Publications by authors named "Tomas Kazda"

43 Publications

Drug interaction profile of TKI alectinib allows effective and safe treatment of ALK+ lung cancer in the kidney transplant recipient.

Int Immunopharmacol 2021 Jul 30;99:108012. Epub 2021 Jul 30.

Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, the Czech Republic; Department of Pharmacology, Faculty of Medicine, Masaryk University, 625 00 Brno, the Czech Republic; Department of Clinical Microbiology and Immunology, University Hospital Brno, Jihlavská 25, 625 00 Brno, the Czech Republic. Electronic address:

ALK targeting with tyrosine kinase inhibitors (TKIs) is a highly potent treatment option for the therapy of ALK positive non-small cell lung cancer (NSCLC). However, pharmacokinetics of TKIs leads to clinically significant drug interactions, and the interfering co-medication may hamper the anti-cancer therapeutic management. Here, we present for the first time a drug interaction profile of ALK-TKIs, crizotinib and alectinib, and immunosuppressive agent cyclosporine A in kidney transplant recipients diagnosed with ALK+ lung cancer. Based on therapeutic drug monitoring of cyclosporin A plasma level, the dose of cyclosporine A has been adjusted to achieve a safe and effective therapeutic level in terms of both cancer treatment and kidney transplant condition. Particularly, 15 years upon the kidney transplantation, the stage IV lung cancer patient was treated with the 1st-line chemotherapy, the 2nd-line ALK-TKI crizotinib followed by ALK-TKI alectinib. The successful therapy with ALK-TKIs has been continuing for more than 36 months, including the period when the patient was treated for COVID-19 bilateral pneumonia. Hence, the therapy of ALK+ NSCLC with ALK-TKIs in organ transplant recipients treated with cyclosporine A may be feasible and effective.
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http://dx.doi.org/10.1016/j.intimp.2021.108012DOI Listing
July 2021

The use of cisplatin in patients after kidney transplantation with chronic renal insufficiency: Is the benefit higher than potential risks in therapy of non-seminomatous germ cell tumors?

Medicine (Baltimore) 2021 Jun;100(24):e26381

Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute.

Rationale: The use of cisplatin in patients with chronic kidney disease (CKD) is risky and depends on a number of factors. The optimal procedure in stage I of a non seminomatous germ cell tumor without proven lymphangioinvasion after orchiectomy is controversial and is the subject of a number of discussions due to the lack of randomized studies assessing individual treatment options. The adjuvant method of choice is surveillance or application of cisplatin-based chemotherapy with the risk of treatment related nephrotoxicity. Information about cisplatin safety in renal transplant patients is particularly limited. The aim of this paper is to share the experience with the application of adjuvant chemotherapy Bleomycin, Etoposide, Cisplatin (BEP) in high-risk patient with nonseminoma after kidney transplantation.

Patient Concerns: We report a case report of rare group of high-risk patient with non-seminomatous germ cell testicular tumor (NSGCT) after kidney transplantation before application of adjuvant chemotherapy BEP. Patient presented with month-long discomfort in the scrotal area. Previously, he was treated with chronic kidney disease based on chronic glomerulonephritis, which was treated with repeated kidney transplantation.

Diagnosis: The ultrasound examination for a month-long discomfort in the scrotal area found a solid mass of the left testis. Radical inguinal orchiectomy confirmed NSGCT with the presence of lymphovascular invasion (LVI). Postoperative staging with computed tomography of the chest and abdomen did not show obvious dissemination of the disease.

Interventions: Reducing original dose of chemotherapeutics according to the recommendations of the summary of product characteristics led to only a transient increase in creatinine levels.

Outcomes: The 5-year risk of relapse in surveillance was reduced to around 3% by applying cisplatin-based chemotherapy.

Lessons: Application of cisplatin-based chemotherapy is safe and effective in patients with CKD and in patients with a kidney transplant.
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http://dx.doi.org/10.1097/MD.0000000000026381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213256PMC
June 2021

Neoadjuvant Chemotherapy of Triple-Negative Breast Cancer: Evaluation of Early Clinical Response, Pathological Complete Response Rates, and Addition of Platinum Salts Benefit Based on Real-World Evidence.

Cancers (Basel) 2021 Mar 30;13(7). Epub 2021 Mar 30.

Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic.

Pathological complete response (pCR) achievement is undoubtedly the essential goal of neoadjuvant therapy for breast cancer, directly affecting survival endpoints. This retrospective study of 237 triple-negative breast cancer (TNBC) patients with a median follow-up of 36 months evaluated the role of adding platinum salts into standard neoadjuvant chemotherapy (NACT). After the initial four standard NACT cycles, early clinical response (ECR) was assessed and used to identify tumors and patients generally sensitive to NACT. mutation, smaller unifocal tumors, and Ki-67 ≥ 65% were independent predictors of ECR. The total pCR rate was 41%, the achievement of pCR was strongly associated with ECR (OR = 15.1, < 0.001). According to multivariable analysis, the significant benefit of platinum NACT was observed in early responders ≥45 years, Ki-67 ≥ 65% and persisted lymph node involvement regardless of status. Early responders with pCR had a longer time to death (HR = 0.28, < 0.001) and relapse (HR = 0.26, < 0.001). The pCR was achieved in only 7% of non-responders. However, platinum salts favored non-responders' survival outcomes without statistical significance. Toxicity was significantly often observed in patients with platinum NACT ( = 0.003) but not for grade 3/4 ( = 0.155). These results based on real-world evidence point to the usability of ECR in NACT management, especially focusing on the benefit of platinum salts.
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http://dx.doi.org/10.3390/cancers13071586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036281PMC
March 2021

Effect of Acupuncture in Pain Management of Head and Neck Cancer Radiotherapy: Prospective Randomized Unicentric Study.

J Clin Med 2021 Mar 7;10(5). Epub 2021 Mar 7.

Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic.

This prospective randomized open-label trial aimed to evaluate the role of acupuncture in the treatment of pain related to curative and adjuvant (chemo)radiotherapy of head and neck cancer. Patients in two arms (30 patients in each arm) underwent standard oncology therapy and standard supportive care with or without acupuncture. The stratification factors were the type of treatment and chemotherapy indication. The toxicity assessed was represented by pain rated on a 10-point pain scale and analgesic use. Average pain (AP) and the worst pain during the day (WP) were significantly lower in the acupuncture arm during radiotherapy (AP median 0.16 vs. 1.36, < 0.001; WP median 0.90 vs. 1.96, < 0.001) and three months after radiotherapy (AP median 0.07 vs. 0.50, < 0.001; WP median 0.30 vs. 0.83, = 0.002). The analgesic consumption between arms was statistically significantly different. A median of the proportion of days when the patients used analgesics was 8% and 32.5% during radiotherapy ( = 0.047) and 0% and 20.8% during three months after radiotherapy ( = 0.006) for the acupuncture and control arm, respectively. Results point out lower analgesic consumption and milder pain in acupuncture arm. Acupuncture consequently offers another alternative to standard treatment leading to a reduction in the toxicity of oncological treatment.
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http://dx.doi.org/10.3390/jcm10051111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961644PMC
March 2021

Penis as a primary site of an extraskeletal Ewing sarcoma: A case report.

