Pre- and Postoperative Antioxidant Use, Aryl Hydrocarbon Receptor (AhR) Activation and Clinical Outcome in Different Treatment Groups of Breast Cancer Patients.

BACKGROUND: Cancer patients often use antioxidants that may interact with adjuvant treatments. The purpose was to investigate pre- and postoperative antioxidant use in relation to clinicopathological characteristics and prognosis in different breast cancer treatment groups. METHODS AND PATIENTS: Pre- and postoperative antioxidant (vitamin A, C, E, carotenoids, or Q10) or multivitamin use was self-reported by patients from Lund (n = 1855) and Helsingborg (n=478), Sweden. Patients were followed for up to 15 years. Clinical data were obtained from patient charts. The aryl hydrocarbon receptor (AhR) was evaluated in tumor tissue arrays from 915 patients from Lund and with Western blot in MCF-7 and MDA-MB-231 cells. RESULTS: About 10% of patients used antioxidants. Nuclear AhR (AhRnuc) positivity was twice as common in preoperative antioxidant users compared to non-users. In mechanistic studies vitamin C increased AhR levels and its downstream target CYP1B1, indicating AhR activation. There were significant interactions between tumor AhRnuc status and preoperative antioxidant use in relation to clinical outcome. In all patients, antioxidant use (other than multivitamins) at both visits was associated with poorer prognosis, while use only at the follow-up visit was associated with better prognosis, compared with no use at either visit. CONCLUSION: The clinical impact of antioxidants depended on antioxidant type, timing of use, and tumor AhR activation. Antioxidants may influence clinical outcome by activation of the master regulator AhR in addition to interference with free radicals. Further studies are needed to identify breast patients that might improve or worsen their prognosis when using antioxidants postoperatively.

Importance of tumor volume, overall treatment time and fractionation sensitivity for p16-positive and p16-negative oropharyngeal tumors.

BACKGROUND: Analyses of clinical outcomes following radiotherapy (RT) have advanced our understanding of fundamental radiobiological characteristics in head and neck squamous cell carcinoma (HNSCC). Low fractionation sensitivity appears to be a common feature, as well as susceptibility to changes in overall treatment time (OTT). Large tumors should be harder to cure if a successful RT requires the sterilization of all clonogenic cells. Congruently, primary tumor volume has proven to be an important parameter. However, most findings come from an era when p16-negative HNSCC was the dominant tumor type. HPV-associated, p16-positive, oropharyngeal tumors (OPSCC) are more radiosensitive and have better outcome. The current study aims to investigate the role of primary tumor volume, OTT and estimate α/ß-ratio for p16-positive OPSCC, and to quantify the differences in radiosensitivity depending on p16-status. METHODS: A cohort of 523 patients treated with RT was studied using a tumor control probability (TCP)-model that incorporates primary tumor volume (V) raised to an exponent c, OTT and α/ß-estimation. The significance of V was also investigated in Cox-regression models. RESULTS: In the p16-positive cohort (n = 433), the volume exponent c was 1.44 (95%CI 1.06-1.91), compared to 0.90 (0.54-1.32) for p16-negative tumors (n = 90). Hazard ratios per tumor volume doubling were 2.37 (1.72-3.28) and 1.83 (1.28-2.62) for p16-positive and p16-negative, respectively. The estimated α/ß-ratio was 9.7 Gy (-2.3-21.6), and a non-significant daily loss of 0.30 Gy (-0.17-0.92) was found. An additional dose of 6.8 Gy (interquartile range 4.8-9.1) may theoretically counteract the more radioresistant behavior of p16-negative tumors. CONCLUSION: Primary tumor volume plays a crucial role in predicting local tumor response, particularly in p16-positive OPSCC. The estimated α/ß-ratio for p16-positive oropharyngeal tumors aligns with previous HNSCC studies, whereas the impact of prolonged OTT was slightly less than previously reported. The differences in radiosensitivity depending on p16-status were quantified. The findings should be validated in independent cohorts.

Evaluation of intensity-modulated electron FLASH radiotherapy in a clinical setting using veterinary cases.

