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Background: To investigate if there are improvements in trabeculectomy outcomes supporting filtration bleb formation caused by Rho-associated protein kinase (ROCK) inhibitors., Methods: This prospective, multicentre, randomised, open-label clinical study examined open-angle glaucoma patients who underwent trabeculectomy or trabeculectomy combined with cataract surgery followed by 3-month postoperative ripasudil treatments. After randomly allocating patients to ripasudil-ROCK inhibitor (ripasudil) or without ripasudil (non-ripasudil) groups. Mean intraocular pressure (IOP) changes, success rate, and number of eyedrops were compared for both groups., Results: A total of 17 and 15 subjects dropped out in the ripasudil group and non-ripasudil group, respectively. At baseline, the mean IOP was 16.8±5.0 mm Hg in the ripasudil group (38 patients) and 16.2±4.4 in the non-ripasudil group (52 patients). The IOP decreased to 11.4±3.2 mm Hg, 10.9±3.9 mm Hg and 10.6±3.5 mm Hg at 12, 24 and 36 months in the ripasudil group, while it decreased to 11.2±4.1 mm Hg, 10.5±3.1 mm Hg and 10.9±3.2 mm Hg at 12, 24 and 36 months in the non-ripasudil group, respectively. There was a significant decrease in the number of IOP-lowering medications after trabeculectomy in the ripasudil group versus the non-ripasudil group at 24 (p=0.010) and 36 months (p=0.016). There was no statistically significant difference between the groups for the 3-year cumulative probability of success., Conclusion: Although ripasudil application did not increase the primary trabeculectomy success rate, it did reduce IOP-lowering medications after trabeculectomy with mitomycin C., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The Korean Society of Pediatric Neuro-Oncology (KSPNO) conducted treatment strategies for children with medulloblastoma (MB) by using alkylating agents for maintenance chemotherapy or tandem high-dose chemotherapy (HDC) with autologous stem cell rescue (ASCR) according to the risk stratification. The purpose of the study was to assess treatment outcomes and complications based on risk-adapted treatment and HDC., Materials and Methods: Fifty-nine patients diagnosed with MB were enrolled in this study. Patients in the standard-risk (SR) group received radiotherapy (RT) after surgery and chemotherapy using the KSPNO M051 regimen. Patients in the high-risk (HR) group received two and four chemotherapy cycles according to the KSPNO S081 protocol before and after reduced RT for age following surgery and two cycles of tandem HDC with ASCR consolidation treatment., Results: In the SR group, 24 patients showed 5-year event-free survival (EFS) and overall survival (OS) estimates of 86.7% (95% confidence interval [CI], 73.6 to 100) and 95.8% (95% CI, 88.2 to 100), respectively. In the HR group, more infectious complications and mortality occurred during the second HDC than during the first. In the HR group, the 5-year EFS and OS estimates were 65.5% (95% CI, 51.4 to 83.4) and 72.3% (95% CI, 58.4 to 89.6), respectively., Conclusion: High intensity of alkylating agents for SR resulted in similar outcomes but with a high incidence of hematologic toxicity. Tandem HDC with ASCR for HR induced favorable EFS and OS estimates compared to those reported previously. However, infectious complications and treatment-related mortalities suggest that a reduced chemotherapy dose is necessary, especially for the second HDC.

Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP ≥ 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Background: As the number and longevity of childhood cancer survivors increases, assessing treatment-associated late effects remains crucial. We longitudinally examined the incidence of and associated risk factors for Leydig cell dysfunction (LCD) and Leydig cell failure (LCF) in men treated for pediatric cancers at our institution., Procedure: We performed a retrospective longitudinal cohort study of adult male survivors treated for various childhood cancers who are at risk for LCD. The outcomes of interest were serum testosterone and luteinizing hormone (LH) levels during childhood and adulthood. Risk factors assessed included treatment with stem cell transplant, total body irradiation (TBI), and exposure to alkylating agents., Results: Out of 118 eligible subjects, 7.6% had LCF and 14.4% had LCD. Median age at last testosterone level was 20 years. Subjects with sufficient testosterone levels in adulthood (N = 105) remained sufficient for a mean of 11.1 years following completion of cancer treatment. We found significant associations between LCF and treatment with TBI (p < .003) and between LCF in adulthood and testosterone insufficiency in childhood (p < .001). No statistically significant association was found between LCF and cyclophosphamide equivalent dose greater than 20 g/m 2 (p = .2). LCF/LCD occurred in a small number of nonirradiated patients treated with the highest doses of alkylators., Conclusions: Incidence of LCF and LCD are low in male survivors of childhood cancer. Longitudinally, there is an association between childhood testosterone insufficiency and LCF in adulthood. Alkylating agents and stem cell transplant without TBI were not associated with LCF in our study., (© 2023 Wiley Periodicals LLC.)

Melphalan flufenamide (melflufen) is a novel lipophilic peptide-drug conjugate recently approved in the European Union and the United Kingdom for the treatment of relapsed refractory multiple myeloma. Melflufen rapidly crosses the cell membrane, and inside tumor cells, melflufen utilizes peptidases and esterases to release entrapped hydrophilic metabolites with alkylating activity. In vitro, in whole blood, melflufen was rapidly distributed into blood cells and quickly converted to its main metabolite melphalan, with maximum cellular concentrations of noncovalently bound melflufen and melphalan after 1 and 6 minutes, respectively. Melphalan outflow from blood cells was slow, with peak concentrations in plasma after 25 minutes. The pharmacokinetics of melflufen was best described by a 2-compartment model. Following a 30-minutes intravenous infusion of 40 mg in 27 patients with relapsed refactory multiple myeloma, mean half-life in the α phase of the curve was 1.24 minutes, half-life in the β phase of the curve 26.7 minutes, and clearance 13.4 L/min. Desethyl-melflufen exposure was below 20% compared to melflufen. Based on population analysis (298 patients with relapsed refactory multiple myeloma), the melphalan pharmacokinetics were well characterized by a 3-compartment model with melflufen dosing into a peripheral compartment, assuming instantaneous distribution of melflufen into cells and subsequent rapid metabolism to melphalan. Mean clearance and central and deep peripheral volumes of distribution were 22.4 L/h, 2.70 L, and 51.3 L, respectively. Clearance increased and maximum concentration decreased with increasing body weight and estimated glomerular filtration rate. In conclusion, melflufen administration differs from melphalan administration by a more rapid distribution into cells, which, in conjunction with a rapid intracellular metabolism, allows for higher maximum concentrations of alkylating agents, and by a more extensive distribution of melphalan to peripheral tissues., (© 2023, The American College of Clinical Pharmacology.)

