Pretreatment Circulating HPV16 DNA Viral Load Predicts Risk of Distant Metastasis in Patients with HPV16-Positive Oropharyngeal Cancer.

BACKGROUND: There are definite reasons to implement molecular diagnostics based on the measurement of human papillomavirus (HPV) DNA in liquid biopsy into clinical practice. It is a quick, repeatable, and health-safe test for cancer biomarkers in the blood. In this study, we investigated whether the circulating tumor-related HPV16 (ctHPV16) viral load (VL) in patients with oropharyngeal squamous cell carcinoma (OPSCC) was important for determining the risk of locoregional recurrence-free survival (LRFS), metastasis-free survival (MFS), and overall survival (OS). METHODS: This study included 91 patients with ctHPV16-positive OPSCC who had been treated with radical radiotherapy and chemotherapy. The VL was measured using quantitative PCR (qPCR) and a probe specific for HPV16. Based on 10 years of follow-up, the 2-, 3-, 5-, and 9-year LRFS, MFS, and OS were estimated. RESULTS: The 5-year actuarial LRFS, MFS, and OS rates of patients with ctHPV16-positive/OPSCC were 88%, 90%, and 81%, respectively. The VL was significantly higher in patients who subsequently developed distant metastases (DM) than in those who did not (VL 4.09 vs. 3.25; p = 0.009). In a Cox proportional hazards regression model for MFS, a higher ctHPV16 VL appeared to be a significant independent prognostic factor for the occurrence of DM (HR 2.22, p = 0.015). The ROC curve revealed a cutoff value of 3.556 for VL (p = 0.00001). CONCLUSIONS: A high VL before treatment indicates patients with a significant risk of DM, and should be used in OPSCC treatment stratification.

Rectum and Bladder Toxicity in Postoperative Prostate Bed Irradiation: Dose-Volume Parameters Analysis.

Although prostate cancer treatment is increasingly effective, its toxicities pose a major concern. The aim of our study was to assess the rate of adverse events (AEs) and the prognostic value of dose-volume histogram (DVH) parameters for the occurrence of treatment toxicity in patients treated with post-prostatectomy prostate bed radiotherapy (RT). The AEs were scored according to the CTCAE v.5.0. The rectum and bladder were contoured according to the RTOG Guidelines. The DVH parameters were assessed using data exported from the ECLIPSE treatment-planning system. Genitourinary (GU) and gastrointestinal (GI) toxicity were analysed using consecutive dose thresholds for the percentage of an organ at risk (OAR) receiving a given dose and the QUANTEC dose constraints. A total of 213 patients were included in the final analysis. Acute grade 2 or higher (≥G2) GU AEs occurred in 18.7% and late in 21.3% of patients. Acute ≥G2 GI toxicity occurred in 11.7% and late ≥G2 in 11.2% of the patients. Five patients experienced grade 4 AEs. The most common adverse effects were diarrhoea, proctitis, cystitis, and dysuria. The most significant predictors of acute ≥G2 GI toxicity were rectum V47 and V46 (p < 0.001 and p < 0.001) and rectum wall V46 (p = 0.001), whereas the most significant predictors of late ≥G2 GI AEs were rectum wall V47 and V48 (p = 0.019 and p = 0.021). None of the bladder or bladder wall parameters was significantly associated with the risk of acute toxicity. The minimum doses to bladder wall (p = 0.004) and bladder (p = 0.005) were the most significant predictors of late ≥G2 GU toxicity. Postoperative radiotherapy is associated with a clinically relevant risk of AEs, which is associated with DVH parameters, and remains even in patients who fulfil commonly accepted dose constraints. Considering the lack of survival benefit of postoperative adjuvant RT, our results support delaying treatment through an early salvage approach to avoid or defer toxicity.

Intracranial Germinoma-Association between Delayed Diagnosis, Altered Clinical Manifestations, and Prognosis.

