSCT). There is paucity of literature describing incidence, risk factors, characteristics, and outcome of cGVHD in children undergoing haploidentical PBSCT with post-transplant cyclophosphamide (PTCy). Here, we describe our experience from our center regarding the same. METHODS: All children who underwent haploidentical PBSCT with PTCy between January 2016 and December 2021 at our center and survived beyond day+100 post-transplant were included in this retrospective study. Conditioning regimens used were: Thiotepa-Fludarabine-Cyclophosphamide with 2 Gy single fraction total body irradiation, Thiotepa-Busulfan-Fludarabine, Fludarabine-total body irradiation and Fludarabine-Melphalan. Peripheral blood was used as stem cell source in all patients. GVHD prophylaxis was PTCy 50 mg/kg on day +3 and +4, Mycophenolate mofetil and Calcineurin inhibitors. Clinical and laboratory data was electronically retrieved and analyzed based on National Institute of Health Consensus Criteria-2014 at regular intervals. Impact of various patient, donor, and transplant-related factors on development of cGVHD were analyzed. Incidence of relapse, event free survival (EFS) and overall survival (OS) were calculated and compared between cGVHD and no cGVHD groups. Patients with rejection were excluded from risk factor analysis for cGVHD but were considered for survival analysis. RESULTS: Fifty-one children included in this study. Median age of transplant of our cohort was 7.5 years with male:female=1.6:1. Eight patients had rejection with autologous recovery. History of acute GVHD (aGVHD) was present in 15/51 (Grade III to IV in 7/51). cGVHD developed in 19/51 patients (mild-9/51, moderate-6/51, and severe-4/51). Skin was the most common organ involved (100%) followed by gastrointestinal tract (47.4%), liver (36.8%), eyes (21%), lungs (21%), mouth (15.7%), and joints (5.2%). Advanced donor age (>30 y) and previous aGVHD were found to be significantly associated with increased risk of developing cGVHD. At last follow-up, complete response and partial response of cGVHD was seen in 6/19 and 4/19 patients, respectively. Overall mortality was 15/51 (cause of mortality was relapse of cancer 8/15, cGVHD-3/15, other 4/15). EFS and OS of full cohort was 55% and 70.6%, respectively. Compared with patients without cGVHD, patients with cGVHD demonstrated a lower relapse (18.2% vs. 40%, P =0.2333), higher EFS (68.4% vs. 53.1%, P =0.283), and higher OS (73.7% vs. 68.8%, P =0.708). CONCLUSION: Incidence of cGVHD was high in children undergoing haploidentical PBSCT with PTCy. Other than PBSC graft source; donor age and previous aGVHD were the risks factors for development of cGVHD. Patients with cGVHD had lower incidence of relapse translating into better survival but this difference was not statistically significant.

Evaluation of a novel medical device for pegfilgrastim administration.

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.

Comparison of CD34+ cell mobilization, blood graft cellular composition, and post-transplant outcome in myeloma patients mobilized with filgrastim or pegfilgrastim added to low-dose cyclophosphamide: A prospective multicenter study.

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.

Influence of Dose on Neutrophil-Mediated Delivery of Nanoparticles for Tumor-Targeting Therapy Strategies.

It is well known that neutrophil-mediated delivery of therapeutic agents is a promising method for treating tumors. However, owing to the limited number and limited uptake ability of neutrophils, determining a reasonable dose has become an urgent problem to be solved. Furthermore, the number of nanoparticles is far greater than the number of neutrophils at normal doses, which causes excessive nanoparticles to reach nontargeted organs or tissues, leading to serious adverse effects. To address these problems, a neutrophil-targeting delivery system (DiR-DADGC-L) based on DiR-labeled and butanedioic acid (DA)-linked 5-amino-3,5-dideoxy-D-Glycerol-D-galactonanulose-cholesterol conjugate (DADGC) was designed to improve the efficiency of hitchhiking neutrophils through the specific binding of sialic acid (SA) to L-selectin (SA-binding receptor, expressed on neutrophils). DiR-DADGC-L was prepared with favorable particle size and encapsulation efficiency (%EE) to deliver DiR into neutrophils. Subsequently, diverse doses of DiR-DADGC-L were injected intravenously into S180 tumor-bearing and cyclophosphamide-depleted (CTX-D) S180 tumor-bearing mice to evaluate the in vivo behavior of liposomes. The results verified the following: a) The content of DiR-DADGC-L in neutrophils accounts for approximately 14.5% of the content of DiR-DADGC-L in plasma, and the uptake capacity of neutrophils remains unchanged under different doses, and b) both neutrophils and the enhanced permeability and retention (EPR) effect might exert significant roles in tumor treatment. As for the neutrophil-mediated delivery system, higher doses are not necessarily appropriate, and a lower dose may achieve an unexpected effect. It will be wise to determine an optimum dose to improve delivery efficiency.

