Aberrant IKZF1 gene as relapse predictor in standard-risk pediatric patients with B-cell precursor acute lymphoblastic leukaemia.

INTRODUCTION: Worldwide, the B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) treatment protocols are based on risk-adaptive therapy, that is on the search for biological markers for stratification by risk groups for optimal management. Depending on the treatment protocol, deletions and overexpression of non-functional IKZF1 isoforms act as relapse predictors in ALL. We investigated the IKZF1 gene aberrations as the substantive marker for predicting the development of relapse or adverse events when using risk stratification from ALL-MB-2002/2008 protocols. METHODS: We retrospectively analysed the bone marrow samples collected from 202 newly diagnosed patients with BCP-ALL harbouring IKZF1 aberrations. RESULTS: In patients of intermediate- and high-risk the presence of IKZF1 aberrations contributed to the delayed clearance of blast cells on the 15th and 36th day of induction therapy, but there was not a significant effect on relapse rate. The comparative analysis demonstrated that standard-risk patients with IKZF1 aberrations have a much higher 5-years cumulative incidence of relapse (66.7 ± 22.7% vs. 11.6 ± 2.9% in the group with normal gene status, p < 0.001) in contrast to intermediate- and high-risk groups. In the competing risk model of relapse, IKZF1 aberrations determine a high risk of relapse only in standard-risk patients (p = 0.025), and it was not significant for patients of other risk groups (p = 0.284 for intermediate, and 0.408 for high-risk groups). CONCLUSION: Our findings support that IKZF1 aberrations are a crucial relapse predictor in standard-risk patients with BCP-ALL, who practically have no significant markers to assess the prognosis during the primary diagnosis.

Comparative pathological characteristics of papillary thyroid carcinoma with second primary non-thyroid malignancies in the region affected by the Chernobyl accident.

The aim was to study the pathological features of papillary thyroid carcinoma diagnosed with or before second primary malignancy in patients exposed to post-Chernobyl exposure. The patients selected (n = 6559) were those exposed to radiation at the age of ≤ 18 years old and developed papillary thyroid carcinoma during the years 1990-2020. Of these, 2.1% (n = 140) had second primary malignancies. To compare the histopathological characteristics of papillary thyroid carcinoma in the group under analysis, 91% (n = 128) with sufficient data were included in further analysis. The control group was formed by matching patients with age at exposure to radiation, age at surgery, gender, and place of residence. Median age at exposure was 14 years old for both groups. Besides, no difference in tumour extension and histological features of papillary thyroid carcinoma was noted between patients with synchronous or metachronous primary malignant tumours. Nevertheless, the time lag to the diagnosis of papillary thyroid carcinoma was shortened in the group with metachronous when compared to patients with synchronous second primaries (p < 0.001). Independent differences between patients with second primaries and their matched peers included tumour size {OR (95%CI) = 0.89 (0.45; 1.04)}, multiple tumours {OR (95% CI) = 1.46 (0.86; 2.42)}, lymphatic vessel invasion (OR (95%CI) 0.92 (0.61; 1.53)), blood vessel invasion (OR (95%CI) 0.41 (0.10; 1.23) and presence of numerous psammomas (OR (95%CI) 0.73 (0.39; 1.31)). The possible influence of radiative iodine treatment for development of second primaries was analysed for the group of patients with metachronous malignancies using the same approach (84 patients were compared to 252 matched patients). Independent differences also included tumour size {OR (95% CI) 0.77 (0.45; 1.30)}, lymphatic vessel invasion {OR (95%CI) 0.75(0.43; 1.28)}, blood vessel invasion {OR (95%CI) 0.17 (0.01; 0.87)}. Besides, multiple tumours were revealed more frequently in patients with metachronous primaries (OR (95%CI) 1.92 (1.0; 3.62)). To conclude, patients exposed to Chernobyl irradiation with the development of papillary thyroid carcinoma and second primary malignancy have less biological aggressive pathological characteristics of their thyroid cancers. Accordingly, these patients were less frequently treated with post-surgical radioactive iodine. Thus, 131I-irradiation may have negligible impact on the development of second primaries.