Background: A growing number of centers worldwide are preserving testicular tissue (TT) of young boys at risk of fertility loss to preserve their fertility. Data in this regard are scarce and experience sharing is essential to the optimization of the process., Objectives: This report of our 10-year activity of pediatric fertility preservation (FP) has the objective to (1) improve knowledge regarding the feasibility, acceptability, safety, and potential usefulness of the procedure; (2) analyze the impact of chemotherapy on spermatogonia in the cryopreserved TT., Materials and Methods: For this retrospective study of data prospectively recorded, we included all boys under 18 years of age referred to the FP consultation of our academic network between October 2009 and December 2019. Characteristics of patients and cryopreservation of testicular tissue (CTT) were extracted from the clinical database. Univariate and multivariate analyses were used to assess factors associated with the risk of absence of spermatogonia in the TT., Results: Three hundred and sixty-nine patients (7.2 years; 0.5-17.0) were referred to the FP consultation for malignant (70%) or non-malignant (30%) disease, of whom 88% were candidates for CTT, after a previous chemotherapy exposure (78%). The rate of recorded immediate adverse events was 3.5%, with painful episodes dominating. Spermatogonia were detected in the majority of TTs: 91.1% of those exposed to chemotherapy and 92.3% of those not exposed (p = 0.962). In multivariate analysis, the risk of absence of spermatogonia was almost three-fold higher in boys > 10 years of age ([OR] 2.74, 95% CI 1.09-7.26, p = 0.035) and four-fold higher in boys exposed to alkylating agents prior to CTT ([OR] 4.09, 95% CI 1.32-17.94, p = 0.028)., Discussion/conclusion: This large series of pediatric FP shows that this procedure is well accepted, feasible, and safe in the short term, strengthening its place in the clinical care pathway of young patients requiring a highly gonadotoxic treatment. Our results demonstrate that CTT post-chemotherapy does not impair the chance to preserve spermatogonia in the TT except when the treatment includes alkylating agents. More data on post-CTT follow-up are still required to ensure the long-term safety and usefulness of the procedure., (© 2023 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Guanine O 6 -alkylating agents are widely used as first-line chemotherapeutic drugs due to their ability to induce cytotoxic DNA damage. However, a major hurdle in their effectiveness is the emergence of chemoresistance, largely attributed to the DNA repair pathway mediated by O 6 -methylguanine-DNA methyltransferase (MGMT). MGMT plays an important role in removing the alkyl groups from lethal O 6 -alkylguanine (O 6 -AlkylG) adducts formed by chemotherapeutic alkylating agents. By doing so, MGMT enables tumor cells to evade apoptosis and develop drug resistance toward DNA alkylating agents. Although covalent inhibitors of MGMT, such as O 6 -benzylguanine (O 6 -BG) and O 6 -(4-bromothenyl)guanine (O 6 -4-BTG or lomeguatrib), have been explored in clinical settings, their utility is limited due to severe delayed hematological toxicity observed in most patients when combined with alkylating agents. Therefore, there is an urgent need to identify new targets and unravel the underlying molecular mechanisms and to develop alternative therapeutic strategies that can overcome MGMT-mediated tumor resistance. In this context, the regulation of MGMT expression via interfering the specific cell signaling pathways (e.g., Wnt/β-catenin, NF-κB, Hedgehog, PI3K/AKT/mTOR, JAK/STAT) emerges as a promising strategy for overcoming tumor resistance, and ultimately enhancing the efficacy of DNA alkylating agents in chemotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

From the 1960s to the early 2000s, alkylating agents (e.g., melphalan, cyclophosphamide, and bendamustine) remained a key component of standard therapy for newly-diagnosed or relapsed/refractory multiple myeloma (MM). Later on, their associated toxicities (including second primary malignancies) and the unprecedented efficacy of novel therapies have led clinicians to increasingly consider alkylator-free approaches. Meanwhile, new alkylating agents (e.g., melflufen) and new applications of old alkylators (e.g., lymphodepletion before chimeric antigen receptor T-cell [CAR-T] therapy) have emerged in recent years. Given the expanding use of antigen-directed modalities (e.g., monoclonal antibodies, bispecific antibodies, and CAR-T therapy), this review explores the current and future role of alkylating agents in different treatment settings (e.g., induction, consolidation, stem cell mobilization, pre-transplant conditioning, salvage, bridging, and lymphodepleting chemotherapy) to ellucidate the role of alkylator-based regimens in modern-day MM management., Competing Interests: Declaration of Competing Interest Bruno Almeida Costa, MD (B.A.C.): Declares no competing interests. Tarek H. Mouhieddine, MD (T.H.M.): Receives advisory board fees from Legend Biotech. Ricardo J. Ortiz, MD (R.J.O.): Declares no competing interests. Joshua Richter, MD (J.R.): Receives consulting fees and fees for serving on a speakers’ bureau from Janssen, Sanofi and Adaptive Biotechnologies; advisory board fees from Celgene/BMS, Janssen, Karyopharm, Sanofi, Adaptive Biotechnologies; consultancy fees from Celgene/BMS, and Takeda., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The inhibition of histone deacetylases (HDACs) holds promise as a potential anti-cancer therapy as histone and non-histone protein acetylation is frequently disrupted in cancer, leading to cancer initiation and progression. Additionally, the use of a histone deacetylase inhibitor (HDACi) such as the class I HDAC inhibitor-valproic acid (VPA) has been shown to enhance the effectiveness of DNA-damaging factors, such as cisplatin or radiation. In this study, we found that the use of VPA in combination with talazoparib (BMN-673-PARP1 inhibitor-PARPi) and/or Dacarbazine (DTIC-alkylating agent) resulted in an increased rate of DNA double strand breaks (DSBs) and reduced survival (while not affecting primary melanocytes) and the proliferation of melanoma cells. Furthermore, the pharmacological inhibition of class I HDACs sensitizes melanoma cells to apoptosis following exposure to DTIC and BMN-673. In addition, the inhibition of HDACs causes the sensitization of melanoma cells to DTIV and BMN-673 in melanoma xenografts in vivo. At the mRNA and protein level, the histone deacetylase inhibitor downregulated RAD51 and FANCD2. This study aims to demonstrate that combining an HDACi, alkylating agent and PARPi could potentially enhance the treatment of melanoma, which is commonly recognized as being among the most aggressive malignant tumors. The findings presented here point to a scenario in which HDACs, via enhancing the HR-dependent repair of DSBs created during the processing of DNA lesions, are essential nodes in the resistance of malignant melanoma cells to methylating agent-based therapies.

Second-line treatment options are limited for patients with small-cell lung cancer (SCLC). We conducted a PRISMA-standard systematic literature review to evaluate the treatment landscape for patients with relapsed SCLC (PROSPERO number: CRD42022299759). Systematic searches of MEDLINE, Embase, and Cochrane Library were performed (October 2022) to identify publications (prior 5 years) from prospective studies of therapies for relapsed SCLC. Publications were screened against predetermined eligibility criteria; data were extracted to standardized fields. Publication quality was assessed using GRADE. The data were analyzed descriptively, grouped by drug class. Overall, 77 publications involving 6349 patients were included. Studies of tyrosine kinase inhibitors (TKIs) with established cancer indications accounted for 24 publications; topoisomerase I inhibitors for 15; checkpoint inhibitors (CPIs) for 11, and alkylating agents for 9 publications. The remaining 18 publications featured chemotherapies, small-molecule inhibitors, investigational TKIs and monoclonal antibodies, and a cancer vaccine. According to GRADE assessment, 69% of the publications reported low-/very-low-quality evidence; quality limitations included lack of randomization and small sample sizes. Only 6 publications/6 trials reported phase 3 data; 5 publications/2 trials reported phase 2/3 results. Overall, the clinical potential of alkylating agents and CPIs remained unclear; investigations of combination approaches and biomarker-directed usage are warranted. Phase 2 data from TKI trials were consistently promising; no phase 3 data were available. Phase 2 data for a liposomal formulation of irinotecan were promising. We confirmed an absence of promising investigational drug/regimens in late-stage development; thus, relapsed SCLC remains an area of high unmet need., (Copyright © 2023. Published by Elsevier Inc.)

