Application of comprehensive molecular genetic profiling in precision cancer medicine, Hungarian experiences.

Recent developments in molecular genetic testing methods (e.g. next-generation sequencing [NGS]-panels) largely accelerated the process of finding the most appropriate targeted therapeutic intervention for cancer patients based on molecularly targetable genetic alterations. In Hungary, a centralized approval system following the recommendation of the National Molecular Tumor Board was launched for the coordination of all aspects of comprehensive genetic profiling (CGP) including patient selection and therapy reimbursement. AIM: The study aims to evaluate the clinical benefit of CGP in our Comprehensive Cancer Center Methods and patients: CGP was introduced into our routine clinical practice in 2021. An NGS-based large (> 500 genes) gene panel was used for cases where molecular genetic testing was approved by the National Molecular Tumor Board. From 2021 until August 2023 163 cases were tested. The majority of them were ECOG 0-1 patients with advanced-stage diseases, histologically rare cancer, or cancers with unknown primary tumours. RESULTS: Seventy-four cases (74 of 163, 45%) had clinically relevant genetic alterations. In 34 patients, the identified variants represented an indication for an approved therapy (approved by the Hungarian authorities, on-label indication), while in 40 cases the recommended therapy did not have an approved indication in Hungary for certain tumour types, but off-label indication could be recommended. Based on our CGP results, 24 patients (24/163; 14.7%) received targeted therapy. Treatment duration was between 1 and 60 months. In total 14 (14/163; 8.5% of the tested cases) patients had a positive clinical response (objective response or stable disease) and were treated for more than 16 weeks. INTERPRETATION: NGS-based CGP was successfully introduced in our institution and a significant number of patients benefited from comprehensive genetic tests. Our preliminary results can serve as the starting point of Drug Rediscovery Protocol (DRUP) studies.

[Long-term experience with multidisciplinary therapy of twenty-six patients with dermatofibrosarcoma protuberans]. / Dermatofibrosarcoma protuberans multidiszciplináris kezelésével szerzett hosszú távú eredmények 26 betegnél.

UNLABELLED: Dermatofibrosarcoma protuberans is a low or moderate grade malignant, uncommon soft tissue tumor. The tumor is characterized by slow, but locally aggressive growth, low metastatic potential and high recurrence rate. Initial treatment is the radical surgical excision, using traditional wide excision or Mohs surgery. In case of positive surgical margin or local recurrence, radio-chemotherapy and recently imatinib mesylate is used as adjuvant therapy. AIMS: Twenty-six patients treated multidisciplinary for dermatofibrosarcoma protuberans were followed up. METHODS AND RESULTS: Mean age of the patients was 44.7 years; mean follow-up time was 60.57 months. In fifteen cases (57.7%) R0 resection was performed, while eleven patients (42,3%) received only R1 resection. An average of 1.87 resections was necessary in order to achieve R0 resection. Six patients (23%) received adjuvant radiotherapy and two patients (7.6%) adjuvant chemotherapy following the removal of the primary tumor. Sixteen patients had no local recurrence. Ongoing treatments were needed in the case of ten patients (38.4%) who developed local recurrence. One patient has deceased due to distant metastases. Using statistical methods we examined the effects indicated as prognostic factors in the literature on local recurrence, precisely, the effect of age above 50 years and surgical radicalism. CONCLUSIONS: Dermatofibrosarcoma protuberans can be successfully treated with multidisciplinary therapy. A larger number of cases and randomized multicenter investigations are needed in order to reach more accurate conclusion.

G72/G30 (DAOA) and juvenile-onset mood disorders.