PURPOSE: The increased normal tissue tolerance for FLASH radiotherapy (FLASH-RT), as compared to conventional radiotherapy, was first observed in ultra-high dose rate electron beams. Initial clinical trials in companion animals have revealed a high risk of developing osteoradionecrosis following high-dose single-fraction electron FLASH-RT, which may be related to inhomogeneities in the dose distribution. In the current study, we aim to evaluate the possibilities of intensity-modulated electron FLASH-RT in a clinical setting to ensure a homogeneous dose distribution in future veterinary and human clinical trials. METHODS: Our beam model in the treatment planning system electronRT (.decimal, LLC, Sanford, FL, USA) was based on a 10-MeV electron beam from a clinical linear accelerator used to treat veterinary patients with FLASH-RT in a clinical setting. In electronRT, the beam can be intensity-modulated using tungsten island blocks in the electron block cutout, and range-modulated using a customized bolus with variable thickness. Modulations were first validated in a heterogeneous phantom by comparing measured and calculated dose distributions. To evaluate the impact of intensity modulation in superficial single-fraction FLASH-RT, a treatment planning study was conducted, including eight canine cancer patient cases with simulated tumors in the head-and-neck region. For each case, treatment plans with and without intensity modulation were created for a uniform bolus and a range-modulating bolus. Treatment plans were evaluated using a target dose homogeneity index (HI), a conformity index (CI), the near-maximum dose outside the target ( D 2 % , Body - PTV ${D_{2{\mathrm{\% }},{\mathrm{\ Body}} - {\mathrm{PTV}}}}$ ), and the near-minimum dose to the target ( D 98 % ${D_{98\% }}$ ). RESULTS: By adding intensity modulation to plans with a uniform bolus, the HI could be improved (p = 0.017). The combination of a range-modulating bolus and intensity modulation provided a further significant improvement of the HI as compared to using intensity modulation in combination with a uniform bolus (p = 0.036). The range-modulating bolus also improved the CI compared to using a uniform bolus, both with an open beam (p = 0.046) and with intensity modulation (p = 0.018), as well as increased the D 98 % ${D_{98\% }}$ (p = 0.036 with open beam and p = 0.05 with intensity modulation) and reduced the median D 2 % , Body - PTV ${D_{2\% ,{\mathrm{\ Body}} - {\mathrm{PTV}}}}$ (not significant). CONCLUSIONS: By using intensity-modulated electron FLASH-RT in combination with range-modulating bolus, the target dose homogeneity and conformity in canine patients with simulated tumors in complex areas in the head-and-neck region could be improved. By utilizing this technique, we hope to decrease the dose outside the target volume and avoid hot spots in future clinical electron FLASH-RT studies, thereby reducing the risk of radiation-induced toxicity.

Effect of Conventional and Ultrahigh Dose Rate FLASH Irradiations on Preclinical Tumor Models: A Systematic Analysis.

PURPOSE: Compared with conventional dose rate irradiation (CONV), ultrahigh dose rate irradiation (UHDR) has shown superior normal tissue sparing. However, a clinically relevant widening of the therapeutic window by UHDR, termed "FLASH effect," also depends on the tumor toxicity obtained by UHDR. Based on a combined analysis of published literature, the current study examined the hypothesis of tumor isoefficacy for UHDR versus CONV and aimed to identify potential knowledge gaps to inspire future in vivo studies. METHODS AND MATERIALS: A systematic literature search identified publications assessing in vivo tumor responses comparing UHDR and CONV. Qualitative and quantitative analyses were performed, including combined analyses of tumor growth and survival data. RESULTS: We identified 66 data sets from 15 publications that compared UHDR and CONV for tumor efficacy. The median number of animals per group was 9 (range 3-15) and the median follow-up period was 30.5 days (range 11-230) after the first irradiation. Tumor growth assays were the predominant model used. Combined statistical analyses of tumor growth and survival data are consistent with UHDR isoefficacy compared with CONV. Only 1 study determined tumor-controlling dose (TCD50) and reported statistically nonsignificant differences. CONCLUSIONS: The combined quantitative analyses of tumor responses support the assumption of UHDR isoefficacy compared with CONV. However, the comparisons are primarily based on heterogeneous tumor growth assays with limited numbers of animals and short follow-up, and most studies do not assess long-term tumor control probability. Therefore, the assays may be insensitive in resolving smaller response differences, such as responses of radioresistant tumor subclones. Hence, tumor cure experiments, including additional TCD50 experiments, are needed to confirm the assumption of isoeffectiveness in curative settings.

Circulating tumour HPV16 DNA quantification - A prognostic tool for progression-free survival in patients with HPV-related oropharyngeal carcinoma receiving curative chemoradiotherapy.

BACKGROUND AND PURPOSE: Circulating tumour (ct) human papillomavirus (HPV) DNA is detectable in HPV-related oropharyngeal carcinoma (OPSCC) patients and has the potential to become an important clinical tool. This study aimed to evaluate the prognostic significance of ctHPV16-DNA kinetics during treatment with chemoradiotherapy in HPV-related OPSCC. Patients with p16-positive OPSCC recruited to the ARTSCAN III trial, comparing radiotherapy plus cisplatin with radiotherapy plus cetuximab, constituted the study cohort. MATERIALS AND METHODS: Blood samples before start and at the end of treatment of 136 patients were analysed. ctHPV16-DNA was quantified by real-time (q)PCR. The correlation between ctHPV16-DNA levels and tumour burden was investigated with Pearson regression analysis. The prognostic value of ctHPV16-DNA levels at baseline and decline during treatment was evaluated by area-under-the-curve (AUC) calculations and analysed with univariable and multivariable Cox proportional hazards models. RESULTS: ctHPV16-DNA was detectable with qPCR in 108/136 patients before start of treatment and cleared in 74% of these patients at the end of treatment. Disease burden was significantly correlated with baseline ctHPV16-DNA levels (R = 0.39, p=<0.001). Both lower baseline levels and AUC-ctHPV16DNA were associated with improved progression-free survival (p = 0.01 and p < 0.001), overall survival (p = 0.013 and p = 0.002), but not local tumour control (p = 0.12 and p = 0.2, respectively), with a stronger association for AUC-ctHPV16DNA (likelihood ratio test 10.5 vs 6.5 in Cox regression analyses of progression-free survival). In multivariable analysis including tumour volume (GTV-T) and treatment allocation (cisplatin vs cetuximab), AUC-ctHPV16DNA remained a significant prognostic marker of progression-free survival. CONCLUSION: ctHPV16-DNA is an independent prognostic factor in HPV-related OPSCC.