Alkylating agents are potent anticancer compounds that exert their anticancer properties through the inhibition of cell replication and transcription leading to cell death. Despite the numerous benefits, these agents also have serious drawbacks such as their high toxicity and low specificity towards cancer cells. As previously reported by our group, conjugation of alkylating agents with azasteroids can reduce their systemic toxicity and enhance their anticancer activity. In this work, novel steroidal alkylating agents bearing POPAM-OH were synthesized and their anticancer efficacy was evaluated in vitro and in vivo. All the novel hybrids demonstrated high antiproliferative effects against 5 different cancer cell lines in the low micromolar range. Treatment of SCID mice bearing SKOV-3 or PC-3 tumor xenografts with the most potent hybrid 19 led to significant reduction of tumor size (tumor inhibition TI = 95% in SKOV3 models and TI = 85.2% in PC3 models). Importantly, the acute toxicity of hybrid 19 (LD 10  = 36 μΜ, LD 50  = 62 μΜ) in CB17 SCID mice exhibited three-fold decrease compared to the acute toxicity of previously reported hybrids of POPAM-NH 2 . This is an important finding since systemic cytotoxicity is a critical limitation of alkylating agents. Collectively, the steroidal conjugates of POPAM-OH displayed significant anticancer efficacy and reduced toxicity in vitro and in vivo rendering them as good candidates for cancer therapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dimitrios T. Trafalis, Vasiliki Sarli reports financial support was provided by GALENICA S.A. and ENERGON BIOTECH S.A. Dimitrios TRAFALIS has patent #US20180194800A1 issued to Energonbio Technologies SA Galenica SA., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Opinion Statement: Primary malignant central nervous (CNS) tumors are a devastating group of diseases with urgent need for improved treatment options. Surgery, radiation, and cytotoxic chemotherapy remain the primary standard treatment modalities, with molecularly targeted therapies having proven efficacy in only small subsets of cases. Poly(ADP-ribose) polymerase (PARP) inhibitors, which have had immense success in the treatment of extracranial cancers with homologous recombination deficiency (HRD), are emerging as a potential targeted treatment for various CNS tumors. Although few primary CNS tumors display canonical BRCA gene defects, preclinical evidence suggests that PARP inhibitors may benefit certain CNS tumors with functional HRD or elevated replication stress. In addition, other preclinical studies indicate that PARP inhibitors may synergize with standard therapies used for CNS tumors including radiation and alkylating agents and may prevent or overcome drug resistance. Thus far, initial clinical trials with early-generation PARP inhibitors, typically as monotherapy or in the absence of selective biomarkers, have shown limited efficacy. However, the scientific rationale remains promising, and many clinical trials are ongoing, including investigations of more CNS penetrant or more potent inhibitors and of combination therapy with immune checkpoint inhibitors. Early phase trials are also critically focusing on determining active drug CNS penetration and identifying biomarkers of therapy response. In this review, we will discuss the preclinical evidence supporting use of PARP inhibitors in primary CNS tumors and clinical trial results to date, highlighting ongoing trials and future directions in the field that may yield important findings and potentially impact the treatment of these devastating malignancies in the coming years., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Pomalidomide is a third generation immunomodulatory drug in the treatment of refractory and relapsed multiple myeloma patients. Our aim was to investigate the efficacy and safety of pomalidomide therapy in a real world setting. Eighty-six Hungarian patients were included, 45 of whom received pomalidomide ± an alkylating agent, while in 38 of them pomalidomide was combined with a proteasome inhibitor. 56 patients (65%) showed any response to the treatment with 18 complete or very good partial remissions and 38 partial remissions. At a median duration of follow-up of 18.6 months, the median progression-free survival (PFS) was 9.03 months, while the median overall survival (OS) was 16.53 months in the whole cohort. Patients with early stage disease (R-ISS 1 and 2) had better survival results than those with stage 3 myeloma ( p = 0.002). Neither the number of prior treatment lines, nor lenalidomide refractoriness had a significant impact on PFS . PFS was found similar between the cohort of patients with impaired renal function and the cohort without kidney involvement. During the study, eight mortal infections and two fatal bleeding complications occurred, however, mild hematologic and gastrointestinal toxicities were identified as the most frequent adverse events. The results of our investigations confirm that pomalidomide is an effective treatment option for relapsed/refractory MM, besides, the safety profile is satisfactory in subjects with both normal and impaired renal function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lovas, Obajed Al-Ali, Varga, Szita, Alizadeh, Plander, Rajnics, Illés, Szemlaky, Mikala and Váróczy.)

Temozolomide (TMZ), an imidazotetrazine, is a second-generation DNA alkylating agent used as a first-line treatment of glioblastoma multiforme (GBM). It was approved by FDA in 2005 and declared a blockbuster drug in 2008. Although TMZ has shown 100% oral bioavailability and crosses the blood-brain barrier effectively, however it suffers from limitations such as a short half-life (∼1.8 h), rapid metabolism, and lesser accumulation in the brain (∼10-20%). Additionally, development of chemoresistance has been associated with its use. Since it is a potential chemotherapeutic agent with an unmet medical need, advanced delivery strategies have been explored to overcome the associated limitations of TMZ. Nanocarriers including liposomes, solid lipid nanoparticles (SLNs), nanostructure lipid carriers (NLCs), and polymeric nanoparticles have demonstrated their ability to improve its circulation time, stability, tissue-specific accumulation, sustained release, and cellular uptake. Because of the appreciable water solubility of TMZ (∼5 mg/mL), the physical loading of TMZ in these nanocarriers is always challenging. Alternatively, the conjugation approach, wherein TMZ has been conjugated to polymers or small molecules, has been explored with improved outcomes in vitro and in vivo. This review emphasized the practical evidence of the conjugation strategy to improve the therapeutic potential of TMZ in the treatment of glioblastoma multiforme., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Ovarian malignant mesoderm mixed tumor (OMMMT) is a rare clinical entity. To provide reference for the treatment and prognosis of OMMMT, we analyzed the clinical features, pathology and molecular biology characteristic of published cases., Methods: The English and Chinese reported cases of OMMMT were selected from PubMed, Clinical Trials.gov and CNKI database from 2000 to December 15th, 2021 following the PRISMA guidelines., Results: A total of 63 literatures including 199 OMMMT cases were included. The average age of patients at diagnosis was 56.46 years, the highest incidence age was 60-65 years, and 82% of them were menopausal women. Most patients were diagnosed in FIGO III stage (59.64%). The most common symptom of OMMMT was abdominal pain (60.5%). 61.6% of patients were accompanied by ascites, while ascites was not associated with metastatic tumor and local recurrence. The CA125 of 88.68% patients increased. The most common reported carcinomatous component and sarcomatous component were serous adenocarcinoma (44.96%) and chondrosarcoma (24.81%), respectively. Initial treatment included surgery (94.97%) and taxanes-based (55.10%) or platinum-based (85.71%) chemotherapy regimens. The median survival time of patients was 20 months. Heterologous sarcoma component did not shorten life expectancy. The optimal ovarian tumor cell debulking surgery (OOTCDS), radiotherapy and chemotherapy could significantly prolong the median survival time of patients. Furthermore, platinum drugs could significantly prolong the survival time after comparing various chemotherapy schemes. Besides, the combination of platinum and taxanes was therapeutically superior to the combination of platinum and biological alkylating agents., Conclusion: The OOTCDS and platinum-based chemotherapy regimen can improve the prognosis of OMMMT. Targeted therapy might become a new research direction in the future. Since the elderly patients are the majority, the toxicity of new drugs on the elderly patients is more noteworthy., (© 2022. The Author(s).)

