Salvage re-irradiation in non-melanoma skin cancers: A multicenter analysis.

BACKGROUND AND PURPOSE: We conducted a multicentre real-world study to assess the outcomes of radical salvage re-irradiation for non-melanoma skin cancer (nMSC) recurrences following definitive or postoperative radiotherapy. MATERIALS AND METHODS: Data on patients treated between 2006 and 2022 with re-irradiation for nMSCs were retrospectively collected from five high-volume brachytherapy centers. The primary endpoint was local control (LC). Secondary endpoints included overall survival, progression-free survival, and adverse events (AEs). The Kaplan-Meier estimator and Cox Proportional-Hazards Model were utilised in the analysis. RESULTS: A total of 58 patients with a median age of 78.4 years with recurrences of previously irradiated nMSC in the head and neck region were included in the analysis. The majority had cutaneous basal cell carcinoma (BCC; 91.4%), and were irradiated with high-dose-rate brachytherapy (HDR-BT; 91.4%). The most common locations included the nasal region (36.2%) and external ear (18.9%). The 1-year LC was 73.1% and decreased to 41.7% at three years. The size of the re-irradiated lesion was the single independent prognostic factor in Cox analysis (per mm; HR 1.07; 95% CI 1.04-1.11; p < 0.001). Grade 3 or worse AEs were reported in 7 cases (12.1%). CONCLUSION: Re-irradiation for nMSCs, predominantly administered with brachytherapy for radiorecurrent BCC, is associated with high recurrence rates, and the risk of failure significantly increases with the size of the treated lesion. Re-irradiation could be an option for selected elderly patients with small, localised, inoperable recurrences after RT to achieve local control or defer systemic treatment; however, prospective trials are necessary to confirm its safety and efficacy.

Stages I-III Inoperable Endometrial Carcinoma: A Retrospective Analysis by the Gynaecological Cancer GEC-ESTRO Working Group of Patients Treated with External Beam Irradiation and 3D-Image Guided Brachytherapy.

BACKGROUND/PURPOSE: Analyse the outcomes of stages I-III inoperable endometrial cancer (IEC) patients treated with external-beam-irradiation (EBRT) and 3D-image-guided-brachytherapy (IGBT). MATERIAL AND METHODS: Medical records of IEC patients receiving EBRT + IGBT in eight European and one Canadian centres (2004-2019) were examined, including: pelvic ± para-aortic EBRT and lymph node boost; anaesthetic procedure, applicators, BT-planning imaging, clinical target volume (CTV), brachytherapy schedule, and EQD2 to the CTV(α/ß=4.5Gy) and D2 cm3(α/ß=3Gy) for organs at risk. Complications are evaluated using CTCAEv4 scores. The 2- and 5-year survival probability according to stages was estimated (cancer-specific survival (CSS), disease-free survival (DFS), local relapse-free survival (LRFS), loco-regional relapse-free survival (LRRFS), and distant metastasis-free survival (DMFS)). STATISTICS: descriptive analysis and the Kaplan-Meier method. RESULTS: 103 patients (stages: I-44, II-14, III-44) were included. Median follow-up: 28 months (7-170). All patients received pelvic ± para-aortic EBRT. Median D90-EQD2(α/ß=4.5) to the CTV:73.3 Gy (44.6-132.7), 69.9 Gy (44.7-87.9 and 75.2 Gy (55.1-97) in stages I, II, and III, respectively. Thirty patients presented relapse (stages: 10-I, 3-II, 17-III): 24 uterine (stages: 7-I, 3-II, 14-III), 15 nodal (stages: 4-I, 1-II, 10-III), and 23 distant (stages: 6-I, 2-II, 15-III). Five year CSS was 71.2% (stages: 82%-I-II and 56%-III) and DFS, LRFS, LRRFS, and DMFS were 55.5%, 59%, 72%, and 67.2%, respectively. Late G3-G4 complications (crude): 1.3% small bowel, 2.5% rectum, and 5% bladder. CONCLUSION: In stages I-III of the IEC, EBRT + IGBT offer good 2- and 5-year CSS of 88.7% and 71.2%, respectively, with the best outcomes in stages I-II. Prospective studies are needed to determine how better outcomes can be achieved.