The chromosome 13q region has been linked to bipolar disorder in a number of genome scans as well as focused linkage studies. Previously we identified linkage to the 13q32 region in a genome scan of 146 affected sibling pair families from Hungary with juvenile-onset mood disorders. Within this region are the overlapping genes G72/G30, with G72 now officially named as D-amino-acid oxidase activator (DAOA). This locus has been associated with panic disorder, schizophrenia, and bipolar disorder. In this study, we tested for association to 11 markers in these genes and mood disorders in a sample of 646 nuclear families identified with a proband with onset of a mood disorder before 14.9 years of age. We identified evidence for association to three markers within the gene (rs2391191, rs3918341, rs1935062), two of which had been associated with bipolar disorder in previous studies. When corrected for the number of markers tested, the results were no longer significant, however the prior evidence for association of this gene in multiple studies points to this gene as a potential contributor to juvenile-onset mood disorders.

Genome scan in sibling pairs with juvenile-onset mood disorders: Evidence for linkage to 13q and Xq.

Mood disorders (bipolar and depressive disorders) in children and adolescents are associated with significant morbidity and mortality. Twin and family studies, for the most part, indicate higher familiality and heritability for mood disorders that onset in childhood/adolescence than those that onset in adulthood. To identify the genetic contribution to mood disorders that onset in childhood/adolescence, we performed a genome scan on 146 nuclear families from Hungary containing an affected proband and affected siblings. In total, the pedigrees contained 303 affected children: 146 probands, 137 siblings with a first episode of mood disorder before 14.9 years of age, and 20 siblings with onset of their first episode after 14.9 years of age but before the age of 18. The results of the genome scan using 405 microsatellite markers did not provide evidence for linkage at the recommended genome wide significance level for any novel loci. However, markers on two chromosomes, 13q and Xq, provided evidence for linkage in regions previously identified as linked to bipolar disorder in multiple studies. For the marker on chromosome 13q the peak non-parametric multipoint LOD score was at the marker D13S779 (LOD = 1.5, P = 0.004). On chromosome Xq, evidence for linkage was observed across a large region spanning two regions previously linked to bipolar disorder; Xq24 to Xq28, with a peak at marker TTTA062 (LOD 2.10, P = 0.0009) in Xq28. Results for these regions exceed the recommended P-value for a replication study of P < 0.01 and thus provide evidence for these two loci as contributing to mood disorders with juvenile onset.

["Risk factors for childhood depression"--research design, implementation, proceedings: history of 13 years: experience in grant preparation, writing, organization in connection with an American NIMH Grant]. / A gyermekkori depresszió rizikótényezio kutatás megtervezése, megvalósítása, lefolyása.

The authors summarize their experiences in research organization accumulated during 13 years. At first they outline preliminary studies which are prerequisites of high prestige international grants. Then they describe the huge administrative apparatus dedicated - besides skilled professionals - for the construction and organization of the research, the management, continuous checking and evaluation of data in such a multisite study. Finally, they report on the scientific results obtained after 13 years of hard work.

Anxiety predicts mortality and morbidity after coronary artery and valve surgery--a 4-year follow-up study.

OBJECTIVE: To explore the long-term effect of anxiety and depression on outcome after cardiac surgery. To date, the relationship between psychosocial factors and future cardiac events has been investigated mainly in population-based studies, in patients after cardiac catheterization or myocardial infarction. METHODS: In total, 180 patients who underwent cardiac surgery using cardiopulmonary bypass were prospectively studied and followed up for 4 years. Anxiety (Spielberger State-Trait Anxiety Inventory, STAI-S/STAI-T), depression (Beck Depression Inventory, BDI), living alone, and education level along with clinical risk factors and perioperative characteristics were assessed. Psychological self-report questionnaires were completed preoperatively and 6, 12, 24, 36, and 48 months after discharge. Clinical end-points were mortality and cardiac events requiring hospitalization during follow-up. RESULTS: Average preoperative STAI-T score was 44.6 +/- 10. Kaplan-Meier analysis showed a significant effect of preoperative STAI-T >45 points (p = .008) on mortality. In multivariate models, postoperative congestive heart failure (OR: 10.8; 95% confidence interval [CI]: 2.9-40.1; p = .009) and preoperative STAI-T (score OR: 1.07; 95% CI: 1.01-1.15; p = .05) were independently associated with mortality. The occurrence of cardiovascular hospitalization was independently associated with postoperative intensive care unit days (OR: 1.41; 95% CI: 1.01-1.96; p = .045) and post discharge 6th month STAI-T (OR: 1.06; 95% CI:1.01-1.13; p = .03). CONCLUSIONS: The results of the present study suggest that the assessment of psychosocial factors, particularly the ongoing assessment of anxiety, could help in risk stratification and identification of patients at risk of mortality and cardiovascular morbidity after cardiac surgery.

