Chemoimmunohormonal therapy with carmustine,dacarbazine, cisplatin,tamoxifen, and interferon for metastatic melanoma: a prospective phase II study

The objective of this study was to investigate the efficacy of our treatment regimen in metastatic melanoma. Thirty patients entered the study after undergoing a thorough metastatic workup. Treatment protocol included carmustine (BCNU) (150 mg/m(2) IV, day 1) every 6 weeks, dacarbazine (DTIC) (220 mg/m(2) IV, days 1-3), and cisplatin (25 mg/m(2) IV, days 1-3) every 3 weeks, interferon A-2B (6 x 10(6) U/m daily s.c. on days 4-8 and 16-20) and tamoxifen 20 mg/day for 6 weeks. Among 29 evaluable patients, overall response was seen in 15 (52%) and complete response in 5 (17%) patients. Median duration of partial response was 4 months (range, 1-12 months); of complete response was 8 months (range, 2-14 months). Complete response continues in two patients with lung metastases. Median survival time was 8.7 months. Side effects were tolerable. Four (13%) patients developed neutropenic fever, and platelet transfusions were required in five (17%) patients. One patient died of neutropenic sepsis. Thrombocytopenia caused prolongation of the median interval between the first and second courses, and drug doses were reduced in the second course in 8 of 26 (31%) patients. Our chemoimmunohormonal regimen is efficient in metastatic malignant melanoma and can induce durable remission. Severe thrombocytopenia leads to a reduction of carmustine dose in a new protocol.     

Serum C-reactive protein levels in the management of infection in acute leukaemia

C-reactive protein (CRP) was measured serially in 29 patients with acute leukaemia. Sixty-four febrile episodes (⩾38°C) occurred during 37 periods of neutropenia (<0.5 × 10⁹/l). In all of 41 microbiologically or clinically documented infections the maximum CRP level exceeded 30 mg/l, and in 25 it was greater than 100 mg/l. In no case in which the CRP level remained below 30 mg/l for 48 hr after the onset of fever was any clinical or microbiological evidence of infection obtained. The CRP level during documented infection began to fall 24–48 hr after appropriate treatment was begun. A CRP level above 30 mg/l in neutropenic patients was associated with early recurrence of fever if systemic antibiotics were discontinued. Graft-vs-host disease, without infection, did not result in high levels of CRP.     

Key pharmacokinetic parameters of isepamicin in febrile neutropenic cancer patients and in women with acute pelvic inflammatory disease

The pharmacokinetics (PK) of isepamicin were studied in 8 febrile neutropenic patients with hematologic malignancy and in 20 young women with acute pelvic inflammatory disease (PID). Isepamicin was given as a slow intravenous infusion over 30 min at a dose of 15 mg/kg once daily (OD). Serum levels of isepamicin were determined by fluorescence polarization immunoassay, and PK analyses were obtained based on a one-compartment open model after 24 hours (steady state) and after 7 days. On day 1, the volume of distribution (Vd) of isepamicin, for both populations, appeared about 30% higher than classically reported in healthy individuals: 0.31 and 0.36 L/kg for neutropenic and PID patients respectively. However on day 7, Vd displayed significant reduction (0.28 and 0.27 L/kg, respectively for neutropenic and PID patients). A reduction of isepamicin clearance was also observed between day 1 and day 7 (137 vs 120 mL/min and 130 vs 101 mL/min for neutropenic and PID populations, respectively). Such changes are consistent with a significant increase in the Cmax concentrations (45 vs 50 mg/L, and 38 vs 49 mg/L) and in the AUC (136 vs 158 and 137 vs 162 mg/L.h) observed after a week of treatment in neutropenic and PID patients, respectively. In conclusion, taking into account the importance of reaching early active concentrations, we recommend the use of higher loading dose of isepamicin (>15 mg/kg) in neutropenic cancer patients and in women with PID, particularly in case of a combination with a possibly ineffective antibacterial agent, in case of infection with bacteria at upper limit of susceptibility, in the presence of high infectious inoculum or in the presence of sequestered sites of infection.     