Clinical Course and Severity of COVID-19 in 940 Infants with and without Comorbidities Hospitalized in 2020 and 2021: The Results of the National Multicenter Database SARSTer-PED.

This study aimed to analyze the differences in severity and clinical characteristics of COVID-19 in infants hospitalized in Poland in 2021, when the dominance of variants of concern (VOCs) alpha and delta was reported, compared to 2020, when original (wild) SARS-CoV-2 was dominant (III-IV vs. I-II waves of the pandemic, respectively). In addition, the influence of the presence of comorbidities on the clinical course of COVID-19 in infants was studied. This multicenter study, based on the pediatric part of the national SARSTer database (SARSTer-PED), included 940 infants with COVID-19 diagnosed between March 1, 2020, and December 31, 2021, from 13 Polish inpatient centers. An electronic questionnaire, which addressed epidemiological and clinical data, was used. The number of hospitalized infants was significantly higher in 2021 than in 2020 (651 vs. 289, respectively). The analysis showed similar lengths of infant hospitalization in 2020 and 2021, but significantly more children were hospitalized for more than 7 days in 2020 (p < 0.009). In both analyzed periods, the most common route of infection for infants was household contact. There was an increase in the percentage of comorbidities, especially prematurity, in children hospitalized in 2021 compared to 2020. Among the clinical manifestations, fever was predominant among children hospitalized in 2021 and 2020. Cough, runny nose, and loss of appetite were significantly more frequently observed in 2021 (p < 0.0001). Severe and critical conditions were significantly more common among children with comorbidities. More infants were hospitalized during the period of VOCs dominance, especially the delta variant, compared to the period of wild strain dominance, even though indications for hospitalization did not include asymptomatic patients during that period. The course of COVID-19 was mostly mild, characterized mainly by fever and respiratory symptoms. Comorbidities, particularly from the cardiovascular system and prematurity, were associated with a more severe course of the disease in infants.

The Influence of SARS-CoV-2 Variants B.1.1.7 and B.1.617.2 on a Different Clinical Course and Severity of COVID-19 in Children Hospitalized in 2021 Compared With 2020.

BACKGROUND: This study aimed to analyze the differences in the epidemiologic and clinical characteristics of coronavirus disease 2019 (COVID-19) in children hospitalized in 2021, when the severe acute respiratory syndrome coronavirus 2 variants B.1.1.7 (alpha) and B.1.617.2 (delta) dominated, compared with 2020. METHODS: In this multicenter study based on the pediatric part of the national SARSTer register (SARSTer-PED), we included 2771 children (0-18 years) with COVID-19 diagnosed between March 1, 2020, and December 31, 2021, from 14 Polish inpatient centers. An electronic questionnaire, which addressed epidemiologic and clinical data, was used. RESULTS: Children hospitalized in 2021 were younger compared with those reported in 2020 (mean 4.1 vs. 6.8 years, P = 0 .01). Underlying comorbidities were reported in 22% of the patients. The clinical course was usually mild (70%). A significant difference in the clinical course assessment between 2020 and 2021 was found, with more asymptomatic patients in 2020 and more severely ill children in 2021. In total, 5% of patients were severely or critically ill, including <3% of the participants in 2020 and 7% in 2021. The calculated mortality rate was 0.1% in general and 0.2% in 2021. CONCLUSION: Infections with severe acute respiratory syndrome coronavirus 2 variants alpha and delta lead to a more severe course of COVID-19 with more pronounced clinical presentation and higher fatality rates than infection with an original strain. Most of the children requiring hospitalization due to COVID-19 do not have underlying comorbidities.

Pre-operative high-dose-rate brachytherapy in early-stage cervical cancer: long-term single-center results.

