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FASEB Journal : Official Publication of... Aug 2018Chemotherapy-induced hemorrhagic cystitis (CHC) can be difficult to manage. Prior work suggests that IL-4 alleviates ifosfamide-induced hemorrhagic cystitis (IHC), but...
Chemotherapy-induced hemorrhagic cystitis (CHC) can be difficult to manage. Prior work suggests that IL-4 alleviates ifosfamide-induced hemorrhagic cystitis (IHC), but systemically administered IL-4 causes significant side effects. We hypothesized that the Schistosoma hematobium homolog of IL-4-inducing principle from Schistosoma mansoni eggs (H-IPSE), would reduce IHC and associated bladder pathology. IPSE binds IgE on basophils and mast cells, triggering IL-4 secretion by these cells. IPSE is also an "infiltrin," translocating into the host nucleus to modulate gene transcription. Mice were administered IL-4, H-IPSE protein or its nuclear localization sequence (NLS) mutant, with or without neutralizing anti-IL-4 antibody, or 2-mercaptoethane sulfonate sodium (MESNA; a drug used to prevent IHC), followed by ifosfamide. Bladder tissue damage and hemoglobin content were measured. Spontaneous and evoked pain, urinary frequency, and bladdergene expression analysis were assessed. Pain behaviors were interpreted in a blinded fashion. One dose of H-IPSE was superior to MESNA and IL-4 in suppressing bladder hemorrhage in an IL-4-dependent fashion and comparable with MESNA in dampening ifosfamide-triggered pain behaviors in an NLS-dependent manner. H-IPSE also accelerated urothelial repair following IHC. Our work represents the first therapeutic exploitation of a uropathogen-derived host modulatory molecule in a clinically relevant bladder disease model and indicates that IPSE may be an alternative to MESNA for mitigating CHC.-Mbanefo, E. C., Le, L., Pennington, L. F., Odegaard, J. I., Jardetzky, T. S., Alouffi, A., Falcone, F. H., Hsieh, M. H. Therapeutic exploitation of IPSE, a urogenital parasite-derived host modulatory protein, for chemotherapy-induced hemorrhagic cystitis.
Topics: Animals; Antineoplastic Agents; Basophils; Cystitis; Egg Proteins; Female; Helminth Proteins; Hemorrhage; Hemorrhagic Disorders; Immunoglobulin E; Interleukin-4; Mice; Mice, Inbred C57BL; Parasites; Schistosoma haematobium; Schistosoma mansoni; Urinary Bladder
PubMed: 29613835
DOI: 10.1096/fj.201701415R -
Pharmaceuticals (Basel, Switzerland) Nov 2021One of the major side effects of cyclophosphamide (CPX)-an alkylating anticancer drug that is still clinically used-is urotoxicity with hemorrhagic cystitis. The present...
One of the major side effects of cyclophosphamide (CPX)-an alkylating anticancer drug that is still clinically used-is urotoxicity with hemorrhagic cystitis. The present study was designed to evaluate the ability of carvedilol to protect rats from cyclophosphamide-induced urotoxicity. Rats were injected intraperitoneally () with CPX (200 mg/kg) and administered carvedilol (2 mg/kg) intragastrically a day before, at the day and a day after a single . injection of CPX, with or without mesna (40, 80, and 80 mg/kg 20 min before, 4 h and 8 h after CPX administration, respectively). Pretreatment with carvedilol partly prevented the CPX-induced increase in urinary bladder and kidney index, and completely protects from CPX-evoked alterations in serum potassium and creatinine level, but did not prevent histological alterations in the urinary bladder and hematuria. However, carvedilol administration resulted in significant restoration of kidney glutathione (GSH) level and a decrease in kidney interleukin 1β (IL-1β) and plasma asymmetric dimethylarginine (ADMA) concentrations. Not only did mesna improve kidney function, but it also completely reversed histological abnormalities in bladders and prevented hematuria. In most cases, no significant interaction of carvedilol with mesna was observed, although the effect of both drugs together was better than mesna given alone regarding plasma ADMA level and kidney IL-1β concentration. In conclusion, carvedilol did not counteract the injury caused in the urinary bladders but restored kidney function, presumably via its antioxidant and anti-inflammatory properties.