Clinical benefits of single vs repeated courses of mesenchymal stem cell therapy in epilepsy patients.

PURPOSE: Epilepsy is defined as "drug-resistant" when existing anti-epileptic drugs (AED) are found to have minimal to no effect on patient's condition. Therefore the search and testing of new treatment strategies is warranted. This study focuses on the effects of autologous mesenchymal stem cells (MSC) in drug-resistant epilepsy patients within a Phase I/II open-label registered clinical trial NCT02497443. MATERIALS/METHODS: A total of 67 patients was included (29 males, 38 females, mean age 33 ± 1.3 yo). The patients received either standard treatment with AEDs, or AEDs supplemented with one or two courses of therapy with autologous bone marrow-derived MSCs expanded in vitro. MSC therapy courses were 6 months apart, and each course consisted of two cell injections: an intravenous infusion of MSCs, followed within 1 week by an intrathecal injection. Primary outcome of the study was safety, secondary outcome was efficacy in terms of seizure frequency reduction and response to treatment. RESULTS: MSC injections proved safe and did not cause any severe side effects. In MSC group (n = 34), 61.7% patients responded to therapy at 6 months timepoint (p < 0.01 vs control, n = 33), and the number rose to 76.5% by 12 months timepoint. Decrease in anxiety and depression scores and paroxysmal epileptiform activity was observed in MSC group based on HADS and EEG, respectively, and MMSE score has also improved. Another observation was that concomitant administration of levetiracetam, but not other AEDs, correlated significantly with the success of MSC therapy. Second course of MSC therapy facilitated further reduction in seizure count and epileptiform EEG activity (p < 0.05 vs single course). CONCLUSIONS: Application of autologous mesenchymal stem cell-based therapy in patients with pharmacoresistant epilepsy demonstrated significant anticonvulsant potential. This effect lasted for at least 1 year, with repeated administration of MSCs conveying additional clinical benefit.

Hyperthermic intraperitoneal chemotherapy in prevention of gastric cancer metachronous peritoneal metastases: a systematic review.

Gastric cancer progression resulting in metachronous peritoneal metastasizing is almost always associated with an adverse prognosis. This review discusses various options of preventing metachronous peritoneal metastases in radically operated gastric cancer patients. Also examined are different hyperthermic intraperitoneal chemotherapy (HIPEC) regimens employed in gastric cancer treatment, postoperative morbidity and mortality rates and long-term treatment outcomes. The authors also review their own experience of using HIPEC based on the combination of cisplatin and doxorubicin in doses of 50 mg/m2 at 42 °C for 1 h to prevent gastric cancer peritoneal dissemination. As a result, progression-free survival rose from 19.6%±5.6% to 47.1%±6.3% (Plog-rank <0.001) and dissemination-free survival-from 22.7%±6.0% to 51.9%±6.3% (Plog-rank <0.001). It is noted that the combination of the described HIPEC regimen with systemic chemotherapy helped raise metastases-free 3-year survival rate to up to 91.0%±9.0% (Plog-rank =0.025) compared with 48.6%±6.4% for patients who underwent only a combined surgery/HIPEC treatment. HIPEC is a promising combined treatment strategy for radically operated gastric cancer patients that can improve patient survival and decrease peritoneal dissemination rate. However, the number of randomized studies on adjuvant HIPEC are still insufficient for a subgroup assessment of efficacy of the given chemotherapy regimens and generation of evidence-based recommendations on the individual use of chemotherapy agents and their combinations, and HIPEC procedural techniques. Further prospective randomized studies are needed to assess the practicability of complementing HIPEC with adjuvant systemic chemotherapies.

Second primary malignancies in patients with papillary thyroid carcinoma after effect of post-chernobyl irradiation: A risk analysis of more than two decades of observations.