Medicine (Baltimore) 2021 Mar;100(11):e25074

Assoc. Prof. Department of Cancer Comprehensive Care Masaryk Memorial Cancer Institute Faculty of Medicine Masaryk University Zluty kopec 7, Brno, Czech Republic.

Rationale: The Ewing sarcoma family of malignant tumors is a group of tumors characterized by morphologically similar round-cell neoplasms and by the presence of a common chromosomal translocation; Ewing sarcoma family of tumors typically occur in children and young adults between 4 to 15 years of age. The primary tumor usually originates in the bone, extraskeletal localization is rare.

Patient Concern: We present a case report concerning a 32-year-old male patient with a primary involvement of the penis.

Diagnosis: The histopathology from the first penile biopsy showed a small-cell neuroendocrine carcinoma; however, that result was based on a sample obtained at a different facility than the Sarcoma Center, where the investigating pathologist did not have the adequate expertise. The patient then underwent a radical penectomy and a second reading of the histology was demanded after a radical penile amputation when Ewing sarcoma with R1 resection was confirmed.

Interventions: The patient was referred to the national Sarcoma Center, where - using a multidisciplinary approach - the treatment was started with curative intent. However, it was preceded by a non-standard initiation of the therapy due to the poor primary diagnosis.

Outcomes: The non-standard therapy at the onset of the disease caused a poor prognosis of an otherwise curable diagnosis. Despite all that, the patient survived for a relatively long time.

Lessons: The treatment of sarcomas with atypical localizations should be conducted by an experienced multidisciplinary team in a center with experience in sarcoma treatment.
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http://dx.doi.org/10.1097/MD.0000000000025074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982170PMC
March 2021

Stereotactic Body Radiotherapy for Lymph Node Oligometastases: Real-World Evidence From 90 Consecutive Patients.

Front Oncol 2020 5;10:616494. Epub 2021 Feb 5.

Department of Radiation Oncology, Masaryk Memorial Cancer Institute, Brno, Czechia.

Aims: To evaluate the efficacy and toxicity of extracranial stereotactic body radiotherapy (SBRT) in the treatment of oligometastatic lymph node involvement in the mediastinum, retroperitoneum, or pelvis, in a consecutive group of patients from real clinical practice outside clinical trials.

Methods: A retrospective analysis of 90 patients with a maximum of four oligometastases and various primary tumors (the most common being colorectal cancers). The endpoints were local control of treated metastases (LC), freedom from widespread dissemination (FFWD), progression-free survival (PFS), overall survival (OS), and freedom from systemic treatment (FFST). Acute and delayed toxicities were also evaluated.

Results: The median follow-up after SBRT was 34.9 months. The LC rate at three and five years was 68.4 and 56.3%, respectively. The observed median FFWD was 14.6 months, with a five-year FFWD rate of 33.7%. The median PFS was 9.4 months; the three-year PFS rate was 19.8%. The median FFST was 14.0 months; the five-year FFST rate was 23.5%. The OS rate at three and five years was 61.8 and 39.3%, respectively. Median OS was 53.1 months. The initial dissemination significantly shortened the time to relapse, death, or activation of systemic treatment-LC (HR 4.8, p < 0.001), FFWD (HR 2.8, p = 0.001), PFS (HR 2.1, p = 0.011), FFST (HR 2.4, p = 0.005), OS (HR 2.2, p = 0.034). Patients classified as having radioresistant tumors noticed significantly higher risk in terms of LC (HR 13.8, p = 0.010), FFWD (HR 3.1, p = 0.006), PFS (HR 3.5, p < 0.001), FFST (HR 3.2, p = 0.003). The multivariable analysis detected statistically significantly worse survival outcomes for initially disseminated patients as well as separately in groups divided according to radiosensitivity. No grade III or IV toxicity was reported.

Conclusion: Our study shows that targeted SBRT is a very effective and low toxic treatment for oligometastatic lymph node involvement. It can delay the indication of cytotoxic chemotherapy and thus improve and maintain patient quality of life. The aim of further studies should focus on identifying patients who benefit most from SBRT, as well as the correct timing and dosage of SBRT in treatment strategy.
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http://dx.doi.org/10.3389/fonc.2020.616494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892582PMC
February 2021

The Impact of Diabetes Mellitus on the Second Primary Malignancies in Colorectal Cancer Patients.

Front Oncol 2020 28;10:573394. Epub 2021 Jan 28.

Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czechia.

Introduction: All colorectal cancer (CRC) survivors have an increased risk of developing second primary malignancies (SPMs). The association between diabetes mellitus (DM) and the risk of cancer is well known. However, the role of DM and its therapy in the development of SPMs in CRC patients is not well described.

Methods: In this single-institutional retrospective analysis we identified 1,174 colorectal carcinoma patients, median follow-up 10.1 years, (median age 63 years, 724 men). All patients over 18 years with histologically confirmed CRC who were admitted in the period 1.1. 2003- 31.12.2013 and followed-up till 31.12. 2018 at the Masaryk Memorial Cancer Institute (MMCI) were screened for eligibility. The exclusion criteria were CRC diagnosed at autopsy, lost to follow-up and high risk of development of SPMs due to hereditary cancer syndrome. Tumours are considered multiple primary malignancies if arising in different sites and/or are of a different histology or morphology group. Comparisons of the basic characteristics between the patients with SPM and the patients without SPM were performed as well as comparison of the occurrence of SPMs by the site of diagnosis between the DM and non-DM cohorts and survival analyses.

Results: A SPM was diagnosed in 234 (20%) patients, DM in 183 (15%) patients. DM was diagnosed in 22.6% of those with SPM vs. in 13.8% of those without SPM (p=0.001). The most common types of SPMs in DM patients were other CRC, kidney, lung, bladder and nonmelanoma skin cancer, but only carcinoma of the liver and bile duct tracts was significantly more common than in the group without DM. Although breast cancer was the second most common in the group with DM, its incidence was lower than in the group without DM, as well as prostate cancer. A significantly higher incidence of SPMs was found in older CRC patients (≥ 65 years) and in those with lower stage colon cancer and DM. No significant difference in DM treatment between those with and without a SPM was observed including analysis of type of insulin.

Conclusion: CRC patients with diabetes mellitus, especially those with older age, and early stages of colon cancer, should be screened for second primary malignancies more often than the standard population. Patients without DM have longer survival. According to the occurrence of the most common second malignancies, a clinical examination, blood count, and ultrasound of the abdomen is appropriate, together with standard breast and colorectal cancer screening, and lung cancer screening under certain conditions, and should be recommended in CRC survivors especially in patients with intercurrent DM, however the necessary frequency of screening remains unclear.
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http://dx.doi.org/10.3389/fonc.2020.573394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878972PMC
January 2021

Second primary malignancies in colorectal cancer patients.