Analysis of the effect of R-CHOP regimen of pegylated liposomal doxorubicin on elderly patients with stage â ¢-â £ diffuse large B-cell lymphoma.

To explore the effect of R-CHOP regimen of pegylated liposomal doxorubicin (PLD) on elderly stage Ⅲ-Ⅳ diffuses large B-cell lymphoma (DLBCL). A retrospective analysis was conducted on the treatment information 80 elderly cases of stage III-IV DLBCL admitted to our hospital from April 2017 to April 2020. According to treatment methods, they were divided into experimental groups (40 cases, using R-CHOP with PLD) and controls group (40 cases, using the traditional R-CHOP regimen). We compared the treatment effect, survival rate, cardiotoxicity and adverse reactions of the patients. (1) The short-term degree of effectiveness treatment in the experimental group was 85%, which was not significantly different from 80% in other patients (p>0.05). (2) 2-year OS or PFS of experimental group were better more (p<0.01) and the treatment advantage of the experimental group increased with time. (3) Incidence of neutropenia and alopecia in experimental group was lower more (p<0.05). (4) Cardiotoxicity indexes of experimental group were lower (p<0.05). The PLD-containing R-CHOP regimen can improve the long-term inventory level elderly cases of stage III-IV DLBCL, reduce the incidence of grade IV neutropenia and alopecia, alleviate the cardiotoxicity caused by chemotherapy, and have better safety.

Haploidentical Stem Cell Transplantation with Post-Transplant Cyclophosphamide in Fanconi Anemia: Improving Outcomes with Improved Supportive Care in India.

Fanconi anemia is the most common inherited bone marrow failure syndrome, and hematopoietic stem cell transplantation (HSCT) is the only curative option. Post-transplant cyclophosphamide (PTCy) is challenging in this group of children, given their increased sensitivity to chemotherapy. We performed a retrospective analysis of the data on children diagnosed with Fanconi anemia who underwent a haploidentical HSCT with PTCy from January 2014 to December 2019. Nineteen children (male/female, 0.75:1) underwent 21 haplo-HSCTs with PTCy. Fludarabine, low-dose cyclophosphamide, and 200 centi-gray total body irradiation were included in the conditioning regimen with 25 mg/kg PTCy on days +3 and +4. Haplo-graft was from a sibling in 38% and father in 57% of transplants. The source of stem cells was peripheral blood stem cells in 81% and bone marrow in 19% of transplants, with a median CD34 dose of 5.0 × 106/kg. We documented engraftment in 84% and primary graft failure in 10% of transplants. N-acetylcysteine (NAC) was infused concomitantly during cyclophosphamide in 13 children. Grade 2 and 3 mucositis was lower among those who received NAC as compared to those who did not (30% and 15% versus 33% and 50%), while transaminitis was higher among those who did not receive the infusion. The incidence of acute graft-versus-host disease (GVHD) was 68%, and 81% of these were steroid responsive (grade I/II). We documented chronic GVHD in 25% children, predominantly involving the skin and mouth, which responded to low-dose steroids and ruxolitinib. Serum ferritin was monitored twice weekly as a surrogate marker for cytokine release syndrome due to nonavailability of IL-6 levels. A 1- or 2-log increase in the titers of ferritin associated with clinical features guided the early addition of steroids in the periengraftment period. The mean survival was found to be less among those with high serum ferritin (>10,000 ng/dL) in the periengraftment period as compared to those with ferritin <10,000 ng/dL (mean survival of 25 ± 10 months versus 50 ± 6 months, respectively). The overall survival in our cohort was 68.4%, with a mean survival time of 41.5 months (95% confidence interval, 29.3 to 53.8 months), with a statistically significant correlation between inferior outcome and having received over 15 transfusions before HSCT (P = .01). PTCy can be considered a viable option in children with Fanconi anemia, particularly in resource-limited settings given the high costs of HSCTs. Focused interventions in this subset of children help improve survival outcomes. Early identification of cytokine release syndrome and risk-adapted steroid therapy during engraftment helps prevent mortality. The concomitant use of NAC during cyclophosphamide infusion helps reduce oxygen free radical related tissue damage and regimen-related toxicity.

