Genetic disorders in primary brain glioblastomas.

Glioblastomas are characterized by a variety of genetic and epigenetic disorders, identification of which allows constantly expanding a list of genes directly involved in carcinogenesis, thus increasing molecular diagnostics, monitoring and predicting disease. Molecular-genetic studies of patients with glioblastomas allowed revealing changes relevant to this disease and determining their prognostic significance. In the future molecular-biological markers along with clinical and therapeutic factors may play a role of separate and independent factors of prognosis in patients with malignant brain lesions.

[Results of surgical and combined treatment for nonsmall cell lung cancer with postoperative radiation therapy in a mode of hypofranctionation. Post II. Relapse-free survival and survival without locoregional recurrence].

Conducting postoperative radiotherapy in a mode of hypofranctionation with SFD-3Gy to TFD-36-39Gy (EQD2 = 43,246,8Gy) in combined treatment of patients with non-small cell lung cancer allows significantly increasing a 5-year disease-free survival at IIB-IIIB stages of the disease (pN1-2) as well as the central cancer, squamous cell morphological type of tumor after surgery in a volume of lob-bilobectomy. The clearest effect of postoperative radiotherapy is assessed by survival without locoregional recurrence where radiation therapy in the adjuvant setting allows achieving a statistically significant increase in local control of the disease to the level of 85-95% regardless of stage of the disease, tumor size, regional lymph nodes lesion and the surgical treatment.

[Results of combined and complex treatment for indolent and aggressive non-Hodgkin lymphoma of the stomach].

There were retrospectively assessed long-term outcomes of 125 patients with primary non-Hodgkin's lymphoma of the stomach (indolent--50, aggressive--75) using different programs of combined and complex treatment. The immediate results of the treatment in the group of indolent lymphomas were: complete remission 39 (78%), partial remission 7 (14%), the stabilization 3 (6%), progression 1 (2%) while in the group of aggressive lymphomas: complete remission 56 (74.7%), partial remission 8 (10.7%), without effect 3 (4%) and progression 8 (10.7%). It was revealed that primary indolent lymphomas of the stomach the efficiency of complex treatment is comparable to the efficiency of local methods of treatment (surgery, radiotherapy or its combination). The combination of chemotherapy and local methods of treatment gave better results compared with chemotherapy (a 5-year overall survival is 100% and 72% respectively). In the group of aggressive lymphomas the best rates in all types of survival were demonstrated by the subgroup of complex treatment as compared with the subgroup of local methods of treatment especially in terms of overall survival (100% and 65% respectively), and as compared with the subgroup where only chemotherapy was conducted, particularly in terms of disease-free survival (100% and 40% respectively). As an adjuvant therapy after surgical treatment it was preferable to use chemotherapy because such treatment program demonstrated the best rates of overall survival, which reached 92% on a 5-year and a 10-year milestone.

[Middle fraction radiotherapy for non-small cell lung cancer. Effect of increasing the total focal dose].

There were evaluated retrospectively the immediate and long-term results of radiotherapy in 259 patients with non-small cell lung cancer stages I-IV who had contraindications to surgery. Irradiation was carried out by middle fraction with single focal dose 3-4 Gr. We compared the results of treatment in two groups of patients differed in volume of total focal dose: I group (124 patients)--45 Gy, II group (125 patients)--60 Gy. An increase of total focal dose from 45 Gy to 60 Gy did not lead to an increase of the toxicity to vital organs including patients older than 60 years and patients with initially poorer somatic status. Disease-free survival significantly increased in total in the group with total focal dose 60 Gy and predominantly in tumors over 5 cm, in patients with ECOG 2-3 and in III-IV stage disease. An increase of total focal dose to 60 Gy in the group was significantly prolonged survival without local recurrences from 37% to 50% and by one-third reduced the frequency of locoregional recurrences. Identified benefits in overall and disease-specific survival the groups of non-small cell lung cancer patients with total focal dose 60 Gy compared with a group of non-small cell lung cancer patients who received radiotherapy in total focal dose 45 Gy at terms more than 5 years did not reach statistical significance.

[Quality of life and socio-medical consequences in adolescent and young adult survivors following treatment for Hodgkin's lymphoma].

