Clinical characteristics and risk factors of acute lymphoblastic leukemia in children with severe infection during maintenance treatment.

BACKGROUND: Infection is the most common adverse event of acute lymphoblastic leukemia (ALL) treatment and is also one of the main causes of death. METHODS: To investigate the clinical characteristics and risk factors of severe infections during the maintenance phase of ALL treatment, we conducted a retrospective study. RESULTS: A total of 181 children were eligible and 46 patients (25.4%) suffered from 51 events of severe infection, most of which occurred in the first half year of the maintenance phase (52.9%). The most common infection was pulmonary infection (86.3%) followed by bloodstream infection (19.6%). The main symptoms of ALL patients with pulmonary infection were fever, cough, and shortness of breath. The main manifestations of computer tomography (CT) were ground glass shadow (56.8%), consolidation shadow (27.3%), and streak shadow (25%). Multivariate binary logistic regression analysis showed that agranulocytosis, agranulocytosis ≥7 days, anemia, and low globulin level were independent risk factors for severe infection during the maintenance phase (all p < 0.05). CONCLUSIONS: Taken together, blood routine examinations and protein levels should be monitored regularly for ALL patients in the maintenance phase, especially in the first 6 months. For ALL patients with risk factors, preventive anti-infective or supportive therapies can be given as appropriate to reduce the occurrence of severe infections.

Efficacy and Safety of the PD-1 Inhibitor Combined with Albumin-Bound Paclitaxel and Nedaplatin in Preoperative Neoadjuvant Therapy of Unresectable Stage III Lung Squamous Cell Carcinoma.

Aim: To investigate the efficacy and safety of preoperative neoadjuvant therapy (PD-1 inhibitor plus nab-PTX and nedaplatin) for resectable stage III lung squamous cell carcinoma (SCC) patients. Methods: Patients with locally advanced lung SCC (stage IIIA, IIIB) who received PD-1 inhibitor combined with nab-PTX and NED between February 2019 and June 2021 in Weihai Municipal Hospital were included and underwent surgical treatment 4 weeks after 2-4 cycles neoadjuvant therapy. The rate of resection R0, the effective rate, the complete pathological remission rate (pCR) and the rate of major pathological remission (MPR) were observed. Results: A total of 14 initially unresectable male patients with lung SCC were included and received neoadjuvant treatment after evaluation. Nine out of 14 patients (64.3%) experienced treatment-related adverse events (TRAE), among which 8 (57.1%) experienced grade (G) I-II TRAEs including nausea, vomiting, fatigue, constipation, elevated ALT and AST, hyperthyroidism, hypothyroidism, rash, granulocytopenia, and thrombocytopenia, and 1 (7.1%) experienced grade III-V TRAEs (G), including granulocytopenia and atelectasis. Thirteen patients (92.86%) achieved RECIST-assessed partial remission (PR), while 1 patient (7.14%) achieved stable disease (SD) on imaging assessment after neoadjuvant treatment and continued to be progression-free for 26 months. Of the 11 patients who underwent resection, all were alive and recurrence/progression-free. MPR and pCR were observed in 2 (18.18%) and 9 (81.82%), respectively. IHC results exhibited that all NSCLC patients exhibited positive PD-L1 expression (9/14, TPS ≥50% or greater; 5/14, 1% < TPS < 50%). Two were negative for ALK, EGFR, and ros-1, and the rest were not examined for driver oncogene mutation. Conclusion: The neoadjuvant therapy of the PD-1 inhibitor combined with nab-PTX and NED demonstrated remarkable therapeutic efficacy and good safety on stage III lung SCC without increasing the risk of TRAE, mortality and surgery-related complications, or impede surgery feasibility.

Serious adverse events with novel beta-lactam/beta-lactamase inhibitor combinations: a large-scale pharmacovigilance analysis.