Impact of Antibiotic Treatment on the Gut Microbiome and its Resistome in Hematopoietic Stem Cell Transplant Recipients.

Antibiotic-resistant bacterial infections are increasingly an issue in allogenic hematopoietic stem cell transplant patients. How antibiotic treatment impacts antibiotic resistance in the human gut microbiome remains poorly understood in vivo. Here, a total of 577 fecal samples from 233 heavily antibiotic-treated transplant patients were examined using high-resolution prescription data and shotgun metagenomics. The 13 most frequently used antibiotics were significantly associated with 154 (40% of tested associations) microbiome features. Use of broad-spectrum ß-lactam antibiotics was most markedly associated with microbial disruption and increase in resistome features. The enterococcal vanA gene was positively associated with 8 of the 13 antibiotics, and in particular piperacillin/tazobactam and vancomycin. Here, we highlight the need for a high-resolution approach in understanding the development of antibiotic resistance in the gut microbiome. Our findings can be used to inform antibiotic stewardship and combat the increasing threat of antibiotic resistance.

Quantitative In Vivo Imaging of the Androgen Receptor Axis Reveals Degree of Prostate Cancer Radiotherapy Response.

Noninvasive biomarkers for androgen receptor (AR) pathway activation are urgently needed to better monitor patient response to prostate cancer therapies. AR is a critical driver and mediator of resistance of prostate cancer but currently available noninvasive prostate cancer biomarkers to monitor AR activity are discordant with downstream AR pathway activity. External beam radiotherapy (EBRT) remains a common treatment for all stages of prostate cancer, and DNA damage induced by EBRT upregulates AR pathway activity to promote therapeutic resistance. [89Zr]11B6-PET is a novel modality targeting prostate-specific protein human kallikrein 2 (hK2), which is a surrogate biomarker for AR activity. Here, we studied whether [89Zr]11B6-PET can accurately assess EBRT-induced AR activity.Genetic and human prostate cancer mouse models received EBRT (2-50 Gy) and treatment response was monitored by [89Zr]11B6-PET/CT. Radiotracer uptake and expression of AR and AR target genes was quantified in resected tissue.EBRT increased AR pathway activity and [89Zr]11B6 uptake in LNCaP-AR and 22RV1 tumors. EBRT increased prostate-specific [89Zr]11B6 uptake in prostate cancer-bearing mice (Hi-Myc x Pb_KLK2) with no significant changes in uptake in healthy (Pb_KLK2) mice, and this correlated with hK2 protein levels. IMPLICATIONS: hK2 expression in prostate cancer tissue is a proxy of EBRT-induced AR activity that can noninvasively be detected using [89Zr]11B6-PET; further clinical evaluation of hK2-PET for monitoring response and development of resistance to EBRT in real time is warranted.

Método simple para minimizar la discrepancia en la longitud de las extremidades y restaurar el offset en la artroplastia total de cadera / A Simple method to minimize limb length discrepancy and restore offset in total hip arthroplasty

Introducción: Existen más de 20 técnicas diferentes para corregir la discrepancia de miembros inferiores. El método que aquí se evalúa se basa en una clavija fija posicionada en el ala ilíaca asociada a un "calibre" móvil, con otra clavija con la que se marca la referencia en el trocánter mayor. Objetivo: Evaluar la confiabilidad de este dispositivo de medición usado durante la artroplastia total de cadera para restaurar la longitud del miembro inferior y el offset femoral. Materiales y Métodos: Se formaron dos grupos: grupo A con pacientes en quienes no se había usado el dispositivo y grupo B con pacientes en quienes sí se había usado el dispositivo. Se realizaron las mediciones en la radiografía panorámica de pelvis obtenida con el paciente de pie, antes de la cirugía y 3 meses después. Resultados: Se obtuvo una muestra de 80 pacientes (40 por grupo). Se logró corregir la discrepancia de la longitud de los miembros, pero no se hallaron diferencias estadísticamente significativas en la corrección promedio, entre ambos grupos (p = 0,07). Sin embargo, al analizar la varianza en la corrección de la discrepancia de la longitud de cada grupo se obtuvo una diferencia estadísticamente significativa (p <0,001). Conclusiones: Este dispositivo que permite una medición cuantificable más objetiva no asegura una corrección de la discrepancia de la longitud exacta a 0 mm, pero sí permite trabajar dentro de un rango más confiable y seguro. Nivel de Evidencia: III

