Analysis of the effectiveness of repeated courses of tuberculosis chemotherapy after inefficient courses

Objectives - to evaluate the main bacteriological indicators for newly diagnosed pulmonary tuberculosis and to compare them with the timing of sputum smear negative reaction and abacillation. Materials and methods. The study included 127 people with newly diagnosed pulmonary tuberculosis. Bacteriological and radiological data were evaluated at 2, 4 and 6 months of the study. The patients were divided into 2 groups: patients with an ineffective course of chemotherapy (1st group, n = 67) and an effective chemotherapy (2d group, n = 60). Results. In the 1 st group, the patients with the following processes prevailed over the 2nd group: destructive (86.4% vs 40.0%; р < 0.001), generalized (76.1% vs 50.0%; р = 0.003), bilateral (62.7% vs 36.7%; р = 0.004), with bacterial excretion (68.7% vs 33.3%; р < 0.001). The difference in mass of bacterial excretion in the compared groups was insignificant (p > 0.050). The Mtb growth in solid medium was absent within 90 days in patients with effective chemotherapy (28.3% vs 1.5% in the 1 st group, р < 0.001). The low intensity of Mtb growth was also observed in the 2nd group (46.5% vs 21.2%; р = 0.006). XDR of Mtb was registered in 16.4% of patients in the 1st group, versus 5% in the 2nd group (p = 0.04). In the 1st group, the sputum smear microscopy was revealing bacteria discharge in 29.8% of patients during 12 months. In the 2nd group, the abacillation was registered in all the patients after 6 months of treatment. During the 6-8 months of chemotherapy, the abacillation was registered in 41.9% of patients in the 2nd group, and in 13.6% of patients in the 1st group (р = 0.020). After 12 months of treatment, the Mtb growth in solid medium was present in 57.6% of patients in the 1st group, compared to the 20.9% in the 2nd group (p < 0.001). Conclusion. The results of our study indicate the relationship of Mtb drug resistance, XDR in particular, and the rate of Mtb division to the generalization of the process, the tendency for destruction of lung tissue, as well as the early appearance of bacterial excretion and, accordingly, the longer periods for sputum negative reaction and abacillation.

Lung cancer is the third most common mortal disease in industrialised countries and the prognosis has been slow to improve. The largest subgroup has locally advanced or metastatic non-small cell lung cancer (NSCLC). Unfortunately, these patients can usually not be cured and the main treatment option is palliative chemotherapy. Given the palliative intention of the chemotherapy, it is clinically highly relevant to establish the optimal treatment duration. While chemotherapy prolongs survival and improves quality of life (QoL), it also has side effects and only a minority of patients achieve an objective treatment response. Clinicians need guidance on treatment duration from controlled trials to balance these aspects. Improvements of the conditions under which chemotherapy is given can increase patient and staff satisfaction and increase system performance. This is especially relevant to incurable patients who spend a lot of their limited time at oncology outpatient clinics. Staffing, infrastructure and organisation of these units are often suboptimal to serve patients with palliative needs and reports of improvement projects can inspire and guide clinicians in improving their microsystems of care. Clinicians, health care administrators and the public need knowledge about the outcomes of palliative chemotherapy in unselected patient populations. The efficacy of palliative chemotherapy for advanced NSCLC has been amply documented in controlled clinical trials. Meanwhile, the elderly and patients with higher performance status have usually been under-represented in these trials and population studies of the effectiveness of chemotherapy are needed. (i) To establish the optimal duration of platinum-based first line chemotherapy for advanced NSCLC; (ii) To improve the care processes at an oncology outpatient clinical microsystem; (iii) To describe the use of chemotherapy in a national population and investigate associations between chemotherapy use and survival; and (iv) To explore approaches to improve the system of chemotherapy from the macro perspective of a whole country. The thesis combines methods from different knowledge domains. In a randomised trial, we compared three with six courses of platinum-based chemotherapy for advanced NSCLC. In a quality improvement study, we used logistic improvement tools, qualitative and quantitative patient and staff satisfaction measurements. Finally using data from the Norwegian cancer and chemotherapy registries, we investigated temporary and geographical variations of chemotherapy use and correlations with the survival of patients with advanced NSCLC. Methods and findings from the three studies were explored to inform a national improvement strategy for the chemotherapy of advanced NSCLC. Survival and QoL were equal with three or six courses of chemotherapy for advanced NSCLC. Systematic process changes at the outpatient clinic led to increased patient and staff satisfaction. Furthermore, the study illustrates the application of established process improvement and evaluation tools in a clinical microsystem. In the registry study, we found delays of the introduction of palliative chemotherapy in Norway and significant associations between the use of chemotherapy and the survival of patients with advanced NSCLC. The general section of the thesis describes approaches to system-wide improvements and introduces a quality improvement matrix. We conclude from our randomised trial and related research that chemotherapy beyond three courses is not beneficial for patients with advanced NSCLC. The report from the oncology outpatient clinic illustrates the value of the clinical microsystem approach for quality improvement at the front line of care. Patient feedback through a focus group, simple methods of assessing and simplifying processes of care, as well as measuring results over time were effective tools in our project. The description of the experiences can serve as an example for the improvement of microsystems in settings with similar problems. Finally, in the registry study of Norwegian patients with lung cancer, we found significant geographical and temporal variations of the utilisation of chemotherapy that were related to survival. Potential areas of improvement in the system of care for lung cancer are recruitment of patients in clinical studies, standardisation of the processes of care in outpatient clinics, definition of strategic aims of quality, development of balanced quality indicators, as well as measuring and reporting of outcomes by means of a quality registry.