Disease intervention at the DNA level generally has been avoided because of off-target effects. Recent advances in genome editing technologies using CRISPR-Cas9 have opened a new era in DNA-targeted therapeutic approaches. However, delivery of such systems remains a major challenge. Here, we report a selective DNA-modifying small molecule that targets a disease-specific structure and mismatches involved in myotonic dystrophy type 1 (DM1). This ligand alkylates T-T mismatch-containing hairpins formed in the expanded CTG repeats (d(CTG) exp ) in DM1. Ligand alkylation of d(CTG) exp inhibits the transcription of d(CAG·CTG) exp , thereby reducing the level of the toxic r(CUG) exp transcript. The bioactivity of the ligand also included a reduction in DM1 pathological features such as disease foci formation and misregulation of pre-mRNA splicing in DM1 model cells. Furthermore, the CTG-alkylating ligand may change the d(CAG·CTG) exp repeat length dynamics in DM1 patient cells. Our strategy of linking an alkylating moiety to a DNA mismatch-selective small molecule may be generally applicable to other repeat expansion diseases such as Huntington's disease and amyotrophic lateral sclerosis.

Cancer treatment is associated with various side effects of antitumor agents, which increase the morbidity and mortality of these patients. Cardiovascular complications are considered to be one of the most important side effect of the anticancer drugs. The antitumor drugs that express cardiovascular effects include anthracyclines, tyrosine kinase inhibitors, taxanes, fluoropyrimidines, alkylating agents, vascular endothelial growth factor inhibitors, immune checkpoint inhibitors, proteasome inhibitors and human epidermal growth receptor type 2 antibodies. The spectrum of cardiovascular effects of anticancer drugs is broad and include, among others, heart failure, arrhythmias such as atrial fibrillation and ventricular tachyarrhythmias, hypertension (systemic or pulmonary), cardiomyopathy, myocarditis, valve disease, pericardial disease, vascular events (arterial thrombosis, venous thromboembolism) and myocardial ischemia (acute coronary syndrome, angina). The molecular mechanisms by which anti-cancer therapies lead to cardiotoxicity are diverse and vary according to the specific type of agent used. They include oxidative stress, topoisomerase 2-β inhibition in cardiomyocytes, inflammation, endothelial dysfunction, apoptosis, disruption of Ca2+ homeostasis, mitochondrial dysfunction, DNA damage, increase in various circulating microRNAs levels, alterations in the function of voltage-gated potassium channels. The management of cardiovascular complications in cancer patients is a new challenge for oncologists and cardiologists. Thus the cardio-oncology field has developed the last decade in order to precisely predict and efficiently treat the cancer treatment-related cardiovascular diseases., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Secondary malignancies including leukemia are an increasing concern in patients with prior primary malignancies treated with alkylating agents or topoisomerase II inhibitors. These can also be referred to as therapy-related leukemia. Therapy-related leukemia most commonly results in myelodysplastic syndrome or acute myeloid leukemia. The alkylating agent can cause chromosomal aberrations typically manifest as deletions in chromosome 11 or loss of part of complete loss of chromosomes 5 and 7. Conversely, acute lymphoblastic leukemia (ALL) has been described following maintenance therapy with immunomodulatory (IMiD) drugs pomalidomide, thalidomide, and lenalidomide. We present a case of a 71-year-old man with a history of multiple myeloma (MM) maintained on lenalidomide after stem cell transplant who presented with treatment-associated ALL. At time of leukemic presentation, chromosomal analysis showed a near-triploid clone consistent with masked double low hyplodiploidy which is associated with a poor prognosis. The patient had a deletion of the long arm of chromosome 5 which has been described in prior case reports with ALL secondary to lenalidomide therapy. There are explicit mechanisms in the literature, which have been attributed to development of ALL after exposure to thalidomide or lenalidomide. At time of submission, there are 20 cases described in the literature linking ALL to IMiD drugs. We describe a case and review the mechanisms of lenalidomide-associated ALL.

Cancer is considered one of the gruelling challenges and poses a grave health hazard across the globe. According to the International Agency for Research on Cancer (IARC), new cancer cases increased to 18.1 million in 2018, with 9.6 million deaths, bringing the global cancer rate to 23.6 million by 2030. In 1942, the discovery of nitrogen mustard as an alkylating agent was a tremendous breakthrough in cancer chemotherapy. It acts by binding to the DNA, and creating cross linkages between the two strands, leading to halt of DNA replication and eventual cell death. Nitrogen lone pairs of 'nitrogen mustard' produce an intermediate 'aziridinium ion' at the molecular level, which is very reactive towards DNA of tumour cells, resulting in multiple side effects with therapeutic consequences. Owing to its high reactivity and peripheral cytotoxicity, several improvements have been made with structural modifications for the past 75 years to enhance its efficacy and improve the direct transport of drugs to the tumour cells. Alkylating agents were among the first non-hormonal substances proven to be active against malignant cells and also the most valuable cytotoxic therapies available for the treatment of leukaemia and lymphoma patients. This review focus on the versatile use of alkylating agents and the Structure Activity Relationship (SAR) of each class of these compounds. This could provide an understanding for design and synthesis of new alkylating agents having enhanced target specificity and adequate bioavailability., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

This is a retrospective study of patients with multiple myeloma (MM) who were >75 years old. We identified 394 patients and for non-trial patients ( n  = 350), immunomodulatory drug (IMiD)+dex (32%) was the most commonly used regimen followed by alkylator with steroids or other therapy (21%), alkylator + proteasome inhibitor (PI)+steroid (18%), and IMiD + PI + dex (13%). Overall, achieving ≥ very good partial response was more in patients receiving a triplet compared to other therapies (46% vs. 21%, p  < 0.0001). Also, the median overall survival (OS) was significantly longer in patients who were treated with a triplet (median OS: 50.2 vs. 32.8 months, p  = 0.0006). In a multivariate for OS, receiving a triplet (HR: 0.65, p  = 0.02), not having an R-ISS stage 3 (HR: 0.36, p  = 0.0003), and bone marrow plasma cell percentage <60% (HR: 0.69, p  = 0.03) were predictive. In conclusion, being able to receive triplet therapy was associated with better survival in our MM patients >75 years old.

Aim: To describe treatment patterns and outcomes in nontransplant newly diagnosed multiple myeloma (NDMM) patients in Spain. Methods: This retrospective study included two cohorts of NDMM patients diagnosed between 1 January 2012 to 31 December 2013 and 1 April 2016 to 31 March 2017. Results: Among 113 patients, proteasome inhibitor (PI) + alkylator combinations (49%) and PI-based regimens without an alkylator (30%) were the most common first-line (1L) therapies. Use of PI + immunomodulatory drug-based regimens increased between the cohorts; PI-based regimens without an alkylator/immunomodulatory drug decreased. Use of 1L oral regimens was low but increased over time; use of maintenance therapy was low across both periods. Median 1L duration of treatment was 6.9 months. Conclusion: Short 1L duration of treatment and low use of 1L oral regimens and maintenance therapy highlight unmet needs in NDMM.

