RESUMO
Rising cure rates in pediatric cancer patients warrants an increased attention toward the long-term consequences of the diagnosis and treatment in survivors. Chemotherapeutic agents can be gonadotoxic, rendering them at risk for infertility post-survival. While semen cryopreservation is an option that can be provided for most (post)pubertal boys before treatment, this is unfortunately not an option prepubertal in age, simply due to the lack of spermatogenesis. Over the last couple of years, studies have thus focused on better understanding the testis niche in response to various chemotherapeutic agents that are commonly administered and their direct and indirect impact on the germ cell populations. These are generally compounds that have a high risk of infertility and have been classified into risk categories in curated fertility guidelines. However, with it comes the lack of evidence and the challenge of using informative models and conditions most reflective of the physiological scenario, in short, the appropriate study designs for clinically relevant outcomes. Besides, the exact mechanism(s) of action for many of these "risk" compounds as well as other agents is unclear. Understanding their behavior and effect on the testis niche will pave the way for incorporating new strategies to ultimately combat infertility. Of the various drug classes, alkylating agents pose the highest risk of gonadotoxicity as per previously established studies as well as risk stratification guidelines. Therefore, this review will summarize the findings in the field of male fertility concerning gonadotoxicity of akylating agents as a result of chemotherapy exposure.
Assuntos
Antineoplásicos Alquilantes , Testículo , Humanos , Masculino , Testículo/efeitos dos fármacos , Criança , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/administração & dosagem , Infertilidade Masculina/induzido quimicamente , Infertilidade Masculina/etiologia , Infertilidade Masculina/diagnóstico , Animais , Espermatogênese/efeitos dos fármacos , Espermatogênese/efeitos da radiação , Neoplasias/tratamento farmacológico , Puberdade/efeitos dos fármacos , Puberdade/fisiologia , Alquilantes/efeitos adversos , Alquilantes/administração & dosagemAssuntos
Glicoproteína Associada a Mielina , Rituximab , Humanos , Rituximab/uso terapêutico , Rituximab/efeitos adversos , Estudos Retrospectivos , Feminino , Masculino , Pessoa de Meia-Idade , Glicoproteína Associada a Mielina/imunologia , Idoso , Adulto , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Alquilantes/uso terapêutico , Alquilantes/efeitos adversosRESUMO
Background: Patients with metastatic medullary thyroid cancer (MTC) who progressed under tyrosine kinase inhibitors can benefit from an alkylating agent such as dacarbazine or temozolomide. Patient Findings: We describe two patients with metastatic MTC who developed a hypermutant phenotype after alkylating agent treatment. This phenotype was characterized by a high tumor mutational burden (TMB) and a mutational signature indicative of alkylating agent mutagenesis (single-base substitution 11). Both patients received immune checkpoint inhibitors, with partial morphological responses, clinical benefit, and progression-free survival of 6 and 9 months, respectively. Summary and Conclusions: Based on the described observations, we suggest that a hypermutant phenotype may be induced after alkylating agent treatment for MTC and the sequential use of immunotherapy should be further explored as a treatment option for MTC patients with increased TMB.
Assuntos
Carcinoma Neuroendócrino , Neoplasias da Glândula Tireoide , Humanos , Alquilantes/efeitos adversos , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genéticaRESUMO
BACKGROUND: Treatment options for premature ovarian insufficiency (POI) are limited to hormone replacement and donor oocytes. A novel induced pluripotent stem cell (iPSC) transplant paradigm in a mouse model has potential translational applications for management of POI. METHODS: Mouse ovarian granulosa cell derived-iPSCS were labelled with green fluorescent protein (GFP) reporter and differentiated in vitro into oocytes. Differentiated cells were assayed for estradiol and progesterone secretion by enzyme-linked immunosorbent assays. After Fluorescence-Activated Cell Sorting (FACS) for the cell surface marker anti-Mullerian hormone receptor (AMHR2), enriched populations of differentiated cells were surgically transplanted into ovaries of mice that had POI secondary to gonadotoxic pre-treatment with alkylating agents. A total of 100 mice were used in these studies in five separate experiments with 56 animals receiving orthotopic ovarian injections of either FACS sorted or unsorted differentiated iPSCSs and the remaining animals receiving sham injections of PBS diluent. Following transplantation surgery, mice were stimulated with gonadotropins inducing oocyte development and underwent oocyte retrieval. Nine transplanted mice were cross bred with wild-type mice to assess fertility. Lineage tracing of resultant oocytes, F1 (30 pups), and F2 (42 pups) litters was interrogated by GFP expression and validation by short tandem repeat (STR) lineage tracing. FINDINGS: [1] iPSCs differentiate into functional oocytes and steroidogenic ovarian cells which [2] express an ovarian (GJA1) and germ cell (ZP1) markers. [3] Endocrine function and fertility were restored in mice pretreated with gonadotoxic alkylating agents via orthotopic transplantation of differentiated iPSCS, thus generating viable, fertile mouse pups. INTERPRETATION: iPSC-derived ovarian tissue can reverse endocrine and reproductive sequelae of POI. FUNDING: Center for Infertility and Reproductive Surgery Research Award, Siezen Foundation award (RMA). Reproductive Scientist Development Program, Marriott Foundation, Saltonstall Foundation, Brigham Ovarian Cancer Research Fund (K.E).