PURPOSE: The aim of the study was to report the outcomes of pre-operative high-dose-rate brachytherapy (pHDR-BT), followed by hysterectomy in patients with early cervical cancer. MATERIAL AND METHODS: From January, 1998 to December, 2003, 113 women with IB1, IB2, and IIA1 cervical cancer (according to International Federation of Gynecology and Obstetrics [FIGO] 2018) were treated with pHDR-BT, and 6 to 8 weeks later followed by radical hysterectomy. Patients found to have positive lymph nodes, residual cervical cancer, involved parametria, or lymphovascular space invasion (LVSI) received post-operative adjuvant therapy. RESULTS: Post-operatively, 81.4% of patients had a complete response to pHDR-BT in the cervix, and 18.6% had residual cervical cancer. Failures occurred in 11/113 (9.7%) patients (all were stage IIA1), with pelvic recurrences in 5/113 (4.4%) and distant metastasis (DM) in 6/113 (5.3%). The 5- and 10-year disease-free survival (DFS) rates were 100% for IB1 and IB2, and 86.4% and 81.3% for IIA1, respectively. Lymph node involvement and/or residual cervical cancer correlated with worse DFS. Two vesicovaginal fistulas were observed (one in a patient treated only with pHDR-BT and one in a woman, who underwent adjuvant external-beam radiotherapy [EBRT]). Two rectovaginal fistulas and one case of proctitis were observed in patients treated with adjuvant EBRT. CONCLUSIONS: pHDR-BT in early cervical cancer is well-tolerated and effective in sterilizing tumor cells in the cervix. The growing number of publications in this area may help define an optimal therapeutic scheme, but randomized trials are required to determine the best candidates for this treatment modality.In our opinion, cervical cancer patients with FIGO stage IIA1 are not good candidates for pHDR-BT, and could be given this treatment only after rigorous selection, including assessment with state-of-the-art imaging, due to higher probability of treatment failure.

Exclusive 3D-brachytherapy as a good option for stage-I inoperable endometrial cancer: a retrospective analysis in the gynaecological cancer GEC-ESTRO Working Group

PurposeAnalyse outcomes of stage-I inoperable endometrial cancer (EC) patients from seven European centres treated with 3D-image-guided brachytherapy (IGBT) alone.Materials and methodsFrom 2004 to 2018, 62 patients (41 stage-IA and 21 IB) were retrospectively studied, analysing anaesthetic procedure, applicator type, BT-planning imaging, clinical target volume (CTV), BT schedule, overall daily-dose equivalent to 2 Gy (EQD2(α/β=4.5 or 3)) to the CTV(α/β=4.5) and D2 cm3(α/β=3) for organs at risk. Complications were evaluated using CTCAEv4 scores. The 2 and 5 year survival was calculated [cancer-specific survival (CSS), disease-free survival (DFS), local relapse-free survival (LRFS), loco-regional relapse-free survival (LRRFS) and distant metastasis-free survival (DMFS)]. Descriptive analysis and the Kaplan–Meier method were used for survival analysis.ResultsMean follow-up: 32.8 months (SD 33.7). Spinal anaesthesia (38/62) followed by none (16/62) were the most common. Y-shaped Rotte applicators were used in 74% of patients. High-dose rate brachytherapy was administered in 89%. Median D90 to the CTV was 58.9 Gy (8.66–144 Gy). Eight patients presented relapse: four uterine, four nodal and four distant. The 2 and 5 year CSS was 93.3 and 80.5%, DFS 84.8 and 80.5%, LRFS was 93.1 and 88.7%, LRRFS was 91 and 91% and DMFS was 90.2 and 90.2%, respectively, CSS was better in stage-IA vs. IB (p = 0.043). Late vaginal and bladder G3-complication rates were 2.1%, respectively.ConclusionInoperable EC patients can be safely treated by BT with 2 and 5 year CSS of 93 and 80.5%, respectively, with even better results for IA cases. Prospective studies on 3D-IGBT are necessary to better analyse EC patient outcomes based on dose and treated volumes.

Exclusive 3D-brachytherapy as a good option for stage-I inoperable endometrial cancer: a retrospective analysis in the gynaecological cancer GEC-ESTRO Working Group.