A rechallenge is common after the initial efficacy of alkylating-based chemotherapy (ALK) in pancreatic neuroendocrine tumors (PanNET). High MGMT expression seems associated with a lower response to ALK. We aimed to evaluate the efficacy and toxicity of ALK rechallenge in PanNET, and to assess the evolution of MGMT expression under ALK. All consecutive patients with advanced PanNETs who received initial ALK (achieving tumor control) followed by a pause of > 3 months, then an ALK rechallenge (ALK2) upon progression were retrospectively studied (cohort A). The primary endpoint was progression-free survival under ALK2 (PFS2). The MGMT expression was retrospectively assessed by immunohistochemistry (H-score) in consecutive PanNET surgically resected following ALK (cohort B). We found that Cohort A included 62 patients (median Ki67 8%), for whom ALK1 followed by a pause achieved an objective response rate of 55% and a PFS1 of 23.7 months (95% IC, 19.8-27.6). ALK2 achieved no objective response and stability in 62% of patients. The median PFS2 was 9.2 months (IC 95% 7.1-11.3). At multivariable analysis, a hormonal syndrome (P = 0.032) and a pause longer than 12 months (P = 0.041) were associated with a longer PFS2. In cohort B (17 patients), the median MGMT H-score increased from 45 (IQR 18-105) before ALK to 100 (IQR 56-180) after ALK (P = 0.003). We conclude that after the initial efficacy of ALK treatment, a pause followed by ALK rechallenge might be appropriate to prolong tumor control, improve quality of life and limit long-term adverse events. Increased MGMT expression under ALK might explain the low efficacy of ALK rechallenge.

Often considered a rare disease, cardiac amyloidosis is increasingly recognized by practicing clinicians. The increased rate of diagnosis is in part due the aging of the population and increasing incidence and prevalence of cardiac amyloidosis with advancing age, as well as the advent of noninvasive methods using nuclear scintigraphy to diagnose transthyretin cardiac amyloidosis due to either variant or wild type transthyretin without a biopsy. Perhaps the most important driver of the increased awareness is the elucidation of the biologic mechanisms underlying the pathogenesis of cardiac amyloidosis which have led to the development of several effective therapies with differing mechanisms of actions. In this review, the mechanisms underlying the pathogenesis of cardiac amyloidosis due to light chain (AL) or transthyretin (ATTR) amyloidosis are delineated as well as the rapidly evolving therapeutic landscape that has emerged from a better pathophysiologic understanding of disease development.

Purpose: To compare between mitomycin C alone, porcine extracellular matrix alone, and combined low dose mitomycin C with porcine extracellular matrix in term of efficacy and safety in phaco-trabeculectomy surgery., Study Design: Prospective comparative., Methods: Sixty eyes of 60 patients complaining of primary open angle glaucoma and cataract, undergoing phaco-trabeculectomy, were distributed into three groups: group I: surgery was augmented with mitomycin C, group II with porcine extracellular matrix, and group III with porcine extracellular matrix combined with low dose mitomycin C. Intraocular pressure was evaluated, postoperatively, at day 1, week 1, and 1, 3, 6, 9, and 12 months. Bleb vascularity, pre- and post-operative intraocular pressure lowering medications, success of IOP control and complications were also evaluated., Results: After 12 months, the mean preoperative intraocular pressure (mm Hg) improved from 30.85 ± 4.7, 33.8 ± 4.2, and 31.05 ± 5.4 mm Hg, in groups I, II, and III respectively, to 13.8 ± 4.7 (55.2%), 15.2 ± 4.8 (55%), and 13 ± 4.9 (58.1%) ( p  > 0.05). Success of IOP control, postoperative IOP lowering medications and complications were comparable ( p  > 0.05). Bleb vascularity was significantly different ( p  < 0.05)., Conclusion: Mitomycin C, porcine extracellular matrix and their combination are equally effective in phacotrabeculectomy.

The efficacy of alkylating agents (temozolomide, dacarbazine, streptozotocin) in patients with advanced neuroendocrine tumors (NETs) has been well documented, especially in pancreatic NETs. Alkylating agents transfer methyl adducts on DNA bases. Among them, O6-methylguanine accounts for many of their cytotoxic effects and can be repaired by the O6-methylguanine-methyltransferase (MGMT). However, whether the tumor MGMT status could be a reliable biomarker of efficacy of alkylating agents in NETs is still a matter of debate. Herein, we sought to provide a critical appraisal of the role of the MGMT status in NETs. After reviewing the molecular mechanisms of repair of DNA damage induced by alkylating agents, we aimed to comprehensively review the methods of determination of the MGMT status and its impact on prognosis, prediction of objective response and progression-free survival in patients with advanced digestive NETs treated by alkylating agents. About half of pancreatic NETs are MGMT-deficient, as determined by impaired tumor MGMT expression or by MGMT promoter methylation. Overall, while published studies are heterogeneous and mostly limited in size, they advocate that MGMT deficiency may be a relevant biomarker for increased objective response rate, prolonged progression-fee survival and overall survival in patients with advanced NETs treated by alkylating agents. While these data require confirmation in prospective controlled studies, future research should focus on the standardization of MGMT status assessment. Additional mechanisms of repair of DNA damages induced by alkylating agents should be explored in order to identify biomarkers complementary to MGMT and targets for potential antitumor synergy, such as PARP.

Despite their toxicity, DNA alkylating drugs remain a cornerstone of anticancer therapy. The classical thinking was that rapidly dividing tumour cells left more of its DNA in an exposed single-stranded state, making these rapidly dividing cells more susceptible to alkylating drugs. As our understanding of DNA repair pathways has matured it is becoming clear that compromised DNA repair - a hallmark of cancer - plays a role as well in defining the therapeutic window of these toxic drugs. Hence, although new alkylating motifs are unlikely to progress through the clinic, the legacy of these medicines is that we now understand the therapeutic potential of targeting DNA damage repair pathways. Here we look at the history of alkylating agents as anticancer drugs, while also summarizing the different mechanistic approaches to covalent DNA modification. We also provide several case studies on how insights into compromised DNA repair pathways are paving the way for potent and less toxic targeted medicines against the DNA damage response.

Background: The alkylating agent cyclophosphamide is used in chemotherapy regimens for various type of cancer. However, cyclophosphamide may lead to toxic side effects on the bladder, namely hemorrhagic cystitis, which can cause hematuria, and, potentially, bladder cancer. These effects are caused by acrolein, a byproduct of cyclophosphamide metabolism. In this study, a method to quantify 3-hydroxypropyl mercapturic acid (3-HPMA) in urine was developed. 3-HPMA is a stable metabolite of acrolein that serves as biomarker of acrolein., Methods: Urine samples were collected 4 hours after cyclophosphamide administration and analyzed to determine the risk of hematuria. 3-HPMA was analyzed by reverse-phase LC-MS/MS using a triple quadrupole electrospray ionization mass spectrometer in the positive-ion mode. The mobile phase was a 90:10 (vol/vol) mixture of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. Multiple reaction monitoring mode was used, with m/z 222.10 → 90.97 for 3-HPMA and 164.10 → 122.02 for the internal standard N-acetyl cysteine (NAC). Samples were prepared by acidification and dilution., Results: The analytical method produced a linear response within the concentration range of 40-10,000 ng/mL. The method was validated in accordance with 2018 FDA guidelines and applied to quantify 3-HPMA in the urine of 40 patients with breast cancer. The measured concentrations ranged from 820.3 to 5596.1 ng/mg creatinine. Seven patients identified with hematuria had low 3-HPMA concentrations of 4445.824 ± 411.17 ng/mg creatinine, and 33 patients without hematuria had low 3-HPMA concentrations of 2419.4 ± 1171.8 ng/mg creatinine., Conclusions: The method was applicable for the quantification of 3-HPMA in human urine. Large variations in 3-HPMA concentrations were found in 40 patients with breast cancer treated with cyclophosphamide, with a significant difference (P < 0.05) observed between patients with hematuria and those without hematuria.