A total of 610 patients with small cell lung cancer were entered into a randomised trial designed to assess the effect of duration of initial chemotherapy on survival. Patients were randomised to receive either four or eight courses of cytotoxic chemotherapy with cyclophosphamide, vincristine and etoposide and also randomised to receive, on disease progression, either second line chemotherapy (methotrexate and doxorubicin) or symptomatic treatment only. In the whole study 196 (32.1%) had limited disease and 414 (67.9%) extensive disease. During initial chemotherapy the response rate (complete and partial responses) after four courses of treatment was 61% with no significant increase in patients receiving eight courses (63%). In those randomised to receive relapse chemotherapy the response rate was improved slightly for those who had originally received four courses of chemotherapy (25.6%) over those receiving eight (18.7%). The overall results show that of the four possible treatment randomizations, four courses of chemotherapy alone is inferior in terms of overall survival (30 weeks median survival) to the other three treatment options (39 weeks median survival, P less than 0.01). In patients responding to initial chemotherapy the disadvantage of four courses of chemotherapy alone was apparent (median survival of 40 weeks versus 49 weeks, P = 0.003) but not if drug treatment was given on relapse. The study shows that limiting treatment to four courses of chemotherapy alone is associated with inferior survival, but this is not the case if chemotherapy is given at relapse.

The cytosolic 5'-nucleotidase-III (NT5C3) is involved in the metabolism of the nucleoside analog, cytosine arabinose (AraC), and the expression level of NT5C3 is correlated with sensitivity to AraC in acute myeloid leukemia (AML) patients. The current study examined whether the NT5C3 polymorphisms could affect chemotherapy outcomes in 103 Korean AML patients. Forty-seven single nucleotide polymorphisms in NT5C3 were genotyped using the Illumina GoldenGate genotyping assay. The genetic effects of the polymorphisms on the outcome of chemotherapy were analyzed using χ and logistic regression models. Although none of the NT5C3 polymorphisms was associated with a complete remission rate, a common single nucleotide polymorphism, rs3750117, showed a significant association with induction rate after the first course of chemotherapy (Pcorr=0.004 and odds ratio=11.28) in AML patients. In addition, NT5C3 expression levels were significantly increased in patients with risk allele homozygote. The data suggest that genotyping the NT5C3 polymorphism may have the potential to identify patients more likely to respond to AraC-based chemotherapy.

