Association of triple positivity with prognostic parameters and overall survival in a population-based study of 6,122 HER2-positive breast cancer patients: analysis of real-world clinical practice based on a research database.

Triple-positive breast cancer (TPBC), i.e. HER2-positive (HER2+) and hormone receptors-positive breast cancer, is a specific subgroup of breast cancers. TPBC biology is characterized by strong mutual interactions between signaling pathways stimulated by estrogens and HER2 amplification. The present study aims to carry out a population-based analysis of treatment outcomes in a cohort of hormone receptor (HR) positive and negative breast cancer patients who were treated with anti-HER2 therapy in the Czech Republic. The BREAST research database was used as the data source for this retrospective analysis. The database covers approximately 95% of breast cancer patients treated with targeted therapies in the Czech Republic. The analysis included 6,122 HER2-positive patients. The patients were divided into two groups, based on estrogen receptor (ER) or progesterone receptor (PR) positivity: hormone receptor negative (HR-) patients had both ER- and PR-negative tumors (n=2,518), unlike positive (HR+) patients (n=3,604). HR+ patients were more often diagnosed premenopausal at the time of diagnosis, presented more often at stage I or II and their tumors were less commonly poorly differentiated. The overall survival (OS) was significantly higher in subgroups of HR+ patients according to treatment setting. When evaluated by stages, significantly higher OS was observed in HR+ patients diagnosed at stages II, III, and IV and regardless of tumor grade.

Is There a Benefit of HER2-Positive Breast Cancer Subtype Determination in Clinical Practice?

BACKGROUND: Breast cancer (BC) with increased expression of human epidermal growth factor receptor 2 with tyrosine kinase activity (HER2+) is a clinically and bio-logically heterogeneous dis-ease. In terms of gene expression, there are four major molecular subtypes - Luminal A, Luminal B, HER2-enriched (HER2-E), and Basal-like. The most common subtype is HER2-E (50- 60%). In hormone-dependent (HR+) HER2-positive tumors, the subgroup HER2-E represents 40- 50% of cases; others are luminal A and B subtypes. PURPOSE: The aim of this review is to provide information on the significance of the distribution of HER2-positive tumors accord-ing to subtype, which is considered a predictive parameter for guid-ing treatment decisions. For example, HER2-E subtype is characterized by a higher probability of achiev-ing complete pathological remission when treated with chemother-apy and antiHER2 ther-apy, and it is thought that it could be treated us-ing a dual HER2 blockade without chemother-apy. Currently, triple-positive tumors, a specific subtype of breast cancer characterized by HER2+ and HR+, are more often subjects of interest. Their unique bio-logical properties are due to complex interactions between HER2 and estrogen receptor (ER) signalling, which result in lower effectiveness of endocrine ther-apy in these patients than in HR+ and HER2-negative patients and, at the same time, the ER positivity in HER2+ tumors can result in resistance to antiHER2 ther-apy. This type of BC is a non-homogeneous group where the impacts of HER2 positivity on tumor malignant behavior and activity of the estrogen-driven signal-ing pathway are inconsistent. Current studies focus on test-ing new treatments such as dual HER2 block-ing or immunother-apy, in combination with antiHER2 targeted ther-apy with fulvestrant, aromatase inhibitors, cyclin dependent kinase 4/ 6 inhibitors, or inhibitors of the PI3K (phosphatidylinositol-3-kinase) pathway. CONCLUSION: The distribution of HER2+ BC accord-ing to individual subtype provides information that can contribute to achiev-ing more accurate decisions about the most appropriate ther-apy. Key words breast cancer - subtype - HER2 - trastuzumab - HER2 positive - triple positive - HER2 enriched The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 27. 9. 2018 Accepted: 26. 11. 2018.

[Five-year results of IMRT for prostate cancer - tumor control]. / Petileté výsledky IMRT karcinomu prostaty - kontrola nádoru.