Background: Epiphora is a common clinical sign whose primary cause is post-canalicular lacrimal obstruction. Treatment is both surgical and non-surgical. In the literature, there is some evidence to suggest that some treatments are superior to others, but there are no direct comparative data in this regard., Objective of Review: To analyse the success rates of all available treatments to resolve post-canalicular acquired lacrimal obstruction., Type of Review: Systematic review and meta-analysis., Search Strategy: A literature search was conducted in the US National Library of Medicine (PubMed), EMBASE, SCOPUS and Cochrane databases with a final search performed in January 2020., Evaluation Method: The search strategy identified articles published later than 2000 with at least 50 procedures performed both surgically (external dacryocystorhinostomy [EXT-DCR], endoscopic dacryocystorhinostomy [END-DCR] and transcanalicular laser dacryocystorhinostomy [TCL-DCR]) and non-surgically (balloon dacryoplasty [DCP], probing-stenting [SP] and polyurethane stent [PoS]). The primary outcome was functional success, defined as symptom resolution or less than MUNK 2 scale; in addition to this, the influence of adjunctive treatments, such as application of mitomycin C and post-procedural silicone stenting, was evaluated., Results: In total, 14 958 papers were selected, 440 of which were reviewed after screening; 55 were included after full-text review, which involved 9337 procedures. Mean success rate was 48.9% (35.7%-62.3%) for DCP, 54.4% (41.8%-66.5%) for SP, 73.6% (59.7%-84%) for PoS, 80% (75.1%-84%) for TCL-DCR, 89.8% (83.3%-93.9%) for EXT-DCR and 89.5% (87.2%-91.5%) for END-DCR. Among all procedures, a difference was noted between DCP and END-DCR (P < .001), DCP and EXT-DCR (P < .001), SP and END-DCR (P < .001), SP and EXT-DCR (P < .001), END-DCR and PoS (P = .016), and END-DCR and TCL-DCR (P = .001); no differences were noted between END-DCR and EXT-DCR (P = 1.00), EXT-DCR and PoS (P = .121) and EXT-DCR and TCL-DCR (P = .223). Considering surgical procedures, no differences were seen if a silicone stenting was applied, whereas, due to heterogeneity of the literature data, no statistical analysis was feasible for application of mitomycin C., Conclusions: Our analyses suggest that, among all procedures available, END-DCR and EXT-DCR should be considered as treatments of choice to resolve distal acquired lacrimal obstruction., (© 2020 John Wiley & Sons Ltd.)

Virotherpay is emerging as a promising strategy against cancer, and three oncolytic viruses (OVs) have gained approval in different countries for the treatment of several cancer types. Beyond the capability to selectively infect, replicate and lyse cancer cells, OVs act through a multitude of events, including modification of the tumour micro/macro-environment as well as a complex modulation of the anti-tumour immune response by activation of danger signals and immunogenic cell death pathways. Most OVs show limited effects, depending on the viral platform and the interactions with the host. OVs used as monotherapy only in a minority of patients elicited a full response. Better outcomes were obtained using OVs in combination with other treatments, such as immune therapy or chemotherapy, suggesting that the full potential of OVs can be unleashed in combination with other treatment modalities. Here, we report the main described combination of OVs with conventional chemotherapeutic agents: platinum salts, mitotic inhibitors, anthracyclines and other antibiotics, anti-metabolites, alkylating agents and topoisomerase inhibitors. Additionally, our work provides an overview of OV combination with targeted therapies: histone deacetylase inhibitors, kinase inhibitors, monoclonal antibodies, inhibitors of DNA repair, inhibitors of the proteasome complex and statins that demonstrated enhanced OV anti-neoplastic activity. Although further studies are required to assess the best combinations to translate the results in the clinic, it is clear that combined therapies, acting with complementary mechanisms of action might be useful to target cancer lesions resistant to currently available treatments., (Copyright © 2020. Published by Elsevier Inc.)

Background: Metastatic phyllodes tumors have poor prognosis with median overall survival of 11.5 months. The objective of this study is to identify prognostic factors and the best options for management of metastatic malignant phyllode tumors (MMPTs)., Patients and Methods: A multicentric retrospective study, including cases of MMPT from 10 sarcoma centers, was conducted. The primary end-point was overall survival (OS), and the secondary end-point was the clinical benefit of chemotherapy (CBCT) rate., Results: 51 MMPT patients were included. Median time from diagnosis to metastatic recurrence was 13 months. Management of MMPT consisted in surgery of the metastatic disease for 16 patients (31.3%), radiation therapy of the metastatic disease for 15 patients (31.9%), and chemotherapy for 37 patients (72.5%). Median follow-up was 62.1 months [95% confidence interval (CI) 31-80 months]. Median OS was 11.5 months (95% CI 7.5-18.7 months). On multivariate analysis, two or more metastatic sites [hazard ratio (HR) 2.81, 95% CI 1.27-6.19; p = 0.01] and surgery of metastasis (HR 0.33, 95% CI 0.14-0.78; p = 0.01) were independently associated with OS. The CBCT rate was 31.4% and 16.7% for the first and second lines. Polychemotherapy was not superior to single-agent therapy. Alkylating-agent-based chemotherapy, possibly associated with anthracyclines, was associated with a better CBCT rate than anthracyclines alone (p = 0.049)., Conclusions: The results of this study emphasize the impact of the number of metastatic sites on survival of MMPT patients and the leading role of metastasis surgery in MMPT management. If systemic therapy is used, it should include alkylating agents, which are associated with a better clinical benefit.

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., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

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., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019. Published by Elsevier Ltd.)

A survey was carried out among EBMT centers about the use of busulfan for conditioning in allogeneic stem cell transplantation. Of 109 responding centers, 106 used busulfan for conditioning, 102 in conventional myeloablative doses, and 93 in reduced doses (RIC). The route of administration was mostly intravenous, but ~10% of the centers gave the drug orally. The number of doses in i.v. administration varied and was in myeloablative conditioning mostly one (50 centers) or four (43 centers) doses a day. Seventeen of the 106 centers used pharmacokinetics for dose adjustment in myeloablative conditioning, nine in RIC. The details of pharmacokinetic monitoring varied markedly. Three quarters of the centers reported adjusting the dose based on obesity in myeloablative conditioning and about 60% in RIC. The most common method for dose calculation was ideal body weight + 0.25 × (actual body weight - ideal body weight). In conclusion, the present survey showed marked heterogeneity in the current practices of busulfan administration for conditioning. The impact of the heterogeneity is not well known. Due to this and the scarcity of support from controlled clinical studies, no clear guidelines can be presented, but some prevailing policies to be recommended were identified.