Sci Rep 2021 Feb 2;11(1):2759. Epub 2021 Feb 2.

Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic.

The prevalence of second primary malignancies (SPMs) in the western world is continually increasing with the risk of a new primary cancer in patients with previously diagnosed carcinoma at about 20%. The aim of this retrospective analysis is to identify SPMs in colorectal cancer patients in a single-institution cohort, describe the most frequent SPMs in colorectal cancer patients, and discover the time period to occurrence of second primary tumors. We identified 1174 patients diagnosed with colorectal cancer in the period 2003-2013, with follow-up till 31.12.2018, and median follow-up of 10.1 years, (median age 63 years, 724 men). A second primary neoplasm was diagnosed in 234 patients (19.9%). Older age patients, those with early-stage disease and those with no relapse have a higher risk of secondary cancer development. The median time from cancer diagnosis to development of CRC was 8.9 years for breast cancer and 3.4 years for prostate cancer. For the most common cancer diagnosis after primary CRC, the median time to development was 0-5.2 years, depending on the type of malignancy. Patients with a diagnosis of breast, prostate, or kidney cancer, or melanoma should be regularly screened for CRC. CRC patients should also be screened for additional CRC as well as cancers of the breast, prostate, kidney, and bladder. The screening of cancer patients for the most frequent malignancies along with systematic patient education in this field should be the standard of surveillance for colorectal cancer patients.
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http://dx.doi.org/10.1038/s41598-021-82248-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854629PMC
February 2021

Recurrent Nasopharyngeal Cancer: Critical Review of Local Treatment Options Including Recommendations during the COVID-19 Pandemic.

Cancers (Basel) 2020 Nov 25;12(12). Epub 2020 Nov 25.

Department of Radiation Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic.

Recurrent nasopharyngeal carcinoma represents an extremely challenging therapeutic situation. Given the vulnerability of the already pretreated neurological structures surrounding the nasopharynx, any potential salvage retreatment option bears a significant risk of severe complications that result in high treatment-related morbidity, quality of life deterioration, and even mortality. Yet, with careful patient selection, long-term survival may be achieved after local retreatment in a subgroup of patients with local or regional relapse of nasopharyngeal cancer. Early detection of the recurrence represents the key to therapeutic success, and in the case of early stage disease, several curative treatment options can be offered to the patient, albeit with minimal support in prospective clinical data. In this article, an up-to-date review of published evidence on modern surgical and radiation therapy treatment options is summarized, including currently recommended treatment modifications of both therapeutic approaches during the coronavirus disease 2019 pandemic.
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http://dx.doi.org/10.3390/cancers12123510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760235PMC
November 2020

Everolimus-related unilateral abdominal lymphedema in a renal cancer patient: A case report.

Medicine (Baltimore) 2020 Oct;99(42):e22634

Clinical Trial Unit, Masaryk Memorial Cancer Institute.

Rationale: Unilateral manifestation of lymphedema during everolimus therapy has been described only rarely, mostly in transplant recipients.

Patient Concerns: We report the first case of a patient who developed unilateral abdominal lymphedema, during a short period of everolimus treatment for renal cancer.

Diagnosis: The abdominal asymmetry occurred only on the right side of the abdomen, neither ultrasound nor CT scan detected ascites but showed enlargement of the abdominal wall. The Naranjo Adverse Drug Reaction Probability scale was evaluated, in this case, a score of 6 indicated a probable adverse reaction to everolimus.

Interventions: Discontinuation of everolimus therapy led to immediate alleviation and reduction of the lymphedema, with worsening once again after initiating retreatment with everolimus at a reduced dose.

Outcomes: The patient's lymphedema recovered after discontinuation of everolimus.

Lessons: This rare case demonstrates the importance of the selection of mammalian target of rapamycin inhibitors using caution, especially for patients with a high risk of developing lymphedema.
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http://dx.doi.org/10.1097/MD.0000000000022634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571978PMC
October 2020

Radical external beam re-irradiation in the treatment of recurrent head and neck cancer: Critical review.

Head Neck 2021 01 30;43(1):354-366. Epub 2020 Sep 30.

Department of Radiation Oncology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.

Management of patients with recurrent head and neck cancer remains a challenge for the surgeon as well as the treating radiation oncologist. Even in the era of modern radiotherapy, the rate of severe toxicity remains high with unsatisfactory treatment results. Intensity-modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), and heavy-ion irradiation have all emerged as highly conformal and precise techniques that offer many radiobiological advantages in various clinical situations. Although re-irradiation is now widespread in clinical practice, little is known about the differences in treatment response and toxicity using diverse re-irradiation techniques. In this review, we provide a comprehensive overview of the role of radiation therapy in recurrent or second primary head and neck cancer including patient selection, therapeutic outcome, and risk using different re-irradiation techniques. Critical review of published evidence on IMRT, SBRT, and heavy-ion full-dose re-irradiation is presented including data on locoregional control, overall survival, and toxicity.
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http://dx.doi.org/10.1002/hed.26485DOI Listing
January 2021

Pre-Radiotherapy Progression after Surgery of Newly Diagnosed Glioblastoma: Corroboration of New Prognostic Variable.

Diagnostics (Basel) 2020 Sep 5;10(9). Epub 2020 Sep 5.

Central European Institute of Technology, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic.

Background: The aim of this retrospective study is to assess the incidence, localization, and potential predictors of rapid early progression (REP) prior to initiation of radiotherapy in newly diagnosed glioblastoma patients and to compare survival outcomes in cohorts with or without REP in relation to the treatment.

Methods: We assessed a consecutive cohort of 155 patients with histologically confirmed irradiated glioblastoma from 1/2014 to 12/2017. A total of 90 patients with preoperative, postoperative, and planning MRI were analyzed.

Results: Median age 59 years, 59% men, and 39 patients (43%) underwent gross total tumor resection. The Stupp regimen was indicated to 64 patients (71%); 26 patients (29%) underwent radiotherapy alone. REP on planning MRI performed shortly prior to radiotherapy was found in 46 (51%) patients, most often within the surgical cavity wall, and the main predictor for REP was non-radical surgery (p < 0.001). The presence of REP was confirmed as a strong negative prognostic factor; median overall survival (OS) in patients with REP was 10.7 vs. 18.7 months and 2-year survival was 15.6% vs. 37.7% (hazard ratio HR 0.53 for those without REP; = 0.007). Interestingly, the REP occurrence effect on survival outcome was significantly different in younger patients (≤ 50 years) and older patients (> 50 years) for OS ( = 0.047) and non-significantly for PFS ( = 0.341). In younger patients, REP was a stronger negative prognostic factor, probably due to more aggressive behavior. Patients with REP who were indicated for the Stupp regimen had longer OS compared to radiotherapy alone (median OS 16.0 vs 7.5; HR = 0.5, = 0.022; 2-year survival 22.3% vs. 5.6%). The interval between surgery and the initiation of radiotherapy were not prognostic in either the entire cohort or in patients with REP.