A pilot study on intermittent every other days of 5-dose Filgrastim compared with single Pegfilgrastim in breast Cancer patients receiving adjuvant Docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy.

Aim To compare the efficacy and safety of intermittent every other days 5-dose filgrastim with single pegfilgrastim in patients with breast cancer receiving adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy. Methods In this pilot study, Korean patients who had undergone complete resection for breast cancer and scheduled for adjuvant TAC chemotherapy were enrolled. Patients were randomized to receive either intermittent 5 doses of filgrastim (5 mcg/kg/day) or once-a-cycle pegfilgrastim (6 mg) as primary prophylaxis during the first three cycles of the TAC chemotherapy. Absolute neutrophil count (ANC) was analyzed as well. Results A total of 22 patients were randomly and equally divided into filgrastim or pegfilgrastim arms. Febrile neutropenia (FN) occurred in 1 patient in the pegfilgrastim arm (1 of 33 cycles) and none in the filgrastim arm. G3 neutropenia occurred in 1 patient (1 of 33 cycles) in the filgrastim arm and 2 patients (4 of 33 cycles) in the pegfilgrastim arm (P = 0.476). G4 neutropenia occurred in 11 patients (28 of 33 cycles) in the filgrastim arm and 9 patients (18 of 33 cycles) in the pegfilgrastim arm (P = 0.476). Except for on day 9 in cycle 3, there was no significant difference between the two groups in terms of ANC. Conclusion We observed no significant differences between the two methods of prophylaxis in terms of FN and G3/4 neutropenia incidence in patients receiving adjuvant TAC chemotherapy. Intermittent every other days 5-dose filgrastim may be available alternative to pegfilgrastim.

Idiopathic multicentric Castleman disease with Sjögren's syndrome and secondary membranous nephropathy: a case report and review of the literature.

BACKGROUND: Idiopathic multicentric Castleman disease (iMCD) is an uncommon lymphoproliferative disorder and lacks treatment consensus. Herein, we report a case of iMCD complicated with Sjögren's syndrome (SS) and secondary membranous nephropathy (SMN). CASE PRESENTATION: A 45-year-old female with dry mouth for 3 months and anasarca and proteinuria for 2 months was admitted. She also experienced chest tightness, wheezing, fever, weight loss, moderate proteinuria and hypoalbuminemia. A computed tomography (CT) scan revealed a tissue mass in the thymus area and enlarged multiple lymph nodes. Her symptoms did not improve after resection of the thymus mass. The pathological findings were "reactive hyperplasia of the mediastinal lymph nodes and thymic hyperplasia". Lymph node biopsy findings confirmed iMCD with human herpes virus-8 (HHV-8) negativity. Based on anti-nuclear antibody (ANA) 1:320, anti-SSA and anti-SSB antibody positivity, salivary flow less than 0.1 ml/min and lip biopsy with focal lymphocytic sialadenitis, SS was diagnosed. Kidney biopsy showed secondary membranous nephropathy with endocapillary cell proliferation and infiltration of plasma cells and lymphocytes in the tubulointerstitium. Serum interleukin-6 (IL-6) levels were significantly increased, and therapy with tocilizumab (anti-IL-6 receptor antibody) worked well. The combination of cyclophosphamide (CyS) with methylprednisolone (MP) maintained satisfactory remission. CONCLUSIONS: Our case of iMCD with SS and SMN is rare. There is a need for increased awareness of the disease to avoid unnecessary procedures and misdiagnoses. IL-6 was extremely high, and there was a rapid response to anti-IL-6 receptor agents. The combination of CyS with MP maintained complete remission.