BACKGROUND: Intracranial germinoma is a rare malignant neoplasm of the central nervous system (CNS) that occurs in children and young adults. The aim of our study was to assess the initial manifestation of the disease, and to find differences in outcomes dependent on time of diagnosis. METHODS: The study group consisted of 35 consecutive patients (adults and children) who were treated for intracranial germinoma with radiotherapy at a tertiary centre, and their data were retrospectively collected. We evaluated time from the first symptoms to diagnosis and divided patients into early and delayed diagnosis groups. Delayed diagnosis has been defined as the time from initial presentation to final diagnosis longer than six months. RESULTS: A total of 17 (48.6%) of the patients had delayed diagnoses. Patient survival data spanned a median of six (interquartile range 3-12) years. At the time of the diagnosis, patients presented exclusively neurological symptoms in 16 (45.7%) cases, exclusively endocrinological symptoms in five (14.3%) cases, and mixed symptoms in the remaining cases (n = 14; 40.0%). Patients with neurological symptoms had shorter time (p < 0.001) from first symptoms to the final diagnosis (5.91 months) than in patients without them (19.44 months). The delayed diagnosis group presented significantly smaller tumour size (mean maximal dimension 2.35 cm) compared to early diagnosis group (3.1 cm). The 5-year and 10-year survival rates of our patients were 94.3% and 83.4%, respectively. Patients with a delayed diagnosis (n = 17) had a significantly worse (p = 0.02) 10-year OS (63%) compared to the early diagnosis group (n = 18; OS = 100%). Importantly, in five patients (14.29%), initial manifestation occurred before radiological signs of the disease. CONCLUSION: Our study stresses the need for timely diagnosis in intracranial germinoma, as a delay has a significant impact on the prognosis. In particular, if the tumour is small or causes exclusively endocrinological symptoms, the diagnosis may be difficult and delayed.

Brachytherapy boost improves survival and decreases risk of developing distant metastases compared to external beam radiotherapy alone in intermediate and high risk group prostate cancer patients.

BACKGROUND AND PURPOSE: Despite several prospective trials showing a clinical benefit of combining external beam radiotherapy (EBRT) with brachytherapy boost (BTB) for the treatment of intermediate- and high-risk prostate cancer (PCa) patients, none of these trials was designed to test for a survival difference. In this study, we aimed to collect a large multi-institutional database to determine whether BT boost was associated with a statistically significant improvement in survival and a reduction of distant metastases based on real-world data. MATERIAL AND METHODS: We collected the data of patients treated for intermediate- or high-risk PCa with definitive EBRT or BTB, with or without androgen deprivation therapy (ADT), between January 2003 and December 2014 at two tertiary institutions. The statistical endpoints included overall survival (OS), freedom from distant metastases (FFDM), and metastases-free survival (MFS). The impact of treatment modality was assessed using Cox regression models and log-rank testing after one-to-one propensity score matching. RESULTS: A total of 1641 patients treated with EBRT (n = 1148) or high-dose-rate BTB (n = 493) were analyzed. The median survival and clinical follow-up were 117.8 (IQR 78-143.3) and 60.7 months, respectively. The radiotherapy modality (BTB) remained an independent prognostic factor for OS (HR 0.75; 95% CI 0.63-0.88; p < 0.001), FFDM (HR 0.54; 95% CI 0.4-0.73; p < 0.001), and MFS (HR 0.72; 95% CI 0.61-0.85; p < 0.001). After propensity score matching, the remaining 986 patients were well-balanced in terms of age, maximum PSA, ISUP grade group, and TNM T stage. OS (p < 0.001), FFDM (p = 0.001) and MFS (p < 0.001) were significantly higher in the BTB group. CONCLUSIONS: There is a strong positive association between BTB and OS, FFDM, and MFS in PCa patients treated with definitive RT for intermediate- or high-risk PCa.