Conclusion: Especially in the subgroup of patients without radical resection, one may recommend as early initiation of radiotherapy as possible. The phenomenon of REP should be recognized as an integral part of stratification factors in future prospective clinical trials enrolling patients before initiation of radiotherapy.
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http://dx.doi.org/10.3390/diagnostics10090676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555958PMC
September 2020

Real-World Evidence in Glioblastoma: Stupp's Regimen After a Decade.

Front Oncol 2020 3;10:840. Epub 2020 Jul 3.

Department of Radiation Oncology, Masaryk Memorial Cancer Institute, Brno, Czechia.

The aim of this retrospective study is to provide real-world evidence in glioblastoma treatment and to compare overall survival after Stupp's regimen treatment today and a decade ago. A current consecutive cohort of histologically confirmed glioblastoma irradiated from 1/2014 to 12/2017 in our cancer center was compared with an already published historical control of patients treated in 1/2003-12/2009. A total of new 155 patients was analyzed, median age 60.9 years, 61% men, 58 patients (37%) underwent gross total tumor resection. Stupp's regimen was indicated in 90 patients (58%), 65 patients (42%) underwent radiotherapy alone. Median progression-free survival in Stupp's regimen cohort was 6.7 months, median OS 16.0 months, and 2-year OS 30.7%. OS was longer if patients were able to finish at least three cycles of adjuvant chemotherapy (median 23.3 months and 43.9% of patients lived at 2 years after surgery). Rapid early progression prior to radiotherapy was a negative prognostic factor with HR 1.87 ( = 0.007). The interval between surgery and the start of radiotherapy (median 6.7 weeks) was not prognostically significant ( = 0.825). The median OS in the current cohort was about 2 months longer than in the historical control group treated 10 years ago (16 vs. 13.8 months) using the same Stupp's regimen. Taking into account differences in patient's characteristics between current and historical cohorts, age, extent of resection, and ECOG patient performance status adjusted HR (Stupp's regimen vs. RT alone) for OS was determined as 0.45 ( = 0.002).
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http://dx.doi.org/10.3389/fonc.2020.00840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348058PMC
July 2020

Acupuncture in the treatment of acute toxicity during and after head and neck cancer radiotherapy: Interim analysis of randomized prospective open-label trial.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2020 Dec 18;164(4):454-460. Epub 2020 Jun 18.

Department of Comprehensive Cancer Care, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic.

Aims: The aim of this investigator-initiated prospective randomized open-label single institutional trial is to evaluate the role of acupuncture in the treatment of acute skin and mucosal toxicity, xerostomia, and perception of taste, pain, and nausea related to curative and adjuvant (chemo)radiotherapy of head and neck cancer. This paper reports pilot data of the first 30 enrolled patients.

Methods: Patients were randomized to undergo standard of care radiotherapy ± chemotherapy and support care defined by our institutional standard operating procedures alone or in the combination with acupuncture which was initiated with the first signs of any toxicity.

Results: Fifteen patients were enrolled in both arms and all finished the treatment as planned.The median pain was significantly lower in the acupuncture arm (median 1.6 points vs. 2.5 points on a 10-item Likert scale; P=0.035) as well as duration of acute pain (median 31 days vs. 54 days; P=0.031). Patients with acupuncture had significantly shorter duration of acute skin (median 44 days vs. 109 days; P<0.001) and mucosal toxicity (median 34 days vs. 109 days; P<0.001) with no difference in grading of toxicity (median grade 1.6 vs. 1.5; P=0.701 and median grade 1.4 vs. 1.6; P=0.204 for skin and mucosa, respectively). No significant difference was found for other toxicity domains, with the exception of salivation toxicity which was significantly lower in acupuncture arm (median grade 1.3 vs. 1.7; P=0.048).

Conclusion: In this interim analysis, acupuncture leads to lower pain andfaster disappearance of skin and mucosal toxicity after (chemo)radiotherapy of head and neck cancer. Description and validation of acupuncture using scientific approaches will further enhance acceptance of this method by both patients and health care providers.

Trial Registration: Clinicaltrials.gov - NCT03751566.
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http://dx.doi.org/10.5507/bp.2020.021DOI Listing
December 2020

Prospective evaluation of contrast-enhanced ultrasound of breast BI-RADS 3-5 lesions.

BMC Med Imaging 2020 06 17;20(1):66. Epub 2020 Jun 17.

The Clinic of Radiology and Nuclear Medicine, The University Hospital Brno, Brno, Czech Republic.

Background: To determine the benefit of contrast-enhanced ultrasound (CEUS) in the assessment of breast lesions.

Methods: A standardized contrast-enhanced ultrasound was performed in 230 breast lesions classified as BI-RADS category 3 to 5. All lesions were subjected to qualitative and quantitative analysis. MVI (MicroVascular Imaging) technique was used to derive qualitative analysis parameters; blood perfusion of the lesions was assessed (perfusion homogeneity, type of vascularization, enhancement degree). Quantitative analysis was conducted to estimate perfusion changes in the lesions within drawn regions of interest (ROI); parameters TTP (time to peak), PI (peak intensity), WIS (wash in slope), AUC (area under curve) were obtained from time intensity (TI) curves. Acquired data were statistically analyzed to assess the ability of each parameter to differentiate between malignant and benign lesions. The combination of parameters was also evaluated for the possibility of increasing the overall diagnostic accuracy. Biological nature of the lesions was verified by a pathologist. Benign lesions without histopathological verification (BI-RADS 3) were followed up for at least 24 months.

Results: Out of 230 lesions, 146 (64%) were benign, 67 (29%) were malignant, 17 (7%) lesions were eliminated. Malignant tumors showed statistically significantly lower TTP parameters (sensitivity 77.6%, specificity 52.7%) and higher WIS values (sensitivity 74.6%, specificity 66.4%) than benign tumors. Enhancement degree also proved to be statistically well discriminating as 55.2% of malignant lesions had a rich vascularity (sensitivity 89.6% and specificity 48.6%). The combination of quantitative analysis parameters (TTP, WIS) with enhancement degree did not result in higher accuracy in distinguishing between malignant and benign breast lesions.

Conclusions: We have demonstrated that contrast-enhanced breast ultrasound has the potential to distinguish between malignant and benign lesions. In particular, this method could help to differentiate lesions BI-RADS category 3 and 4 and thus reduce the number of core-cut biopsies performed in benign lesions. Qualitative analysis, despite its subjective element, appeared to be more beneficial. A combination of quantitative and qualitative analysis did not increase the predictive capability of CEUS.
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http://dx.doi.org/10.1186/s12880-020-00467-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302394PMC
June 2020

The tumor immune microenvironment and its implications for clinical outcome in patients with oropharyngeal squamous cell carcinoma.

J Oral Pathol Med 2020 Oct 2;49(9):886-896. Epub 2020 Jul 2.

First Department of Pathology, St. Anne's University Hospital, Brno, Czech Republic.