BACKGROUND: Intensity-modulated radiation therapy (IMRT) is the method of choice in external-beam radiotherapy tolocalized prostate cancer. This work analyses five year results of IMRT with a dose of 78/82 Gy. PATIENTS AND METHODS: From June 2003 to December 2007, the IMRT technique was employed to treat 233 patients with T1-3 N0 M0 prostate cancer. It was supplemented by hormone therapy especially in high-risk patients. Two IMRT techniques were applied - IMRT with a dose of 78 Gy in 39 fractions to prostate and seminal vesicles (SV) (IMRT 78) and IMRT with simultaneous integrated 82 Gy boost to prostate concurrently with 73,8 Gy in 41 fractions to SV (IMRT SIB 82). The IMRT 78 technique was used in 160 patients (69%). Seventy-three (31%) patients with intermediate (IR) or high-risk (HR) prostate cancer without SV involvement were treated with IMRT SIB 82 technique. The PSA relapse was defined as an increase in PSA of at least 2.0 ng/mL above the nadir or in comparison to the value at the initiation of hormone therapy. Clinical relapse was defined as an occurence of distant metastases and/or local recurrence. RESULTS: The median follow-up of our patients´ population was 4.3 years (range 0.6-8.9 years). The estimated 5-year PSA relapse-free survival in low-risk (LR), IR and HR patients was 86%, 89% and 83%, respectively (p = NS). In a multivariate analysis, Gleason score (GS) 8-10 was associated with significantly higher risk of PSA relapse (RR 2.76), while higher age at the time of diagnosis significantly decreased the PSA relapse risk (RR 0.94). The estimated 5-year clinical relapse-free survival in LR, IR and HR patients was 100%, 99% and 95%, respectively (p = NS). In a univariate analysis, both GS and PSA had a significant impact on the 5-year clinical relapse-free survival - GS 2-7 97 % vs GS 8-10 88 % (p = 0.03), PSA 20 98 % vs PSA > 20 85 % (p < 0.01). CONCLUSION: Treatment of localized prostate cancer using IMRT with a dose 78/82 Gy yielded an excellent 5-year tumour control with a risk of clinical relapse being less than 5%.

Experience with intensity-modulated radiotherapy in the treatment of head and neck cancer.

PURPOSE: Studies using intensity-modulated radiation therapy (IMRT) in the treatment of head and neck tumors have shown to decrease acute and late radiation toxicity. However, the high conformity of this technique can increase the risk of recurrence due to geographic miss. The aim of this study was to analyze whether the results of IMRT met the theoretical expectations concerning treatment efficacy. METHODS: From a total of 185 patients (152 males and 33 females, mean age 58±10.36 years) 176 were evaluable and were studied. Eighty-nine (48.1%) patients had surgical treatment and 50 of them were scheduled for concomitant cisplatin chemotherapy. Irradiation was performed using IMRT, a sliding window with 9 fields in a Varian 2100 C/D linear accelerator, X-ray beam, 6 MeV. The prescribed dose in the planning treatment volume (PTV1), i.e., the area of the primary tumor and nodal area, was 66 Gy/2.2 Gy-70 Gy/2.12 Gy. In the PTV2 (the area at high risk) the dose was 60Gy/2 Gy-59.4 Gy/ 1.8 Gy, and in the PTV 3 (the area treated with prophylactic irradiation) the prescribed dose was 54 Gy/1.8 Gy/50.4 Gy/1.53 Gy. RESULTS: The 3-year overall survival (OS) and relapse-free survival (RFS) of IMRT-treated patients, most of whom were in stages III and IV (158 out of 177), were 50 and 57%, respectively. Using postoperative radiotherapy/chemoradiotherapy 3-year locoregioncal control was achieved in 75% of the cases as compared with 35% in non-operated patients. CONCLUSIONS: The worst outcomes were found in oral cavity and hypopharyngeal tumors, and the best in laryngeal and oropharyngeal tumors. Better results were found in surgically treated patients, and in lower disease stages. Despite the high conformity of dose distribution and efforts to spare healthy tissues, most cases of locoregional relapse occurred in areas receiving the full radiation dose. If dividing relapses into cases of persistence and local recurrence, the former predominated.

