Clinical Outcome of Neoadjuvant Radiochemotherapy in Locally Advanced Cervical Cancer: Results of an Open Prospective, Multicenter Phase 2 Study of the North-Eastern German Society of Gynecological Oncology.

OBJECTIVE: The aim of this study was to determine the response rate, toxicity, operability, and surgical complication rate of neoadjuvant concomitant radiochemotherapy (cRCH) (ifosfamide + carboplatin) followed by radical hysterectomy plus external-beam radiotherapy with curative intention in locally advanced primary inoperable stages IIB and IIIB squamous cell cervical cancer. METHODS: Patients with cervical cancer from 8 departments were enrolled. Patients received 3 cycles of ifosfamide 1.2 mg/m (+mesna 20%) plus carboplatin (area under the curve = 4), every 21 days, and concomitant external-beam radiotherapy (50.4 Gy [1.8 Gy/d]). Operability and remission were evaluated by clinical gynecological examination in general anesthesia (magnetic resonance imaging was optional), 4 weeks after the third cycle of cRCH. In case of achieved operability, a radical hysterectomy with pelvic lymphadenectomy was performed within 6 weeks after cRCH. If surgery was not performed because of incomplete remission or patient preferences, vaginal brachytherapy (15 Gy [5 Gy/d]) was given additionally. RESULTS: Forty-four patients were enrolled. Distribution of FIGO (International Federation of Gynecology and Obstetrics) tumor stage was as follows: IIB (19 patients) and IIIB (25 patients). All patients completed cRCH. Grade 3/4 hematologic toxicities (% of all cycles) were moderate: leukopenia, 7.3; thrombocytopenia, 2.4; and anemia, 3.2. In 13.8%, treatment cycles were delayed because of hematologic toxicity. Blood transfusions were given in 17.7% and granulocyte colony-stimulating factor in 39.5%. Overall, grade 3/4 nonhematologic toxicities were seldom (6.5%). Clinical overall response rate was 95.2%. Operability was achieved in 85.7%. Surgery was performed in 83.3%. Pathological response rates were as follows: pathological complete remission, 33.3%; partial remission, 63.3%; stable disease, 3.3%. CONCLUSIONS: Our study demonstrates that cRCH is an effective and tolerable regimen in locally advanced cervical cancer treatment.

Toxic epidermal necrolysis due to therapy with cyclophosphamide and mesna. A case report of a patient with seronegative rheumatoid arthritis and rheumatoid vasculitis.

Rheumatoid vasculitis usually occurs on the background of seropositive rheumatoid arthritis, although in rare cases the patients can be seronegative. We report a woman with seronegative rheumatoid arthritis with rheumatoid vasculitis who developed toxic epidermal necrolysis involving most of her body surface area, while on therapy with intravenous cyclophosphamide and mesna. After withdrawal of suspected offending agents, administration of intravenous immunoglobulin, and supportive therapy, she had a favorable outcome. Such an occurrence is rare and serves to educate about a potentially life-threatening adverse event associated with a commonly used immunosuppressive agent.

[Drug patch tests in the investigation of a fixed drug eruption subsequent to 2 courses of cyclophosphamide in combination with mesna]. / Tests épicutanés pour un érythème pigmenté fixe après prise de cyclophosphamide associé au mesna.

BACKGROUND: When fixed drug eruption occurs following use of cyclophosphamide and mesna, it is difficult to establish which drug is responsible. We report a new case of patch tests that resulted in withdrawal of mesna and enabled continued treatment with cyclophophamide. PATIENTS AND METHODS: A 57-year-old female patient with multiple sclerosis presented increasingly severe cutaneous lesions after successive courses of cyclophosphamide. Twenty-four hours after her latest treatment, she presented at the ER with a worse eruption than those to date and including facial lesions. The clinical diagnosis was a fixed drug eruption, and patch tests for mesna one month later were positive. CONCLUSION: Fixed drug eruption always occurs after recurrent treatment and the investigation must be precise. Patch tests may be used to determine which drug could be responsible. The most conclusive test comprises withdrawal of the incriminated drug with no further signs of drug eruption on resumption of the other medication.

Neoadjuvant and adjuvant chemotherapy with modified mesna, adriamycin, ifosfamide, and dacarbazine (MAID) regimen for adult high-grade non-small round cell soft tissue sarcomas.