Background: We examined PD-L1 expression on tumor cells (TCs) and immune cells (ICs) and density of CD3 and CD8 tumor-infiltrating lymphocytes (TILs) in patients with oropharyngeal squamous cell carcinoma (OPSCC) and investigated their significance on clinicopathological characteristics and clinical outcomes.

Methods: In a cohort of 65 patients treated by definitive intensity-modulated radiotherapy (IMRT) with curative intent, immunohistochemical analysis of PD-L1 expression on TCs and ICs, and TIL subtyping was performed on primary biopsy tumor tissues, followed by prognostic evaluation of these immune response-related parameters including classification into four tumor immune microenvironment (TIM) types. To evaluate HPV status, p16 immunohistochemistry was performed.

Results: Densities of CD3 and CD8 TILs and PD-L1 expressions on TCs and ICs were significantly higher in p16+/HPV-mediated OPSCC. Patients with high densities of stromal CD8 TILs displayed significantly better overall survival (OS) and progression-free survival (PFS). PD-L1 expression neither on tumor cells nor on immune cells affected survival outcomes. Distribution of TIM types based on the combination of PD-L1 expression on TCs and densities of CD8 TILs is significantly different in p16+ compared with p16- OPSCC. In type III TIM (TC-PD-L1+/low CD8 TIL density), significantly better OS was shown in p16+ group compared with p16- OPSCC.

Conclusion: The prognostic and predictive role of tumor immune microenvironment was confirmed for patients with OPSCC. Combining HPV status with the evaluation of densities of CD8 TILs and PD-L1 expression including TIM classification might be of high clinical interest and warrants further prospective evaluation.
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http://dx.doi.org/10.1111/jop.13055DOI Listing
October 2020

Targeted Radiotherapy of the Tumor Cavity after Surgical Resection of Aggressive Recurrent Brain Metastasis: A Case Report.

Case Rep Oncol 2020 Jan-Apr;13(1):233-238. Epub 2020 Mar 19.

Department of Radiation Oncology, Masaryk Memorial Cancer Institute, Brno, Czechia.

Postoperative management of patients with brain metastases is controversial. Besides local control, cognitive function and quality of life are the most important outcomes of postoperative radiotherapy. In this case report, we introduce a patient with aggressive recurred solid metastasis treated with repeated surgery and an individual radiotherapy approach in order to highlight that close mutual collaboration leads to a clear benefit for our patients. The local targeted radiotherapy with 35 Gy in 10 fractions was performed with the volumetric modulated arc technique, leading to more than 2.5 years of local control and survival without any of the side effects usually attributed to whole brain radiotherapy.
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http://dx.doi.org/10.1159/000506328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154243PMC
March 2020

Stereotactic Body Radiotherapy of Lymph Node Oligometastases.

Klin Onkol 2020 ;33(2):114-122

Background: The aim of this retrospective study is to evaluate the efficacy and toxicity of extracranial stereotactic radiotherapy for the treatment of oligometastatic lymph node involvement in the mediastinum, retroperitoneum, and pelvis in a consecutive group of patients from real clinical practice.

Material And Methods: Of a total of 50 patients treated between 2011 and 2017, 29 were men and 21 were women, and the mean age was 62 years (median 66 years, range 25-81 years). Patients were most often irradiated in five fractions; the dose was selected according to dose-volume histograms of organs-at-risk in proximity to the planning target volume. The primary objectives were local control (LC), progression-free survival (PFS), time to multiple dissemination not allowing the use of local treatment methods (freedom from widepread dissemination - FFWD), and overall survival (OS). Acute and delayed toxicity were evaluated as well.

Results: The median dose equivalent at α/β = 10 (BED10) was 54 Gy (range 48-80 Gy). The median follow-up period was 40.4 months. LC after irradiation was 90% in 1 year and 75% in 3 years. Median time to local progression was not achieved. Patients irradiated with a high dose had significantly better LC than patients irradiated with a low dose; the cut-off was the median of the applied dose (ie BED10 = 54 Gy). Pathological node localization had no significant effect on LC. The median PFS was 8.2 months (95% CI 7.4-11.6 months). PFS in 1 year was 38.5% and 17% in 3 years. The median OS was 37.3 months (95% CI 23.2-51.4 months). One-year OS was 83% and 3-year OS was 51%. The median FFWD was 13.6 months (range 8.7-18.5 months). The one-year FFWD was 55% and the 3-year FFWD was 24%. None of these parameters (PFS, OS, FFWD) was dose or localization dependent. No grade III or IV toxicity was reported.

Conclusion: Our study shows that targeted stereotactic radiotherapy is a very effective low toxic treatment for oligometastatic lymph node involvement. It can delay cytotoxic chemotherapy and thus improve/maintain the quality of life of patients. Approximately one fifth of patients treated with extracranial stereotactic radiotherapy for oligometastatic lymph node involvement survived without signs of disease for prolonged periods. Future studies should aim at identifying patients who would benefit most from this treatment, adjusting the timing of extracranial stereotactic radiotherapy depending on the treatment strategy, and optimizing the dose prescription. This work was supported by grant of the Ministry of Health of the Czech Republic AZV 19-00354 and by grant of the Ministry of Health of the Czech Republic - Conceptual development of a research organization (MMCI 00209805). 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.
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http://dx.doi.org/10.14735/amko2020114DOI Listing
January 2021

Salivary microRNAs identified by small RNA sequencing as potential predictors of response to intensity-modulated radiotherapy in head and neck cancer patients.

Cell Oncol (Dordr) 2020 Jun 7;43(3):505-511. Epub 2020 Apr 7.

Central European Institute of Technology, Masaryk University, Brno, Czech Republic.

Purpose: Progress in radiation therapy of head and neck squamous cell carcinomas (HNSCCs) is logically linked to the development of molecular predictors that would help to enhance individually tailored treatment. MicroRNA (miRNA) expression profiles in tumors have repeatedly been tested to optimize the molecular diagnostics of HNSCC. In addition to tumor tissues, miRNAs are stably present in body fluids, including saliva, and can thus be collected non-invasively. The aim of our current study was to evaluate whether salivary miRNAs have potential as response predictors in HNSCC patients treated with intensity modulated radiation therapy (IMRT).

Methods: In total 48 HNSCC patients treated by definitive IMRT were enrolled in our prospective study. To identify predictive salivary miRNAs, we used small RNA sequencing in 14 saliva samples of HNSCC patients and qRT-PCR validation of selected miRNA candidates in an independent set of 34 patients.

Results: We found that salivary miR-15a-5p and miR-15b-5p exhibited differential levels between patients with and without complete remission (p = 0.025 and p = 0.028, respectively). Subsequent Kaplan-Meier analysis confirmed that patients with higher levels of miR-15a-5p reached a significantly longer locoregional progression-free survival (LPFS) than those with low levels (p = 0.024). Finally, multivariate Cox regression analysis revealed that miR-15a-5p may serve as an independent predictive biomarker of LPFS in HNSCC patients treated with IMRT (HR 0.104; 95% CI 0.004-0.911; p = 0.04).