血清C反应蛋白水平与非小细胞肺癌患者近期疗效及预后的关系

[目的]探讨非小细胞肺癌(NSCLC)患者治疗前后血清C反应蛋白(CRP)的水平及其与肿瘤近期疗效及预后的关系.[方法]用免疫比浊法分别检测215例NSCLC患者(其中105例患者行手术治疗,110例患者行化疗)和102名健康对照者血清中的CRP表达水平,并进行24个月的随访.[结果] NSCLC患者手术后血清CRP浓度(12.52±4.37)mg/L与术前(18.13±5.78)mg/L相比,差异有统计学意义(P＜0 05).经化疗后,30例缓解组患者血清CRP浓度(10.49±3.85)mg/L与治疗前(18.64±4.63)mg/L相比显著下降(P＜0.05);44例进展组患者血清CRP浓度(20.14±7.68)mg/L与治疗前(14.53±4.56)mg/L相比显著升高(P＜0.05); 36例稳定组患者血清CRP浓度治疗前后差异无统计学意义(P＞0.05).手术后CRP阳性率显著下降,而化疗后阳性率下降不明显.手术前CRP阳性患者肿瘤复发或转移率(26.7％)高于术前阴性患者(7.5％).[结论]检测NSCLC患者血清CRP水平对预测肿瘤转移有一定的临床意义,有助于疗效的评估以及预后的预测.     

Paclitaxel, carboplatin, and oral etoposide in advanced gastric adenocarcinoma

The prognosis of locally advanced or metastatic adenocarcinoma of the stomach is poor. In an attempt to improve therapeutic results, we undertook a phase II trial to investigate a combination of paclitaxel, carboplatin, and oral etoposide, all active drugs in this malignancy and with a synergistic effect in combination. Fourteen patients with advanced gastric adenocarcinoma were treated with paclitaxel 200 mg/m² iv, carboplatin AUC-6 iv on d 1, and oral etoposide 50 mg/d alternating with 100 mg/d on d 1–10. Cycles were repeated every 3 wk. Of the 14 patients treated, partial response was observed in 3/12 (25%) evaluable patients. Median survival for the entire group was 7 mo. The treatment was associated with severe myelotoxicity. Neutropenic fever that required hospitalization developed in 7/14 (50%) of patients, and symptomatic anemia that required red blood cell transfusion was noted in 8/14 (57%). There was one drug-related death associated with neutropenic fever, Gram negative sepsis, grade 4 thrombocytopenia, and gastrointestinal bleeding. Nonhematological toxicity was moderate. We conclude that the current regimen of paclitaxel, carboplatin, and oral etoposide is not recommended in advanced gastric carcinoma owing to unacceptable myelotoxicity.     

Phase II trial of plicamycin and hydroxyurea in acute myelogenous leukemia

Summary A total of 23 patients with high-risk acute myelogenous leukemia (AML) at diagnosis (2 patients), relapsing AML (14) or resistant AML (6) were treated with 25 g/kg i. v. plicamycin every other day for 3 weeks and 500–4,000 mg hydroxyurea per day p. o. according to the WBC count. Aplasia was observed in only two patients. Severe extrahematologic toxicity included sepsis (four cases), vomiting (four patients), toxic hepatitis (three cases), and fibrinopenia (one patient). No partial or complete responses were observed. The 95% confidence interval limit of the overall response rate (CR+PR) was 0–14%.     

急性白血病患者化疗后发热时IL-6检测的意义

目的 :研究中性粒细胞缺乏伴发热患者血浆中 IL - 6浓度和 C反应蛋白之间的关系 ,探讨 IL - 6在预测感染方面的作用。方法 :对 32例接受化疗的急性白血病患者的 5 0例次发热 ,采用 EL ISA法检测患者血浆 IL - 6浓度。结果 :有感染证据的病例 IL - 6水平均有不同程度的增高 ,且峰值较 C反应蛋白峰值提前 1d～ 3 d;在发热首日 ,革兰氏阴性菌血症患者 IL - 6水平 (中位数 195 2 ng/ L ,范围 10 5 3 ng/ L～ 2 0 794ng/ L )较革兰氏阳性菌血症患者 IL - 6水平 (中位数 2 83 ng/ L ,范围 91ng/ L～ 1496 ng/ L )显著增高 (P<0 .0 0 1)。不明原因发热患者 IL - 6水平也较肿瘤发热或治疗相关发热患者 IL - 6水平明显增高 (P<0 .0 0 5 )。结论 :IL - 6可作为早期预测感染的敏感指标 ,检测 IL - 6将有助于对急性白血病化疗后发热原因的判断。     