Hypersensitivity and infusion-site adverse events with intravenous fosaprepitant after anthracycline-containing chemotherapy: a retrospective study.

AIM: Fosaprepitant, an intravenous neurokinin-1 receptor antagonist for chemotherapy-induced nausea and vomiting, contains polysorbate 80, which is associated with infusion-site adverse events (ISAEs) and hypersensitivity systemic reactions (HSRs). This study investigated ISAEs/HSRs following fosaprepitant with anthracycline-containing chemotherapy. PATIENTS & METHODS: This retrospective chart review noted ISAEs/HSRs following the anthracycline doxorubicin+cyclophosphamide and a three-drug fosaprepitant regimen, via peripheral line. RESULTS: 35/127 patients (28%) developed ISAEs/HSRs with chemotherapy and antiemetic therapy: 32 developed 137 individual ISAEs, primarily erythema, pain and catheter-site swelling; 16 developed 50 individual HSRs, primarily edema/swelling, erythema or dermatitis (no anaphylaxis). CONCLUSION: Fosaprepitant is associated with a significant ISAE/HSR rate following anthracycline-containing chemotherapy via peripheral line. Polysorbate 80-free intravenous neurokinin-1 receptor antagonist may provide a safer chemotherapy-induced nausea and vomiting prophylaxis option.

Non-invasive Imaging of Sendai Virus Infection in Pharmacologically Immunocompromised Mice: NK and T Cells, but not Neutrophils, Promote Viral Clearance after Therapy with Cyclophosphamide and Dexamethasone.

In immunocompromised patients, parainfluenza virus (PIV) infections have an increased potential to spread to the lower respiratory tract (LRT), resulting in increased morbidity and mortality. Understanding the immunologic defects that facilitate viral spread to the LRT will help in developing better management protocols. In this study, we immunosuppressed mice with dexamethasone and/or cyclophosphamide then monitored the spread of viral infection into the LRT by using a noninvasive bioluminescence imaging system and a reporter Sendai virus (murine PIV type 1). Our results show that immunosuppression led to delayed viral clearance and increased viral loads in the lungs. After cessation of cyclophosphamide treatment, viral clearance occurred before the generation of Sendai-specific antibody responses and coincided with rebounds in neutrophils, T lymphocytes, and natural killer (NK) cells. Neutrophil suppression using anti-Ly6G antibody had no effect on infection clearance, NK-cell suppression using anti-NK antibody delayed clearance, and T-cell suppression using anti-CD3 antibody resulted in no clearance (chronic infection). Therapeutic use of hematopoietic growth factors G-CSF and GM-CSF had no effect on clearance of infection. In contrast, treatment with Sendai virus-specific polysera or a monoclonal antibody limited viral spread into the lungs and accelerated clearance. Overall, noninvasive bioluminescence was shown to be a useful tool to study respiratory viral progression, revealing roles for NK and T cells, but not neutrophils, in Sendai virus clearance after treatment with dexamethasone and cyclophosphamide. Virus-specific antibodies appear to have therapeutic potential.

PEG-L-CHOP treatment is safe and effective in adult extranodal NK/T-cell lymphoma with a low rate of clinical hypersensitivity.

