Autoimmune bullous diseases (AIBDs) are a group of rare cutaneous disorders affecting cornified skin and mucous membranes. They are characterized by tense or flaccid blistering and erosions due to autoantibodies against desmosomal and hemidesmosomal structural proteins of the skin. This group of disorders can be divided into those of pemphigoid and those of pemphigus diseases. If left untreated, these autoimmune diseases can cause serious or even life-threatening complications such as loss of fluid, superinfections or impaired food intake. Due to modern standardized serological assays, the diagnosis of AIBDs can usually be confirmed in combination with their clinical appearance. Whereas for a long time corticosteroids were the major players in the treatment of these diseases, with the approval of rituximab and other immunosuppressive agents, the therapy has increasingly improved.In this study, we aimed to investigate epidemiologic and clinical features as well as diagnostics and therapy of bullous autoimmune diseases in Middle Franconia, a governorate within the German federal state of Bavaria. Patients diagnosed or treated because of a AIBDs between 01.04.2013 and 31.03.2019 at the dermatological department of the university hospital Erlangen were included in this retrospective study (n = 242). Patients were either diagnosed for the first time (n=176) or the diagnosis has been confirmed (n=66) at the department. The respective incidence was calculated among the 176 subjects who had been diagnosed at the center in this period. Data was taken from patient records and analyzed with Microsoft® Excel. The evaluation included the diagnoses of pemphigus vulgaris (PV), pemphigus foliaceus (PF), bullous pemphigoid (BP), mucous membrane pemphigoid (MMP), linear IgA dermatosis (LAD), epidermolysis bullosa acquisita (EBA), and dermatitis herpetiformis (DH).This study shows that the incidence of each AIBDs in Middle Franconia is low and comparable  or lower  than in other studies and regions. BP is the most common newly diagnosed AIBD in Middle Franconia.Due to the chronic and sometimes severe course of AIBDs, repeated in-house treatments are often necessary. To date, mainly topically and systemically applied corticosteroids in combination with immunomodulators are used as first-line therapy. Depending on the type of disease and its severity, the clinical features range from erythema on the skin and mucous membranes to excoriations, vesicles, blisters or even erosions. In patients with severe disease progression, old age or inadequate therapy, these diseases can lead to increased mortality , 2. A ro1.1Pemphigoid diseases are characterized by the formation of subepidermal blisters along the dermo-epidermal junction zone. Autoantibodies are directed against hemidesmosomal structural proteins, which disrupts the connection of the basal keratinocytes with the basement membrane zone . BP is t1.2Pemphigus diseases, in contrast to pemphigoid diseases, are distinguished by intraepidermal and therefore more unstable blister formation. The two most frequent representatives of this group are pemphigus vulgaris (PV) and pemphigus foliaceus (PF) . The inc22.1® Excel.Data of patients presenting with AIBDs at the department from 04/01/2013 to 03/31/2019 were included. The electronic patient records were screened with regard to keywords of bullous autoimmune dermatoses. 464 patients were detected, of which the diagnosis of AIBDs was finally confirmed in 242. The diagnosis or confirmation of the diagnosis of AIBDs was made on the basis of the clinical presentation and - depending on availability – serologic and immunofluorescence microscopic results. If the diagnosis was previously made externally, it had to be reconfirmed again at the dermatology clinic. For calculation of incidence, all patients with first diagnosis of a AIBDs in the given period were included. This criterion was met by 176 patients. The data analysis was done with Microsoft2.2The description and localization of the patients’ skin manifestations were taken from their initial presentation at the Department of Dermatology of the University Hospital Erlangen. Only the symptoms recorded by the treating physicians were included, whereas anamnestic data given by the patients were not considered. Skin biopsies were collected (peri-)lesionally and examined both histologically and by immunofluorescence. Serological tests were performed by indirect immunofluorescence  and ELISA (MESACUP™). When DH and celiac disease were suspected, the patient’s serum was tested for G-Transglutaminase-IgA antibodies.2.3The catchment area of the Department of Dermatology at Erlangen University Hospital was determined on the basis of the postal codes of all patients (n = 464). Patients who came from a federal state other than Bavaria (n = 6) or from abroad (n = 2) were not taken into account. The catchment area is shown in 2.4® Excel was used for the statistical analysis of the data as well as the creation of the diagrams. Continuous variables are presented with the arithmetic mean, median and standard deviation.Microsoft3In total, the electronic medical records of 464 patients were analyzed. For 242 of these patients, the final diagnosis of a AIBDs was made. The following results refer to data from these 242 patients.In 75.2% (n = 182) the initial diagnosis was confirmed at the Department of Dermatology Erlangen. In 176 patients (72.7%), the initial diagnosis (ID) date was between 01.04.2013 and 31.03.2019. Based on this group of patients, the incidence calculation was performed. The frequency distribution of the individual AIBDs is shown in The overall incidence of AIBDs was 10.9 per 1 million per year. The gender-related incidence was higher in males (11.5) than in females (10.4).3.1A total of 49 cases with PV were analyzed. The incidence of PV was 1.8 per 1 million and year Table 2 Regarding clinical symptoms, 65.3% of patients reported pain and 14.3% reported pruritus Figure 4Skin biopsy with subsequent histopathologic examination was performed in 30 of the 49 patients (61.2%). The histopathological findings supported the diagnosis of PV in 83.3%. 79.6% of sera were tested on monkey esophagus by IIF and 29/39 showed positive test results. DIF examination was performed in 29 of the 49 patients (59.2%). In almost three-fourths of the cases (72.4%), the result was positive with the characteristic intercellular pattern. 50.0% of serological examinations showed elevated autoantibody concentrations against Dsg 1. Concentrations of autoantibodies against Dsg 3 were elevated in 95.7% (≥20 U/ml).48 of the 49 patients (98.0%) received systemic therapy, all of them systemic corticosteroids while 87.8% were also started on an immunomodulatory drug (azathioprine (AZA) 55.1%, mycophenolate mofetil (MMF) 22.4%, methotrexate (MTX) 8.1%, dapsone 2.0%).3.2PF was much less common, with an incidence of 0.4 per 1 million per year. The incidence in men  was three times higher than in women . At first manifestation, patients were 67± 19 years of age on average with a median of 72 years. 61.5% of patients reported pruritus in their anamnesis. Weight loss and mucosal involvement have not been observed. PF manifested as plaques and erythema in approximately three-quarters (76.9%) of patients. Scaling (61.5%), erosions (53.8%), crusts (38.5%) and blisters (15.4%) were also found. In 9 of the 13 patients (69.2%), a skin biopsy was taken for histopathological examination, which supported the diagnosis in 2/3. In 10 patients (76.9%), an IIF examination for monkey esophagus was performed, which resulted in a diagnosis in 70%. All patient specimens examined showed elevated anti-Dsg1 autoantibody concentrations. 84.6% of patients received systemic therapy .3.3BP was by far the most common diagnosis among the AIBDs studied (n=165). The incidence was 8.3 per million per year with no correlation to gender. The average age at the time of the first symptoms of the disease was 75 ± 12 years, the median age 78 years.In BP, itching was the leading symptom in a large proportion of patients (81.8%). 10.9% suffered from pain and 2.4% reported weight loss. Oral involvement was diagnosed in 16.4% of patients. Approximately three quarters (72.1%) of the cases presented with firm blisters on the skin. Furthermore, erythema (62.4%), erosions (58.8%), plaque (38.8%), (scratch) excoriations (26.1%), and crusts (23.6%) were observed. In 152 of the 165 patients (92.1%), a tissue specimen was obtained and examined histopathologically. In 79.0%, the evaluation resulted in a diagnosis compatible with BP. IIF examination on monkey esophagus was performed in 142 of the 165 patients (86.1%). In 43.7%, a matching linear IgG deposit at the basement membrane could be found. An elevated anti-BP180 antibody concentration was detected in 79.3% of the sera tested and an elevated anti-BP230 antibody concentration in 54.8%. 73 of the patients (44.2%) showed increased autoantibody concentration against both BP180 and BP230. 74.6% received systemic corticosteroids, in 59.9% of patients combined with immunomodulatory drugs such as dapsone (48.5%) (50 -150 mg/d), azathioprine (9.6%) (0.5 - 2.0 mg/d), or MMF (1.8%) (2000 mg/d). 18 patients (11.5%) received monotherapy with dapsone and one (0.6%) received monotherapy with doxycycline.3.4The incidence of MMP was 0.1 per million per year. Patients presenting with MMP were on average 72 ± 8 years old. The median age was 71 years. The most common complaint was pain (71.4%), with only 14.3% reporting pruritus. In addition, nearly one-third (28.6%) of the patients reported weight loss. By definition, all patients had oral mucosal lesions. Additional involvement of the conjunctiva was documented in 57.1% and of the anogenital mucosa in 14.3%. In 85.7% a MMP manifested as erosions. Erythema (28.6%) and blisters (28.6%) were less common. Six of the seven patients (85.7%) had a biopsy taken for histopathologic examination, which supported the diagnosis in 50%. Similarly, in 50%, DIF examination could provide matching results. 71.4% were tested using IIF on monkey esophagus. With 100% positive results for IgG, this showed a higher sensitivity. In addition, four patient sera (66.7%) showed an increased concentration of autoantibodies against BP180. All 7 patients were systematically treated .3.5LAD also had an incidence of 0.1 per million per year. The two male patients with LAD were 51 and 72 years old. Pruritus was the main symptom in both cases. One patient had oral and anogenital mucosal involvement. Both patients clinically showed mainly erythema on their skin. In one patient, the diagnosis of LAD was supported histopathologically. Evidence of linear IgA deposition in the DIF was conclusive for the diagnosis in both cases. Linear IgA deposits were also found in IIF. In addition, antibodies against BP180 were elevated. One patient was treated with internal corticosteroids while the other patient was administered dapsone.3.6During the observation period, only one 65-year-old man was diagnosed with EBA, resulting in an incidence of 0.1 per million per year. He suffered from acrally located blisters, erosions and crusts and reported itching and pain. Histopathologic evaluation of the specimen examined raised suspicion of EBA. Fluorescence microscopy showed a linear pattern along the basement membrane with IgG, IgM and C3 deposition. While IIF examination with monkey esophagus did not reveal any findings, salt split skin showed a linear IgG deposition along the blister basement. Autoantibodies against BP180, BP230, or collagen VII could not be detected in serum. The detection of collagen 7 antibodies is of high importance in the diagnosis of EBA. According to current recommendations, one of the following findings should be made when establishing the diagnosis. 