PURPOSE: Analyse outcomes of stage-I inoperable endometrial cancer (EC) patients from seven European centres treated with 3D-image-guided brachytherapy (IGBT) alone. MATERIALS AND METHODS: From 2004 to 2018, 62 patients (41 stage-IA and 21 IB) were retrospectively studied, analysing anaesthetic procedure, applicator type, BT-planning imaging, clinical target volume (CTV), BT schedule, overall daily-dose equivalent to 2 Gy (EQD2(α/ß=4.5 or 3)) to the CTV(α/ß=4.5) and D2 cm3(α/ß=3) for organs at risk. Complications were evaluated using CTCAEv4 scores. The 2 and 5 year survival was calculated [cancer-specific survival (CSS), disease-free survival (DFS), local relapse-free survival (LRFS), loco-regional relapse-free survival (LRRFS) and distant metastasis-free survival (DMFS)]. Descriptive analysis and the Kaplan-Meier method were used for survival analysis. RESULTS: Mean follow-up: 32.8 months (SD 33.7). Spinal anaesthesia (38/62) followed by none (16/62) were the most common. Y-shaped Rotte applicators were used in 74% of patients. High-dose rate brachytherapy was administered in 89%. Median D90 to the CTV was 58.9 Gy (8.66-144 Gy). Eight patients presented relapse: four uterine, four nodal and four distant. The 2 and 5 year CSS was 93.3 and 80.5%, DFS 84.8 and 80.5%, LRFS was 93.1 and 88.7%, LRRFS was 91 and 91% and DMFS was 90.2 and 90.2%, respectively, CSS was better in stage-IA vs. IB (p = 0.043). Late vaginal and bladder G3-complication rates were 2.1%, respectively. CONCLUSION: Inoperable EC patients can be safely treated by BT with 2 and 5 year CSS of 93 and 80.5%, respectively, with even better results for IA cases. Prospective studies on 3D-IGBT are necessary to better analyse EC patient outcomes based on dose and treated volumes.

A new prognostic score for predicting survival in patients treated with robotic stereotactic radiotherapy for brain metastases.

The study aimed to analyze potential prognostic factors in patients treated with robotic radiosurgery for brain metastases irrespective of primary tumor location and create a simple prognostic score that can be used without a full diagnostic workup. A retrospective analysis of 142 patients with 1-9 brain metastases treated with stereotactic radiosurgery (1-4 fractions) was performed. Volumes of all lesions were calculated using linear dimensions of the tumors (CC, LR, AP) and 4/3*π*(CC/2)*(LR/2)*(AP/2) formula. Kaplan-Meier method and log-rank test were used to analyze survival. Variables significantly associated with overall survival in univariate analysis were included in Cox multivariate analysis. The validity of the model was tested with the bootstrap method. Variables from the final model were used to construct a new prognostic index by assigning points according to the impact of a specific variable on overall survival. In the multivariate analysis, four factors: Karnofsky Performance Status (p = 0.000068), number of brain metastases (p = 0.019), volume of the largest lesion (p = 0.0037), and presence of extracerebral metastases (p = 0.0017), were independent predictors of survival. Total scores ranged from 0 to 12 points, and patients were divided into four groups based on median survival of each subgroup: 0-1 points-18.8 months, 2-3 points-16.9 months, 4-5 points-5.6 months, and ≥ 6 points-4.9 months (p < 0.001). The new prognostic index is simple to calculate. It has a strong prognostic value in a heterogeneous population of patients with a various number of brain metastases, but its value requires confirmation in another cohort.

Advanced dose calculation algorithm in superficial brachytherapy - the impact of tissue inhomogeneity on treatment plan dosimetry.

PURPOSE: Given tissue inhomogeneity and lack of backscatter media, superficial brachytherapy necessitates more accurate dosimetry than TG-43 formalism. However, the introduction of modern model-based dose calculation algorithms into clinical practice should be carefully evaluated. The aim of this work was to compare dose distributions calculated with TG-43 and advanced collapsed cone engine (ACE) algorithms for individual multi-catheter moulds, and investigate the impact of target size and the lack of bolus to differences between plans. MATERIAL AND METHODS: Eleven treatment plans for individual mould multi-catheter high-dose-rate brachytherapy (IMM HDR) were selected for retrospective analysis. All treatment plans were initially calculated with TG-43 formula and re-calculated using ACE algorithm. Plan re-calculation with ACE was repeated for each plan in order to assess the impact of bolus. To evaluate differences between TG-43 and ACE dose distributions, dose-volume histogram (DVH) parameters for each ROI were compared. Dmax (maximal point dose), D0.1cc, and D2cc were calculated for each risk's organ (OARs) and for external contour. For clinical target volume (CTV), D98, D90, D50, CTV coverage (CTV-V100), and dose delivered to reference point were compared between the plans. RESULTS: A significantly lower values (p < 0.05) of CTV parameters were observed for treatment plans calculated with ACE algorithm comparing to TG-43. Further analysis showed that differences between CTV-V100 for ACE and TG-43 plans depended on CTV volume. Dosimetric parameters for OARs were significantly lower in ACE plans than those of TG-43. Only D2cc for external and D0.1cc for both eye lenses in ACE plans were insignificantly different comparing to TG-43 plans. CONCLUSIONS: Results show that differences between dosimetric parameters are statistically significant. However, their clinical relevance is still undetermined. Careful re-evaluation of the clinical results based on long-term research on TG-43 is necessary to safely introduce modern algorithms to clinical practice.