Introduction: There are more than 20 different techniques to correct lower limb length discrepancy. The method evaluated in this study is based on a fixed pin in the iliac wing connected to a mobile gauge and another pin in the greater trochanter with which the reference is marked. The objective is to evaluate the reliability of this measurement device used during THA to restore lower limb length and femoral offset. Materials and Methods: Two groups were formed: Group A (patients who did not use the device) and Group B (patients who did use the device). Measurements were taken in the pre-surgery panoramic pelvic radiograph with the patient standing and three months later. Results: A sample of 80 patients was obtained, with 40 in each group. The difference in limb length could be corrected in each group, however the average correction achieved by both groups did not result in a statistically significant difference (p=0.07). However, when the variance in the correction of the difference in length of each group was examined, a statistically significant difference (p<0.001) was obtained. Conclusions: We can conclude that while this device, which serves as a more objective quantifiable measurement technique, does not guarantee a correction of the exact length discrepancy to 0 mm, it does allow us to work within a more dependable and safe range. Level of Evidence: III

Comment on Russo et al. Does Tumor Volume Have a Prognostic Role in Oropharyngeal Squamous Cell Carcinoma? A Systematic Review and Meta-Analysis. Cancers 2022, 14, 2465.

I read the article by Russo et al. [...].

Comparable Long-Term Tumor Control for Hypofractionated FLASH Versus Conventional Radiation Therapy in an Immunocompetent Rat Glioma Model.

Purpose: To ensure a clinical translation of FLASH radiation therapy (FLASH-RT) for a specific tumor type, studies on tumor control and toxicity within the same biological system are needed. In this study, our objective was to evaluate tumor control and toxicity for hypofractionated FLASH-RT and conventional radiation therapy (CONV-RT) in an immunocompetent rat glioma model. Methods and Materials: Fisher 344 rats (N = 68) were inoculated subcutaneously with NS1 glioma cells and randomized into groups (n = 9-10 per group). CONV-RT (∼8 Gy/min) or FLASH-RT (70-90 Gy/s) was administered in 3 fractions of either 8 Gy, 12.5 Gy, or 15 Gy using a 10-MeV electron beam. The maximum tumor diameter was measured weekly, and overall survival was determined until day 100. Long-term tumor control was defined as no evident tumor on day 100. Animals were evaluated for acute dermal side effects at 2 to 5 weeks after completed RT and for late dermal side effects at 3 months after initiation of treatment. Results: Survival was significantly increased in all irradiated groups compared with control animals (P < .001). In general, irradiated tumors started to shrink at 1 week post-completed RT. In 40% (23 of 58) of the irradiated animals, long-term tumor control was achieved. Radiation-induced skin toxic effects were mild and consisted of hair loss, erythema, and dry desquamation. No severe toxic effect was observed. There was no significant difference between FLASH-RT and CONV-RT in overall survival, acute side effects, or late side effects for any of the dose levels. Conclusions: This study shows that hypofractionated FLASH-RT results in long-term tumor control rates similar to those of CONV-RT for the treatment of large subcutaneous glioblastomas in immunocompetent rats. Neither treatment technique induced severe skin toxic effects. Consequently, no significant difference in toxicity could be resolved, suggesting that higher doses may be required to detect a FLASH sparing of skin.

The Role of Arthroereisis in Improving Sports Performance, Foot Aesthetics and Quality of Life in Children and Adolescents with Flexible Flatfoot.

Flexible flatfoot represents one of the most common deformities of the lower limb, affecting children and adolescents. Aesthetic aspect, abnormal gait, pain and fatigue are by far the most important symptoms which determine parents to bring their children to the orthopedist. We set out to conduct a prospective study, case-controlled, including patients with symptomatic flexible flatfeet operated on by arthroereisis surgery and comparing them to a normal feet group of children age- and sex-matched (control group). Minimum follow-up time was 2 years. In total, 33 patients with bilateral arthroereisis were included and 36 patients formed the control group (12.12 +/− 1.85 years vs. 11.81 ± 2.40 years, p = 0.54). Quality of life improved postoperatively (p = 0.18) and was not different from the control group. Median running time improved postoperatively by 2.25 s (p < 0.0001) and got closer to the median running time from the control group (22.30 s compared to 20.94 s, p = 0.01). All radiological angles improved (p < 0.0001), but quality of life improvement was correlated with talonavicular coverage angle and Meary angle measurements. Flatfoot in children and adolescents may be a condition in which the quality of life and sports performance are decreased, compared to healthy children. Arthroereisis is a minimally invasive surgical procedure with a short recovery time and a short period before resumption of sport activities, which can be useful in certain types of flexible flatfoot due to its effectiveness on symptom reduction.

Hypoxia in relationship to tumor volume using hypoxia PET-imaging in head & neck cancer - A scoping review.