Circulating HPV16 DNA in Blood Plasma as Prognosticator and Early Indicator of Cancer Recurrence in Radio-Chemotherapy for Anal Cancer.

BACKGROUND: Implementation of anal squamous cell carcinoma (ASCC) treatment modifications requires reliable patient risk stratification. The circulating tumor-related human papillomavirus type 16 (ctHPV16) may play a role in predicting survival or assessing treatment response. METHODS: The study included 62 ASCC patients treated with chemoradiotherapy. A threshold of 2.5 was used to determine the maximum standardized uptake value (SUVmax). The ctHPV16 viral load (VL) was quantified by qPCR. RESULTS: In the multivariate Cox analysis, lower SUVmax (p = 0.047) and ctHPV16-positive (p = 0.054) proved to be independent prognostic factors for favorable overall survival (OS). In the subgroup with the higher SUVmax, ctHPV16 and nodal (N) status were independent prognostic factors with p = 0.022 for ctHPV16 and p = 0.053 for N. The best survival rate (95%) presented ctHPV16-positive/N-negative patients. High ctHPV16 VL tended to be slightly specific for patients younger than 63 years (p = 0.152). The decrease in ctHPV16 VL to undetectable level after the end of treatment correlated with the overall clinical response. CONCLUSIONS: A prognostic stratification by SUVmax, ctHPV16 and N-positive status allows consideration of more aggressive treatment in high-risk patients (those with high SUVmax, ctHPV16-negative, and N-positive) or de-intensification of therapy in low-risk patients (those with low SUVmax, ctHPV16-positive and N-negative). However, prospective clinical trials on a large group are needed.

Pre-Treatment Hemoglobin Concentration and Absolute Monocyte Count as Independent Prognostic Factors for Survival in Localized or Locally Advanced Prostate Cancer Patients Undergoing Radiotherapy.

The prognostic value of inflammatory indices, such as the absolute monocyte count (AMC), has been a subject of interest in recent prostate cancer (PCa) studies, while hemoglobin concentration (HGB) has been recognized as a survival factor in castration-resistant metastatic prostate cancer, but its value remains unclear in localized diseases. The aim of this study was to test the prognostic value of these two simple and inexpensive biomarkers for survival and was based on a cohort of 1016 patients treated with primary radiotherapy and androgen deprivation therapy for localized or locally advanced intermediate- or high-risk PCa. Complete survival data were available for all cases and were based on the National Cancer Registry, with a median observation time of 120 months (Interquartile Range (IQR) 80.9-144.7). Missing blood test data were supplemented using the Nearest Neighbor Imputation, and the Cox Proportional Hazards Regression model was used for analysis. The median age was 68.8 years (IQR 63.3-73.5). The five-year overall survival was 82.8%, and 508 patients were alive at the time of analysis. The median time between blood tests and the first day of radiotherapy was 6 days (IQR 0-19). HGB (p = 0.009) and AMC (p = 0.003) were independent prognostic factors for survival, along with age, Gleason Grade Group, clinical T stage and maximum prostate-specific antigen concentration. This study demonstrates that HGB and AMC can be useful biomarkers for overall survival in patients treated with radiotherapy for localized intermediate- or high-risk PCa.

The Reassessed Potential of SARS-CoV-2 Attenuation for COVID-19 Vaccine Development-A Systematic Review.