BACKGROUND: Good local control of high-grade non-small round cell soft tissue sarcomas (NSRCSTSs) has been achieved with significant advances in surgical techniques and radiotherapy. However, the role of chemotherapy remains controversial. Our aim was to investigate the efficacy, feasibility and adverse effects of neoadjuvant and adjuvant chemotherapy with modified mesna, adriamycin, ifosfamide and dacarbazine (MAID) regimen for NSRCSTSs. METHODS: We conducted a retrospective review of 40 consecutive patients (29 men, 11 women; median age 47 years) with high-grade NSRCSTSs treated in two referral centers between 2004 and 2009 (median follow-up 38.5 months). Patients with distant or nodal metastases at diagnosis were excluded. The regimen consisted of ifosfamide 2,500 mg/m(2)/6 h (days 1-3), mesna 2,500 mg/m(2)/6 h (days 1-3), tetrahydropyranyl adriamycin 20 mg/m(2)/0.5 h (days 1-3), and dacarbazine 300 mg/m(2)/1 h (days 1-3). RESULTS: Among the 26 evaluable patients, there were 8 with a partial response, 15 with stable disease, and 3 with progressive disease. Two- and 5-year overall survival rates were 92 and 86%, respectively, and corresponding disease-free survival rates were 80 and 77%. All relapses were metastases without local recurrence. Grade 3-4 neutropenia, anemia and thrombocytopenia were observed in 38, 18, and 21 patients, respectively. No serious infectious complications occurred due to the administration of granulocyte colony-stimulating factor and prophylactic antibiotics. No other life-threatening serious adverse events were observed. CONCLUSION: The modified MAID regimen achieved a better outcome with less serious adverse events than previously reported and is a potential option in the management of NSRCSTSs. Further evaluation with long-term follow-up is required.

[8] and [10]-Gingerol reduces urothelial damage in ifosfamide-induced hemorrhagic cystitis via JAK/STAT/FOXO signaling pathway via IL-10.

Acrolein is the main toxic metabolite of ifosfamide (IFO) that causes urothelial damage by oxidative stress and inflammation. Here, we investigate the molecular mechanism of action of gingerols, Zingiber officinale bioactive molecules, as an alternative treatment for ifosfamide-induced hemorrhagic cystitis. Female Swiss mice were randomly divided into 5 groups: control; IFO; IFO + Mesna; and IFO + [8]- or [10]-gingerol. Mesna (80 mg/kg, i.p.) was given 5 min before, 4 and 8 h after IFO (400mg/kg, i.p.). Gingerols (25 mg/kg, p.o.) were given 1 h before and 4 and 8 h after IFO. Animals were euthanized 12 h after IFO injection. Bladders were submitted to macroscopic and histological evaluation. Oxidative stress and inflammation were assessed by malondialdehyde (MDA) or myeloperoxidase assays, respectively. mRNA gene expression was performed to evaluate mesna and gingerols mechanisms of action. Mesna was able to protect bladder tissue by activating NF-κB and NrF2 pathways. However, we demonstrated that gingerols acted as an antioxidant and anti-inflammatory agent stimulating the expression of IL-10, which intracellularly activates JAK/STAT/FOXO signaling pathway.

Evaluation of the Efficacy of Lactobacillus acidophilus in the Treatment of Cyclophosphamide-induced Hemorrhagic Cystitis in Wistar Rats.

BACKGROUND: Hemorrhagic cystitis is an inflammatory complication that can be caused by the administration of cyclophosphamide, which is widely used as an antineoplastic agent. In the search for new therapeutic alternatives, probiotics can suppress the inflammatory process and, therefore, can be used to prevent this disease. OBJECTIVE: Thus, this study aimed to evaluate the effects of using Lactobacillus acidophilus NCFM in the treatment of cyclophosphamide-induced hemorrhagic cystitis in Wistar rats. METHODS: Lactobacillus acidophilus NCFM (2x108 CFU) was used in the treatment of cyclophosphamide- induced hemorrhagic cystitis (200 mg/kg, intraperitoneal) in 77 female Wistar rats. Rats were distributed into experimental groups (n = 9): control group (GC), zero control group (GCZ), inflammation group (GI), 24-hour acute treatment groups: 24-hour lactobacilli treatment group (GL24H) and mesna group (GM), and 30-day chronic treatment groups: lactobacilli treatment group (GTL) and mesna+lactobacilli group (GM+L). After treatment, animals were euthanized and biological materials were collected for blood count, biochemical analyses, examination of abnormal sediment elements (EAS), and histopathological analysis. RESULTS: GI results showed development of edema, macroscopic alterations, and signs of bleeding in the bladder; in addition, lesions in the urothelium and hemorrhage were also found. GL24H and GM presented intact urothelium, without inflammatory reaction and hematological or biochemical urine alterations. CONCLUSION: Therefore, this study demonstrated that L. acidophilus presented uroprotective effect against the action of cyclophosphamide in both the short and long term.