BACKGROUND: The combination of chemotherapy and L-asparaginase (L-ASP) treatment significantly increased survival rate in an adult patient with extranodal natural killer (NK)/T-cell lymphoma (NKTCL). However, hypersensitivity reactions of L-ASP in some patients limited its application. Polyethylene glycol-conjugated asparaginase (PEG-ASP) has a lower immunogenicity and longer circulating half-life than unconjugated L-ASP, and has been reported to be effective and well-tolerated in children with acute lymphoblastic leukemia. Cyclophosphamide, hydroxydaunorubicin (doxorubicin), oncovin (vincristine), and prednisolone (CHOP) is the most common chemotherapy for non-Hodgkin lymphoma. In this report, we sought to study the efficacy and safety of PEG-L- CHOP in NKTCL in adult Chinese patients. METHODS: Our study is a prospective, multi-center, open-label clinical trial. Patients with newly diagnosed adult NKTCL and an ECOG performance status of 0 to 2 were eligible for enrollment. Treatment included six cycles of PEG-L-CHOP regimen. Radiotherapy was scheduled after 2-4 cycles of PEG-L-CHOP regimen, depending on the stage and primary anatomic site. RESULTS: We enrolled a total of 33 eligible patients. All 33 patients completed 170 cycles of chemotherapy combined with radical radiotherapy. The overall response rate was 96.9% (32/33) with 75.8% (25/33) achieving complete responses and 21.2% (7/33) achieving partial responses. The overall survival (OS) at 1, 2, 3-year were 100, 90.61 and 80.54%, respectively. The major adverse effects were bone marrow suppression, reduction of fibrinogen level, liver dysfunction, and digestive tract toxicities. No allergic reaction and no treatment-related mortality or severe complications were recorded. CONCLUSIONS: PEG-L-CHOP chemotherapy in combination radiotherapy is safe and durably effective treatment for adult extranodal NK/T-cell lymphoma with fewer allergic reactions. This study was approved by the Peking University Beijing Cancer Hospital Ethics Review Committee (reference number: 2011101104). The clinical trial registration number ChiCTR1800016940 was registered on July 07, 2018 at the Chinese Clinical Trial Registry ( http://www.chictr.org.cn/index.aspx ). The clinical trial was registered retrospectively.

Effectiveness of biosimilar filgrastim vs. original granulocyte colony-stimulating factors in febrile neutropenia prevention in breast cancer patients.

PURPOSE: The purpose of this study is to describe the effectiveness of biosimilar filgrastim and original granulocyte colony-stimulating factors (G-CSFs), lenograstim and pegfilgrastim, in febrile neutropenia (FN) prevention in breast cancer patients receiving docetaxel/doxorubicin/cyclophosphamide (TAC) as adjuvant/neoadjuvant treatment and to analyze their treatment patterns. METHODS: A pharmacoepidemiology cohort study was developed in a university hospital (with 23 healthcare centers) with retrospective data collection (2012-2014). Effectiveness of G-CSFs was assessed by the FN incidence. Other parameters analyzed were as follows: moderate and severe neutropenia incidence, neutropenia-related hospitalizations, dosage, and duration. Data was analyzed using each cycle as a unit of analysis. RESULTS: We identified 98 patients representing 518 chemotherapy cycles, 215 with original G-CSFs (35 lenograstim and 180 pegfilgrastim) and 303 with biosimilar filgrastim. The FN incidence was similar in both groups (3.7% original vs. 3.3% biosimilar; p = 0.79). No statistically significant differences were found in moderate and severe neutropenia incidence (4.7 vs. 6.3%; p = 0.43) or neutropenia-related hospitalizations (3.3 vs. 3.6%; p = 0.19). When the three drugs were evaluated separately, a higher FN incidence was observed with lenograstim than with pegfilgratim or biosimilar (p = 0.024). The dosage and duration of biosimilar were lower than lenograstim (4.9 vs. 5.7 µg/kg/day; 5 vs. 7 days; p < 0.001). CONCLUSION: An abbreviated 5-day course of biosimilar filgrastim provided optimal primary prophylaxis against FN post-chemotherapy TAC in patients with breast cancer. The clinical relevance of the highest FN incidence in the lenograstim cohort needs further attention.

MDA-5 associated rapidly progressive interstitial lung disease with recurrent Pneumothoraces: a case report.