Objectives: To evaluate recent studies on available and experimental therapies in preventing or minimizing corneal stromal scarring after injury., Methods: We performed an Entrez PubMed literature search using keywords "cornea," "scarring," "haze," "opacity," "ulcer," "treatments," "therapies," "treatment complications," and "pathophysiology" resulting in 390 articles of which 12 were analyzed after filtering, based on English language and publication within 8 years, and curation for relevance by the authors., Results: The 12 articles selected included four randomized control trials (RCTs) (two were double-blinded placebo-controlled RCTs, one was a prospective partially masked RCT, and one was an open-label RCT), two retrospective observational studies, and six laboratory-based studies including two studies having in vivo and in vitro experiments, one was in vivo study, one was ex vivo study, and the last two were in vitro studies. The current mainstay for preventing or minimizing corneal scarring involves the use of topical corticosteroids and local application of mitomycin C. However, supportive evidence for their use in clinical practice from well-designed RCTs is lacking. Laboratory studies on topical rosiglitazone therapy, vitamin C prophylaxis, gene therapy, and stem cell therapy have shown promising results but have yet to be translated to clinical research., Conclusion: There is a need for more robust randomized controlled trials to support treatments using topical corticosteroids and mitomycin C. Furthermore, their clinical efficacy and safety profile should be compared with new treatments that have shown promising results in the laboratory setting. Ultimately, the goal should be to personalize cornea scarring treatment according to the most effective treatment for the specific underlying pathology.

Postintubation stenosis is a frequent complication of long-term endotracheal anesthesia. In the last few decades, its incidence showed an increasing tendency particularly among children and premature infants. It mostly affects the subglottic area and avoidance of a tracheotomy could lead to better life quality of the patient. We present the treatment of a glotto-subglottic stenosis in a 4-year-old girl. Ultra Dream Pulse Laser surgery was performed with mometason (Elocom) and mitomycin (Mitomycin-C) submucosal injections to prevent refibrosis. Minimally invasive operations play a key role in the treatment of laryngotracheal stenosis. Ultra Dream Pulse Laser surgeries could be safely applied in pediatric patients. Patient follow-up revealed wide glottis without any fibrosis. Ultra Dream Pulse Laser intervention completed with steroid-mitomycin infiltration is an efficient method of treating postintubation stenosis. Orv Hetil. 2019; 160(20): 792-796.

Background: The study aimed to assess the role of intraoperative mitomycin-C (MMC) application during hyperopic LASIK correction (+ 1.00 D to + 6.00 D) by examining topographic corneal changes and incidence of regression over a one-year follow-up period., Methods: This comparative randomized control study included 68 hyperopic patients (136 eyes) divided into two groups; Group A included 34 patients (68 eyes) that had LASIK with the application of 0.02% MMC for 10 s on the stromal bed after excimer laser treatment, and group B included 34 patients (68 eyes) that had LASIK without MMC application. Uncorrected distance visual acuity (UDVA), refraction, keratometry and topography were recorded at 1st week and 1st, 3rd, 6th, and 12th months postoperation. Predictability and treatment efficacy were also recorded at the end of the follow-up period., Results: Better predictability was noted in group A than in group B at the 6 month and 12 month follow-up visits, with a mean cycloplegic refraction SE of + 0.5 ± 0.31 D in group A and + 0.67 ± 0.39 D in group B at the 6 month visit, and + 0.63 ± 0.37 D in group A and + 0.89 ± 0.48 D in group B at the 12 month visit. The efficacy of the treatment at the end of the follow up period was better in group A than in group B. Group A showed fewer topographic corneal changes than group B., Conclusions: Intraoperative MMC application during hyperopic LASIK achieves better predictability and efficacy and induces fewer topographic changes and lower regression rate of hyperopia during the first postoperative year., Trial Registration: the Pan African Clinical Trial Registry PACTR201901543722087 , on 29 January 2019.

Uveitis is a spectrum of inflammatory disorders characterized by ocular inflammation and is one of the leading causes of preventable visual loss. The main aim of the treatment of uveitis is to control the inflammation, prevent recurrences of the disease and preserve vision while minimizing the adverse effects associated with the therapeutic agents. Initial management of uveitis relies heavily on the use of corticosteroids. However, monotherapy with high-dose corticosteroids is associated with side effects and cannot be maintained long term. Therefore, steroid-sparing agents are needed to decrease the burden of steroid therapy. Currently, the therapeutic approach for non-infectious uveitis (NIU) consists of a step-ladder strategy with the first-line option being corticosteroids in various formulations followed by the use of first-, second- and third-line agents in cases with suboptimal steroid response. Unfortunately, the agents currently at our disposal have limitations such as having a narrow therapeutic window along with their own individual potential side-effect profiles. Therefore, research has been targeted to identify newer drugs as well as new uses for older drugs that target specific pathways in the inflammatory response. Such efforts are made in order to provide targeted and safer therapy with reduced side effects and greater efficacy. Several specially designed molecular antibodies are currently in various phases of investigations that can potentially halt the inflammation in patients with NIU. In the review, we have provided a comprehensive overview of the current and upcoming therapeutic options for patients with NIU., (© 2019 Royal Australian and New Zealand College of Ophthalmologists.)

Purpose: To investigate the potential of colchicine to improve bleb function after trabeculectomy., Methods: To find the maximum usable colchicine concentration, an ocular irritation study was performed with the Draize test at concentrations of 0.001%, 0.01% and 0.1%. Additionally, the synergistic effect of topical colchicine instillation and MMC application to surgical site was evaluated in a rabbit model by measuring changes after trabeculectomy in intraocular pressure (IOP) and bleb morphology score at 3, 7, 14, 21, 28, 35, 42, and 49 days., Results: Experiments with a rabbit model of trabeculectomy showed that 0.04% MMC plus 0.01% colchicine was more effective than saline and 0.04% MMC alone in maintaining IOP reduction at days 7-49 (P < 0.01 at all time points) and day 49 (P < 0.05), respectively, while 0.04% MMC alone was more effective than saline only at days 7-35 (P < 0.05 at all time points). 0.04% MMC plus 0.01% colchicine and 0.04% MMC alone were more effective than saline at preserving bleb score at days 7-21 and 35-49 (P < 0.05 at all time points) and at days 7-35 (P < 0.05 at all time points), respectively., Conclusion: Colchicine may be a promising adjuvant for strengthening the effect of MMC and improving the survival of the filtering bleb in trabeculectomy., Competing Interests: Funding support for this research was provided by Santen, Co, Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To analyze prognostic factors in the management of patients with choanal atresia., Study Design: This is a review of 114 patients operated on for choanal atresia in a tertiary care center between November 1986 and November 2016, including clinical characteristics, surgical management, and postoperative course with final nasal patency. The data were collected in a database that was updated over time., Results: Among the 114 patients, 78 were female, 77 presented with unilateral choanal atresia, and 37 presented with bilateral unilateral choanal atresia, corresponding to 151 nasal fossae. Forty-seven patients had associated abnormalities (41.2%), including CHARGE, diagnosed in 20 children (17.5%). At the end of follow-up, 91 patients (79.8%) had normal choanal patency. The identified risk factors of surgical failure were age <6 months (P = .004), weight <5 kg (P = .007), and bilateral choanal atresia (P < .001). The type of atresia, presence of associated abnormalities, surgical approach, stenting, and use of mitomycin were not significantly linked with the surgical results., Conclusions: This series highlights the importance of the timing of surgery, which is guided by the clinical ability of the infant to tolerate the procedure. Endoscopic approaches are widely performed, but a transpalatal approach, necessary in some cases of bilateral choanal atresia, does not alter the results. Unilateral choanal atresia surgery should be delayed after age 6 months and/or weight >5 kg when possible., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective:  Recurrent esophageal strictures (ESs) following esophageal atresia repair or caustic ingestion represent a common clinical problem. Recently, Mitomycin C was reported to improve the outcome of patients by reducing the number of endoscopic dilatations. However, other groups failed to exhibit a beneficial effect. We report on our experience with topic Mitomycin C application following endoscopic dilatation for recurrent ES., Methods:  Retrospective chart review of patients with ES treated at the Hannover Medical School (Location A) and the University of Leipzig (Location B) between 2009 and 2015. A Mitomycin C-soaked cotton swab was endoscopically placed at the area of stricture in all subjects. Successful treatment was defined as resolution of stricture after Mitomycin C therapy with not more than three dilatations thereafter. Our results were compared with published outcomes of alternative studies that involved 10 or more patients., Results:  A total of 11 children received Mitomycin C concurrently with endoscopic dilatations. Seven children (64%) had gross type C esophageal atresia, two patients (18%) gross type A esophageal atresia, and two children (18%) caustic injury.After a median follow-up of 34 months (range, 14-75 months) and a median number of 3 ± 2.5 dilatations with Mitomycin C application per patient (range, 1-9), 6 of 11 patients (55%) achieved a resolution of their strictures. Five patients (45%) did not respond to Mitomycin C therapy, of which two needed esophageal redo-surgery., Conclusion:  We failed to confirm the high success rates of Mitomycin C treatment for recurrent ESs. Given the fact that there is limited data to prove the beneficial effect of Mitomycin C treatment, pediatric surgeons should carefully consider whether the advantages of this therapy outweigh the necessity of life-long endoscopic follow-ups. Further randomized controlled studies are recommended., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)