How to improve timing and duration of adjuvant chemotherapy

Patients with locally advanced, inoperable squamous cell carcinoma of the head and neck were offered three courses of cisplatin and 96-h 5-fluorouracil (5-FU) infusion. Subsequent therapy included surgery when feasible, irradiation therapy, and a maintenance program of methotrexate (MTX)-5-FU. Thirty-three patients were evaluated prospectively. Seven patients underwent a single course of chemotherapy. Five patients underwent two courses of chemotherapy. Twenty-one patients underwent three courses of adjuvant chemotherapy. The overall response rate was 48% (16 of 33). Fifteen of 21 patients (76%) receiving three courses of chemotherapy evidenced a response; this included three complete responses (CRs) (9%). No responses were seen in patients receiving only one or two courses of chemotherapy. Among responding patients, the initial favorable response to chemotherapy was apparent after the first course of chemotherapy. Patients who failed to demonstrate any response after two courses of chemotherapy did not respond after a third course. A significant group of patients fail to respond and should be offered participation in other investigational protocols as they become available.

An increased human parvovirus B19 infection rate has been observed in immunocompromised hosts. In this study, we sought to determine the prevalence of parvovirus B19 infection in adult cancer patients receiving multiple courses of systemic chemotherapy. From March 1999 through April 2000, 59 men and 68 women, with a median age of 49 (18 to 79) years, were enrolled in this study. They had received an average of 7.1 (4 to 32) courses of systemic chemotherapy. The median duration from the date of starting chemotherapy to the date of blood sampling was 11 (4 to 88) months. Serum B19 immunoglobulin G (IgG) and IgM levels were examined by an enzyme-linked immunosorbent assay, and B19 DNA was examined by a nested PCR. A group of 400 healthy blood donors served as the control group. The overall prevalences of anti-B19 IgG in adult cancer patients and healthy blood donors were 61.4 and 25.0%, respectively (P < 0.01). Anti-B19 IgM and B19 DNA were not detectable in these anti-B19 IgG-seropositive individuals. A further age-stratified comparison revealed that only patients younger than 40 years had a significantly higher anti-B19 IgG seropositivity rate than the controls (19 of 39 versus 53 of 310; P < 0.001). The increased prevalence of B19 infection in these 39 adult patients younger than 40 years might be clinically significant, since unexplained anemia, a common sequela of B19 infection, was detected in 3 of 20 seronegative patients (15.0%) and in 12 of 19 seropositive patients (63.2%) (P < 0.005). The results of this study suggest that adult patients younger than 40 years and receiving multiple courses of systemic chemotherapy may have a significantly increased risk of B19 infection. Prospective studies to define the time course and clinical consequence of B19 infection in this group of patients are needed.

To assess how well chemotherapy is tolerated after solid organ transplantation, we reviewed our experience at the Children's Hospital of Pittsburgh with five patients aged 1 to 12 years. Four patients had a liver transplant, indications for which were hepatoblastoma in two patients, hepatic failure secondary to Wilms' tumor chemoradiotherapy in one patient, and familial intrahepatic cholestasis in one patient. A fifth patient received a cardiac transplant for unresectable angiosarcoma of the right atrium. After transplant, chemotherapy was given for the treatment of the primary malignancy in four of the patients. The patient with familial intrahepatic cholestasis received chemotherapy for secondary lymphoproliferative disease that had not responded to the cessation of immunosuppression. All patients other than this patient were on immunosuppression with prednisone (0.5 to 2 mg/kg daily) and cyclosporine (to maintain serum levels at 800 to 1000 ng/ml radioimmunoassay) throughout the duration of chemotherapy. Courses of chemotherapy included one or more of the following agents: Adriamycin (Adr, 20 mg/m2 daily, three patients), Cyclophosphamide (Ctx, 1 gm/m2, one patient), cisplatin (CDDP, 90 mg/m2, one patient), Vincristine (Vcr, greater than 0.75 to 1.5 mg/m2, three patients), Actinomycin D (Act-D, 7.5 micrograms/kg, one patient), Ifosfamide (I, 1800 mg/m2, one patient) and Etoposide (VP-16, 100 mg/m2, one patient). All patients received greater than or equal to 3 courses (range, 3 to 9; mean, 5) of chemotherapy every 3 to 4 weeks. Dose reductions were made because of neutropenia in three patients but none were greater than 50%. Severe rejection was seen in one patient who had, however, manifested evidence of rejection prior to his first postoperative course of chemotherapy. No nephro or cardiac toxicity was seen. This preliminary experience suggests that chemotherapy is well tolerated after solid organ transplantation.