BACKGROUND: Clinically hypomyopathic dermatomyositis is a rare disease that is important to recognize, investigate and treat early as it is associated with poor prognosis. In a proportion of patients, myositis specific antibodies could be negative, but with high clinical suspicion, myositis associated antibodies should be ordered. Anti-MDA-5 antibodies was reported in literature to be associated with severe and rapidly progressive interstitial lung disease, with few case reports of pneumothorax and/or pneumomediastinum. CASE PRESENTATION: A 49-year-old previously healthy lady, presented with a 6 week history of skin rash, photosensitivity, mouth ulcers, fatiguability, arthralgia and myalgia. She denied subjective weakness, respiratory symptoms or dysphagia. She had Raynaud's phenomenon affecting her fingers only. Initial examination showed synovitis in her hands with skin rash. Autoimmune screen was negative. She was started on hydroxychloroquine. 4 weeks later on follow-up, she developed proximal muscle pain, dysphagia, dyspnea and dry cough. Examination showed mild proximal muscle weakness and bi-basal crackles. She was admitted and extended myositis screen was sent. She had mild anemia, lymphopenia and neutropenia, normal inflammatory markers, liver and renal panels. Capillaroscopy showed pattern of systemic sclerosis. CT chest showed early ILD. Electromyography and MRI showed features of mild myositis. PFT showed muscle weakness with low DLCO. She was given intravenous steroid and Rituximab. As she continued to deteriorate, intravenous immunoglobulins and cyclophosphamide were given. There was a brief clinical response that was short-lived with increasing oxygen dependency necessitating transfer to the ICU. At this point, the extended myositis screen confirmed the presence of anti-MDA-5 antibodies. She commenced plasmapharesis and required intubation. Unfortunately, she developed multiple pneumothoraces, and was transferred urgently for ECMO. Subsequent immunosuppression included rituximab and tacrolimus. There was progression of her ILD and recurrent pneumothoraces and pneumomediastinum. Unfortunately, she passed away as a consequence of her disease. CONCLUSION: This case highlights a number of considerations in approaching patients with inflammatory myositis, particularly to pulmonary involvement. It is important to highlight the utility of extended myositis antibody testing in predicting disease phenotypes and its impact on therapeutic decisions. From a management perspective, aggressive immunosuppression should be considered with potential need of earlier utilization of ECMO.

Combination Cyclophosphamide/Glucocorticoids Provide Better Tolerability and Outcomes versus Glucocorticoids Alone in Patients with Sjogren's Associated Chronic Interstitial Nephritis.

BACKGROUND: Steroid therapy has become an effective option for patients with primary Sjogren's syndrome with tubulointerstitial nephritis (TIN), while the use of cytotoxic agents is still debated. Our study aimed to compare the clinical outcomes of patients treated with cyclophosphamide (CTX) combined with glucocorticoids with those of patients treated with glucocorticoids alone. METHODS: All patients with primary Sjogren's syndrome with chronic TIN admitted to the Division of Nephrology, Ruijin Hospital, from January 1, 2002, to April 30, 2016, and treated with steroids alone or combined with CTX were included. The immunological prognosis, improvements of renal function, and acquired tubular defects of the patients were retrospectively compared between the 2 therapeutic groups. RESULTS: A total of 70 cases were included. Of these, 36 were diagnosed by renal biopsy. A total of 56 patients were treated with glucocorticoids alone, while 14 patients received glucocorticoids combined with CTX. There were no significant differences in clinical characteristics and laboratory parameters between the 2 therapeutic groups at baseline. Compared with patients in the steroid group, patients in the CTX group showed better estimated glomerular filtration rate (eGFR) improvement (21.35 ± 19.63 vs. 2.72 ± 19.11 mL/min/1.73 m2, p = 0.006) but a similar decline in immunoglobulin G (IgG; 450 [interquartile range, IQR 910] vs.176 [IQR 1,910] mg/dL, p = 0.93) at 12 months of follow-up. CTX therapy was associated with better eGFR improvement (ß = 12.96 [2.95-22.97]) even after adjusting for dry mouth, anti-Sjögren's-syndrome-related antigen A and anti-Sjögren's-syndrome-related antigen B positivity, hemoglobin, initial steroid dose, and baseline eGFR by linear regression analyses. Subgroup analyses revealed that the beneficial effects of CTX therapy on renal function were only observed in patients with baseline IgG ≥1,560 mg/dL or eGFR <90 mL/min/1.73 m2. The urine α1-microglobulin improvement was better in the CTX group than in the steroid group at 12 months of follow-up (ß = 1.29, 95% CI 0.56-2.02, p = 0.001). CONCLUSIONS: CTX therapy is suggested for primary Sjogren's syndrome patients with chronic TIN, especially those with higher IgG levels and abnormal renal function at baseline.

Efficacy of reduced dose of pegfilgrastim in Japanese breast cancer patients receiving dose-dense doxorubicin and cyclophosphamide therapy.