Markov model-based estimation of individual survival probability for medullary thyroid cancer patients.

UNLABELLED: The relatively benign, but occasionally rapidly fatal clinical course of medullary thyroid cancer (MTC) has raised the need for individual survival probability estimation. A retrospective study on 91 MTC clinical case histories with a mean follow-up of 6 years indicated prevalences of local, regional and distant residual tumor on primary care completion of 23%, 54% and 54%, respectively. Local, regional and distant relapses during follow-up occurred in 8%, 23% and 26% of the patients, with a cause-specific death in 26% of the cases. Prognostic factors statistically significantly influencing the cause-specific survival were selected by uni- and multivariate analysis. A Markov method-based model was developed for the estimation of individual time-dependent local, regional and distant relapse-free and cause-specific survival probability functions, with parameters numerically determined via a maximum likelihood procedure. These parameters include relative risk factors related to prognosticators, a residual or recurrent local/regional/distant tumor, and combinations of these entities. In multivariate studies, the patient s age and gender, the genetic basis of the dis-ease, lymph node involvement, the existence of a general symptom (diarrhoea) at presentation, and the dosage of external irradiation proved to be prognosticators. The cause-specific survival function of the study population indicated mean 5, 10 and 15-year survival probabilities of 69%, 62% and 58%. CONCLUSION: Survival probabilities can be predicted for extrastudy cases provided that the same laws and principles govern the clinical course of these cases and those comprising the study. For individual survival probability estimation, a Pascal program (MEDUPRED) was written and is available on the home page of the National Institute of Oncology, Budapest (www.oncol.hu).

[Radiotherapy of MALT-lymphoma of the stomach]. / A gyomor MALT-lymphomák sugárkezelése.

INTRODUCTION: The stomach is the most common extranodal site of the low-grade MALT lymphoma. This lymphoma usually appears in elderly patients, with typically indolent signs. At the time of the diagnosis, the lymphoma is usually localized in the stomach and/or the adjacent lymph nodes. The choice in these cases is local treatment, which in the past involved only a surgical approach (total/partial gastrectomy), whereas more recently radiotherapy is preferred. PURPOSE: The radiation fields cover the whole stomach and the paragastric lymph nodes. The radiation doses range from 30 to 40 Gy, given in 1.5 Gy fractions 5 days a week. An adequate dose distribution to the target volume can be achieved by 3D treatment planning and conformal irradiation. METHODS: At our institute, 5 patients were treated with this method, the intention was curative in 3 cases, and palliative in 2 cases. The median dose in the 4 cases completed as initially planned was 33.6 Gy, delivered at 1.5 Gy per fraction. The adjacent critical organs do not exceed the tolerance doses by this method. RESULTS: In these 4 cases, complete regression was achieved, as determined by endoscopy and biopsy. In the fifth, locally advanced case, irradiation had to be terminated because of gastric bleeding. During irradiation, no other severe acute side-effects were detected. CONCLUSION: The literature and our preliminary results confirm that radiation therapy for early, localized MALT lymphoma of the stomach, or in disseminated cases, can be not only effective and safe, but offers the significant advantages of low treatment-related morbidity and preservation of the gastric function.

[Cost-effective PET scans in oncology]. / Költséghatékony onkológiai PET-vizsgálatok.