1) u-serration pattern in DIF, 2) ELISA, indirect IF microscopy-based test, or immunoblotting for type VII collagen, 3) fluorescence overlay antigen mapping (FOAM) technique, or 4) direct immunogold electron microscopy . The inv3.7In summary, four patients with DH were included in this study. However, only one male patient presented with newly diagnosed disease resulting in an incidence of 0.1 per million per year. DH showed the lowest mean age at first manifestation with 29 ± 11 years and a median at 27 years. The age range was from 16 to 47 years. The main symptom was pruritus (80%). Clinically, predominant erythema (60.0%), vesicles (40.0%), and erosions (40.0%) could be objectified. A skin biopsy was taken in 4/5 patients, which confirmed the diagnosis in 75%. DIF showed IgA deposits in 75%. Serologically, G-transglutaminase IgA antibodies were detected using ELISA in 75% of the patients investigated. As first-line therapy, all five patients (100.0%) received systemic therapy with dapsone (50 - 100 mg/d).3.8In 7 patients (2.9%), a malignant tumor was known at the time of AIBDs diagnosis. In addition, 20 patients (8.3%) were in remission from a malignant disease. One patient (2.0%) with PV suffered from prostate carcinoma at diagnosis, and another patient was in remission of colon and prostate carcinoma. Three patients (23.1%) with PF were in remission . Six patients with BP (3.6%) had a known malignancy at diagnosis . In addition, 16 patients with BP were in remission. Here, the most common diagnoses were breast carcinoma (31.3%), prostate carcinoma (18.8%) and urothelial carcinoma (12.5%). LAD, EBA and DH patients had no malignancy in their medical history.4This study compiled relevant epidemiological data for AIBDs in a defined area of Germany. For PV, our study showed an incidence of 1.8 per million population per year. Somewhat lower incidence values between 0.5 - 1.5 for PV disease result from studies in Lower Franconia (2001 - 2002), Lübeck (2004 - 2007) as well as France (2004 - 2013) , 12, 30.LAD was also underrepresented in our study with only one case and also had an incidence of 0.1 per million per year. Studies from Lower Franconia showed a 10-fold higher incidence . A more Concerning the case with EBA, we want to point out a certain diagnostic uncertainty. This again points to the need for further studies and guidelines in order to clarify this vagueness. One possibility would be to establish the examination and evaluation of the different immunodeposition patterns in DIF. Here it has already been shown that the pattern of U-serrated pattern distinguishes type VII collagen-targeted bullous diseases from other subepidermal bullous autoimmune diseases . A subseIn the present study, histopathological findings supported the diagnosis of PV in 83.3% and 66.6% in PF patients. This illustrates that histopathology plays an important, yet not exclusive role in the diagnostic process, but should not be used as the only method. The same is true for BP. Here, the suspicion of BP could be substantiated histopathologically by the subepidermal cleft formation in 79% of the patients . This neWe also demonstrated that AIBDs frequently occur in the context of malignant disease. The German and European guidelines also refers to this correlation –41. TherIn our study, the majority of patients received internal systemic therapy with corticosteroids. Although these show rapid therapeutic success, they are accompanied by unavoidable long-term side effects. As shown in The study shows some limitations, especially due to the retrospective monocentric design. The partly deviating incidences in the different studies mentioned can be explained by the overall low case numbers and different study designs. Even though the Department of Dermatology Erlangen is the only university hospital within a radius of 100 km, patients with AIBDs could have been diagnosed in other hospitals. In addition, cases may be underdiagnosed and not amply collected. To obtain more reliable data on the incidence of blistering diseases, large registries or the error-prone analysis of data from health insurance companies are needed. With regard to the diagnostics, we did not repeat the DIF examination for sample biopsies that had already been performed externally if suitable circulating antibodies were detectable by IIF or ELISA. The diagnosis was always made according to the current guidelines by a board-certified dermatologist , 41.In summary, this retrospective data analysis provided epidemiologic data similar to those obtained in other regional evaluations from central Europe. AIBDs often pose diagnostic as well as therapeutic challenges to both patients and treating physicians. Further research is needed for better understand this group of disorders and identify new treatment options.The datasets for this article are not publicly available due to concerns regarding participant/patient anonymity. Requests to access the datasets should be directed to the corresponding author.LS: Writing – original draft. VS: Writing – original draft. MS: Writing – review & editing.


HPV16-positive samples were analysed for variants by type-specific PCR spanning L1, E2 and E6 regions. Results: HPV16 was the commonest genotype in cases  and controls  (p = 0.30), followed by HPV18  (p = 0.08). Furthermore, 90% (20/22) of cases and 84.1% (58/69) of controls were positive for HPV16 or 18 (p = 0.42); 100% (22/22) of cases and 95.7% (66/69) of controls had at least one genotype targeted by the nonavalent vaccine (p = 0.3). The majority of HPV16 variants  were of European lineage. The proportion of unique nucleotide substitutions was significantly higher in cases  compared with controls , . Conclusions: Virological factors may account for the differences in CCs observed in younger compared with older women. All CCs in young women in this study had preventable 9vHPV types, which is important messaging for health provider adherence to new cervical screening guidelines.Background: In 2007, Australia introduced a national human papillomavirus (HPV) vaccination program. In 2017, the onset of cervical screening changed from 18 to 25 years of age, utilising human papillomavirus (HPV) nucleic acid testing. The objective of the study is to describe the HPV genotypes and HPV16 variants in biopsies from women ≤ 25 years of age with cervical carcinoma (CC) (cases), compared with those aged >25 years (controls), in a pre-vaccination cohort. Methods: HPV genotyping of archival paraffin blocks ( For the total study population, HPV18 was more common in adenocarcinoma (AC)  than in squamous cell carcinoma (SCC)  . However, the proportion with HPV16 was not significantly different between the two morphological types (50.0% (8/16) for AC and 73.0% (46/63) for SCC) . In women aged ≤25 years alone, there was no significant difference in the proportion of SCC  and AC  due to HPV16 (p = 0.30); however, HPV18 was less common in SCC  than in AC  (p = 0.02).Overall, 90.8% (20/22) of women aged ≤25 years were positive for HPV16 or 18 compared with 84.0% (58/69) of women aged >25 years (p = 0.3) . There wp = 0.02).In cases, five-year survival for those who were HPV18-positive was 57.1% (4/7) compared with 78.6% (11/14) for non-HPV18-related cases . For thop = 0.4, OR 0.4 [0.0–3.6]) (The proportion of women with multiple infections was 8.8% (8/91). There was a trend for women aged ≤25 years to have a lower proportion of multiple infections  compared with women aged >25 years , but this was not statistically significant (.0–3.6]) .p = 0.3, OR 0.6, 95%CI 0.3–1.6). For all subjects tested, genomic variability was 1.1% (2/169) in L1, 4.5% (5/110) in E2, 5.9% (7/118) in E6 and 3.9% (4/102) in E6 350. The proportion of unique substitutions was significantly higher in cases  compared with controls  , which translated to a difference in the proportion of unique aa changes between cases  and controls  .Fifty-eight HPV16-positive subjects  were eligible for variant analysis. Of these, testing was not performed in one case and one control in time for the study. In one control, the variant could not be classified due to an invalid result (a substitution in E6 (T145) was seen on reverse hybridisation, but forward hybridisation failed). Total nt variability was similar in cases  and controls  . Genomicp = 0.7, χ2, OR 1.6, 95%CI 0.6-), nor in the proportion of the T350G variant  .The vast majority of isolates  were characteristic of the European lineage . There wp > 0.05) (The European variant was the most common variant in both SCC and AC . AA vari > 0.05) .There is a paucity of research examining early-onset cancers in young women. This is one of the first studies to examine the genotypes and HPV16 variants in young women to assess if virological factors contribute to a more rapid progression to invasive cancer. In this pre-vaccination study, we found a very high proportion of CCs in women aged ≤25 years attributable to HPV16 and 18 (90.8%), suggesting a predilection of these types for young women. Women aged ≤25 years were found to have restricted HR-HPV genotype distribution (2 types apart from HPV16/18) compared with controls (7 types apart from HPV16/18). Although the total nt and genomic variability were similar between cases and controls, the proportion of unique substitutions was significantly higher in cases (83.5%) compared with controls (34.1%), which translated to a higher proportion of unique aa changes found in cases. Further studies are required to determine if these changes may contribute to differences in viral adaptation, proliferation and, ultimately, early-onset carcinoma.In a worldwide study of over 10,000 CCs, the proportion of HPV16/18 genotypes found in a subset of 170 CCs from Australia was 79%, with the commonest genotypes being HPV16 (59%), 18 (20%) and 45 (5%), followed by 33, 39 and 53 at 2% each . A studyThere is limited data published on HPV variant analysis in young women with CCs. A strength of our analysis was the blinded histology review. Lagstrom et al. found an average of 48.3 variants (range 15–82) per whole HPV16 genome in 15 Dutch women aged 16–29 years; however, the population were women from the community invited for screening . A populWe chose variant analysis of HPV16 as it is the dominant genotype in cervical cancer. A limitation of this study is that we did not evaluate the variants of HPV18. There was a trend for HPV18 to be more common in cases with CCs (36.3%) compared with controls (17.3%), suggesting an age-related predilection of HPV18 in cervical neoplastic transformation in younger women. In the absence of other strong biological factors, longer exposure to HPV through unwanted genital contact at a young age may be an important aetiological factor, as it has been shown to independently increase the risk of early-onset cervical disease 5–6-fold .The high proportion of CCs due to HPV16 and 18 (90.8%) suggests that a higher-than-expected proportion of CCs may be prevented in young women with universal vaccination coverage. It is noteworthy that all CCs in young women in this study had preventable 9vHPV types, thus it is likely a very rare outcome in future cohorts, with the potential exception of sexual abuse survivors . Such inAnother limitation of this study is that we found that a significant proportion of CC specimens only had residual high-grade disease left within the paraffin block and had to be excluded . This waHPV genotype variation over time in CCs is another important factor in estimating the long-term impact of vaccines. We demonstrated that the L1 gene was highly conserved in young women and controls (genomic variability 1.1%), and this together with the knowledge that HPV types have evolved very slowly, and have diverged since the origin of humanity only by about 5% , means tWhile HPV genotyping in nationally reported CCs is unknown for this age group, this study provides important baseline data for the monitoring of 4vHPV and 9vHPV and predicting the impact of the revised cervical screening guidelines in those aged <25 years. All CCs in young women in this study had preventable 9vHPV types, which is important messaging for health provider adherence to the new cervical screening guidelines. Accordingly, we advise genotyping surveillance of all CCs diagnosed.