Between 1997 and 2008, 97 adolescents and young adults with a median age 18.9 years (range, 15.0-33.6) with all stages Hodgkin's lymphoma (HL) were treated by a pediatric protocol DAL-HD-90m. The 12-year event-free survival and overall survival was 73.4 ± 4.8% and 81.5 ± 4.7% respec- tively. The frequency of secondary malignancies was 2.1%. In the study of quality of life (QOL), 47 patients were included with duration of complete remission at least 5 years who had no relapses and other adverse events. The median age of the patients at the time of testing was 28.0 years (range, 23.2- 41.0). Reference values of age-adjusted 85 healthy volunteers were used for comparison. The QOL was measured through the questionnaire EORTC QLQ-C30. In total, the QOL of survivors was comparable to that of our control and reference values of EORTC. The only factor that influenced the QOL of long-term survivors was the presence or absence of their children. Among patients who did not have their own children was increased activity of the fatigue (+14.4 points; p = 0.035), insomnia (+25; p = 0.003) and anorexia (+16.7; p = 0.009). The deficit on the overall QOL score was -14.6 points (p = 0.005).

[Results of surgical and combined treatment for non-small cell lung cancer with postoperative hypofractionated radiotherapy: overall and disease-specific survival].

Compared with surgical treatment the combined treatment of patients with non-small cell lung cancer accompanied by post-operative radiotherapy in the mode of hypofractionation from 3 Gy to SOD-36-39 Gy (EQD2 = 43,2-46,8 Gy) allowed statistically significant increasing a 5- and 10-year overall and disease-specific survival in patients with metastases to regional lymph nodes (pN1-2). The increase of overall and disease-specific survival was also observed in patients older than 60 years with the worst initial status (70-80 by the Karnofsky scale), II stage of disease, peripheral cancer and adenocarcinoma however for these groups survival differences did not reach a statistically significant level. The presented method of postoperative irradiation did not have severe toxicity and did not lead to a decrease in survival of elderly and functionally debilitated patients.

[Economic and logistical problems of radiation oncology].

An analysis of economic and logistical problems of radiation oncology is presented based on domestic and foreign literature. Despite the high efficacy of radiotherapy this branch of oncology is not financed enough in most countries. As a consequence, it is ubiquitously marked radiotherapy capacity deficit that does not allow to fully realize its therapeutic potential. Medical electron accelerators and related equipment have become increasingly complex and expensive and radiotherapy techniques more consuming. Even in developed countries growing waiting times for radiotherapy, not using the most modern and efficient radiotherapy technologies (image guiding, etc.) has become a daily reality. Based on these data, we assessed the prospects and possibilities of upgrading the technical base of radiation oncology in Russia including the development of hadron therapy.

[The optimal total focal radiotherapy dosage after first-line chemotherapy in patients with Hodgkin lymphoma].

Based on the treatment results of 300 Hodgkin lymphoma patients the authors formulated the basic approaches for radiation treatment in ABVD and BEACOPP-21 chemotherapy regimens recipients. In patients with complete response to chemotherapy any dose regimen (26 to 44 Gr) leads to 100% local disease control. In patients with major response to chemotherapy (PR> or =80%) the 36 Gr total focal dose allows an adequate local control, more intensive local control doesn't yield better results. In patients with PR 0-79% the implication of total focal doses less than 40 Gr leads to statistically significant increase of nodal relapse rate. These treatment approaches may be implied by specialists conducting chemotherapy and radiation therapy in Hodgkin lymphoma patients.

[The optimal radiation volume after first-line chemotherapy in Hodgkin lymphoma].

Radiation therapy has evolved from extended-field radiation therapy (EFRT) to involved-field radiation therapy (IFRT), reducing toxicity while maintaining high cure rates. Recent publications recommend a further reduction to involved-nodal radiation therapy (INRT); however, this has not been clinically validated. The need for irradiation or optimal radiation volume after chemotherapy are not defined. The treatment results of 296 Hodgkin's disease patients receiving ABVD or BEACOPP-21 chemotherapy with consequent EFRT demonstrate CR/PR > or = 80% and 99% local disease control rate. Beam therapy with EFRT is possible to use if dose levels don't exceed 30 Gy. Higher doses demands reduction of volume of radiating target. In our opinion the optimum program of beam therapy involves 2 stages with maximal possible dose level EFRT followed by additional INRT. Those approaches offer perspectives for Hodgkin's disease treatment.