Conclusions: We conclude that salivary miR-15a-5p may represent a potential biomarker for individualized treatment decision-making in HNSCC patients.
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http://dx.doi.org/10.1007/s13402-020-00507-7DOI Listing
June 2020

Cerebrospinal Fluid MicroRNA Signatures as Diagnostic Biomarkers in Brain Tumors.

Cancers (Basel) 2019 Oct 12;11(10). Epub 2019 Oct 12.

Department of Neurosurgery, University Hospital Brno, Brno 625 00, Czech Republic.

Central nervous system (CNS) malignancies include primary tumors that originate within the CNS as well as secondary tumors that develop as a result of metastatic spread. Circulating microRNAs (miRNAs) were found in almost all human body fluids including cerebrospinal fluid (CSF), and they seem to be highly stable and resistant to even extreme conditions. The overall aim of our study was to identify specific CSF miRNA patterns that could differentiate among brain tumors. These new biomarkers could potentially aid borderline or uncertain imaging results onto diagnosis of CNS malignancies, avoiding most invasive procedures such as stereotactic biopsy or biopsy. In total, 175 brain tumor patients (glioblastomas, low-grade gliomas, meningiomas and brain metastases), and 40 non-tumor patients with hydrocephalus as controls were included in this prospective monocentric study. Firstly, we performed high-throughput miRNA profiling (Illumina small RNA sequencing) on a discovery cohort of 70 patients and 19 controls and identified specific miRNA signatures of all brain tumor types tested. Secondly, validation of 9 candidate miRNAs was carried out on an independent cohort of 105 brain tumor patients and 21 controls using qRT-PCR. Based on the successful results of validation and various combination patterns of only 5 miRNA levels (miR-30e, miR-140, let-7b, mR-10a and miR-21-3p) we proposed CSF-diagnostic scores for each tumor type which enabled to distinguish them from healthy donors and other tumor types tested. In addition to this primary diagnostic tool, we described the prognostic potential of the combination of miR-10b and miR-196b levels in CSF of glioblastoma patients. In conclusion, we performed the largest study so far focused on CSF miRNA profiling in patients with brain tumors, and we believe that this new class of biomarkers have a strong potential as a diagnostic and prognostic tool in these patients.
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http://dx.doi.org/10.3390/cancers11101546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826583PMC
October 2019

In silico study of pseudoprogression in glioblastoma: collaboration of radiologists and radiation oncologists in the estimation of extent of high dose RT region.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2020 Sep 13;164(3):307-313. Epub 2019 Sep 13.

Department of Radiation Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno, Czech Republic.

Background And Aim: Oncologists play a vital role in the interpretation of radiographic results in glioblastoma patients. Molecular pathology and information on radiation treatment protocols among others are all important for accurate interpretation of radiology images. One important issue that may arise in interpreting such images is the phenomenon of tumor "pseudoprogression"; oncologists need to be able to distinguish this effect from true disease progression.Exact knowledge about the location of high-dose radiotherapy region is needed for valid determination of pseudoprogression according to RANO (Response Assessment in Neuro-Oncology) criteria in neurooncology. The aim of the present study was to evaluate the radiologists' understanding of a radiotherapy high-dose region in routine clinical practice since radiation oncologists do not always report 3-dimensional isodoses when ordering follow up imaging.

Methods: Eight glioblastoma patients who underwent postresection radiotherapy were included in this study. Four radiologists worked with their pre-radiotherapy planning MR, however, they were blinded to RT target volumes which were defined by radiation oncologists according to current guidelines. The aim was to draw target volume for high dose RT fields (that is the region, where they would consider that there may be a pseudoprogression in future MRI scans). Many different indices describing structure differences were analyzed in comparison with original per-protocol RT target volumes.

Results: The median volume for RT high dose field was 277 ccm (range 218 to 401 ccm) as defined per protocol by radiation oncologist and 87 ccm (range 32-338) as defined by radiologists (median difference of paired difference 31%, range 15-112%). The Median Dice index of similarity was 0.46 (range 0.14 - 0.78), the median Hausdorff distance 25 mm.

Conclusion: Continuing effort to improve education on specific procedures in RT and in radiology as well as automatic tools for exporting RT targets is needed in order to increase specificity and sensitivity in response evaluation.
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http://dx.doi.org/10.5507/bp.2019.039DOI Listing
September 2020

Current Perspective on HPV-Associated Oropharyngeal Carcinomas and the Role of p16 as a Surrogate Marker of High-Risk HPV.

Klin Onkol 2019 ;32(4):252-260

Background: The incidence of oropharyngeal carcinomas associated with human papillomavirus (HPV) is continuously increasing. HPV-positive and -negative oropharyngeal carcinomas have different epidemiological, clinical, and molecular features, with HPV-positive tumors having a better response to treatment and better prognosis. An adequate staging system for HPV-related oropharyngeal carcinomas is needed, as the American Joint Committee on Cancer 7th Edition did not consider their unique biological behavior. At present, oropharyngeal carcinomas are subdivided into p16 positive and p16 negative tumors, based on their expression of p16, a surrogate marker of high-risk HPV.

Purpose: This review summarizes current knowledge of HPV-associated oropharyngeal carcinomas with emphasis on their molecular features and histopathology, as well as summarizes and compares HPV detection methods and genotyping techniques. This review also describes the prognostic significance of p16 expression in these tumors and significant changes in the staging of oropharyngeal carcinomas based on p16 expression, together with the justifications for these changes. Finally, this review reports the recommendations of the College of American Pathologists for testing HPV in head and neck cancers, supported by the American Society of Clinical Oncology. This work was supported by the Ministry of Health of the Czech Republic, grant No. 15-31627A. All rights reserved. Autoři deklarují, že v souvislosti s předmětem studie nemají žádné komerční zájmy. Redakční rada potvrzuje, že rukopis práce splnil ICMJE kritéria pro publikace zasílané do biomedicínských časopisů. Submitted: 18. 2. 2019 Accepted: 30. 5. 2019.
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http://dx.doi.org/10.14735/amko2019252DOI Listing
January 2020

Effectiveness of Neoadjuvant Therapy with Platinum-Based Agents for Patients with BRCA1 and BRCA2 Germline Mutations - A Retrospective Analysis of Breast Cancer Patients Treated at MMCI Brno.

Klin Onkol 2019 ;32(Supplementum2):31-35

Background: Mutations in the BRCA1 and BRCA2 genes are associated with a high risk of developing breast cancer. Tumors arising from this mutation are expected to be more sensitive to platinum-based drugs. The role of platinum-based drugs in systemic neoadjuvant BRCA1/2 breast cancer therapy, and its efficacy in increasing the probability of pathological complete remission (pCR) are discussed repeatedly; however, there are no clear recommendations.

Patients And Methods: We retrospectively evaluated the contribution of a platinum-based antineoplastic drug to the achievement of pCR in a set of patients with BRCA1/2 mutant breast cancer treated with neoadjuvant chemotherapy from 2010 to 2017. The response to neoadjuvant chemotherapy was evaluated by a pathologist using definitive surgical specimens. A pCR was defined as a condition in which complete invasive breast cancer, and (eventually) positive lymph nodes, had disappeared.