Live-attenuated SARS-CoV-2 vaccines received relatively little attention during the COVID-19 pandemic. Despite this, several methods of obtaining attenuated coronaviruses are known. In this systematic review, the strategies of coronavirus attenuation, which may potentially be applied to SARS-CoV-2, were identified. PubMed, Scopus, Web of Science and Embase databases were searched to identify relevant articles describing attenuating mutations tested in vivo. In case of coronaviruses other than SARS-CoV-2, sequence alignment was used to exclude attenuating mutations that cannot be applied to SARS-CoV-2. Potential immunogenicity, safety and efficacy of the attenuated SARS-CoV-2 vaccine were discussed based on animal studies data. A total of 27 attenuation strategies, used to create 101 different coronaviruses, have been described in 56 eligible articles. The disruption of the furin cleavage site in the SARS-CoV-2 spike protein was identified as the most promising strategy. The replacement of core sequences of transcriptional regulatory signals, which prevents recombination with wild-type viruses, also appears particularly advantageous. Other important attenuating mutations encompassed mostly the prevention of evasion of innate immunity. Sufficiently attenuated coronaviruses typically caused no meaningful disease in susceptible animals and protected them from challenges with virulent virus. This indicates that attenuated COVID-19 vaccines may be considered as a potential strategy to fight the threat posed by SARS-CoV-2.

Volumetric staging in radiotherapy for oropharyngeal cancers.

INTRODUCTION: Despite routine use of 3D radiotherapy planning in radical radio(chemo)therapy for oropharyngeal cancers, volumetric data have not been implemented in initial staging. We analyzed 228 oropharyngeal cancer cases treated at one institution between 2004 and 2014 to compare the predictive value of volumetric staging and tumor nodal metastasis staging system (TNM) and determine whether they could be complementary for the estimation of survival. METHODS: This retrospective study analyzed 228 consecutive oropharyngeal cancer cases treated with radiotherapy (76.9%) or concurrent radiochemotherapy (23.1%) between 2004 and 2014. The volumetric parameters included primary gross tumor volume (pGTV), metastatic lymph nodes gross tumor volume (nGTV), and total gross tumor volume (tGTV), and were compared with the 7th edition of the TNM staging system. RESULTS: Median overall survival (OS) was 30.3 months. In the receiver operating characteristic analysis, tGTV had the highest area under the curve (AUC) of 0.66, followed by pGTV (AUC,0.64), nGTV (AUC 0.62), and TNM (AUC 0.6). The median OS for patients with tGTV ⩽32.2 mL was 40.5 months, compared to 15.4 months for >32.2 mL (p < 0.001). This threshold allowed for a statistically significant difference in survival between TNM stage IV cases with low and high tumor volume (p < 0.001). Despite both TNM and tGTV reaching statistical significance in univariate analysis, only the tGTV remained an independent prognostic factor in the multivariate analysis (hazard ratio 1.07, confidence interval 1.02-1.12, p = 0.008). CONCLUSIONS: tGTV is an independent prognostic factor, characterized by a higher discriminatory value than the TNM staging system, and can be used to further divide stage IV cases into subgroups with significantly different prognosis.

Prognostic factors in postoperative radiotherapy for prostate cancer - tertiary center experience.

BACKGROUND: The aim of the study was to analyse the prognostic factors in postoperative prostate cancer irradiation and develop a nomogram for disease-free survival (DFS). PATIENTS AND METHODS: This retrospective study included 236 consecutive prostate cancer patients who had radical prostatectomy followed by radiotherapy (RT) at a single tertiary institution between 2009 and 2014. The main outcome was DFS analysed through uni- and multivariable analysis, Kaplan-Meier curves, log-rank testing, recursive partitioning analysis, and nomogram development. RESULTS: The median follow up was 62.3 (interquartile range [IQR] 38.1-79) months. The independent clinical factors associated with increased risk of recurrence or progression in the multivariate analysis (MVA) were prostate-specific antigen (PSA) level before RT, pT3 characteristic, and local failure as salvage indication. The value of PSA nadir had a significant impact on the risk of biochemical failure. Biochemical control and DFS were significantly different depending on treatment indication (p < 0.0001). The recursive partitioning analysis highlighted the importance of the PSA level before RT, Gleason Grade Group, PSA nadir, and local failure as a treatment indication. Finally, the nomogram for DFS was developed and is available online at https://apps.konsta.com.pl/app/prostate-salvage-dfs/. CONCLUSIONS: The Pre-RT PSA level, pT3 characteristic and local failure as salvage indication are pivotal prognostic factors associated with increased risk of recurrence or progression. The Gleason grade group of 4-5 and PSA nadir value allow for further risk stratification. The treatment outcomes in postoperative prostate cancer irradiation are significantly different depending on treatment indication. An online nomogram comprising of both pre-treatment and current data was developed allowing for visualization of changes in prognosis depending on clinical data.