Treatment of Burkitt lymphoma in equatorial Africa using a simple three-drug combination followed by a salvage regimen for patients with persistent or recurrent disease.

Prior to the introduction of the International Network for Cancer Treatment and Research (INCTR) protocol INCTR 03-06, survival of patients with Burkitt lymphoma at four tertiary care centres in equatorial Africa was probably no more than 10-20%. The results reported here for 356 patients have demonstrated marked improvement in survival through the use of a uniform treatment protocol consisting of cyclophosphamide, methotrexate, vincristine, and intrathecal therapy, and the introduction of non-cross resistant second-line (salvage) therapy, consisting of ifosfamide, mesna, etoposide and cytarabine, when patients failed to achieve a complete response to first-line therapy or relapsed early. Overall survival rates of 67% and 62% were observed at 1 and 2 years (relapse is rare after 1 year of remission). Of interest was the small impact of cerebrospinal fluid (CSF) and bone marrow involvement on outcome. However, the presence or absence of abdominal involvement clearly defined two prognostic groups. An additional finding was the association between CSF pleocytosis and orbital tumours, suggesting that spread of tumour cells to the central nervous system may sometimes occur via direct involvement of cranial nerves in the orbit. Survival rates may be increased in patients with abdominal involvement by combining first- and second-line therapy, but verification will require a further clinical study.

High-dose chemotherapy consolidation for chemosensitive advanced soft tissue sarcoma patients: an open-label, randomized controlled trial.

BACKGROUND: Metastatic soft tissue sarcoma (STS) prognosis remains poor and few cytotoxic agents offer proven efficacy. This randomized open phase III study examines whether high-dose (HD) chemotherapy with peripheral blood stem cells (PBSCs) could improve overall survival (OS) of chemosensitive patients. PATIENTS AND METHODS: Advanced STS patients aged 18-65 years received four courses of standard mesna, adryamycin, ifosfamide and dacarbazine (MAID) treatment. Chemotherapy-responding patients and patients with at least stable disease amenable to complete surgical resection were randomized to receive standard dose (SD) with two successive MAID cycles or HD treatments of one MAID then MICE intensification: mesna (3.6 g/m(2), day 1-5), ifosfamide (2.5 g/m(2), day 1-4), carboplatin [area under the curve (AUC) 5/day 2-4] and etoposide (300 mg/m(2), day 1-4) with PBSC reinjection at day 7. RESULTS: From 2000 to 2008, 207 patients received four cycles of MAID and 87 assessable patients were randomly assigned to receive the following: 46 SD, 41 HD, with 45 and 38 maintained for analyses after secondary centralized histological review. Futility analyses led to study closure in November 2008. Three-year OS was 49.4% for the SD group versus 32.7% for HD arm, hazard ratio= 1.26, 95% confidence interval 0.70-2.29; progression-free survival was 32.4% and 14.0%, respectively. HD treatment led to higher grades 3-4 toxicity. CONCLUSION: This study failed to show an OS advantage for advanced STS patients treated with dose-intensified chemotherapy with PBSC.

Mesna-induced photodistributed dermatosis.

We present the case of a 41-year-old man who developed a photodistributed eruption 1 month after being started on 2-mercaptoethane sulfonate sodium (mesna) for treatment of cyclophosphamide-induced haemorrhagic cystitis. The patient had a background history of Wegener granulomatosis, and had been taking cyclophosphamide at a stable dose of 150 mg daily for the previous 3 years. Complete resolution of the rash occurred within 8 weeks of cessation of mesna. This is the first reported case, to our knowledge, of mesna-induced photodistributed dermatosis. Early recognition of this condition will ensure prompt cessation of the culprit medication, and consideration of alternative management of haemorrhagic cystitis.

Severe allergic reactions to thiol-based cytoprotective agents mesna and amifostine in a child with a supratentorial primitive neuroectodermal tumor.

