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Open access

Nina Boc, Ibrahim Edhemovic, Bor Kos, Maja M. Music, Erik Brecelj, Blaz Trotovsek, Masa Bosnjak, Mihajlo Djokic, Damijan Miklavcic, Maja Cemazar and Gregor Sersa

Abstract

Background

The aim of the study was to characterize ultrasonographic (US) findings during and after electrochem-otherapy of liver tumors to determine the actual ablation zone and to verify the coverage of the treated tumor with a sufficiently strong electric field for effective electrochemotherapy.

Patients and methods

US findings from two representative patients that describe immediate and delayed tumor changes after electrochemotherapy of colorectal liver metastases are presented.

Results

The US findings were interrelated with magnetic resonance imaging (MRI). Electrochemotherapy-treated tumors were exposed to electric pulses based on computational treatment planning. The US findings indicate immediate appearance of hyperechogenic microbubbles along the electrode tracks. Within minutes, the tumors became evenly hyperechogenic, and simultaneously, an oedematous rim was formed presenting as a hypoechogenic formation which persisted for several hours after treatment. The US findings overlapped with computed electric field distribution in the treated tissue, indicating adequate coverage of tumors with sufficiently strong electric field, which may predict an effective treatment outcome.

Conclusions

US provides a tool for assessment of appropriate electrode insertion for intraoperative electrochemo-therapy of liver tumors and assessment of the appropriate coverage of a tumor with a sufficiently strong electric field and can serve as predictor of the response of tumors.

Open access

Barbara Breznik, Clara Limback, Andrej Porcnik, Andrej Blejec, Miha Koprivnikar Krajnc, Roman Bosnjak, Janko Kos, Cornelis J.F. Van Noorden and Tamara T. Lah

Abstract

Background

Glioblastoma is a highly aggressive central nervous system neoplasm characterized by extensive infiltration of malignant cells into brain parenchyma, thus preventing complete tumor eradication. Cysteine cathepsins B, S, L and K are involved in cancer progression and are overexpressed in glioblastoma. We report here for the first time that cathepsin X mRNA and protein are also abundantly present in malignant glioma.

Materials and methods

Gene expression of cathepsins K and X was analyzed using publically-available tran-scriptomic datasets and correlated with glioma grade and glioblastoma subtype. Kaplan-Maier survival analysis was performed to evaluate the predictive value of cathepsin K and X mRNA expression. Cathepsin protein expression was localized and semi-quantified in tumor tissues by immunohistochemistry.

Results

Highest gene expression of cathepsins K and X was found in glioblastoma, in particular in the mesenchymal subtype. Overall, high mRNA expression of cathepsin X, but not that of cathepsin K, correlated with poor patients’ survival. Cathepsin K and X proteins were abundantly and heterogeneously expressed in glioblastoma tissue. Immuno-labeling of cathepsins K and X was observed in areas of CD133-positive glioblastoma stem cells, localized around arterioles in their niches that also expressed SDF-1α and CD68. mRNA levels of both cathepsins K and X correlated with mRNA levels of markers of glioblastoma stem cells and their niches.

Conclusions

The presence of both cathepsins in glioblastoma stem cell niche regions indicates their possible role in regulation of glioblastoma stem cell homing in their niches. The clinical relevance of this data needs to be elaborated in further prospective studies.

Open access

Martina Vrankar and Mojca Unk

Abstract

Background

Uncommon response during immunotherapy is a new challenging issue in oncology practice. Recently, new criteria for evaluation of response to immunotherapy immune response evaluation criteria in solid tumors (iRECIST) were accepted. According to iRECIST, worsening of performance status (PS) accompanied to pseudoprogression reflects most probably the true progression of the malignant disease.

Methods

A systematic review of the literature was made by using several electronic database with the following search criteria: symptomatic pseudoprogression, atypical response, immunotherapy and lung cancer.

Results

In the literature, we identified five reports of seven patients treated with immunotherapy that met the inclusion criteria. We also report our experience of patient with pseudoprogression and almost complete response after one dose of immunotherapy.

Conclusions

As seen from our review, iRECIST criteria might be insufficient in distinguishing true progression from pseudoprogression in some patients with advanced NSCLC treated with immunotherapy. More precise assessment methods are urgently needed.

Open access

Magdalena Mileva, Bojana Stoilovska, Anamarija Jovanovska, Ana Ugrinska, Gordana Petrushevska, Slavica Kostadinova-Kunovska, Daniela Miladinova and Venjamin Majstorov

Abstract

Background

Ultrasound guided fine-needle aspiration (FNA) is a standard procedure for thyroid nodules management and selecting patients for surgical treatment. Atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS), as stated by The Bethesda System for Reporting Thyroid Cytopathology, is a diagnostic category with an implied malignancy risk of 5–15%. The aim of our study was to review cytology and histopathology reports, as well as clinical and ultrasound data, for thyroid nodules reported as AUS/FLUS, in order to evaluate the malignancy rate and to assess factors associated with malignant outcome.

