A 13-year-old female developed L-asparaginase (L-ASP) -associated thrombosed external hemorrhoids (TEH) during chemotherapy for Philadelphia chromosome-positive acute lymphoblastic leukemia. While undergoing induction therapy combined with imatinib, she experienced intense anal pain a day after the four-time administration of L-ASP. The anal verge contained painful bluish hemorrhoids, which reportedly were absent before the therapy commencement. Hemorrhoids occurred 5-9 days after every L-ASP treatment, which was eventually diagnosed as L-ASP-associated TEH. After the failure of conservative treatment, opioid therapy was initiated. During myeloid reconstitution, she underwent divided ligation of hemorrhoids; however, the hemorrhoids became necrotic and formed an ulcerated tissue bed. This case suggests that while undertaking L-ASP therapy in adolescents and young adults with acute lymphoblastic leukemia, physicians should monitor signs of hemorrhoids and consider divided ligation when appropriate.

Cyclophosphamide is an alkylating agent used as chemotherapy for cats with lymphoma, carcinomas and sarcomas. Clinical and pharmacokinetic studies of cyclophosphamide in normal and tumor-bearing cats have shown minimal toxicity and cyclophosphamide at clinically used dosages rarely requires dosage adjustment or treatment delays. Dose intensity appears important for treatment of most cancers; the aim of this study was to perform a modified dose escalation study of cyclophosphamide to establish the maximally tolerated dosage (MTD) for intravenous cyclophosphamide in cats. The dose limiting toxicity appeared to be neutropenia, and 30% of cats experienced grade 3 or grade 4 neutropenia at a cyclophosphamide dosage of 480mg/m2, which was determined as the MTD. Delayed neutropenia was observed commonly at higher dosages. Thrombocytopenia was less common than neutropenia, and always transient. Gastrointestinal toxicities were uncommon even at MTD. The recommended dosage for single agent cyclophosphamide in cats is 460mg/m2 with a post-treatment interval of three weeks, with hematology performed before any subsequent chemotherapy is administered. This dosage appears safe in combination with prednisolone and l-asparaginase; but has not been evaluated in combination with other chemotherapy agents, or with a post-treatment interval shorter than 3 weeks. Such combinations and shorter intervals are found in some protocols, so this recommended cyclophosphamide dose cannot be considered a direct substitute for cyclophosphamide dosages in existing protocols. There is a suggestion that inadequate renal function may exacerbate the myelosuppression of cyclophosphamide which should be further evaluated.

Natural-killer/T cell lymphoma (NKTCL) represents the most common subtype of extranodal lymphoma with aggressive clinical behavior. Prevalent in Asians and South Americans, the pathogenesis of NKTCL remains to be fully elucidated. Using system biology techniques including genomics, transcriptomics, epigenomics, and metabolomics, novel biomarkers and therapeutic targets have been revealed in NKTCL. Whole-exome sequencing studies identify recurrent somatic gene mutations, involving RNA helicases, tumor suppressors, JAK-STAT pathway molecules, and epigenetic modifiers. Another genome-wide association study reports that single nucleotide polymorphisms mapping to the class II MHC region on chromosome 6 contribute to lymphomagenesis. Alterations of oncogenic signaling pathways janus kinase-signal transducer and activator of transcription (JAK-STAT), nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), WNT, and NOTCH, as well as epigenetic dysregulation of microRNA and long non-coding RNAs, are also frequently observed in NKTCL. As for metabolomic profiling, abnormal amino acids metabolism plays an important role on disease progression of NKTCL. Of note, through targeting multiple omics aberrations, clinical outcome of NKTCL patients has been significantly improved by asparaginase-based regimens, immune checkpoints inhibitors, and histone deacetylation inhibitors. Future investigations will be emphasized on molecular classification of NKTCL using integrated analysis of system biology, so as to optimize targeted therapeutic strategies of NKTCL in the era of precision medicine.

L-Asparaginase is an enzyme that hydrolyses the amino acid L-Asparagine into aspartic acid and ammonia. As a medication, L-Asparaginase is used in chemotherapy to treat acute lymphoblastic leukaemia by depleting circulating Asparagine and depriving tumor cells. Interest in Actinomycetes as potential producers of antibiotics and enzymes encouraged us to investigate an isolated strain (CA01) from soft wheat bran.The Actinomycete strain was characterized based on its morphological and biochemical characteristics and selected due to a proved promising ability to produce L-Asparaginase optimized in both solid and liquid media cultures.The conditions of enzyme production were standardized according to a one-factor-at-a-time (OFAT) experimental design.To obtain optimal medium combination, a Box-Behnken Response Surface Methodology (RSM) has been adopted by choosing the most influential factors. The optimal conditions for the enzyme production were (g/l): L-Asparagine 10.7; Glucose 2.7; starch 7, in based medium containing (g/l): K2HPO4 0.5; MgSO4, 7H2O 0.1, corresponding to an optimal enzymatic activity of 8.03 IU/ml at 27.83°C. The maximum production of enzyme was reached on the sixth day of experiment. The ANOVA test (P value ˂ 0.05) and adjusted R2 values close to the experimental R2 show that the obtained model of the active L-Asparaginase of CA01 strain production is significant with the following linear terms: temperature, substrate concentration, Glucose concentration and there squared.

L-Asparaginase amidohydrolase (EC 3.5.1.1) has received significant attention owing to its clinical use in acute lymphoblastic leukemia treatment and non-clinical applications in the food industry to reduce acrylamide (toxic compound) formation during the frying of starchy foods. In this study, a sequential optimization strategy was used to determine the best culture conditions for L-asparaginase production from filamentous fungus Aspergillus terreus CCT 7693 by submerged fermentation. The cultural conditions were studied using a 3-level, central composite design of response surface methodology, and biomass and enzyme production were optimized separately. The highest amount of biomass (22.0 g·L-1) was obtained with modified Czapek-Dox medium containing glucose (14 g·L-1), L-proline (10 g·L-1), and ammonium nitrate (2 g·L-1) fermented at 37.2 °C and pH 8.56; for maximum enzyme production (13.50 U·g-1), the best condition was modified Czapek-Dox medium containing glucose (2 g·L-1), L-proline (10 g·L-1), and inoculum concentration of 4.8 × 108 espore·mL-1 adjusted to pH 9.49 at 34.6 °C. The L-asparaginase production profile was studied in a 7 L bench-scale bioreactor and a final specific activity of 13.81 U·g-1 was achieved, which represents an increase of 200% in relation to the initial non-optimized conditions.

Hepatosplenic γδ T-cell lymphoma (HSTCL) is a rare aggressive peripheral T-cell lymphoma. Prognosis is usually poor with a median survival between 8 and 16 months after traditional chemotherapy. Stem cell transplantation (SCT) is promising and with a more intense induction regimen, has yielded positive results. We report the use of pegylated-asparaginase (PEG-asparaginase) along with a conventional anthracycline-containing regimen in a 51-year-old male who was diagnosed with HSTCL, achieved a complete remission, and subsequently underwent peripheral blood SCT and remained in remission at the time of this case report.