PubMed: 34959638
DOI: 10.3390/ph14121237 -
Cureus Feb 2024Polyarteritis nodosa (PAN) is a connective tissue disease that affects arteries, causing necrotizing inflammation that can weaken the arterial walls, dilatation into...
Polyarteritis nodosa (PAN) is a connective tissue disease that affects arteries, causing necrotizing inflammation that can weaken the arterial walls, dilatation into aneurysms, and rupture in some cases. We present a case of a male with acute abdomen from aneurysmal rupture. The 48-year-old patient with a history of polysubstance use including cocaine and methamphetamines was admitted for acute hypoxic respiratory failure secondary to coronavirus disease 2019 (COVID-19) pneumonia and treated with broad-spectrum antibiotics and steroids. He also reported generalized abdominal pain and discomfort, and examination revealed abdominal distension that was diffusely tender on palpation, bowel sounds intact. Laboratory workup showed a progressive drop in hemoglobin requiring blood transfusions, no coagulopathy, anion gap metabolic acidosis, and lactic acidosis. Abdominal CT showed a 2 cm lobulated saccular aneurysm involving either the left gastric artery or splenic artery, associated with an extensive moderate amount of hemoperitoneum with hematomas (largest measuring up to 8.6 cm) abutting the gastric fundus and greater curvature of the stomach, which was likely secondary to aneurysmal rupture. Additionally, several other mesenteric vessels displayed some degree of dilation. Interventional radiology (IR)-guided splenic artery embolization for splenic artery aneurysm was done, after which his hemoglobin remained stable. The patient was given vaccine recommendations since splenic artery embolization would lead to asplenia. The aneurysms were attributed to either cocaine-related aneurysms or polyarteritis nodosa with visceral artery aneurysms. He denied rashes, oral ulcers, joint pain, subcutaneous nodules, blood in the urine, history of hepatitis or syphilis. Tertiary syphilis was ruled out after the Venereal Disease Research Laboratory (VDRL) test and rapid plasma reagin (RPR) test were negative. Complement C3 and C4 levels were normal. He was treated with high-dose IV methylprednisone after infection was ruled out. Due to the severity of PAN, therapy with IV cyclophosphamide therapy 15 mg/kg once every two weeks for three doses was initiated, followed by 15 mg/kg once every three weeks for three to six months (in combination with glucocorticoids prednisone 1 mg/kg body weight with slow taper). Cyclophosphamide was given with IV hydration and mesna. The presentation of PAN can vary widely. Most commonly, individuals experience symptoms such as fatigue, weight loss, fever, and chills. However, in rare cases, patients may present with isolated abdominal pain, similar to our patient. It's crucial to note that the rupture of an aneurysm can manifest as an acute abdominal issue, potentially leading to life-threatening situations. Immediate interventions to control bleeding are imperative in such cases. The treatment of PAN has a high success rate when a combination of cyclophosphamide and steroids is administered.
PubMed: 38558645
DOI: 10.7759/cureus.55143 -
Clinical Lymphoma, Myeloma & Leukemia Sep 2019Multiple myeloma (MM) usually follows a clinical course leading to refractoriness and limited treatment options in advanced stages, which might need bridge therapies to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Multiple myeloma (MM) usually follows a clinical course leading to refractoriness and limited treatment options in advanced stages, which might need bridge therapies to either autologous stem cell transplantation or novel therapies. We report our experience with the high-dose chemotherapy mCBAD (modified cyclophosphamide, bortezomib, doxorubicin, and dexamethasone) regimen in newly diagnosed MM (NDMM), relapsed/refractory MM (RRMM), and plasma cell leukemia (PCL) patients.
PATIENTS AND METHODS
We searched our electronic records database for MM patients who received mCBAD from 2010 to 2016 for 28-day cycles of cyclophosphamide 350 mg/m intravenously (I.V.) twice daily with mesna 400 mg/m I.V. daily (days 1-4), bortezomib 1.3 mg/m subcutaneously/I.V. (days 1, 4, 8, 11), doxorubicin 9 mg/m daily continuous infusion (days 1-4), dexamethasone 40 mg orally daily (on days 1-4, 9-12, 17-20). International Myeloma Working Group (IMWG) criteria were used for response assessment and diagnosis. Descriptive statistics, Fisher exact test, χ, Wilcoxon rank sum, and Kaplan-Meier were used for statistical purposes.