Assuntos
Antineoplásicos , Células-Tronco Pluripotentes Induzidas , Insuficiência Ovariana Primária , Humanos , Feminino , Camundongos , Animais , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/terapia , Fertilidade , Antineoplásicos/efeitos adversos , Alquilantes/efeitos adversos , Alquilantes/metabolismoRESUMO
Acrolein is a metabolite of cyclophosphamide (CYP), an alkylating agent used for a wide range of benign and malignant diseases. CYP treatments are known to trigger hemorrhagic cystitis in patients and animals. Significant effort has been made to prevent CYP/acrolein-induced cystitis, while still maintaining its therapeutic benefits. As a result, supplementary therapeutic options to mediate the protective role against CYP/acrolein and lower doses of CYP are currently given to targeted patients, as compared to past treatments. There is still a need to further study the effects of the repeated low-dose CYP/acrolein on the pathophysiology of the urinary bladder. In our study, a one-time treatment of acrolein and repeated low-dose acrolein triggered the thickening of the smooth muscle and lamina propria in the urinary bladder of C57BL/6J mice, respectively. The first dose of acrolein did not trigger voiding dysfunction, but the second dose triggered high-volume low-frequency voiding. Interestingly, our new scoring criteria and concurrent behavioral assessment revealed that mice with repeated low-dose acrolein had a wider opening of eyes in response to mechanical stimuli. Our study suggests that clinical symptoms among patients undergoing prolonged low-dose CYP may differ from previously reported symptoms of CYP-induced hemorrhagic cystitis.
Assuntos
Edema/prevenção & controle , Hemorragia/prevenção & controle , Mucosa/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Acroleína/efeitos adversos , Acroleína/farmacologia , Alquilantes/efeitos adversos , Alquilantes/farmacologia , Animais , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/farmacologia , Ciclofosfamida/efeitos adversos , Ciclofosfamida/farmacologia , Cistite/induzido quimicamente , Cistite/tratamento farmacológico , Cistite/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/patologia , Hemorragia/induzido quimicamente , Hemorragia/tratamento farmacológico , Hemorragia/patologia , Humanos , Camundongos , Mucosa/patologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/patologia , Bexiga Urinária/patologiaRESUMO
Replication-associated single-ended DNA double-strand breaks (seDSBs) are repaired predominantly through RAD51-mediated homologous recombination (HR). Removal of the non-homologous end-joining (NHEJ) factor Ku from resected seDSB ends is crucial for HR. The coordinated actions of MRE11-CtIP nuclease activities orchestrated by ATM define one pathway for Ku eviction. Here, we identify the pre-mRNA splicing protein XAB2 as a factor required for resistance to seDSBs induced by the chemotherapeutic alkylator temozolomide. Moreover, we show that XAB2 prevents Ku retention and abortive HR at seDSBs induced by temozolomide and camptothecin, via a pathway that operates in parallel to the ATM-CtIP-MRE11 axis. Although XAB2 depletion preserved RAD51 focus formation, the resulting RAD51-ssDNA associations were unproductive, leading to increased NHEJ engagement in S/G2 and genetic instability. Overexpression of RAD51 or RAD52 rescued the XAB2 defects and XAB2 loss was synthetically lethal with RAD52 inhibition, providing potential perspectives in cancer therapy.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Quebras de DNA de Cadeia Dupla , Reparo do DNA por Junção de Extremidades/genética , Autoantígeno Ku/metabolismo , Fatores de Processamento de RNA/metabolismo , Alquilantes/efeitos adversos , Alquilantes/farmacologia , Camptotecina/efeitos adversos , Camptotecina/farmacologia , Linhagem Celular Tumoral , Endodesoxirribonucleases/metabolismo , Glioblastoma/tratamento farmacológico , Recombinação Homóloga/genética , Humanos , Proteína Homóloga a MRE11/metabolismo , Interferência de RNA , Fatores de Processamento de RNA/genética , RNA Interferente Pequeno/genética , Rad51 Recombinase/metabolismo , Proteína Rad52 de Recombinação e Reparo de DNA/metabolismo , Temozolomida/efeitos adversos , Temozolomida/farmacologiaRESUMO
The relationship between human papillomavirus (HPV) and esophageal cancer (EC) has been controversial, which may be caused by the difference in geographic regions of sample origin. Thus, we conducted a case-control study to find that HPV increased the risk of esophageal cancer, and the HPV18 detection rate is the highest (24.2%) among patients with EC, suggesting that HPV18 could be the most risk subtype of HPV infected. We then identified high-risk HPV18 and N-methyl-N'-nitro-N-nitroso-guanidine (MNNG) to establish a model on the viral etiology cooperating with environmental carcinogens. Het-1A cells containing HPV18 were continuously exposed to MNNG or not; then the morphological phenotype and function assays were performed in 25th passage cells. MNNG promoted the proliferation and invasion abilities and inhibited apoptosis both in Het-1A-HPV18 and control group. However, the Het-1A-HPV18 had a stronger change in phenotypic features and formed more transformed foci in soft agar. Further, Western blot found p53 and p21 were down-regulated, and expression of c-Myc, MMP-2, and MMP-9 and Bcl-2/Bax ratio were up-regulated. Our results revealed that MNNG was easier to induce malignant transformation of Het-1A cells transfected with HPV18. It is good evidence for the close relationship between HPV and the etiology of EC, providing foundation for further study in molecular mechanism and specific intervention targets.