[Role of response to first-line chemotherapy and of the primary lesion in Hodgkin lymphoma].

Based on the results of combined treatment with inclusion of ABVD and BEACOPP-21 chemotherapy regimens the basic principles of therapy depending on the nodal relaps criterium were developed. The most rational approach to treatment results evaluation concerns the lesions with the least response to chemotherapy. The groups of "adequate" and "inadequate" response to chemotherapy should be formed. The initial lesion localisation doesn't play an important part in the modern chemotherapy settings and should not be concerned while choosing tactics of radiation therapy. The method described should interest oncologists and radiologists involved in the treatment of Hodgkin lymphoma.

[Risk factors for hematologic toxicity and multifaceted analysis of blood in Hodgkin's disease: a model for hematologic toxicity].

Basic hematological features of CEA/ABVD medication for Hodgkin's disease were studied. An effective model was worked out on the principle of data discrimination for predicting different leukocytic toxicities induced by cytostatics-1 administration, once in two weeks. It might predict individual limits (dosage and intervals) of a chemotherapy course unless a colony-stimulation technique is used.

[The role of adjuvant radiotherapy in the complex treatment of stage III-IV aggressive non-Hodgkin's lymphoma].

Immediate and end results of chemoradiotherapy of 225 patients (average age--43 years) with primary aggressive non-Hodgkin's lymphomas stage III-IV were evaluated. Stage 1 of treatment included 4-8 cycles of chemotherapy (ACOP and other standard protocols); stage 2--irradiation of residual foci with 20-50 Gy, or 20-36 Gy for originally extensive and extralymphatic foci when in full remission. The latter's rate rose from 24 to 65% (p < or = 0.05) following adjuvant radiotherapy although that of failures remained unchanged. The disease is specific, so relapse-free survival in cases of generalized primary aggressive lymphoma in full remission remained unchanged too whatever the stage at which full remission emerged.

[Multivariate analysis of risk of cardiac complications in Hodgkin's lymphoma].

A computer database was created to take care of a wide range of protocols for combined treatment of Hodgkin's disease stage I-IV (n=1,573). Early-onset radiation-related injuries (pneumonitis) and exposure of lung tissues to radiation were identified as the main risk factors for cardiopathology development. It is suggested that total focal dosage used after chemotherapy be reviewed since total dosage for the entire lymph collector in excess of 30 Gy might contribute to hazards of cardiopathology. However, a locally administered TTD ranging 36-44 Gy to deal with residual tumor offers best advantage in preventing local relapse. Nor does it increase the risk of future complications. Our approach might promote individualization of prognosis as far as cardiac complications involved in Hodgkin's lymphoma are concerned.

[The glucagon test in diagnosis of secondary adrenal insufficiency after craniospinal irradiation: the feasibility of application, the features of performing the test, and its diagnostic informativity].