Both 2-mercaptoethane sulfonate sodium (mesna) and amifostine's active metabolite WR-1065 are thiol-based cytoprotective agents that are critical components of high-dose chemotherapy regimens used to treat various cancers in both adults and children. This case report describes a patient with a supratentorial primitive neuroectodermal tumor who developed severe drug reactions to both mesna and amifostine/WR-1065, suggesting that the thiol component of these agents triggered the adverse reactions. This report highlights the clinical presentation of drug-induced hypersensitivity syndrome in the context of pediatric oncology and the supportive care measures that, if implemented rapidly, may diminish the reaction severity and allow successful completion of chemotherapy.

Use of high-dose mesna and hyperhydration leads to lower incidence of hemorrhagic cystitis after posttransplant cyclophosphamide-based allogeneic transplantation.

Currently, there is no consensus on best practices to prevent hemorrhagic cystitis (HC) in patients receiving posttransplant cyclophosphamide (PTCy). We retrospectively reviewed 194 patients undergoing their first hematopoietic cell transplant (HCT) who received PTCy from 2014 to 2018 to describe the incidence and severity of HC, identify potential risk factors, and impact of HC on HCT outcomes. Standard HC prophylaxis was hyperhydration with forced diuresis and mesna at 320% the daily dose of PTCy. Incidence of HC was 31.4% at day +100 of HCT. Median onset of HC was 12 days with 11.5% grade 3 HC and no Grade 4 HC. Patients with chemical HC experienced earlier onset (7 days vs. 34 days, p < 0.001) with a shorter median resolution time (5 days vs. 14 days, p = 0.001) when compared to BK-associated HC. In multivariate analysis, age above 60 years (HR 4.16, p = 0.006) and myeloablative conditioning (HR 2.44, p = 0.054) were associated with higher risk for HC, but overall, HC did not affect nonrelapse mortality or overall survival. In conclusion, hyperhydration with forced diuresis combined with aggressive mesna dosing is an effective strategy in preventing severe PTCy-associated HC, subsequently preventing any negative impact on transplant outcome.

Immediate type hypersensitivity to chemotherapeutic agents in pediatric patients.

Nine patients (3 boys and 6 girls) with a median age of 9.5 years, with immediate type hypersensitivity reactions to chemotherapeutic agents were reviewed. The presenting symptoms were urticaria (4/9) and anaphylaxis (5/9). The causative agents were vincristine (2/9), L-asparaginase (2/9), mesna (1/9), cyclosporine (1/9), carboplatin (2/9) and cyclophosphamide (1/9). Three of the five patients with anaphylaxis were changed to alternative chemotherapeutic agents. In two cases alternative drugs were not available and the patients underwent safe and successful desensitization. Three of the 4 patients with urticaria were successfully exposed to graded challenges with cyclosporine, carboplatin and cyclophosphamide, respectively. In the other case with generalized urticaria, mesna was withdrawn due to a positive intradermal test. In patients with immediate type hypersensitivity reactions to chemotherapeutic drugs, if effective alternative chemotherapeutic agents are not available and/or the skin test is negative, a careful drug challenge and/or desensitization should be performed.

The Effects of MESNA on the Facial Nerve, an Experimental Animal Study.

OBJECTIVE: MESNA (Sodium-2-mercaptoethanesulfonate) is a mucolytic substance that is used for chemically assisted tissue dissection in various surgical operations. The aim of this study was to address the issue of possible neurotoxicity from topical administration of MESNA solution on the facial nerve. We used different concentrations of MESNA solution and evaluated their effects on facial nerve by histopathological and functional analysis. MATERIALS AND METHODS: These groups were the saline administered group (control) (3 rats, 6 facial nerves), the 25% MESNA solution group (3 rats, 6 facial nerves), and the 100% MESNA solution group (3 rats, 6 facial nerves). Under general anesthesia (ketamine 150 mg/kg, xylocaine 4 mg/kg), the bilateral facial nerves of rats were dissected. The saline, 25% MESNA, and 100% MESNA solutions. Facial nerve functions of the rats were evaluated using mustachewhisker and blink reflex scores at day 20 days. On day 20, the rats were sacrificed and the buccal and marginal mandibular branches of the facial nerve were removed. The specimens were examined in terms of inflammation, granulation tissue, and foreign body reaction formation around the nerve. The functional and histopathological changes on facial nerves were compared between groups. RESULTS: Mustache and blink reflex scores of the rats were 5 (normal) in both the control and study groups. There were no statistically significant differences between the three groups in terms of facial nerve functions (p=1.00). On histopathologic examination, the 25% and 100% MESNA groups had significantly more inflammation compared with the control group (p=0.038 and p=0.007, respectively). There were no statistically significant differences between the 25% and 100% MESNA groups in term of inflammation (p > 0.05). There were no statistically significant differences between the three groups in terms of foreign body reaction formation (p > 0.05). CONCLUSION: Topical administration of MESNA solution onto the facial nerve causes increased inflammation in both the 25% and 100% concentrations. Nevertheless, it does not cause any facial nerve dysfunction.