RESULTS
One hundred forty patients met the inclusion criteria. A median of 2 cycles of therapy was administered. The overall response rate was 85% in patients with RRMM (n = 116) and 100% in NDMM (n = 13) and PCL (n = 11) patients. Respective median progression-free survival (mPFS) for NDMM, PCL, and RRMM were 19.61 months (95% confidence interval [CI], 5.26 to not applicable [NA]), 7.56 months (95% CI, 4.7 to NA), and 4.64 months (95% CI, 3.75-6.73). Patients with RRMM who used mCBAD as a bridge to autologous transplant (36.2%) had mPFS (11.48 months; 95% CI, 7.52-15.9 months) compared with those who did not (mPFS: 3.19 months; 95% CI, 2.4-3.75 months). Cytopenias occurred in more than 90% of patients, and febrile neutropenia was noted in 26%. All cases of treatment-related mortality (8%) occurred in patients with RRMM, except for 1 patient with PCL.
CONCLUSION
mCBAD results in high response rates in myeloma and PCL, however, with high treatment-related mortality. Its use in RRMM should be limited to patients who have immediate need for therapy without other treatment options and who have good performance status (score of 0-1) or NDMM if novel agents are not available depending on practice setting. mCBAD can be a treatment option for patients with PCL.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Cyclophosphamide; Dexamethasone; Doxorubicin; Drug Resistance, Neoplasm; Female; Humans; Leukemia, Plasma Cell; Male; Middle Aged; Multiple Myeloma; Neoplasm Staging; Prognosis; Recurrence; Research Design; Retreatment; Treatment Outcome; Young Adult
PubMed: 31201134
DOI: 10.1016/j.clml.2019.05.001 -
Journal of B.U.ON. : Official Journal... 2016One half of high-risk germ cell tumor (HRGCT) patients relapse after standard chemotherapy. This phase II study evaluated prospectively the toxicity and efficacy in...
A phase II single institution single arm prospective study with paclitaxel, ifosfamide and cisplatin (TIP) as first-line chemotherapy in high-risk germ cell tumor patients with more than ten years follow-up and retrospective correlation with ERCC1, Topoisomerase 1, 2A, p53 and HER-2 expression.
PURPOSE
One half of high-risk germ cell tumor (HRGCT) patients relapse after standard chemotherapy. This phase II study evaluated prospectively the toxicity and efficacy in first-line of the paclitaxel-ifosfamide-cisplatin combination (TIP) in HRGCT patients and tried to identify biomarkers that may allow patient-tailored treatments.
METHODS
Between October 1997- September 2000, 28 chemo-naive HRGCT patients were enrolled. Patients received 4 cycles of TIP (paclitaxel 175 mg/m(2) day 1/; ifosfamide 1.2 g/m(2)/day, days 1-5; Mesna 1.2 g/m(2)/day, days 1-5; and cisplatin 20 mg/m(2)/day, days 1-5 every 3 weeks). A non-randomized comparison was made between HRGCT patients treated in the same period with first-line TIP and bleomycin-etoposide-cisplatin (BEP) (28 patients vs 20). In 17 HRGCT patients treated between 1998-2006, ERCC1, Topoisomerase 1 and 2A, p53 and HER-2 expression was retrospectively analysed by immunohistochemistry (IHC) (7 patients with TIP, 10 with BEP), and correlations were made with response to chemotherapy and survival.
RESULTS
With a median follow-up of 72 months [range 48+...89+], 5-year disease free survival (DFS) was 55%, with 95% CI 36-72, and the overall survival (OS) was 63%, with 95% CI 44-78. In June 2015, with a median follow-up of 196.47 months (range 177.30-209.27) (>15 years), 12 [%?] patients were alive and disease-free, and 16 [%?] had died (12 specific causes). There was no significant correlation between the expression of ERCC1, Topoisomerase 1 and 2A, HER-2 and p53 and response to treatment.
CONCLUSION
Long-term follow-up showed no difference in OS between TIP vs BEP as first-line therapy. Both regimens had mild toxicity.
Topics: Adult; Aged; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; DNA Topoisomerases, Type I; DNA Topoisomerases, Type II; DNA-Binding Proteins; Endonucleases; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasms, Germ Cell and Embryonal; Prospective Studies; Receptor, ErbB-2; Retrospective Studies; Testicular Neoplasms; Tumor Suppressor Protein p53
PubMed: 27569093
DOI: No ID Found -
International Journal of Experimental... Dec 2015Oxidative damage is a central feature of ulcerative colitis. Here, we tested whether the antioxidant Mesna, when administered alone or in combination with n-3...