The purpose of this study is to characterize adverse events (AEs) of clinical interest reported with ceftolozane-tazobactam and ceftazidime-avibactam, as an aid in monitoring patients affected by severe multidrug-resistant Gram-negative infections. We queried the worldwide FDA Adverse Event Reporting System (FAERS) and performed disproportionality analysis, selecting only designated medical events (DMEs) where ceftolozane-tazobactam and ceftazidime-avibactam were reported as suspect. Serious neurological AEs were further investigated. The reporting odds ratios were calculated, deemed significant by the lower limit of the 95% confidence interval (LL95% CI) > 1. All other drugs/events recorded in FAERS and cephalosporins showing clinical evidence of neurological AEs were respectively selected as comparator for analysis of DMEs and neurotoxicity. Qualitative analysis including case-by-case assessment and deduplication was also performed. Overall, 654 and 506 reports mentioning respectively ceftolozane-tazobactam and ceftazidime-avibactam were found, with DMEs accounting respectively for 13.1% and 10.9% of cases. Agranulocytosis (N = 12; LL95% CI = 12.40) and pancytopenia (14; 6.18) emerged as unexpected AEs with ceftolozane-tazobactam, while acute pancreatitis (7; 8.63) was an over-reported unexpected DME with ceftazidime-avibactam. After deduplication, four unequivocally different cases of agranulocytosis with ceftolozane-tazobactam were retained, occurring on average after 8.8 days. Causality was probable and possible respectively in three and one case. Among neurological AEs exhibiting significant disproportionality, encephalopathy with both antibiotics and mental status changes with ceftazidime-avibactam were retained in at least three cases after deduplication. Although rare, clinicians should monitor high-risk patients (i.e. individuals affected by haematological malignances, HIV infection, or treated with concomitant myelotoxic agents) for early unexpected occurrence of agranulocytosis with ceftolozane-tazobactam.

Effective Preoperative Plasmapheresis Treatment of Severe Hyperthyroidism in a Patient with Giant Toxic Nodular Goiter and Methimazole-Induced Agranulocytosis.

Agranulocytosis is a rare but very serious complication of thyrostatic therapy. In severe hyperthyroidism, the removal of circulating thyroid hormones by plasmapheresis may be an effective therapeutic option. This report describes the therapeutic difficulties and successful preoperative treatment with plasmapheresis in a 63-year-old patient admitted to the Endocrinology Clinic with severe hyperthyroidism, during the course of giant toxic nodular goiter and agranulocytosis, which occurred after 2 weeks of taking methimazole. During hospitalization, methimazole treatment was discontinued and therapy with steroids, a beta blocker, propylthiouracil, Lugol's solution, lithium carbonate, and antibiotics were initiated. Granulocyte colony growth stimulating factor was also used to resolve agranulocytosis. Due to the failure to achieve euthyreosis using this approach, we decided to conduct thyroid surgery, as a life-saving action, after preparation of the patient by plasmapheresis. Two plasmapheresis procedures were performed, resulting in a decrease in the concentration of free thyroid hormones. Total thyroidectomy was performed and there were no complications during surgery. We conclude that plasmapheresis may be considered as an effective alternative treatment option for the preparation of patients with hyperthyroidism for surgery, when the clinical situations prevent the use of conventional treatments for hyperthyroidism and when immediate life-saving surgery is necessary.

'Metaphyseal dysplasia without hypotrichosis' can present with late-onset extraskeletal manifestations.

BACKGROUND: Metaphyseal dysplasia without hypotrichosis (MDWH) is a rare form of chondrodysplasia with no extraskeletal manifestations. MDWH is caused by RMRP mutations, but it is differentiated from the allelic condition cartilage-hair hypoplasia (CHH), which in addition to chondrodysplasia is characterised by thin hair, immunodeficiency and increased risk of malignancy. The long-term outcome of MDWH remains unknown. OBJECTIVE: We diagnosed severe agranulocytosis in a subject with RMRP mutations and normal hair. Based on this observation, we hypothesised that MDWH may, similar to CHH, associate with immune deficiency and malignancy. METHODS: We collected clinical and laboratory data for a cohort of 80 patients with RMRP mutations followed for over 30 years and analysed outcome data for those with features consistent with MDWH. RESULTS: In our cohort, we identified 10 patients with skeletal but no extraskeletal features during preschool age. Eight of these patients developed malignancy or clinically significant immunodeficiency during follow-up. Two of them died during chemotherapy for malignancy. At the time of the first extraskeletal manifestation, patients were school aged, 20, 43 and 50 years old. Laboratory signs of immunodeficiency (impaired lymphocyte proliferative responses) were demonstrated in four patients before the onset of symptoms. The patient outside this cohort, who had RMRP mutations, skeletal dysplasia, normal hair and severe agranulocytosis at 18 years of age, underwent haematopoietic stem cell transplantation. CONCLUSIONS: MDWH can present with severe late-onset extraskeletal manifestations and thus should be reclassified and managed as CHH.

Neutropenia and Life-threatening Agranulocytosis Among Children With ß-Thalassemia Treated With Oral Iron Chelators in a Community With Background of Ethnic Neutropenia.