BACKGROUND: This retrospective study aimed to evaluate the efficacy of a 3.6-mg dose of pegfilgrastim for primary prophylaxis in Japanese breast cancer patients receiving dose-dense chemotherapy. METHODS: Patients treated with adjuvant or neoadjuvant chemotherapy for early-stage breast cancer at the Tokyo-West Tokushukai Hospital were included in this analysis. Because 6 mg pegfilgrastim has not yet been approved for use in Japan, we compared the outcomes of a dose-dense doxorubicin and cyclophosphamide regimen plus 3.6 mg pegfilgrastim support with a conventional dose epirubicin and cyclophosphamide regimen. The incidence of febrile neutropenia, relative dose intensity, dose delay, dose reduction, regimen change and hospitalization because of neutropenia were assessed. RESULTS: From November 2013 to March 2016, 97 patients with stage I-III invasive breast cancer were analyzed (dose-dense doxorubicin and cyclophosphamide plus 3.6-mg pegfilgrastim group, n  =  41; epirubicin and cyclophosphamide group, n  =  56; median ages, 49.0 and 48.5 years, respectively). Febrile neutropenia occurred during the first chemotherapy cycle in 7 of 56 patients (12.5%) in the epirubicin and cyclophosphamide group and 0 of 41 patients in the dose-dense doxorubicin and cyclophosphamide group (P  =  0.02). The average relative dose intensities were 97.9% and 96.8%, respectively (P  =  0.28), with corresponding dose delay rates of 4.9% (2/41) and 16.1% (9/56), respectively (P  =  0.11) and dose reduction rates of 0% (0/41) and 7.1% (4/56), respectively (P  =  0.16). CONCLUSIONS: Our results indicate the efficacy of a 3.6-mg pegfilgrastim dose for the primary prevention of febrile neutropenia in dose-dense doxorubicin- and cyclophosphamide-treated Japanese breast cancer patients.

A randomized, double-blind trial of pegfilgrastim versus filgrastim for the management of neutropenia during CHASE(R) chemotherapy for malignant lymphoma.

Pegfilgrastim is a pegylated form of the granulocyte-colony stimulating factor, filgrastim. Herein, we report the results of a multicentre, randomized, double-blind phase III trial comparing the efficacy and safety of pegfilgrastim with filgrastim in patients with malignant lymphoma. Patients were randomized to receive either a single subcutaneous dose of pegfilgrastim or daily subcutaneous doses of filgrastim on day 4 after the completion of cyclophosphamide, cytarabine, etoposide and dexamethasone ± rituximab (CHASE(R); day 1-3) chemotherapy. The primary endpoint was the duration of severe neutropenia (DSN), defined as the number of days with neutrophil count <0·5 × 10(9) /l in the first cycle of chemotherapy. A total of 111 lymphoma patients were randomized to either the pegfilgrastim or filgrastim group. 109 patients received either pegfilgrastim (n = 54) or filgrastim (n = 55). Efficacy data were available for 107 patients (pegfilgrastim: n = 53, filgrastim: n = 54). Both groups were well balanced in terms of gender, age, performance status and other variables. The mean DSN (±S.D.) was 4·5 (±1·2) and 4·7 (±1·3) d in the pegfilgrastim and filgrastim groups. No significant difference in safety was observed. This trial verified the non-inferiority of a single subcutaneous dose of pegfilgrastim compared with daily subcutaneous doses of filgrastim, considering DSN as an indicator.

Pegylated Liposomal Doxorubicin Is an Active Agent for Chemotherapy-Resistant Choriocarcinoma: A Report of Two Cases.