Assuntos
Alquilantes/efeitos adversos , Transformação Celular Neoplásica/induzido quimicamente , Neoplasias Esofágicas/etiologia , Papillomavirus Humano 18/isolamento & purificação , Infecções por Papillomavirus/complicações , Idoso , Linhagem Celular , Neoplasias Esofágicas/induzido quimicamente , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Recently, encouraging data provided long-awaited hope for gene therapy as a cure for sickle cell disease (SCD). Nevertheless, the transient suspension of the bluebird bio gene therapy trial (clinicaltrials.gov: NCT02140554) after participants developed acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) raised concerns. Potential possibilities for these cases include busulfan, insertional mutagenesis, both, or neither. Busulfan was considered the cause in the first reported case because the transgene was not present in the AML/MDS. However, busulfan is unlikely to have contributed to the most recent case. The transgene was present in the patient's malignant cells, indicating they were infused after busulfan treatment. Several lines of evidence suggest an alternative explanation for events in the bluebird bio trial, including that SCD population studies show an increased relative, but a low absolute, risk of AML/MDS. We propose a new hypothesis: after gene therapy for SCD, the stress of switching from homeostatic to regenerative hematopoiesis by transplanted cells drives clonal expansion and leukemogenic transformation of preexisting premalignant clones, eventually resulting in AML/MDS. Evidence validating our hypothesis will support prescreening individuals with SCD for preleukemic progenitors before gene therapy. While presumed viable, safe strategy has been implemented to resume gene therapy in adults with severe SCD, reasonable alternative curative therapy should be considered for children and adults with severe SCD. Currently, open multicenter clinical trials are incorporating nonmyeloablative conditioning, related haploidentical donors, and posttransplantation cyclophosphamide. Preliminary results from these trials appear promising, and National Institutes of Health-sponsored trials are ongoing in individuals with SCD using this platform.
Assuntos
Alquilantes/efeitos adversos , Anemia Falciforme/terapia , Bussulfano/efeitos adversos , Terapia Genética/efeitos adversos , Leucemia Mieloide Aguda/etiologia , Síndromes Mielodisplásicas/etiologia , Anemia Falciforme/genética , Ensaios Clínicos como Assunto , Edição de Genes/métodos , Terapia Genética/métodos , Humanos , Leucemia Mieloide Aguda/genética , Mutagênese Insercional/métodos , Síndromes Mielodisplásicas/genéticaRESUMO
Two mixed-valence octadecavanadates, (NH4)2(Me4N)5[VIV12VV6O42I]·Me4NI·5H2O (V18I) and [{K6(OH2)12VIV11VV7O41(PO4)·4H2O}n] (V18P), were synthesized and characterized by single-crystal X-ray diffraction analysis and FTIR, Raman, 51V NMR, EPR and UV/Vis/NIR spectroscopies. The chemoprotective activity of V18I and V18P towards the alkylating agent diethyl sulfate was assessed in E. coli cultures. The complex V18I was nontoxic in concentrations up to 5.0 mmol L-1, while V18P presented moderate toxicity in the concentration range 0.10 - 10 mmol L-1. Conversely, a ca. 35% enhancement in culture growth as compared to cells treated only with diethyl sulfate was observed upon addition of V18I (0.10 to 2.5 mmol L-1), while the combination of diethyl sulfate with V18P increased the cytotoxicity presented by diethyl sulfate alone. 51V NMR and EPR speciation studies showed that V18I is stable in solution, while V18P suffers partial breakage to give low nuclearity oxidometalates of vanadium(V) and (IV). According to the results, the chemoprotective effect depends strongly on the direct reactivity of the polyoxidovanadates (POV) towards the alkylating agent. The reaction of diethyl sulfate with V18I apparently produces a new, rearranged POV instead of poorly-reactive breakage products, while V18P shows the formation and subsequent consumption of low-nuclearity species. The correlation of this chemistry with that of other mixed-valence polyoxidovanadates, [H6VIV2VV12O38PO4]5- (V14) and [VIV8VV7O36Cl]6- (V15), suggests a relationship between stability in solution and chemoprotective performance.