The introduction of ibrutinib has grossly changed the treatment landscape in patients with Waldenström's Macroglobulinemia. Nevertheless, chemotherapy in combination with rituximab is still a cornerstone treatment. Among chemotherapeutics, alkylating agents are most frequently used. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is a highly effective but potentially neurotoxic regimen. Dexamethasone, rituximab, and cyclophosphamide (DRC) induces long responses and has a favorable toxicity profile. Bendamustine was shown to be among the most potent chemotherapeutics in combination with rituximab. Future studies must define the role of alkylating agents, which compete with highly effective chemotherapy-free targeted therapies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Traditionally, surgical excision has been the treatment of choice for ocular surface squamous neoplasia (OSSN). Recurrences after surgery are high. To reduce the risk of recurrence, adjuvant therapies have been increasingly used., Purpose: We compared recurrences and complications of 3 forms of treatment for OSSN: surgical excision (group A), surgical excision plus adjuvant topical mitomycin C (MMC) (group B), and surgical excision plus subconjunctival interferon-α-2b (IFN-α-2b) (group C)., Methods: A retrospective comparative study was conducted between January 2006 and March 2016 at the Ocular Oncology Service of the Catholic University of Rome. Seventy-nine patients with a confirmed histological diagnosis of OSSN were included: 43 were treated with surgical excision (group A), 16 underwent surgical excision plus topical MMC (group B), and 20 underwent surgical excision plus adjuvant subconjunctival IFN-α-2b (group C)., Results: The recurrences were different in the 3 groups. Thirty-one recurrences (72%) were seen in group A, 5 (31%) were found in group B, and 3 (15%) were seen in group C. Eight (50%) patients who received MMC 0.02% complained of ocular discomfort, 10 (62.5%) presented conjunctival hyperemia, while conjunctival chemosis and corneal epitheliopathy were noticed in 2 (13%) and 2 (13%) patients, respectively. All patients treated with subconjunctival IFN-α-2b reported flu-like symptoms. Two patients (10%) complained of ocular discomfort., Conclusions: Our study revealed that OSSN is not always manageable with simple excision. Adjuvant chemotherapy is strongly advisable after surgery to reduce recurrences. Interferon injections and MMC drops are effective in preventing recurrences and should be administered after surgery.

PurposeTo determine the long-term outcomes of same-site revision of failed filtering blebs with mitomycin C application.Patients and methodsNoncomparative retrospective case series of 45 eyes of 39 patients. Main outcome measures were surgical success (≤21, ≤18, and ≤16 mm Hg reduction in intraocular pressure (IOP)). Other outcome measures included best-corrected visual acuity (VA), visual field loss, number of glaucoma medications, need for further interventions, time from surgery to recommencement of medications or interventions, and complications.ResultsMean follow-up was 126±59.6 months (range 16-227 months). The overall success proportion at last follow-up was 96% for IOP ≤21 mm Hg (criterion 1), 91% for IOP ≤18 mm Hg (criterion 2), and 84% for IOP ≤16 mm Hg (criterion 3). Absolute success at last follow-up was 64%, 38%, and 33% for criteria 1, 2, and 3, respectively. Mean baseline IOP was reduced from 24.2±5.5 to 12.4±5.5 mm Hg at last follow-up. Ten eyes (22%) had early and 3 (7%) eyes had late complications. None of these complications resulted in visual loss or surgery failure. Nine eyes (20%) required further glaucoma surgery. Nine eyes (20%) required further glaucoma laser.ConclusionsSame-site, augmented, bleb revision is a safe and effective technique to control IOP and prevent further visual loss in patients with failed trabeculectomies.

Waldenström macroglobulinemia (WM) is a rare lymphoma with 1000 to 1500 new patients diagnosed per year in the United States. Patients with WM can experience prolonged survival times, which seem to have increased in the last decade, but relapse is inevitable. The identification of recurrent mutations in the MYD88 and CXCR4 genes has opened avenues of research to better understand and treat patients with WM. These developments are giving way to personalized treatment approaches for these patients, focusing on increasing depth and duration of response alongside lower toxicity rates. In the present document, we review the diagnostic differential, the clinical manifestations, and the pathological and genomic features of patients with WM. We also discuss the safety and efficacy data of alkylating agents, proteasome inhibitors, monoclonal antibodies, and Bruton tyrosine kinase inhibitors in patients with WM. Finally, we propose a genomically driven algorithm for the treatment of WM. The future of therapies for WM appears bright and hopeful, but we should be mindful of the cost-effectiveness and long-term toxicity of novel agents., Competing Interests: Conflict-of-interest disclosure: J.J.C. has received research funds and honoraria from Abbvie, Gilead, Janssen, Millennium, and Pharmacyclics. S.P.T. has received research funds and honoraria from Janssen and Pharmacyclics., (© 2016 by The American Society of Hematology. All rights reserved.)

Purpose: This study compared the efficacy and safety of suberoylanilide hydroxamic acid (SAHA) and mitomycin C (MMC) up to 4 months in the prevention of corneal haze induced by photorefractive keratectomy (PRK) in rabbits in vivo., Methods: Corneal haze in rabbits was produced with -9.00 diopter PRK. A single application of SAHA (25 μM) or MMC (0.02%) was applied topically immediately after PRK. Effects of the two drugs were analyzed by slit-lamp microscope, specular microscope, TUNEL assay, and immunofluorescence., Results: Single topical adjunct use of SAHA (25 μM) or MMC (0.02%) after PRK attenuated more than 95% corneal haze and myofibroblast formation (P < .001). SAHA did not reduce keratocyte density, cause keratocyte apoptosis, or increase immune cell infiltration compared to MMC (P < .01 or .001). Furthermore, SAHA dosing did not compromise corneal endothelial phenotype, density, or function in rabbit eyes, whereas MMC application did (P < .01 or .001)., Conclusions: SAHA and MMC significantly decreased corneal haze after PRK in rabbits in vivo. SAHA exhibited significantly reduced short- and long-term damage to the corneal endothelium compared to MMC in rabbits. SAHA is an effective and potentially safer alternative to MMC for the prevention of corneal haze after PRK. Clinical trials are warranted. [J Refract Surg. 2017;33(12):834-839.]., (Copyright 2017, SLACK Incorporated.)