BACKGROUND: Second primary malignancy in patients with papillary thyroid carcinoma after Chernobyl accident is an emerging problem. The aims of the study are to investigate the rates and distribution of second primary malignant tumours in Belarus survivors of post-Chernobyl papillary thyroid carcinoma and the cumulative rate of developing a second primary malignancy in a group of patients with metachronous second primaries. METHODS: Patients aged 18 or younger at the time of Chernobyl accident who were diagnosed with papillary thyroid carcinoma after 1986 were identified from the Belarus Cancer Registry. The clinical and demographic of these patients were analysed to correlate with the factors for the development of secondary primary cancer. RESULTS: Secondary primary cancer was detected in 1.8 % (119 of 6559) of the patients with papillary thyroid carcinoma. The cumulative incidence tended to rise with increasing age of the cohort and varied depending on the sex of patients. In female patients, breast carcinoma and genital tract carcinomas prevailed, in men patients - lymphoma/ leukaemia and the alimentary tract malignancies predominated. A significant excess risk was revealed for breast carcinoma in females, colon carcinoma in males, and the urinary system carcinomas in males (absolute excess risk [AER] = 3.23, 3.01 and 2.17 correspondingly). Overall, our results pointed to the increased risk of new solid primaries in females, males and both genders (AER = 3.31, 7.19, 4.28 correspondingly) as well as increase risk of lymphoid/hematopoietic malignancies in females and both genders (AER = 1.24) and leukaemia in male patients (AER = 1.45). CONCLUSION: Patients with papillary thyroid carcinoma after Chernobyl accident are at risk of secondary primary malignancy. Awareness and screening of secondary cancer is needed for patients with papillary thyroid carcinoma after Chernobyl accident.

Factors affecting the approaches and complications of surgery in childhood papillary thyroid carcinomas.

BACKGROUND: The aim of the study is to analyse the factors related to permanent surgical complications in children and adolescents with papillary thyroid carcinoma treated by total thyroidectomy with central and bilateral neck dissections. METHODS: Children and adolescents aged ≤18-year-old at presentation with papillary thyroid carcinoma during the years 1988-2010 underwent thyroid and lymph-node surgeries (with a median follow-up of 19.6 years) were analysed for post-surgical complications. RESULTS: Permanent surgical morbidity occurred in 14% (n = 70) of patients who underwent total thyroidectomy as well as bilateral central and lateral neck dissections (n = 509). Factors associated with permanent complications included pN1 with extra-nodal extension, > 4 metastatic lymph nodes in the central neck compartment, presence of distant metastases and younger age of patients at surgery. Patients who received extensive surgery had better relapse-free survival rates (p < 0.001). CONCLUSION: Total thyroidectomy and bilateral central as well as lateral neck dissections for children and adolescents with papillary thyroid carcinoma was associated with substantial postoperative complications. Nevertheless, it is associated with better prognosis for young patients with thyroid cancer. Prophylactic compartment-oriented lymph node dissections to these patients could be the management protocol in experienced hands.

Optimizing treatment for children and adolescents with papillary thyroid carcinoma in post-Chernobyl exposed region: The roles of lymph node dissections in the central and lateral neck compartments.

There is lack of data to predict lymph node metastases in pediatric thyroid cancer. The aims are to study (1) the factors affecting the lymph node metastases in children and adolescence with papillary thyroid carcinoma in region exposed to radiation and (2) to evaluate the predictive significance of these factors for lateral compartment lymphadenectomy. Five hundred and nine patients with papillary thyroid carcinoma underwent total thyroidectomy and lymph nodes resection (central and lateral compartments of the neck) surgery during the period of 1991-2010 in Belarus were recruited. The factors related to lymph node metastases were studied in these patients. In the patients with papillary thyroid carcinoma, increase number of cancer-positive lymph nodes in the central neck compartment were associated with a risk to develop lateral nodal disease as well as bilateral nodal disease. Futhermore, positive lateral compartment nodal metastases are associated with age and gender of the patients, tumour size, minimal extra-thyroidal extension, solid architectonic, extensive desmoplasia in carcinoma, presence of psammoma bodies, extensive involvement of the thyroid and metastatic ratio index revealed after examination of the central cervical chain lymph nodes. The presence of nodal disease, degree of lymph node involvement and the distribution of lymph node metastases significantly increase the recurrence rates of patients with papillary thyroid carcinoma. To conclude, the lymph nodes metastases in young patients with papillary thyroid carcinoma in post-Chernobyl exposed region are common and the pattern could be predicted by many clinical and pathological factors.