INTRODUCTION: Neutropenia and agranulocytosis are rare side effects of deferiprone (DFP) in patients treated for iron overload. Unfortunately, no study directly addressed special risks in countries with a background of ethnic neutropenia, such as Oman. AIM: The aim of this study was to report the incidence of neutropenia in Omani children with ß-thalassemia treated with different iron chelators. METHODS/DESIGN: This was a retrospective study that included 179 Omani pediatric patients. For patients who developed neutropenia, demographic data, iron-chelating agent, clinical presentation, management, and outcome were recorded. Detailed clinical, laboratory±radiologic information was added for patients with agranulocytosis. RESULTS: Neutropenia was encountered in 43.6% of patients: severe neutropenia in 10 patients, moderate in 29, and mild in 69 patients. Severe and moderate neutropenia had similar incidence among DFP-exposed and DFP-naive patients (P=0.515 and 0.421, respectively), while mild neutropenia was common among DFP-naive patients (P=0.0001). A higher incidence of DFP-related agranulocytosis (4.1%) was noted compared with previous reports, but none had a fatal outcome. CONCLUSIONS: In a community with ethnic neutropenia, mild to moderate neutropenia is common. Higher incidence of severe neutropenia and agranulocytosis mandates careful monitoring and rational modification of iron-chelating agents to avoid life-threatening complications.

PROGNOSIS OF THE COURSE OF CHORNOBYL-ORIGINATED ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDREN IN UKRAINE DEPENDING ON THE REASON OF STANDARD CHEMOTHERAPY INTERRUPTION. / PROGNOZ PEREBIGU GOSTRYKh LIMFOBLASTNYKh LEY̆KEMIY̆ ChORNOBYL'S'KOGO POKhODZhENNIa U DITEY̆ UKRAÏNY ZALEZhNO VID PRYChYN PERERV PRY PROVEDENNI STANDARTNOÏ KhIMIOTERAPIÏ.

OBJECTIVE: Estimation of the bone marrow haemopoietic status depending on the reasons and duration of breaks in a standard chemotherapy (BFM-ALL protocol) to predict the course of acute lymphoblastic leukemia (ALL) in chil- dren exposed to low doses of ionizing radiation after the Chornobyl accident. MATERIALS AND METHODS: The ALL patients (n = 34) were examined within 5 stages of a program chemotherapy. The clinical symptoms, hemogram and myelogram data were analyzed. The radiation dose on bone marrow, initial leuko- cyte count, variants and prognosis of ALL course were accounted. Days of the stopped chemotherapy, type and fre- quency of complications (septic processes, febrile neutropenia, toxic hepatitis, granulocytopenia degree), and the prognosis of disease course (child living status, i.e. alive or died) were estimated. RESULTS: There were abnormal differentiation processes and high percentage of lymphoblasts (86.2 ± 3.3) % in bone marrow in the 1st acute period. Hematological remission was established in all patients on the 33rd day of chemothe- rapy. In a half of cases the haematopoietic recovery occurred by a granulocyte-monocyte type. One third of patients presenting an erythroid type of haemopoiesis died later. The inverse correlation was found between the number of myelocaryocytes and disease prognosis (rs = -0.49). Breaks in chemotherapy for various reasons were recorded. The number of patients with granulocytopenia was greater at the phase 1 and 2 of protocol I and protocol M application, coinciding with a higher incidence of complications. An inverse correlations between the prediction of ALL course and sum of days of breaks between the protocol M and phase 1 of protocol II (rs = -0.56), as well as the duration of the phase 2 of protocol II (rs = -0.62) were found. The radiation dose on bone marrow was (5.37 ± 1.23) mSv. No relationship was found between the radiation doses, ALL variants and disease course. CONCLUSIONS: Prognosis of ALL course in children depends on the type of haemopoietic recovery and reasons of breaks in a standard chemotherapy. Interaction between the haemopoiesis functioning and microenvironment and that of their regulation are the key mechanisms of above-mentioned abnormalities, which is the basis for further research.

Alcohol abuse and disorder of granulopoiesis.