Assuntos
Escherichia coli/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Vanadatos/química , Vanadatos/farmacologia , Alquilantes/efeitos adversos , Cristalografia por Raios X/métodos , Espectroscopia de Ressonância Magnética/métodos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Ésteres do Ácido Sulfúrico/efeitos adversos , Vanádio/química , Difração de Raios X/métodosRESUMO
INTRODUCTION: In AL amyloidosis, a usually small plasma cell clone secretes unstable, amyloid-forming light chains, causing cytotoxicity and progressive (multi)organ function deterioration. Treatment aims at reducing/eradicating the underlying clone, to reduce/zero the supply of the amyloidogenic protein and halt the amyloidogenic cascade. AREAS COVERED: Safety data of alkylating agents, proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies from clinical trials are reviewed. EXPERT OPINION: Drugs used to treat AL amyloidosis are derived from experience with multiple myeloma or other B cell malignancies. However, treating AL amyloidosis is particularly challenging, as it implies delivering anti-neoplastic therapy to a hematologic malignancy directly causing (multi)organ function deterioration, often in elderly subjects with other comorbidities and polypharmacotherapy. This unique combination translates in increased patients' frailty and higher sensitivity toward treatment-related toxicities. Therefore, dose/schedule adjustments and special precautions are needed when translating treatment experience from multiple myeloma or other B cell malignancies to AL amyloidosis. Treatment of patients with AL amyloidosis should be risk adapted, tailored to individual patients' risk profile, considering the type and extent of organ involvement, and eventual comorbidity. As several classes of effective anti-plasma cell or B cell drugs are available, therapeutic choices are also influenced by individual drug's safety profile.
Assuntos
Amiloidose de Cadeia Leve de Imunoglobulina/tratamento farmacológico , Idoso , Alquilantes/administração & dosagem , Alquilantes/efeitos adversos , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Relação Dose-Resposta a Droga , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/fisiopatologia , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/administração & dosagem , Inibidores de Proteassoma/efeitos adversosRESUMO
The cellular outcomes of chemical exposure are as much about the cellular response to the chemical as it is an effect of the chemical. We are growing in our understanding of the genotoxic interaction between chemistry and biology. For example, recent data has revealed the biological basis for mutation induction curves for a methylating chemical, which has been shown to be dependent on the repair capacity of the cells. However, this is just one end point in the toxicity pathway from chemical exposure to cell death. Much remains to be known in order for us to predict how cells will respond to a certain dose. Methylating agents, a subset of alkylating agents, are of particular interest, because of the variety of adverse genetic end points that can result, not only at increasing doses, but also over time. For instance, methylating agents are mutagenic, their potency, for this end point, is determined by the cellular repair capacity of an enzyme called methylguanine DNA-methyltransferase (MGMT) and its ability to repair the induceed methyl adducts. However, methyl adducts can become clastogenic. Erroneous biological processing will convert mutagenic adducts to clastogenic events in the form of double strand breaks (DSBs). How the cell responds to DSBs is via a cascade of protein kinases, which is called the DNA damage response (DDR), which will determine if the damage is repaired effectively, via homologous recombination, or with errors, via nonhomologous end joining, or whether the cell dies via apoptosis or enters senescence. The fate of cells may be determined by the extent of damage and the resulting strength of DDR signaling. Therefore, thresholds of damage may exist that determine cell fate. Such thresholds would be dependent on each of the repair and response mechanisms that these methyl adducts stimulate. The molecular mechanism of how methyl adducts kill cells is still to be fully resolved. If we are able to quantify each of these thresholds of damage for a given cell, then we can ascertain, of the many adducts that are induced, what proportion of them are mutagenic, what proportion are clastogenic, and how many of these clastogenic events are toxic. This review examines the possibility of dose and damage thresholds for methylating agents, from the perspective of the underlying evolutionary mechanisms that may be accountable.