Objective of the study is definition of cytokine balance and the outcomes of chemotherapy of tuberculosis patients depending on their thyroid state. Materials and methods: 60 tuberculosis patients with pulmonary: 30 persons with unchanged thyroid gland and 30 persons with autoimmune thyroiditis and followed subclinical hypothyroidism were compared for the structure and the function of thyroid gland, cytokine balance and outcomes of antituberculosis chemotherapy. Thyroid glands of all patients were scanned by ultrasound. The levels of free thyroxine, thyroid stimulating hormone and antibodies to thyroglobulin and thyroid peroxidase in the serum were defined. At the same time the levels of tumor necrosis factor-α, interferon- γ and interleukins-2, -6, and -4 were measured. Outcomes of chemotherapy was estimated on the ground of general cri­terions: term and rate of stopping of bacilli excretion and healing of caverns in lungs. Results and discussion: In a com­parative analysis of the data obtained, it was found that in tuberculosis patients with autoimmune thyroiditis and subclinical hypothyroidism compared with tuberculosis patients without thyroid pathology free thyroxine values in average decrease, the level of thyroid-stimulating hormone increases and levels of antibodies to both thyroglobulin and especially to thyroid peroxidase increase. In patients with concomitant autoimmune thyroiditis with subclinical thy­roiditis, levels of pro-inflammation cytokines TNF-α, INF-γ, IL-2, IL-6 were significantly lower when compared with patients without thyroid pathology, and the level of anti-inflammation cytokine IL IL-4 was higher in a group of patients with autoimmune thyroiditis. Efficacy of chemotherapy was better in tuberculosis patients without thyroid pathology. These changes can be explained by a lower level of T4 in the systemic circulation of people with autoimmune thyroiditis and subclinical hypothyroidism. Conclusion: subclinical hypothyroidism accompanying concomitant autoimmune thyroiditis suppresses cytokine response in tuberculosis patients. That is followed worsening of treatment response during antituberculosis chemotherapy. Screening of thyroid state is recommended for TB patients for timely definition of thyroid pathology and its compensation if needed for improvement of the outcomes of antituberculosis chemotherapy.

The addition of combination chemotherapy to standard radiation therapy has improved treatment for locally unresectable non-small-cell lung cancer. In this phase II study, we evaluated the toxicity and efficacy of a novel chemotherapy regimen that included paclitaxel, cisplatin, and etoposide plus concurrent radiation therapy in this group of patients. Thirty-three patients with previously untreated, unresectable stage III non-small-cell lung cancer (stage IIIA, 11 patients; stage IIIB, 22 patients) initially received two courses of chemotherapy, which included paclitaxel 135 mg/m2 by 1-hour infusion on day 1, cisplatin 60 mg/m/ intravenously (i.v.) on day 2, and etoposide 100 mg/m2 i.v. on days 1, 2 and 3. On week 6, radiation therapy (60 Gy in 30 fractions) was initiated in conjunction with two additional courses of chemotherapy: paclitaxel 135 mg/m2 i.v. by 1-hour infusion on day 1, cisplatin 5 mg/m2 i.v. on days 2- to 10, and etoposide 25 mg/m2 on days 1 to 10. This combined modality program was feasible and well tolerated by most patients. During the two courses of induction chemotherapy, grade 3 or 4 myelosuppression occurred in only six patients (18%). Esophagitis was common during combined modality therapy (grade 3, 10 patients; grade 4 five patients). Forty-two percent of patients had partial response after two courses of induction therapy, and 82% of patients had an objective response at completion of therapy. Twelve patients (36%) had a complete response. Nineteen patients remain progression-free at a median of 8 months; the median survival time has not been reached. This paclitaxel-containing combined modality therapy is feasible and highly active in patients with inoperable stage III lung cancer. Esophagitis is the most common severe toxicity with this program. Further studies with paclitaxel-containing combination regimens in patients with stage III non-small-cell lung cancer are indicated.