Oxidative damage is a central feature of ulcerative colitis. Here, we tested whether the antioxidant Mesna, when administered alone or in combination with n-3 polyunsaturated fatty acids (n-3 PUFAs), affects the outcome of dextran sodium sulphate (DSS)-induced ulcerative colitis in rats. After the induction of colitis, DSS-treated rats were further treated orally (p.o), intraperitoneally (i.p) or intrarectally (i.r) for either 7 or 14 days with Mesna, n-3 PUFAs or both. Rats were euthanized at the end of each treatment period. Clinical disease activity index was recorded throughout the experiment. At necropsy colorectal gross lesions were scored. Colitis was scored histologically, and the expression of myeloperoxidase (MPO), caspase-3, inducible nitric oxide synthase (iNOS) and nuclear factor κB (NF-κΒ) in colonic tissue was assessed by immunohistochemistry. Mesna alone was sufficient to significantly reduce colorectal tissue damage when administered orally or intraperitoneally. Orally coadministered n-3 PUFAs enhanced this effect, resulting in the significant suppression of DSS colitis after 7 days, and a remarkable recovery of colorectal mucosa was evident after 14 days of treatment. The amelioration of colon pathology co-existed with a significant decrease in MPO expression, overexpression of iNOS and reduction of nuclear NF-κB p65 in inflammatory cells, and the suppression of apoptosis in colonic epithelial cells. The simultaneous administration of Mesna and n-3 PUFAs is particularly effective in ameliorating DSS colitis in rats, by reducing oxidative stress, inflammation and apoptosis, probably through a mechanism that involves the inhibition of NF-κB and overexpression of iNOS.
Topics: Animals; Antioxidants; Apoptosis; Biomarkers; Caspase 3; Colitis, Ulcerative; Colon; Cytoprotection; Dextran Sulfate; Disease Models, Animal; Fatty Acids, Omega-3; Intestinal Mucosa; Male; Mesna; Nitric Oxide Synthase Type II; Oxidative Stress; Peroxidase; Rats, Wistar; Time Factors; Transcription Factor RelA
PubMed: 26852691
DOI: 10.1111/iep.12163 -
Journal of Bacteriology Jun 2019Methanogenesis from methylated substrates is initiated by substrate-specific methyltransferases that generate the central metabolic intermediate methyl-coenzyme M. This...
Methanogenesis from methylated substrates is initiated by substrate-specific methyltransferases that generate the central metabolic intermediate methyl-coenzyme M. This reaction involves a methyl-corrinoid protein intermediate and one or two cognate methyltransferases. Based on genetic data, the MtpC (corrinoid protein) and MtpA (methyltransferase) proteins were suggested to catalyze the methylmercaptopropionate (MMPA):coenzyme M (CoM) methyl transfer reaction without a second methyltransferase. To test this, MtpA was purified after overexpression in its native host and characterized biochemically. MtpA catalyzes a robust methyl transfer reaction using free methylcob(III)alamin as the donor and mercaptopropionate (MPA) as the acceptor, with of 0.315 s and apparent for MPA of 12 μM. CoM did not serve as a methyl acceptor; thus, a second unidentified methyltransferase is required to catalyze the full MMPA:CoM methyl transfer reaction. The physiologically relevant methylation of cob(I)alamin with MMPA, which is thermodynamically unfavorable, was also demonstrated, but only at high substrate concentrations. Methylation of cob(I)alamin with methanol, dimethylsulfide, dimethylamine, and methyl-CoM was not observed, even at high substrate concentrations. Although the corrinoid protein MtpC was poorly expressed alone, a stable MtpA/MtpC complex was obtained when both proteins were coexpressed. Biochemical characterization of this complex was not feasible, because the corrinoid cofactor of this complex was in the inactive Co(II) state and was not reactivated by incubation with strong reductants. The MtsF protein, composed of both corrinoid and methyltransferase domains, copurifies with the MtpA/MtpC, suggesting that it may be involved in MMPA metabolism. Methylmercaptopropionate (MMPA) is an environmentally significant molecule produced by degradation of the abundant marine metabolite dimethylsulfoniopropionate, which plays a significant role in the biogeochemical cycles of both carbon and sulfur, with ramifications for ecosystem productivity and climate homeostasis. Detailed knowledge of the mechanisms for MMPA production and consumption is key to understanding steady-state levels of this compound in the biosphere. Unfortunately, the biochemistry required for MMPA catabolism under anoxic conditions is poorly characterized. The data reported here validate the suggestion that the MtpA protein catalyzes the first step in the methanogenic catabolism of MMPA. However, the enzyme does not catalyze a proposed second step required to produce the key intermediate, methyl coenzyme M. Therefore, the additional enzymes required for methanogenic MMPA catabolism await discovery.