The association between RDW and survival of patients with squamous cell carcinoma of the tongue. Simple, cheap and convenient?

AIM: The purpose of this study was to evaluate the prognostic impact of red-cell distribution width (RDW) on the overall survival (OS) of patients with squamous cell carcinoma (SCC) of the tongue. BACKGROUND: Development of cancer is connected with an ongoing inflammatory process which is reflected by laboratory indices, such as RDW that can be used as prognostic tools. MATERIAL AND METHODS: The study group consists of 74 consecutive patients treated with radical radiotherapy or chemo-radiotherapy for SSC of the tongue at one institution between 2005-2014. RDW was assessed based on routine blood tests done before the start of the treatment. ROC curve was applied to assess value of RDW in prediction of OS, and a cut-off value for further tests was obtained using the Younden index. The survival analysis was performed using the Kaplan-Meier method, log-rank testing and Cox regression model. RESULTS: The AUC for RDW in ROC analysis was 0.703, and the optimal cut-off value was 13.5%. 5-year OS was significantly lower in patients with RDW ≥ 13.5% compared with patients with RDW < 13.5% (67% vs. 26%, p-value = 0.0005). Additionally, high RDW was associated with a greater odds ratio for 5-year OS in a multivariate Cox proportional hazards regression analysis (3.43, 1.62-7.25; p = 0.001). CONCLUSION: Our study demonstrated that pre-treatment RDW ≥ 13,5% is an indicator of poor overall survival in patients with SCC of the tongue. Since RDW is a cheap and convenient marker, usually routinely assessed during complete blood count tests, it could be further used as an additional prognostic tool in patients with tongue cancers.

The results of 394 consecutive cases of knee joint radiation synovectomy (radiosynoviorthesis) using 90Y.

OBJECTIVE: The aim of this study was to assess the treatment results of 90Y radiation synovectomy for chronic exudative synovitis of knee joints. METHODS: The retrospective data consist of 394 consecutive knee radiation synovectomies performed using 6 mCi (222 MBq) of 90Y. The assessment included 3-point custom pain and joint mobility scale, evaluation of joint's circumference, binary joint's temperature evaluation, patellar ballottement test, indications for puncture and its volume in applicable cases. 21 cases had to be forfeited due to missing data regarding follow-up. RESULTS: The final analysis of 373 treatment procedures performed in 253 patients yielded following results-at 6 months after treatment, 80.9% of the patients reported at least partial pain relief (including 33.3% with complete pain relief), which increased to 86.7% at one year. The pain intensity decreased over time, however, the outcomes were worse in older patients. The probability of pain recurrence was 15% at 6 months, and 28% at one year. It was highest in post-traumatic synovitis, and lowest in pigmented villonodular synovitis. The circumference of the treated knee joints decreased over the course of follow-up, however, the decrease was significantly lower in older patients. The fraction of patients with full knee joint mobility increased from 34.6 to 40.6% at 6 months and 49.2% at one year. The percentage of patients that required articular puncture decreased from 62.8% at baseline to about 35.6% at 6 months, and 32.8% at one year. Positive patellar ballottement was found in 68.5% before treatment and remained at about 40-50% during the course of follow-up. The increased temperature of the joint was reported in 51.2% at baseline and decreased to 33% at 6 months and 28.3% at one year. CONCLUSIONS: (1) Radiation synovectomy is a safe and effective method of treatment in patients with exudative synovitis, however, the pain recurrence rate is significantly higher in post-traumatic exudative synovitis compared to pigmented villonodular, undifferentiated, and rheumatoid arthritis. (2) Our results suggest that older patients have worse treatment results with radiation synovectomy compared to younger patients.