BACKGROUND: The glucagon test (GT) is a promising alternative to the insulin hypoglycemia test (IHT) in diagnosis of secondary adrenal insufficiency (SAI). AIM: To study the feasibility of using the GT in patients after craniospinal irradiation and to determine the cut-off value to rule out SAI. METHODS: A total of 28 patients (14 males and 14 females) with the median age of 19 years (17; 23) who had undergone combination treatment (surgery, craniospinal irradiation (35 Gy) with boost to the tumor bed, and polychemotherapy) of extrapituitary brain tumors no later than 2 years before study initiation and 10 healthy volunteers of matching sex and age were examined. All the subjects underwent the GT and IHT with an interval of at least 57 days. The cortisol, ACTH, and glucose levels were measured. RESULTS: Twelve out of 28 patients were diagnosed with SAI according to the IHT results. ROC analysis revealed that cortisol release during the GT 499 nmol/L ruled out SAI [100% sensitivity (Se); 62% specificity (Sp)], while the absence of a rise 340 nmol/l verified SAI (Sp 100%; 55% Se). For GT, the area under a curve (AUC) was 93.6%, which corresponds to a very good diagnostic informativity. In 19 patients, the IHT and GT results were concordant (in ten patients, the release of cortisol occurred above the cut-off value in both tests; no release was detected in nine patients). In nine cases, the results were discordant: the maximum cortisol level detected in the GT was 500 nmol/l, but the IHT results ruled out SAI (the GT yielded a false positive outcome). Contrariwise, in three (10.7%) patients the release of cortisol detected in the GT was adequate, while being insufficient in the IHT test. Adverse events (nausea) were reported during the GT test in 9 (25%) subjects; one patient had hypoglycemia (1.8 mmol/l). CONCLUSION: GT is highly informative and can be used as a first-level stimulation test for ruling out SAI in patients exposed to craniospinal irradiation performed to manage brain tumors. The cortisol level of 500 nmol/L is the best cut-off value for ruling out SAI according to the GT results. The insulin hypoglycemia test is used as the second-level supporting test in patients with positive GT results.

[Clinical features and diagnosis of secondary adrenal insufficiency followed complex treatment nonpituitary brain tumors].

BACKGROUND: The most of the current studies include patients who are different by the etiology of secondary adrenal insufficiency (SAI), or investigate SAI among other late effects of the radiation therapy. AIMS: To describe the features of SAI and to select the best method of screening SAI in adult patients followed complex treatment of nonpituitary brain tumors in childhood. MATERIALS AND METHODS: It was the retrospective cross-sectional study. 31 patients after the complex treatment of nonpituitary brain tumors in childhood and 20 healthy volunteers were examined. Age and sex ratio were comparable between the groups. Biochemical and clinical blood tests, levels of cortisol, ACTH, DHEA-C were evaluated. The insulin tolerance test (ITT) was performed for all patients and 11 volunteers. RESULTS: The prevalence of SAI by ITT was 45.2%. The levels of basal cortisol (BC) were significantly higher in patients without SAI in comparison with the SAI group and volunteers (505 [340; 650] vs 323 [233; 382] and 372 [263; 489] nmol / l; pSAI- without_SAI=0.001; pwihtout_SAI-healthy = 0.04). The SAI group had DHEA-C significantly lower than in other groups one (3.1 [1.8; 3.4] vs 5.1 [2.5; 6.4] and 6.8 [4.1; 8.9]; рSAI- without_SAI = 0.036; pSAI-healthy = 0.001). ROC analysis showed that BC and DHEA-S can be used as high-quality screening tests for SAI (AUC = 89.3% and 88.3%). The maximum level of cortisol (656 [608-686] vs 634 [548-677]; p = 1) and the time of its increase (45 and 60 min) did not differ during ITT in patients without SAI and volunteers. Side effects: delayed hypoglycemia occurred in 4/14 patients of the SAI group 4090 minutes late of injection 60-80 ml of 40% glucose solution for stopping hypoglycemia in the test. CONCLUSIONS: 45.2% of patients followed craniospinal irradiation had SAI that is characterized by a decrease in DHEA-C levels. A highly normal level of basal cortisol was observed in 45% of patients without SAI. DHEA-C and blood cortisol can be used for SAI screening.

[Prognostic models for Hodgkin's disease].

A prognostic model for Hodgkin's disease was worked out using the data on disease-free survival among patients receiving 4-8 courses of COOP(MOPP)/ABVD plus (sub)total irradiation. Patients with stage I-II Hodgkin's disease (less then 4 lesions) without large involved mediastinal masses, intoxication symptoms and focal splenic involvement were referred to the favorable prognosis group. The poor prognosis group featured stage III(2)-IV tumor as well as large masses of involved mediastinal tissue, focal splenic involvement at any stage plus 7 or more lesions. An assessment of tumor advancement across lesions is more significant for radiotherapy planning rather than that of organ involvement. It is reasonable to distinguish two substages--III(1) and III(2). Our model was compared with GHSG and it was suggested that ways be found to use both of them in prognosing of disease outcome.

[Five-year outcome of a new combination chemotherapy with CEA/ABVD for advanced Hodgkin's disease with poor prognosis].