Granulocytes are the major type of phagocytes constituting the front line of innate immune defense against bacterial infection. In adults, granulocytes are derived from hematopoietic stem cells in the bone marrow. Alcohol is the most frequently abused substance in human society. Excessive alcohol consumption injures hematopoietic tissue, impairing bone marrow production of granulocytes through disrupting homeostasis of granulopoiesis and the granulopoietic response. Because of the compromised immune defense function, alcohol abusers are susceptible to infectious diseases, particularly septic infection. Alcoholic patients with septic infection and granulocytopenia have an exceedingly high mortality rate. Treatment of serious infection in alcoholic patients with bone marrow inhibition continues to be a major challenge. Excessive alcohol consumption also causes diseases in other organ systems, particularly severe alcoholic hepatitis which is life threatening. Corticosteroids are the only therapeutic option for improving short-term survival in patients with severe alcoholic hepatitis. The existence of advanced alcoholic liver diseases and administration of corticosteroids make it more difficult to treat serious infection in alcoholic patients with the disorder of granulopoieis. This article reviews the recent development in understanding alcohol-induced disruption of marrow granulopoiesis and the granulopoietic response with the focus on progress in delineating cell signaling mechanisms underlying the alcohol-induced injury to hematopoietic tissue. Efforts in exploring effective therapy to improve patient care in this field will also be discussed.

[Eosinopenia in 2018]. / L'éosinopénie en 2018.

Since 1893, eosinopenia is a biological test to help a diagnosis of bacterial infection. Several publications have confirmed this hypothesis, particularly in the intensive care, pneumology and pediatric units. The value of this marker has been identified in vascular cerebral diseases and coronary bypass. Its contribution seems as relevant as procalcitonin, without extra cost. The diagnostic performance of this test was reinforced by a composite score (CIBLE score) that may improve its value in daily routine. Finally, monitoring eosinopenia appears to be a reliable mortality marker.

Plasma and Urine Levamisole in Clinical Samples Containing Benzoylecgonine: Absence of Aminorex.

Aminorex has been reported as a metabolite of levamisole in man, but data on the aminorex concentrations in clinical samples are scant. We thus measured levamisole, aminorex and benzoylecgonine in urine, and levamisole and aminorex in plasma using achiral liquid chromatography-high resolution mass spectrometry. Centrifuged urine (50 µL) was diluted with LC eluent containing internal standard (benzoylecgonine-D3, 25 µg/L) (450 µL). For plasma, sample (200 µL) and Tris solution (2 mol/L, pH 10.6, 100 µL) were added to a 60.5 × 7.5 mm i.d. glass test tube. Internal standard solution (ketamine-D4, 200 µg/L) (10 µL) was added and the tube contents vortex-mixed (5 s). Butyl acetate:butanol (9 + 1, v/v; 200 µL) was added and after vortex-mixing (30 s) and centrifugation (13,680 × g, 4 min), the extract was evaporated to dryness and reconstituted in 10 mmol/L aqueous ammonium formate containing 0.1% (v/v) formic acid (150 µL). Prepared samples and extracts (100 µL) were analyzed using an AccucoreTM Phenyl-Hexyl column (2.6 mm a.p.s., 100 × 2.1 mm i.d.) maintained at 40°C. MS detection was in positive mode using heated electrospray ionization (ThermoFisher Q-ExactiveTM). Intra- and inter-assay accuracy and precision were ±20%, and ≤11%, respectively, for all analytes in both matrices. Lower limits of quantitation were 0.1 and 1 µg/L (all analytes) in plasma and urine, respectively. Of 100 consecutive urine samples submitted for drugs of abuse screening containing benzoylecgonine, levamisole was detected in 72 (median 565, range 4-72,970 µg/L). Levamisole was also measured in eight plasma samples (median 10.6, range 0.9-64.1 µg/L). A number of metabolites of levamisole (4-hydroxylevamisole, levamisole sulfoxide, levamisole glucuronide, and hydroxylevamisole glucuronide) were tentatively identified in urine. Neither aminorex, nor any of its reported metabolites were detected in any sample.

Granulocytopenia.

Granulocytopenia is defined as a decrease of peripheral blood granulocytes below lower limit of normal range. Patients with severe granulocytopenia - agranulocytosis exhibit < 0.5 × 109/l granulocytes in peipheral blood. Granulocytopenia may result from congenital or acquired defective production of granulocyte precursors or it may be a consequence of increased destruction of mature granulocytes, most frequently caused by immune mechanisms. Investigation of origin of granulocytopenia must be connected with exclusion of etiological agents causing secondary neutropenia (infections, autoimmune disorders, drugs, LGL syndrome). Patients with > 0.5 × 109/l of granulocytes usually do not exhibit clinical symptoms unless they do not suffer from a concomitant disease (especially immunodeficiency). Patients with severe granulocytopenia are indicated for supportive treatment and for administration of G-CSF. Children with severe congenital neutropenia (SCN) are at risk of later development of MDS or AML and are candidates for SCT when signs of disease progression appears. Key words: diagnosis - granulocytopenia - growth factors - pathogenesis - transplantation -treatment.

Agranulocytosis Associated with Waldenström Macroglobulinemia.