Analysis of the Effect of Serum Estradiol Concentration on Facial Skin Moisture, Pore Width, Discoloration and Smoothness in 16- to 50-Year-Old Women at the 5th and 25th Days of the Menstrual Cycle.

BACKGROUND/AIMS: Analysis of the relationship between the estradiol blood concentration and the skin moisture, pore width, discoloration and smoothness in differently aged women on the 5th and 25th days of the menstrual cycle. METHODS: The study involved 57 women divided into 4 age groups. Measurements of skin moisture, pore width, discoloration and smoothness were performed using the Aramo SG Aram Huvis device. The estradiol serum concentration was determined by radioimmunoassay. RESULTS: In the luteal phase of the cycle, facial skin moisture increases from 93.5% of the correct standard moisture index in the youngest to 115.5% in the oldest group. A positive correlation (r2 = 0.45) between estradiol concentration and skin moisture was observed on the 5th day of the cycle in 40- to 50-year-olds. For women on the 25th day of the menstruation cycle, estrogen concentration below the normal range was more beneficial for skin smoothness and pore width for the oldest group. The difference was not statistically significant (p > 0.05); how-ever, in the 40- to 50-year age group, skin smoothness was much better (43.5 ± 6.7%) for low estradiol while it was 37.5 ± 4.7% in the 20- to 29-year age group. Similarly, in the 40- to 50-year age group, skin pore width was much smaller (35.2 ± 15.7%) for low estradiol while it was 54.3 ± 28.8% in the 20- to 29-year age group. CONCLUSIONS: Skin moisture was related to the concentration of estradiol only in the oldest examined group of women regardless of the phase of menstrual cycle. In the 40- to 50-year-old group of women, the low level of estradiol on the 25th day of the cycle is better used to maintain a good facial skin appearance and has a positive influence not only on skin moisture, but also on pore width and skin smoothness.

Concentration of platelet derived-growth factors in concentrates used to regenerate injured bone tissue.

UNLABELLED: BACKGROUND. Bone union disorders of various kinds, of both iatrogenic and biological origin, are a common problem in the treatment of compound fractures. Impairment of bone regeneration often results from lack of biological potential for healing and lack of stimulation of osteogenesis at the site of bone loss. Bone union is stimulated by topical administration of a concentrate of platelet-derived growth factors. The aim of the study was to assess the concentration of platelet-derived growth factors in a concentrate before and after activation with a mixture of thrombin and calcium chloride. MATERIAL AND METHODS: The study comprised 30 samples of platelet-derived growth factor concentrates. Platelets were activated with CaCl 2 and 20 IU of thrombin. The resultant clot was incubated for 30 min at 37°C and then centrifuged again. The platelet count and PDGF AB, TGFß 1 , VEGF and IGF-1 concentrations were determined in each sample. The measurements were performed in accordance with recommended procedures. In the case of PDGF AB, the procedure was modified by changing the number of dilutions. A nonparametric test (Spearman rank correlation) was used for the statistical analysis. RESULTS. The study showed that the platelet count in a PDGF concentrate was 6.27 times higher than in whole blood. PDGF AB concentration in the PDGF concentrate in our study increased 5-6 times after activation. Concentrations of other growth factors increased 1.2- to 2-fold after CaCl 2 - and thrombin-induced activation in comparison to whole blood levels. There were no statistically significant correlations between the platelet count and the concentration of particular growth factors. CONCLUSIONS. The study's findings showed that the method of obtaining a platelet-derived growth factor concentrate may be an effective method of obtaining a platelet-rich preparation with a high platelet count. The concentrations of the measured platelet-derived growth factors in the concentrate were several times higher than in whole blood samples.