The tumor response to neoadjuvant radiochemotherapy is one of the most important prognostic factors in patients with locally advanced rectal cancer. Locally advanced rectal cancer contains migrant cell populations, the source of locoregional metastases. Neoadjuvant radiochemotherapy treatment identifies with pathological certainty lymph node metastatic radiochemoresistance. These patients have a higher risk biology for regional and systemic migrant recurrence that requires consideration of an evidence-based change in therapeutic strategy. The aim of this work is to analyze the impact of post-neoadjuvant nodal status as an independent prognostic factor in locally advanced rectal cancer to implement adjuvant chemotherapy administration tailored to each patient’s individualized risk response. The hypotheses that we evaluate in this study can guide the individualization of the therapeutic approach in patients with post-neoadjuvant metastatic lymph node persistent rectal cancer, as well as the definition of subgroups based on certain patient characteristics and tumor biology.p = 0.009) between the ypN groups: age ≥ 65 was 57.6% in pN0 and 43.5% in ypN+ and patients aged < 65 constituted 42.4% of pN0 and 56.5% of ypN+. According to the clinical stage there were statistically significant differences (p = 0.001) in the categories’ distribution: ypN+ patients 10.8% were stage II and 89.2% were stage III. Univariant analysis on outcome variables showed statistically significant differences in overall survival at 7 years  disease-free survival (DFS)  and local recurrence-free survival (LRFS) . Conclusions: The presence of nodal metastases (ypN+) after neoadjuvant therapy containing long-course pelvic irradiation severely impacts the long-term outcome for patients with locally advanced rectal cancer and correlates with multiple clinical and therapeutic variable metrics. Implementation of local and systemic therapies should be adapted and intensified in relation to the finding of ypN+ category in surgical specimens.Background: The purpose of this study was to evaluate the long-term oncological progression pattern of locally advanced rectal cancer patients with post-neoadjuvant nodal metastatic disease (ypN+) and correlate potential prognostic features associated with proven radiochemoresistant nodal biology. Methods: Individual patient data (100 variables) from a 20-year consecutive single-institution multidisciplinary experience (1995–2015), delivering multimodal therapy to rectal cancer patient candidates for radical treatment, including a neoadjuvant component and surgical resection with or without intraoperative radiotherapy followed by optional adjuvant chemotherapy. The ypN+ disease data was registered in the context of initial staging categories post-neoadjuvant T status (ypT). Results: Data on 487 patients showed histologically confirmed diagnoses of metastatic nodal disease in 108 specimens . There was a significant age difference ( The tumor response to neoadjuvant radiochemotherapy is one of the most important prognostic factors in patients with locally advanced rectal cancer. The clinical and histological response is higher when the cellular grade (G) is lower. The lower the T and N stage, the higher the radiation dose and the longer the interval between neoadjuvant and surgery (6–8 weeks); a total of 80% of patients with pathological complete response (pCR) undergo surgery within 60 days after the end of irradiation .Locally advanced rectal cancer contains migrant cell populations, the source of locoregional metastases. Neoadjuvant radiochemotherapy treatment identifies with pathological certainty lymph node metastatic radiochemoresistance. These patients have a higher risk biology for regional and systemic migrant recurrence that requires consideration of an evidence-based change in therapeutic strategy. There are prognostic factors that may guide individualization of the therapeutic approach in patients with post-neoadjuvant nodal persistent metastatic rectal cancer (ypN+). This pathological subcategory is associated with adverse prognosis in long-term survival .The aim of this work is to analyze the impact of post-neoadjuvant nodal status as an independent prognostic factor in locally advanced rectal cancer in an attempt to implement adjuvant chemotherapy administration tailored to each patient’s individualized risk response. We evaluate hypotheses of possible prognostic factors that can guide the individualization of the therapeutic approach in patients with post-neoadjuvant metastatic lymph node persistent rectal cancer (ypN+), as well as the definition of subgroups based on certain patient characteristics and tumor biology that can guide us in making therapeutic decisions regarding the intensity and selection of anti-neoplastic agents.To evaluate the oncological progression pattern of post-neoadjuvant ypN+ patients, potential prognostic factors related to radiochemoresistant rectal cancer are analyzed. The risk of oncological progression is categorized in relation to individual clinical and therapeutic data. Therapeutic effect is correlated with progressive clinical outcomes and oncological prognostic categories of interest.The setting of the study is institutional: Hospital General Universitario Gregorio Marañón . Methodologically it is an observational, analytical–descriptive, epidemiological study, with prospective registration of data in a consecutive controlled cohort of patients with locally advanced rectal cancer treated with neoadjuvant radiochemotherapy followed by surgery and occasional posterior hemipelvis boost irradiation during the procedure. The study period spans 20 years, from April 1995 to March 2015.The target population of the study included 488 patients with a histologically confirmed diagnosis of locally advanced rectal adenocarcinoma (cT3-4 N0 or N+ M0) referred to the Hospital General Universitario Gregorio Marañón . The inclusion criteria was patients who were candidate for radical treatment with a neoadjuvant component and surgical resection with or without intraoperative radiotherapy followed by adjuvant chemotherapy if required by non-randomized consecutive sampling. The definitive pathology report of the surgical specimen should be completed. The database includes 100 variables of diagnostic, clinical, pathological and evolutive items of interest per patient. The external beam radiotherapy technique was 3D conformal irradiation in all patients. Neoadjuvant induction oxaliplatin-based chemotherapy was introduced in practice on 05/1998 upon an institutional intramural research program. Adjuvant postoperative chemotherapy practice was implemented with oxaliplatin-based regimes in 2000 for patients with high-risk pathological findings for recurrence (high ypT and/or ypn+ categories).All the participants included in the study were assessed by physical and clinical examination, colonoscopy, imaging study and biopsy with confirmation histology. The clinical assessment of the lymph node involvement of the disease was carried out with different tests: 44.2% were diagnosed by MRI, 32.9% by endorectal ultrasound, 22.3% by CT and only 6% were diagnosed with lymph node involvement by PET/CT. No significant differences were detected between the two study groups. Data was recorded on the tables assuming the non-available information in the following variables: quality of mesorectum (15.1%), ASA category (51.9%), clinical node staging (cNx status) (21%), unknown lymphovascular (29.8%) or perineural invasion (30%).The program used to carry out the statistical analysis of the data is SPSS 20.0 for Windows (version 20.0.0). The statistical analysis consists of a descriptive part detailing the characteristics and distribution of the different variables included in the database .t-test if the dependent variable followed a normal distribution, and using the Mann–Whitney U-test in case of non-normal distribution. For qualitative variables, results were presented as absolute counts and percentages. The association between two dichotomous qualitative variables was studied using the Chi-square test if the expected frequency in all cells was not less than five and otherwise using Fisher’s exact test. For polychotomous variables, only the Chi-square test was used. Subsequently, a univariable logistic regression analysis of clinical, pathological, and therapeutic factors that could influence the occurrence of local or distant recurrence or survival was performed. Variables that showed significant differences in the univariable analysis were analyzed using the Cox multiple-factor analysis method. Survival probability was calculated using the Kaplan–Meier method. Comparison of survival between groups according to different prognostic factors was performed using the log-rank test. For quantitative variables, normality was verified using the Shapiro–Wilks test for samples of less than 50 patients or the Kolmogorov–Smirnov test for samples of more than 50 patients. Quantitative variables with normal distribution were presented as mean and standard deviation, and those without as median and interquartile range (P75-P25). Comparison of independent groups was performed using Student’s Overall survival, disease-free survival and local and distant recurrence-free intervals were computed from the date of surgical treatment. Patients who were alive without disease at the time of study completion or those who died without evidence of tumor recurrence were considered censored. Relapse-free survival and overall survival were estimated at 7 years to explore the potential incidence of late relapses in the context of proven metastatic nodal cancer biology.To study the association of the probability of survival with different qualitative and quantitative predictor variables, the Cox proportional hazards model was used, first univariable and then multivariable. The Cox model relates the relative risk of death or the occurrence of an event to the different selected prognostic factors and calculates the risk ratio (hazard ratio) and the 95% confidence interval for each of these variables. This study was conducted in accordance with the standards of good clinical practice with full acceptance of the ethical standards in force  and respecting all aspects established in the current legislation on clinical research. This study is limited by the methodological deficits inherent in descriptive, observational, non-randomized analyses of an institutional cohort.Descriptive statistical analysis examines data from 488 patients with a histologically confirmed diagnosis of locally advanced adenocarcinoma (ADC) of the rectum treated from April 1995 to March 2015.p = 0.699). The mean age was 64 years (sd +/− 12 years) so that 45.5% were <65 years and 54.5% were ≥65 years. There was a significant age difference (p = 0.009) between the two groups, thus, age ≥ 65 was 57.6% in pN0 and 43.5% in ypN+ and patients aged <65 constituted 42.4% of pN0 and 56.5% of ypN+. The sex distribution was 60.9% male and 39.1% female, distributed homogeneously in both groups (p = 0.057). When considering the existence of previous abdominal surgery, 73.7% had no previous abdominal surgery and 26.3% had another previous surgical procedure, with no statistically significant differences between the two groups (p = 0.778)  and 20.2% high ASA (ASA III-IV) with no differences between the ypN0 and ypN+ groups (= 0.778) .p = 0.075). Of the entire series, 5.9% were cT2, 74.6% cT3, 17.2% cT4 and only 2.3% cTx. In clinical nodal stage (cN), significant differences (p = 0.001) were observed between the two groups. Among the ypN0 patients, 26.8% were cN0, 69.2% cN+ and 3.9% cNx. In the ypN+ group, 10.2% were cN0, 84.3% cN+ and 5.6% cNx. The clinical tumor stage (cT) was similar in both groups with no significant differences between them (p = 0.001), so that in the ypN0 group 27.9% of the patients belonged to stage II and 72.1% were stage III, on the other hand, among the ypN+ patients 10.8% were stage II and 89.2% were stage III . Time from end of neoadjuvant to surgery was <8 weeks in 80.3% and ≥8 weeks in 19.7% of patients. External beam radiotherapy characteristics have been described previously [Regarding the chemotherapy regimens received in the context of neoadjuvant therapy, 69.8% received induction with oxaliplatin and 30.2% did not. Regarding concomitant chemotherapy, 8% received continuous infusion 5FU, 2.5% Xelox, 18.3% oral tegafur and 62.2% oral oxaliplatin-tegafur [p = 0.634).The surgical techniques employed are as follows: low anterior resection 41.3%, abdominoperineal amputation 29.7%, anterior resection 11.2%, ultra-low anterior resection 15.3% and pelvic exenteration 1.4%. There were no significant differences between the two groups. Total mesorectal excision (TME) was performed in 88.5% of all patients in the series. In the ypN0 group 88.2% and in the ypN+ group 89.8% (p = 0.34).Intraoperative radiotherapy as a method of presacral boosting ,6 was adp = 0.001) in the proportion of more advanced ypT stage tumors in the ypN+ group.The histological “T” stage distribution observed after analyzing the post-neoadjuvant surgical specimen (ypT), was: 59 patients (12%) with pathological T complete response were found, all of them were