Background: Hypoxia and large tumor volumes are negative prognostic factors for patients with head and neck squamous cell carcinoma (HNSCC) treated with radiation therapy (RT). PET-scanning with specific hypoxia-tracers (hypoxia-PET) can be used to non-invasively assess hypoxic tumor volume. Primary tumor volume is readily available for patients undergoing RT. However, the relationship between hypoxic volume and primary tumor volume is yet an open question. The current study investigates the hypotheses that larger tumors contain both a larger hypoxic volume and a higher hypoxic fraction. Methods: PubMed and Embase were systematically searched to identify articles fulfilling the predefined criteria. Individual tumor data (primary tumor volume and hypoxic volume/fraction) was extracted. Relationship between hypoxic volume and primary tumor volume was investigated by linear regression. The correlation between hypoxic fraction and log2(primary tumor volume) was determined for each cohort and in a pooled analysis individual regression slopes and coefficients of determination (R2) were weighted according to cohort size. Results: 21 relevant articles were identified and individual data from 367 patients was extracted, out of which 323 patients from 17 studies had quantifiable volumes of interest. A correlation between primary tumor volume and PET-determined hypoxic volume was found (P <.001, R2 = 0.46). Larger tumors had a significantly higher fraction of hypoxia compared with smaller tumors (P<.01). The weighted analysis of all studies revealed that for each doubling of the tumor volume, the hypoxic fraction increased by four percentage points. Conclusion: This study shows correlations between primary tumor volume and hypoxic volume as well as primary tumor volume and the hypoxic fraction in patients with HNSCC. The findings suggest that not only do large tumors contain more cancer cells, they also have a higher proportion of potentially radioresistant hypoxic cells. This knowledge can be important when individualizing RT.

Pelvic U-Net: multi-label semantic segmentation of pelvic organs at risk for radiation therapy anal cancer patients using a deeply supervised shuffle attention convolutional neural network.

BACKGROUND: Delineation of organs at risk (OAR) for anal cancer radiation therapy treatment planning is a manual and time-consuming process. Deep learning-based methods can accelerate and partially automate this task. The aim of this study was to develop and evaluate a deep learning model for automated and improved segmentations of OAR in the pelvic region. METHODS: A 3D, deeply supervised U-Net architecture with shuffle attention, referred to as Pelvic U-Net, was trained on 143 computed tomography (CT) volumes, to segment OAR in the pelvic region, such as total bone marrow, rectum, bladder, and bowel structures. Model predictions were evaluated on an independent test dataset (n = 15) using the Dice similarity coefficient (DSC), the 95th percentile of the Hausdorff distance (HD95), and the mean surface distance (MSD). In addition, three experienced radiation oncologists rated model predictions on a scale between 1-4 (excellent, good, acceptable, not acceptable). Model performance was also evaluated with respect to segmentation time, by comparing complete manual delineation time against model prediction time without and with manual correction of the predictions. Furthermore, dosimetric implications to treatment plans were evaluated using different dose-volume histogram (DVH) indices. RESULTS: Without any manual corrections, mean DSC values of 97%, 87% and 94% were found for total bone marrow, rectum, and bladder. Mean DSC values for bowel cavity, all bowel, small bowel, and large bowel were 95%, 91%, 87% and 81%, respectively. Total bone marrow, bladder, and bowel cavity segmentations derived from our model were rated excellent (89%, 93%, 42%), good (9%, 5%, 42%), or acceptable (2%, 2%, 16%) on average. For almost all the evaluated DVH indices, no significant difference between model predictions and manual delineations was found. Delineation time per patient could be reduced from 40 to 12 min, including manual corrections of model predictions, and to 4 min without corrections. CONCLUSIONS: Our Pelvic U-Net led to credible and clinically applicable OAR segmentations and showed improved performance compared to previous studies. Even though manual adjustments were needed for some predicted structures, segmentation time could be reduced by 70% on average. This allows for an accelerated radiation therapy treatment planning workflow for anal cancer patients.

Primary tumor volume and prognosis for patients with p16-positive and p16-negative oropharyngeal squamous cell carcinoma treated with radiation therapy.

BACKGROUND: The prescribed radiation dose to patients with oropharyngeal squamous cell carcinoma (OPSCC) is standardized, even if the prognosis for individual patients may differ. Easy-at-hand pre-treatment risk stratification methods are valuable to individualize therapy. In the current study we assessed the prognostic impact of primary tumor volume for p16-positive and p16-negative tumors and in relationship to other prognostic factors for outcome in patients with OPSCC treated with primary radiation therapy (RT). METHODS: Five hundred twenty-three OPSCC patients with p16-status treated with primary RT (68.0 Gy to 73.1 Gy in 7 weeks, or 68.0 Gy in 4.5 weeks), with or without concurrent chemotherapy, within three prospective trials were included in the study. Local failure (LF), progression free survival (PFS) and overall survival (OS) in relationship to the size of the primary gross tumor volume (GTV-T) and other prognostic factors were investigated. Efficiency of intensified RT (RT with total dose 73.1 Gy or given within 4.5 weeks) was analyzed in relationship to tumor volume. RESULTS: The volume of GTV-T and p16-status were found to be the strongest prognostic markers for LF, PFS and OS. For p16-positive tumors, an increase in tumor volume had a significantly higher negative prognostic impact compared with p16-negative tumors. Within a T-classification, patients with a smaller tumor, compared with a larger tumor, had a better prognosis. The importance of tumor volume remained after adjusting for nodal status, age, performance status, smoking status, sex, and hemoglobin-level. The adjusted hazard ratio for OS per cm3 increase in tumor volume was 2.3% (95% CI 0-4.9) for p16-positive and 1.3% (95% 0.3-2.2) for p16-negative. Exploratory analyses suggested that intensified RT could mitigate the negative impact of a large tumor volume. CONCLUSIONS: Outcome for patients with OPSCC treated with RT is largely determined by tumor volume, even when adjusting for other established prognostic factors. Tumor volume is significantly more influential for patients with p16-positive tumors. Patients with large tumor volumes might benefit by intensified RT to improve survival.