Assuntos
Alquilantes/efeitos adversos , Inibidores Enzimáticos/efeitos adversos , O(6)-Metilguanina-DNA Metiltransferase/antagonistas & inibidores , Alquilantes/química , Animais , Inibidores Enzimáticos/química , Humanos , Metilação/efeitos dos fármacos , O(6)-Metilguanina-DNA Metiltransferase/genética , O(6)-Metilguanina-DNA Metiltransferase/metabolismoRESUMO
BACKGROUND: About 80% of children with steroid-sensitive nephrotic syndrome (SSNS) have relapses. Of these children, half relapse frequently, and are at risk of adverse effects from corticosteroids. While non-corticosteroid immunosuppressive medications prolong periods of remission, they have significant potential adverse effects. Currently, there is no consensus about the most appropriate second-line agent in children who are steroid sensitive, but who continue to relapse. In addition, these medications could be used with corticosteroids in the initial episode of SSNS to prolong the period of remission. This is the fourth update of a review first published in 2001 and updated in 2005, 2008 and 2013. OBJECTIVES: To evaluate the benefits and harms of non-corticosteroid immunosuppressive medications in SSNS in children with a relapsing course of SSNS and in children with their first episode of nephrotic syndrome. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 10 March 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs were included if they involved children with SSNS and compared non-corticosteroid immunosuppressive medications with placebo, corticosteroids (prednisone or prednisolone) or no treatment; compared different non-corticosteroid immunosuppressive medications or different doses, durations or routes of administration of the same non-corticosteroid immunosuppressive medication. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study eligibility, risk of bias of the included studies and extracted data. Statistical analyses were performed using a random-effects model and results expressed as risk ratio (RR) for dichotomous outcomes or mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). The certainty of the evidence was assessed using GRADE. MAIN RESULTS: We identified 43 studies (91 reports) and included data from 2428 children. Risk of bias assessment indicated that 21 and 24 studies were at low risk of bias for sequence generation and allocation concealment respectively. Nine studies were at low risk of performance bias and 10 were at low risk of detection bias. Thirty-seven and 27 studies were at low risk of incomplete and selective reporting respectively. Rituximab (in combination with calcineurin inhibitors (CNI) and prednisolone) versus CNI and prednisolone probably reduces the number of children who relapse at six months (5 studies, 269 children: RR 0.23, 95% CI 0.12 to 0.43) and 12 months (3 studies, 198 children: RR 0.63, 95% CI 0.42 to 0.93) (moderate certainty evidence). At six months, rituximab resulted in 126 children/1000 relapsing compared with 548 children/1000 treated with conservative treatments. Rituximab may result in infusion reactions (4 studies, 252 children: RR 5.83, 95% CI 1.34 to 25.29). Mycophenolate mofetil (MMF) and levamisole may have similar effects on the number of children who relapse at 12 months (1 study, 149 children: RR 0.90, 95% CI 0.70 to 1.16). MMF may have a similar effect on the number of children relapsing compared to cyclosporin (2 studies, 82 children: RR 1.90, 95% CI 0.66 to 5.46) (low certainty evidence). MMF compared to cyclosporin is probably less likely to result in hypertrichosis (3 studies, 140 children: RR 0.23, 95% CI 0.10 to 0.50) and gum hypertrophy (3 studies, 144 children: RR 0.09, 95% CI 0.07 to 0.42) (low certainty evidence). Levamisole compared with steroids or placebo may reduce the number of children with relapse during treatment (8 studies, 474 children: RR 0.52, 95% CI 0.33 to 0.82) (low certainty evidence). Levamisole compared to cyclophosphamide may make little or no difference to the risk for relapse after 6 to 9 months (2 studies, 97 children: RR 1.17, 95% CI 0.76 to 1.81) (low certainty evidence). Cyclosporin compared with prednisolone may reduce the number of children who relapse (1 study, 104 children: RR 0.33, 95% CI 0.13 to 0.83) (low certainty evidence). Alkylating agents compared with cyclosporin may make little or no difference to the risk of relapse during cyclosporin treatment (2 studies, 95 children: RR 0.91, 95% CI 0.55 to 1.48) (low certainty evidence) but may reduce the risk of relapse at 12 to 24 months (2 studies, 95 children: RR 0.51, 95% CI 0.35 to 0.74), suggesting that the benefit of the alkylating agents may be sustained beyond the on-treatment period (low certainty evidence). Alkylating agents (cyclophosphamide and chlorambucil) compared with prednisone probably reduce the number of children, who experience relapse at six to 12 months (6 studies, 202 children: RR 0.44, 95% CI 0.32 to 0.60) and at 12 to 24 months (4 studies, 59 children: RR 0.20, 95% CI 0.09 to 0.46) (moderate certainty evidence). IV cyclophosphamide may reduce the number of children with relapse compared with oral cyclophosphamide at 6 months (2 studies, 83 children: RR 0.54, 95% CI 0.34 to 0.88), but not at 12 to 24 months (2 studies, 83 children: RR 0.99, 95% CI 0.76 to 1.29) and may result in fewer infections (2 studies, 83 children: RR 0.14, 95% CI 0.03 to 0.72) (low certainty evidence). Cyclophosphamide compared to chlorambucil may make little or no difference in the risk of relapse after 12 months (1 study, 50 children: RR 1.31, 95% CI 0.80 to 2.13) (low certainty evidence). AUTHORS' CONCLUSIONS: New studies incorporated in this review indicate that rituximab is a valuable additional agent for managing children with steroid-dependent nephrotic syndrome. However, the treatment effect is temporary, and many children will require additional courses of rituximab. The long-term adverse effects of this treatment are not known. Comparative studies of CNIs, MMF, levamisole and alkylating agents have demonstrated little or no differences in efficacy but, because of insufficient power; clinically important differences in treatment effects have not been completely excluded.