ypN0. In the ypN0 group 62.2% were ypT1, T2 and 35.8% ypT3, T4; on the other hand, in the ypN+ group 24.1% were classified as ypT1, T2 and 75.9% as ypT3, T4, with a statistically significant difference  due to previous understaging. In the ypN+ group, a favorable response to neoadjuvant therapy was observed in 36.5% of patients, of whom 1.7% experienced a 1T downstaging and 4.8% had a 2T downstaging. No patient had a 3T downstaging. However, 59.6% of the ypN+ patients were chemo-radioresistant, i.e., there was no downstaging. A total of 3.8% did not respond or worsened from pre-treatment classification (cT). p = 0.001)  it was observed that of the 113 cN0 patients, cN+ 354 and cNx 21. In the pathological restaging 102 patients (20.9%) were ypN0, and 11 patients (2.25%) were ypN+ potentially understaged with imaging tests. Of the 354 cN+ patients, 263 patients (53.8%) were reclassified as ypN0 and therefore assumed to be responders. In 91 patients (18.6%) ypN+ status was ascertained and therefore interpreted as a group of non-responders. On the other hand, there were 21 cNx patients and of these 15 (3%) were ypN0 and 6 patients (1.2%) were ypN+. In the analyses of nodal downstaging by ypN, 28% of the ypN0 group did not experience any downstaging or improvement in nodal classification, it can be speculated that prior to neoadjuvant treatment they were cN0, while 72% of the ypN0 patients exhibit some degree of downstaging post-neoadjuvant. As for the ypN+ group 89.2% of patients did not experience any degree of nodal downstaging (non-responders). In addition, 10.8% had worsening, either patient who were cN0 and despite neoadjuvant treatment, pathology revealed that they were ypN+ patients and therefore clinically understaged. Significant differences were observed between the two groups (= 0.001) .p < 0.01) because, although the absolute difference in radial circumferential margin involvement between the two groups is very small (3.9%), the sample size is large enough (478 patients) to reach significance.In 98.4% of all patients the radial circumferential margin was >1mm, while it was found to be involved (<1 mm) in 1.6% of all study participants. The ypN0 patients had a free radial margin (>1 mm) in 99.2% and only 0.8% (three patients) were found to be affected. While in the ypN+ group 95.3% of patients had a free radial margin and 4.7% were affected (five patients). These differences were statistically significant (p < 0.01) with a higher rate of perineural and lymphovascular invasion in ypN+ patients. This is because radioresistant tumors (ypN+) are usually aggressive tumor biology neoplasms and therefore have a greater presence of perineural and lymphovascular invasion  the following events occurred in the series: a total of 182 deaths, overall survival (OS) of 62% and a total of 131 recurrences of any type were diagnosed, giving an event free survival (EFS) for the entire series of 72.7%. Systemic recurrence (metastases only): seen in 90 patients; 58 (15.5%) in the ypN0 group and in 32 patients (30.2%) in the ypN+ group;Local recurrence : this was found in 16 patients, 9 (2.4%) in the ypN0 group and in 7 patients (6.6%) in the ypN+ group;p = 0.001), with a higher percentage of recurrences of any type in the ypN+ group;Mixed relapse : 25 patients were targeted, 15 (4%) in the ypN0 group and in 10 patients (9.4%) in the ypN+ group. Statistically significant differences were observed between the two groups (p = 0.002).Local recurrence-free survival (LRFS): a total of 41 local recurrences  were reported, giving an LRFS of 91.4%. In the ypN0 group there were 24 local recurrences (6.4%) and in the ypN+ group 17 patients (16%) had some form of LR  among ypN0 patients and 0 (0%) in ypN+ patients;Central recurrence: 11 (2.9%) were diagnosed among ypN0 patients and 3 (2.9%) among ypN+ patients;Lateral recurrence: There was 1 (0.3%) among ypN0 patients and 5 (4.8%) in ypN+ patients;Presacral recurrence: 9 (2.4%) were detected among ypN0 patients and 8 (7.6%) among ypN0 patients.According to the location of the recurrence, the results were as follows:Univariable analysis for overall recurrence according to the main variables influencing recurrence . The varUnivariable analysis for local recurrence according to the main variables influencing local recurrence were as follows : anestheWith a median follow up of 7 years (P25 48 months-P75 134.8 months) the following events occurred in the series:Overall survival (OS) ypN0/ypN+. Statistically significant differences in overall survival at 7 years were found between the ypN0 and ypN+ groups after analysis using the log-rank test: OS at 7 years 63.8% vs. 55.7%, respectively, (p = 0.016). The overall mortality rate in the ypN+ group is 1.51 times higher than in the ypN0 group. HR 1.51; CI (1.08–2.10); p = 0.016  ypN0/ypN+. Statistically significant differences in disease-free survival at 7 years were found between the ypN0 and ypN+ groups after analysis using the log-rank test; 7-year DFS in the ypN0 group is 78% and in the ypN+ group 53.8%. The overall recurrence rate in the ypN+ group is 2.46 times higher than in the ypN0 group. HR 2.46; CI (1.72–3.5) (.72–3.5) .Local recurrence-free survival (LRFS) ypN0/ypN+. Statistically significant differences in local recurrence-free survival at 7 years were found between the ypN0 and ypN+ groups after log-rank test analysis: SLRL at 7 years in the ypN0 group is 93.6% and in the ypN+ group it is 84%. The local recurrence rate in the ypN+ group is 2.71 times higher than in the ypN0 group. HR 2.71; CI (1.46–5.06); p = 0.002 ( = 0.002 .p = 0.019), higher lymph node ratio (p = 0.001) and higher stage (p = 0.038) [In patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation followed by total mesorectal excision (TME), the categorization of ypN+ tumors is relevant as they are a particular group of neoplasms that are made up of radiochemoresistant cell populations, which are related to an adverse prognosis. In early studies exploring protracted pelvic fractionated preoperative irradiation and fluopirimidins as potentiating agents, Sauer et al. found that all patients who developed recurrence had post-treatment lymph node involvement (ypN+) . In this= 0.038) .The introduction of oxaliplatin-based induction chemotherapy in the neoadjuvant segment of treatment , the sysp = 0.0004). In multivariable analysis, ypN stage was confirmed as an independent prognostic factor for recurrence and overall survival. In a subsequent update [p < 0.001).The importance of pathological nodal stage ypN as a post-neoadjuvant factor has been reported by multiple groups. Rödel et al. , identift update , in thisRather than assessing ypT or ypN separately, some studies have evaluated ypTN as a single predictor of long-term oncological outcome ,17,18. KIn our study, in the univariable analysis, post-neoadjuvant pathological lymph node stage (ypN) significantly influenced the three oncological events : In overall survival, the overall mortality rate in the ypN+ group was observed to be 1.51 times higher than in the ypN0 group; In disease-free survival, the overall recurrence rate in the ypN+ group was evidenced to be 2.46 times higher than in the ypN0 group and in local recurrence-free survival, the local recurrence rate in the ypN+ group was found to be 2.71 times higher than in the ypN0 group.p < 0.001). In multivariable analysis, GLC was also shown to be a statistically significant independent prognostic factor for GLC3: ≤0.4 and GLC4: >0.4  (p = 0.005). Dekker et al. [p < 0.001). The same was true for SLRL (HR 1.65 p < 0.001).Kim et al. performed a retrospective study  in whichr et al.  conductep < 0.001) and GC ≥ 50% . The overall recurrence rate was threefold for GC ≥ 16% (HR 3.61: p < 0.001) and twofold for GC ≥ 50% . The local recurrence rate was four-fold higher for GC ≥ 25% (HR 4.13: p < 0.001) and three-fold higher for GC ≥ 50% . However, the relationship between metastatic lymph nodes and poor oncologic outcomes in patients treated with preoperative CRT followed by radical surgery implies that the value of the lymph node ratio after CRT is still controversial and under study, although it is true that the data so far show that a high positive ratio is associated with poor survival.In our series, the best cut-off point for each of the study events was estimated using the ROC curve  and the p > 0.001). However, the oncological impact of “less than 12 lymph nodes” in post-neoadjuvant patients is still uncertain and it is unknown whether the prognosis of the number of metastatic lymph nodes differs between patients with only a small number of nodes harvested compared to those with a larger number. In our series, only 25.6% of patients had 12 or more lymph nodes collected. In the univariable analysis, no statistically significant differences were observed between the two groups (<12 or ≥12 nodes) for any of the events.There is a consensus that the greater the number of lymph nodes collected and analyzed, the greater the likelihood of finding metastatic lymph nodes, which allows for correct staging of the disease and consequently for planning the most appropriate adjuvant treatment and the best approximation of the patients’ long-term prognosis . Conversp < 0.001) and SLE (HR 2.35 p = 0.002), compared to those with <2 affected nodes, with a much higher local recurrence rate, four times higher in patients with 3 or more positive nodes, SLRL (HR4.13 p < 0.001). Considering that the ypN stage is the most influential and discriminative independent prognostic factor [p < 0.001) than ypN0, more patients with no tumor downstaging (59.6% vs. 25.5% p < 0.001), a higher rate of patients with little tumor regression (TRG 1–2) (84% vs. 42.2% p < 0.001), and a higher proportion of patients with little tumor regression (TRG 1–2) (84% vs. 42.2% p < 0.001) and a higher proportion of ypT3- T4 patients with tumor regression (84% vs. 42.2% p < 0.001) and a higher proportion of patients with perineural (48.7% vs. 8.1% p < 0.001) and lymphovascular invasion (54.5% vs. 7.6% p < 0.001), all of which were statistically significantly associated in the univariable analysis with worse oncological outcomes .In the univariable analysis of our series, we observed that patients with ≥3 positive nodes have worse prognosis, OS  and the evidence of intranodal metastatic colonization and persistence. In terms of the local effects of treatment on the ypN disease category, the effect of neoadjuvant oxaliplatin-based chemotherapy of significantly decreasing the incidence of ypN+ surgical specimens has been seldom described. Local treatment was intensified by the administration of an intraoperative pelvic electron beam boost (80% of patients treated); no differences in local recurrence among ypN groups were observed. The adversity of ypN+ biology was also significant related to surgical local factors such as R status and circumferential margin involvement. To decrease a 26% local recurrence rate at 7 years in the ypN+ patients after local and systemic intensified treatment programs is not a minor challenge. In terms of radiotherapy opportunities proton therapy is a valid available option. The dosimetry of protons can be well adapted to the posterior pelvic space and this boosting decision can be taken once the ypN+ status postoperatively . SpecialOn the other hand, it is also suggested that ypN+ patients with higher nodal tumor burden, i.e., with high GLC, should receive a personalized or risk-adapted adjuvant QT, different from conventional and more intense than the rest of the patients , as a diThis study has several limitations which potentially can bias the interpretations of results. It has the known limitations of observational descriptive studies, collecting data in a prolonged period in a multidisciplinary treatment oncological program. It is an unicentric experience with the bias introduced by the institutional performance of multi-specialist teams based on changing technological pharmacological resources. On the other hand, the plethora of relevant medical variables, the systematic data registration along a prolonged period and the homogeneity of a single-institution medical and surgical practice standards are factor to partially balance the intrinsic limitations of the methodology employed.The presence of nodal metastases (ypN+) after neoadjuvant therapy containing long-course pelvic irradiation severely impacts long-term outcome of patients with locally advanced rectal cancer and correlates with multiple clinical and therapeutic variable metrics. The data generated in a 20-year period, including elements of treatment intensifications, both for local tumor control promotion (intraoperative electron boost) and to decrease systemic risk , indicates that resistant metastatic nodal disease in locally advanced rectal cancer patients should be considered a subcategory for specific trial design. The remaining systemic treatment component in multimodal management should be risk-adapted to the ypN status (not to insist in agents used in the neoadjuvant segment if proven resistance is present). Additional intensification for pelvic tumor control promotion in ypN+ patients can be further explored using a combination of strategies including the use of spacers and proton therapy .