Topics: Catalysis; Mercaptopurine; Mesna; Methanosarcina; Methylation; Methyltransferases; Vitamin B 12
PubMed: 30936368
DOI: 10.1128/JB.00130-19 -
Urology Case Reports May 2022Prostate embryonal rhabdomyosarcoma (ERMS) is a common tumour in infants and children, but it is rare in adults. It is characterized by a high degree of malignancy, both...
Prostate embryonal rhabdomyosarcoma (ERMS) is a common tumour in infants and children, but it is rare in adults. It is characterized by a high degree of malignancy, both local rapid growth with formation of large pelvic masses, often leading to renal failure due to bladder outlet obstruction, and systemic spread, commonly to the lungs, liver and bone. We report on a case of a stage III prostate ERMS, approached with combined-modality treatment, with the administration of 5 courses of doxorubicin, ifosfamide and 2-mercaptoethane sulfonate sodium (mesna), with planned subsequent radiotherapy to the prostatic bed (60 Gy/30 fractions).
PubMed: 35530538
DOI: 10.1016/j.eucr.2022.102027 -
JCEM Case Reports Sep 2023Primary pituitary T-lymphoblastic lymphoma is a rare clinical entity. A 45-year-old woman presented with headache, left-eye blurry vision, diplopia, ophthalmoplegia, and...
Primary pituitary T-lymphoblastic lymphoma is a rare clinical entity. A 45-year-old woman presented with headache, left-eye blurry vision, diplopia, ophthalmoplegia, and ptosis. Magnetic resonance imaging of the brain showed a sellar mass most likely consistent with a pituitary macroadenoma. Laboratory evaluation disclosed secondary hypothyroidism, secondary adrenal insufficiency, and hyperprolactinemia. The mass was removed by transsphenoidal resection, and subsequent immunophenotyping revealed T-cell lymphoblastic lymphoma. Secondary workup confirmed lymphomatous confinement to the central nervous system. Following resection, the patient's headaches improved, but she experienced persistent visual deficits and palsies of cranial nerves III, IV, and VI. The chemotherapy regimen consisted of high-dose methotrexate, followed by alternating cycles of cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride (Adriamycin), dexamethasone (cyclophosphamide, mesna, vincristine sulfate, doxorubicin hydrochloride, dexamethasone), and methotrexate/cytarabine. Since receiving chemotherapy, there has been an improvement in numbness, ptosis, left orbital pressure, and headaches. This case represents only the eighth example of T-cell primary pituitary lymphoma, and the youngest patient to receive the diagnosis.
PubMed: 37908217
DOI: 10.1210/jcemcr/luad097 -
Cureus Aug 2017Cyclophosphamide-induced bladder malignancy is a well-known entity mediated by its metabolic product, acrolein. There is a significant association between...
Cyclophosphamide-induced bladder malignancy is a well-known entity mediated by its metabolic product, acrolein. There is a significant association between the incidence of hemorrhagic cystitis during treatment and the later development of malignancies. We report a case of multifocal urothelial carcinoma occurring in a patient treated with ifosfamide 19 years ago. No case report of ifosfamide-induced malignancy could be identified in the literature. A brief review of the literature on the relative risks of ifosfamide therapy, the mechanism of bladder toxicity, and suggestions to minimize the deleterious effects of the drug have been done. Ifosfamide should be used in the lowest possible dose and that patients receiving more than 20 grams of the drug should undergo a routine urinalysis for microscopic hematuria. Prophylactic measures such as high fluid intake, frequent voiding, day time administration of the drug, and concomitant use of mesna may decrease the contact time and the concentrations of toxic metabolites on the bladder urothelium.
PubMed: 29062626
DOI: 10.7759/cureus.1594