Serial measurement of serum C-reactive protein levels can identify patients at risk for severe complications following autologous stem cell transplantation

The value of serum C-reactive protein (CRP) levels as a predictor of complications in neutropenic patients needs to be further defined. We sought to identify an association between severe complications and daily CRP levels measured in 104 multiple myeloma patients during the 3 week period following high-dose melphalan and autologous transplant. Significantly higher mean CRP levels and CRP velocity of increase were observed among patients with severe complications. A cut-off point of 100 mg/l (CRP levels) and 15 mg/l/day (CRP velocity) identified patients likely to suffer severe complications with 86 and 75% sensitivity, respectively. Prospective validation of this model is currently underway.     

Dynamics of procalcitonin and bacteremia in neutropenic adults with acute myeloid leukemia

Sensitive markers of infection are rare or of limited validity in neutropenic patients. Procalcitonin (PCT), a precursor protein of calcitonin, is a specific and sensitive marker of severe bacterial infections during short-term neutropenia. Because the value of PCT measurements among patients undergoing long periods of neutropenia remains uncertain and because several mechanisms, such as bacterial or fungal infections, reactions to drugs or blood products or tumor-associated events, can cause fever, we described the dynamics of PCT in 29 acute myeloid leukemia (AML) patients with 39 instances of chemotherapy-induced neutropenia. Plasma levels of PCT were determined prospectively by an immunoluminometric assay every four days starting at the onset of chemotherapy and continuing until the resolution of fever. We found that bacteremia did increase PCT levels above 0.5 ng/mL and these levels predicted bacteremia at day 15 of chemotherapy. This finding may be relevant in the decision to alter antibiotic regimens to decrease toxicity and cost when patients remain febrile at day 15.     

Impact of Fluoroquinolone Prophylaxis on Neutropenic Fever,Infections, and Antimicrobial Resistance in Newly Diagnosed AML Patients

IntroductionFluoroquinolone prophylaxis is recommended during induction chemotherapy for patients with acute myeloid leukemia (AML) to reduce risk of neutropenic fever and systemic bacterial infections. We evaluated the effectiveness of primary fluoroquinolone prophylaxis in an area with high fluoroquinolone resistance.Materials and MethodsWe performed a retrospective chart review of newly diagnosed adult AML patients who received frontline therapy at Mount Sinai Hospital in New York, NY, between 2012 and 2019. Primary outcome was development of neutropenic fever. Secondary outcomes were development of systemic bacterial infections and infections with multidrug-resistant organisms and Clostridioides difficile. Infectious outcomes were collected through 6 months after therapy initiation. We estimated the effect of fluoroquinolone prophylaxis with a time-dependent Cox proportional hazards model.ResultsOf 121 included patients, 87 received antibiotic prophylaxis and 34 did not. There was no difference in baseline characteristics, although the prophylaxis group had longer neutropenia duration (median 30 vs. 23 days, P = .013). The prophylaxis group had a reduced risk of neutropenic fever (hazard ratio 0.59, P = .039). The prophylaxis group had fewer gram-positive (P = .043) and gram-negative (P = .049) bloodstream infections and fewer clinically documented infections during frontline therapy (P = .005) and follow-up (P = .026). There was no difference in incidence of C. difficile or infection with fluoroquinolone-resistant or multidrug-resistant organisms. There was no mortality difference between groups.ConclusionIn an area with high fluoroquinolone resistance, primary fluoroquinolone prophylaxis in newly diagnosed AML patients reduced the risk of neutropenic fever and systemic bacterial infections without increased antimicrobial resistance. Prospective, randomized studies are needed to confirm these observations.     