Perioperative interstitial CT-based brachytherapy boost in breast cancer patients with breast conservation after neoadjuvant chemotherapy.

Intraoperative placement of catheters in the tumor bed during breast-conserving surgery (BCS) enables postponed targeted boost irradiation in high risk breast cancer patients. Twenty-three patients with high risk breast cancer underwent neoadjuvant chemotherapy and multifractionated perioperative brachytherapy as a boost to the tumor bed using three-dimensional (3D) CT-based planning. Plastic catheters for brachytherapy were implanted during surgery and targeted irradiation was delivered in the course of 2-3 weeks. Acute and late toxicities were scored according to the RTOG Common Toxicity Criteria. Cosmetic outcomes were assessed using the Harvard criteria. No major perioperative complications were recorded. Circumscribed wound infection occurred in one patient (4.3%). Only 3 patients (13%) experienced acute skin toxicity Grade 1. We observed no teleangiectasias or pigmentations. The cosmetic outcome at last follow-up visit was rated as excellent/good, in 82.6%, fair, in 13% and poor in 4.4% of patients, respectively. There was no evidence of disease recurrence after median follow-up of 43. 4 months. Systematic integration of the perioperative fractionated 3D CT-based HDR brachytherapy as a boost for patients with breast cancer after BCS is feasible and seems safe. It might be beneficial especially for women with high risk of local recurrence.

PET/CT significance for planning radiotherapy of head and neck cancer.

The combination of positron emission tomography and computed tomography (PET/CT) offers metabolic mapping in addition to anatomic information of the primary lesion, nodal and distant metastases in patients with head and neck tumors, and may be therefore beneficial for radiotherapy planning. The aim of our study was to evaluate benefits of combined PET and CT imaging for staging and target volume delineation in this group of patients.Fifty three patients (40 men and 13 women) with confirmed advanced, inoperable or non-radically operated head and neck cancer were assessed based on the results of PET/CT as well as standard diagnostic examinations. All patients were subsequently treated with intensity modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) of 6 MV X-rays. There was an agreement between the standard examinations results and results of PET/CT in 30 cases. In 23 cases there was disagreement either in tumor size, nodal involvement or presence of distant metastases. Results of the tumor size assessment differed significantly in 5 cases. There was no agreement found in nodal involvement in 10 cases. The cancer confirmed by standard examination was not found by PET/CT in 2 cases; 3 PET/CT positive findings were not confirmed by standard examinations. In 3 patients PET-CT revealed new distant metastatic disease. Based on PET/CT assessment we changed treatment strategy and applied potentially curative dose of radiotherapy to previously undiscovered regions in 9 patients. We decided to change the treatment intent in 3 cases and only palliative treatment was applied. Based on our experience and the literature review, PET/CT may be considerable contribution to the standard diagnostic procedures in approximately one third of cases.

[Adaptive IG-IMRT for prostate cancer]. / Adaptivní IG-IMRT karcinomu prostaty.