Assuntos
Imunossupressores/uso terapêutico , Síndrome Nefrótica/tratamento farmacológico , Adolescente , Alquilantes/efeitos adversos , Alquilantes/uso terapêutico , Azatioprina/efeitos adversos , Azatioprina/uso terapêutico , Criança , Pré-Escolar , Clorambucila/efeitos adversos , Clorambucila/uso terapêutico , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Ciclosporina/efeitos adversos , Ciclosporina/uso terapêutico , Humanos , Imunossupressores/efeitos adversos , Lactente , Levamisol/efeitos adversos , Levamisol/uso terapêutico , Ácido Micofenólico/efeitos adversos , Ácido Micofenólico/uso terapêutico , Síndrome Nefrótica/prevenção & controle , Prednisolona/efeitos adversos , Prednisolona/uso terapêutico , Prednisona/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Ribonucleosídeos/uso terapêutico , Rituximab/efeitos adversos , Rituximab/uso terapêutico , Prevenção SecundáriaRESUMO
Central hypogonadism, also defined as hypogonadotropic hypogonadism, is a recognized complication of hypothalamic-pituitary-gonadal axis damage following treatment of sellar and parasellar masses. In addition to radiotherapy and surgery, CTLA4-blocking antibodies and alkylating agents such as temozolomide can also lead to hypogonadism, through different mechanisms. Central hypogonadism in boys and girls may lead to pubertal delay or arrest, impairing full development of the genitalia and secondary sexual characteristics. Alternatively, cranial irradiation or ectopic hormone production may instead cause early puberty, affecting hypothalamic control of the gonadostat. Given the reproductive risks, discussion of fertility preservation options and referral to reproductive specialists before treatment is essential. Steroid hormone replacement can interfere with other replacement therapies and may require specific dose adjustments. Adequate gonadotropin stimulation therapy may enable patients to restore gametogenesis and conceive spontaneously. When assisted reproductive technology is needed, protocols must be tailored to account for possible long-term gonadotropin insufficiency prior to stimulation. The aim of this review was to provide an overview of the risk factors for hypogonadism and infertility in patients treated for parasellar lesions and to give a summary of the current recommendations for management and follow-up of these dysfunctions in such patients. We have also briefly summarized evidence on the physiological role of pituitary hormones during pregnancy, focusing on the management of pituitary deficiencies.
Assuntos
Alquilantes/efeitos adversos , Irradiação Craniana/efeitos adversos , Glucocorticoides/efeitos adversos , Hipogonadismo/etiologia , Doenças Hipotalâmicas/terapia , Fatores Imunológicos/efeitos adversos , Infertilidade/etiologia , Procedimentos Neurocirúrgicos/efeitos adversos , Doenças da Hipófise/terapia , Feminino , Humanos , Hipogonadismo/induzido quimicamente , Hipogonadismo/tratamento farmacológico , Hipogonadismo/metabolismo , Infertilidade/induzido quimicamente , Infertilidade/tratamento farmacológico , Infertilidade/metabolismo , MasculinoRESUMO
OBJECTIVES: This study describes the hormone profiles for gonadal late effects after alkylator-based hematopoietic stem cell transplant (HSCT) regimens used for sickle-cell disease (SCD). METHODS: This is a retrospective chart review of subjects followed in the post-HSCT clinic for sickle-cell disease. Patient demographics, pubertal development, characteristics of pre-HSCT disease severity, treatment before HSCT, conditioning regimens, presence of graft versus host disease and follicle-stimulating hormone, anti-Müllerian hormone (AMH), luteinizing hormone and testosterone were abstracted from the medical record. RESULTS: Forty subjects (24 female individuals) with SCD were 9 (±4.3) years old at HSCT and 7.9 years (±5.6) from HSCT. At the time of transplant, 8% of female individuals and no male individuals were pubertal and 58% of female individuals and 38% of male individuals had been treated with hydroxyurea. Post-HSCT, all of the female individuals had diminished ovarian reserve on the basis of low AMH values and 10 of the pubertal female individuals (71%) had premature ovarian insufficiency defined as follicle-stimulating hormone >40 mIU/mL ×2. There was no ovarian recovery and AMH remained very low or undetectable up to 13 years post-HSCT. In male individuals, luteinizing hormone and testosterone levels were normal for age. CONCLUSIONS: Post-HSCT for SCD, all female individuals had diminished ovarian reserve and most female individuals had POI, whereas male individuals had normal testosterone hormone production.