Results: Of 76 patients (median age, 39 years; 62% with triple negative breast cancer (TNBC); 70% with BRCA1 positivity), 37 were treated with platinum-based drugs. More patients treated with platinum derivatives achieved pCR (57% vs. 23%, p = 0.005). Patients treated in a neoadjuvant setting with platinum-based antineoplastic drugs had a 4.4× greater chance of achieving pCR than those not treated with platinum, assuming the same tumor phenotype (TNBC or SR+/HER2).

Conclusion: Neoadjuvant platinum-based chemotherapy for patients with a BRCA1/2 mutation is associated with a higher probability of achieving pCR, which is important for subsequent prognosis. This treatment should be considered particularly for patients with BRCA1 mutation and a TNBC phenotype. This work was supported by grant of the Ministry of Health of the Czech Republic - Conceptual. Development of a Reaserch Organization (MMCI 00209805). This work was supported by grant of the Ministry of Education, Youth and Sport of the Czech Republic (NPU I - LO1413). The authors declare they have no potential confl icts 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: 21. 3. 2019 Accepted: 14. 5. 2019.
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http://dx.doi.org/10.14735/amko2019S31DOI Listing
January 2020

MicroRNA-15b-5p Predicts Locoregional Relapse in Head and Neck Carcinoma Patients Treated With Intensity-modulated Radiotherapy.

Cancer Genomics Proteomics 2019 Mar-Apr;16(2):139-146

Central European Institute of Technology, Masaryk University, Brno, Czech Republic

Background/aim: Head and neck cancers are a heterogenous group of epithelial tumors represented mainly by squamous cell carcinomas (HNSCC), which are the sixth most common type of cancer worldwide. Surgery together with radiotherapy (RT) is among the basic treatment modalities for most HNSCC patients. Various biomarkers aiming to predict patients' response to RT are currently investigated. The reason behind this effort is, on one hand, to distinguish radioresistant patients that show weak benefit from RT and, on the other hand, reduce the ionizing radiation dose in less aggressive radiosensitive HNSCC with possibly less acute or late toxicity.

Materials And Methods: A total of 94 HNSCC patients treated by definitive intensity-modulated radiotherapy were included in our retrospective study. We used a global expression analysis of microRNAs (miRNAs) in 43 tumor samples and validated a series of selected miRNAs in an independent set of 51 tumors.

Results: We identified miR-15b-5p to be differentially expressed between patients with short and long time of locoregional control (LRC). Kaplan-Meier analysis confirmed that HNSCC patients with higher expression of miR-15b-5p reach a significantly longer locoregional relapse-free survival compared to patients expressing low levels. Finally, multivariable Cox regression analysis revealed that miR-15b-5p is an independent predictive biomarker of LRC in HNSCC patients (HR=0.25; 95% CI=0.05-0.78; p<0.016).

Conclusion: miR-15b-5p represents a potentially helpful biomarker for individualized treatment decisions concerning the management of HNSCC patients.
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http://dx.doi.org/10.21873/cgp.20119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489689PMC
June 2019

Incidence of Hippocampal Metastases: Laterality and Implications for Unilateral Hippocampal Avoiding Whole Brain Radiotherapy.

Biomed Res Int 2018 13;2018:2459608. Epub 2018 Dec 13.

Department of Comprehensive Cancer Care, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic.

Introduction: Hippocampi sparing whole brain radiotherapy (WBRT) is an evolving approach in the treatment of patients with multiple brain metastases, pursuing mitigation of verbal memory decline as a consequence of hippocampal radiation injury. Accumulating data are showing different postradiotherapy changes in the left and right hippocampus with a theoretical proposal of only unilateral (dominant, left) hippocampal sparing during WBRT.

Method: The aim of this retrospective study is to describe spatial distribution of brain metastases on MRI in a cohort of 260 patients (2595 metastases) and to evaluate distribution separately in the left and right hippocampus and in respective hippocampal avoiding zones (HAZ, region with subtherapeutic radiation dose), including evaluation of location of metastatic mass centre.

Results: The median number of brain metastases was three, with lung cancer being the most common type of primary tumour; 36% had single metastasis. Almost 8% of patients had metastasis within hippocampus (1.1% of all metastases) and 18.1% of patients within HAZ (3.3% of all metastases). No statistically significant difference was observed in the laterality of hippocampal involvement, also when the location of centre of metastases was analyzed. There were more patients presenting the centre of metastasis within left (15) versus right (6) HAZ approaching the borderline of statistical significance.

Conclusion: No significant difference in the laterality of BM seeding within hippocampal structures was observed. The hypothesized unilateral sparing WBRT would have theoretical advantage in about 50% reduction in the risk of subsequent recurrence within spared regions.
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http://dx.doi.org/10.1155/2018/2459608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311293PMC
April 2019

Expression of CD44, EGFR, p16, and their mutual combinations in patients with head and neck cancer: Impact on outcomes of intensity-modulated radiation therapy.

Head Neck 2019 04 15;41(4):940-949. Epub 2018 Dec 15.

Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic.

Background: Progress in radiation treatment of head and neck squamous cell carcinoma (HNSCC) deserves the studies focused on molecular predictors that would help to enhance individually tailored treatment.

Methods: p16/epidermal growth factor receptor (EGFR)/cluster of differentiation-44 (CD44) was immunohistochemically analyzed in 165 HNSCC patients.

Results: In the entire group and the p16 negative cohort, better 3-year overall survival and locoregional control correlated with p16 positivity, CD44, and EGFR negativity were observed. Combined analysis revealed the worst results in the CD44+/p16-, EGFR+/p16-, and EGFR+/CD44+ groups and in the EGFR+/CD44+ within p16 negative cohort. Multivariate analysis found tumor stage, Karnofsky index, p16, and CD44 as prognostic factors of overall survival and clinical stage, and p16 as a prognostic factor for locoregional control. Clinical stage and Karnofsky index affected overall survival and tumor stage. EGFR affected locoregional control in the p16 negative subgroup.

Conclusion: Our study confirmed the negative effect of CD44 and EGFR and the positive effect of p16 on radiotherapy results.
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http://dx.doi.org/10.1002/hed.25533DOI Listing
April 2019

Prognostic impact of combined immunoprofiles in oropharyngeal squamous cell carcinoma patients with respect to AJCC 8th edition.

J Oral Pathol Med 2018 Oct 25;47(9):864-872. Epub 2018 Aug 25.

Central European Institute of Technology, Masaryk University, Brno, Czech Republic.

Objectives: To examine combined immunoprofiles of epidermal growth factor receptor (EGFR), CD44, and p16 in oropharyngeal squamous cell carcinoma (OPSCC) and to correlate them with radiotherapy treatment outcomes and clinicopathological parameters. Prognostic impact of the American Joint Committee on Cancer (AJCC) 8th edition staging system in comparison with 7th edition was analyzed.