Despite the introduction of new anti-tuberculosis drugs, the problem of treating tuberculosis patients with a broad drug-resistant pathogen (XDR MBT) remains relevant.Aim of the study. Тo increase the effectiveness of treatment of this category of patients using an autologous composition based on dendritic cells activated by a specific antigen.Research materials and methods. А prospective study conducted in 2016-2019 included 52 patients, 36 (69.2%) men and 16 (30.8%) women, average age 43.2 ± 1.5 years. All patients received antituberculosis therapy in accordance with existing regulatory documents and recommendations. The main group consisted of 25 patients (48.1%) who agreed to immunotherapy with the introduction of an autologous composition with activated specific peptides ESAT-6 and SFP-10 dendritic cells against the background of anti-tuberculosis therapy. Statistical processing of the material carried out using the Statistica 10.0 application software package.Results. In 70.0% of cases (n = 14), there were no adverse reactions to suspension administration in patients of the main group. One patient (7.2%) had a general reaction in the form of tremor, chills after the first injection. In 5 (38.7%) patients on the 8th and 9th administration, a skin reaction was noted at the injection sites in the form of a papule, with a final regression of these changes after 8 weeks. By 18– 24 months of the course, anti-tuberculosis therapy in combination with immunotherapy in the first month of treatment allowed to obtain a positive effect according to clinical, bacteriological and radiological data in 64% of cases. It was not possible to obtain this result during therapy at the previous stages of treatment. In the comparison group, a positive result achieved only in 45.5% of cases.Conclusion. The results of the study suggest a positive effect of complex treatment with the inclusion of immunotherapy with an autologous composition based on dendritic cells in the most severe contingent of patients with pulmonary tuberculosis with broad drug resistance of the pathogen, even with an ineffective course of chemotherapy at the previous stage in 64% of cases.

Aims To evaluate the renin gene (RG) expression pattern in newly diagnosed patients with acute myeloid leukemia (AML), aiming to figure out its prognostic value in correlation with clinical characteristics and outcomes of the chemotherapy course. Settings and design This study was clinical trial performed in the National Cancer Institute (NCI), Cairo University. Patients and methods We investigated the expression of the RG in 90 patients with AML using real-time PCR. Levels of RG were correlated with the different patients’ characteristics and outcomes of chemotherapy. Statistical analysis used χ 2 test and Student t test were used to compare between RG positive and negative groups. SPSS software was used to perform the statistical analysis. Results RG presented in 90 (72%) patients with AML. Both renin positive and negative populations showed no statistically significant difference, regarding all clinical parameters evaluated and the prognostic outcomes. Positive gene patients were associated with nonsignificantly lower percentages of bone marrow and peripheral blood blasts (P=0.534 and 0.074, respectively). In addition, they showed nonsignificant difference regarding the incidence of all types of cytogenetics (P=0.467) and the same results for Flt3 gene expression (P=0.751). Moreover, they showed nonsignificant difference regarding complete response rates, relapse rates, and survival rates (P=0.473, 0.636, and 0.152, respectively). Conclusion RG expression has no significant role in determining the prognosis of patients with AML. This includes different prognostic outcomes, including response to treatment, survival rates, relapses, and disease-free periods.