The authors have reviewed the financial considerations of oncological FDG PET examinations by the guidelines of the Health Care Financing Administration (USA). By critical assessment of large number of clinical investigations, the cost-effectiveness of FDG PET scans has been confirmed in the following cases: differential diagnosis of solitary pulmonary nodule, diagnosis, staging and restaging of non-small cell lung cancer, colorectal cancer, malignant lymphomas, melanoma malignum, esophageal neoplasms and cancers of the head and neck. The role of this method in breast cancer is currently under intensive investigation. Due to the correct staging, PET examinations in these indications enable the clinicians to choose the optimal treatment ensuring the maximum probability of recovery and being cost-effective as unnecessary medical interventions become avoidable.

[The role of PET scan in the investigation of the lymphatic spreading of Hodgkin's disease]. / A PET szerepe a Hodgkin-kór nyirokterjedésének vizsgálatában.

The authors investigated the role of PET, as a non-invasive diagnostic method, in the analysis of lymphatic spreading of Hodgkin's disease (HD). Whole-body FDG scans were carried out in 71 patients along with [11C]-methionine examinations, if necessitated by inconclusive FDG results. Based on these findings involvement-frequencies were calculated for each lymphatic region. The three most frequently involved lymphatic regions were the mediastinum (83.1%), the left cervical and left supraclavicular regions (78.9%) and the right cervical and right supraclavicular regions (76.1%). These data support the hypothesis that HD originates from the cervical or supraclavicular regions and reaches the distant sites by basically retrograde spreading in a non-random manner. The appropriate values of site involvement-rate were compared with those obtained by other authors based on pathologic staging and a good correlation was found. The high level of correspondence between these involvement-frequencies supported the general validity (i.e. valid for both treated and untreated cases) of the principles governing lymphatic spreading of HD.

[Cost-effective PET investigations in oncology]. / Költség-hatékony onkológiai PET-vizsgálatok.

The authors have reviewed the financial considerations of oncological FDG PET examinations by the guidelines of the Health Care Financing Administration (USA). By critical assessment of large number of clinical investigations,the cost-effectiveness of FDG PET scans has been confirmed in the following cases: differential diagnosis of solitary pulmonary nodule, diagnosis,staging and restaging of non-small cell lung cancer, colorectal cancer, malignant lymphomas, melanoma malignum, esophageal neoplasms and cancers of the head and neck. The role of this method in breast cancer is currently under intensive investigation. Due to the correct staging, PET examinations in these indications enable the clinicians to choose the optimal treatment ensuring the maximum probability of recovery and being cost-effective as unnecessary medical interventions become avoidable.

Psychosocial factors and major adverse cardiac and cerebrovascular events after cardiac surgery.

Our aim was to prospectively examine the association of psychosocial factors with adverse outcome after cardiac surgery. One hundred and eighty cardiac surgery patients were enrolled and contacted annually by mail. Depression [Beck depression inventory (BDI)], anxiety [state anxiety subscale in Spielberger State-Trait Anxiety Inventory (STAI-S) and trait anxiety subscale in Spielberger State-Trait Anxiety Inventory (STAI-T)] were investigated annually, social support, negative affectivity, social inhibition (SI), illness intrusiveness, self-rated health and sleeping disorders were investigated by standardized tests at the second and fifth year. The end-point was the major adverse cardiac and cerebrovascular event (MACCE) including death. Twenty-eight (15.5%) patients died by the end of the fifth year. At the end of the second and fifth years, 146 (81.1%) and 118 (65.5%) patients fulfilled the tests, respectively. At the end of the second year after adjustment for medical and perioperative factors worse self-rated health [adjusted hazard ratio (AHR): 0.67, P=0.006], sleeping disorders (AHR: 1.14, P=0.001), higher illness intrusiveness (AHR: 1.03, P=0.018), higher BDI (AHR: 1.12, P=0.001), STAI-S (AHR: 1.09, P=0.001) and higher STAI-T scores (AHR: 1.08, P=0.002) showed higher risk for MACCE. Significant individual elevation in scores of sleeping disorders, illness intrusiveness and SI were observed over the three-year period in the MACCE group. Assessment of psychosocial factors could help in identifying patients at high-risk for MACCE after cardiac surgery.