BACKGROUND: Despite advances in chemotherapy, radiation, surgery, and supportive treatments, a significant proportion of high-risk metastatic gestational trophoblastic disease patients develop resistant disease and die. Of those cured, protracted treatments can lead to long-term morbidity or later toxicity and death. Here we describe 2 patients with brain metastases who failed multiple lines of standard chemotherapy and radiation but had complete response to pegylated liposomal doxorubicin (PLD). CASE 1: A 35-year-old woman presented with choriocarcinoma in the brain, lungs, and subcutaneous tissues 11 months after full-term delivery. Her FIGO risk score was 14. Over 3 years she was treated with EMA-CO, EMA-CE, Taxol, gemcitabine, brain radiation, and excisional craniotomy for recurrent choriocarcinoma. She showed complete response of choriocarcinoma brain metastases following 2 cycles of PLD. She was choriocarcinoma free until her death 9 months later from acute myelogenous leukemia. CASE 2: A 52-year-old multigravid woman presented with choriocarcinoma 3 years following miscarriage. Her FIGO score was 16. Over 18 months she was treated with EMA-CO, TP/TE and IT MTX, and radiation. Her disease proved resistant and midbrain tumor unresectable. She showed complete response to PLD following 3 cycles but ultimately died from neurologic complications. CONCLUSION: PLD is an active agent in the treatment of high-risk choriocarcinoma.

[Autoimmune disorder secondary to DiGeorge syndrome: a long-term follow-up case report and literature review].

DiGeorge syndrome is the most common chromosome microdeletion disease. The classical complications include congenital heart disease, hypothyroidism, immunodeficiency, facial abnormalities, and hypocalcemia. According to whether there is an absence or hypoplasia of the thymus, DiGeorge syndrome can be divided into two types, complete DiGeorge syndrome and partial DiGeorge syndrome. The patient was a female born with congenital heart disease, facial abnormalities and cleft palate. When the patient went to school, she had learning difficulty and had problems in communication and personal social behavior. Breath-holding occurred when she was 6 years old. She got infections about 2-3 times a year, which was easy to be cured each time. Chromosome microdeletion test of peripheral blood showed the classical 22q11.2 microdeletion, and no evidence showed that she has thymus absence, thus her disease was diagnosed as partial DiGeorge syndrome. When the patient was 6 years old, the blood routine test showed slight thrombocytopenia, and reexaminations after that indicated the similar result. When 9 years old, she was found with anemia and severe thrombocytopenia. At the age of 10, the patient was admitted to our hospital, complaining of petechia in the body and mucous of mouth. According to the various examinations results, doctors eventually considered the situation as an autoimmune disorder phenomenon. After being treated by pulse-dose methylprednisolone for three days, the bleeding ceased. Then the patient orally took prednisone acetate and pulse-dose cyclophosphamide, however the thrombocyte and hemoglobin levels had not been back to a normal range. But when the dose of prednisone acetate was reduced, the blood platelet count declined again while the hemoglobin kept normal. The long-term follow-up of this case lasted for more than 20 years. Until now, the patient is taking orally prednisone acetate as a maintainance treatment, and the anemia has been improved since, but thrombocytopenia still exists. The mechanism of DiGeorge syndrome in combination with immunodeficiency is still unclear. The most likely reason is that this phenomenon has some relationship with the dysfunction of the thymus and finally had an effect on the function of T cells. The clinical manifestation is always stubborn and need treatment and follow-up visit for a long time.

Dose response of pegfilgrastim in Japanese breast cancer patients receiving six cycles of docetaxel, doxorubicin, and cyclophosphamide therapy: a randomized controlled trial.

PURPOSE: A phase II, open-label, dose-finding, randomized study was performed to evaluate the recommended dose of pegfilgrastim in Japanese breast cancer patients. METHODS: Patients received 1.8, 3.6, or 6.0 mg of pegfilgrastim once per chemotherapy cycle for up to 6 cycles. Patients received docetaxel, doxorubicin, and cyclophosphamide (TAC) therapy followed by pegfilgrastim on the next day. RESULTS: Pegfilgrastim was administered to 87 women with stage II/III invasive breast carcinoma. The duration of grade 4 neutropenia in the first cycle, the primary endpoint, was 2.2 ± 0.9 days, 1.5 ± 0.9 days, and 1.4 ± 0.7 days in the 1.8, 3.6, and 6.0 mg groups, respectively. This finding indicated that pegfilgrastim efficacy peaked at 3.6 mg. Pegfilgrastim doses up to 6.0 mg were considered safe. CONCLUSION: A 3.6-mg pegfilgrastim dose may be safe and effective for Japanese patients. A confirmatory study is required to establish safety and efficacy at this dose for intensive anti-cancer chemotherapy.