Patients and methods

A total of 112 AUS/FLUS thyroid nodules in 105 patients were evaluated, of which 85 (75.9%) were referred to surgery, 21 (18.8%) were followed-up by repeat FNA and 6 nodules (5.3%) were clinically observed. Each was categorized in two final diagnostic groups - benign or malignant, which were further compared to clinical data of patients and ultrasonographic features of the nodules.

Results

Final diagnosis of malignancy was reached in 35 cases (31.2%) and 77 (68.8%) had benign lesions. The most frequent type of cancer was papillary thyroid carcinoma (PTC) - 58.1% PTC and 25.8% had follicular variant of PTC. Patients’ younger age, smaller nodule size, hypoechoic nodule and presence of calcifications were shown to be statistically significant risk factors for malignancy.

Conclusions

The rate of malignancy for the AUS/FLUS diagnostic category in our study was higher than estimated by the Bethesda System. Clinical and ultrasound factors should be considered when decision for patient treatment is being made.

Open access

Nikola Besic, Marta Dremelj and Gasper Pilko

Abstract

Background

Locoregional recurrence is common in patients with locally advanced differentiated thyroid carcinoma (DTC). Our aim was to find out the rate of locoregional control of the disease after external beam radiotherapy (EBRT) of the neck and mediastinum in patients with DTC and pT4 tumor.

Patients and methods

Altogether 91 patients (47 males, 44 females, median age 61 years) with DTC had EBRT of the neck and mediastinum as part of the multimodal treatment of pT4 tumor (63 cases pT4a, 28 cases pT4b) from the year 1973 to 2015. Data on clinical factors, histopathology and recurrence were collected. Disease-free, disease-specific and overall survival was calculated.

Results

Median tumor size was 5 cm (range 1–30 cm). Out of 91 patients, 23 had distant and 38 regional metastases. A total or near-total thyroidectomy, lobectomy, subtotal thyroidectomy and lymph node dissection was performed in 70%, 14%, 2% and 30% of cases, respectively. Thirteen percent of patients were not treated with surgery. All patients had EBRT and 39 had chemotherapy. Radioiodine (RAI) ablation of thyroid remnant and RAI therapy was applied in 90% and 40% of cases, respectively. Recurrence was diagnosed in 29/64 patients without a persistent disease: locoregional and distant in 16 and 13 cases, respectively. Five-year and ten-year disease-free survival rate was 64% and 48%, respectively.

Conclusions

The majority of patients with DTC and pT4 tumors who were treated with EBRT of the neck and mediastinum region as part of multimodal treatment have long-lasting locoregional control of the disease.

Open access

Urska Ivanus, Tine Jerman, Alenka Repse Fokter, Iztok Takac, Veronika Kloboves Prevodnik, Mateja Marcec, Ursula Salobir Gajsek, Maja Pakiz, Jakob Koren, Simona Hutter Celik, Kristina Gornik Kramberger, Ulrika Klopcic, Rajko Kavalar, Simona Sramek Zatler, Biljana Grcar Kuzmanov, Mojca Florjancic, Natasa Nolde, Srdjan Novakovic, Mario Poljak and Maja Primic Zakelj

Abstract

Background

To overcome obstacles within the Slovenian organised cervical cancer screening programme, a randomised pilot study of human papillomavirus (HPV) self-sampling among non-attenders was performed, aiming to assess three different screening approaches.

Participants and methods

Non-attenders aged 30–64 years from two Slovenian regions were randomised to two HPV self-sampling groups–the opt-in (I1, n = 14.400) and the opt-out (I2, n = 9.556), with a control group (P, n = 2.600). Self-collected samples were analysed using the Hybrid Capture 2 assay. HPV-positive women were invited to a colposcopy. The overall and type-specific intention-to-screen response rates and histological outcomes with a positive predictive value (PPV) according to the women’s age, the screening approach, the level of protection resulting from previous screening history, and the region of residence were assessed.

Results

Of the 26.556 women enrolled, 8.972 (33.8%) responded with self-sample for HPV testing and/or traditional cytology within one year of enrolment. Response rates were 37.7%, 34.0% and 18.4% (p < 0.050) for opt-out, opt-in and control groups. Cervical intraepithelial neoplasia (CIN)2+ was diagnosed in 3.9/1.000, 3.4/1.000, and 3.1/1.000 women (p > 0.050), respectively. PPV of the HPV self-sampling was 12.0% and 9.6% for CIN2+ and CIN3+. The highest PPV was obtained in non-attenders in screening programme for more than 10-years and concordant results of HPV testing with 40.8% for CIN2+ and 38.8% for CIN3+.