12077 Background: Anthracyclines are highly effective chemotherapeutic agents, used for a wide variety of malignancies. Despite their antitumor efficacy there is a risk of cardiotoxic manifestations that reduce the time and quality of life of patients. The purpose was to study the effectiveness of molecular genetic tests based on rs4673 CYBA genotyping (c.242C &gt; T) and measurement of plasma paraoxonase 1 (PON1) level in patients with breast cancer (BC) for predicting and diagnosing anthracycline-mediated cardiotoxicity (AMC). Methods: The study included 256 Caucasian patients (median age - 55 years) with a diagnosis of breast cancer normal cardiovascular system parameters at baseline, who were treated with anthracyclines in 2019-2020. For rs4673 genotyping, DNA was extracted from the blood by using DNA-sorb-B (AmpliSens, Russia). HRM-PCR was performed on a CFX96 amplifier (Bio-Rad, USA). The presence of polymorphism was confirmed by the Sanger method on a Genetic Analyzer 3500 (ABI, USA). The concentration of PON1 in blood plasma was measured at baseline and after 4 course of chemotherapy with anthracyclines using ELISA kits (Cloud-Clone Corp., China/USA). Results: During the follow-up period 21 (8.2%) patients developed signs of subacute (changes developed within several weeks after the last course of therapy) or early chronic AMC (changes developed within a year after completion of anthracycline therapy). In the group of patients without AMC the frequency of the minor allele rs4673 (c.214C &gt; T CYBA) was 0.38, the frequency of genotypes C/C was 0.4, C/T - 0.43, and T/T - 0.17. The risk of AMC increased by 6.49 times in the presence of the rs4673 polymorphic allele (p = 0.002). The area under the ROC curve of the test based on rs4673 genotyping was 71.9%. The concentration of PON1 after the 4 courses of chemotherapy increased by 19.57% in the group of patients without cardiotoxic manifestations (p = 0.018) and in the group of patients with AMC by 20.23% (p = 0.007) as compared to the initial level. Besides, after 4 courses of chemotherapy the PON1 level was higher in patients with AMC by 25.08% (p = 0.026) than in patients without cardiovascular complications. The sensitivity of the test based on the measurement of the PON1 level in the blood plasma after 4 courses of chemotherapy was 100%, the specificity was 70.8% with a cut-off value of 2.9 ng/ml. Conclusions: This study has showed that genotyping of patients for the rs4673 polymorphism allows pre-stratification of the risk group white determination of the PON1 level in blood plasma after 4 courses of chemotherapy gives the opportunity to identify patients with AMC and promptly correct the chosen treatment.

Timely diagnosis of community-acquired pneumonia (CAP) and optimal timing of initiation of antibiotic therapy are important for reducing mortality in patients with HIV infection. It is reported that the assessment of procalcitonin (PCT) levels in this category of patients can be a useful diagnostic tool. Aim. To determine the levels of a new semi-quantitative rapid test (RT) for PCT in patients with CAP depending on the presence or absence of HIV infection. Design. Cross-sectional comparative study. Material and methods. The study involved 123 patients hospitalized with a diagnosis of CAP. 15 (12.2%) patients, including 10 (66.7%) men and 5 (33.3%) women (average age 59.3 ± 22.4 years), were diagnosed with HIV infection 3th stage. The comparison group included 108 people (48 (44.4%) men and 60 (55.6%) women, average age 48.1 ± 20.5 years) who did not have HIV infection. Before starting antibacterial therapy, all patients underwent a general clinical examination, the concentration of PCT in plasma was determined quantitatively using the enzyme-linked immunosorbent assay, as well as using a new semi-quantitative ET method using a one-step immunochromatographic analysis. Results. In the group of patients with CAP without HIV infection, borderline values of PCT ET (0.5 to &lt; 2 ng/ml) were encountered 3.3 times more often than in patients with concomitant HIV infection (0.5 to &lt; 2 ng/ml) — 22.2% versus 6.7 %; p = 0.030. High levels of PCT ET (from 2 to &lt;10 ng/ml) were 7 times more likely to be detected in patients with CAP and HIV infection than without it - 13.3% versus 1.9%; p = 0.030. The quantitative content of PCT in the blood was also 4.5 times higher in patients with CAP in the presence of HIV infection (0.49 [0.11; 0.76] and 0.11 [0.01; 0.52] ng/ml; p = 0.038) relative to the comparison group. In the group of patients with CAP and HIV infection, a positive correlation was established between PCT RT and the degree of respiratory failure (r = 0.656; p = 0.008) and quantitative PCT (r = 0,453; р = 0,048), test negative correlations with the content of platelets (r = –0.542; p = 0.037), sodium (r = –0.700; p = 0.016 ) and saturation level (r = 0.335; p = 0.022). Conclusion. Patients with CAP and HIV infection in comparison with persons without HIV infection are characterized by higher PCT values determined by both classical quantitative and new semi-quantitative RT, which makes it possible to use the latter for rapid diagnosis of CAP in this group of patients. Key words: community-acquired pneumonia, HIV infection, diagnostics, procalcitonin, procalcitonin rapid test

Influence of Prophylactic Platelet Transfusions on the Recovery of Bone Marrow Function After Intensive Chemotherapy for Acute Myeloid Leukemia.