Assuntos
Anemia Falciforme/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Hipogonadismo/epidemiologia , Hipogonadismo/etiologia , Condicionamento Pré-Transplante/efeitos adversos , Alquilantes/efeitos adversos , Hormônio Antimülleriano/sangue , Criança , Feminino , Humanos , Estudos Longitudinais , Hormônio Luteinizante/sangue , Masculino , Reserva Ovariana/efeitos dos fármacos , Insuficiência Ovariana Primária/induzido quimicamente , Estudos Retrospectivos , Testosterona/sangue , Condicionamento Pré-Transplante/métodosRESUMO
Administration of cyclophosphamide (CYC), an alkylating agent used to treat malignancies and severe rheumatic diseases, creates a risk of ovarian insufficiency that is related to the intensity and duration of therapy and the age of the patient. To preserve reproductive capacity in the appropriate clinical setting, oocyte, embryo, and/or ovarian tissue cryopreservation are recommended. Medical protection with depot gonadotropin-releasing hormone agonists (GNRHa) has emerged as a potential means to preserve both fertility and ovarian function through the suppression of ovarian activity during treatment with alkylators. We review the trials of GNRHa for ovarian protection in both cancer and rheumatic disease patients. Trials in cancer patients receiving CYC alone, or in combination with other gonadotoxic agents that have employed several different GNRHa have yielded mixed results. Trials in lupus patients receiving lower doses of CYC alone utilizing depot leuprolide acetate have tended to show favorable results.
Assuntos
Alquilantes/efeitos adversos , Ciclofosfamida/efeitos adversos , Hormônio Liberador de Gonadotropina/administração & dosagem , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Insuficiência Ovariana Primária/prevenção & controle , Alquilantes/administração & dosagem , Alquilantes/uso terapêutico , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Feminino , Fármacos para a Fertilidade Feminina , Humanos , Leuprolida , Lúpus Eritematoso Sistêmico/complicações , Insuficiência Ovariana Primária/etiologiaRESUMO
We describe a case of a 37-year-old veteran with recurrent conjunctival hyperemia 5 years after an eye-whitening conjunctivectomy procedure with mitomycin C who desired to have a repeat procedure by the original surgeon. Instead, the patient was counseled and successfully fitted with white sclera painted contact lenses to mask the regrowth of his conjunctival vasculature with excellent cosmetic results and comfort. Further eye-whitening surgery was, therefore, avoided. We conclude that hand-painted white sclera contact lenses with regular ocular surface health monitoring can be offered as a cosmetic, safer, and economical alternative to patients in order to avoid eye-whitening procedures known to induce ocular ischemia.
Assuntos
Alquilantes/efeitos adversos , Túnica Conjuntiva/irrigação sanguínea , Lentes de Contato Hidrofílicas , Hiperemia/terapia , Mitomicina/efeitos adversos , Neovascularização Patológica/terapia , Adulto , Cor , Técnicas Cosméticas/efeitos adversos , Humanos , Hiperemia/induzido quimicamente , Masculino , Neovascularização Patológica/induzido quimicamenteRESUMO
BACKGROUND: MNNG HOS transforming gene (MET) exon 14 mutations in lung cancer, including exon 14 skipping and point mutations, have been attracting the attention of thoracic oncologists as new therapeutic targets. Tumors with these mutations almost always acquire resistance, which also occurs in other oncogene-addicted lung cancers. However, the resistance mechanisms and treatment strategies are not fully understood. METHODS: We generated Ba/F3 cells expressing MET exon 14 mutations by retroviral gene transfer. The sensitivities of these cells to eight MET-tyrosine kinase inhibitors (TKIs) were determined using a colorimetric assay. In addition, using N-ethyl-N-nitrosourea mutagenesis, we generated resistant clones, searched for secondary MET mutations, and then examined the sensitivities of these resistant cells to different TKIs. RESULTS: Ba/F3 cells transfected with MET mutations grew in the absence of interleukin-3, indicating their oncogenic activity. These cells were sensitive to all MET-TKIs except tivantinib. We identified a variety of secondary mutations. D1228 and Y1230 were common sites for resistance mutations for type I TKIs, which bind the active form of MET, whereas L1195 and F1200 were common sites for type II TKIs, which bind the inactive form. In general, resistance mutations against type I were sensitive to type II, and vice versa. CONCLUSIONS: MET-TKIs inhibited the growth of cells with MET exon 14 mutations. We also identified mutation sites specific for TKI types as resistance mechanisms and complementary activities between type I and type II inhibitors against those mutations. These finding should provide relevant clinical implication for treating patients with lung cancer harboring MET exon 14 mutations.