The most common treatment-related adverse events were cytokine release syndrome in 71.2% of patients, which was managed with antipyretic drugs (66.1%), intravenous fluids (28.6%) and systemic corticosteroids or tocilizumab (5.4%), and skin toxicity in 53.8%, which was managed with topical corticosteroids (38.1%) or antihistamines (45.2%).Tebentafusp has recently been approved for the treatment of metastatic uveal melanoma (mUM). We performed a retrospective, multicenter study to analyze the outcomes and safety of tebentafusp therapy in 78 patients with mUM. Patients treated with tebentafusp had a median PFS of 3 months (95% CI 2.7 to 3.3) and a median OS of 22 months (95% CI 10.6 to 33.4). In contrast to a published Phase 3 study, our cohort had a higher rate of patients with elevated LDH (65.4% vs. 35.7%) and included patients with prior systemic and local ablative therapies. In patients treated with tebentafusp following ICI, there was a trend for a longer median OS  compared to the inverse treatment sequence . The most common treatment-related adverse events were cytokine release syndrome in 71.2% and skin toxicity in 53.8% of patients. Tumor lysis syndrome occurred in one patient. Conclusions: Data from this real-life cohort showed a median PFS/OS similar to published Phase 3 trial data. Treatment with ICI followed by tebentafusp may result in longer PFS/OS compared to the inverse treatment sequence.Background: Tebentafusp has recently been approved for the treatment of metastatic uveal melanoma (mUM) after proving to have survival benefits in a first-line setting. Patients and Methods: This retrospective, multicenter study analyzed the outcomes and safety of tebentafusp therapy in 78 patients with mUM. Results: Patients treated with tebentafusp had a median PFS of 3 months (95% CI 2.7 to 3.3) and a median OS of 22 months (95% CI 10.6 to 33.4). In contrast to a published Phase 3 study, our cohort had a higher rate of patients with elevated LDH (65.4% vs. 35.7%) and included patients with prior systemic and local ablative therapies. In patients treated with tebentafusp following ICI, there was a trend for a longer median OS  compared to the inverse treatment sequence (24 months, 95% CI 13.0 to 35.0,  Uveal melanoma (UM) is a rare intraocular tumor that is located either in the choroid 90%), ciliary body 6%) or iris 4%) . Almost % . Almos% or iris0%, ciliaTebentafusp is the first drug that has been approved for the treatment of unresectable or metastatic UM by the FDA and EMA after showing a survival of 21.7 months compared to 16.0 months in the control group in a Phase 3 study. It belongs to a new class of bispecific fusion proteins—the so-called immune mobilizing monoclonal T-cell receptors against cancer (ImmTAC), or T cell engagers (TCEs) . Tebentap < 0.001).In an open-label phase 3 trial, HLA-A*02:01-positive patients with mUM were either assigned to treatment with tebentafusp or to the control group, in which patients received either ipilimumab, pembrolizumab or dacarbazine as the investigator’s choice of treatment . PatientThe most frequently observed treatment-related adverse events (TRAE) were either cytokine-related—including pyrexia (76%), chills (47%) and hypotension (38%)—or cutaneous side effects, including exanthema (83%), pruritus (69%) and erythema (23%).While patients in prospective clinical trials form a homogenous population regarding comorbidities, baseline laboratory values and prior or concomitant therapies, data from real-life studies represent the actual, heterogeneous patient population more realistically. In this retrospective multicenter study, we present the clinical outcomes of 78 patients with mUM who were treated with tebentafusp in a real-life setting. Importantly, this cohort also included patients who received second-line tebentafusp after progression under therapy with ICI.This retrospective multicenter study included all patients with mUM who received at least one dose of tebentafusp at any of the seven participating skin cancer centers in two countries . Altogether, 78 patients were identified. The baseline was defined as the date of the first tebentafusp treatment. Clinical data at the baseline were extracted from electronic medical records—including patient demographics, Eastern Cooperative Oncology Group (ECOG) performance status, tumor genotype (as assessed by next-generation sequencing), sites and number of organ systems affected by metastases, level of lactate dehydrogenase (LDH) and previous local and systemic antitumor therapies. During the treatment period, data on safety  and efficacy  were collected. Adverse events assigned to cytokine release syndrome (CRS) were classified according to American Society for Transplantation and Cellular Therapy Consensus Grading  . Other aProgression-free survival, overall survival and best overall response were assessed locally. Tumor assessment was performed according to RECIST  version 1.1.t-test. Categorical variables were compared using Fisher’s exact test. Progression-free survival 1 , PFS2 (PFS on second-line treatment) and overall survival (OS) were compared between patients who were treated with first-line tebentafusp and patients who were treated with first-line immune checkpoint inhibitors (ICI). Log-rank tests were performed to compare PFS1, PFS2 and OS between the two groups. p values < 0.05 were considered statistically significant. Statistical analyses were conducted with SPSS Version 27 . Diagrams were created using Excel 2016 . Continuous data are presented as median or ranges and categorical data are presented as percentages. Continuous variables were compared using the unpaired Student’s The study was approved by the institutional review board of the medical faculty of the Munich University Hospital (reference number 20-1122) and was conducted in accordance with the principles of the Helsinki Declaration.A total of 78 patients with mUM were included in this multicenter retrospective study and analyzed for PFS and OS after receiving tebentafusp as a first- or second-line therapy. Patients had a median age of 63 years (range 27–91 years) and a sex ratio of 1:1. In our study cohort, enucleation was only performed in 12 patients as a therapy for primary UM; data on histological type as well as the status of monosomy 3 were not available, as the analysis of monosomy 3 is not standard care at the involved centers. Mutations were not assessed specifically for the retrospective trial, but were collected if data was available. Mutations (including BAP1 mutations) were assessed via Next-Generation Sequencing in 37 patients. In 16 patients a mutation  was detected. The majority (51.3%) of patients were still on tebentafusp therapy at the time of data collection; 28.2% were deceased and 20.5% had stopped treatment with tebentafusp due to disease progression (16.7%) or side effects (3.8%). LDH at the beginning of treatment with tebentafusp was normal in 34.6% of patients, above the upper limit of normal (ULN) in 44.6% of patients and >2× ULN in 21.8% of patients. Distant metastases were exclusively hepatic in 43.6%, both hepatic and extrahepatic in 53.8%, and only extrahepatic in 2.6% of patients. Prior to tebentafusp, 35.9% of the patients had already been treated with liver-directed therapies and 51.3% had already received a systemic anti-tumor therapy, including combined ipilimumab and nivolumab, anti-PD1 monotherapy or chemotherapy .Among the 78 tebentafusp treated patients, at least one radiologic examination after treatment start was available for 69 patients: five patients had died before the first radiologic examination and four patients were lost to follow-up. Of the 69 evaluable patients, the best overall response was partial remission in six patients (8.7%), stable disease in 19 patients (27.5%) and progressive disease in 44 patients (63.8%)—or 49 patients (66.2%), when including the five patients who died before the first staging. The median PFS was 3 months (95% CI 2.7 to 3.3) and the median OS was 22 months  of treated patients experienced Treatment-Related Adverse Events (TRAE) within 24 h of tebentafusp infusion. Cytokine release syndrome (CRS) was the most frequently reported side effect and occurred in 71.2% (n = 56) of patients. In 66.1% (n = 37), only pyrexia and chills occurred, and were classified as Grade 1 according to ASTCT Consensus Grading and treated symptomatically with antipyretic drugs. Grade 2 CRS  was detected in 28.6% (n = 16) of the patients. Grade 3 CRS with hypotension, requiring systemic corticosteroids or tocilizumab, was observed in 5.4% (n = 3) of the patients. There was no grade 4 CRS in our cohort. Skin toxicity was observed in 53.8% (n = 42) of the patients and was of grade 1 (according to CTCAE v.5) in 59.5% (n = 25), grade 2 in 35.7% (n = 15) and grade 3 in 2.4% (n = 1) of patients. In one patient, a bullous drug reaction was observed. Topical therapy with corticosteroids was applied in 38.1% (n = 16) and symptomatic treatment for pruritus with antihistamines was given in 45.2% (n = 19). Nausea and vomiting were observed in 14.1% (n = 11) of the patients and managed with antiemetic drugs. Two patients suffered from abdominal pain, which had to be treated with opioids. In one patient, a tumor lysis syndrome occurred after the first dose of tebentafusp—including a decrease in prothrombin time and highly elevated LDH, C-reactive protein, uric acid and creatinine in serum. Treatment included intravenous liquids and rasburicase. To reduce the severity or prevent the onset of TRAE, premedication was administered in 34.6% of patients. Premedication encompassed antihistamines , antipyretics , intravenous liquids , systemic corticosteroids  and/or anti-emetics . TRAE that emerged more than 24 h after application of tebentafusp appeared in 16.6% (n = 13) of patients; these included vitiligo-like hypo- and depigmentation of the skin (MAH = melanoma associated hypopigmentation) in 11.5% (n = 9), leukotrichia (depigmentation of the hair) in 5.1% (n = 4), fatigue in 3.8% (n = 3) and pancreatitis in 2.6% (n = 2) of patients. In our patient cohort, three patients (3.8%) discontinued tebentafusp due to adverse events, and no treatment-related deaths were documented .To investigate the influence of the treatment sequence of tebentafusp and ICI therapy, patients who were treated with both were analyzed for PFS1, PFS2 and OS. In our cohort, 40 such patients were identified—of which nine were treated with first-line tebentafusp and second-line ICI, and 31 with first-line ICI and second-line tebentafusp . p = 0.111).Patients treated with second-line tebentafusp after ICI therapy showed a longer median PFS2 of 4 months (95% CI 2.9 to 5.1), compared to a median PFS1 of 3 months (95% CI 2.5 to 3.5) for patients treated with first-line tebentafusp (p = 0.123). Patients who were treated with first-line ICI showed a longer median PFS1 of 5 months (95% CI 2.6 to 7.4), compared to a median PFS2 of 3 months (95% CI 1.5 to 4.5) for patients treated with first-line tebentafusp and second-line ICIs  first-line ICI therapy as compared to 24 months (95% CI 13.0 to 35.0) for first-line tebentafusp treatment  with patients who did not receive any local treatment (n = 42). Local therapies included selective internal radiation therapy (n = 16), brachytherapy (n = 6), stereotactic body radiation therapy (n = 4), chemosaturation (n = 4), transarterial chemoembolization (n = 3), radiofrequency ablation (n = 2) and microwave ablation (n = 1). Those patients showed a median OS of 22 months (95% CI 6.6 to 37.4) compared to a median 24 months (95% CI 10.5 to 37.5) for patients who had no local liver-directed therapy (This real-life multicenter study investigated the outcome of tebentafusp therapy and shows a median PFS of 3.0 months and a median OS of 22.0 months in a cohort of 78 patients with metastatic UM. Compared to the data of the Phase 3 trial, Nathan et al. reported a similar median PFS of 3.3 months and median OS of 21.7 months —even thoIn addition to this, this is the first study to investigate sequential therapies, as in the Phase 3 trial no previous systemic or local tumor therapy was allowed apart from surgical metastasectomy. In the published Phase 2 trial, all patients had at least one prior systemic treatment before tebentafusp therapy . Of thosIn our patient cohort, 51% had a systemic treatment prior to the first application of tebentafusp and 27% had a local liver-directed treatment. Of those patients who were treated with ICI prior to or after therapy with tebentafusp, 95% were treated with combined ipilimumab and nivolumab and 5% were treated with anti-PD1-antibodies as a monotherapy. There was a trend for a longer median PFS1 in patients who were treated with first-line ICI, reaching 5.0 months—compared to 3.0 months for patients who were treated with first-line tebentafusp. Additionally, in patients treated with second-line tebentafusp, there was a trend towards a longer PFS2, at 4.0 months—compared to 3.0 months in patients who were treated with second-line ICI. Regarding survival, there was a trend towards a longer median survival of 28.0 months for patients who were treated with first-line ICI followed by tebentafusp, as compared to 24.0 months for patients treated with first-line tebentafusp followed by ICI therapy. In an analysis of 55 independent studies with 2682 patients with mUM, tebentafusp had a higher median OS of 22.4 months, compared to 15.7 months for patients who were treated with a combined immune checkpoint blockade .A possible mechanism of improved survival for ICI followed by tebentafusp could be that after ICI-induced T cell expansion , a higheTRAE that occurred within 24 h of tebentafusp application were observed in 88.5% of the patients in our cohort, of which 71.2% were attributed to cytokine release and 53.8% were skin-related. Compared to the data of the Phase 3 study, in 99% of the patients a treatment-related adverse event occurred, with 89% experiencing CRS and 83% a rash . The lowThe main limitation of this study is its retrospective design, with an assessment of side effects documented only in the patients’ records. Diagnostic work-up and treatment decisions were made according to local standards. Thus, optional examinations such as mutation analyses were not performed in every patient.Our retrospective study confirms the efficacy and safety of tebentafusp in patients with mUM in a real-life setting, with comparable response rates and overall survival. First-line treatment with ICI followed by tebentafusp was associated with longer PFS and OS than the inverse sequence and warrants further investigation.