Impact of combining vitamin C with radiation therapy in human breast cancer: does it matter?

Vitamin C may impact the efficiency of radiation therapy (RT) in breast cancer. The effects of RT alone or in combination with vitamin C in SKBR3, MDA-MB-231, and MCF7 cells were compared using clonogenic assay, proliferation assay (MTT), cell cycle analysis, and Western blot. Vitamin C use was assessed in 1803 breast cancer patients 2002-2017 in relation to clinicopathological features and recurrences after RT. Vitamin C combined with RT resulted in non-significant increases in colony formation and minor differences in cell cycle arrest and expression of studied proteins, compared to RT alone. Lower vitamin C doses alone or in combination with RT, resulted in higher proliferation with MTT than higher vitamin C doses in a cell line-dependent manner. Vitamin C use was associated with lower histological grade and BMI but not recurrence risk in RT-treated patients (LogRank P = 0.54). Vitamin C impacted RT efficiency differently depending on breast cancer subtype and vitamin C concentration. Lower doses of vitamin C, achievable with oral administration, might increase breast cancer cell proliferation and decrease radiosensitivity. Despite vitamin C users having less aggressive tumors than non-users, the recurrence risk in RT-treated patients was similar in vitamin C users and non-users.

In vitro assays for investigating the FLASH effect.

FLASH radiotherapy is a novel technique that has been shown in numerous preclinical in vivo studies to have the potential to be the next important improvement in cancer treatment. However, the biological mechanisms responsible for the selective FLASH sparing effect of normal tissues are not yet known. An optimal translation of FLASH radiotherapy into the clinic would require a good understanding of the specific beam parameters that induces a FLASH effect, environmental conditions affecting the response, and the radiobiological mechanisms involved. Even though the FLASH effect has generally been considered as an in vivo effect, studies finding these answers would be difficult and ethically challenging to carry out solely in animals. Hence, suitable in vitro studies aimed towards finding these answers are needed. In this review, we describe and summarise several in vitro assays that have been used or could be used to finally elucidate the mechanisms behind the FLASH effect.

Prevalencia y resultados de cultivos positivos inesperados en revisiones de reemplazo total de cadera presumiblemente asépticas / Prevalence and outcomes of unexpected positive cultures in presumed aseptic revision total hip arthroplasty

Introducción: Las tasas de infección periprotésica, a veces, son subestimadas, ya que muchos casos de presunta falla aséptica pueden deberse a una infección no reconocida. Los objetivos de este estudio fueron: 1) estimar la prevalencia de cultivos positivos intraoperatorios inesperados, 2) determinar si las comorbilidades o los factores de riesgo de los pacientes tuvieron relación con la presencia de cultivos positivos inesperados, 3) determinar la supervivencia del implante en un seguimiento mínimo de 12 meses. Materiales y Métodos: Se realizó un estudio retrospectivo y observacional. En las historias clínicas electrónicas, se identificaron todas las revisiones de artroplastia total de cadera de una única institución entre 2014 y 2021. Resultados: De las 49 revisiones de artroplastia total de cadera en un tiempo, 9 pacientes (18,4%) tuvieron un resultado positivo inesperado. Los microorganismos aislados fueron: Staphylococcus aureus (3), Pseudomonas aeruginosa (1), Staphylococcus lugdunensis (1), Staphylococcus epidermidis (2), Staphylococcus haemolyticus (1), Streptococcus epidermidis (1). Ninguna comorbilidad tuvo significancia estadística para favorecer cultivos positivos inesperados en las revisiones asépticas. El 2% de la muestra, con un período de seguimiento de 49 meses, se reinfectó. Conclusiones: Nuestro estudio arrojó una prevalencia de cultivos positivos inesperados del 18,4%. Ninguno de los factores de riesgo reportados en la bibliografía se asoció con un mayor riesgo de cultivos positivos inesperados, excepto los niveles altos de velocidad de sedimentación glomerular. Nuestros hallazgos son compatibles con los publicados y sugieren que los cultivos positivos inesperados en revisiones presumiblemente asépticas no tienen consecuencias significativas en la supervivencia del implante. Nivel de Evidencia: III