Association of TNF-α and CCL5 with response to interferon-based therapy in patients with HCV 1 genotype.

AIM OF THE STUDY: To evaluate the role of potential genetic predictors -308G/A TNF-α and -403G/A CCL5 in treatment for HCV 1 genotype. MATERIAL AND METHODS: Treatment results of 130 patients with chronic hepatitis C 1 genotype according to different genotypes of IL28B, CCL5, and TNF-α were analysed using multiple logistic regression. RESULTS: IL28B genotypes CC/CT/TT were found in 27 (20.8%), 74 (56.9%), and 29 (22.3%) patients. Genotypes GG/GA/AA of -308G/A TNF-α were revealed in 98 (75.4%), 30 (23.1%), and 2 (1.5%) patients. Genotypes GG/GA/AA of -403G/A CCL5 were revealed in 86 (66.2%), 39 (30%), and 5 (3.8%) patients, respectively. The previously known effect of IL28B was observed. IL28B TT genotype decreased end of treatment response (EOTR) rates by a factor of 29.0 (95% CI: 6.4-183). The combination of CCL5 GG and IL28B CT genotypes increased the risk of failure to achieve EOTR by a factor of 28.5 (95% CI: 7.2-160). Genotypes GA and AA of TNF-α (-308) G/A SNP increased the risk of relapse in patients who achieved EOTR (OR = 9.4; 95% CI: 2.4-48). CONCLUSIONS: Practitioners may benefit from using these predictors when considering indications for the antiviral therapy and deciding on the treatment regimen.

Characteristics of young adults of Belarus with post-Chernobyl papillary thyroid carcinoma: a long-term follow-up of patients with early exposure to radiation at the 30th anniversary of the accident.

OBJECTIVES: Studies of thyroid cancer related to the Chernobyl accident have focused on children as they are the most vulnerable group with the highest risk of developing radiation-associated cancer. In contrast, our research aimed to look at the clinical and pathological features of patients with post-Chernobyl papillary thyroid carcinoma that were 2 years old or less at the time of the Chernobyl accident. DESIGN: The study subjects were patients (n = 359) aged 0 to 2 at the time of the Chernobyl accident and aged ≥19 years at presentation/surgery who were treated in Belarus for papillary thyroid carcinoma during the period 2003-2013. RESULTS: In conventional or oncocytic variant of papillary thyroid carcinoma, the prevalence of extra-thyroidal extension, nodal disease, infiltrative growth or lymphatic vessel invasion was above 50%. These features were less pronounced when compared to tall cell or diffuse sclerosing variants of papillary thyroid carcinoma. The highest frequency of central lymph node metastases was found in patients aged 1-2 years at exposure (P = 0·004). Subjects exposed in utero were characterized by absent/insignificant lymphocytic infiltration around the carcinoma (P = 0·025), predominance of conventional papillary architecture and an association with lymphocytic thyroiditis. CONCLUSIONS: A number of features were associated with this group of patients that were very young at the time of radiation exposure. In addition, the incidence and basic characteristics of adult papillary thyroid carcinoma varied depending on the types of exposure conditions.

Morphological Changes Induced by Bipolar Radiofrequency Ablation in Thyroid Nodules - a Preclinical Ex Vivo Investigation.