BACKGROUNDS: Adaptive image-guided intensity-modulated radiation therapy (IG-IMRT) is a perspective method for the treatment of localized prostate cancer. Validate optimal protocols for IG-IMRT using kilovoltage cone-beam CT (CBCT) are required. PATIENTS AND METHODS: Seventy-six patients with prostate cancer were treated using adaptive IG-IMRT. Based on the CBCT performed during the first 10 fractions of radiotherapy, an average prostate position in relation to the pelvic bones was determined in antero-posterior AP, supero-inferior SI, and right-left axes. An adapted treatment plan for the second phase of the treatment included an isocenter shift into its average position (correction of the systematic error sigma). A margin between a clinical and planned target volume (CTV-PTV) was adjusted according to the magnitude of random error sigma. During the second phase of radiotherapy, set-up of patients was performed daily on pelvic bones using kilovoltage skiagraphic imaging in two projections (kV-kV). Follow-up CBCTs were repeated once a week. RESULTS: An average isocenter position differed from the position of a reference planning CT isocenter in at least one axis in 63 patients (83%). Major changes were recorded in AP axis - shift > or = 2 mm in 33 patients (43%), shift > or = 5 mm in 7 patients (9%). PTV for the second phase of radiotherapy was in the range of 6-10 mm in AP axis, 6-8 mm in SI axis, and 6 mm in RL axis. Mean sigma value in the AP axis was smaller in patients with a specific diet compared to patients without the diet (2.2 mm vs. 2.7 mm, p = 0.05). We evaluated 446 follow-up CBCT images from the second phase of radiotherapy (66 patients had 6 CBCT, 10 patients had 5 CBCT). Set-up error exceeding CTV-PTV margin occurred in 4 cases with no more than once per patient. Safety margin was sufficient in 72/76 patients (95%). CONCLUSION: IG-IMRT protocol integrating CBCT and kV-kV imaging provided adequate coverage of the target volume and proved to be compatible with departmental workflow. Margin reduction around the CTV is a prerequisite for dose escalation aimed at a intraprostatic lesion.

Time course of late rectal toxicity after radiation therapy for prostate cancer.

Rectum and bladder are the crucial organs at risk for curative radiation therapy of localized prostate cancer. We analyzed the incidence, profile and time course of late rectal radiation toxicity. A total of 320 patients with T1-3 prostate cancer were treated with three-dimensional conformal radiation therapy (3D-CRT). The prescription dose was 70 Gy for T1 and T2 patients (n=230) and 74 Gy for patients with locally advanced T3 tumors (n=90). Late rectal toxicity was graded according to the Fox Chase modification of the Radiation Therapy Oncology Group (RTOG) and Late Effects Normal Tissue Task Force (LENT) criteria. The median follow-up time was 6.2 years (range 0.2-10.7 years). At 5 years, the risk for the development of grade 2 and 3 rectal toxicities was 15.6 and 7.0%, respectively. All new cases of grade 2 and 3 rectal toxicities were observed within 5 years after treatment. Prevalence of grade 2 and 3 rectal symptoms showed fluctuation with maximum at 1.5 years and the minor peak at 4.5 years. Toxicity profile changed significantly over time. The proportion of rectal bleeding within grade 2 and 3 toxicity decreased from 85% at 1.5 years to 46% at 4.5 years. Conversely, the proportion of fecal incontinence among grade 2 and 3 rectal symptoms gradually increased (0% at 1.5 years vs 27% at 4.5 years). Late rectal radiation toxicity represents a dynamic process. Rectal bleeding decreases and fecal incontinence increases over time.

[Use of PET/CT examination in head and neck cancer radiotherapy planning]. / Vyuzití PET/CT vysetrení pri plánování radioterapie nádoru ORL oblasti.

BACKGROUND: Using conformal techniques and IMRT in radiotherapy allows dose increase in the target volume and sparing of healthy tissues. In comparison with conventional techniques it requires more accuracy in the target volume delineation. It is important to use all relevant diagnostic methods to reduce the risk of relapse.The basic method is CT examination which allows the dose distribution to be calculated. New imaging dimensions are associated with PET (positron emission tomography), which supplements the morphological image (CT or MRI) with a functional view.The aim of this study was to evaluate the benefit of PET/CT fusion in radiotherapy planning for head and neck cancer. PATIENTS AND METHODS: 40 head and neck cancer patients treated by definitive radiotherapy were evaluated. The patient group consisted of 30 men and 10 women, with a median age of 56 years (range 34-81 years). Postoperative radiotherapy was used in 10 cases and 30 patients were irradiated without prior surgery. IMRT technique with simultaneous integrated boost was used with 6 MV photons. RESULTS: Comparing diagnostic CT with planning PET/CT, there was no difference in tumour extent in 20 out of 40 patients. In 6 cases (15%) the nodal involvement was more extensive according to PET/CT while in 3 cases (7.5%) the nodal involvement was detected to be less extensive. In 2 patients (5%) the primary tumour was reclassified, in both cases towards tumour enlargement. Two patients with positive histopathological margin were PET/CT negative. PET/CT imaging resulted in a change in the target volume in 11 (27.5%) patients and the treatment strategy was changed in 3 cases. CONCLUSION: We tested use of the PET/CT examination in radiotherapy treatment planning of the head and neck carcinoma and it was introduced as a standard clinical practice at our department.