Conclusions

The results of our study show that a high response to HPV self-sampling can be achieved also in an opt-in approach, if women are encouraged to choose between self-sampling at home and screening with gynaecologist. In addition, clinically important risk difference for a high-grade cervical lesion exists in the case of a positive result of HPV testing on self-collected samples, depending on the length of the interval since last screening. Stratified management of these women should be strongly considered. Women who were not screened with cytology for at least 10 years should be referred to immediate colposcopy for histology verification instead to delayed re-testing.

Open access

Sanda Lah Kravanja, Irena Hocevar-Boltezar, Maja Marolt Music, Ana Jarc, Ivan Verdenik and Maja Ovsenik

Abstract

Background

Tongue posture plays an important role in the etiology of anterior open bite (AOB) and articulation disorders, and is crucial for AOB treatment planning and posttreatment stability. Clinical assessment of tongue posture in children is unreliable due to anatomical limitations. The aim of the study was to present functional diagnostics using three-dimensional ultrasound (3DUS) assessment of resting tongue posture in comparison to clinical assessment, and the associations between the improper tongue posture, otorhinolaryngological characteristics, and articulation disorders in preschool children with AOB.

Patients and methods

A cross-sectional study included 446 children, aged 3–7 years, 236 boys and 210 girls, examined by an orthodontist to detect the prevalence of AOB. The AOB was present in 32 children. The control group consisted of 43 children randomly selected from the participants with normocclusion. An orthodontist, an ear, nose and throat (ENT) specialist and a speech therapist assessed orofacial and ENT conditions, oral habits, and articulation disorders in the AOB group and control group. Tongue posture was also assessed by an experienced radiologist, using 3DUS. The 3DUS assessment of tongue posture was compared to the clinical assessment of orthodontist and ENT specialist.

Results

The prevalence of AOB was 7.2%. The AOB group and the control group significantly differed regarding improper tongue posture (p < 0.001), and articulation disorders (p < 0.001). In children without articulation disorders from both groups, the improper tongue posture occured less frequently than in children with articulation disorders (p < 0.001). After age adjustment, a statistical regression model showed that the children with the improper tongue posture had higher odds ratios for the presence of AOB (OR 14.63; p < 0.001) than the others. When articulation disorders were included in the model, these odds ratios for the AOB became insignificant (p = 0.177). There was a strong association between the improper tongue posture and articulation disorders (p = 0.002). The 3DUS detected the highest number of children with improper resting tongue posture, though there was no significant difference between the 3DUS and clinical assessments done by orthodontist and ENT specialist.

Conclusions

The 3DUS has proved to be an objective, non-invasive, radiation free method for the assessment of tongue posture and could become an important tool in functional diagnostics and early rehabilitation in preschool children with speech irregularities and irregular tongue posture and malocclusion in order to enable optimal conditions for articulation development.

Open access

Borut Kobal, Marco Noventa, Branko Cvjeticanin, Matija Barbic, Leon Meglic, Marusa Herzog, Giulia Bordi, Amerigo Vitagliano, Carlo Saccardi and Erik Skof

Abstract

Background

The aim of the study was to analyze the overall survival (OS) and progression free survival (PFS) of patients with high grade and advanced stage epithelial ovarian cancer (EOC) with at least 60 months of follow-up treated in a single gynecologic oncology institute. We compared primary debulking surgery (PDS) versus neoadjuvant chemotherapy plus interval debulking surgery (NACT + IDS) stratifying data based on residual disease with the intent to identify the rationale for therapeutic option decision and the role of laparoscopic evaluation of resectability for that intention.

Patients and methods

This is observational retrospective study on consecutive patients with diagnosis of high grade and International Federation of Gynecology and Obstetrics (FIGO) stage III/IV EOC referred to our center between January 2008 and May 2012. We selected only patients with a follow-up of at least 60 months. Primary endpoint was to compare PDS versus NACT + IDS in term of progression free survival (PFS) and overall survival (OS). Secondary endpoints were PFS and OS stratifying data according to residual disease after surgery in patients receiving PDS versus NACT + IDS. Finally, through Cox hazards models, we tested the prognostic value of different variables (patient age at diagnosis, residual disease after debulking, American Society of Anesthesiologists (ASA) stage, number of adjuvant-chemotherapy cycles) for predicting OS.