Methods: The study included 77 OPSCC patients treated by definitive intensity-modulated radiotherapy (IMRT). Clinical staging was assessed according to the AJCC, both 7th and 8th edition. Immunohistochemical (IHC) analysis of CD44 and EGFR was performed on primary biopsy tumor tissues. To evaluate the HPV status, IHC detection of p16 was employed.

Results: The AJCC 8th edition staging system revealed correlations between overall survival (OS), progression-free survival (PFS), locoregional control (LRC), and clinical stage. EGFR and CD44 positivity (+) and p16 negativity (-) were associated with clinical stage IV of the disease. CD44+ and EGFR+ OPSCC displayed worse OS and LRC, and these cases also showed the worst 3-year OS and LRC. Combined analysis of protein expressions identified an association between p16- and EGFR+, p16- and CD44+, EGFR+, and CD44+. Combined immunoprofiles CD44+/p16-, EGFR+/p16-, and EGFR+/CD44+ were associated with worst OS and LRC.

Conclusions: Combined immunoprofiles of p16, EGFR, and CD44 might provide valuable prognostic and predictive information for the individual OPSCC patients, especially in terms of response to IMRT and prediction of treatment outcomes. Application of the AJCC 8th edition staging for HPV+ OPSCC proved to improve hazard discrimination and prognostication of OPSCC.
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http://dx.doi.org/10.1111/jop.12772DOI Listing
October 2018

Radiotherapy of Glioblastoma 15 Years after the Landmark Stupp's Trial: More Controversies than Standards?

Radiol Oncol 2018 Jun 6;52(2):121-128. Epub 2018 Jun 6.

Department of Comprehensive Cancer Care, Faculty of Medicine, Masaryk University, Brno, Czech Republic.

Background: The current standard of care of glioblastoma, the most common primary brain tumor in adults, has remained unchanged for over a decade. Nevertheless, some improvements in patient outcomes have occurred as a consequence of modern surgery, improved radiotherapy and up-to-date management of toxicity. Patients from control arms (receiving standard concurrent chemoradiotherapy and adjuvant chemotherapy with temozolomide) of recent clinical trials achieve better outcomes compared to the median survival of 14.6 months reported in Stupp's landmark clinical trial in 2005. The approach to radiotherapy that emerged from Stupp's trial, which continues to be a basis for the current standard of care, is no longer applicable and there is a need to develop updated guidelines for radiotherapy within the daily clinical practice that address or at least acknowledge existing controversies in the planning of radiotherapy.The goal of this review is to provoke critical thinking about potentially controversial aspects in the radiotherapy of glioblastoma, including among others the issue of target definitions, simultaneously integrated boost technique, and hippocampal sparing.

Conclusions: In conjunction with new treatment approaches such as tumor-treating fields (TTF) and immunotherapy, the role of adjuvant radiotherapy will be further defined. The personalized approach in daily radiotherapy practice is enabled with modern radiotherapy systems.
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http://dx.doi.org/10.2478/raon-2018-0023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043880PMC
June 2018

Second cancers in Hodgkin's lymphoma long-term survivals: A 60-year single institutional experience with real-life cohort of 871 patients.

Int J Clin Pract 2018 Jul 16:e13235. Epub 2018 Jul 16.

Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic.

Background And Purpose: Appropriate surveillance guidelines for patients after successful treatment of Hodgkin's lymphoma (HL) are needed to reduce mortality of iatrogenic secondary cancers (SC). This large single institutional retrospective study analyses the risk of SC in HL patients treated outside of clinical trials over past decades.

Material And Methods: Consecutive series of HL patients were analysed with median follow-up 12 years. Standardised incidence ratio (SIR) and absolute excess risk (AER) were calculated for site-specific risk of SC.

Results: In total of 871 patients (491 men; median age 34 years), chemotherapy alone, radiotherapy alone, and combined treatment underwent 36%, 40%, and 24% patients. 154 SC were found with significantly increased SIR = 2.9 and AER = 80.8 for all cancers except of nonmelanoma-skin cancer. SC-related death occurred in 71 patients (15% of those who died, 8% of whole cohort). The most common SC were lung (17.5% of all malignancies, SIR = 3.2), breast carcinoma (15.6%, SIR = 4.4), and haematological malignancy (non-Hodgkin's lymphoma SIR = 13.1; leukaemia SIR = 5.8). For SC within radiation field, the highest AER was in breast (AER = 46.9), colorectal (AER = 22.8), and lung cancer (AER = 17).

Conclusions: Patients with HL are generally at great risk of developing SC, which is significantly increased especially by the use of radiotherapy. We suggested special follow-up schema for patients after initial HL treatment suitable for daily real-world clinical practice. The system depends on gender, form of HL treatment and especially the form of radiation therapy in terms of location of radiation fields.
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http://dx.doi.org/10.1111/ijcp.13235DOI Listing
July 2018

Dosimetric impact of amino acid positron emission tomography imaging for target delineation in radiation treatment planning for high-grade gliomas.

Phys Imaging Radiat Oncol 2018 Apr 22;6:94-100. Epub 2018 Jun 22.

Department of Radiation Oncology, Mayo Clinic, Rochester, MN, United States.

Background And Purpose: The amino-acid positron emission tomography (PET) tracer 3,4-dihydroxy-6-[F] fluoro-l-phenylalanine (F-DOPA) has increased sensitivity for detecting regions of biologically aggressive tumors compared to T1 contrast-enhanced (T1-CE) magnetic resonance imaging (MRI). We performed dosimetric evaluation of treatment plans prepared with and without inclusion of F-DOPA-based biological target volume (BTV) evaluating its role in guiding radiotherapy of grade III/IV gliomas.

Materials And Methods: Eight patients (five T1-CE, three non-contrast-enhancing [NCE]) were included in our study. MRI only-guided anatomic plans and MRI+FDOPA-PET-guided biologic plans were prepared for each patient, and dosimetric data for target volumes and organs at risk (OAR) were compared. High-dose BTV was defined as regions with tumor to normal brain (T/N) >2.0, while low-dose BTV was initially based on T/N >1.3, but refined per Nuclear Medicine expert.

Results: For T1-CE tumors, planning target volumes (PTV) were larger than MRI-only anatomic target volumes. Despite increases in size of both gross target volumes and PTV, with volumetric-modulated arc therapy planning, no increase of dose to OAR was observed while maintaining similar target dose coverage. For NCE tumors, MRI+F-DOPA PET biologic imaging identified a sub-region of the large, T2-FLAIR abnormal signal which may allow a smaller volume to receive the high dose (60 Gy) radiation.

Conclusions: For T1-CE tumors, PTVs were larger than MRI-only anatomic target volumes with no increase of dose to OARs. Therefore, MRI+F-DOPA PET-based biologic treatment planning appears feasible in patients with high-grade gliomas.
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http://dx.doi.org/10.1016/j.phro.2018.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807641PMC
April 2018
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