Evidence suggests that majority of patients with diabetes mellitus in Uganda have poor glycaemic control as well as periodontal disease. This study set out to determine the association between periodontitis and insulin resistance in adult patients with diabetes mellitus in Uganda using the triglyceride glucose index.2) and laboratory parameters including fasting blood sugar (mmol/L), glycated hemoglobin levels  and serum triglycerides (mmol/L) using a study questionnaire. Data were analyzed using R version 4.10. The glucose triglyceride index was used as a measure of insulin resistance. Logistic regression analysis carried out to determine the factors associated insulin resistance.Two hundred and twenty-three adult study participants with confirmed diabetes mellitus were enrolled in a cross-sectional study. Oral examination was carried with the aid of a periodontal probe to determine the periodontal status and findings recorded using the WHO Oral Health Assessment Tool for Adults, 2013. We recorded clinical details for body mass index (BMI in kg/m2 (SD+/- 5.82). The mean serum triglyceride index was 9.48 (SD+/- 0.675). Eighty-six-point 1% of the participants had periodontal disease. Bivariate analysis revealed high odds for male sex  and periodontitis  but low odds for a high BMI . Multivariate regression revealed a significant association between insulin resistance and periodontitis. .The majority of the study participants was female (70%) with an average age of 48.5 years (SD+/- 11.1). The mean body mass index was 29.6 kg/mInsulin resistance is highly prevalent in patients with diabetes mellitus in Uganda and is associated with periodontitis and low body weight. Despite the different clinical and public health interventions, the prevalence of diabetes mellitus keeps on rising, with an estimated about 463 million people reported to be affected globally by 2019   . Particig/dL)/2] . The incData were entered in Microsoft excel (version 16.75.2), cleaned and exported to R (version 4.10) for analysis. Descriptive statistics were used to summarize the data. Logistic regression analysis was performed to determine the association between the different variables. The independent variables were age, BMI and periodontitis while the dependent variable was insulin resistance. All variables were retained in the Multivariate model because of their biological plausibility. The results were presented as Odds ratio with a 95% confidence interval. P-values less or equal to 0.05 were reported to be statistically significant.2) was 29.6 (SD+/-5.82) with 30% of the participants being underweight or normal (BMI ≤ 24.9) and the rest being overweight or obese (BMI > 24.9). The majority of participants had attained formal education. About 55.6% of the study participants were on oral hypoglycemics, 12.1% on insulin and 32.3% on combination therapy. Only 17.9% of the participants were earning more than Uganda shillings 400,000= (about United States Dollars 108) per month. The mean triglyceride glucose index was 9.48 (SD+/- 0.675) mg/dL. About 93% of the study participants had insulin resistance while 58.3% of the participants had periodontitis  years.  and periodontitis  but low odds for high BMI . Logistic regression revealed a significant association between insulin resistance and periodontitis.  . BMI poorly correlates with visceral adiposity compared with waist circumference and waist -hip ratio .


Mycobacterium tuberculosis complex has an impact on public health and is responsible for over one million deaths per year. Substantial numbers of people infected with M. tuberculosis can develop tuberculosis lymphadenitis; however, there is a limited study in Adama, Ethiopia. The aim of this study was to determine the magnitude of Tuberculosis lymphadenitis, its predictors, and rifampicin-resistance gene-positive M. tuberculosis. A total of 291 patients with enlarged lymph nodes were recruited from May 2022 to August 30 at Adama Comprehensive Specialized Hospital Medical College (ACSHMC). GeneXpert, Ziehl–Neelsen staining, and cytology were used for the diagnosis of TB lymphadenitis from the Fine Needle Aspirate (FNA) specimen. Rifampicin-resistant gene was detected using GeneXpert. For data entry and analysis, Epi Data version 3.0 and SPSS version 25 were used respectively. A binary logistic regression model was used to identify predictors of TB lymphadenitis. A p < 0.05 with a 95% confidence interval (CI) was taken as a cut point to determine the significant association between dependent and independent variables. The prevalence of TB lymphadenitis using GeneXpert, Ziehl–Neelsen staining, and cytology were 138 (47.4%) (95% CI 41.70–53.10), 100 (34.4%) (95% CI 28.94–39.85), and 123 (42.3%) (95% CI 36.63–47.00) respectively. Nine (3.1%) participants were infected with rifampicin-resistant gene-positive M. tuberculosis. Out of the total M. tuberculosis detected by GeneXpert (n = 138), 9 (6.5%) were positive for rifampicin resistance-gene. Participants with a chronic cough had 2 times odds of developing TB lymphadenitis . Close to half of patients with enlarged lymph nodes were positive for M. tuberculosis by the GeneXpert method in the study area. Chronic cough was significantly associated with TB lymphadenitis. Rifampicin-resistant gene-positive M. tuberculosis was relatively prevalent among patients with enlarged lymph node in the study area. TB lymphadenitis is the most common type of extrapulmonary tuberculosis that occurs outside of the lungs2. According to Stop TB Partnership, Ethiopia is among 30 countries suffering from high tuberculosis burden. In Ethiopia, about one-third of cases of tuberculosis are attributed to TB lymphadenitis3.Tuberculosis is one of the leading causes of death, killing 2 million people each year4.Lymphadenitis refers to lymph nodes that are abnormal in size, number, or consistency and can have etiologic agents ranging from infectious processes to malignant disease. The cause of lymphadenitis is difficult to diagnose based on history and physical examination alone. Fine needle aspiration cytology (FNAC) is a widely accepted, cost-effective, and safe method for the diagnosis of TB lymphadenitis and other lymph node abnormalitiesMycobacterium tuberculosis or related bacteria. T cell lymphocytes and fibroblasts granulomatous tuberculosis eventually lead to the development of central caseous necrosis and a tendency to merge with the replacement of lymphoid tissue5. TB lymphadenitis  can be caused by the spread of M. tuberculosis from a lung infection6.TB lymphadenitis is a chronic specific granulomatous inflammation of the lymph node with caseous necrosis caused by infection with 7.Currently, lymphadenitis is a common pathological problem in the world. Many studies have been conducted to determine the magnitude and etiology of lymphadenitis. The pattern of the disease varies across different ethnic backgrounds and countries. Information regarding the magnitude and etiology of lymphadenitis in a specific geographic area is essential for a better diagnosis, treatment, and control of the diseaseM. tuberculosis isolated from enlarged lymph nodes belongs to different lineages8. In a review and meta-analysis conducted in Africa, a total of 6746 TB lymphadenitis cases were identified. The majority of the cases (70.6%) were from Ethiopia. Over 77% and 88% of identified TB lymphadenitis involved the cervical region and did not receive anti-TB drugs9.According to a study conducted in Ethiopia, 196 11.In addition to TB lymphadenitis, there are various causes of pathologies of lymph nodes; the most common are malignant tumor, reactive hyperplasia, Hodgkin lymphoma, non-Hodgkin lymphoma, purulent abscess, and other chronic inflammation. Lymph nodes have a characteristic presentation depending on the etiology and can present as acute painful swelling due to infection or chronic painless swellingEven though Ethiopia is among high TB burden countries, there is limited data of TB lymphadenitis from Adama, East Shoa zone, Oromia Regional State. In this study, we aimed to determine the magnitude of TB lymphadenitis among patients with enlarged lymph nodes at ACSHMC using GeneXpert, Ziehl–Neelsen (ZN) staining, and cytology.An institutional-based prospective cross-sectional study was conducted from May, 2022, to August, 2022. The study was conducted in the East Shoa zone, Oromia Regional State, Ethiopia, ACSHMC, Adama, Ethiopia. Adama city is located in the East-South direction about 100 km from the capital city of Ethiopia. Based on the 2021/2022 TB data, Adama Comprehensive Specialized Hospital Medical College (ACSHMC) has suspected a total of 1458 all forms of TB cases, from this 456 were confirmed TB Lymphadenitis in cytological diagnosis methods only. Gene X pert and AFB are not in use in the study site for the diagnosis of the disease.12 and 95% confidence level. After considering 10% for the non-response rate, the total sample size was 291. We have used convenient sampling technique to recruit study participants.All patients with enlarged lymph nodes who visited ACSHMC, the pathology department for FNAC examination during the study period were considered for the study. The required sample size was determined using a single population proportion formula by considering prevalence reported from Bahirdar, Ethiopia (22.1%)All patients who had enlarged lymph nodes and visited the pathology department at ACSHMC were included.The patient who had enlarged lymph node but the FNA sample is not sufficient for the laboratory test and patents not voluntary for this study were excluded.Dependent variable: TB Lymphadenitis diagnosed by GeneXpert.Independent variables: Socio-demographic and clinical characteristics.14. About 1.5–3 ml Fine Needle Aspirate (FNA) specimens were collected from enlarged lymph nodes to be diagnosed using GeneXpert16, ZN staining17, and Cytology18.For the collection of demographic and clinical characteristics, we used an interviewer-based structured questionnaire prepared after reviewing similar studiesThe questionnaire was pre-tested on a population representing 5% of the sample size to check its consistency before the actual data collection. Each day, after data collection, collected data were checked and evaluated for completeness, accuracy, and clarity. The sample processing control contains non-infectious spores in the form of a dry spore cake that is included in each cartridge to verify adequate processing of TB. To control bias that could arise from laboratory investigation, smear microscopy were read by three professionals before the final issuance of the result.p < 0.25 were further analyzed by multivariable logistic retrogression. The statistical significance was considered at a p < 0.05.Data were entered into the computer using Epi Data version 3.1 and exported to SPSS version 25  software for analysis. Bivariable and multivariable binary logistic regression were used to determine the association between dependent and independent variables. Initially, data were analysed using bivariable logistic regression; variables with Ethical clearance was obtained from the nationally registered ethical institutional review board of Hawassa University medical college (Ref No. IRB\148\14). All participants were informed of the purpose, risk, and benefit of the study and their participation was voluntary. Written informed consent was obtained from all participants. For minors, consent from the parents or legal guardians and assent from minors were obtained. The identifier of study participants were removed from all formats. All methods were carried out in accordance with relevant guidelines and regulation as mentioned by Declaration of Helsinki.A total of 291 study participants with enlarged lymph nodes were included in this study, of which 121 (41.8%) were males. The mean age of study participants was 28 (SD ± 14.8). Most of the patients did not have history of treatment for TB , weight loss (50.9%), night sweating (54.6%), and fatigue 52.6%). The most involved body sites (lymph nodes) were cervical (54.6%), axillary (11.3%) supraclavicular (10.3%), and submandibular (15.5%). The least affected lymph node were the auricular and inguinal lymph node with (1.4%), and (6.9%) respectively  (95% CI 41.70–53.10) were MTB positive by the GeneXpert method. Whereas 100 (34.4%) (95% CI 28.94–39.85) and 123 (42.3%) (95% CI 36.63–47.00) were positive by ZN staining and cytology respectively. 