Assuntos
Transformação Celular Neoplásica/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia/patologia , Neoplasias Pulmonares/patologia , Mutação , Células Precursoras de Linfócitos B/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/genética , Alquilantes/efeitos adversos , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Células Cultivadas , Etilnitrosoureia/efeitos adversos , Éxons , Humanos , Técnicas In Vitro , Interleucina-3/genética , Interleucina-3/metabolismo , Leucemia/tratamento farmacológico , Leucemia/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Células Precursoras de Linfócitos B/efeitos dos fármacos , Células Precursoras de Linfócitos B/metabolismo , Proto-Oncogene MasRESUMO
Late-onset noninfectious pulmonary complications (LONIPCs) are life-threatening complications after hematopoietic stem cell transplantation (HSCT). Pleuroparenchymal fibroelastosis (PPFE) is a LONIPC, but its etiology remains elusive. Chronic graft-versus-host disease (cGVHD) and alkylating agents used for conditioning have been considered possible causes of PPFE. Therefore, to investigate the primary cause of PPFE in allogeneic HSCT, we compared three secondary PPFE groups, namely, the post-lung-transplantation, post-autologous-HSCT or chemotherapy-alone, and post-allogeneic-HSCT groups, and focused on the coexistence of bronchiolitis obliterans (BO), a typical phenotype of cGVHD. We found a trend towards higher rates of PPFE with BO in the post-allogeneic-HSCT and post-lung-transplantation groups (71% and 90%, respectively) than in the post-autologous-HSCT or chemotherapy-alone group (25%). The incidence of BO following allogeneic HSCT is reportedly <10%. If PPFE in the post-allogeneic-HSCT group has no association with BO and is induced by alkylating agents rather than cGVHD, the incidence of BO in PPFE in this group is estimated to be <10%, which is inconsistent with our data (71%). Thus, this study suggests that PPFE following allogeneic HSCT could be mainly induced by cGVHD because the majority of cases are associated with BO, a typical phenotype of cGVHD.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doenças Pulmonares Intersticiais/etiologia , Doenças Pleurais/etiologia , Complicações Pós-Operatórias/etiologia , Alquilantes/efeitos adversos , Aloenxertos , Bronquiolite Obliterante/complicações , Doença Crônica , Tecido Elástico/patologia , Doença Enxerto-Hospedeiro/complicações , Humanos , Doenças Pulmonares Intersticiais/patologia , Tecido Parenquimatoso/patologia , Doenças Pleurais/patologia , Complicações Pós-Operatórias/patologiaRESUMO
Previously, we reported that the frequency of micronucleated reticulocytes (MNRETs) in the peripheral blood of male C3H/He mice intraperitoneally administered ethylnitrosourea (ENU) (25 mg/kg body weight) in the dark period (zeitgeber time, ZT15) was higher than in the light period (ZT3). In this study, to clarify the mechanism underlying this phenomenon, we investigated the differences in micronucleus (MN) induction observed between ZT3 and ZT15 using five chemicals, methylnitrosourea (MNU), ethylmethane sulfonate (EMS), mitomycin C, cyclophosphamide and vincristin. MNU and EMS, monofunctional alkylating agents, showed higher frequencies of MNRETs in the ZT15 than the ZT3 treatment similar to ENU. However, no differences were observed for the other chemicals. In the comet assay, more DNA damage was induced by ENU in the ZT15 than the ZT3 treatment. Furthermore, the plasma erythropoietin (EPO) level, a known effector of MN induction with anti-apoptotic activity mediated by Bcl-xL expression, was higher in the dark than in the light period. EPO did not increase the frequency of MNRETs. However, in the ENU treatment group at ZT3 following EPO injection a significant increase of MNRETs was observed similar to the ZT15 treatment. Higher expression of apoptosis-related genes such as Bcl-xL was induced in bone marrow cells from mice treated with ENU at ZT15 compared with ZT3. From these results, it was speculated that the differences in MN induction in the peripheral blood of mice exposed to monofunctional alkylating agents such as ENU depend on apoptotic or anti-apoptotic conditions related to the circadian rhythms of EPO in bone marrow.
Assuntos
Administração Metronômica , Alquilantes/administração & dosagem , Alquilantes/efeitos adversos , Nucléolo Celular/efeitos dos fármacos , Nucléolo Celular/patologia , Ritmo Circadiano/fisiologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/farmacologia , Eritropoetina/fisiologia , Metanossulfonato de Etila/farmacologia , Metilnitrosoureia/administração & dosagem , Metilnitrosoureia/efeitos adversos , Mitomicina/administração & dosagem , Mitomicina/efeitos adversos , Reticulócitos/citologia , Reticulócitos/efeitos dos fármacos , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/patologia , Nucléolo Celular/genética , Dano ao DNA/efeitos dos fármacos , Escuridão , Eritropoetina/metabolismo , Eritropoetina/farmacologia , Metanossulfonato de Etila/administração & dosagem , Luz , Masculino , Camundongos Endogâmicos C3H , Tempo , Proteína bcl-X/metabolismoRESUMO
Treatment for Hodgkin (HL) and non-Hodgkin's lymphoma (NHL) has changed dramatically in the last fifty years. While there are increasing numbers of long-term survivors, there has been increasing recognition of the long-term toxicities of treatments, particularly therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML). The survival for t-MDS/AML is extremely poor. Multiple heterogeneous retrospective studies have reported risk factors for the development of t-MDS/AML. Chemotherapy and radiation therapy have been most closely examined as possible t-MDS/AML risk factors. In this paper, we will review the risks of t-MDS/AML for HL and NHL patients as reported in the literature and assess for any changes over time. In HL patients, the incidence of t-MDS/AML has decreased with a reduction in alkylating agents. In indolent NHL patients, we anticipate decreased incidence of t-MDS/AML as targeted therapies begin to replace cytotoxic chemotherapy.