Radiotherapy following radical prostatectomy in patients with adenocarcinoma of the prostate

From 1973 to 1986, 160 patients with adenocarcinoma localized to the prostate were treated with radical prostatectomy and pelvic lymphadenectomy. In 78 (49%) patients more advanced stage of disease was found at surgery and they received local pelvic irradiation (RT). This consisted of 45 Gy for microscopic and 55 Gy for macroscopic residual disease. RT was given at 1.8 Gy a day, using the four-field "box" technique with the 23 MV X ray beam. Pelvic lymph node metastases were found in 28 (36%) patients who, in addition to RT, received systemic therapy: 20 with cyclophosphamide alone, 4 combined with 5-Fluorouracil, and 4 patients received DES. The 5- and 10-year overall actuarial survival was 95 and 77%, respectively, and the 5- and 10-year disease-free survival was 58 and 43%, respectively. Recurrent tumor was found in 34 (44%) patients. Of these 34 patients, 32 (94%) had distant metastatic tumor and 2 (6%) had local recurrence in the pelvis. The presence of metastatic disease in pelvic lymph nodes had clinical significance since it influenced disease-free survival and the incidence of tumor recurrence. The 10-year disease-free survival for the 50 patients with no lymph node metastases was 51%, as compared to 28% for the 28 patients with such metastases, p = 0.001. Similarly, recurrent tumor was found in 28% of the former and 68% of the latter patients, p = 0.002. Other important parameters predicting recurrence were: clinical stage, p = 0.018, histological grade, p = 0.013, and Gleason's grade, p = 0.002. This treatment program was very well tolerated and of low toxicity. There was no surgical mortality. Surgical complications were seen in 10 (13%) patients including: minor in 5 and major in 5. At 1 year, 77% of the patients remained continent, while 10% had mild stress incontinence. Of the remaining 13% only 3 (4%) patients had severe incontinence (greater than 5 pads daily). RT toxicity was mild with 38% experiencing diarrhea. Severe toxicity was seen in 2 (3%) patients who, early in the study, developed scrotal and lower extremity edema. Severe chemotherapy complications were seen in 1 (4%) patient who had severe neutropenic sepsis. Postoperative radiotherapy is a well tolerated, safe and effective treatment in patients who have microscopic or macroscopic residual tumor following radical prostatectomy.     

Cytokine concentrations are not predictive of bacteremia in febrile neutropenic patients

Assay of cytokines and C reactive protein (CRP) in different periods of febrile neutropenia may be helpful for early defining the risk in severe infections. We determined serum interleukin-6 (IL-6), interleukin-8 (IL-8), soluble interleukin-2 receptor (sIL-2R), tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and CRP in 22 previously untreated patients with various malignancies. Samples were obtained in four different clinical periods of febrile neutropenia; prior to chemotherapy, afebrile neutropenic period after chemotherapy, febrile neutropenic period, and recovery period. When compared to sex-and age-matched group of healthy subjects, IL-6, IL-8, sIL-2R, and CRP levels were found to be elevated in all periods. The highest levels were encountered in the febrile neutropenic period. For predictivity purposes, the afebrile neutropenic period was the most important period. Serum sIL-2R, IL-6, IL-8 and CRP levels were elevated in this period. IL-8 levels showed the most stable elevation through different stages of febrile neutropenia. Serum IL-8 levels were found to have the most reliable and stable elevation in different clinical stages of febrile neutropenia. Nevertheless, IL-8 is not able to discriminate among risk groups and cannot be used as a predictive factor.     

Key Pharmacokinetic Parameters of Isepamicin in Febrile Neutropenic Cancer Patients and in Women with Acute Pelvic Inflammatory Disease

Abstract

The pharmacokinetics (PK) of isepamicin were studied in 8 febrile neutropenic patients with hematologic malignancy and in 20 young women with acute pelvic inflammatory disease (PID). Isepamicin was given as a slow intravenous infusion over 30 min at a dose of 15 mg/kg once daily (OD). Serum levels of isepamicin were determined by fluorescence polarization immunoassay, and PK analyses were obtained based on a one-compartment open model after 24 hours (steady state) and after 7 days.