85 (29.2%) were positive in all three methods; 102 (35%) positive by AFB and GeneXpert; 116 (39.9%) were positive by GeneXpert and cytology. Non-acid fast bacilli Bacteria were detected among 33 (11.3%) participants using Gram staining technique, out of which 32/33 (97%) were Gram—positive cocci and 1/33 (3%) were Gram—negative rods. Moreover, cytological diagnosis revealed 89 (30.6%) reactive lymphadenitis, 27 (9.3%) lymphoma, 16 (5.5%) chronic abscess, 6 (2.1%) malignancy and 8 (2.7%) carcinoma, 8 (2.7%) pyogenic, 5 (1.7%) benign, 3 (1.0%) hematoma 3 (1.0%) granuloma and 3 (1.0%) abscess.M. tuberculosis while 3 (1.0%) of them were infected with M. tuberculosis which was rifampicin-intermediate. Overall, 9 out of 138 M. tuberculosis (6.5%) were positive for the rifampin-resistant gene.Out of 291 participants, 9 (3.1%) were infected with rifampicin-resistant genes positive p < 0.25 in bivariable analysis and were selected for multivariable analysis. In multivariable analysis, TB lymphadenitis was significantly associated with chronic cough 15. However, higher prevalence TB lymphadenitis was reported from Gondar, Ethiopia (65.7%)13, Jimma, Ethiopia (58.0%)14, Butajira, Ethiopia (72.8%)19 and Tanzania (69.5%)20. In contrast to our study, low prevalence of TB lymphadenitis was reported from Nigeria (24.45%)21 and Pakistan (44%)22. The variation might be due to socio-demographic factors and the laboratory method used. Some of the studies used cytological methods whereas others used molecular method which might be responsible for the differences observed.Many studies including our study revealed high prevalence of TB lymphadenitis among patients with enlarged lymph nodes as compared to other clinical conditions. In the current study, the overall prevalence of TB lymphadenitis using GeneXpert was 47.4%. Our finding is in line with the prevalence of TB lymphadenitis reported from Hawassa, Ethiopia (48.8%)16. A study conducted in a Sudan also reported low AFB positivity (9%) of lymphadenitis23.The prevalence of TB lymphadenitis using ZN staining method was 34.4%. This finding is high compared to study conducted in Addis Ababa, Ethiopia (14.5%) which used a similar laboratory methods—ZN staining method12. Another study from South Ethiopia showed a higher prevalence of TB lymphadenitis (68.7%) using cytological diagnosis15.According to the cytological examination (FNAC) of the present study, the prevalence of TB lymphadenitis was 42.3%. Reactive lymphadenitis was the second most frequent cause of enlarged lymph nodes. Lymphoma and the chronic abscess was the third and fourth frequent cause of enlarged lymph nodes respectively. The prevalence of TB lymphadenitis identified by cytological methods correlates with a study conducted in different parts of EthiopiaOverall, the performance of GeneXpert in diagnosing TB lymphadenitis was superior (47.4%) compared to the cytological method (42.3%) and ZN staining (34.4%). From the total study participants (N = 291), 29.2%, 35%, and 39.9% were positive for MTB by all three methods, AFB and GeneXpert, GeneXpert, and cytology respectively. Bacteria other than MTB were detected from 11.3% of participants with enlarged lymph nodes; the predominant bacteria were Gram-positive cocci. This indicates the role of other bacteria in lymphadenitis or it can be a super infection and need further study.13, in the current study male participants were more affected by lymphadenitis (48.8%) than their female counterparts (46.5%). This could be due to differences in lifestyle among males and females in different localities.In contrast to a study conducted in Gondar15. Review and Meta-analysis conducted in Africa indicated a high frequency of enlarged lymph nodes among individuals within the 20–40 years age group24.The majority of participants with enlarged lymph nodes were adults. 46% of participants within the age group of 25–34 years had enlarged lymph nodes whereas those within 15–24 years old accounted for 25%. This finding is inconsistent with other studies done in Ethiopia; where 25–34 years old are the commonest age group affected14; however, it is not comparable to a study conducted in Gondar, Ethiopia13.Chronic cough was the only independent variable significantly associated with TB lymphadenitis. Patients who had a history of chronic cough had 2 times odds of developing TB lymphadenitis as compared to those who had no history of cough. This finding is in line with the finding reported from Jimma, Ethiopia12. Hawassa, Ethiopia (57.1%)7, and Gondar, Ethiopia (47.5%)13. In addition, a report from India indicated a high prevalence of lymphadenitis involving cervical lymph nodes4.In this study, the cervical lymph node was found to be the most commonly affected site (54.6%). Similar finding was reported from northern parts of Ethiopia (57.1%)15.The history of drinking raw milk among TB lymphadenitis cases was (21.0%). However, the history of drinking uncooked milk was not significantly associated with the occurrence of TB lymphadenitis. This finding is in line with the studies conducted in Addis Ababa, EthiopiaM. tuberculosis which is in line with the study conducted in Gondar, Ethiopia 3.9%24, India (2.9%)25, and Kenya (3.7%)26. A study conducted in Hawassa, Ethiopia among patients suspected of pulmonary TB revealed a prevalence of rifampicin resistance of 1.24% which is lower than the current study27. Out of 138 M. tuberculosis detected in this study, 9 were positive for the rifampin-resistant gene giving a proportion of 6.5%. Additionally, several studies reported a high prevalence of rifampicin resistance gene positive M. tuberculosis such as study from Nigeria (14.7%)28, India (5.4%)4, Addis Ababa, Ethiopia (9.9%)29, and Adigrat, Ethiopia (9.1%)30.In this study, 3.1% of participants were infected with rifampicin-resistant gene positive As this study is a cross-sectional study, it will not establish the cause and effect. The participants might forget some variables which asks about their previous experience and might have led to recall bias. Use of convenient sampling technique might have introduced selection bias.M. tuberculosis was relatively prevalent among patients with enlarged lymph node in the study area.Close to 50% of patients with enlarged lymph node were positive for TB lymphadenitis by GeneXpert in the study area. GeneXpert detected high number of TB lymphadenitis as compared to cytology and ZN staining technique. Chronic cough was significantly associated with TB lymphadenitis. The prevalence of rifampicin-resistant gene positive


Surgical repair of complex congenital heart defects with hypoplasia or atresia of the right ventricular outflow tract (RVOT) may require pulmonary valve implantation or replacement during the primary repair or reoperation. The purpose of this study is to evaluate the outcomes of cryopreserved homografts, bovine jugular vein conduits and decellularized Matrix P Plus N conduits in patients undergoing RVOT reconstruction at a single centre.Retrospective, single-centre review of 173 patients with 199 conduits undergoing right ventricle-to-pulmonary artery reconstruction with valved conduit from 2002 to 2022.A total of 199 conduits were implanted in 173 patients , with a mean age of 8.97 ± 8.5 years. The following 3 types of conduits were used: homografts 129 (64.8%), bovine jugular vein conduits 45 (22.7%) and Matrix P Plus N 25 (12.5%). During the mean follow-up duration of 8.6 ± 5.8 years, there were 20 deaths, 35 conduit reoperations and 44 catheter reinterventions. Overall survival, reoperation-free and catheter reintervention-free survival at 20 years were 83%, 67.8% and 65.6%, respectively. Multivariable Cox analysis identified younger patient age, smaller conduit size, low patient weight and primary diagnosis of common arterial trunk as risk factors for reoperation and catheter reintervention.Long-term outcomes of reconstruction of the RVOT using homografts, bovine jugular vein and Matrix P Plus N conduits were acceptable. The reoperation rate for conduit dysfunction did not differ significantly among groups. Over time, the need for conduit replacement was higher in smaller conduits and in patients with common arterial trunk diagnosis. Right ventricle-to-pulmonary artery (RV–PA) conduits have allowed for the repair of a large number of congenital cardiac defects with hypoplasia or atresia of the right ventricular outflow tract (RVOT). Right ventricle-to-pulmonary artery (RV–PA) conduits have allowed for the repair of a large number of congenital cardiac defects with hypoplasia or atresia of the right ventricular outflow tract (RVOT). These fundamental defects include common arterial trunk (CAT), transposition of the great arteries with ventricular septal defect and pulmonary stenosis or atresia, tetralogy of Fallot (TOF) with absent pulmonary valve, TOF with anomalous coronary artery crossing the RVOT, pulmonary atresia with ventricular septal defect and different forms of double-outlet right ventricular. Conduits have also made it feasible to replace the aortic root with a pulmonary autograft (Ross operation) .Valved homografts, first described by Ross and Somerville  in 1966,The goal of this study is to compare homografts, BJVC and decellularized Matrix P Plus N conduits with respect to patient survival, reoperation-free and catheter reintervention-free survival in paediatric patients and adolescents with congenital heart defects requiring primary conduit implantation or replacement for RVOT reconstruction.The study was approved by the Institutional Review Board of the National Institute of Cardiovascular Diseases, Bratislava, Slovakia, on 8 February 2023 , and the informed consent was not required, as the study was retrospective.The study population