Electrophysiological and Histopathological Evaluation of Effects of Sodium-2 Mercaptoethanesulfonate Used for Middle Ear Surgery on Facial Nerve Functions.

OBJECTIVE: Sodium-2-mercaptoethanesulfonate (MESNA) is widely used in medicine because of its antioxidant and mucolytic effects. In recent years, it has been used in otologic surgery. Because it cleaves disulfide bonds, it is used to easily dissect the epithelial matrix in cholesteatoma and atelectasis. In this study, we hypothesized that MESNA does not have any toxic effect on the facial nerve, and the effects of MESNA on the facial nerve were examined histologically and electrophysiologically. MATERIALS AND METHODS: Twenty Wistar albino rats were used. Groups A and B were designated as the control and sham groups, respectively. The animals in groups C and D were administered 20% and 50% of MESNA solution, respectively, after the facial nerve was exposed in the parotid region. Electromyography (EMG) measurements were performed preoperatively and postoperatively at 4 weeks. The animals were subsequently euthanized; facial nerve samples were taken for histopathological examination. RESULTS: When EMG parameters were compared within and between each group, preoperative and postoperative results were not statistically significantly different. Histopathological examination showed that MESNA did not cause any inflammation, granulation tissue, or foreign body reaction. CONCLUSION: To the best of our knowledge, the effects of MESNA on facial nerve functions have not been investigated. In this study, the effects of MESNA after direct application to the facial nerve were examined electrophysiologically and histologically, and it was determined that MESNA did not cause any toxic effects. It was concluded that MESNA can, therefore, be safely used during middle ear surgery.

Long-term Effects of Intravenous Cyclophosphamide in Combination with Mesna Provided Intravenously and via Bladder Perfusion in a Patient with Severe Multifocal Motor Neuropathy.

A 25-year-old woman presenting with progressive muscle weakness in the distal extremities in the absence of sensory involvement for 2 years was diagnosed with multifocal motor neuropathy (MMN). Her disease was difficult to manage with various immunosuppressants, and the muscle weakness eventually progressed to involve the respiratory muscles, necessitating mechanical ventilation. Intravenous cyclophosphamide (CY) dramatically improved her symptoms, and she has since maintained her ambulatory status for 18 years with intermittent CY therapy. Because the patient presented with hemorrhagic cystitis due to CY, we also implemented mesna administration by bladder perfusion. The administration of CY should therefore be considered in patients with severe MMN that is unresponsive to standard therapy.

Phase II study of ifosfamide-etoposide-mesna in adults with advanced nonosseous sarcomas.

Between April 1987 and July 1988, 44 adults with histologically proven, objectively assessable advanced nonosseous sarcomas were treated with 2.5 g of ifosfamide/m2, 100 mg of etoposide/m2, and 2.5 g of mesna/m2 (500 mg/m2 X 5) daily for 3 consecutive days every 4 weeks. This regimen was generally well tolerated as outpatient treatment. Because of the potential CNS effects of ifosfamide, we recommended that elderly patients, persons receiving high doses of opiates, and patients susceptible to the syndrome of vertigo, perspiration, and hypotension (without tachycardia) be hospitalized for treatment. At initial treatment, leukocyte count nadirs were less than 1,000/microL and platelet count nadirs were less than 100,000/microL in 38% and 15%, respectively, of the 39 patients for whom such data were available. Objective tumor regression occurred in approximately 16% (95% confidence interval, 7%-30%) of the 44 patients (six, partial responses; one, complete response). For the 44 patients, median time to disease progression was 2.3 months; median time to death was 9.4 months. While this regimen was effective in three of 20 patients who had been previously treated with a doxorubicin-based regimen, only one of the 12 patients whose tumors had been primarily refractory to the doxorubicin-based regimen experienced objective tumor regression on our ifosfamide-based regimen.