Introduction: Recently, radiofrequency ablation (RFA) has been increasingly used for the treatment of thyroid nodules. However, immediate morphological changes associated with bipolar devices are poorly shown. Aims: To present the results of analysis of gross and microscopic alterations in human thyroid tissue induced by RFA delivered through the application of the original patented device. Materials and methods: In total, there were 37 surgically removed thyroid glands in females aged 32-67 at presentation: 16 nodules were follicular adenoma (labelled as 'parenchymal' solid benign nodules) and adenomatous colloid goitre was represented by 21 cases. The thyroid gland was routinely processed and the nodules were sliced into two parts - one was a subject for histological routine processing according to the principles that universally apply in surgical pathology, the other one was used for the RFA procedure. Results: No significant difference in size reduction between parenchymal and colloid nodules was revealed (p>0.1, t-test) straight after the treatment. In addition, RFA equally effectively induced necrosis in follicular adenoma and adenomatous colloid goitre (p>0.1, analysis of variance test). As expected, tumour size correlated with size reduction (the smaller the size of the nodule, the greater percentage of the nodule volume that was ablated): r=-0.48 (p<0.0001). Conclusion: The results make it possible to move from ex vivo experiments to clinical practice.

Morphological and clinical presentation of papillary thyroid carcinoma in children and adolescents of Belarus: the influence of radiation exposure and the source of irradiation.

OBJECTIVE: The aims were to analyse the features of papillary thyroid carcinoma in a large cohort of children and adolescents in Belarus and to study the influence of radiation exposure as well as the source of irradiation on the morphological and clinical presentations of tumours. DESIGN AND PATIENTS: The clinical and pathological features of 1086 young patients (age range=4 to 18 inclusive, followed up for ≥18years) with papillary thyroid carcinoma diagnosed during the years 1990 to 2010 were reviewed. The patients were divided into three groups: "external radiation-related", "post-Chernobyl" (internal irradiation-related) and "sporadic". Besides, patients from "post-Chernobyl" cohort (n=936) were further divided into the three equal subgroups according to the dates of surgery, which were corresponding to the early (4-9years), intermediate (10-12years) and long (14-18years) latency periods. RESULTS: Patients in the "external radiation-related" group often showed extra-thyroidal extension in tumours sized ≤10mm (p=0.002). Distant metastases were more frequently (p=0.006) discovered in patients with papillary thyroid carcinoma in post-Chernobyl group (104 of 936, 11.1%) when compared to juveniles from other two groups. Lateral nodal disease and distant metastases were often noted in post-Chernobyl patients operated during the early and intermediate latency periods only. CONCLUSION: Young patients in Belarus with papillary thyroid carcinoma in the "post-Chernobyl" group differed in many clinical and pathological parameters from those in the "sporadic" group. "External radiation related" papillary thyroid carcinomas were distinguished from other two groups of carcinoma in more advanced local spread and more aggressive behaviour of micro-carcinomas.

Initial presentation and late results of treatment of post-Chernobyl papillary thyroid carcinoma in children and adolescents of Belarus.

BACKGROUND: The aim of this population-based study was to evaluate the clinical and pathological characteristics and outcome of papillary thyroid carcinoma (PTC) that have arisen in the Belarusian childhood population exposed to the radioactive fallout from the Chernobyl accident within a long-term period. PATIENTS AND METHODS: The long-term treatment results were investigated in 1078 children and adolescents (<19 years old) with PTC who were surgically treated during the years 1990 through 2005. RESULTS: Patients had high rates of metastatic PTC at presentation, with 73.8% of cases having lymph node involvement and 11.1% having distant spread. The most influential factor for lymph node metastases at initial treatment was lymphatic vessel invasion (P < .0001) and for distant metastases, lateral lymph node involvement (P < .0001). The overall survival was 96.9% ± 0.9% with a median follow-up of 16.21 years, and 20-year event-free survival and relapse-free survival were 87.8% ± 1.6% and 92.3% ± 0.9%, respectively. Patients had significantly lower probability of both loco-regional (P < .001) and distant relapses (P = .005) after total thyroidectomy (TT) and radioactive iodine therapy (RAI). For loco-regional relapses after TT, only RAI influenced the prognosis significantly (P < .001). For distant relapses after TT, the refusal to treat with RAI (hazard ratio [HR] = 9.26), vascular invasion (HR = 8.68), and age at presentation (HR = 6.13) were significant risk factors. For loco-regional relapses after non-TT, the principal risk factors were age less than 15 years old at presentation (HR = 5.34) and multifocal growth of tumor (HR = 5.19). For distant relapses after non-TT, the lateral neck metastases were the only unfavorable factor (HR = 9.26). CONCLUSION: The outcome of PTC both in children and in adolescents exposed to the post-Chernobyl radioiodine fallout was rather favorable. TT with RAI is recommended for minimizing loco-regional or distant relapses.