consisted of patients who underwent RVOT conduit implantation or replacement at the Department of Paediatric Cardiac Surgery, Children's Heart Centre, Bratislava, Slovakia, between 1 January 2002 and 31 June 2022. The patients’ medical records were retrospectively reviewed.Patients with congenital heart defects receiving cryopreserved homografts, BJVC (Contegra) or Matrix P Plus N conduits at the time of primary repair or reoperation were included. Exclusion criteria included patients whose medical records or operative notes were not retrievable as well as those who had an RV–PA conduit implanted and underwent heart transplantation due to myocardial dysfunction. Additionally, all other conduit types were excluded.Demographic data, cardiac diagnosis, sex, Aristotle score , age at The RV–PA conduits were classified into 3 groups: homograft (aortic and pulmonary), BJVC and Matrix P Plus N conduit. In Slovakia, cryopreserved homografts (aortic and pulmonary) are provided by the Central Tissue Bank at the Medical faculty of Comenius University, Bratislava. Cryopreservation was performed using Dulbecco’s Modified Eagle Medium 1% containing bovine serum and dimethylsulphoxide for preservation and homografts were stored in liquid nitrogen at −150°C.A total of 199 conduits were implanted in 173 patients. Of these, 114 (57.2%) were pulmonary homografts, 15 (7.6%) were aortic homografts, 45 (22.7%) were BJVC and 25 (12.5%) were Matix P Plus N conduits. The median follow-up for the entire cohort was 8.4 (0.008–20.5) years. The median follow-up was 11.36 (0.008–20.5) years for homografts, 2.09 (0.18–12.7) years for BJVC and 5 (0.008–9) years for Matrix P Plus N conduits.Propensity score-matching analysis was done, and 82 conduits  were chosen for comparison.The study end points included freedom from reoperation, freedom from catheter reintervention and survival. Freedom from conduit reoperation was defined as the time period between operative conduit implantation and operative conduit replacement. Freedom from catheter reintervention was defined as the time period between operative conduit implantation and catheter intervention; balloon valvuloplasty, stent implantation or percutaneous pulmonary valve implantation (PPVI). The orthotopic placement was defined as the implantation of the conduit within the normally situated RVOT (Ross procedure), and the conduit was placed in a heterotopic position in all other patients.Decisions about the primary operation, the reoperation or catheter reintervention were made individually in a multidisciplinary conference. Our current practice is to minimize implanting valved conduits and we prefer to use native tissue if possible in primary operations. However, we still use valved conduits in some diagnoses and surgical repairs, such as TOF with absent pulmonary valve, TOF with anomalous coronary artery crossing the RVOT, e.g. the left anterior descending artery from right coronary artery, CAT type A2–A3, CAT type A4 with interrupted aortic arch, Ross and Ross–Konno procedure, Yasui procedure and in Senning–Rastelli operation. The indications for the replacement of existing RV–PA conduits included infective endocarditis, severe conduit stenosis with a peak gradient >50 mmHg and/or severe regurgitation and conduit aneurysm or pseudoaneurysm. Echocardiography and cardiac MRI were used to evaluate the RV–PA conduit function and determine the severity of right ventricle dilatation and/or dysfunction. Bovine jugular vein (BJV) and Matrix P Plus N conduits patients received aspirin for 6 months postoperatively.The national population register of Slovakia was used to verify the patient's survival status.Reoperations conducted on patients following initial RV–PA conduit implantation were assessed using either our congenital heart disease database in Children’s Heart Centre, Bratislava, or external databases maintained by 3 departments of adult cardiac surgery in Slovakia. Catheter reinterventions were analysed using a registry run by the Division of Paediatric and Adult Cardiology in Bratislava, Slovakia.2) or Fisher’s exact test. Continuous variables are expressed as means and standard deviations or medians with interquartile ranges (IQR). The Shapiro–Wilk test was used to assess the normality of the distribution. Comparisons for continuous variables in the unmatched cohort were calculated with the unpaired t-test unless the data were not normally distributed; in these instances, the Mann–Whitney U-test was utilized for comparison. Comparisons in the matched cohort were done using a paired-sample t-test, or Wilcoxon signed rank test, where appropriate.Categorical variables are presented as numbers with percentages. Comparisons for categorical variables were calculated with chi-square  and BJVC (n = 45)] on a set of 5 covariates . The propensity score was estimated using a logistic regression model with 1:1 nearest neighbour matching without replacement based on an acceptable calliper width of 0.2 times the standard deviation of the logit of the propensity score [Propensity score-matching method was used to match 2 groups [homografts . Propensity score-matching and Nelson–Aalen cumulative hazard analysis were performed with XLSTAT Statistical Software for Excel, version 2022.4.1 .For all tests, a Baseline characteristics in each group are given in Table P = 0.78). Overall survival according to the type of conduit is shown in Fig. The survival rate at 1, 10, 15 and 20 years was 92.9%, 91%, 87% and 83%, respectively . No deaths were related to the structural failure of the conduit.Five patients (2.8%) died within the postoperative period of 30 days. The 30-day mortality was 3.1% in the homograft group, 0% in the BJVC group and 4% in the Matrix P Plus N group (P = 0.043). Overall survival according to the type of conduit in the PSM subgroup is shown in Fig. For the propensity score-matched subgroup, the survival rate at 1, 10, 15 and 20 years was 91.2%, 91.2%, 81% and 81%, respectively , 9 in the BJVC group  and 7 in the Matrix P Plus N group . The indications for catheter reintervention were severe conduit stenosis , with a mean gradient of 62 mmHg, and severe regurgitation .During the study period, 44 conduits (22.1%) underwent at least 1 catheter reintervention, with an incidence of 28 (21.7%), 9 (20%) and 7 (28%) in homograft, BJV and Matrix P Plus N conduits, respectively. The overall median time to first catheter reintervention was 3.4 years . Initial catheter reintervention was required in 28 conduits in the homograft group . Freedom from first catheter reintervention according to the type of conduit is shown in Fig. Overall freedom from first catheter reintervention at 5, 10 and 20 years was 83.1%, 71.8% and 65.6%, respectively   had at least 1 catheter reintervention, with an incidence of 16 (39%), and 7 (17%) in homograft, and BJVC, respectively. The median time to first catheter reintervention was 2.3 years . The overall 20-year freedom from first catheter reintervention was 45.3% , and with Matrix P Plus N conduits (P = 0.01). However, the cumulative hazards were similar between BJVC and Matrix P Plus N conduits (P = 0.87)  Fig. A.P = 0.67) , low body weight < 10 kg , younger patient age at conduit implantation <1 year  and the diagnosis of CAT  as risk factors for conduit catheter reintervention. The results of the Cox regression analysis of risk factors for catheter reintervention are presented in Table The univariable and multivariable Cox regression analyses identified a smaller conduit diameter <16 mm  conduit reoperations performed. The overall median time to first reoperation was 4.3 years . Overall freedom from reoperation at 5, 10 and 20 years was 87.6%, 79.4% and 67.8%, respectively . Freedom from reoperation according to the type of conduit is shown in Fig. Freedom from reoperation at 5, 10 and 20 years was 88%, 81.7% and 69.7% in the homograft group, respectively. Freedom from reoperation at 5 and 10 years was 75.7% and 63% in the BJVC group, respectively, and freedom from reoperation at 5 and 9 years was 91.3% and 83% in the Matrix P Plus N group, respectively. No statistically significant difference regarding the reoperation rate was observed among the 3 groups (P = 0.88)  conduits underwent reoperation. The median time to first reoperation was 4 years . The overall 20-year freedom from reoperation was 44.4% , low body weight < 10 kg , younger patient age at conduit implantation <1 year  and the diagnosis of CAT  as risk factors for conduit reoperation. Neither the conduit type nor the anatomic position of the conduit had a significant influence on conduit durability. The results of the Cox regression analysis of risk factors for conduit reoperation are presented in Table The univariable and multivariable Cox regression analyses identified a smaller conduit diameter <16 mm , BJVC and Matrix P Plus N, which were implanted in paediatric, adolescent and young adult patients at our institution as measured by survival, freedom from catheter reintervention, and reoperation. In addition, we performed propensity score-matching analysis between 2 groups of our patients (homograft and BJVC) to look for differences in conduit function. We investigated risk factors for conduit reintervention and reoperation Table .A survival rate of 91.1% at 10 years and 83% at 20 years in our cohort is satisfactory and comparable to similar reports , 15.et al. [Overall freedom from first catheter reintervention in homografts at 10 years was better (77.3%) compared to the BJVC group (38%). However, in the propensity score-matched subgroup, freedom from first catheter reintervention was similar, and no statistically significant difference was found in our study. Additionally, the Nelson–Aalen analysis supported these findings; this reflects the same results in a study from Lewis et al. .et al. [et al. [et al. [Overall freedom from reoperation for the entire group at 10, 15 and 20 years was 79.4%, 70.9% and 67.8%, respectively. Freedom from reoperation for propensity score-matched subgroup at 10, 15 and 20 years was 55.7%, 46.2% and 44.4%, respectively. This is comparable to studies from Falchetti et al. , Tweddel [et al.  and Star [et al. , who rep [et al. , 17.In the propensity score-matched subgroup, the freedom from reoperation and freedom from catheter reintervention were equal for homografts and BJVC. Between the 2 groups, there was no statistically significant difference. This compares favourably with similar studies , 13, whiP < 0.001) and catheter reintervention  in our multivariable Cox regression analysis. This reflects similar results from multiple studies [A smaller conduit size <16 mm was associated with the need for conduit reoperation  and catheter reintervention  in our multivariable Cox regression analysis. Similar results were observed in previous studies [et al. [et al. [The patients with the diagnosis of CAT were found to be more at risk for earlier conduit reoperation , BJV and Matrix P Plus N conduits. Over time, the need for conduit replacement was higher in smaller conduits and in patients with CAT diagnosis.