On day 1, the volume of distribution (V_d) of isepamicin, for both populations, appeared about 30% higher than classically reported in healthy individuals: 0.31 and 0.36 L/kg for neutropenic and PID patients respectively. However on day 7, V_d displayed significant reduction (0.28 and 0.27 L/kg, respectively for neutropenic and PID patients). A reduction of isepamicin clearance was also observed between day 1 and day 7 (137 vs 120 mL/min and 130 vs 101 mL/min for neutropenic and PID populations, respectively). Such changes are consistent with a significant increase in the C_max concentrations (45 vs 50 mg/L, and 38 vs 49 mg/L) and in the AUC (136 vs 158 and 137 vs 162 mg/L.h) observed after a week of treatment in neutropenic and PID patients, respectively.

In conclusion, taking into account the importance of reaching early active concentrations, we recommend the use of higher loading dose of isepamicin (>15 mg/kg) in neutropenic cancer patients and in women with PID, particularly in case of a combination with a possibly ineffective antibacterial agent, in case of infection with bacteria at upper limit of susceptibility, in the presence of high infectious inoculum or in the presence of sequestered sites of infection.     

Effect Of Granulocyte-Macrophage Colony-Stimulating Factor (Gm-Csf) On Hematologic Toxicity Induced By High-Dose Chemotherapy In Patients With Metastatic Breast Cancer

Twenty patients with recurrent metastatic breast cancer treated with high-dose myelosuppressive antineoplastic drugs (cyclophosphamide 2.5 g/m² or epirubicin 130 mg/m², both every 3 weeks) as first or second line chemotherapy were randomized in a prospective study to GM-CSF 5 μg/kg per day (n = 11) or control (n = 9). Significant reduction in granulocyte nadir duration (2 days with GM-CSF vs. 7 days) and severity (0.4 10⁹/1 with GM-CSF vs. 0.2 10⁹/1) was found. No difference in frequency of neutropenic fever or antibiotic use could be observed. Even though the patients treated with GM-CSF at random were more heavily pretreated with chemotherapy, there was a surprisingly higher response rate in these patients as compared to the control-arm, namely 64% vs. 28.5%. However, this difference was not statistically significant. No severe side-effects were seen, but presumably due to GM-CSF one patient developed an allergic type 1 reaction and one patient a possible pericardial exudation. Both were fully reversible after cessation of the cytokine treatment.     

Mitoxantrone, etoposide, and intermediate-dose cytarabine: an effective and tolerable regimen for the treatment of refractory acute myeloid leukemia

Thirty-two patients with refractory acute myeloid leukemia (AML) received salvage therapy with a single course of mitoxantrone 6 mg/m2 intravenous (IV) bolus, etoposide 80 mg/m2 IV for a period of 1 hour, and cytarabine (Ara-C) 1 g/m2 IV for a period of 6 hours daily for 6 days (MEC). Eighteen patients were primarily resistant to conventional daunorubicin and Ara-C induction treatment; eight patients had relapsed within 6 months from initial remission; six patients had relapsed after a bone marrow transplantation (BMT) procedure. Overall, 21 patients (66%) achieved a complete remission (CR), two (6%) died of infection during induction, and nine (28%) had resistant disease. Age greater than 50 years was the only factor predictive for a significantly lower response rate (P = .03). The median remission duration was 16 weeks; the overall median survival was 36 weeks. Severe myelosuppression was observed in all patients resulting in fever or documented infections in 91% of patients. Nonhematologic toxicity was minimal. We conclude that the MEC regimen has significant antileukemic activity and acceptable toxicity in salvage AML. Its benefit in front-line AML therapy is being investigated.     