Currently, there are only 2 case reports of Waldenström macroglobulinemia (WM) associated with severe neutropenia. This is a case report of a woman with a past medical history of WM who presented with neutropenic fever. The patient's febrile neutropenia resolved after RCD chemotherapy (cyclophosphamide 750 mg/m2, dexamethasone 20 mg, and rituximab 375 mg/m2). Fourteen days after administration, the neutrophil level had started to rise and normalized after 6 days. To the best of our knowledge, this is the 3rd reported case of agranulocytosis due to WM.

Minimization of the perianal infection rate of hematological malignancies with agranulocytosis by quality control circle activity and patient-hospital-student win-win concept.

Objective The agranulocytosis-associated perianal infection (PI) rate ranges from 60% to 100% among patients with hematopoietic malignancies. In this study, we assessed the efficacy of a quality control circle (QCC) to minimize the PI rate. Methods Among 274 patients with severe immunodeficiency (agranulocytosis of ≥2 weeks) in our bone marrow transplantation center, the PI rate was 17.20%. A QCC was established following the 10 steps of the plan-do-check-act (PDCA) model; this was scientifically supported by culturing the bacterial colony from patients' perianal skin to determine the sanitization effect and interval time. Because a warm aqueous solution of potassium permanganate is recommended for sanitization, the bacterial colony culture was also used to determine the proper drug concentration, water temperature, and soaking time. All procedures were standardized. Patients, hospital staff, and medical students were enrolled into the QCC team based on the patient-hospital-student (PHS) win-win concept. Results After establishment of the PDCA model, the PI rate among 253 patients decreased from 17.20% to 5.93% and remained at 5.25% during the following year. The medical expenses and length of hospital stay consequently decreased. Conclusion The QCC and PHS win-win concept can reduce the PI rate and promote medical quality.

Transient immune-mediated agranulocytosis following Mycoplasma pneumoniae infection.

Mycoplasma pneumoniae is a common respiratory pathogen which may cause haematological manifestations including haemolytic anaemia and thrombocytopaenia. Severe neutropaenia is rare with very few cases reported in the literature. An 85-year-old man was transferred to our facility with agranulocytosis in the context of an infective exacerbation of chronic obstructive pulmonary disease with positive serological testing for M. pneumoniae. No alternative infective, autoimmune or lymphoproliferative cause of the neutropaenia was identified. Granulocyte autoantibody testing was performed with a positive result for neutrophil-bound IgG and IgM autoantibodies and significant agglutination reactions. The patient was treated with azithromycin and granulocyte colony-stimulating factor which resulted in a sustained resolution of his neutropaenia.

Long-Term Survival Analysis of Intraperitoneal versus Intravenous Chemotherapy for Primary Ovarian Cancer and Comparison between Carboplatin- and Cisplatin-based Intraperitoneal Chemotherapy.

In epithelial ovarian cancer (EOC), intraperitoneal (IP) administration of chemotherapy is an effective first-line treatment and may improve outcomes, compared with intravenous (IV) chemotherapy. We used Kaplan-Meier survival analysis to compare long-term survival between propensity score-matched patients with advanced EOC receiving IP (n = 34) vs. IV (n = 68) chemotherapy. Additionally, clinical features associated with carboplatin-based (n = 21) and cisplatin-based (n = 16) IP chemotherapy were analyzed and compared with those associated with IV chemotherapy. The IP and IV chemotherapy groups had a median follow-up duration of 67 (range, 3-131) and 62 (range, 0-126) months, respectively, with no significant difference in progression-free survival (PFS) (P = 0.735) and overall survival (OS) (P = 0.776). A significantly higher proportion of patients in the IV (91.2%) than in the IP (67.6%) chemotherapy group (P = 0.004) received ≥ 6 cycles. However, the frequency of toxic events (anemia, granulocytopenia, nausea/vomiting, abdominal pain, hepatotoxicity, neuromuscular effects) was significantly higher in the IP than in the IV group. Within the IP group, no significant differences were observed in PFS (P = 0.533) and OS (P = 0.210) between the cisplatin-based and carboplatin-based chemotherapy subgroups. The 10-year OS was 28.6% and 49.2% in carboplatin-based and cisplatin-based IP chemotherapy groups, respectively. Toxic events (granulocytopenia, leukopenia, nausea/vomiting, abdominal pain, hepatotoxicity, neuromuscular effects) were significantly more common in the cisplatin-based subgroup. In patients with EOC, cisplatin-based IP chemotherapy may be an acceptable alternative to IV chemotherapy regarding long-term survival, but toxicity must be addressed.