Daily oral versus pulse intravenous cyclophosphamide in the therapy of ANCA-associated vasculitis--preliminary single center experience.

The aim of the multicentric randomized trial CYCLOPS is to optimize the treatment of induction of remission in patients with generalized, but not immediately life-threatening ANCA (antineutrophil cytoplasmic antibodies) -associated vasculitis. This will be achieved by reducing the dose of cyclophosphamide by administering it as intermittent pulses. The lower cumulative dose will be very probably accompanied with lower toxicity, whereas the effectivity should be comparable. We have enrolled 28 patients to the study. At present, 18 of them are suitable for evaluation. Our preliminary results show that pulse intermittent administration of cyclophosphamide is safer from the point of morbidity and mortality due to infectious complications. In our hands, this treatment modality does not seem to be less effective than the conventional daily oral cyclophosphamide. However, unambiguous results and treatment recommendations will not be available until the final evaluation of all patients enrolled in the trial.

Antineutrophil cytoplasmic antibodies, anti-Saccharomyces cerevisiae antibodies, and specific IgE to food allergens in children with inflammatory bowel diseases.

Differential diagnosis between ulcerative colitis (UC) and Crohn's disease (CD) is difficult in the initial phases in pediatric patients with inflammatory bowel diseases (IBD). This study was performed to determine the significance of anti-neutrophil cytoplasmic antibodies (ANCA) and anti-Saccharomyces cerevisiae antibodies (ASCA) in IBD. ANCA were specified with regard to their antigenic specifity, significance to the diagnosis, and correlation of titer with the disease activity. The occurrence of food allergy was questioned, too. Serum samples from 44 children with UC (n = 23) or CD (n = 21) and from disease-control children (coeliac disease, n = 21) were analyzed for IgG ANCA, ANCA target antigens, IgA and IgG ASCA, and IgE to food allergens. Results show that ANCA occur more frequently in UC than in CD and disease-control (74, 24, and 10%, respectively). The presence of ANCA does not reflect disease activity. Antigenic specificity does not differ in any group. IgA-ASCA are found more often in patients with CD (76% versus 17% in UC). The testing for both ANCA and ASCA enabled clear-cut differential diagnosis between UC and CD based on the high specificity (ANCA+ ASCA- 92.5% for UC, ANCA- ASCA+ 93.2% for CD). Specific IgE to food allergens were found in 8.7, 14.3, and 23.8% of patients with UC, CD, and coeliac disease, respectively. We conclude that combined testing of ANCA and ASCA represents a valuable tool in the differential diagnosis between UC and CD in pediatric patients, minimizing invasive diagnostic procedures. Monitoring of ANCA, its specificity, and titer determination does not bring more information. Testing for specific IgE to food allergens may be considered in individual patients.

Antineutrophil cytoplasmic autoantibodies (ANCA) in children with cystic fibrosis.