Clinical and volumetric predictors of local control after robotic stereotactic radiosurgery for cerebral metastases: active systemic disease may affect local control in the brain.

BACKGROUND: The aim of the study was to assess the association between physical and biological dose normalized to volume of the metastatic tumor as well as clinical factors with local control in patients with brain metastases who underwent robotic stereotactic radiosurgery. PATIENTS AND METHODS: A cohort of 69 patients consecutively treated with robotic radiosurgery between 2011 and 2016 was analyzed. The patients were treated with either single fraction radiosurgery or hypofractionated regimens. Biologically effective dose (BED) was calculated assuming alpha/beta value = 10 and both physical dose and BED were normalized to the tumor volume to allow dose-volume effect evaluation. Moreover, clinical and treatment-related variables were evaluated to asses association with local control. RESULTS: A total of 133 tumors were irradiated and their volumes ranged between 0.001 and 46.99 cm3. Presence of extracranial progression was associated with worse local control whereas higher total dose, BED10 > 59 Gy and single metastasis predicted statistically significantly better local outcome. BED10/cm3 > 36 Gy, and BED2 > 60 Gy negatively affected local control in univariate analysis. In multivariate analysis performed on all these variables, presence of a single metastasis, BED10 > 59 Gy and extracranial progression retained their significance. Excluding a priori the BED2/ cm3 parameter resulted with a Cox model confirming significance of all remaining variables. CONCLUSIONS: Hypofractionated treatment schemes have similar efficiency to single fraction treatment in terms of local control and the effect depends on BED irrespective of fractionation schedule. Effective control of extracranial sites of the disease is associated with higher probability of local control in the brain which in turn is consistently lower in patients with multiple lesions.

Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial.

BACKGROUND: Tenecteplase is a newer thrombolytic agent with some pharmacological advantages over alteplase. Previous phase 2 trials of tenecteplase in acute ischaemic stroke have shown promising results. We aimed to investigate the safety and efficacy of tenecteplase versus alteplase in patients with acute stroke who were eligible for intravenous thrombolysis. METHODS: This phase 3, randomised, open-label, blinded endpoint, superiority trial was done in 13 stroke units in Norway. We enrolled adults with suspected acute ischaemic stroke who were eligible for thrombolysis and admitted within 4·5 h of symptom onset or within 4·5 h of awakening with symptoms, or who were eligible for bridging therapy before thrombectomy. Patients were randomly assigned (1:1) to receive intravenous tenecteplase 0·4 mg/kg (to a maximum of 40 mg) or alteplase 0·9 mg/kg (to a maximum of 90 mg), via a block randomisation schedule stratified by centre of inclusion. Patients were not informed of treatment allocation; treating physicians were aware of treatment allocation but those assessing the primary and secondary endpoints were not. The primary outcome was excellent functional outcome defined as modified Rankin Scale (mRS) score 0-1 at 3 months. The primary analysis was an unadjusted and non-stratified intention-to-treat analysis with last observation carried forward for imputation of missing data. This study is registered with ClinicalTrials.gov, number NCT01949948. FINDINGS: Between Sept 1, 2012, and Sept 30, 2016, 1107 patients met the inclusion criteria and seven patients were excluded because informed consent was withdrawn or eligibility for thrombolytic treatment was reconsidered. 1100 patients were randomly assigned to the tenecteplase (n=549) or alteplase (n=551) groups. The median age of participants was 77 years (IQR 64-79) and the median National Institutes of Health Stroke Scale score at baseline was 4 points (IQR 2-8). A final diagnosis other than ischaemic stroke or transient ischaemic attack was found in 99 (18%) patients in the tenecteplase group and 91 (17%) patients in the alteplase group. The primary outcome was achieved by 354 (64%) patients in the tenecteplase group and 345 (63%) patients in the alteplase group (odds ratio 1·08, 95% CI 0·84-1·38; p=0·52). By 3 months, 29 (5%) patients had died in the tenecteplase group compared with 26 (5%) in the alteplase group. The frequency of serious adverse events was similar between groups (145 [26%] in the tenecteplase group vs 141 [26%] in the alteplase group; p=0·74). INTERPRETATION: Tenecteplase was not superior to alteplase and showed a similar safety profile. Most patients enrolled in this study had mild stroke. Further trials are needed to establish the safety and efficacy in patients with severe stroke and whether tenecteplase is non-inferior to alteplase. FUNDING: Research Council of Norway.