Pilot study of Mylotarg,idarubicin and cytarabine combination regimen in patients with primary resistant or relapsed acute myeloid leukemia

PURPOSE: Mylotarg has moderate activity as a single agent in patients with CD33-positive refractory or relapsed acute myelogenous leukemia (AML). A combination of an anthracycline and cytarabine (ara-C) is the core of most AML induction regimens. We conducted a pilot study of Mylotarg combined with idarubicin and ara-C in patients with refractory or relapsed AML. METHODS: Mylotarg was administered at 6 mg/m(2) intravenously on days 1 and 15, idarubicin 12 mg/m(2) daily on days 2 through 4, and ara-C at 1.5 g/m(2) daily on days 2 through 5 (MIA) RESULTS: Of 14 patients were treated, 4 (29%) had primary resistant AML, and 10 (71%) relapsed AML. The median age of the patients was 61 years (range 34-74 years). MIA induced complete remission (CR) in three patients (21%) and CR with incomplete platelet recovery (CRp) in three patients (21%). The median survival was 8 weeks (range 2-64 weeks), and the median failure-free survival of CR patients was 27 weeks (range 11-64 weeks). All patients developed grade 3/4 myelosuppression - severe sepsis occurred in ten patients (71%). Other grade 3/4 nonhematologic toxicities included hepatic transaminitis, oral mucositis, and diarrhea. Two patients (14%) developed hepatic venoocclusive disease (VOD). CONCLUSIONS: The addition of Mylotarg to idarubicin and ara-C is feasible. MIA has significant activity in patients with refractory AML. Hepatotoxicity and VOD are significant toxicities of Mylotarg-based combinations.     

Mylotarg,fludarabine, cytarabine (ara-C), and cyclosporine (MFAC) regimen as post-remission therapy in acute myelogenous leukemia

Purpose Mylotarg, a humanized anti-CD33 antibody linked to an antitumor antibiotic, is approved for the treatment of patients with relapsed acute myeloid leukemia (AML). Its role as a component of post-remission therapy in AML has not been established. The Mylotarg, fludarabine, cytarabine, and cyclosporine (MFAC) regimen was evaluated in patients in complete remission following Mylotarg-containing regimens.Methods The MFAC regimen comprised: Mylotarg 4.5 mg/m² intravenously (i.v.) over 2 h after a loading dose of cyclosporine A (CSA) on day 1; fludarabine 15 mg/m² i.v. over 30 min every 12 h for six doses on days 2 through 4; ara-C 0.5 g/m² over 2 h every 12 h for six doses on days 2 through 4, 4 h after fludarabine started; CSA 6 mg/kg over 2 h, followed by 16 mg/kg continuous i.v. infusion on days 1 and 2. Patients in complete remission (CR) commenced idarubicin and ara-C (IA) alternating with MFAC or vice versa for 9 months from the date of CR. Idarubicin was administered at 8 mg/m² on days 1 and 2 and ara-C at 1.5 g/m² on days 1 and 2.Results A total of 22 patients received 76 courses of MFAC (35 courses) alternating with IA (41 courses) or vice versa. The interval between courses, and degrees of myelosuppression, were equivalent in the alternating regimens. Failure-free and 12-month survival rates of were 32% and 55%, respectively. Grade 3/4 toxicities, including sepsis, neutropenic fever, and nausea/vomiting, were equivalent with MFAC and IA.Conclusions Post-remission therapy with MFAC is feasible and well tolerated in patients with AML.     

Severity of enterocolitis is predicted by IL-8 in paediatric oncology patients

Enterocolitis in oncology patients remains an important complication, but there is a lack of insight into its likely severity from microbial, pathological and inflammatory aspects. Paediatric oncology patients admitted with neutropenic fever, who developed abdominal pain and diarrhoea, were monitored by the takers of rectal biopsies, cultures, and inflammatory marker measurements. Twenty-five patients were included (mean age 7.1 years). 8 patients (32%) needed intensive care treatment, 3 (12%) patients died. Gram-positive bacteraemia was diagnosed in 4 patients (16%). Most patients had negative blood and stool cultures. Predictors of a severe clinical course of the enterocolitis were an increased serum interleukin-8 (IL-8) (>1000 pg/ml) level and an increased serum C-reactive protein level (CRP) (>150 mg/l) level, both measured on the first day of clinical illness. Relative risks (RR) for admission to an Intensive Care Unit (ICU) were 11.3 (95% Confidence Interval (CI) 1.6-77.9) for elevated IL-8 levels and 6.4 (95% (CI) 0.92-45.1) for increased CRP levels. Rectal biopsies and pathology could not predict outcome (P=0.22). IL-8 analysis at the onset of enterocolitis symptoms can identify high-risk patients, which might be used clinically to design future intervention trials.     