Anti-neutrophil cytoplasmic antibodies (ANCA) represent a useful diagnostic tool in patients with small vessel vasculitis. Circulating ANCA specific for bactericidal/permeability increasing protein (BPI) have been recently reported in adult patients with cystic fibrosis (CF), an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene with consequent impaired function of a transmembrane chloride channel. To contribute to the better understanding of the significance of ANCA in this disease, we investigated ANCA presence and antigenic specificity in children with CF. Results were correlated with clinical status, immunological data, age and genotype. The indirect immunofluorescence pattern of a total of 71 children with CF indicated that 31 were c-ANCA positive, while seven were p-ANCA positive. In further ELISA studies of ANCA antigenic specificity, 51 out of 66 investigated samples were positive for BPI, and 14 out of 28 were positive for proteinase 3 (PR3). We found an association between levels of antibodies against PR3 with age and Pseudomonas infection. We did not, however, find any correlation between CFTR genotypes, Pseudomonas infection or paediatric parameters and the level of anti-BPI antibodies. High positivity of anti-BPI antibodies were seen even among the youngest CF patients, before the development of clinical signs of CF, indicating that formation of ANCA might be a very early event in the disease. Both anti-BPI and anti-PR3 antibodies may play a significant, although variable role, in the pathogenesis of CF.

Antineutrophil cytoplasmic antibodies in children.

UNLABELLED: To define the diagnostic meaning of antineutrophil cytoplasmic antibodies (ANCA) positivity in children, we analysed 1485 consecutive sera sent for routine immunological investigation to our department from January to August 1996. Using this large screening, we identified the most typical clinical disorders associated with ANCA in childhood. Out of 1485 indirect immunofluorescence (IIF) tests for ANCA, 143 were ANCA positive, 70 had a cytoplasmic IIF pattern (c-ANCA), and 73 a perinuclear IIF pattern (p-ANCA). The ANCA associated diseases in childhood were cystic fibrosis (CF) (31 c-ANCA, 7 p-ANCA positive out of 71 CF children investigated), juvenile chronic arthritis (JCA) (21 p-ANCA positive out of 78), auto-immune hepatitis (AIH) (4 c-ANCA and 12 p-ANCA positive out of 19), and ulcerative colitis (UC) (2 c-ANCA, 5 p-ANCA positive out of 15). In cases of c-ANCA positivity we determined the antigenic specificity of ANCA for proteinase 3 and/or bactericidal/permeability increasing protein. Borderline anti-proteinase 3 levels were found in CF, and in high levels in one boy with Wegener granulomatosis. Bactericidal/permeability increasing protein was characteristic target antigen in children with CF. p-ANCA positive children were further tested for the specificity for myeloperoxidase, which was detected mostly in children with JCA. CONCLUSION: The spectrum of diseases associated with ANCA in children includes, besides the diagnostic associations typical for adults, several typical pediatric entities, mainly juvenile chronic arthritis and cystic fibrosis.

Contribution to the serological diagnosis of sarcocystosis.

The importance of the IFA-test (Indirect Fluorescent Antibody Test) in the diagnosis of sarcocystosis in the intermediate host has been confirmed in the present paper. We assessed the time of the first appearance of serum antibodies in the intermediate host in mice inoculated experimentally with the species Sarcocystis dispersa. By means of the IFA-test, the first antibodies were found on day 20 p.i. Cross-reactions among antisera of S. dispersa and a heterologous antigen of S. cernae disclosed that the reaction was not species-specific, but genus-specific. In addition, we confirmed serologically that the antigenic structure of the genus Frenkelia was identical to that of the genus Sarcocystis, because the results of cross reactions obtained with the IFA-test were identical.

Contribution to the problem of cyst-producing coccidians.

The problem of life cycles of cyst-producing coccidians, mainly those of the genus Sarcocystis, from carnivorous birds has been discussed. Oocysts of the "sarcocystic" type have been recovered from 9 species of birds of prey and owls from Czechoslovakia. The course of experimental infection in a group of birds consisting of the species Tyto alba, Asio otus, Strix aluco, Buteo buteo has been described. We inoculated these birds with cystic stages of the genus Sarcocystis obtained from white laboratory mice (Mus musculus) infected previously with oocysts from Tyto alba. The nomenclature of heteroxenous coccidians of the genus Sarcocystis has been discussed and suggestions have been made for the use of simple, one-word specific names. A description is given of a new species of the genus Sarcocystis--Sarcocystis dispersa sp. n. Its asexual development and cyst production in Mus musculus (intermediate host), and cyst production in Tyto alba and Asio otus (definitive hosts) have been studied.