Cardiomyopathy development protection after myocardial infarction in rats: Successful competition for major dihydropyridines' common metabolite against captopril.

During the last 25 years angiotensin-converting enzyme inhibitors spectacularly conquered the field of cardiovascular diseases therapy. Nevertheless, lack of new studies concerning side effects associated with their chronic administration seems to be rather confusing. In our previous research, we proved that the main furnidipines' metabolite (M-2) possess multiple cardioprotective actions. Currently, we compared effects of post-infarction long-term oral treatment with M-2 and captopril on hemodynamic parameters and "ischemic cardiomyopathy" development in rats. Myocardial infarction was evoked by permanent left anterior descending coronary artery occlusion for 35 days. Surviving rats were treated with captopril (2 × 25 mg/kg) or M-2 (4 mg/kg) from 6th- 35th day. At 35th day rats' hearts were tested on working heart setup, where following parameters were measured: heart rate, preload pressure, aortic systolic and diastolic pressures, aortic maximum rise and fall, aortic and coronary flow, myocardial oxygen consumption and oximetry in perfusate. Subsequently, heart tissue specimens were assessed during morphological estimation. Captopril caused significant heart rate increase and markedly diminished preload pressure in comparison to M-2. Both drugs evoked essential aortic pressure increase. Aortic flow was significantly decreased after M-2, whereas captopril increased this parameter in comparison to M-2. Both agents caused marked coronary flow increase. Morphologic examination in captopril revealed cardiomyopathic process in 70% of hearts, whereas in M-2 this value reached 30%. Neovascularization of post-infarcted myocardium was visible only after M-2 therapy. Concluding, M-2 presented itself as more attractive agent in long-term post-infarction treatment by preventing cardiomyopathy development, angiogenesis stimulation and preserving cardiac performance.

Hypoglycemic episodes are associated with inflammatory status in patients with type 1 diabetes mellitus.

BACKGROUD: Glycemic control may be associated with inflammatory status in type 1 diabetes (T1DM). We examined the association between glucose control parameters and circulating inflammation markers in T1DM. METHODS: The study included 101 T1DM patients treated with personal insulin pumps (T1DM duration 15.2 + 7.3 years). The analysed glycemic parameters included HbA1c, mean glucose level, standard deviation and number of hypoglycemic episodes (glucose <55 mg/dL) from the last 7 days. Blood was collected for testing inflammatory markers (IL-6, VCAM, ICAM, E-selectin). RESULTS: The T1DM cohort had good glycemic control (HbA1c 7.1 ± 0.8%, mean daily glucose 141.5 ± 27.1 mg/dL and the mean number of hypoglycemic episodes was 5.6 ± 4.0/week). In a forward stepwise multiple linear regression analysis the number of hypoglycemic episodes predicted the levels of the investigated markers (sICAM p = 0.0019, sVCAM p = 0.021, sE-selectin p = 0.048, and IL-6 p = 0.049). None of the other glycemic parameters was shown to be an independent predictor. CONCLUSIONS: For the first time, we report an association between the number of mild hypoglycemic episodes, recorded in a real life setting, and the level of inflammatory markers in T1DM patients with good glycemic control.