Clinical Implication of Toll-Like Receptors (TLR2 and TLR4) in Acute Myeloid Leukemia Patients

Backgrounds: Toll-like receptors 2; 4 (TLR2;4) are an essential component of the innate immunity and play an important role in immune-surveillance and immune response to various microorganisms. This study aimed to investigate the association between TLR2 and TLR4 polymorphism and the risk of acquiring severe infections, and impact on AML patient’s outcome. Subjects and methods: Using polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP); we analyzed three SNPs in the TLR2 (Arg753Gln) and TLR4 (Asp299Gly and Thr399Ile) in 120 AML patients and 100 healthy control subjects. Results: No significant differences in genotype or alleles frequency between healthy controls and AML patients regarding TLR2 Arg753Gln, TLR4 Asp299Gly and TLR4 Thr399Ile polymorphisms (P>0.05 for all). Neutropenic fever was detected in 110 out of 120 (91.7%) of the studied AML patients. The sepsis and pneumonia were identified in 20 out of 120 patients (16.7%). The incidence of sepsis was associated with TLR2 Arg753Gln: AG genotypes, A allele and TLR4 Asp299Gly: CT genotype and C allele as compared to other genotypes and alleles. Moreover; TLR2 (Arg753Gln) GG polymorphisms significantly associated with shortest overall survival (OS) and shortest disease-free survival (DFS); while TLR4 polymorphisms affect the DSF only but not OS. In AML patients TLR2 Arg753Gln gene polymorphism is associated with high susceptibility to sepsis and TLR4 (Asp299Gly and Thr399Ile) gene polymorphism is associated with high susceptibility for both pneumonia; and sepsis. Conclusion: TLR2 Arg753Gln (AG; GG genotype) polymorphisms are associated with shortest OS and DFS. Moreover; significant association between TLR2 polymorphisms, TLR4 Arg753Gln polymorphisms and risk of severe infections in AML patients was documented.     

Significance of oral Candida infections in children with cancer

Candidiasis is common in children with cancer, particularly during periods of severe immunosuppression and neutropenia. Our aim was to study the microbiological changes in the oral cavity of children with newly diagnosed cancer. The study group consisted of 30 consecutive children and adolescents, 16 with acute lymphoblastic leukemia and 14 with solid tumors. Oral cultures to detect fungi and bacteria were conducted for all patients before treatment, during and after neutropenic episodes. In 23 patients developing fever simultaneous throat, urine and blood sampling was carried out. No pathogens were found in the cultures taken before the outset (30 cultures) or after recovery from (30 cultures) the neutropenic episodes. In the 45 oral cultures taken during the neutropenic episodes 38 (84.4%) proved positive. Fungi were the most frequently isolated oral pathogens: 33/38 yeast and 6/38 bacterial infections were identified. There was no association between the underlying malignancy and the occurrence of the positive cultures. Of the 30 patients, all 23 (76.7%) who have developed moderate-to-severe neutropenia, developed oral fungal colonization or clinically obvious fungal infection at least on one occasion during the study. In addition to oral samples, fungi were identified in 9/23 pharyngeal swabs, 6/23 urine and 1/23 blood cultures. The initial fungal pathogen was exclusively (33/33) Candida albicans. In extended severe neutropenic states, C. albicans was replaced by non-albicans species (C. kefyr, C. lusitaniae, C. sake, C. tropicalis) in 5 patients between 4 to 6 days of the neutropenic episodes. Four of the nonalbicans Candida strains were resistant to azole-type antifungal agents. Neutropenic episodes of children with cancer are associated with an increased risk of developing oral and even systemic infections with C. albicans that can be replaced by azole-resistant nonalbicans strains in prolonged neutropenia contributing to morbidity of these patients.