Clinical and pathologic features of "sporadic" papillary thyroid carcinoma registered in the years 2005 to 2008 in children and adolescents of Belarus.

BACKGROUND: A systematic analysis of the clinical and pathologic patterns of childhood "sporadic" thyroid carcinoma in Belarus, in the absence of the "Chernobyl radioactive iodine factor," has never been performed. The aim of this study was to establish the essential features of "sporadic" papillary thyroid carcinoma (PTC) in Belarusian children and adolescents, and the relationship of tumor pathology to extrathyroidal extension (ETE) and lymph node metastases. METHODS: This was a retrospective population-based study with assessment of histological samples of 119 cases of thyroid cancer in Belarusian children and adolescents of 0-18 years old registered during 2005-2008 years. Sporadic PTC was noted in 94 children who were not exposed to the Chernobyl radiation release. None of the 119 cases of thyroid were follicular thyroid cancer. RESULTS: The incidence rate of PTC was 1.13 per 100,000 persons. The median age at diagnosis was 15.1 years with fourfold predominance of diagnosis in female patients. Relapse was detected in 2% of cases with median follow-up of 4.2 years. Median tumor size was 12 mm. Three percent of the cases of PTC had multifocal growth. The classical variant of PTC was registered in 46% of the patients with thyroid cancer, the follicular variant of PTC was noted in 20% of the cases. The percent of rare types of PTC (tall cell and diffuse sclerosing) were equal to that for solid PTCs (13%, 12%, and 10%, respectively). Adolescents had a pure papillary carcinoma more often compared to children who represented tumors with mixed papillary/follicular patterns more frequently (p<0.05). Two-thirds of the patients with PTC had regional lymph node metastases. ETE was established in 39 of 74 patients in whom ETE could be assessed by morphology. Multivariate analysis showed that lymphatic invasion was the strongest independent factor associated with both ETE (p<0.0001) and lymph node metastases (p<0.0001). CONCLUSION: In 2005-2008, sporadic thyroid cancer in children of Belarus was represented by high prevalence of PTC and absence of follicular thyroid cancer. Sporadic cases of PTC in Belarus were characterized by smaller tumor size, a small number of cases with multifocal growth, an equal number of rare types and solid PTCs, a relatively high prevalence of pure papillary variant of PTC in adolescents, and a low frequency of early relapses. A high frequency of ETE and lymph node metastases was detected. The strongest morphologic factor associated with both of them was lymphatic invasion.

Prognostic value of MRD-dynamics in childhood acute lymphoblastic leukemia treated according to the MB-2002/2008 protocols.

Detection of minimal residual disease (MRD) during the treatment of acute lymphoblastic leukemia (ALL) by RQ-PCR analysis of clonal Ig/TCR rearrangements is used for risk group stratification in European treatment protocols. In Belarus patients with childhood ALL are treated according to ALL-MB protocols, which do not use MRD-based risk stratification. To evaluate the prognostic significance of MRD for ALL-MB-2002/2008 protocols, MRD was quantified by RQ-PCR in 68 ALL patients at four time points: on day 15, on day 36, before and after maintenance therapy (MT). MRD positivity, as well as quantitative level of MRD were analyzed and compared between patients who stayed in remission and relapsed. Relapse-free survival revealed to be significantly associated with MRD levels at different time points. Unfavorable prognosis was shown for MRD≥10(-3) on day 36 (p<0.001), and any positive MRD before (p<0.001) and after (p=0.001) MT. Multivariate Cox regression analysis proved MRD as independent significant prognosis factor at day 36 (p=0.005) and before MT (p=0.001). We conclude, that MRD quantified by RQ-PCR in children with ALL treated with ALL-MB protocols is feasible and independently associated with outcome. MRD may be a suitable parameter for treatment stratification in MB protocols in future.