Results

A total number of 157 patients were included in data analysis. Comparing PDS arm (108 patients) and NACT + IDS arm (49 patients) we found no significant differences in term of OS (41.3 versus 34.5 months, respectively) and PFS (17.3 versus 18.3 months, respectively). According to residual disease we found no significant differences in term of OS between NACT + IDS patients with residual disease = 0 and PDS patients with residual disease = 0 or residual disease = 1, as well as no significant differences in PFS were found comparing NACT + IDS patients with residual disease = 0 and PDS patients with residual disease = 0; contrarily, median PFS resulted significantly lower in PDS patients receiving optimal debulking (residual disease = 1) in comparison to NACT + IDS patients receiving complete debulking (residual disease = 0). PDS arm was affected by a significant higher rate of severe post-operative complications (grade 3 and 4). Diagnostic laparoscopy before surgery was significantly associated with complete debulking.

Conclusions

We confirm previous findings concerning the non-superiority of NACT + IDS compared to PDS for the treatment of EOC, even if NACT + IDS treatment was associated with significant lower rate of post-operative complications. On the other hand, selecting patients for NACT + IDS, based on laparoscopic evaluation of resectabilty prolongs the PFS and does not worse the OS compared to the patients not completely debulked with PDS.

Open access

Nurdan Gül, Ayşe Kubat Üzüm, Özlem Soyluk Selçukbiricik, Gülçin Yegen, Refik Tanakol and Ferihan Aral

Abstract

Background

The association of subacute thyroiditis (SAT) and papillary thyroid carcinoma is a rare finding. In this study, we aimed to investigate the prevalence of differentiated thyroid cancer in a cohort of patients followed with the diagnosis of SAT.

Patients and methods

We retrospectively screened medical records of Endocrinology and Metabolism outpatient clinic in the past 20 years for patients with SAT. Patients with nodules and suspicious ultrasonography findings who underwent fine needle aspiration biopsy (FNAB) and operated due to malignancy risk were identified.

Results

We identified 137 (100 females, 37 males) patients with reliable records to confirm the diagnosis of SAT. The mean age of female patients was 41.1 ± 9.1 (range, 20–64) and of male patients was 43.0 ± 9.3 (range, 20–65). One or more FNAB was performed in 23 of the patients (16.8%) at the beginning and/or during the follow-up period when needed. Seven patients with suspicious FNAB findings were operated, and histopathological examination of the nodules confirmed the diagnosis of papillary thyroid carcinoma in 6 patients (4.4%).

Conclusions

Our observations suggesting a relatively higher prevalence of thyroid cancer in a small series of SAT patients warrant further studies to identify the real frequency of differentiated thyroid cancer and its association with inflammatory pathogenesis of SAT. This finding is compatible with the trend of increased thyroid cancer incidence all over the world. A repeat ultrasonography after resolution of clinical and inflammatory findings, and FNAB should be recommended to all patients with suspicious nodules.

Open access

Vladimir Gasic, Branka Zukic, Biljana Stankovic, Dragana Janic, Lidija Dokmanovic, Jelena Lazic, Nada Krstovski, Vita Dolzan, Janez Jazbec, Sonja Pavlovic and Nikola Kotur

Abstract

Background

Response to glucocorticoid (GC) monotherapy in the initial phase of remission induction treatment in childhood acute lymphoblastic leukemia (ALL) represents important biomarker of prognosis and outcome. We aimed to study variants in several pharmacogenes (NR3C1, GSTs and ABCB1) that could contribute to improvement of GC response through personalization of GC therapy.

Methods

Retrospective study enrolling 122 ALL patients was carried out to analyze variants of NR3C1 (rs33389, rs33388 and rs6198), GSTT1 (null genotype), GSTM1 (null genotype), GSTP1 (rs1695 and rs1138272) and ABCB1 (rs1128503, rs2032582 and rs1045642) genes using PCR-based methodology. The marker of GC response was blast count per microliter of peripheral blood on treatment day 8. We carried out analysis in which cut-off value for GC response was 1000 (according to Berlin-Frankfurt-Munster [BFM] protocol), as well as 100 or 0 blasts per microliter.

Results

Carriers of rare NR3C1 rs6198 GG genotype were more likely to have blast count over 1000, than the non-carriers (p = 0.030). NR3C1 CAA (rs33389-rs33388-rs6198) haplotype was associated with blast number below 1000 (p = 0.030). GSTP1 GC haplotype carriers were more likely to have blast number below 1000 (p = 0.036), below 100 (p = 0.028) and to be blast negative (p = 0.054), while GSTP1 GT haplotype and rs1138272 T allele carriers were more likely to be blasts positive (p = 0.034 and p = 0.024, respectively). ABCB1 CGT (rs1128503-rs2032582-rs1045642) haplotype carriers were more likely to be blast positive (p = 0.018).

Conclusions

Our results have shown that NR3C1 rs6198 variant and GSTP1 rs1695-rs1138272 haplotype are the most promising pharmacogenomic markers of GC response in ALL patients.