Data are presented on our 5-year experience with combination chemotherapy of stage II-IV Hodgkin's disease (110), the unfavorable prognosis group, using a novel regimen of chemotherapy--CEA/ABVD (belustin, etoposide, doxorubicin, bleomycin, vinblastine, dacarbazine). Complete remission after 4 courses of CEA/ABVD chemotherapy was reported in 31.8%, unconfirmed complete remission--45.5%, objective effect--100% and an 80% regression of tumor mass--93.2%. No chemo-resistant forms were identified. Five-year actuarial relapse-free survival was 96.4%; overall 5-year survival--97.7%. Death from complications recorded during medication period occurred in 2.3% (1 out of 44), recurrence--2.3% (1 out of 44). Recurrence-free survival rose by 25% (p < 0.05) while overall survival--by 20% (p = 0.04 in year 3), as compared with COOP(MOPP)/ABVD (179 patients with poor prognosis). Our regimen opens up new vistas in managing Hodgkin's disease.

[Ten-year outcomes of lymphogranulomatosis treatment according to the protocol MOPP-ABVD+radiotherapy].

AIM: To analyse overall recurrence-free survival of lymphogranulomatosis (LGM) patients given polychemotherapy (PCT) MOPP (mustargen-caryolisin, vincristine, natulan, prednisolone) - ABVD (adriamycin, bleomycin, vinblastin, dacarbasin) in combination with radiotherapy (RT) for 10 years. MATERIAL AND METHODS: The trial included 211 LGM patients admitted to Hematological Research Center in 1990-1996 from other hospitals without random selection. The patients were examined by the standard program including biopsy of the affected organ or lymph node, bilateral trephine biopsy. Splenectomy was performed in 17 patients, 83 patients received PCT in other hospitals, 128 untreated patients received MOPP-ABVD therapy (3 courses of MOPP and 3 courses of ABVD). Forty one patients had defects in PCT, 16 of them rejected PCT and RT. The latter was performed 4 weeks after the 6th course, contraceptives were not prescribed to women. At LGM stage II-III RT was performed by the subradical program (no radiation to ilioinguinal lymph nodes) in doses 40-44 Gy on the foci and 32-36 Gy preventively, on massive and residual foci after PCT - 5-10 Gy additionally. RESULTS: Ten-year overall and recurrence-free survival in the untreated group reached 83 and 80%, respectively, for pretreated patients - 46 and 36%, respectively. Causes of death of 26 patients were LGM progression, infection (tuberculosis, as a rule), secondary tumors and acute myeloblastic leukemia (AML). After remission 25 women gave birth to a healthy child and 12 healthy children were born to 9 males. CONCLUSION: MOPP-ABVD plus radiotherapy program according to subradical and radical variants was in the past effective but invalidating rescue therapy. Present-day programs consider the histological variant, stage and prognostic factors allowing an individual therapeutic approach with step-by-step reduction of RT in the treatment of LGM patients. Involvement of the bone marrow in primary patients had no influence on the treatment results. This refers this affection not to a generalized stage IV, but to stage III along with involvement of the lymph nodes and the spleen.

[Novel approaches to combination therapy of Hodgkin's disease].

Data on 668 patients receiving 4-8 cycles of chemotherapy were used to suggest the following approach to complex therapy of Hodgkin's disease: devise a simplified model for Hodgkin's disease, develop a new modality of chemotherapy, demonstrate feasibility of only four chemotherapy cycles in the poor prognosis group, partial response as the ultimate goal of chemotherapy as well as the importance of subtotal dosage under 26-36 Gy sufficient for irradiation of the entire lymphatic collector. Said measures will, in their totality, offer fresh opportunities in treatment of Hodgkin's disease.

[Current problems of postoperative radiotherapy for non-small cell lung cancer].

The review considers the history of evolution and the present state of the problem of postoperative radiotherapy for non-small cell lung cancer. The randomized trials and meta-analyses given in recent publications provide evidence that it should be used in radically operated patients with morphologically verified regional metastases. The paper also shows promises of hypofractionation and a postoperative radiation/chemotherapy ratio for non-small cell lung cancer.