Introduction: Periprosthetic infection rates are sometimes underestimated, given that many cases of presumed aseptic failure may be due to unrecognized infection. The objectives of this study were: (1) to estimate the prevalence of unexpected positive intraoperative cultures; (2) to determine if any of the patient's comorbidities or risk factors were related to the presence of unexpected positive cultures; (3) to determine the implant survival during a follow-up of at least 12 months. Materials and Methods: A retrospective and observational study was carried out where, through electronic medical records, all revision total hip arthroplasties (THAs) from a single institution between 2014 and 2021 were identified. Results: Out of 49 single-stage revision THAs, 9 patients (18.4%) had an unexpected positive culture. The isolated microorganisms were Staphylococcus aureus (3), Pseudomonas aeruginosa (1), Staphylococcus lugdunensis (1), Staphylococcus epidermidis (2), Staphylococcus haemolyticus (1), Streptococcus epidermidis (1). In addition, when we evaluated the comorbidities of the patients, none had statistical significance in favoring unexpected positive cultures in aseptic revisions. We discovered that 2% of our sample with a follow-up period of 49 months developed reinfection. Conclusion: Our study showed a prevalence of unexpected positive cultures of 18.4%. None of the risk factors reported in the literature was associated with a higher risk of unexpected positive cultures, except for high ESR values. Our findings in the analyzed sample suggest that unexpected positive cultures in presumably aseptic revisions do not have significant consequences on implant survival, as found in the literature. Level of Evidence: III

Prática da episiotomia: uma revisão integrativa / Practice of episiotomy: an integrative review / Práctica de la episiotomía: una revisión integrativa

OBJETIVO: Conhecer os aspectos acerca da prática da episiotomia no parto vaginal. METODOLOGIA: Revisão integrativa realizada em outubro de 2021. Foram coletadas 81 publicações na biblioteca Catálogo de Teses e Dissertações Capes, 24 publicações na base de dados Literatura Latino-americana y del Caribe en Ciencias de la Salud (LILACS), 891 publicações na base de dados Public Medline (PubMed) e 20 publicações na base de dados Scientific Eletronic Library Online (SciELO). Após leitura dos títulos e resumos, e da aplicação dos critérios de inclusão e exclusão, 44 publicações foram selecionadas para leitura na íntegra, resultando em 13 publicações, as quais compuseram o escopo de análise deste estudo. RESULTADOS: Foram evidenciados os seguintes aspectos sobre a prática da episiotomia: fatores associados à prática da episiotomia; prevalência/taxas de episiotomia; comparação entre a prática da episiotomia e a não prática da episiotomia; fatores associados à proteção e integridade perineal; fatores associados a lacerações perante a prática da episiotomia; comparação entre o reparo da episiotomia e laceração espontânea; orientações sobre a prática da episiotomia a pacientes; posicionamentos de profissionais a respeito da prática da episiotomia; percepção de mulheres sobre a prática da episiotomia.CONCLUSÕES: Foi possível conhecer a natureza das publicações científicas, identificando quais aspectos essas publicações abordam acerca da episiotomia, observando os prós e contras da sua realização.

OBJECTIVE: To know the aspects about the practice of episiotomy in vaginal delivery. METHODOLOGY: Integrative review carried out in October 2021. 81 publications were collected in the Catálogo de Teses e Dissertações Capeslibrary, 24 publications in the Literatura Latino-americana y del Caribe en Ciencias de la Salud (LILACS)database, 891 publications in the database Public Medline (PubMed) data and 20 publications in the Scientific Electronic Library Online (SciELO) database. After reading the titles and abstracts, and applying the inclusion and exclusion criteria, 44 publications were selected for full reading, resulting in 13 publications, which comprised the scope of analysis of this study. RESULTS:The following aspects about the practice of episiotomy were evidenced: factors associated with the practice of episiotomy; episiotomy prevalence/rates; comparison between the practice of episiotomy and the non-practice of episiotomy; factors associated with perineal protection and integrity; factors associated with lacerations in relation to the practice of episiotomy; comparison between episiotomy repair and spontaneous laceration; guidelines on the practice of episiotomy to patients; professional positions regarding the practice of episiotomy; perception of women about the practice of episiotomy. CONCLUSIONS: It was possible to know the nature of scientific publications, identifying which aspects these publications address about episiotomy, observing the pros and cons of its realization

OBJETIVO: Conocer los aspectos sobre la práctica de la episiotomía en el parto vaginal. METODOLOGÍA: Revisión integradora realizada en octubre de 2021. Se recolectaron 81 publicaciones en la biblioteca Catálogo de Teses e Dissertações Capes, 24 publicaciones en la base de datos Literatura Latinoamericanay del Caribe en Ciencias de la Salud (LILACS), 891publicaciones en la base de datos Public Medline (PubMed)data y 20 publicaciones en la base de datos Scientific Eletronic Library Online (SciELO). Luego de la lectura de los títulos y resúmenes, y aplicando los criterios de inclusión y exclusión, se seleccionaron 44 publicaciones para lectura completa, resultando en 13 publicaciones, que comprendieron el ámbito de análisis de este estudio. RESULTADOS: Se evidenciaron los siguientes aspectos sobre la práctica de episiotomía: factores asociados a la práctica de episiotomía; prevalencia/tasas de episiotomía; comparación entre la práctica de episiotomía y la no práctica de episiotomía; factores asociados a la protección e integridad perineal; factores asociados a laceraciones en relación con la práctica de episiotomía; comparación entre reparación de episiotomía y laceración espontánea; lineamientos sobre la práctica de episiotomía a pacientes; posiciones profesionales respecto a la práctica de la episiotomía; percepción de las mujeres sobre la práctica de la episiotomía.CONCLUSIONES: Se pudo conocer la naturaleza de las publicaciones científicas, identificando qué aspectos abordan estas publicaciones sobre la episiotomía, observando los pros y los contras de su realización

Factores de riesgo de inestabilidad en el reemplazo total de cadera por fractura medial de cadera / Instability risk factors in total hip arthroplasty for femoral neck fracture

Introducción: Una de las complicaciones más importantes de la artroplastia total de cadera en el tratamiento de las fracturas es la luxación, con una tasa del 10%, cinco veces mayor que la de la artroplastia total de cadera por osteoartrosis. El objetivo de este estudio fue conocer nuestra incidencia de luxación en pacientes sometidos a artroplastia total de cadera por fractura del cuello femoral y evaluar la causa de la luxación. Materiales y Métodos: Estudio retrospectivo en 110 pacientes sometidos a artroplastia total de cadera por fractura medial de cadera (edad promedio 69 años; 71% mujeres). Se evaluaron el tipo de fijación de la prótesis, el tamaño de la cabeza, el offset y el abordaje quirúrgico. Se midieron los ángulos de inclinación y de anteversión acetabulares y se registraron las comorbilidades. Resultados: El 72% de las cirugías fueron por vía posterolateral. La vía anterolateral se asoció con una copa 7° más vertical (p = 0,001). El 65,4% de las cabezas eran de 32 mm. El 15% (3/20) de las cabezas chicas (22 y 28 mm) y el 1% (1/90) de las grandes se luxaron (p = 0,0027). No se luxó ninguna cabeza de 36 mm. Las comorbilidades neurológicas más frecuentes fueron depresión, Parkinson y Alzheimer. Conclusiones: Las cabezas de pequeño diámetro junto con el mal posicionamiento de la prótesis y las enfermedades neurocognitivas se asocian a una inestabilidad mayor. El uso de cabezas de 36 mm y la correcta orientación de los componentes son suficientes para asegurar la estabilidad. Nivel de Evidencia: III

Introduction: One of the most relevant complications of total hip arthroplasty (THA) in the treatment of fractures is a dislocation rate of 10%, which is 5 times higher than that of THA for osteoarthritis. Our objective was to determine the dislocation rate in patients treated with THA due to femoral neck fracture and to evaluate the cause of dislocation. Materials and Methods: We carried out a retrospective study on 110 THAs in patients with femoral neck fractures (the average age was 69 years, and 71% were women). The type of fixation of the prosthesis, the size of the head, the offset, and the surgical approach were evaluated. The angle of acetabular inclination and anteversion and the comorbidities were measured. Results: 72% of surgeries were performed through the posterolateral approach. The anterolateral approach is associated with a 7° more vertical cup (p=0.001). 65.4% of the heads were 32 mm. 15% of the small heads (22 and 28mm) (3/20) and only 1% of the large heads (1/90) dislocated (p=0.0027). No 36-mm heads were dislocated. Depression, Parkinson's, and Alzheimer's disease were the most frequent neurological comorbidities. Conclusions: Small-diameter heads, in combination with poor positioning of the prosthesis and neurocognitive diseases, are associated with greater instability. Using prosthetic heads with a diameter of 36 mm and a correct orientation of the components is sufficient to ensure stability. Level of Evidence: III

Cancer Cells Can Exhibit a Sparing FLASH Effect at Low Doses Under Normoxic In Vitro-Conditions.

BACKGROUND: Irradiation with ultra-high dose rate (FLASH) has been shown to spare normal tissue without hampering tumor control in several in vivo studies. Few cell lines have been investigated in vitro, and previous results are inconsistent. Assuming that oxygen depletion accounts for the FLASH sparing effect, no sparing should appear for cells irradiated with low doses in normoxia. METHODS: Seven cancer cell lines (MDA-MB-231, MCF7, WiDr, LU-HNSCC4, HeLa [early passage and subclone]) and normal lung fibroblasts (MRC-5) were irradiated with doses ranging from 0 to 12 Gy using FLASH (≥800 Gy/s) or conventional dose rates (CONV, 14 Gy/min), with a 10 MeV electron beam from a clinical linear accelerator. Surviving fraction (SF) was determined with clonogenic assays. Three cell lines were further studied for radiation-induced DNA-damage foci using a 53BP1-marker and for cell cycle synchronization after irradiation. RESULTS: A tendency of increased survival following FLASH compared with CONV was suggested for all cell lines, with significant differences for 4/7 cell lines. The magnitude of the FLASH-sparing expressed as a dose-modifying factor at SF=0.1 was around 1.1 for 6/7 cell lines and around 1.3 for the HeLasubclone. Similar cell cycle distributions and 53BP1-foci numbers were found comparing FLASH to CONV. CONCLUSION: We have found a FLASH effect appearing at low doses under normoxic conditions for several cell lines in vitro. The magnitude of the FLASH effect differed between the cell lines, suggesting inherited biological susceptibilities for FLASH irradiation.